FDA Administrative Enforcement Manual

Author: Florence R. Parker

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FDA Administrative Enforcement Manual

© 2005 by CRC Press LLC

FDA Administrative Enforcement Manual

Florence R. Parker

Boca Raton London New York Singapore

A CRC title, part of the Taylor & Francis imprint, a member of the Taylor & Francis Group, the academic division of T&F Informa plc.

© 2005 by CRC Press LLC

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Library of Congress Cataloging-in-Publication Data Parker, Florence R. FDA administration enforcement manual/ Florence R. Parker p. cm. Includes bibliographical references and index. ISBN 0-8493-3067-X (alk. paper) 1. Drugs—Law and legislation—United States. 2. United States Food and Drug Administration— Rules and practice. I. Title: Food and Drug Administration enforcement manual. II. Title. KF3885.P37 2005 344.7304′233—dc22 2004058496

This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microﬁlming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Speciﬁc permission must be obtained in writing from CRC Press LLC for such copying. Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identiﬁcation and explanation, without intent to infringe.

Visit the CRC Press Web site at www.crcpress.com © 2005 by CRC Press LLC No claim to original U.S. Government works International Standard Book Number 0-8493-3067-X Library of Congress Card Number 2004058496 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper

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Preface Administrative Enforcement is a peculiar and speciﬁcally carved-out authority delegated by the United States Congress to federal government agencies such as the Department of Health and Human Services, U.S. Food and Drug Administration. As a federal government executive agency of the United States, the Commissioner of the FDA has extensive and in some cases exclusive Administrative Enforcement authority. The speciﬁc enforcement authority empowering the FDA can be found in the Food, Drug, and Cosmetic Act of 1938 and amendments thereto, with enforcement rules codiﬁed in Title 21 of the Code of Federal Regulations (Title 21 CFR) Parts 1 through 7 et seq. The Administrative Procedures Act controls the FDA’s Administrative Enforcement rules and procedures. Chapter 1 of this book discusses the FDA’s statutory authority and responsibility and provides an overview of the ten administrative enforcement areas important to practitioners, manufacturers, and educators and candidates in drug programs at law, pharmacy, and graduate schools. The areas covered are recall, administrative actions, civil actions, application integrity, injunction, seizure, consent decrees, criminal actions, disqualiﬁcation, and debarment. Chapter 2 discusses recalls. Recalls occur throughout the FDA-regulated healthcare industry and in other regulated industries. A recall occurs when something goes wrong with a product in either a pre- or postmarket setting. A problem, for example, can involve prescription drug administration by a physician, self-administration as directed by a physician, or self-medication using an over-thecounter (OTC) drug. The purpose of a recall is to remove the product from the market or to correct the problems immediately. Failure to remove adulterated or misbranded products from the market immediately will result in regulatory sanctions. Continued sales harm the public and may result in death or temporary or permanent disability. Refusal to recall violative product subjects the sponsor, manufacturer, and distributor to administrative, civil, or criminal sanctions, which may include injunction, seizure, debarment, large ﬁnes, shutdown, and imprisonment. If the FDA ﬁnds through an inspection or other avenues that a product is not safe or is ineffective, it may: (1) force the manufacturer to recall, (2) request the ﬁrm to conduct a ﬁrm-initiated recall, (3) enjoin continued shipment of the product, (4) seize the product in the warehouse or market, (5) detain its entry into the United States via Customs, or (6) enter into a consent decree with the manufacturer. Due to the expenses associated with litigation, the FDA has the ability to exercise nonlitigation actions against market participants to expedite corrective responses and eliminate these costs of litigation. If the actions are of a serious nature, the FDA may also use civil actions available against a participant. Chapter 3 discusses civil actions involving seizures, injunctions, and consent decrees. Seizure involves arresting and taking into custody violative products. Injunction is the method used to stop sponsors from manufacturing and distributing violative products. A consent decree, a type of injunction, is an agreement between the FDA and the sponsor who has violated the law to correct processes, functions, and practices to avoid shutdown or other regulatory sanctions. Chapter 4 discusses criminal actions available to the FDA that are litigated by the U.S. Department of Justice on its behalf. The FDA’s authority to assert criminal actions against sponsors, ﬁrms, and individuals stems from its application integrity scrutiny and disqualiﬁcation or debarment actions. If an application raises suspicions with regard to data reliability, it may come under application integrity scrutiny. In this case, the FDA has reason to believe that the supporting data provided by the sponsor seeking approval to market a new drug contain fraudulent, false, or misleading statements about the safety or efﬁcacy of that product.

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Chapter 5 provides case studies pertaining to these various areas that are designed to enhance understanding of the issues impacting FDA-regulated industries and regulatory affairs practitioners. The appendices provide relevant portions of the Federal Food, Drug, and Cosmetic Act, as well as the FDA Administrative Procedures Act (FAPA), a synopsis of drug law history, and further information on clinical investigators. The appendices are followed by a glossary of important terms. As with any profession that is dynamic, it is recommended that practitioners in this ﬁeld develop methods to keep abreast of changes in regulatory affairs such as continued education, legislative review, and keeping current with industry publications.

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The Author Florence R. Parker, J.D., has worked professionally in the pharmaceutical industry for approximately 10 years and has attained senior executive management levels in several multinational ﬁrms. In her career, she has dealt with both national and international regulatory authorities such as the Food and Drug Administration (FDA), European Medicines Agency (EMEA), Health Professions Bureau (HPB), Medicines Control Agency (MCA), Japanese Ministry of Health, and China State FDA Administration; additionally, she has managed involvement with various state departments of health. She has resolved many issues for her employers and as a consultant in the industry with regard to FDA Administrative Enforcements, CGMPs, GLPs, GCPs, and advertising and promotional literature matters. She has also participated in the regulatory affairs units of various companies to resolve problems related to consent decrees, recalls, and seizures. Dr. Parker also worked for the U.S. Congress in a legislative capacity in the General Accounting Ofﬁce in Washington, D.C. Dr. Parker has lectured for the Regulatory Affairs Professional Society and other organizations. She holds a Bachelor of Science degree in Biology and Information Systems; additionally, she has earned a Master of Science in Drug Regulatory Affairs and a Jurist Doctorate. Dr. Parker is chief executive ofﬁcer and president of her consulting ﬁrm, the Institute of Human Health and Research (IHH&R). Through IHH&R, she collaborates with industry and national and international professionals on various health- and research-related projects, lectures, and teaches regulatory concepts and issues to both professional and novice audiences.

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Acknowledgments Often times, when undertaking a project, an author wonders should I? could I? … Then, again, the author may also consider why not? Those with a passion to write and share their knowledge must ﬁnd the answers to these and other questions as they proceed with their projects. My answers were found among those who supported me throughout this work. Through thick, thin, and transparently thin, those who stuck by me included my family and friends, especially my friend Mary Frances Bilodeau. Of all the people who could have provided editorial assistance with this project, Mary Frances was the one who stuck with me to the end. I have toiled in many universities during my career, but Mary Frances was the one who unknotted the complex language that is part of the legal and pharmaceutical regulatory industry in the United States. Over the years, we came to know each other better, and in her I have found a very intelligent, insightful, and humorous friend who, upon achieving octogenarian status in life, is still as sharp as a tack. I am greatly indebted to her. Without her assistance, this work would still be on the drawing board. Thank you, Mary Frances Bilodeau.

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Contents Introduction .................................................................................................................................. xix Chapter 1. Department of Health and Human Services, U.S. Food and Drug Administration: Authority and Responsibility............................................................1 1.1 Statutory Authority ...................................................................................................................1 1.2 Laws Enforced by the FDA .....................................................................................................1 1.2.1 Recommendations for Understanding the Act...........................................................12 1.2.2 U.S. Drug Law History ..............................................................................................12 1.3 Jurisdiction..............................................................................................................................13 1.4 Statute of Limitations .............................................................................................................13 1.5 Administrative Law and Procedures Act ...............................................................................13 1.6 Code of Federal Regulations..................................................................................................14 1.7 Authority, Scope, and Facility Inspections ............................................................................14 1.8 Inspection Process and Procedures ........................................................................................15 1.9 U.S. Constitutional Rights of Defendant Firms and Individuals ..........................................17 1.10 Evidence, Administrative Agencies, and Federal Courts .......................................................17 1.11 Case Studies............................................................................................................................17 DHHS–FDA Exhibits.......................................................................................................................17 Summary ..........................................................................................................................................23 Practicum..........................................................................................................................................24 The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective.........................24 WLF v. Henney .......................................................................................................................28 Did You Know… ............................................................................................................................32 Notes: Drug Law..............................................................................................................................32 Endnotes ...........................................................................................................................................32 Other Resources ...............................................................................................................................33 General....................................................................................................................................33 Drug, Biologic, and Cosmetic Regulations ...........................................................................34 Food, Device, and Veterinary Medicine Regulation..............................................................36 Off-Label Uses .......................................................................................................................37 Chapter 2. Recalls: Corrections and Withdrawals ....................................................................41 2.1 Statutory Authority .................................................................................................................41 2.2 Recall Type and Class ............................................................................................................42 2.2.1 Recall Types ...............................................................................................................42 2.2.2 Regulated Product Problem Notiﬁcation ...................................................................48 2.2.2.1 Preventative Controls ..................................................................................48 2.2.2.2 Defective Controls.......................................................................................48 2.2.3 Controllable vs. Uncontrollable Regulated Product Problems..................................48 2.2.4 Recall Classes.............................................................................................................50 2.2.4.1 Prior Notice ............................................................................................... 50 2.2.4.2 Class I FDA-Requested Recall ...................................................................50 2.2.4.3 Class II Firm-Initiated Recall .....................................................................50 2.2.4.4 Class III Firm-Initiated Recall....................................................................51 2.2.5 Communication...........................................................................................................51

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2.3 Recall Effectiveness Monitoring ............................................................................................51 2.4 Strategy ...................................................................................................................................52 2.5 Public Notiﬁcation..................................................................................................................52 2.6 Status Reports.........................................................................................................................52 2.7 Termination.............................................................................................................................52 2.8 Regulated Product Withdrawals .............................................................................................53 2.9 FDA Recall Facts ...................................................................................................................53 2.10 Case Studies ...........................................................................................................................53 Recall Exhibits .................................................................................................................................53 Summary ..........................................................................................................................................64 Practicum..........................................................................................................................................65 Title 21 CFR 7........................................................................................................................65 Company Z Recall..................................................................................................................70 Endnotes ...........................................................................................................................................72 Other Resources ...............................................................................................................................73 U.S. Federal Government Laws, Regulations, and Guides Concerning Protection of Human Subjects: Journal Articles ............................................................73 U.S. Federal Government Laws, Regulations, and Guides Concerning Protection of Human Subjects: Books............................................................................74 Chapter 3. Civil Actions ................................................................................................................75 3.1 Seizure ....................................................................................................................................75 3.1.1 Statutory Authority .....................................................................................................75 3.1.2 Jurisdiction..................................................................................................................75 3.1.3 Purpose of Seizure......................................................................................................75 3.1.4 Seizures: Lot, Multiple, and Mass .............................................................................76 3.1.5 Disposition of Seized (Arrested) Goods ....................................................................76 3.1.6 Penal Bond .................................................................................................................77 3.1.7 Seizure Violations.......................................................................................................78 3.1.8 Case Studies ...............................................................................................................78 Seizure Exhibits......................................................................................................................78 Summary.................................................................................................................................88 Reading Reference Section ....................................................................................................88 Discussion Questions..............................................................................................................89 3.2 Injunctions ..............................................................................................................................89 3.2.1 Statutory Authority .....................................................................................................89 3.2.2 Jurisdiction..................................................................................................................89 3.2.3 Civil Action Penalties and Fines................................................................................90 3.2.4 Contest Injunction or Opt for Consent Decree..........................................................92 3.2.5 Case Study: Schering Plough Corporation Permanent Injunction ............................93 3.2.6 Consent Decree and Its Resolution..........................................................................115 3.2.6.1 Prohibitory Actions ...................................................................................115 3.2.6.2 Mandatory Actions ....................................................................................116 3.2.6.3 Fines and Penalties....................................................................................116 3.2.7 Requirements after the Consent Decree ..................................................................116 3.2.8 Background for Case Study .....................................................................................117 3.2.9 Program Implementation Case Study ......................................................................118 3.2.9.1 Overview of the Problem..........................................................................118 3.2.9.2 Prior Notice Information...........................................................................119 3.2.9.3 Analysis .....................................................................................................119

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3.2.9.4 CGMP Workplan To Resolve Injunction..................................................121 3.2.9.5 Suggested Solution....................................................................................121 3.2.9.6 Nonconformance .......................................................................................123 3.2.9.7 Summary of Consent Decree Solutions....................................................126 Endnotes .........................................................................................................................................129 Chapter 4. Criminal Actions: Debarment, Disqualiﬁcation, and Application Compliance and Integrity ..............................................................................133 4.1 Statutory Authority ...............................................................................................................133 4.2 Jurisdiction............................................................................................................................133 4.3 Debarment.............................................................................................................................134 4.3.1 Generic Drug Enforcement Act of 1992..................................................................134 4.3.2 Who May Be Debarred ............................................................................................134 4.3.3 Debarment for Direct or Indirect Conduct ..............................................................136 4.3.4 Debarment Types: Mandatory and Permissive ........................................................137 4.3.5 Criminal Mental State Required To Convict ...........................................................137 4.3.6 Scope of Debarment .................................................................................................138 4.3.7 People, Services, and Those Afﬁliated or Who May Be Affected by Debarment .....................................................................138 4.3.8 Debarment Crimes....................................................................................................139 4.3.9 306(k)(2) Conviction Information Requirements ....................................................139 4.3.10 Debarment Effects ....................................................................................................140 4.3.11 Debarment Periods ...................................................................................................140 4.3.12 Debarring Period Consideration Factors..................................................................140 4.3.13 Terminating Debarment............................................................................................141 4.3.14 Suspension Authority for ANDA Product Distribution ...........................................141 4.4 Disqualiﬁcations ...................................................................................................................144 4.4.1 IRB Responsibilities.................................................................................................144 4.4.1.1 Regulatory Responsibilities of IRB to Human Clinical Trial Patients and Clinical Investigators .....................................144 4.4.1.2 Regulatory Sanctions IRBs May Face in a Disqualiﬁcation Action........145 4.4.1.3 Impact of IRB Disqualiﬁcation.................................................................145 4.4.2 Clinical Investigator Responsibilities.......................................................................145 4.4.2.1 Regulatory Responsibilities of Clinical Investigators ..............................146 4.4.2.2 Regulatory Sanctions Clinical Investigators May Face in a Disqualiﬁcation Action ......................................................................146 4.4.2.3 Impact of Clinical Investigator Disqualiﬁcation ......................................146 4.5 Applications: Compliance and Validity Issues ....................................................................146 4.5.1 Application Compliance...........................................................................................146 4.5.2 Application Integrity Policy .....................................................................................152 4.5.2.1 Applications Involved in AIP Reviews.....................................................153 4.5.2.2 Deferral of Scientiﬁc Review ...................................................................153 4.5.2.3 Untrue Statement or Material Fact ...........................................................153 4.5.2.4 Validity Assessment ..................................................................................153 4.5.2.5 Wrongful Acts ...........................................................................................153 4.5.2.6 Invoking and Revoking AIP......................................................................154 4.5.3 Corrective Actions ....................................................................................................156 4.6 Case Studies .........................................................................................................................157 Summary ........................................................................................................................................186 Reading Reference Section............................................................................................................186

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Practicum........................................................................................................................................186 Investigators’ Reports: Counterfeit Baby Formula Lands Fugitive in Jail .........................186 Endnotes .........................................................................................................................................188 Chapter 5. Case Studies ..............................................................................................................189 5.1 Program Implementation ......................................................................................................189 5.2 FDA 483 Forms, Recalls, Corrections, and Market Withdrawals.......................................189 5.2.1 Abbott Laboratories, Inc., FDA 483 Notice of Observations .................................189 5.2.2 Abbott Laboratories, Inc., Recalls ...........................................................................194 5.2.3 Abbott Laboratories Firm-Initiated Recall of HIV p24 Antigen Test Kit ..............195 5.2.4 Abbott Laboratories, Inc., Warning Letter...............................................................196 5.2.5 Schering Corporation Recall of Interferon alfa-2b (Recombinant), Powder for Injection, Intron A.................................................................................198 5.2.6 Wyeth-Ayerst Firm-Initiated Recall of Haemophilus b Conjugate Vaccine ...........198 5.2.7 Wyeth-Ayerst Withdrawal of Rotavirus Vaccine, Live, Oral, Tetravalent (RotaShield)..................................................................................199 5.3 Mass Seizure Actions ...........................................................................................................200 5.4 Injunction Actions ................................................................................................................201 5.5 Consent Decrees ...................................................................................................................202 5.5.1 Warner-Lambert Consent Decree .............................................................................202 5.5.2 Parkedale Pharmaceuticals, Inc., Consent Decree Notiﬁcation Letter 1 ................203 5.5.3 Parkedale Pharmaceuticals, Inc., Consent Decree Notiﬁcation Letter 2 ................209 5.6 Criminal Indictments, Process, and FDA Procedures .........................................................212 5.7 FDA Prosecution ................................................................................................................ 214 5.7.1 Ofﬁce of Criminal Investigations .............................................................................214 5.7.2 Criminal Prosecution after Section 305 Notice .......................................................214 5.7.3 Criminal Prosecution without Section 305 Notice ..................................................215 5.7.4 Contempt of Court and Violation of Probation ..................................................... 216 5.7.5 Development of Felony Violation ............................................................................216 5.8 Debarment.............................................................................................................................217 5.8.1 Example 1.................................................................................................................217 5.8.2 Example 2.................................................................................................................218 Case Study Exhibits .......................................................................................................................222 Endnotes .........................................................................................................................................241 Appendix 1. FD&C Act of 1938 .................................................................................................243 Chapter III. Prohibited Acts and Penalties ....................................................................................243 Seizure ............................................................................................................................................243 Hearing Before Report of Criminal Violation .....................................................................246 Debarment, Temporary Denial of Approval, and Suspension .............................................246 Civil Penalties.......................................................................................................................253 Authority To Withdraw Approval of Abbreviated Drug Applications ................................255 Report of Minor Violations ..................................................................................................255 Proceedings in Name of United States; Provision as to Subpoenas ...................................255 Chapter V. Drugs and Devices.......................................................................................................256 Subchapter A. Drugs and Devices .......................................................................................256 Adulterated Drugs and Devices ...........................................................................................256 Misbranded Drugs and Devices ...........................................................................................258 Exemptions and Considerations for Certain Drugs, Devices, and Biological Products ......261 Veterinary Feed Directive Drugs..........................................................................................268

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New Drugs............................................................................................................................268 Authority To Designate Ofﬁcial Names ..............................................................................293 Nonapplicability to Cosmetics .............................................................................................294 Registration of Producers of Drugs and Devices ................................................................294 New Animal Drugs...............................................................................................................297 Classiﬁcation of Devices Intended for Human Use ............................................................297 Device Classes..........................................................................................................297 Classiﬁcation; Classiﬁcation Panels.........................................................................299 Classiﬁcation Panel Organization and Operation ....................................................301 Classiﬁcation.............................................................................................................302 Classiﬁcation Changes..............................................................................................302 Initial Classiﬁcation and Reclassiﬁcation of Certain Devices ................................302 Information ...............................................................................................................304 Deﬁnitions.................................................................................................................305 Performance Standards.........................................................................................................306 Provision of Standards .............................................................................................306 Establishment of a Standard.....................................................................................307 Recognition of a Standard........................................................................................309 Premarket Approval ..............................................................................................................310 General Requirement .....................................................................................................................310 Regulation to Require Premarket Approval .............................................................310 Application for Premarket Approval........................................................................311 Action on Application for Premarket Approval.......................................................311 Withdrawal and Temporary Suspension of Approval of Application .....................314 Product Development Protocol ................................................................................314 Review ..................................................................................................................................317 Service of Orders.......................................................................................................318 Revision .....................................................................................................................318 Banned Devices ....................................................................................................................318 General Rule.............................................................................................................318 Special Effective Date ..............................................................................................319 Judicial Review.....................................................................................................................319 Application of Section..............................................................................................319 Additional Data, Views, and Arguments..................................................................320 Standard for Review .................................................................................................320 Finality of Judgment ................................................................................................320 Remedies...................................................................................................................320 Statement of Reasons ...............................................................................................320 Notiﬁcation and Other Remedies ......................................................................................321 Notiﬁcation ...............................................................................................................321 Repair, Replacement, or Refund ..............................................................................321 Reimbursement .........................................................................................................322 Effect on Other Liability ..........................................................................................322 Recall Authority........................................................................................................323 Records and Reports on Devices.......................................................................................323 General Rule.............................................................................................................323 User Reports .............................................................................................................324 Persons Exempt ........................................................................................................326 Device Tracking........................................................................................................326 Reports of Removals and Corrections .....................................................................327 General Provisions Respecting Control of Devices Intended for Human Use...................327

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General Rule.............................................................................................................327 Custom Devices........................................................................................................327 Trade Secrets ............................................................................................................328 Notices and Findings................................................................................................328 Restricted Devices ....................................................................................................328 Good Manufacturing Practice Requirements...........................................................329 Exemption for Devices for Investigational Use.......................................................330 Release of Information Respecting Safety and Effectiveness.................................333 Proceedings of Advisory Panels and Committees ...................................................334 Traceability ...............................................................................................................334 Research and Development ......................................................................................334 Transitional Provisions for Devices Considered as New Drugs .............................334 Humanitarian Device Exemption .............................................................................337 State and Local Requirements Respecting Devices ..........................................................338 General Rule.............................................................................................................338 Exempt Requirements ..............................................................................................338 Postmarket Surveillance ...........................................................................................338 Subchapter B. Drugs for Rare Diseases or Conditions ......................................................341 Recommendations for Investigations of Drugs for Rare Diseases or Conditions ..............341 Designation of Drugs for Rare Diseases or Conditions ......................................................341 Protection for Drugs for Rare Diseases or Conditions........................................................342 Open Protocols for Investigations of Drugs for Rare Diseases or Conditions ...................342 Subchapter C. Electronic Product Radiation Control .........................................................343 Deﬁnitions.............................................................................................................................343 Electronic Product Radiation Control Program...................................................................343 Studies by the Secretary.......................................................................................................344 Performance Standards for Electronic Products ..................................................................345 Notiﬁcation of Defects in and Repair or Replacement of Electronic Products..................347 Imports..................................................................................................................................349 Inspection and Reports .........................................................................................................350 Prohibited Acts .....................................................................................................................351 Enforcement..........................................................................................................................351 Annual Report ......................................................................................................................352 Federal–State Cooperation ...................................................................................................353 State Standards .....................................................................................................................353 Subchapter D. Dissemination of Treatment Information .....................................................353 Subchapter E. General Provisions Relating to Drugs and Devices....................................360 Chapter VIII. Imports and Exports................................................................................................362 Imports and Exports .............................................................................................................362 Exports of Certain Unapproved Products ............................................................................364 Ofﬁce of International Relations..........................................................................................368 Chapter IX. Miscellaneous ............................................................................................................369 Separability Clause...............................................................................................................369 Effective Date and Repeals ..................................................................................................369 Appendix 2. Drug Law History Synopsis..................................................................................375 Appendix 3. Clinical Investigators .............................................................................................381 Clinical Investigator Regulatory Sanctions ...................................................................................381 The Disqualiﬁcation Process................................................................................................381

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Informal Conference or Written Explanation ..........................................................381 Notice of an Opportunity for Hearing on Proposed Disqualiﬁcations ...................381 Part 16 Hearing and Final Order on Disqualiﬁcation .............................................382 Actions Upon Disqualiﬁcation .................................................................................382 Public Disclosure of Information Regarding Disqualiﬁcation ................................383 Reinstatement of a Disqualiﬁed Investigator...........................................................383 Consent Agreements.............................................................................................................383 Criminal Prosecutions ..........................................................................................................384 Additional Information.........................................................................................................384 Investigator Responsibilities ..........................................................................................................384 FDA Inspections of Clinical Investigators ....................................................................................386 Background...........................................................................................................................386 Clinical Investigator Inspection Programs ...........................................................................386 Study-Oriented Inspections ......................................................................................387 Investigator-Oriented Inspections.............................................................................387 Inspection Findings ..............................................................................................................388 Additional Information.........................................................................................................388 FDA Institutional Review Board Inspections................................................................................388 Background...........................................................................................................................388 IRB Review Program ...........................................................................................................389 Additional Information.........................................................................................................389 Contact Person for Inspection Problems..................................................................390 Appendix 4. FDA Administrative Procedures Act (FAPA) .....................................................391 Title 21 (Food and Drugs) CFR 10.1–10.206 ...............................................................................391 Subchapter A — General .....................................................................................................391 Subpart A — General Provisions.............................................................................391 Subpart B — General Administrative Procedures ...................................................393 Subpart C — Electronic Media Coverage of Public Administrative ......................427 Glossary ........................................................................................................................................433

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Introduction In the United States, drug development and manufacturing regulations comprise one of the most rigorous sets of minimum standards to achieve full compliance. The minimum standards to be met in developing premarket and distributing postmarket regulated products compared to other standards can be confusing and exceedingly complex. The goal of this book is to explore the regulations controlling drug research and manufacturing industries regulated by the U.S. Food and Drug Administration (FDA), to share basic industry experiences and techniques, and to present exercises that allow readers to apply the theory presented here. It is hoped that this approach will assist educators teaching FDA drug law in pharmacy and other graduate programs and candidates in these programs to develop an understanding of FDA Administrative Enforcement issues. The drug development process in most countries has two broad distinct phases: preapproval and postmarket. Preapproval drug development requires the sponsor to conduct clinical trials before products are approved for sale. Clinical trials have various phases involving both animals and humans. With each progressive step along the clinical trial path, protecting human patients and ensuring the safety, efﬁcacy, or immune responses of the product are the primary consumer protection aims of the FDA. Postmarket approved products are monitored through safety and surveillance programs. When the clinical trials and postmarket safety surveillance programs fail, Administrative Enforcement rules of the FDA may be applied to the acts of individuals, sponsors, manufacturers, or distributors of drug products. The FDA’s enforcement activities can involve recalls as well as administrative, civil, and criminal actions. My regulatory affairs, regulatory compliance, and quality assurance experiences in the healthcare industry have presented me with many Administrative Enforcement issues to resolve. Some of these responsibilities are remembered with joy, others with reservations. Having earned degrees in pharmacy regulatory affairs programs, I believe these programs are important not only to teach theory and practice but also to assist in developing an understanding of the intent of regulations controlling drug research and manufacturing industries and what the FDA can do to ﬁrms or individuals when these regulations are not followed. The reality is that drugs are developed using a cost–beneﬁt analysis. The idea behind this analysis is that the beneﬁt of developing drugs, vaccines, medical devices, and biotechnology products that reduce or eradicate disease in a large population outweighs the risk of experiencing an insigniﬁcantly small number of adverse reactions or even deaths from administration of the product. Some consider this approach to be the cost of doing business. Those who are harmed say it is just plain bad science. If the risk of harm begins to outweigh the utility of the drug product’s intended beneﬁt, however, approval to market the product can be withdrawn. In the market, an approved product can quickly change from being acceptable to unacceptable, and it is my opinion that the notion of acceptable vs. unacceptable is determined by those who are at risk and by the availability of a suitable alternative. The efforts of a regulatory affairs professional determined to achieve regulatory compliance for a ﬁrm can be compared to a person walking up a seesaw and trying to achieve balance by reaching the exact middle. When a bird sits on one end of the seesaw, tilting it ever so slightly, the regulatory affairs professional must adjust his position to rebalance the seesaw. Just when balance has once again been restored, another bird might alight on the seesaw. The point of the illustration is this: Ensuring that a company is in compliance at all times in all departments is a never-ending process. Failure to get it right, even just once, means that the company could be subject to excessive ﬁnes and penalties later in a consent decree or criminal regulatory action initiated by the FDA. xix

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xx

In this publication, topic areas covered are supplemented with regulations, lawsuit case studies, and enforcement information and reference materials. The information and reference materials provided here will give educators in relevant university graduate programs and their candidates insight into the impact of FDA enforcement on the industry and its practitioners.

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of Health and 1 Department Human Services, U.S. Food and Drug Administration: Authority and Responsibility The Department of Health and Human Services (DHHS) is the U.S. government’s principal agency charged with protecting the health of all Americans and providing essential human services to U.S. citizens. To perform its functions, the DHHS budget for FY2002 was $460 billion, and it currently has 65,110 employees.1 Its programs are administered by 11 operating divisions, including eight agencies in the U.S. Public Health Service and three human services agencies. The agency is organized as shown in Figure 1.1.2 Before turning our attention to the U.S. Food and Drug Administration (FDA), we will ﬁrst focus on the three healthcare DHHS divisions shown in Table 1.1, which details the functions, number of employees, and ﬁscal budgets of these divisions. As can be seen in the table, the National Institutes of Health (NIH), the oldest of these three operating divisions, has been around since 1887. The FDA was created in 1906, followed 40 years later by the Centers for Disease Control (CDC). Each of these healthcare-related agencies was established in response to speciﬁc events that prompted passage of new government regulations to ensure the public’s safety. The FDA’s delegated statutory authority is discussed in this book, but further research into the events leading to the development of the NIH and CDC and their authority is well worth the reader’s time.

1.1 STATUTORY AUTHORITY Statutory authority for the FDA’s actions is contained in the Federal Food, Drug, and Cosmetic Act of 1938, Pub. L. 102-282, and amendments thereto. An outline of the Federal Food, Drug, and Cosmetic Act of 1938, as amended by 21 United States Code (USC) 301, is presented in Table 1.2. Placing it here serves two purposes: (1) to introduce the reader to the act as enacted in 1938, with amendments thereto, and (2) to serve as a readily available reference resource while reading subsequent chapters of this publication.

1.2 LAWS ENFORCED BY THE FDA In addition to enforcing the Federal Food, Drug, and Cosmetic Act of 1938, the FDA Commissioner,4 solely or in conjunction with other federal agencies, enforces numerous other federal laws. When federal laws are jointly enforced, written authority is established for each agency involved under a speciﬁc law; for example, the Commissioner of the FDA has authority under the Public Health Service Act (PHSA) along with the NIH and CDC. For an example of how joint authority is handled by multiple agencies, look at the FDA Delegated Authority, 21 USC 301, Parts (a)(2) and (a)(3)

1

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The Secretary Deputy Secretary Chief of Staff

Director, Intergovernmental Affairs & Secretary's Regional Representatives

Executive Secretary

Assistant Secretary for Health

Assistant Secretary Administration for Children and Families (ACF)

Commissioner, Food and Drug Administration (FDA)

General Counsel

Assistant Secretary for Administration & Management

Assistant Secretary, Administration on Aging (AoA)

Administrator, Health Resources and Services Administration (HRSA)

Assistant Secretary for Public Health Emergency Preparedness

Administrator, Centers for Medicare & Medicaid Services (CMS) Director, Agency for Healthcare Research and Quality (AHRQ)

Director, Indian Health Service (IHS)

Director, Center for Faith-Based and Community Initiatives

Director, National Institutes of Health (NIH)

Director, Office for Civil Rights

Assistant Secretary for Legislation

Director, Centers for Disease Control and Prevention (CDC)

Administrator, Substance Abuse and Mental Health Svcs. Administration (SAMHSA)

Inspector General

Assistant Secretary for Public Affairs

Administrator, Agency for Toxic Substances and Disease Registry (ATSDR)

Director, Program Support Center (PSC)

Chair, Departmental Appeals Board

Assistant Secretary for Budget, Technology, & Finance Assistant Secretary for Planning & Evaluation

FIGURE 1.1 Department of Health and Human Services.

(provided below). The FDA’s full regulatory authority involves food,5 drugs, medical devices, and cosmetics.6 Our focus here will be on enforcement issues7 involving drugs,8 biologics, biotechnology, and medical devices.9 In each of these areas, the dates when speciﬁc regulations were enacted, their purpose, and their impact on industry are discussed. The detailed U.S. drug law history provided in Appendix 2 serves as a reference for the reader interested in a concise review of current U.S. drug law. Understanding what the FDA can enforce requires information about authority delegated to it by Congress. In 1906,10 the sole role of the FDA was to ensure that drugs were safe. Today, the FDA has 37 delegated authorities under 21 USC 301 et seq., Food and Drugs, Chapter I, FDA, DHHS. The Secretary of the DHHS11 is a presidential cabinet position, and authority is delegated to the Secretary. The Secretary, in turn, delegates authority to the Commissioner of the FDA.12

SECTION 5.10 DELEGATIONS FROM THE SECRETARY, THE ASSISTANT SECRETARY FOR HEALTH, AND PUBLIC HEALTH OFFICIALS (a) The Assistant Secretary for Health has redelegated to the Commissioner of Food and Drugs, with authority to redelegate except when speciﬁcally prohibited, all authority delegated to the Assistant Secretary for Health by the Secretary of Health and Human Services, as follows: (1) Functions vested in the Secretary under the Federal Food, Drug, and Cosmetic Act (21 USC 301 et seq.), the Filled Milk Act (21 USC 61–63), the Federal Import Milk Act (21 USC 141 et seq.), the Tea Importation Act (21 USC 41 et seq.), the Federal Caustic Poison Act (44 Stat. 1406), and the Fair Packaging and Labeling Act (15 USC 1451 et seq.), pursuant to Section 12 of Reorganization Plan No. IV and Reorganization Plan No. 1 of 1953, including authority to administer oaths vested in the Secretary of Agriculture by 7 USC 2217. (2) Functions vested in the Secretary under Section 301 (Research and Investigations); Section 307 (International Cooperation); and Section 311 (Federal–State Cooperation) of the Public Health Service Act (42 USC 241, 242l, 243), as amended, which relate to the functions of the Food and Drug Administration.

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TABLE 1.1 Department of Health and Human Services Divisions3 Division Name

Function

Employees

FY02 Budget

National Institutes of Health (NIH)

NIH is the world’s premier medical research organization, supporting some 35,000 research projects nationwide in diseases such as cancer, Alzheimer’s disease, diabetes, arthritis, heart ailments, and AIDS. NIH includes 18 separate health institutes, the National Center for Complementary and Alternative Medicine, and the National Library of Medicine. It was established in 1887 as the Hygienic Laboratory, Staten Island, NY. Its headquarters are in Bethesda, MD.

17,471

$20.9 billion

Centers for Disease Control (CDC)

Working with states and other partners, the CDC provides a system of health surveillance to monitor and prevent disease outbreaks (including bioterrorism), implement disease prevention strategies, and maintain national health statistics. The CDC provides for immunization services, workplace safety, and environmental disease prevention and guards against international disease transmission, with personnel stationed in more than 25 foreign countries. It was established in 1946 as the Communicable Disease Center. Its headquarters are in Atlanta, GA.

8627

$3.7 billion

Food and Drug Administration (FDA)

The FDA assures the safety of foods and cosmetics and the safety and efﬁcacy of pharmaceuticals, biological products, and medical devices — products that represent 25¢ out of every dollar in U.S. consumer spending. The FDA was established in 1906. Its headquarters are in Rockville, MD.

9989

$1.3 billion

(3) Functions vested in the Secretary under Sections 354 through 360F of the Public Health Service Act (42 USC 263b–263n), as amended, which relate to electronic product radiation control. (4) Functions vested in the Secretary under Section 361 of the Public Health Service Act (42 USC 264), as amended, which relate to the law enforcement functions of the Food and Drug Administration concerning the following products and activities: biologicals (including blood and blood products); interstate travel sanitation (except interstate transportation of etiologic agents under 42 CFR 72); food (including milk and food service sanitation and shellﬁsh sanitation); and drugs, devices, cosmetics, electronic products, and other items or products regulated by the Food and Drug Administration. (5) Functions vested in the Secretary under Sections 351 and 352 of Part F, subpart 1, of the Public Health Service Act (42 USC 262 and 263), as amended, Biological Products, insofar as they relate to the functions assigned to the Food and Drug Administration. (6) Functions vested in the Secretary under Section 302(a) of the Public Health Service Act (42 USC 242(a)), as amended, which relate to the determination and reporting requirements with respect to the medicinal and scientiﬁc requirements of the United States for controlled substances.

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TABLE 1.2 Federal Food, Drug, and Cosmetic Act of 1938 Industry Impacted Section

Drugs

Biologics

Biotechnology

Medical Devices

Cosmetics

X

Chapter III 304: Seizure

X

X

X

X

305: Hearing Before Criminal Violation

X

X

X

X

X

306: Debarment, Temporary Denial of Approval, and Suspension

X

X

X

X

X

307: Civil Penalties

X

X

X

X

308: Authority To Withdraw Abbreviated New Drug Applications

X

309: Report of Minor Violation

X

X

X

X

X

310: Proceedings in the Name of the United States and Subpoenas

X

X

X

X

X

X

X

X

X

X

X X

Chapter V 501: Adulteration

X

502: Misbranded

X

X

503: Exemptions and Considerations for Certain Drugs, Biologics, and Medical Devices

X

X

X

X

X

X

505: New Drugs

X

505a: Pediatric Studies of Drugs

X

X

506: Fast Track for Drugs

X

X

506a: Manufacturing Changes

X

X

506b: Postmarketing Studies

X

X

508: Authority To Designate Ofﬁcial Names

X

510: Registration of Producers of Drugs and Devices

X

X

X X

513: Classiﬁcation of Devices Intended for Human Use

X

514: Performance Standards

X

515: Premarket Approval

X

516: Banned Devices

X

517: Judicial Review

X

519: Records and Reports on Devices

X

520: General Provisions Respecting Control of Devices Intended for Human Use

X

521: State and Local Requirements Respecting Devices

X

522: Postmarket Surveillance

X Chapter V, Subchapter B

525: Recommendations for Investigations of Drugs for Rare Diseases or Conditions

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X

X

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TABLE 1.2 (cont.) Federal Food, Drug, and Cosmetic Act of 1938 Industry Impacted Section

Drugs

Biologics

Biotechnology

Medical Devices

Cosmetics

Chapter V, Subchapter B (cont.) 526: Designation of Drugs for Rare Diseases of Conditions

X

528: Open Protocols for Investigations of Drugs for Rare Diseases or Conditions

X

Chapter V, Subchapter C 532: Electronic Product Radiation Control Program

X (electronic products)

534: Performance Standards for Electronic Product

X

535: Notiﬁcation of Defects in and Repair or Replacement of Electronic Products

X

536: Imports

X

537: Inspection and Reports

X

538: Prohibited Acts

X

539: Enforcement

X

540–542: Annual Report — State Standards

X Chapter V, Subchapter D

551–555: Requirements for Dissemination of Treatment Information on Drugs or Devices et al.

X

X (devices)

X

X

X

X

X

X

X

Chapter V, Subchapter E 561–563: Expanded Access to Unapproved Therapies and Diagnostics

X

Chapter VIII 801: Imports and Exports

X

802: Export of Certain Unapproved Product

X

X

X

803: Ofﬁce of International Relations

X

X

X

X

X

903: Food and Drug Administration

X

X

X

X

X

X

X

X

Chapter IX 901: Separability Clause

X

X

902: Effective Date and Repeals

X

X

X

X

X

904: Scientiﬁc Review Groups

X

X

X

X

X

905: Loan Repayment Program

X

X

X

X

X

906: Practice of Medicine

X

X

X

X

X

907: Contract Expert Review

X

X

X

X

X

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(7) Functions vested in the Secretary under Section 303 of the Public Health Service Act (42 USC 242a), as amended, which relate to the authorization of persons engaged in research on the use and effect of drugs to protect the identity of their research subjects with respect to drugs scheduled under Pub. L. 91-513 for which an investigational new drug application is ﬁled with the Food and Drug Administration and with respect to all drugs not scheduled under Pub. L. 91-513. (8) Functions vested in the Secretary pertaining to Section 4 of the Comprehensive Drug Abuse Prevention and Control Act of 1970 (84 Stat. 1241) which relate to the determination of the safety and effectiveness of drugs or to approve new drugs to be used in the treatment of narcotic addicts. (9) Functions vested in the Secretary pertaining to Section 303(f) of the Controlled Substances Act (21 USC 823(f)) which relate to the determination of the qualiﬁcations and competency of practitioners wishing to conduct research with controlled substances listed in Schedule I of the Act, and the merits of the research protocol. (10) Functions vested in the Secretary pertaining to provisions of the Controlled Substances Act (21 USC 801 et seq.) which relate to administration of the Federal Food, Drug, and Cosmetic Act (21 USC 301 et seq.). (11) Functions vested in the Secretary under Section 409(b) of the Federal Meat Inspection Act (21 USC 679(b)) which relate to the detention of any carcass, part thereof, meat, or meat product of cattle, sheep, swine, goats, or equines. (12) Functions vested in the Secretary under Section 24(b) of the Poultry Products Inspection Act (21 USC 467f(b)) which relate to the detention of any poultry carcass, part thereof, or poultry product. (13) Functions vested in the Secretary under the Egg Products Inspection Act (21 USC 1031 et seq.). (14) Functions vested in the Secretary by amendments to the foregoing statutes subsequent to Reorganization Plan No. 1 of 1953. (15) Function of issuing all regulations of the Food and Drug Administration, except as provided in Section 5.11. The reservation of authority contained in Chapter 2-000 of the Department Organization Manual shall not apply. (16) Functions vested in the Secretary under Section 1103 of Executive Order 11490, as amended by Executive Order 11921, which relate to emergency health functions as they pertain to the operations and functional responsibilities assigned to the agency. This authority shall be exercised in accordance with Section 102 and pertinent sections of Part 30 of Executive Order 11490 and guidelines promulgated by the Federal Preparedness Agency of the General Services Administration; Ofﬁce of the Secretary, HHS; and Ofﬁce of the Assistant Secretary for Health. (17) Function vested in the Secretary of authorizing and approving miscellaneous and emergency expenses of enforcement activities. (18) Functions vested in the Secretary under the Federal Advisory Committee Act, Public Law 92-463, to make determinations that advisory committee meetings are concerned with matters listed in 5 USC 552(b) and therefore may be closed to the public for those committees under the administrative jurisdiction of the Commissioner of Food and Drugs. This authority may be redelegated to a single ofﬁcial who reports directly to the Commissioner of Food and Drugs. This authority is to be exercised in accordance with the requirements of the Federal Advisory Committee Act and only with respect to the following:

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(i) Meetings, to the extent that they directly involve review, discussion, or consideration of records of the Department which are exempt from disclosure under 5 USC 552(b)(4), (6), and (7), namely (a) records containing trade secrets and commercial or ﬁnancial information obtained from a person and privileged or conﬁdential; (b) personnel, medical, and similar ﬁles the disclosure of which would constitute a clearly unwarranted invasion of personal privacy; and (c) investigatory ﬁles compiled for law enforcement purposes; (ii) Meetings to the extent that they involve the review, discussion, and evaluation of speciﬁc drugs and devices regulated by FDA which are intended to result in recommendations for regulatory decisions under the Federal Food, Drug, and Cosmetic Act and which are concerned with matters listed in 5 USC 552(b)(4), (5), and (7); (iii) Meetings held for the sole purpose of considering and formulating advice which the committee will give or any ﬁnal report it will render, provided: (A) The meetings will involve solely the internal expression of views and judgments of the members and it is essential to close the meeting or portions thereof to protect the free exchange of such views and avoid undue interference with agency or committee operations, and such views if reduced to writing would be protected from mandatory disclosure under 5 USC 552(b); (B) The meeting is closed for the shortest time necessary, summarizing the work of the committee during the closed session, and a report, prepared by the executive secretary, will be made available promptly to the public; (C) When feasible, the public is given a timely opportunity to present relevant information and views to the committee; and (D) Concurrence for closing the meetings for such purpose is obtained from the Ofﬁce of the General Counsel and the Ofﬁce of Public Affairs. (19) Functions vested in the Secretary under the second sentence of Section 310(a) and under Section 310(b) (Health Conferences and Health Education Information) of the Public Health Service Act (42 USC 242o), as amended, to call for a conference and invite as many health authorities and ofﬁcials of State or local public or private agencies or organizations as deemed necessary or proper on subjects related to the functions of the Food and Drug Administration, and to issue information related to health for the use of the public and other pertinent health information for the use of persons and institutions concerned with health services when such information is related to the functions of the Food and Drug Administration. (20) Functions vested in the Secretary under Section 2101 of the Public Health Service Act (42 USC 219) as amended, to accept offers of gifts, excluding the acceptance of gifts of real property. Only the authority to accept unconditional gifts of personal property valued at $5000 or less may be redelegated. (21) Functions vested in the Secretary under Section 362 of the Public Health Service Act (42 USC 265), as amended, which relate to the prohibition of the introduction of foods, drugs, devices, cosmetics, electronic products, and other items or products regulated by the Food and Drug Administration into the United States when it is determined that it is required in the interest of public health when such functions relate to the law enforcement functions of the Food and Drug Administration. (22) Functions vested in the Secretary under Section 1003(b)(3), Title X, of the Public Works and Economic Development Act of 1965 (42 USC 3246b(b)(3)) to waive any matching requirements for programs or projects of State and local governments funded under Title X of that act where it is determined that State or local governments concerned cannot reasonably obtain any non-Federal contributions.

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(23) Functions vested in the Secretary under Section 401(a) of the Lead-Based Paint Poisoning Prevention Act, as amended by Pub. L. 94-317 (42 USC 4831(a)) relating to the prohibition of the application of lead-based paint to cooking, drinking, or eating utensils. (24) Functions vested in the Secretary for the health information and health promotion program under Title XVII of the Public Health Service Act (42 USC 300u et seq.), as amended, insofar as the authorities pertain to functions assigned to the Food and Drug Administration. The delegation includes, but is not limited to, the authorities under: Sections 1702(a)(1) and (3) and Sections 1704(1), (2), and (6). The delegation excludes the authority to select all Senior Executive Service, super grade and equivalent, and Schedule C (GS-12 and above) positions; promulgate regulations; and submit reports to the President. (25) To administer a Small Business Innovation Research Program under Section 9 of the Small Business Act (15 USC 638), as amended. The delegation excludes the authority to promulgate regulations, establish advisory councils and committees, appoint members to advisory councils and committees, and submit reports to Congress. (26) Functions vested in the Secretary under Sections 982 and 983 of the Consumer–Patient Radiation Health and Safety Act of 1981 (42 USC 10007 and 10008), as amended. The delegation excludes the authority to promulgate regulations and submit reports to Congress. The authority delegated under Section 983 of the Act may only be exercised as it relates to functions assigned to the Food and Drug Administration. (27) Functions vested in the Secretary under Section 156 of Title 35 of the U.S. Code (35 USC 156), as amended, which allows for the extension of patent terms for human drug products, medical devices, food additives, and color additives subject to the Federal Food, Drug, and Cosmetic Act. These authorities may be redelegated except the authority to make due diligence determinations under Section 156(d)(2)(B), which may not be redelegated to an Ofﬁce below the Ofﬁce of the Commissioner of Food and Drugs. (28) Functions vested in the Secretary under Sections 1862(h)(1), (2)(A), and (3) of the Social Security Act (42 USC 1395y(h)(1), (2)(A), and (3)), as amended, which provides for a registry of all cardiac pacemaker devices and pacemaker leads for which payment was made under this title. The approval and issuance of regulations under that section are reserved to the Secretary, as provided in 21 CFR 5.11. (29) Functions vested in the Secretary under the Stevenson–Wydler Technology Innovation Act of 1980 (15 USC 3701 et seq.) (the Act), as amended, and under Executive Order No. 12591 of April 10, 1987, as they pertain to the functions of the Food and Drug Administration. The delegation excludes the authority to promulgate regulations and submit reports to Congress; under Section 11(a)(2) of the Act (15 USC 3710a(a)(2)) to approve agreements and contracts with invention management organizations; and under Section 11(c)(3)(B) of the Act (15 USC 3710a(c)(3)(B)) to propose necessary statutory changes regarding conﬂict of interest. (i) The authorities under Sections 11(c)(5)(A) and (B) of the Act (15 USC 3710a(c)(5)(A) and (B)) to disapprove or require the modiﬁcation of cooperative research and development agreements and licensing agreements after the agreement is presented to the Commissioner of Food and Drugs by the head of the laboratory concerned, and to transmit written explanation of such disapproval or modiﬁcation to the head of the laboratory concerned, may be redelegated only to a senior ofﬁcial in the immediate ofﬁce of the Commissioner. (ii) The following authorities may not be redelegated: The authority under Section 11(b)(3) of the Act (15 USC 3710a(b)(3)) to waive a right of ownership which the Federal Government may have to an invention made under a cooperative research and development agreement; the authority under Section 11(b)(4) of the Act (15 USC

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3710a(b)(4)) to permit employees or former employees to participate in efforts to commercialize inventions they made while in the service of the United States; the authority under Section 11(c)(3)(A) of the Act (15 USC 3710a(c)(3)(A)) to review employee standards of conduct for resolving potential conﬂicts of interest; the authority under Section 13(a)(1) of the Act (15 USC 3710c(a)(1)) to retain any royalties or other income, except as provided in Section 13(a)(2) of the Act (15 USC 3710c(a)2)); and the authority under Section 13(a)(1)(A)(i) of the Act (15 USC 3710c(a)(1)(A)(i)) to pay royalties or other income the agency receives on account of an invention to the inventor if the inventor was an employee of the agency at the time the invention was made. (iii) Any authorities under paragraph (a)(29) of this section delegated by the Commissioner of Food and Drugs may not be further redelegated. (30) Functions vested in the Secretary under Sections 4702, 4703, and 4704 of the Pesticide Monitoring Improvements Act of 1988 (21 USC 1401–1403) which relate to pesticide monitoring and enforcement information, foreign pesticide information, and pesticide analytical methods. The delegation excludes the authority to submit reports to Congress. (31) Functions vested in the Secretary under the Government Patent Policy Act of 1980 as amended by the Federal Court Reorganization Act of 1984, as they pertain to the functions of the Food and Drug Administration (FDA). The delegated authorities, to be exercised in compliance with all existing rules and regulations regarding patent and invention rights and responsibilities, are restricted to the extent that 35 USC 203, as amended, may not be redelegated and that under 35 USC 207(a) the Assistant Secretary for Health is to be notiﬁed of any signiﬁcant invention, patent, or license, so that the Assistant Secretary for Health may decide whether or not documentation concerning any such invention, patent, or license should be submitted to the Assistant Secretary for Health for signature. All other authorities may be redelegated to ofﬁcials at the level equivalent to bureau and institute directors. (i) Disposition of rights, 35 USC 202(c)(7), as amended: The authority to permit a nonproﬁt organization to assign the rights to a subject invention in the United States to organizations which do not have as one of their primary functions the management of inventions. (ii) Disposition of rights, 35 USC 202(d), as amended: The authority to permit a contractor to grant requests for retention of rights by the inventor. (iii) Disposition of rights, 35 USC 202(e), as amended: The authority to transfer or assign whatever rights FDA may acquire in the subject invention in any case when an agency employee is a co-inventor of any invention made under a funding agreement with a nonproﬁt organization or small business ﬁrm. Such rights may be transferred or assigned from the FDA employee to the contractor subject to the conditions set forth in this chapter. (iv) March-in-rights, 35 USC 203, as amended: The authority to require the contractor to grant nonexclusive, partially exclusive, or exclusive licenses to responsible applicant(s), or the authority for FDA to grant such licenses, provided such action would be in the best interest of FDA, in accordance with all provisions of this section. (v) Preference for United States industry, 35 USC 204, as amended: The authority to waive the preference for U.S. industry requirement. (vi) Domestic and foreign protection of federally owned inventions, 35 USC 207(a) as amended, the authority to: (A) Apply for, obtain, and maintain patents or other forms of protection in the United States and in foreign countries on inventions in which the Federal Government owns a right, title, or interest;

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(B) Grant nonexclusive, exclusive, or partially exclusive licenses under federally owned patent applications, patents, or other forms of protection obtained, royalty-free or for royalties or other consideration, and on such terms and conditions, including the grant to the licensee of the right of enforcement pursuant to the provisions of chapter 29 of Title 35 as determined appropriate in the public interest; (C) Undertake all other suitable and necessary steps to protect and administer rights to federally owned inventions on behalf of the Federal Government either directly or through contract; and (D) Transfer custody and administration, in whole or in part, to another Federal agency, of the right, title, or interest in any federally owned invention. (vii) Determination as to domestic rights and notice to employee of determination, 45 CFR 7.3 and 7.7, as amended, authority to: (A) Leave title to invention in the FDA employee inventor where the Government has insufﬁcient interest in an invention to obtain the entire domestic right, title, and interest therein; and (B) Notify the FDA employee inventor of the determination in writing. (32) Functions vested in the Secretary under Sections 2312(a)(1) and (2)(B), (b), and (c) (Use of Investigational New Drugs with Respect to Acquired Immunodeﬁciency Syndrome); 2314(c) (Scientiﬁc and Ethical Guidelines for Certain Treatments); and 2317(d) and (e) (Information Services) of Title XXIII of the Public Health Service Act (42 USC 300cc12(a)(1) and (2)(B), (b) and (c), 300cc-14(c) and 300cc-17(d) and (e)), as amended, insofar as these authorities pertain to the functions assigned to the Food and Drug Administration. The delegation excludes the authority to promulgate regulations, submit reports to the Congress, establish advisory committees or national commissions, and appoint members to such committees or commissions. (33) Functions vested in the Secretary under Section 2672(a)(1)(A) and (B) (Provisions Relating to Blood Banks) and Section 2672(a)(2) (Information and Training Programs) of the Public Health Service Act (42 USC 300ff et seq.), as amended, insofar as these authorities pertain to the functions assigned to the Food and Drug Administration. The delegations exclude the authority to promulgate regulations, submit reports to the Congress, establish advisory committees or national commissioners, and appoint members to such committees or commissions. (34) Functions vested in the Secretary under Sections 1322(b) and (c) of the Food, Agriculture, Conservation, and Trade Act of 1990 (the National Laboratory Accreditation Program) (7 USC 138a), as amended hereafter, which relate to setting standards for the National Laboratory Accreditation Program and approving State agencies or private, nonproﬁt entities as accrediting bodies to implement certiﬁcation and quality assurance programs in accordance with the requirements of this section. The delegation excludes the authority to submit reports to Congress. (35) Functions vested in the Secretary under Part C, Subtitle 2, of Title XXI of the Public Health Service Act (42 USC 300aa-25 et seq.), as amended, and the National Childhood Vaccine Injury Act of 1986 (42 USC 300aa-1 note), as amended hereafter, as follows: (i) Section 2125 of the Public Health Service Act (42 USC 300aa-25) — Recording and reporting of information. (ii) Section 2127 of the Public Health Service Act (42 USC 300aa-27) — Mandate for safer childhood vaccines.

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(iii) Section 2128 of the Public Health Service Act (42 USC 300aa-28) — Manufacturer recordkeeping and reporting. (iv) Section 312 of the National Childhood Vaccine Injury Act of 1986 — Related studies. (v) Section 313 of the National Childhood Vaccine Injury Act of 1986 — Study of other vaccine risks. (vi) Section 314 of the National Childhood Vaccine Injury Act of 1986 — Review of warnings, use instructions, and precautionary information. (vii) The delegation excludes the authority to issue regulations and submit reports to Congress. (36) Functions vested in the Secretary under Section 354(b) through (l) and (n), (o), (q), and (r) of the Public Health Service Act (Section 2 of the Mammography Quality Standards Act of 1992 (Pub. L. 102-539)), as amended, which deal with the certiﬁcation of mammography facilities. The delegation excludes the authority to submit reports to Congress. (37) Functions vested in the Secretary under Section 811(h)(4) of the Controlled Substances Act (Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970, as amended) to provide responses to the Drug Enforcement Administration’s temporary scheduling notices. The delegation excludes the authority to submit reports to Congress. (b) The Chief Counsel of the Food and Drug Administration (i.e., the Associate General Counsel in charge of the Food and Drug Division) has been authorized to report apparent violations to the Department of Justice for the institution of criminal proceedings, pursuant to Section 305 of the Federal Food, Drug, and Cosmetic Act, Section 4 of the Federal Import Milk Act, and Section 9(b) of the Federal Caustic Poison Act. (c) The Director, Ofﬁce of Management, Public Health Service, has redelegated to the Commissioner of Food and Drugs, with authority to redelegate, the authority to certify true copies of any books, records, or other documents on ﬁle within the Food and Drug Administration or extracts from such; to certify that true copies are true copies of the entire ﬁle of the Administration; to certify the complete original record or to certify the nonexistence of records on ﬁle within the Administration; and to cause the Seal of the Department to be afﬁxed to such certiﬁcations and to agreements, awards, citations, diplomas, and similar documents. (d) The Executive Ofﬁcer, Public Health Service, has redelegated to the Commissioner of Food and Drugs appeal authority to take ﬁnal action upon an individual’s appeal of a refusal to correct or amend the individual’s record when the appeal has been made by the individual under Privacy Act regulations (part 21 of this chapter and 45 CFR Part 5b). The authority may not be redelegated. (e) [Reserved] (f) The Secretary of Health and Human Services has redelegated to the Commissioner of Food and Drugs, or his designee, the authority to take ﬁnal action on matters pertaining to Section 203 of the Equal Access to Justice Act (5 USC 504), and to develop procedures and regulations where necessary to supplement the Department’s regulations, 45 CFR Part 13. [42 FR 15560, Mar. 22, 1977]

SECTION 5.11

RESERVATION

OF

AUTHORITY

(a) Notwithstanding provisions of Section 5.10 or any previous delegations of authority to the contrary, the Secretary reserves the authority to approve regulations of the Food and Drug Administration, except regulations to which Sections 556 and 557 of Title 5 USC apply, which:

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(1) Establish procedural rules applicable to a general class of foods, drugs, cosmetics, medical devices, or other subjects of regulation; or (2) Present highly signiﬁcant public issues involving the quality, availability, marketability, or cost of one or more foods, drugs, cosmetics, medical devices, or other subjects of regulation. (b) Nothing in this section precludes the Secretary from approving a regulation, or being notiﬁed in advance of an action, to which Sections 556 and 557 of Title 5 USC apply, which meets one of the criteria in paragraph (a) of this section. (c) This reservation of authority is intended only to improve the internal management of the Department of Health and Human Services and is not intended to create any right or beneﬁt, substantive or procedural, enforceable at law by a party against the United States; the Department of Health and Human Services; the Food and Drug Administration; any agency, ofﬁcer, or employee of the United States; or any person. Regulations issued by the Food and Drug Administration without the approval of the Secretary are to be conclusively viewed as falling outside the scope of this reservation of authority. [47 FR 16318, Apr. 16, 1982].

In addition to the 37 delegated authorities of the FDA Commissioner, nine chapters of the Federal Food, Drug, and Cosmetic Act are enforced by the agency through facility inspections, new drug and medical device application reviews, and postmarket surveillance programs. Arranging each of these chapters into digestible portions (except deﬁnitions) and identifying regulated industry segments impacted by the Act will facilitate understanding its plenary impact and magnitude on industry practices. Discussing impacted industry segments chapter by chapter will help national and international practitioners to focus on pertinent areas of enforcement for their speciﬁc industries; also, educators can emphasize certain sections for teaching purposes, and law and pharmacy degree candidates will ﬁnd such an approach helpful to developing an understanding of regulatory requirements for various segments of industry. Refer back to Table 1.2 for an overview of sections of the Federal Food, Drug, and Cosmetic Act, relevant chapters of the law, and the industries impacted (i.e., drugs, biologics, biotechnology, medical devices, cosmetics); for example, the row for Chapter III, Section 304 (Seizures), indicates that all segments are impacted, so this speciﬁc section of the Act is applicable to drugs, biologics, biotechnology, and medical devices. The row for Chapter V, Section 513 (Classiﬁcation of Devices Intended for Human Use), indicates that the impacted industry is medical devices, so this particular section of the Act applies only to medical devices, not to the other industries. When the regulated product is a combination of drug and device, the segment of industry impacted by the Federal Food, Drug, and Cosmetic Act states whether the drug or device segment is impacted (see Appendix 1 of this book).

1.2.1 RECOMMENDATIONS

FOR

UNDERSTANDING

THE

ACT

The latest major amendment to the Federal Food, Drug, and Cosmetic Act of 1938 was the Food and Drug Modernization Act of 1997. Because writing and enacting these laws took considerable time and effort, it would be imprudent to believe that a cursory reading of the Act could result in a full understanding. A recommended approach to learning more about this Act is to refer to speciﬁc segments impacted and areas regulated while proceeding through the remainder of this book.

1.2.2 U.S. DRUG LAW HISTORY Appendix 2 provides a chronological summary of all the laws currently enforceable by the FDA and the purpose of each law. The reader’s area of involvement in the regulated industries will determine the selection of speciﬁc laws for more detailed research and study.

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1.3 JURISDICTION The term jurisdiction is a comprehensive one that embraces every kind of judicial action. It is the authority by which courts and judicial ofﬁcers take notice of and decide cases. It is the legal right by which judges exercise authority. It exists when a court has authority over a particular class of cases and the power to decide such cases. The scope and extent of jurisdictions of the federal courts and government administrative adjudications are the focus of this section. Federal court jurisdiction is governed by 28 USC 125 et seq.; additionally, federal courts may take jurisdiction over FDArelated matters through admiralty and maritime laws (28 USCA 1333). FDA jurisdiction is determined by the Federal Food, Drug, and Cosmetic Act of 1938. In the federal courts, the three potential types of jurisdiction are in personam, in rem, and quasi in rem. In personam jurisdiction is the power of a court over the defendant’s person.13 In rem jurisdiction is the power of a court to deal with a thing, which is usually chattel or property, and to determine its status in relation to the legal rights of everyone involved in the thing being disputed; the decision of the court is binding to all possible interested parties. Quasi in rem jurisdiction is the power of a court over the defendant’s interest in property, real or personal, that is within the geographical limits of that court. In federal court, cases are brought in the name of the United States using in rem jurisdiction against the regulated property (i.e., drugs, biologics, biotechnology, medical devices, or cosmetics).

1.4 STATUTE OF LIMITATIONS A statute of limitations is a law that states the time period within which a legal dispute must be initiated by ﬁling a complaint with a competent court. After the stated period has elapsed, action cannot be taken regarding the dispute, and plaintiffs are unable to bring a claim of civil or criminal action in any court against potential defendants. The statutes of limitations for actions brought by the FDA against a ﬁrm, individual, consultant, or contractor vary from 5 to 10 years from the date of the last act. This means that an industry that has engaged in any Federal Food, Drug, and Cosmetic Act Chapter III prohibited acts within the past 5 to 10 years may have regulatory sanctions brought against it in the form of a civil or criminal action.

1.5 ADMINISTRATIVE LAW AND PROCEDURES ACT Administrative law encompasses laws and legal principles governing the administration and regulation of government agencies. Federal agencies are delegated authority by Congress (in the case of a state agency, the state legislature) to act as agents for the Chief Executive (President). Generally, administrative agencies are created to protect a public interest rather than to advocate private rights. The law administered by the FDA is codiﬁed in the Code of Federal Regulations (CFR), Title 21. Administrative law is a body of law created by administrative agencies to implement their powers and duties in the form of rules, regulations, orders, and decisions. An administrative order is the ﬁnal disposition of a matter before an administrative agency or the product of an administrative adjudication. An administrative order may be declaratory or it may contain an afﬁrmative or negative command.14 An administrative regulation issued by an agency interpreting or applying the provision of a statute has the force of law and is used sometimes to design, clarify, or implement a law or policy. The FDA obtains authority to act from provisions of the Federal Food, Drug, and Cosmetic Act; however, in enforcing the Act, the process by which an administrative agency issues an order (afﬁrmative, negative, injunctive, or declaratory in form) is governed by the Federal Administrative Procedures Act (FAPA), Section 551.15 Governmental agencies must act within constitutional parameters when enforcing administrative authority. These and other limits have been codiﬁed into

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statutes such as the FAPA and similar state codes. The FAPA is a remedial statute designed to ensure uniformity and openness in the procedures used by federal agencies. The Act is comprised of a comprehensive regulatory scheme governing regulations, adjudications, and rulemaking in general terms. The FAPA is the major source for federal administrative agency law. The administration and regulation of state agencies are governed by similarly enacted state laws. The FDA’s primary administrative procedure acts are codiﬁed in Title 21 CFR 10 and 12 et seq. These sections are seldom read but are of major importance in understanding the FDA’s administrative procedures. The methods and processes of administrative procedures brought before an administrative agency are different from judicial procedures that apply to courts. Procedural rules and regulations of most federal agencies are set forth in the Code of Federal Regulations, whereas for courts they are found in civil or criminal procedure rules. Remedies or decisions from a government agency are nonjudicial and are provided by an agency, board, commission, or the like within a governmental agency. In a courtroom, the trier of fact is the jury, and the judge generally makes the decision in a case. In most instances, all administrative remedies must have been exhausted before a court will take jurisdiction of a case. To exhaust administrative remedies means that all levels of review within the agency must be utilized before seeking court involvement.

1.6 CODE OF FEDERAL REGULATIONS The Code of Federal Regulations is the accumulation of executive agency regulations and is published annually, although prior regulations remain in effect. The CFR is divided into various titles and currently has 1299 sections, each representing a broad subject area. Individual volumes of the CFR are revised at least once each calendar year and issued on a staggered quarterly basis. The CFR contains the general body of regulatory laws governing practice and procedure before federal administrative agencies. The Title 21 CFR contains Sections 1 through 1300, which are enforced by the FDA. When the FDA corresponds with industry participants after facility inspections, it refers to the Title 21 CFR.

1.7 AUTHORITY, SCOPE, AND FACILITY INSPECTIONS The FDA authority for Compliance Ofﬁcers to enter and inspect establishments is deﬁned by the Federal Food, Drug, and Cosmetic Act of 1938, Section 704 (21 USC 374). The courts have upheld the legality of an FDA inspection if it is conducted at a reasonable time, within reasonable limits, and in a reasonable manner.16 A reasonable time is any time when the ﬁrm is operating. If a ﬁrm operates a second and third shift, an FDA inspection during those times is reasonable. Refusal to allow a properly identiﬁed Compliance Ofﬁcer to inspect subjects any person responsible for such refusal to criminal penalties.17 The scope of an inspection can involve any and all laws, regulations, or orders enforced by the FDA. Generally, the facility inspection will evaluate the use of current good manufacturing practices (CGMPs), good laboratory practices (GLPs), and good clinical practices (GCPs). Routinely, reviews of advertising and promotional literature are reserved for speciﬁc FDA department centers; however, labels and labeling may fall within the scope of a facility inspection. A few documents are not reviewed by the FDA for public policy reasons; for example, FDA access to results of quality assurance program audits and inspections is limited. While the FDA does not review such audits, it may request records that verify the performance documented in the ﬁrm’s quality assurance programs to ensure that the ﬁrm follows its own policies and procedures. Within the FDA organization are ﬁve department centers: Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), Center for Veterinary Medicine (CVM), and Center for Food Safety

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15 Foods 50,254

Miscellaneous Warehouses 2516 Color Additives 136 Vitamins 2194 Cosmetics 2865 Radiological Health 4745 Biologics 4296 Animal Drugs and Feeds 4654 Medical Devices 32,368

Human Drugs 18,174

FIGURE 1.2 FDA inspection areas and responsibilities (number of establishments).18

and Applied Nutrition (CFSAN). The relevant areas of inspection are obvious except perhaps for the CFSAN, which is responsible for food safety, nutrition, and cosmetics. When products cross over the lines of responsibility for the various center departments, the approach to regulation combines these departments’ functional responsibilities. A summary of FDA inspection responsibilities is provided in Figure 1.2.

1.8 INSPECTION PROCESS AND PROCEDURES Inspections by the FDA may be routine, follow-up, or for cause. The FDA’s goal is to inspect ﬁrms every 2 years. A follow-up inspection may be performed to conﬁrm that a ﬁrm has implemented required corrective actions to remedy past compliance issues or problems. For both routine and follow-up inspections, the Safety Compliance Ofﬁcer shows identiﬁcation upon arrival and requests the name of the most responsible person, who is issued a Form FDA 482, Notice of Inspection. During the course of a routine or follow-up inspection, interviews are held, documents are requested, personnel are questioned about the documents, and copies of the documents are made for the Compliance Ofﬁcer’s ﬁles. The ﬁndings or observations at the conclusion of the inspection are issued on a Form FDA 483 Notice of Observations. Form FDA 483 may be followed up with a warning letter. A warning letter, unlike the FDA 483, identiﬁes serious deviations from regulations that warrant senior management attention. It also requires a written response that states corrective actions the ﬁrm’s management will take to alleviate the compliance problems. If a warning letter issued after a follow-up investigation notes previous commitments made but not implemented, the FDA may exercise a heightened level of regulatory sanctions against the ﬁrm, such as recall, seizure, injunction, disqualiﬁcation, application integrity, or criminal prosecution. If a Compliance Ofﬁcer arrives and shows identiﬁcation but does not issue a Form FDA 482, Notice of Inspection, the inspection is for cause. In this case, the FDA personnel may be accompanied by a U.S. Marshal. For-cause inspections are compliance-based inspections. Such audit review inspections are conducted to investigate speciﬁc problems that have been brought to the attention of the agency. The concerns may be voiced by sources within the ﬁrm through Field Alert Reports (FARs), industry complaints, product complaints, or recalls. A compliance-based inspection is an attempt to determine whether, for example, a drug ﬁrm is operating in a state of control as intended by Section 501(a)(2)(B) of the Act and by Title 21 CFR 210–211 CGMP regulations as they pertain to internal systems and processes. A drug ﬁrm is in control of its compliance programs, systems, and processes when it produces ﬁnished drug products with an adequate level of assurances of quality, strength, identity, and purity for the products that are consistent with approved applications. A ﬁrm is out of control if any one system is out of control, and a system is out of control

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TABLE 1.3 Interrelatedness of Full Compliance Achievement Programs

3. GCP for Human Study 1. GCP in Animal Study

Title 21 CFR 50, 56, 58

Title 21 CFR 312.21 2. CGMP Sponsors and Manufacturers

6. Postmarketed Products Title 21 CFR 314

Title 21 CFR 210–211 and others

4. GLP in Animal Care Title 21 CFR 54

5. Advertising Labeling Title 21 CFR 201

if the quality, identity, strength, or purity of the products resulting from any of these systems cannot be adequately assured. As a baseline indication, documented CGMP deﬁciencies provide evidence for concluding that a system is not operating in a state of control. Because many ﬁrms’ systems policies and procedures develop out of need, enhancements, or incremental improvements, the areas of compliance are approached one at a time (i.e., CGMP and GCP issues are addressed separately) and at different times. A systematic approach to compliance is not the usual situation, and ﬁrms tend to approach regulatory compliance in a piece-meal fashion, developing systems, policies, and procedures that are inconsistent. Some ﬁrms go so far as determining their level of compliance by a sliding scale of increased proﬁts. Due to the interrelatedness of systems, policies, and procedures, the entire system of processes, procedures, and functions must be in compliance to achieve full regulatory compliance. For example, Table 1.3 provides a basic overview of how all functions of a compliance program are interrelated, from a clinical trial and postmarketed product perspective. Table 1.3 shows the four primary regulated compliance areas of GCPs, GLPs, CGMPs, and advertising and promotional literature (labels, labeling, and advertising); the regulations used to enforce those areas; and the ways in which they may be interrelated for compliance purposes. These minimum standards apply to all industry segments: drugs, biologics, medical devices, biotechnology, and cosmeticeuticals (cosmetic drugs prescribed by a licensed dermatologist’s prescription). In each document box, a CFR section is noted. Because the marketing of most new drug products begins with a clinical trial and continues through to postmarket surveillance, a logical path that demonstrates the interrelatedness necessary to achieve full regulatory compliance would, for example, begin in box 1. The regulated product manufactured for a clinical trial must be made consistent with provisions of CGMPs. If the product under study is made with quality, strength, and purity problems, it would be considered adulterated; alternatively, a clinical trial product that is not properly identiﬁed is considered to be mislabeled. In either instance — adulteration or mislabeling — the product would be subject to recall. If a clinical trial does not take the necessary precautions to ensure the safety of the humans consistent with Institutional Review Board requirements, the research project is not well controlled and documented, subjecting the results to a refusal to ﬁle or clinical hold decision by the FDA. If a product was tested for safety in animals that were not properly housed, fed, maintained, or used, the FDA will not permit a ﬁrm to go to phases II and III to test for efﬁcacy

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in humans. Brochures, labeling, advertising, or promotional materials for a product that are mislabeled or misbranded are in violation of Chapter III (Prohibited Acts) of the Federal Food, Drug, and Cosmetic Act, thus subjecting the product to a recall, seizure, or injunction. Finally, a clinical trial product with such violations will not be given the approval for postmarket surveillance programs that would report the occurrence of adverse events. Without an interrelated compliance approach, a ﬁrm can easily operate out of control. The point is that no matter where a process begins within the FDA regulation scenario, the systems, processes, and functions are necessarily interrelated. Current good manufacturing practices are not separate and distinct from the development of advertising and promotional literature; postmarket product surveillance of adverse events is not separate and distinct from good clinical practices. Full compliance is not achieved department by department; it is achieved through the melding of seamless, continuous processes, systems, and functions into a cohesive unit incorporating the entire process from start to ﬁnish.

1.9 U.S. CONSTITUTIONAL RIGHTS OF DEFENDANT FIRMS AND INDIVIDUALS Persons brought into U.S. federal courts are afforded U.S. constitutional rights under the Fourth Amendment (right against unreasonable searches and seizure), Fifth Amendment (right against selfincrimination), and Sixth Amendment (right to counsel).

1.10 EVIDENCE, ADMINISTRATIVE AGENCIES, AND FEDERAL COURTS Both administrative agencies and trial courts have evidence standards that litigants must meet to prove a case, as well as certain elements necessary for a successful action. Administrative evidence standards are not as rigorous as court standards. An administrative hearing evidentiary standard requires the agency to ﬁnd evidence of proof using a substantial evidence19 standard. In a de novo20 review of an agency decision in a U.S. Court of Appeals, the evidence standard for a civil action is a preponderance of the evidence; in a criminal prosecution, the evidence standard is beyond a reasonable doubt.

1.11 CASE STUDIES Personal jurisdiction: Pennoyer v. Neff, 95 U.S. 714, 24 L.Ed. 565 FDA exclusive jurisdiction: Breitmeyer v. Califano, E.D. Mich. 1978, 463 F. Supp. 810

DHHS–FDA EXHIBITS

FDA Documents Issued to Industry Item 1 2

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Document Form FDA 482 Notice of Inspection Form FDA 483 Notice of Observation

Page 18 22

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FORM FDA 482 Department of Health and Human Services Public Health Service Food and Drug Administration

2. NAME AND TITLE OF INDIVIDUAL Robert K. Thompson, Plant Manager

1. DISTRICT ADDRESS AND PHONE NUMBER Rm. 508, Federal Ofﬁce Building 30 U.N. Plaza San Francisco, CA 94102 (415) 556-2062

3. DATE 5/15/1985

8:30

a.m.

4. FIRM NAME Garden City Nut Shellers To

5.

HOUR p.m.

6. NUMBER AND STREET 2704 Sellers Avenue

7. CITY, STATE, AND ZIP CODE San Jose, CA 95131

8. PHONE NUMBER (WITH AREA CODE) (408) 123-4567

Notice of Inspection is hereby given pursuant to Section 704(a)(1) of the Federal Food, Drug, and Cosmetic Act (21 USC 374(1))1 and/or Part F or G, Title III, of the Public Health Service Act (42 U.S.C. 262-264).2

9. Signature (Food and Drug Administration Employee) Sidney H. Rogers

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10. Type or Print Name and Title (FDA Employee) Sidney H. Rogers, Investigator

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Note 1: Applicable portions of Section 704 and other sections of the Federal Food, Drug, and Cosmetic Act (21 USC 374) are quoted below:

Note 2: Applicable sections of Parts F and G of Title III, Public Health Service Act (42 USC 262–264), are quoted below:

Section 704(a)(1) For purposes of enforcement of this Act, ofﬁcers or employees duly designated by the Secretary, upon presenting appropriate credentials and a written notice to the owner, operator, or agent in charge, are authorized (A) to enter, at reasonable times, any factory, warehouse, or establishment in which food, drugs, devices, or cosmetics are manufactured, processed, packed, or held, for introduction into interstate commerce or after such introduction, or to enter any vehicle being used to transport or hold such food, drugs, devices, or cosmetics in interstate commerce; and (B) to inspect, at reasonable times and within reasonable limits and in a reasonable manner, such factory, warehouse, establishment, or vehicle and all pertinent equipment, ﬁnished and unﬁnished materials, containers, and labeling therein. In the case of any factory, warehouse, establishment, or consulting laboratory in which prescription drugs, nonprescription drugs intended for human use, or restricted devices are manufactured, processed, packed, or held, the inspection shall extend to all things therein (including records, ﬁles, papers, processes, controls, and facilities) bearing on whether prescription drugs, nonprescription drugs intended for human use, or restricted devices which are adulterated or misbranded within the meaning of this Act, or which may not be manufactured, introduced into interstate commerce, or sold, or offered for sale by reason of any provision of this Act, have been or are being manufactured, processed, packed, transported, or held in any such place, or otherwise bearing on violation of this Act. No inspection authorized by the preceding sentence or by paragraph (3) shall extend to ﬁnancial data, sales data other then shipment data, pricing data, personnel data (other than data as to qualiﬁcations of technical and professional personnel performing functions subject to this Act), and research data (other than data relating to new drugs, antibiotic drugs, and devices, subject to reporting and inspection under regulations, lawfully issued pursuant to Section 505(i) or (k), Section 507(d) or (g), Section 519, or Section 520(g), and data relating to other drugs or devices which in the case of a new drug would be subject to reporting or inspection under lawful regulations issued pursuant to Section 505(j) of the title). A separate notice shall be given for each such inspection, but a notice shall not be required for each entry made during the period covered by the inspection. Each such inspection shall be commenced and completed with reasonable promptness. Section 704(e) Every person required under Section 519 or 520(g) to maintain records and every person who is in charge or custody of such records shall, upon request of an ofﬁcer or employee designated by the Secretary, permit such ofﬁcer or employee at all reasonable times to have access to and to copy and verify, such records.

Part F — Licensing — Biological Products and Clinical Laboratories and *** Section 351(c) Any ofﬁcer, agent, or employee of the Department of Health and Human Services, authorized by the Secretary for the purpose, may during all reasonable hours enter and inspect any establishment for the propagation or manufacture and preparation of any virus, serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or other product aforesaid for sale, barter, or exchange in the District of Columbia, or to be sent, carried, or brought from any State or possession into any other State or possession or into any foreign country, or from any foreign country into any State or possession.

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Part F — *** Control of Radiation Section 360A(a) If the Secretary ﬁnds for good cause that the methods, tests, or programs related to electronic product radiation safety in a particular factory, warehouse, or establishment in which electronic products are manufactured or held may not be adequate or reliable, ofﬁcers or employees duly designated by the Secretary, upon presenting appropriate credentials and a written notice to the owner, operator, or agent in charge, are thereafter authorized (1) to enter, at reasonable times, any area in such factory, warehouse, or establishment in which the manufacturer’s tests (or testing programs) required by Section 358(h) are carried out, and (2) to inspect, at reasonable times and within reasonable limits and in a reasonable manner, the facilities and procedures within such area which are related to electronic product radiation safety. Each such inspection shall be commenced and completed with reasonable promptness. In addition to other grounds upon which good cause may be found for purposes of this subsection, good cause will be considered to exist in any case where the manufacturer has introduced into commerce any electronic product which does not comply with an applicable standard prescribed under this subpart and with respect to which no exemption from the notiﬁcation requirements has been granted by the Secretary under Section 359(a)(2) or 359(e). Section 360A(b) Every manufacturer of electronic products shall establish and maintain such records (including testing records), make such reports, and provide such information as the Secretary may reasonably require to enable him to determine whether such manufacturer has acted or is acting in compliance with this subpart and standards prescribed pursuant to this subpart and shall, upon request of an ofﬁcer or employee duly designated by the Secretary, permit such ofﬁcer or employee to inspect appropriate books, papers, records, and documents relevant to determining whether such manufacturer has acted or is acting in compliance with standards prescribed pursuant to Section 359(a).

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Section 704(f)(1) A person accredited under Section 523 to review reports under Section 510(k) and make recommendations of initial classiﬁcations of devices to the Secretary shall maintain records documenting the training qualiﬁcations of the person and the employees of the person for handling conﬁdential information, the compensation arrangements made by the person, and the procedures used by the person to identify and avoid conﬂicts of interest. Upon the request of an ofﬁcer or employee designated by the Secretary, the person shall permit the ofﬁcer or employee, at all reasonable times, to have access to, to copy, and to verify, the records. Section 512(l)(1) In the case of any new animal drug for which an approval of an application ﬁled pursuant to subsection (b) is in effect, the applicant shall establish and maintain such records, and make such reports to the Secretary, of data relating to experience and other data or information, received or otherwise obtained by such applicant with respect to such drug, or with respect to animal feeds bearing or containing such drug, as the Secretary may by general regulation, or by order with respect to such application, prescribe on the basis of a ﬁnding that such records and reports are necessary in order to enable the Secretary to determine, or facilitate a determination, whether there is or may be ground for invoking subsection (e) or subsection (m)(4) of this section. Such regulation or order shall provide, where the Secretary deems it to be appropriate, for the examination, upon request, by the persons to whom such regulation or order is applicable, of similar information received or otherwise obtained by the Secretary. Section 512(l)(2) Every person required under this subsection to maintain records, and every person in charge or custody thereof, shall, upon request of an ofﬁcer or employee designated by the Secretary, permit such ofﬁcer or employee at all reasonable times to have access to and copy and verify such records.

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(Reverse Side Form FDA 482) The Secretary may by regulation (1) require dealers and distributors of electronic products, to which there are applicable standards prescribed under this subpart and the retail prices of which are not less than $50, to furnish manufacturers of such products such information as may be necessary to identify and locate, for purposes of Section 359, the ﬁrst purchasers of such products for purposes other than resale, and (2) require manufacturers to preserve such information. Any regulation establishing a requirement pursuant to clause (1) of the preceding sentence shall (A) authorize such dealers and distributors to elect, in lieu of immediately furnishing such information to the manufacturer to hold and preserve such information until advised by the manufacturer or Secretary that such information is needed by the manufacturer for purposes of Section 359, and (B) provide that the dealer or distributor shall, upon making such election, give prompt notice of such election (together with information identifying the notiﬁer and the product) to the manufacturer and shall, when advised by the manufacturer or Secretary of the need therefore for the purposes of Section 359, immediately furnish the manufacturer with the required information. If a dealer or distributor discontinues the dealing in or distribution of electronic products, he shall turn the information over to the manufacturer. Any manufacturer receiving information pursuant to this subsection concerning ﬁrst purchasers of products for purposes other than resale shall treat it as conﬁdential and may use it only if necessary for the purpose of notifying persons pursuant to Section 359(a). Section 360B(a) It shall be unlawful — (1) *** (2) *** (3) for any person to fail or to refuse to establish or maintain records.

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Section 360B(a) It shall be unlawful — (1) *** (2) *** (3) for any person to fail or to refuse to establish or maintain records required by this subpart or to permit access by the Secretary or any of his duly authorized representatives to, or the copying of, such records, or to permit entry or inspection, as required or pursuant to Section 360A. Part G — Quarantine and Inspection Section 361(a) The Surgeon General, with the approval of the Secretary is authorized to make and enforce such regulations as in his judgment are necessary to prevent the introduction, transmission, or spread of communicable diseases from foreign countries into the States or possessions, or from one State or possession into any other State or possession. For purposes of carrying out and enforcing such regulations, the Surgeon General may provide for such inspection, fumigation, disinfection, sanitation, pest extermination, destruction of animals or articles found to be so infected or contaminated as to be sources of dangerous infection to human beings, and other measures, as in his judgment may be necessary.

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FDA Administrative Enforcement Manual

FORM FDA 483 Department of Health and Human Services Food and Drug Administration DISTRICT OFFICE ADDRESS AND PHONE NUMBER Minneapolis District 240 Hennipin Avenue Minneapolis, MN 55401 (612) 787-3904

DATES OF INSPECTION 1/5–1/7, 2004 FEI NUMBER 0000112233

NAME AND TITLE OF INDIVIDUAL TO WHOM REPORT IS ISSUED To: William S. Gundstrom, Vice President, Production FIRM NAME Topline Pharmaceuticals (“T.L.P.”)

STREET ADDRESS 2136 Elbe Place

CITY, STATE, AND ZIP CODE Jackston, MN 55326

TYPE OF ESTABLISHMENT INSPECTED Tablet repacker

This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations and do not represent a ﬁnal agency determination regarding your compliance. If you have an objection regarding an observation or have implemented, or plan to implement, corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to the FDA at the address above. If you have any questions, please contact the FDA at the phone number and address above. During an inspection of your ﬁrm (I) (we) observed: [List observations in a logical and concise manner. See IOM 512, 512.01, and 512.02.]

SEE REVERSE OF THIS PAGE.

EMPLOYEE SIGNATURE Sidney H. Rogers

EMPLOYEE NAME AND TITLE (PRINT OR TYPE) Sidney H. Rogers, Investigator

DATE ISSUED 1/7/2004

(Reverse Side of Form FDA 483) The observations of objectionable conditions and practices listed on the front of this form are reported: 1. Pursuant to Section 704(b) of the Federal Food, Drug, and Cosmetic Act, or 2. To assist ﬁrms inspected in complying with the Acts and regulations enforced by the Food and Drug Administration. Section 704(b) of the Federal Food, Drug, and Cosmetic Act (21 USC 374(b)) provides: “Upon completion of any such inspection of a factory, warehouse, consulting laboratory, or other establishment, and prior to leaving the premises, the ofﬁcer or employee making the inspection shall give to the owner, operator, or agent in charge a report in writing setting forth any conditions or practices observed by him which, in his judgment, indicate that any food, drug, device, or cosmetic in such establishment (1) consists in whole or in part of any ﬁlthy, putrid, or decomposed substance or (2) has been prepared, packed, or held under unsanitary conditions whereby it may have become contaminated with ﬁlth or whereby it may have been rendered injurious to health. A copy of such report shall be sent promptly to the Secretary.”

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SUMMARY A. Statutory authority: Congress delegated authority to the Secretary, who vested authority in the FDA Commissioner to act, under the Federal Food, Drug, and Cosmetic Act of 1938 (Pub. L. 102-282). The FDA Commissioner has 37 delegated authorities. B. Laws enforced by the FDA: Along with other federal government agencies, the FDA enforces some 37 laws; to see details, review the drug law history provided in Appendix 2. C. Jurisdiction: U.S. district courts and the federal court system have jurisdiction in FDAinitiated food and drug matters. D. Statutes of limitations: Matters involving violations of the Federal Food, Drug, and Cosmetic Act of 1938 have statutes of limitations spanning 10 years from the date the act ﬁrst occurred. E. Federal Administrative Procedures Act (FAPA): Orders from the FDA and other government agencies are deﬁned by the Administrative Procedures Act, Section 551. F. Code of Federal Regulations (CFR): The Code of Federal Regulations is an accumulation of federal agency regulations (FDA regulations are found at Title 21). The CFR currently consists of Parts 1 through 1300. G. Authority, scope, and facility inspections: The FDA’s authority to inspect is provided in the Federal Food, Drug, and Cosmetic Act of 1938. H. Inspection process and procedures: The FDA conducts several types of inspections; depending on the type of inspection, the process and procedures may differ. I.

Constitutional rights of defendant ﬁrms or individuals and federal rules of evidence: U.S. constitutional rights and evidence rules may be invoked.

J. Evidence for administrative agencies and federal courts: The evidence standards are not as rigorous in administrative proceedings as in federal courts

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PRACTICUM Read the Federal Food, Drug, and Cosmetic Act of 1938 in Appendix 1. This practicum examines the authority of the FDA, as delegated to the Commissioner, and its responsibility to protect the public; it also reviews the stated goals and objectives to ascertain whether or not it has met them. Presented in the chapter were details of the authority and responsibility of the FDA Commissioner. Review this chapter and read the article that follows, then analyze the authority and responsibility delegated to the FDA by the Federal Food, Drug, and Cosmetic Act of 1938 (see Appendix 1) to discuss and resolve the practicum problems. Article for practicum: Meadows, M., The FDA’s drug review process: ensuring drugs are safe and effective, FDA Consumer, July–August, 2002 (revised September 2002).21

The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective by Michelle Meadows The path a drug travels from a lab to your medicine cabinet is usually long, and every drug takes a unique route. Often, a drug is developed to treat a speciﬁc disease. An important use of a drug may also be discovered by accident. For example, Retrovir (zidovudine, also known as AZT) was ﬁrst studied as an anti-cancer drug in the 1960s with disappointing results. It wasn’t until the 1980s that researchers discovered the drug could treat AIDS, and the Food and Drug Administration approved the drug, manufactured by GlaxoSmithKline, for that purpose in 1987. Most drugs that undergo pre-clinical (animal) testing never even make it to human testing and review by the FDA. The drugs that do must undergo the agency’s rigorous evaluation process, which scrutinizes everything about the drug — from the design of clinical trials to the severity of side effects to the conditions under which the drug is manufactured.

STAGES

OF

DRUG DEVELOPMENT

AND

REVIEW

1. Investigational New Drug Application The FDA ﬁrst enters the picture when a drug sponsor submits an investigational new drug application (INDA) to the agency. Sponsors — companies, research institutions, and other organizations that take responsibility for marketing a drug — must show the FDA results of pre-clinical testing they’ve done in laboratory animals and what they propose to do for human testing. At this stage, the FDA decides whether it is reasonably safe to move forward with testing the drug on humans. 2. Clinical Trials Drug studies in humans can begin only after an IND is reviewed by the FDA and a local institutional review board (IRB). The board is a panel of scientists and non-scientists in hospitals and research institutions that oversees clinical research. IRBs approve the clinical trial protocols, which describe the type of people who may participate in the clinical trial, the schedule of tests and procedures, the medications and dosages to be studied, the length of the study, the study’s objectives, and other details. IRBs make sure the study is acceptable, that participants have given consent and are fully informed of their risks, and that researchers take appropriate steps to protect patients from harm. Phase 1 studies are usually conducted in healthy volunteers. The goal here is to determine what the drug’s most frequent side effects are and, often, how the drug is metabolized and excreted. The number of subjects typically ranges from 20 to 80.

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Phase 2 studies begin if Phase 1 studies don’t reveal unacceptable toxicity. While the emphasis in Phase 1 is on safety, the emphasis in Phase 2 is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. For controlled trials, patients receiving the drug are compared with similar patients receiving a different treatment — usually a placebo or a different drug. Safety continues to be evaluated, and short-term side effects are studied. Typically, the number of subjects in Phase 2 studies ranges from a few dozen to about 300. Phase 3 studies begin if evidence of effectiveness is shown in Phase 2. These studies gather more information about safety and effectiveness, studying different populations and different dosages and using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3000 people. Phase 4 studies occur after a drug is approved. They may explore such areas as new uses or new populations, long-term effects, and how participants respond to different dosages. 3. New Drug Application The new drug application (NDA) is the formal step a drug sponsor takes to ask that the FDA consider approving a new drug for marketing in the United States. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured. When an NDA comes in, the FDA has 60 days to decide whether to ﬁle it so that it can be reviewed. The FDA can refuse to ﬁle an application that is incomplete. For example, some required studies may be missing. In accordance with the Prescription Drug User Fee Act (PDUFA), the FDA’s Center for Drug Evaluation and Research (CDER) expects to review and act on at least 90% of NDAs for standard drugs no later than 10 months after the applications were received. The review goal is six months for priority drugs. (See “The Role of User Fees.”) The Tufts Center for the Study of Drug Development in Boston estimates that about 1 in 5 drugs that enter clinical testing ultimately are approved by the FDA. How often the FDA meets with a drug sponsor varies, but the two most common meeting points are at the end of Phase 2 clinical trials and pre-NDA — right before a new drug application is submitted. At the end of Phase 2, the FDA and sponsors try to come to an agreement on how the largescale studies in Phase 3 should be done. The pre-NDA meeting is for discussing what the FDA expects to see in the application. There is also continuous interaction throughout the review process. For example, over roughly six years, the sponsor Merck Research Laboratories of West Point, Pa., and the FDA had a halfdozen face-to-face meetings and about 28 teleconferences regarding the asthma drug Singulair (montelukast sodium). In 1992, Merck submitted an IND for Singulair so that it could begin conducting studies in humans. After clinical trials were complete, the company submitted a new drug application in February 1997. The FDA approved Singulair in February 1998. “It’s the clinical trials that take so long — usually several years,” says Sandra Kweder, M.D., deputy director for the Ofﬁce of New Drugs in CDER. “The emphasis on speed for FDA mostly relates to review time and timelines of being able to meet with sponsors during a drug’s development,” she says.

REVIEWING APPLICATIONS Though FDA reviewers are involved with a drug’s development throughout the IND stage, the ofﬁcial review time is the length of time it takes to review a new drug application and issue an action letter, an ofﬁcial statement informing a drug sponsor of the agency’s decision.

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Once a new drug application is ﬁled, an FDA review team — medical doctors, chemists, statisticians, microbiologists, pharmacologists, and other experts — evaluates whether the studies the sponsor submitted show that the drug is safe and effective for its proposed use. No drug is absolutely safe; all drugs have side effects. “Safe” in this sense means that the beneﬁts of the drug appear to outweigh the risks. The review team analyzes study results and looks for possible problems with the application, such as weaknesses of the study design or analyses. Reviewers determine whether they agree with the sponsor’s results and conclusions, or whether they need any additional information to make a decision. Each reviewer prepares a written evaluation containing conclusions and recommendations about the application. These evaluations are then considered by team leaders, division directors, and ofﬁce directors, depending on the type of application. Steven Hirschfeld, M.D., Ph.D., a medical ofﬁcer in CDER’s Division of Oncology Drug Products, says, “It is impossible to have all the information we wish to have at the time we need it.” One factor is the practical size of clinical trials, which typically include several thousand subjects at the most. “We are using information about past experience from a select group of people — those enrolled in particular clinical trials — and attempting to predict the future experience of the population at large.” For Hirschfeld, recognizing uncertainty and attempting to minimize it is one of the greatest challenges in reviewing information about health products. Recommending designs for clinical trials is one way to ask for more information and resolve unanswered questions, he says. Controlled clinical trials allow the FDA to conclude whether a new drug has shown substantial evidence of safety and effectiveness. In Hirschfeld’s opinion, some aspects of the job are similar to the responsibilities of air trafﬁc controllers in the sense that they also analyze information that’s available to them and make recommendations that can be acted on. “People bringing planes in have to balance weather, other planes in the sky, ground trafﬁc, and arrival and departure schedules, all without placing people at greater risk,” he says. They can rearrange ﬂight schedules and use different runways to lower the risk of problems, and the FDA can limit a drug’s use or take other steps to lower the risk of problems, he says. “We all have responsibilities to protect or guide those who are vulnerable, and we use the best analytic tools at our disposal.” Reviewers receive training that fosters consistency in drug reviews, and good review practices remain a high priority for the agency. For example, CDER recently held a two-day retreat in which clinical reviewers discussed review priorities, including improved communication between drug review divisions in CDER regarding drugs being reviewed for more than one indication. Sometimes the FDA calls on advisory committees made up of outside experts who help the agency decide on drug applications. Whether an advisory committee is needed depends on many things. “Some considerations would be if it’s a drug that has signiﬁcant questions, if it’s the ﬁrst in its class, or the ﬁrst for a given indication,” says Mark Goldberger, M.D., director of CDER’s ofﬁce that evaluates drugs to treat infectious diseases and immunosuppressive agents. “Generally, FDA takes the advice of advisory committees, but not always,” he says. “Their role is just that — to advise.”

ACCELERATED APPROVAL Traditional approval requires that clinical beneﬁt be shown before approval can be granted. Accelerated approval is given to some new drugs for serious and life-threatening illnesses that lack satisfactory treatments. This allows an NDA to be approved before measures of effectiveness that would usually be required for approval are available. Instead, less traditional measures called “surrogate endpoints” are used to evaluate effectiveness. These are laboratory ﬁndings or signs that may not be a direct measurement of how a patient feels, functions, or survives, but are considered likely to predict beneﬁt. For example, a surrogate endpoint could be the lowering of HIV blood levels for short periods of time with anti-retroviral drugs.

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Gleevec (imatinib mesylate), an oral treatment for patients with a life-threatening form of cancer called chronic myeloid leukemia (CML), received accelerated approval. The drug was also approved under the FDA’s orphan drug program, which gives ﬁnancial incentives to sponsors for manufacturing drugs that treat rare diseases. Gleevec blocks enzymes that play a role in cancer growth. The approval was based on results of three large Phase 2 studies, which showed the drug could substantially reduce the level of cancerous cells in the bone marrow and blood. The sponsor, Novartis Pharmaceuticals Corp. of East Hanover, N.J., submitted the IND in April 1998. The FDA received the NDA in February 2001, and the drug was approved two and a half months later in May 2001. Novartis has made commitments to conduct Phase 4 studies that investigate Gleevec’s clinical beneﬁt, such as increased progression-free survival in the treatment of CML. Most drugs to treat HIV have been approved under accelerated approval provisions, with the company required to continue its studies after the drug is on the market to conﬁrm that its effects on virus levels are maintained and that it ultimately beneﬁts the patient. Under accelerated approval rules, if studies don’t conﬁrm the initial results, the FDA can withdraw the approval. Because premarket review can’t catch all potential problems with a drug, the FDA continues to track approved drugs for adverse events through a postmarketing surveillance program.

BUMPS

IN THE

ROAD

If the FDA decides that the beneﬁts of a drug outweigh the risks, the drug will receive approval and can be marketed in the United States. But if there are problems with an NDA, the FDA may decide that a drug is “approvable” or “not approvable.” A designation of approvable means that the drug can probably be approved, provided that some issues are resolved ﬁrst. This might involve the sponsor and the FDA coming to a ﬁnal agreement on what should go on the drug’s label, for example. It could also involve more difﬁcult issues, such as the adequacy of information on how people respond to various dosages of the drug. A designation of “not approvable” describes deﬁciencies signiﬁcant enough that it is not clear that approval can be obtained in the future, at least not without substantial additional data. Common problems include unexpected safety issues that crop up or failure to demonstrate a drug’s effectiveness. A sponsor may need to conduct additional studies — perhaps studies of more people, different types of people, or for a longer period of time. Manufacturing issues are also among the reasons that approval may be delayed or denied. Drugs must be manufactured in accordance with standards called good manufacturing practices, and the FDA inspects manufacturing facilities before a drug can be approved. If a facility isn’t ready for inspection, approval can be delayed. Any manufacturing deﬁciencies found would need to be corrected before approval. “Sometimes a company may make a certain amount of a drug for clinical trials. Then when they go to scale up, they may lose a supplier or end up with quality control issues that result in a product of different chemistry,” says the FDA’s Kweder. “Sponsors have to show us that the product that’s going to be marketed is the same product that they tested.” John Jenkins, M.D., director of CDER’s Ofﬁce of New Drugs, says, “It’s often a combination of problems that prevent approval.” Close communication with the FDA early on in a drug’s development reduces the chance that an application will have to go through more than one cycle of review, he says. “But it’s no guarantee.” The FDA outlines the justiﬁcation for its decision in an action letter to the drug sponsor. When the action is either approvable or not approvable, CDER gives the sponsor a chance to meet with agency ofﬁcials to discuss the deﬁciencies. At that point, the sponsor can choose to ask for a hearing or correct any deﬁciencies and submit new information. Michelle Meadows is a staff writer for FDA Consumer.

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WLF v. Henney UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA WASHINGTON LEGAL FOUNDATION ) ) Plaintiff, ) ) v. ) ) JANE E. HENNEY, M.D., in her ) ofﬁcial capacity as Commissioner, ) Food and Drug Administration ) ) and ) ) DONNA SHALALA, in her ofﬁcial ) capacity as Secretary, United ) States Department of Health and ) Human Services, ) ) Defendants. ) ____________________________________

Civil Action No. 94-1306 (RCL) Honorable Magistrate _________________

MEMORANDUM AND ORDER Now before the Court is a motion by the plaintiff to conﬁrm and enforce a permanent injunction issued by this Court on July 28, 1999. See Washington Legal Found. v. Henney, 56 F. Supp. 2d81, 88-89 (D.D.C. 1999) (“WLF III”). The defendants claim that they are not in violation of the injunction and therefore oppose the plaintiff’s motion. After considering the parties’ memoranda of points and authorities, and for the following reasons, the Court DENIES the plaintiff’s motion. BACKGROUND This opinion only summarizes the facts relevant to the instant matter. A fuller explanation of the facts, as well as the procedural history of this case, are recounted in Washington Legal Found. v. Henney, 202 F.3d 331 (D.C. Cir. 2000) (“WLF IV”); Washington Legal Found. v. Henney, 56 F. Supp. 2d 81 (D.D.C. 1999) (“WLF III”); Washington Legal Found. v. Friedman, 13 F.Supp. 2d 51 (D.D.C. 1998) (“WLF II”); In re Kessler, 100 F.3d 1015 (D.C. Cir. 1996); Washington Legal Found. v. Kessler, 880 F.Supp. 26 (D.D.C. 1995) (“WLF I”). This matter is yet another episode in a six-year controversy. Beginning as far back as 1994, these two parties have sparred over the extent to which the federal government can regulate speech regarding the “off-label” uses of prescription drugs. The most recent dispute concerns two commands from the federal government: the Food and Drug Administration Modernization Act passed by Congress (the “FDAMA”), and the “Guidance for Industry: Industry-Supported Scientiﬁc and Educational Activities” issued by the FDA (the “CME Guidelines”). See Pub. L. No. 105-115, 111 Stat. 2296; 62 Fed. Reg. 64,093 (1997). On July 28, 1999, this Court concluded that the FDAMA and CME Guidelines were “contrary to the rights secured by the United States Constitution,” speciﬁcally the First Amendment. Washington Legal Found. v. Henney, 56 F. Supp. 2d 81, 87 (D.D.C. 1999) (“WLF III”). The government

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appealed. According to the Court of Appeals, the government’s briefs were “quite confusing as to the meaning of the [FDAMA] and the CME Guidance. Washington Legal Found. v. Henney, 202 F.3d 331, 335 (D.C. Cir. 2000) (“WLF IV”). The confusion however — as well as the controversy itself — abated at oral argument. During oral argument, the government clariﬁed its interpretation of the FDAMA and the CME Guidance. With respect to the FDAMA, the government explained that, although the FDAMA seeks to restrict the dissemination of information in certain ways, it does not grant the FDA authority to prosecute those who transgress the restrictions. Id. According to the government, the FDAMA creates a “safe harbor” for manufacturers who follow its provisions; i.e., manufacturers who disseminate information in accordance with the FDAMA will not be prosecuted under the FDA’s misbranding authority using the information disseminated as evidence. Id. Of course, a misbranding suit might still continue and succeed using other forms of evidence, but as long as a manufacturer complies with the FDAMA provisions, it can be conﬁdent that the dissemination will not be held against it at a later date. On the other side of the coin, drug manufacturers who disseminate information in ways contrary to the FDAMA take themselves out of the safe harbor and open themselves up to the possibility that, if the FDA should bring a suit under its misbranding authority, the dissemination could be used against them. The key distinction to note in this situation, as well as in the previous one, is that the FDA’s prosecutorial power ﬂows from its long-established authority to prosecute manufacturers for misbranding, not from the newly created FDAMA. As the Court of Appeals summarized the government’s position: “Nothing in [the FDAMA] provides the FDA with independent authority to regulate manufacturer speech.” A similar interpretation applies to the CME Guidelines. The CME Guidelines order manufacturers to follow certain procedures in planning and promoting medical seminars. Although a manufacturer who violates these provisions might be prosecuted by the FDA, the prosecution will be pursuant to its misbranding enforcement power and not some independent power created in theme Guidelines. Id. at 335–36. With the revelation of the government’s interpretation at oral argument, WLF admitted that it no longer had a constitutional objection to the FDAMA or CME Guidelines. Id. Seeing this, the Court of Appeals found there to be no case or controversy and declined to issue what would amount to an advisory opinion on the constitutionality of the FDAMA and CME Guidelines. Id. The Court then went a step further and vacated the district court’s previous holdings and injunctions “insofar as they declared the FDAMA and the CME Guidelines unconstitutional.” Id. at 337. What brings the parties back to court is the FDA’s March 16, 2000 Notice printed in the Federal Register. See 65 Fed. Reg. 14286 (Mar. 16, 2000). The Notice explains — from the FDA’sperspective — the parameters of its regulatory authority in light of the Court of Appeals’ opinion vacating this Court’s July 28, 1999, injunction. According to the Notice, the FDA may, when appropriate, “proceed, in the context of case-by-case enforcement, to determine from a manufacturer’s written materials and activities how it intends that its products be used.” Id. A drug manufacturer’s intent to promote an unapproved use, together with certain predicate acts, may in turn be used to make out a misbranding case. The WLF argues that such a practice is exactly what this Court prohibited in its July 16, 2000, injunction. Although the Court of Appeals vacated a portion of this injunction, WLF argues that the Court of Appeals expressly recognized that “part of [the] injunction still stands.” WLF IV, 202 F.3d at 337. ANALYSIS I. The Nature of the Plaintiff’s Claim By the title of its motion, the plaintiff asks to the Court to “conﬁrm and enforce [its] continuing injunction.” Although this appears relatively straightforward, it is instructive to notice what the plaintiff is not claiming. The plaintiff is not claiming that the defendant’s Notice violates the First Amendment, either facially or as applied. The plaintiff is also not claiming that the Notice is contrary to the FDA’s ofﬁcial interpretation of the FDAMA and the CME Guidelines announced

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at the oral argument on appeal. Rather, the plaintiff is only claiming that the defendant’s Notice is facially violative of the Court’s July 28, 1999, injunction as modiﬁed by the Court of Appeals. Thus, to resolve this matter, the Court must analyze the exact scope of its injunction as well the exact nature of the defendant’s Notice. II. The Scope of the Modified Injunction The proper place to start is with the text of the injunctions as it was originally issued. On July 28, 1999, this Court ordered that the FDA shall not in any way prohibit, restrict, sanction, or otherwise seek to limit any pharmaceutical or medical device manufacturer or any other personnel from disseminating or redistributing to physicians or other medical professionals any article concerning prescription drugs or medical devices previous published in a bona ﬁde peer-reviewed professional journal, regardless of whether such article includes a signiﬁcant or exclusive focus on unapproved uses for drugs or medical devices that are approved by FDA for other uses and regardless of whether such article reports the original study on which FDA approval of the drug or device in question was based; from disseminating or redistributing to physicians or other medical professionals any reference textbook (including any medical textbook or compendium) or any portion thereof published by a bona ﬁde independent publisher and otherwise generally available for sale in bookstores or other distribution channels where similar books are normally available, regardless of whether such reference textbook or portion thereof includes a signiﬁcant or exclusive focus on unapproved uses for drugs or medical devices that are approved by FDA for other uses; from suggesting content or speakers to an independent program provider in connection with a continuing medical education seminar program or other symposium regardless of whether unapproved uses for drugs or medical devices that are approved by FDA for other uses are to be discussed. WLF III, 56 F. Supp. 2d at 88. The Court supplemented these orders with deﬁnitions for “bona ﬁde peer-reviewed journal,” “bona ﬁde independent publisher,” and “independent program provider.” Id. The Court concluded the injunction by clarifying that nothing herein shall be construed to limit defendants’ application or enforcement of any rules, regulations, guidance’s, statutes, or other provisions of law that sanction the dissemination or redistribution of any material that is false or misleading. In addition, defendants may require any pharmaceutical or medical device manufacturer that sponsors or provides ﬁnancial support for the dissemination or redistribution of articles or reference textbooks or for seminars that include references to unapproved uses for drugs or medical devices that are approved by FDA for other uses to disclose (i) its interest in such drugs or devices, and (ii) the fact that the use discussed has not been approved by FDA. Id. On February 11, 2000, the Court of Appeals vacated this injunction “insofar as [it] declare[s] the FDAMA and the CME Guidance unconstitutional.” WLF IV, 202 F.3d at 337. The pertinent question is thus: What portion of the injunction was grounded in law other than the federal constitution? One sentence in the Court of Appeals’ opinion might suggest to the contrary. In a footnote on the ﬁnal page of its opinion, the Court of Appeals stated: “As we have made clear, we do not reach the merits of the district court’s First Amendment holdings and part of its injunction still stands.” WLF, 202 F.3d at 337 n. 7. One might construe this statement as implying that part of the injunction was, in the Court of Appeals view, not constitutionally based, not therefore vacated, and thus “still stands.” Such a construction would be unreasonable. It is illogical to conclude that the court — without any review of the injunction — would declare that part of it still stands. It is much more logical to think that the court, in a measure of prudence considering that it had not reviewed the text of the injunction, sought to clarify that, if the injunction was in any way not constitutionally based, then that part of the injunction would still stand. Thus, the best reading of the footnote is that the Court of Appeals found the injunction to “still stand [to the extent it is not constitutionally based].”

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The answer, quite simply, is none. A thorough review of the Court’s July 28, 1999, opinion reveals only one source of law: the United States Constitution. The opinion’s discussion section begins with a declaration that the Central Hudson commercial speech doctrine applies to the case. WLF III, 56 F. Supp. 2d at 84–85. The opinion then proceeds to apply the constitutional doctrine to the relevant facts of the case, concluding that the FDAMA and the CME Guidelines were facially unconstitutional. Id. at 85–87. No other law was ever discussed, much less referenced. Thus, as the injunction was completely based on constitutional law, and the Court of Appeals vacated the “injunction insofar as [it] declared the [disputed provisions] unconstitutional,” this Court has no choice but to declare the injunction wholly vacated as to the FDAMA and the CME Guidelines. III. The FDA’s March 16, 2000, Notice Given the above discussion, it makes little difference what the FDA’s March 16, 2000, Notice contained. Since the injunction has been wholly vacated by the Court of Appeals, there is nothing for the Notice to violate. Therefore, the Court ﬁnds that the FDA’s notice is not in violation of any order issued by this Court. CONCLUSION Today, the Court adds another order to this case’s voluminous ﬁle; yet, the order will do little to resolve the issue that lies at the heart of this dispute: whether the FDA violates the First Amendment by penalizing drug manufacturers for sending scientiﬁc literature to physicians regarding off-label uses. After six years’ worth of briefs, motions, opinions, Congressional acts, and more opinions, the issue remains 100% unresolved, and the country’s drug manufacturers are still without clear guidance as to their permissible conduct. To say that the FDA’s March 16, 2000, Notice ﬁnally clariﬁes the situation is a farce; the Notice speciﬁcally invites a constitutional challenge to each and every one of its enforcement actions. That is no way to establish policy on an issue that both sides argue is of — quite literally — life and death proportions. This year, the Court of Appeals was poised to ﬁnally galvanize a rule of law in this area. Yet, for whatever reason, the opportunity was spent debating not the U.S. Constitution’s First Amendment, but its Article III case or controversy requirement. Thus, we have a little more law on advisory opinions and nothing at all to say about our citizenry’s First Amendment rights. In fact, after the Court of Appeals’ opinion, we have even less First Amendment law than before; this is because the Court vacated all of this Court’s previous constitutional rulings on the matter. As for this Court’s part in the controversy, the Court is conﬁdent that it has done its best at every step of the process. It has decided the underlying issue at least twice and senses that it will be called on to do so again before the controversy is concluded. For now, however, the issue must be given a temporary rest. For the foregoing reasons, it is hereby ORDERED that the plaintiff’s motion to conﬁrm and enforce the July 28, 1999, injunction [75-1] is DENIED. SO ORDERED.

Date:_____________________

_____________________________ ROYCE C. LAMBERTH UNITED STATES DISTRICT JUDGE

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DID YOU KNOW … • • • •

FDA approves new drugs in the United States as fast as, or faster than, anywhere else in the world? FDA helps select the ﬂu strains to be included in each year’s ﬂu vaccine and participates in the development of ﬂu and other vaccines? FDA scientists have developed an inexpensive seafood freshness indicator called “Fresh Tag” that changes color to indicate when the product has spoiled? FDA tests homestyle meals prepared from ingredients purchased in grocery stores nationwide to check for pesticide residues and other food contaminants?

NOTES: DRUG LAW Use the FDA article, “The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective,” the U.S. drug law information provided in Appendix 2, and information provided in this chapter to analyze the following issues: 1. Assess the opinions of your family, friends, colleagues, industry sponsors, and manufacturers and your feelings with regard to whether the FDA has fulﬁlled its authority, responsibility, and goals of consumer protection. 2. Read the case WLF v. Henney (above). Develop a reasonable way to evaluate how industry believes the FDA is fulﬁlling its authority, responsibility, and goals. 3. Analyze the reasons for the current shift of consumers from Western allopathic to alternative naturopathic modalities. 4. Discuss the reason for this shift with people who use alternative health modalities. Inquire about the trust these same consumers have in the ability of the FDA to fulﬁll its responsibilities to protect the public compared to that of alternative modalities. 5. Develop teams, discuss ﬁndings, and reach conclusions on whether the FDA has exceeded its authority, has fulﬁlled its responsibility, or has met its stated goals to protect the public.

ENDNOTES 1. 2. 3. 4.

5.

6.

7.

www.dhhs.gov. Ibid., revised December 3, 2003. Ibid., revised June 29, 2002. In the Federal Food, Drug, and Cosmetic Act, Chapter II (Deﬁnitions), Section 201[321], 21 USC 321(ee), the term Commissioner means the Commissioner of Food and Drugs; in Section 201[321], 21 USC 321(f), the term food means (1) articles used for food for drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article. In the Federal Food, Drug, and Cosmetic Act, Chapter II (Deﬁnitions), 21 USC 321(f), the term food means (1) articles used for food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article. In the Federal Food, Drug, and Cosmetic Act, Chapter II (Deﬁnitions), 21 USC 321(i), the term cosmetic means (1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced onto, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and (2) articles intended for use as components of any such articles, except that such term shall not include soap. In the Federal Food, Drug, and Cosmetic Act, Chapter II (Deﬁnitions), 21 USC 321(g)(1), the term drug means (A) articles recognized in the ofﬁcial United States Pharmacopeia, ofﬁcial Homeopathic Pharmacopoeia of the United States, ofﬁcial National Formulary, or any supplement to them; (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; (C) articles (other than food) intended to affect the structure or any function of the

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10.

11. 12.

13. 14. 15. 16.

17. 18. 19. 20.

21.

33

body of man or other animals; and (D) articles intended for use as a component of any article speciﬁed in clause (A), (B), or (C). A food or dietary supplement for which a claim, subject to Sections 403(r)(1)(B) and 403(r)(3) of this title or Sections 403(r)(1)(B) and 403(r)(5)(D) of this title, is made in accordance with the requirements of Section 403(r) of this title is not a drug solely because the label or the labeling contains such a claim. A food, dietary ingredient, or dietary supplement for which a truthful and not misleading statement is made in accordance with Section 403(r)(6) of this title is not a drug under clause (C) solely because the label or the labeling contains such a statement. CFSAN-regulated cosmetics; the Cosmetic Toiletries and Fragrance Association (CTFA) is an industry association that makes recommendations for cosmetic standards. In the Federal Food, Drug, and Cosmetic Act, Chapter II (Deﬁnitions), 21 USC 321(h), the term device (except when used in paragraph (u) of this section and in Sections 301(i), 403(f), 502(c), and 602(c)) means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is (1) recognized in the ofﬁcial National Formulary, or the United States Pharmacopoeia, or any supplement to them; (2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals; or (3) intended to affect the structure or any function of the body of man or other animals and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes. Pure Food and Drugs Act of 1906, U.S. Statutes at Large (59th Cong., Sess. I, Chp. 3915, pp. 768–772). Dr. Harvey W. Wiley, referred to as the father of the FDA, headed the Agriculture Department in 1906. In the Federal Food, Drug, and Cosmetic Act of 1938, Section 201[321], 21 USC 321(d), the term Secretary means the Secretary of Health and Human Services. Title 21, Food and Drugs, Chapter I, Food and Drug Administration, Department of Health and Human Services, Part 5, Delegations of Authority and Organization, Section 5.10, Delegations from the Secretary, the Assistant for Health and Public Health Service Ofﬁcials. Pennoyer v. Neff, 95 U.S. 714, 24 L.Ed. 565. 21 CFR Part 10, Sections 10.0 through 10.206, Administrative Procedures Act. Federal Administrative Procedures Act, a federal law (60 Stat. 237, 5 USCA) enacted in 1946 that governs practices of and proceedings before federal administrative agencies. United States v. Biswell, 92 S.Ct., 1593 (1972); United States v. Del Campo Baking Mfg. Company, 345 F. Supp. 1371 (D., Del., 1972); United States v. Business Builders, Inc., 353 F. Supp. 1333 (N.D. Okla., 1973). 21 USC 331(f) and 333. www.fda.gov; FDA inspection responsibilities: 122,133 total establishments. Universal Camera v. NLRB, 340 U.S. 474 (1951): “Substantial evidence is more than a mere scintilla. It means such relevant evidence as a reasonable mind might accept as adequate to support a conclusion.” In the Federal Administrative Procedures Act, Title 5, Government Organization and Employees, Section 552, Public Information, Agency Rules, Opinions, Orders, Records, and Proceedings, 4(A)(vii), de novo is deﬁned as “anew.” The matter is treated as if it had not been heard before and as if no decision was previously reached. Article available at www.fda.gov (originally appeared in July–August 2002 issue of FDA Consumer, revised September 2002).

OTHER RESOURCES GENERAL Anderson, Oscar E., Jr. 1958. The health of a nation: Harvey W. Wiley and the ﬁght for pure food, Chicago: University of Chicago Press. Masterful biography that provides an excellent early history of the 1906 act and the predecessor agency of the FDA. Brannon, Michael. 1984. Organizing and reorganizing FDA. In Seventy-ﬁfth anniversary commemorative volume of food and drug law, pp. 135–173. Washington, D.C.: Food and Drug Law Institute. Documents the myriad structural changes within the agency.

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Christopher, Thomas W. 1958. Articles on food and drug law. Food, Drug, Cosmetic Law Journal 13:487–498. Dated but useful bibliography drawn exclusively from legal periodicals, arranged by subject. Food and Drug Administration. 1981. Special issue. FDA Consumer, 15(5). Issue commemorating the 75th anniversary of the Pure Food and Drugs Act of 1906 that includes a variety of historical articles. Jackson, Charles O. 1970. Food and drug legislation in the New Deal. Princeton: Princeton University Press. Discusses the formation of the Federal Food, Drug, and Cosmetic Act of 1938. Junco, Suzanne White. 1988. The class of ’39: Implementing the 1938 Food, Drug, and Cosmetic Act, Journal of the Association of Food and Drug Ofﬁcials of the United States 52(4):10–25. Provides a history of the implementation of selected provisions of the Federal Food, Drug, and Cosmetic Act of 1938. Kay, Gwen. 2001. Healthy public relations: The FDA’s 1930s legislative campaign. Bulletin of the History of Medicine 75:446–487. Lamb, Ruth deForest. 1936. American chamber of horrors: The truth about food and drugs. New York: Farrar and Rinehart. Exposes the many shortcomings of the 1906 act and explains why a new law was needed; written by the Chief Educational Ofﬁcer at the FDA. Swann, John P. 1998. Food and Drug Administration. In A historical guide to the U.S. Government, ed. George Thomas Kurian, pp. 248–254. New York: Oxford University Press. Traces general trends in food, drug, cosmetic, and device regulation, from the FDA’s origins to the present. Wiley, Harvey W. 1930. An autobiography. Indianapolis: Bobbs-Merrill. An illustrated and indexed life and career of the father of the FDA. Young, James Harvey. 1967. The medical messiahs: A social history of health quackery in twentieth-century America. Princeton: Princeton University Press. Indicative subtitle; includes much on the FDA. Young, James Harvey. 1983. Food and Drug Administration. In Government agencies, ed. Donald R. Whitnah, pp. 251–257. Westport, CN: Greenwood Press. A brief but succinct history of the FDA, with a short bibliography. Young, James Harvey. 1985. The pig that fell into the privy: Upton Sinclair’s The Jungle and the Meat Inspection Amendments of 1906, Bulletin of the History of Medicine 59:467–480. History of events spurring passage of the Pure Food and Drugs Act of 1906. Young, James Harvey. 1987. From oysters to after-dinner mints: The role of the early food and drug inspector, Journal of the History of Medicine and Allied Sciences 42:30–53. Creation, training, and work of the ﬁrst FDA inspectors. Young, James Harvey. 1989. Pure food: securing the federal food and drugs act of 1906. Princeton: Princeton University Press. Deﬁnitive history of this landmark Progressive-era legislation, including an historiography of the subject. Young, James Harvey. 1992. Food and drug enforcers in the 1920s: Restraining and educating business, Business and Economic History, 2d ser. 21:119–128. Enforcement policy under the Pure Food and Drugs Act of 1906.

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AND

COSMETIC REGULATIONS

Anderson, Ann. 2000. Snake oil, hustlers, and hambones: The American medicine show. Jefferson, NC: McFarland & Co. Excellent, readable history of the American medicine show from its origins in medieval Europe to its heyday in the 1890s and ﬁnal curtain call in the mid-twentieth century; includes discussion of Dudley J. LeBlanc’s outrageous showmanship promoting Hadacol. Anderson, Lee, and Gregory J. Higby. 1995. The spirit of voluntarism, a legacy of commitment and contribution: The United States Pharmacopeia, 1820–1995. Rockville, MD: U.S. Pharmacopeia, 1995. Comprehensive history of the private but ofﬁcially recognized drug-standard-setting compendium. Blake, John B., ed. 1970. Safeguarding the public: Historical aspects of medicinal drug control. Baltimore, MD: The Johns Hopkins University Press. Several useful papers and discussions thereof, including those on nineteenth-century drug regulation, drug regulation under the 1906 act, and regulation after 1938. Cooper, Dale E. 2002. Adequate controls for new drugs: Good manufacturing practice and the 1938 Food, Drug, and Cosmetic Act, Pharmacy in History 44(1):12–23. How the 1938 act incorporated manufacturing controls. Donegan, Thomas J. 1995. Fifty years of cosmetic safety: A government and industry partnership. Food and Drug Law Journal [special issue] 50:151–162.

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Dowling, Harry F. 1970. Medicines for man: The development, regulation, and use of prescription drugs. New York: Alfred A. Knopf. Internalistic but very useful overview of the subject. Gostin, Lawrence O., Peter S. Arno, and Allan M. Brandt. 1997. FDA regulation of tobacco advertising and youth smoking: Historical, social, and constitutional perspectives. JAMA 277:410–418. Hilts, Philip J. 1996. Smokescreen: The truth behind the tobacco industry cover-up. Reading, MA: Addison–Wesley, 1996. Hutt, Peter Barton. 1983. Investigations and reports respecting FDA regulation of new drugs. Clinical Pharmacology and Therapeutics 33:537–548, 674–687. Primarily descriptive, serves as an excellent reference source on the role of outsiders (e.g., advisory committees) in shaping the drug regulation policy of the FDA from 1939 to 1983. Janssen, Wallace. 1981. Outline of the history of U.S. drug regulation and labeling. Food, Drug, Cosmetic Law Journal 36:420–441. A useful overview, especially with respect to misbranding. Junod, Suzanne White. 2000a. Diethylene glycol deaths in Haiti, Public Health Reports 115(1):78–86. Ofﬁcial history of the deaths in Haiti from diethylene-glycol-contaminated glycerine in the summer of 1996. Junod, Suzanne White. 2000b. An alternative perspective: Homeopathic drugs, Royal Copeland, and federal drug regulation, Food, Drug, Cosmetic Law Journal 55(1):161–183; see also Pharmacy in History 42(1–2), 13–35, 2000. Exploration of the origins of the Homeopathic Pharmacopeia in the 1938 Food, Drug, and Cosmetic Act of 1938 and its sponsorship by Senator Royal Copeland, as well as the FDA’s subsequent regulation of homeopathy. Kaplan, Alan H. 1995. Fifty years of drug amendments revisited: In easy-to-swallow capsule form. Food and Drug Law Journal [special issue] 50:179–196. Kay, Gwen. 1997. Regulating beauty: Cosmetics in American culture from the 1906 Pure Food and Drugs Act to the 1938 Food, Drug, and Cosmetic Act, Ph.D. thesis. New Haven, CT: Yale University. Kessler, David A. 2001. A question of intent: A great American battle with a deadly industry. New York: Public Affairs Press. FDA Commissioner’s personal account of the agency’s decision to declare nicotine a drug and assert jurisdiction over tobacco. Kondratas, Ramunas. 1982. Biologics Control Act of 1902. In The early years of federal food and drug control, ed. James Harvey Young, pp. 8–27. Madison, WI: American Institute of the History of Pharmacy. On the coming of the federal statute that brought vaccines, sera, and antitoxins under regulation. Korwek, Edward L. 1995. Human biological drug regulation: Past, present, and beyond the year 2000. Food and Drug Law Journal [special issue] 50:123–150. Lederer, Susan E. 1995. Subjected to science: Human experimentation in America before the second World War. Baltimore, MD: The Johns Hopkins University Press. Examines the development of medical research ethics before World War II; includes background on informed consent, animal research, and ethics in human trials. Maeder, Thomas. 1994. Adverse reactions. New York: William Morrow. Good regulatory history of an early antibiotic, chloramphenicol, and its rare but fatal side effect, aplastic anemia. Marks, Harry M. 1995. Revisiting “The Origins of Compulsory Drug Prescriptions.” American Journal of Public Health 85:109–115. Analysis of the inﬂuences leading to the 1951 Durham–Humphrey Amendment. Marks, Harry M. 1997. The progress of experiment: Science and therapeutic reform in the United States, 1900–1990. London: Cambridge University Press. History of the development of clinical trial research in the United States. McFadyen, Richard E. 1973. Estes Kefauver and the drug industry, Ph.D. thesis. Atlanta, GA: Emory University. A background for the enactment of the drug amendments of 1962. McFadyen, Richard E. 1976. Thalidomide in America: A brush with tragedy. Clio Medica 11(2):79–93. Good companion piece to Young’s article on sulfanilamide, because thalidomide had a similar impact on the passage of major drug regulatory legislation, resulting in the Kefauver–Harris Drug Amendments of 1962. Solomon, Joel M. 1981. Legislation and regulation in blood banking. In Federal legislation and the clinical laboratory, ed. Morris Schaeffer, pp. 143–171. Boston: G. K. Hall. Sonnedecker, Glenn. 1982. Drug standards become ofﬁcial. In The early years of federal food and drug control, ed. James Harvey Young, pp. 28–39. Madison, WI: American Institute of the History of Pharmacy. How the United States Pharmacopoeia and the National Formulary became ofﬁcial drug compendia under the 1906 act.

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Swann, John P. 1994. FDA and the practice of pharmacy: Prescription drug regulation to 1951. Pharmacy in History 36:55–70. Reference to the basic drug laws from the nineteenth to mid-twentieth centuries and the cooperation and conﬂict between organized pharmacy industry and the FDA, especially regarding amphetamines and barbiturates. Swann, John P. 1997. Sure cure: Public policy on drug efﬁcacy before 1962. In The inside story of medicines: A symposium, eds. Gregory J. Higby and Elaine C. Stroud, pp. 223–261. Madison, WI: American Institute for the History of Pharmacy. Evolution of policies of public and private organizations in the United States and their effect on medicines from the nineteenth century through to the 1962 Kefauver– Harris amendments. Swann, John P. 1999. The 1941 sulfathiazole disaster and the birth of good manufacturing practices. PDA Journal of Pharmaceutical Science & Technology 53:148–153; see also Pharmacy in History 41, 16–25, 1999. Story of the hundreds of deaths and injuries caused by barbiturate-tainted sulfa, and the impact of this tragedy on the shaping of FDA-mandated manufacturing controls. Taylor, Michael R. 1982. History of cosmetic color additive regulation: Creative maneuvering by FDA bodes well for the future. Food, Drug, Cosmetic Law Journal 37:152–162. Temin, Peter. 1980. Taking your medicine: Drug regulation in the United States. Cambridge, MA: Harvard University Press. This economist raises many interesting issues deserving further study; his interpretations follow rather predictably from his free-market underpinnings. Ward, Patricia Spain. 1984. Who will bell the cat? Andrew C. Ivy and Krebiozen, Bulletin of the History of Medicine 58:28–52. History of the quack cancer drug, Krebiozen, and the strange story of the scientist, Andrew C. Ivy, who endorsed it and thus ended his professional career. Young, James Harvey. 1961. The toadstool millionaires: A social history of patent medicines in America before federal regulation. Princeton: Princeton University Press. The subtitle conveys the subject of this pioneering study. Young, James Harvey. 1983. Sulfanilamide and diethylene glycol. In Chemistry and modern society: Historical essays in honor of Aaron J. Ihde, eds. John Parascandola and James C. Whorton, pp. 105–125. Washington, D.C.: American Chemical Society. On the key event in 1937 that precipitated statutory drug safety. Young, James Harvey. 1992. American health quackery. Princeton: Princeton University Press. A collection of his published essays on this theme, with a new essay on AIDS quackery.

FOOD, DEVICE,

AND

VETERINARY MEDICINE REGULATION

Anon. 1993. Symposium: Use of FDA-approved drugs in veterinary medicine: Prohibitions, prerogatives, and responsibilities. Journal of the American Veterinary Medical Association 202:1601–1745. Apple, Rima D. 1996. Vitamania: Vitamins in American culture. New Brunswick, NJ: Rutgers University Press. A discussion of America’s love affair with vitamins; incorporates the FDA’s regulatory perspective. Belasco, Warren J. 1989. Appetite for change: How the counter culture took on the food industry, 1966–1988. New York: Pantheon Books. Discusses the counter-cultural critique of governmental policy toward food and food additives between the 1960s and the 1980s. Bosso, Christopher J. 1987. Pesticides and politics: The life cycle of a public issue. Pittsburgh, PA: University of Pittsburgh Press. Good general history of pesticides regulation but contains a few errors regarding regulation. Foote, Susan Bartlett. 1992. Managing the medical arms race: Public policy and medical device innovation. Berkeley: University of California Press. Mostly oriented toward contemporary policy but much is on the history of medical device regulation. Hochheiser, Sheldon. 1982. Synthetic food colors in the United States: A history under regulation, Ph.D. thesis. Madison: University of Wisconsin. Hutt, Peter Barton. 1989. A history of government regulation of adulteration and misbranding of medical devices. Food, Drug, Cosmetic Law Journal 44:99–117. A good, succinct survey of the history of device regulation outside of quackery. Hutt, Peter Barton, and Peter Barton Hutt, II. 1984. A history of government regulation of adulteration and misbranding of food. Food, Drug, Cosmetic Law Journal 39:2–73. Contains complete overview of governmental food regulation.

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Ihde, Aaron J. 1982. Food controls under the 1906 act. In The early years of federal food and drug control, ed. James Harvey Young, pp. 40–50. Madison, WI: American Institute of the History of Pharmacy. Enforcement policy under the Pure Food and Drugs Act of 1906, including the role of outsiders. Janssen, Wallace F. 1987. Inside the poison squad: How food additive regulation began. Association of Food and Drug Ofﬁcials Quarterly Bulletin 51(2):68–72. Story of Wiley’s famous experiment to illustrate the hazards of additives using volunteer subjects. Soave, Orland. 1991. History of veterinary medicine in the Food and Drug Administration. Journal of the American Veterinary Medical Association 199:38–42. On the regulation of products for veterinary use from 1906 to 1990. Whitaker, Adelyne Hiller. 1974. A history of federal pesticide regulation in the United States to 1947, Ph.D. thesis. Atlanta, GA: Emory University. White, Suzanne. 1994. Chemistry and controversy: Regulating the use of chemicals in foods, 1883–1959, Ph.D. thesis. Atlanta, GA: Emory University. Whorton, James. 1974. Before Silent Spring: Pesticides and public health in pre–DDT America. Princeton: Princeton University Press. Deﬁnitive history of pesticides regulation before World War II. Young, James Harvey. 1968. The science and morals of metabolism: Catsup and benzoate of soda, Journal of the History of Medicine and Allied Sciences 23:86–104. Young, James Harvey. 1975. Saccharin: a bitter regulatory controversy. In Research in the Administration of Public Policy, eds. Frank B. Evans and Harold T. Pinkett, pp. 39–49. Washington, D.C.: Howard University Press. Young, James Harvey. 1976. Botulism and the ripe olive scare of 1919–1920, Bulletin of the History of Medicine 50:372–391.

OFF-LABEL USES Abeloff, M. D. 1991. Off-label uses of anticancer drugs [letter]. JAMA 267(18):2473–2474. Anon. 1986. Dangerous “therapies” from abroad. FDA Consumer 20(9):2–3. Anon. 1989a. Blue Cross/Blue Shield recommending coverage for off-label drug uses: Policy against routine payment for Treatment IND, Group C drugs stands. FDC Reports Pink Sheet 51(44):13–14. Anon. 1989b. Blue Cross recommending coverage for off-label drug uses, against routine payment for Treatment INDs. Drug Research Reports Blue Sheet 32(44):2–3. Anon. 1989c. Off-label drug uses, new technology adoption could be ﬁnanced through a trust fund. FDC Reports Pink Sheet 51(23T&G):5–6. Anon. 1990. APhA supports reimbursement for off-label drug uses. Hospital Formulary 25(6):597. Anon. 1991a. Americans want choice to use unapproved drugs. Hospital Formulary 26(12):922, 924. Anon. 1991b. BLR update: John and Mary Doe appeal refusal of request for preliminary injunction: Judge Harris had declined to forbid use of unapproved drugs in Persian Gulf without individual informed consent. Biotechnology Law Report 10(3):216–217. Anon. 1991c. FDA standards for cancer approvals are not prime cause of off-label use, Mayo oncologist argues; compendia approach has shortcomings, GAO says. FDC Report Pink Sheet 53(49):6–7. Anon. 1991d. FDA watching prescription drug promotion. FDA Consumer 25(8):2. Anon. 1991e. FDA’s Kessler on warpath. Chemical Market Reporter 239(24):41. Anon. 1991f. Kessler warns about drug, device promotion. FDA Consumer 25(7):3. Anon. 1991g. Medicare will continue covering NCI’s Group C but not Treatment IND drugs, HCFA draft rules direct. Drug Research Report Blue Sheet 34(3):6–7. Anon. 1991h. Off-label use of cancer drugs: Oncologists report increased denials for reimbursement, GAO survey. Drug Research Report Blue Sheet 34(10):5–6. Anon. 1991i. Reimbursement denials growing for off-label uses of cancer therapies. Hospital Formulary 26(6):446, 448. Anon. 1992a. FDA encouraging supplemental NDA ﬁlings for off-label uses of cancer drugs; agency already has approached two oncology companies, Kessler tells NCAB. FDC Report Pink Sheet 54(5):8–9. Anon. 1992b. FDA letters to industry requesting information on unapproved indications will issue shortly; NDA supplement backlog has been reduced to 50. FDC Report Pink Sheet 54(19):14. Anon. 1992c. FDA is putting ﬁnal touches on off-label drug letter to industry and medical societies; agency seeking information on extent of use, existing research data. FDC Report Pink Sheet 54(24):7.

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Appler, W. D. 1988. The FDA’s treatment IND rule: A glimpse into the future of drug regulation in the U.S. Food, Drug, Cosmetic Law Journal 43(4):649–658. Beardsley, T. 1986. Unapproved drugs for export [news]. Nature 323(6090):657. Calandra, G. B., J. P. Garelik, P. T. Kohler, and K. R. Brown. 1987. Problems and beneﬁts of an antibiotic compassionate therapy program. Reviews in Infectious Disease 9(6):1095–1101. Cardinale, V. 1991. Off-label potential of biotech drugs is signiﬁcant: Huber. Hospital Pharmacy Report 5(2):19. Carey, J., and J. Weber. 1991. The FDA is growling at drug makers, too: It gets tough with companies that promote drugs for unapproved uses. Business Weekly 220:34–35. Conlan, M. F. 1991. FDA scrutinizing promotion of unapproved uses. Drug Topics 8135(13):53–55. FDA. 1985. Guidance for the emergency use of unapproved medical devices; availability: FDA Notice. Federal Register 50(204):42866–42867. Flannery, E. J. 1986. Should it be easier or harder to use unapproved drugs and devices? Hastings Center Report 16(1):17–23. Freudenheim, M. 1991. FDA gets tough on drugs offered for unapproved uses. The New York Times, June 29, pp. 1, 9. GAO. 1991a. Off-label drugs, initial results of a national survey: Brieﬁng report to the chairman, Committee on Labor and Human Resources, U.S. Senate. Washington, D.C.: General Accounting Ofﬁce. GAO. 1991b. Off-label drug reimbursement policies constrain physicians in their choice of cancer therapies: Report to the Chairman, Committee on Labor and Human Resources, U.S. Senate. Special Report No. GAO/PEMD-91-14. Washington, D.C.: General Accounting Ofﬁce. Gatty, B. 1991. FDA warns against promoting unapproved drugs, uses. Dermatology Times 12(8):15. Gebhart, F. 1991. This off-putting problem of off-label drugs. Hospital Pharmacy Report 5(4):24–25. Graham, M. 1991. The quiet drug revolution. Medical Economics 68(4):129–133. Haakenson, C., C. L. Fye, M. R. Sather, and D. J. Toussaint. 1987. The investigator-sponsored IND in clinical trials. Controlled Clinical Trials 8(2):101–109. Hayman, S. 1991. BLR update: Request denied for preliminary injunction enjoining DoD from using unapproved drugs without individual informed consent. Biotechnology Law Report 10(2):106–107. HCFA. 1989a. Medicare coverage draft list of over 100 drugs includes 14 chemotherapy agents, speciﬁes reimbursable off-label indications. FDC Report Pink Sheet 51(22):3–4. HCFA. 1989b. Reimbursement for off-label uses of approved drugs: Medicare contractors will review reimbursement on a drug-by-drug basis, HCFA’s Buto. FDC Report Pink Sheet 51(12):9. Kessler, D. A. 1989. The regulation of investigational drugs. New England Journal of Medicine 320(5):281–288. Klecker, R. J., and R. J. Cipolle. 1987. Procedures for emergency or treatment use of investigational drugs. American Journal of Hospital Pharmacy 44(5):1086–1089. Laetz, T., and G. Silberman. 1991. Reimbursement policies constrain the practice of oncology. JAMA 266(21):2996–2999. Lasagna, L. 1991. Practice needs and concerns with regard to unlabeled uses of drugs. Physical Therapy 16(3):235–236, 238. Lee, P. P., and J. C. Yang. 1991. The nonapproved use of medications. Ophthalmology 98(7):1071–1074. Levine, R. J. 1987. AIDS treatment drugs: Clinical trials and compassionate use. AIDS Public Policy Journal 2(2):6–8. Leyland-Jones, B., B. R. Davies, K. Clagett-Carr, D. Shoemaker, D. Macfarlane, C. Fortner, P. J. O’Dwyer, G. Sarosy, B. J. Foster, H. G. Chun, D. F. Hoth, and L. V. Rubinstein. 1992. Patient treatment on a compassionate basis: documentation of high adverse drug reaction rate. Annals of Oncology 3(1):59–62. Margolis, R. E. 1988. Investigational new drug regs: Icing or cake? Healthspan 5(11):25–26. McClung, H. J., and R. E. Kauffman. 1992. Use of nonapproved drugs in children, 12. Journal of Pediatrics 120(4I):668–669. Merz, B. 1990. Quicker release of drugs spurs logistical challenges. American Medical News 33(9):2, 9. Moertel, C. G. 1991. Off-label drug use for cancer therapy and national health care priorities. JAMA 266(21):3031–3032. Nightingale, S. L. 1992. Action against illegally promoted, foreign–manufactured, unapproved prescription drugs. JAMA 267(11):1442.

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Pier, N. H. 1989. Compassionate release of anti-HIV drugs, II. Lancet 2(8676):1399–1400. Pugh, M. C. 1987. Unlabeled uses for approved drugs. American Druggist 195:127–128, 130, 133–134. Randall, T. 1991. FDA scrutinizes “off-label” promotions [news]. JAMA 266(1):11. Serradell, J., and J. T. Patwell. 1991. Unlabeled drug use patterns in a contemporary outpatient setting. Journal of Pharmacoepidemiology 2(2):19–43. Thompson, R. C. 1987. Playing hide and seek with the FDA. FDA Consumer 21(3):36–37. Wagner, M. 1992. Hospital pharmacies watch prescriptions as debate rages over “off-label” drug use. Modern Healthcare 22(19):62. Weber, J. 1991. An FDA rule that’s poor science and poor policy. Business Week 3243:36. Weitzman, S.A., and T. Marcy. 1987. FDA treatment use regulations: A compassionate response. AIDS Public Policy Journal 2(2):22–32. Williams, H. M. 1992. Cancer therapy: Reimbursement of new therapeutic technologies. Yale Journal of Biology and Medicine 65(2):83–97. Winslow R. 1991. Report says health insurers’ policies put constraints on treatment of cancer. The Wall Street Journal, December 4, p. B4.

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Corrections 2 Recalls: and Withdrawals Recalls of regulated product generally mean that the product became adulterated or misbranded while in the market; alternatively, the product distributed could be counterfeit, subjecting the product not only to a recall but also to other regulatory sanctions discussed in subsequent chapters. When a company discovers that a product it has placed into interstate commerce has become adulterated or misbranded, it is the responsibility of that ﬁrm to remove the product from any and all sources that received it. The health hazard seriousness or class of the recall will determine the actions taken. Recalls must be communicated to the public and healthcare practitioners, as well as, in some instances, internationally. Frequently, recalls are voluntary; however, if a sponsor or distributor has not taken steps to remove such product voluntarily, a FDA-requested recall may be demanded. This chapter examines the FDA’s statutory recall authority, recall types and classes, recall communications, FDA recall effectiveness monitoring, recall strategy, public notiﬁcation, status reports, recall termination, regulated product withdrawals, and other pertinent recall facts.

2.1 STATUTORY AUTHORITY Statutory authority to recall regulated product is delegated to the FDA through the Federal Food, Drug, and Cosmetic Act of 1938, 21 CFR Part 7 et seq. A recall is the removal or correction22 of approved or unapproved product that the FDA considers violates the law.23 Recalls are voluntary actions of industry participants to remove regulated product from the market. They are also administrative or legal measures the FDA may use to remove regulated drugs or medical device product labeling24,25 and/or promotional literature from interstate commerce.26,27 A regulated product is removed when it has become adulterated or misbranded during interstate commerce. Products are considered adulterated if they contain ﬁlthy, putrid, or decomposed substances;28 if they have been prepared, packed, or held under unsanitary conditions whereby they may have been contaminated with ﬁlth or rendered injurious to health;29 if they fail to conform to current good manufacturing practices (CGMPs);30 if they are held in inadequate containers that may render the contents injurious to health;31 if they bear or are unsafe color additives; if they fail to conform to ofﬁcial compendia as represented;32 if they fail to conform to their own represented standards of strength, purity, or quality;33 or if they are mixed with or are substitutions of ingredients of reduced quality or strength.34 A regulated product is misbranded35 when it has false or misleading statements in any particular;36 when it fails to bear the name and address of the manufacturer, packer, or distributor and quantity of contents;37 or when the article does not bear the required information prominently and conspicuously enough for ordinary individuals to read and understand.38 Recalls afford the FDA a process for more efﬁcient and timely removal of products for consumer protection as compared to formal administrative or civil actions, especially for product that has been widely distributed.

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2.2 RECALL TYPE AND CLASS 2.2.1 RECALL TYPES The two types of recalls are ﬁrm initiated39 or FDA requested.40 Both recall types are designed to protect the public health and well being by immediately removing product from the market. In addition to these two general types of recalls are three mandatory recalls for medical devices,41 biological products,42 and human tissue intended for transplantation.43 The authority for mandatory recalls has been recognized in the following sources: •

•

•

The Safe Medical Devices Act, Section 518(e), gave the FDA mandatory recall authority. Devices are generally regulated by the FDA Center for Devices and Radiological Health (CDRH); however, the mandatory recall authority is not limited to the CDRH, as any FDA center can initiate a mandatory recall for a medical device. The National Childhood Vaccine Injury Act of 1986, also known as the Public Health Service Act (PHS Act), was amended to provide recall authority for biological products (42 USC 262). If a batch, lot or other quantity of product regulated by the Center for Biologics Evaluation and Research (CBER) presents an imminent or substantial hazard to the public health, the FDA Secretary has the authority to cause a mandatory immediate recall of the batch, lot, or other quantity of that biologic product. Title 21 CFR Part 1270 establishes requirements for certain infectious disease testing, donor screening, and recordkeeping to help prevent the transmission of human immunodeﬁciency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) through the transplantation of human tissues. Title 21 CFR 1270.43 authorized the FDA to initiate mandatory recalls involving banked human tissue such as bone, ligaments, tendons, cartilage, skin, fascia, and corneas intended for transplantation. It does not apply to vascularized organs (e.g., livers, hearts, or kidneys), bone marrow, semen, human milk, or any tissue currently regulated by the FDA as a human drug, medical device (e.g., heart valves, corneal lenticles, dura mater), or biological product. Following is an example of a human tissue recall that occurred at Cryolife, Inc.; the public notiﬁcation and warning letter issued to the company by the FDA are shown.

FDA Issues Order To Recall and To Prevent Further Use of Human Tissue Processed at Cryolife, Inc. FOR IMMEDIATE RELEASE P02-27 August 14, 2002

Media Inquiries: 301-827-6242 Consumer Inquiries: 888-INFO-FDA

Processed Human Tissue Recalled by Cryolife, Inc. The Food and Drug Administration (FDA) has ordered Cryolife, Inc. (“Cryolife”) of Kennesaw, Ga., a human tissue-processing ﬁrm, to recall distributed human tissue processed from October 3, 2001, to the present. Under the order, the ﬁrm must also withhold from the market or destroy tissue processed after that date. FDA is taking this action because it has determined that Cryolife cannot ensure that the human tissue it processes for transplantation is free from fungal and bacterial contaminants.

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Tissue from a donor processed by Cryolife on and after October 3, 2001, has been associated with the November 7, 2001, death of a patient who received a soft tissue implant during reconstructive knee surgery. “This order not only protects patients from the unacceptable level of risk associated with tissue processed by Cryolife, it also sends a clear signal that FDA stands ready to take whatever action is necessary to ensure the safety of human tissue,” said Dr. Lester M. Crawford, FDA Deputy Commissioner. During its inspection of Cryolife from March 25 through April 12, 2002, FDA found numerous, signiﬁcant violations of FDA regulations. FDA issued a warning letter to Cryolife on June 17, 2002, after determining, among other things, that the ﬁrm had neither adequately investigated its validation of processing and testing methods nor implemented recommendations from the Centers for Disease Control and Prevention (CDC), or any other procedures, to ensure that tissue processed by the ﬁrm is not contaminated. After determining that Cryolife had failed to take adequate corrective measures to address possible infectious disease contamination of tissue in inventory and distribution, and after reviewing information provided by the ﬁrm in response to FDA’s warnings, FDA issued the present order. Current federal regulations for human tissue require ﬁrms to prepare, validate, and follow written procedures to prevent infectious disease contamination or cross-contamination during tissue processing. Contamination may be caused by a variety of infectious disease agents including viruses, bacteria, fungi, and transmissible spongiform encephalopathy (TSE)-associated prions. FDA’s concerns described in the order relate speciﬁcally to bacterial and fungal contamination of soft tissues such as cartilage and tendons. FDA’s investigation revealed, among other things, that of those standard operating procedures implemented by Cryolife to prevent infectious disease contamination or cross-contamination many were not followed. In addition, Cryolife improperly distributed tissue from a donor after the ﬁrm conﬁrmed the presence of harmful microorganisms in tissue samples from the same donor. If a bacterial or fungal infection were to occur following a tissue transplant, the signs and symptoms would usually appear within days to weeks after transplantation. Therefore, it is unlikely that patients who have not recently received a transplant are likely to be at future risk. However, concerned patients are encouraged to contact their physicians. FDA’s Center for Devices and Radiological Health (CDRH) is currently evaluating whether similar risks may be posed by Cryolife’s heart valves and will take further regulatory action if appropriate.

Source: FDA Public Health Web Notiﬁcation: Human Tissue Processed by Cryolife, Inc., http:// www.fda.gov/cdrh/safety/humantissue.html.

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Warning Letter Issued to Cryolife, Inc. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Atlanta District Ofﬁce 60 Eighth Street N.E. Atlanta, GA 30309 Telephone: 404-253-1161 FAX: 404-253-1202 June 17, 2002 (02-ATh30) Steven G. Anderson, President and CEO Cryolife, Inc. 1655 Roberts Blvd. NW Kennesaw, GA 30144 WARNING LETTER Dear Mr. Anderson: During an inspection of your ﬁrm located in Kennedy, GA, conducted March 25 through April 12, 2002, our investigators determined that your ﬁrm manufactures and distributes cryopreserved heart valves. This product is a device as deﬁned by Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act), Our investigators documented signiﬁcant deviations from the Quality System Regulation (QSR), as set forth in Title 21 Code of Federal Regulation (21 CFR), Part 820. Those deviations cause your devices to be adulterated within the meaning of Section 501(h) of the Act, pursuant to 21 CFR 820.1(c). These deviations include: 1. Failure to fully validate and approve a process whose results cannot be fully veriﬁed by subsequent inspection and test, as required by 21 CFR 820.75(a). For example, review of the validation studies for the [redacted] System (a.k.a., [redacted]) revealed that you did not use positive and negative controls with the samples, which were testes, for the study. Your validation work does not support the reduction of culture incubation from [redacted] to [redacted] days. No growth promotion testing of the [redacted] media bottles and the anaerobic blood agar plates was done as part of the study. You did challenge the [redacted] media with a full range of challenge organisms (aerobic and anaerobic) from known traceable sources to show that the media can support the growth over a wide range of challenge organisms. No data were available to support your use of the worst case situation [redacted]. Your validation study did not show that you continued to monitor the samples beyond the [redacted]-day incubation period in the study to ensure detection of slow growing organisms or fungi. 2. Failure to use sample plans, which are based on a documented valid statistical rationale, as required by 21 CFR 820.250(b). For example, the [redacted] unit sample size which was used for the ﬁnal method study to compare culture results of the [redacted] system versus the old method [redacted] is not based on a documented valid statistical rationale. 3. Failure to revalidate a process in response to changes or process deviations, as required by 21 CFR 820.75(c). For example, Cryolife did not revalidate when it changed the [redacted] anaerobic media bottle from regular media to the anaerobic [redacted] bottle on/about 3/15/02. Also, the Tissue Processing Laboratory (TPL) autoclave time was changed on 4/26/01. Review of processing and maintenance records indicated continuing problems with the TPL autoclave dating back to 1999. Sterilization cycle failures of this autoclave were encountered during September and October of 2001.

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4. Failure to adequately inspect or test incoming product to verify conformance of incoming product to speciﬁcations, as required by 21 CFR 820.80(b). For example, your ﬁrm had not performed a [redacted] growth promotion test utilizing all the challenge organism shown on the certiﬁcates of conformance for the anaerobic media. Your ﬁrm routinely only uses [redacted] selected organisms for growth promotion testing on new lots of media that you receive. Without using a comprehensive list of various organisms for growth promotion, your ﬁrm has no assurance that your use of the [redacted] challenge organisms is sufﬁcient to demonstrate that each lot of media will enable detection of all the aerobic and anaerobic contaminants that might be present on the heart valves. 5(a). Failure to fully document process validation activities and results, as required by 21 CFR 820.75(a). For example, the Antimicrobial Cocktail Comparison Study (Protocol 0004261, dated April 1999) lacked documentation of review of all data to support acceptance of the study. Information on study conditions was not documented, and several sample processing records (i.e., cardiac tissue samples 461516 and 43609) were not available. This study failed to show data to support your stated speciﬁcations of [redacted] hours’ treatment to heart valves in the Antimicrobial Cocktail. None of the samples in the study was processed and evaluated at the lower and upper limits of treatment processing times permitted by that speciﬁcation. 5(b). Another example of failure to fully document process validation activities is the lack of any testing of the [redacted] Biological Safety Cabinet and the [redacted] Laminar Flow Hood under dynamic or fully operational conditions to ensure the air ﬂow functions as needed for aseptic processing conditions during tissue dissection and during packaging/labeling operations. Testing and validation work on these units is not considered complete and/or meaningful without testing under dynamic conditions. Additionally, our investigators noted that the polylined drapes used to prepare the sterile ﬁeld covered a major section of the perforated front grill, thus interfering with the designed air ﬂow of the cabinet. 6. Failure to fully monitor and control the component and device characteristics during production, as required by 21 CFR 820.70(a)(2). For example, your ﬁrm does not monitor or evaluate the bioburden level or microbial load on recovered cadaveric heart valves prior to exposure to antibiotic treatment. Without knowing and monitoring the incoming bioburden level or microbial load on the heart valves, your ﬁrm cannot fully assure the consistency and control of your operations. Our investigators also determined that your ﬁrm processes human tissues intended for transplantation. Our investigators documented signiﬁcant violations of the requirements for human tissue intended for transplantation as set forth by Title 21 Code of Federal Regulation (21 CFR), Part 1270, promulgated under the authority of Section 361 of the Public Health Service Act. These violations include: Failure to prepare, validate, and follow written procedures for prevention of infectious disease contamination and cross-contamination during processing, as required by 21 CFR 1270.31(d); for example: 1. Written procedures were not validated in that: • There was no evaluation that included bacteriostasis and/or fungistasis testing with the current antibiotic/antifungal cocktail(s), and your ﬁrm did not have data to ensure that the antibiotic/antifungal cocktail(s) did not interfere with or inhibit the growth of microorganisms in culture media(s) during postprocessing culturing of tissues. Your ﬁrm has not validated its microbiology testing to ensure that residual antibiotic/antifungal cocktail(s) do not result in false-negative microbiological testing results.

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• There were no data to support the use of the processing parameters of [redacted] hours for cardiac and orthopedic tissues and for the use of [redacted] hours for vascular tissue. • There were no validation studies to justify that the sample sizes obtained for postprocessing microbiology quality assurance (QA) testing are adequate and representative of the tissues being processed. • There was no information to validate procedures that did not provide for testing of incoming tissues prior to being processed. For example, there are no current studies showing that your ﬁrm has knowledge of the average bioburden of tissues received from your suppliers. 2. Written procedures were not followed for speciﬁc antibiotic treatment periods where: • Tissue was packaged and subsequently prior to completion of the speciﬁed antibiotic treatment periods. This letter is not intended to be an all-inclusive list of deﬁciencies at your facility. It is your responsibility to ensure adherence to requirements of the FD&C Act, Section 361 of the Public Health Service Act, and the federal regulations. The speciﬁc violations noted in this letter and in the FDA 483 Notice of Observations, issued on 4/12/02 at the closeout of the inspection (copy enclosed), may be symptomatic of serious underlying problems in your manufacturing and quality assurance systems. You are responsible for investigating and determining causes of the violations identiﬁed by the FDA. If the causes are determined to be a systems problem, you must promptly initiate permanent corrective actions. Federal agencies are advised of the issuance of all warning letters about devices so that they may take this information into account when considering the award of contracts. Additionally, no premarket submission for devices to which the quality system/good manufacturing practice (GNP) deﬁciencies are reasonably related will be cleared until the device violations described above have been corrected Also, no requests for Certiﬁcates for Export will be approved until the violations related to the subject devices have been corrected. You should take prompt action to correct these deviations. FDA may take additional regulatory action without further informal notice, including, but not limited to, seizure, injunction, civil penalties, and/or an order for retention recall and/or destruction. Please notify this ofﬁce, in writing, within ﬁfteen (15) working days of receipt of this letter, of the steps you have taken to correct the noted violations, including an explanation of each step being taken to identify and make corrections to any underlying systems problems necessary to ensure that similar violations will not recur. If corrective actions cannot be completed within ﬁfteen (15) working days, state the reason for the delay and the time within which corrections will be completed. We acknowledge receipt of your May 15, 2002, letter responding to the inspectional observations. We have reviewed your response and determined that it is inadequate. Your response does not fully address the issues raised during the inspection. Without the supporting documentation that you promised to send as an appendix, we cannot evaluate the quality of your response. Where corrective actions were promised in your response, you did not provide written documentation of policies and procedures to verify that corrective actions have been implemented. When we receive the additional information promised in your letter, as well as any additional information in response to this letter, we will evaluate it. We encourage you to meet with us at the Atlanta District Ofﬁce to discuss corrective actions in further detail. Your response should be sent to Serene A. Kimel, Compliance Ofﬁcer, at the address noted in the letterhead. Sincerely, /s/ Dan L. Murrell for Ballard H. Graham, Director, Atlanta District Source: Warning Letters and Responses, http://www.fda.gov/foi/warning_letters/g3355d.htm.

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Recall of regulated product is an involved process within the industry and at the FDA. Normal business of the ﬁrm is interrupted. Staff members from numerous disciplines are immediately assembled to assess the issue. In some pharmaceutical companies, the decision to recall is the sole responsibility of one person or a small group of regulatory affairs personnel; in others, such decisions are made by a team of diverse personnel. Recall processes require large amounts of staff resources and effort with regard to making a decision to recall and to effectively perform the process of removal and destruction. Once the decision to recall product is made, the ﬁrm’s regulatory affairs staff, FDA center, and district ofﬁces of each entity begins a process to remove the product from the market. Table 2.1 shows the departments most likely to be involved in a recall and their function, as well as the FDA staff that

TABLE 2.1 Product Recall Staff and Functions Staff of Firm Involved in Recall Department

FDA Department Staff

Function

Department

Function

Regulatory Affairs

Directs internal recall functions and reviews complaints and adverse events for lot. Interacts with the FDA on all aspects of recall from notiﬁcation to termination.

Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), or Center for Food Safety and Nutrition (CFSAN)

Establishes and oversees recall, including actions of the Health Hazard Evaluation Committee

Quality Assurance

Assesses any and all quality issues in records and found subsequently

Ofﬁce of Regulatory Affairs

May assess need for heightened regulatory sanctions

Information Systems

Produced inventory list of lots and customers

Ofﬁce of Criminal Investigations

May assess need for criminal actions

Sales/Marketing

Identiﬁes customers who received product

Division of Compliance Management and Operations

Reviews and resolves compliance issues related to recall.

Quality Control

Reviews records to determine if analytical testing deviations occurred with recalled lot

Medical Products Quality Assurance

May assess recall quality issues for products sold to the Department of Defense, Veterans Affairs, General Services Administration, and Health Resource Services Administration

Medical Affairs

Assesses health hazard

Health Hazard Evaluation Committee

Performs health hazard evaluation

Legal Affairs

Monitors for potential lawsuits

District personnel

Monitors pre- and postrecall efforts

Manufacturing

Reviews lot records to determine if manufacturing deviations occurred with recalled lot

District Recall Coordinator

Receives periodic status report

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may be involved. The regulatory affairs staff, solely or in conjunction with a recall team, advises senior executive management of their ﬁndings, and a decision is made as to whether or not to recall the product. Within the FDA, depending upon the health hazard of the recalled product, various departments within the agency may become involved with the recall. Once the FDA is notiﬁed of a potential recall and its reasons (i.e., adulterated or misbranded product) it has but one goal: to immediately remove the product from the market.

2.2.2 REGULATED PRODUCT PROBLEM NOTIFICATION Discovering a problem with a regulated product may result from routine internal surveillance or monitoring of compliance activities, as well as from external sources. Methods for revealing regulated product problems may be divided into two broad categories: preventative or detective. A preventative approach relies upon routine analytical testing,44 retained sample examinations,45 or product stability testing46 to determine if the life of a product is being maintained. The beneﬁt of preventative controls is directly related to the level and rigor of regulatory compliance measures implemented at a ﬁrm. A detective approach is not directly related to the ﬁrm’s internal compliance measures but instead is related to vigilant notice of product problems from outside sources, such as practitioners, customers, or the FDA. In such cases, ﬁrms become aware of product problems through adverse events,47 serious adverse events,48 product complaints,49 or failure notiﬁcations.50 2.2.2.1 Preventative Controls As noted previously, preventative controls used to identify product problems are directly related to the rigor of regulatory compliance processes instituted at a ﬁrm. Effectively operated FDA-regulated ﬁrms document policy positions related to the business of making and selling regulated products. Firms are also required to document and maintain compliant standard operating procedures and work instruction. The policies of such ﬁrms, while generally company-beneﬁt driven, also include measures taken to meet contract arrangements with the FDA and other legal issues. Standard operating procedures and work instructions are required regulatory compliance documents but are also used internally by each company to control performance of internal functions consistent with requirements of current good manufacturing practices.51 All procedures are required to be current,52 in compliance, and followed by personnel trained in and involved with the regulated processes. 2.2.2.2 Defective Controls Detective controls operate when a ﬁrm is notiﬁed by an outside source that a problem has occurred with a product that may warrant a recall. In this instance, someone may have been harmed by the use, administration, or application of the product or it did not work as intended. If the use or intended use resulted in a serious adverse event for premarketed product under study or postmarket products already approved, the ﬁrm must investigate and report its ﬁndings to the FDA. When a patient is harmed or has a related or unrelated issue with a regulated product, healthcare professionals or the patient may report the incident to the sponsor, manufacturer, or distributor by completing a MedWatch form FDA-3500A53 (page 60) for drugs and medical devices or a Vaccine Adverse Event Reporting System (VAERS) form for vaccine biologics.54

2.2.3 CONTROLLABLE

VS.

UNCONTROLLABLE REGULATED PRODUCT PROBLEMS

Problems with regulated products may be controllable or uncontrollable. Examples of issues that are controllable by a ﬁrm are human clinical trial population enrollments and related adverse events of the product being studied. Speciﬁcally, when a ﬁrm enrolls a patient in a drug or medical device development study, it controls the process by selecting candidates based on multiple criteria, one of which is the beneﬁts brought to the study by the candidates. Perspective enrollees who are compromised in some way may adversely affect the study outcome and are therefore excluded from

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TABLE 2.2 Controllable Current Good Manufacturing Practice (CGMP) Regulatory Compliance 21 CFR 211.160 (Laboratory Controls, General Requirements)

Rigorous Firm A

Not Rigorous Firm Z

A

Establishment of any speciﬁcations, standards, sampling plans, test procedures, or other laboratory control mechanisms required.

Yes

Yes

B

Establishment of scientiﬁcally sound and appropriate speciﬁcations, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.

Yes

No

C

Determination of conformance to appropriate written speciﬁcations for the acceptance of each lot within each shipment of components, drug product containers, closures, and labeling used in the manufacture, processing, packing, or holding or drug products.

Yes

No

D

Determination of conformance to written speciﬁcations and a description of sampling and testing procedures for in-process materials; such samples shall be representative and properly identiﬁed.

Yes

Yes

E

Determination of conformance to written descriptions of sampling procedures and appropriate speciﬁcations for drug products; such samples shall be representative and properly identiﬁed.

Yes

Yes

F

Calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing speciﬁc directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met.

Yes

No

6

3

Analytical laboratory controls in place

participation; however, after approval of the regulated product, it may be prescribed to patients who would perhaps have been excluded from the clinical trials. In such instances, unrecognized sensitivities or unknown drug-to-drug, drug-to-food, or drug-to-environment conditions may result in regulated product problems not identiﬁed during a clinical trial. A ﬁrm has no control over how a physician prescribes its product to a patient, the food a patient may eat, or the patient’s environment (work or home). Yet, previously undetected drug-to-drug, drug-to-food, or drug-to-environment sensitivities may result in a regulated product problem that warrants a recall. Controllable ﬁrm issues are the basis on which regulatory compliance standards are developed, achieved, and maintained. Table 2.2 illustrates an example of CGMP analytical testing requirements for regulated ﬁrms A and Z. Firm A’s rigorous compliance standard operating procedures fully establish processes for all six analytical testing requirements; however, Firm Z has compliance standards in place for only three of the required six analytical testing procedures. Having fewer than the six required laboratory controls indicates potential gaps in Company Z’s methods for identifying regulated product problems. Keep in mind that these are only examples. It would be imprudent to believe that Firm A has no FDA regulatory issues just because it documents its analytical testing requirements and has the necessary controls in place, as these standards must also be compliant, current, and followed to be effective. The FDA and the ﬁrm involved must decide if the regulated product problem is one of adulteration or misbranding and must then classify its level. The FDA assigns a recall classiﬁcation number for each recall that is determined by the degree of health hazard presented to the public

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by the product. Product recalls that fall into one or both categories of adulterated or misbranded are also classiﬁed based on the potential hazard. In the case of Cryolife, Inc., the FDA found the regulated product to be adulterated, but it then had to be further classiﬁed based on the hazard presented. After reading the following section on the three types of classes, it would be worthwhile for the reader to determine where the Cryolife, Inc., recall classiﬁcation belongs.

2.2.4 RECALL CLASSES 2.2.4.1 Prior Notice Understanding a class I FDA-requested recall ﬁrst requires a brief discussion of prior notice, which is knowledge a ﬁrm had about existing regulatory compliance issues due to receipt of prior written information regarding compliance problems found with its operations and documented by the FDA. The compliance problems found may involve current good manufacturing practices, good laboratory practices, good clinical practices, or advertising and promotional literature. The notice is given or addressed to the most senior authorized person at the facility inspected by a Compliance Ofﬁcer of the FDA or via other means and explains that the FDA has obtained sufﬁcient information and evidence to justify Administrative Enforcement or for requesting the ﬁrm to recall product. The written notice to the ﬁrm could be in the form of a Notice of Observations (FDA 483), warning letters, cease and desist notices, or other FDA regulatory means. The intent of prior notice is to document observations or problems found by the FDA regarding a ﬁrm’s compliance standards and to allow the ﬁrm an opportunity to respond in writing to the FDA. A ﬁrm’s written response may agree with, disagree with, or justify the ﬁndings. The ultimate reason for giving prior notice is to gather evidence regarding the FDA’s experience with compliance failures at the ﬁrm and to obtain the ﬁrm’s response regarding its duty to achieve full compliance, as well as to prevent such repeated compliance failures and to keep adulterated or misbranded product that might harm the public out of interstate commerce. In the case of Cryolife, the FDA issued a warning letter. A review of the warning letter of June 17, 2002, indicates that the FDA gathered information about this company’s compliance program through on-site inspection of that facility. The letter states that Cryolife experienced multiple failures of FDA regulations. Almost two months later (August 14, 2002), the FDA issued an order to recall the human tissue distributed by Cryolife, Inc. 2.2.4.2 Class I FDA-Requested Recall Class I FDA-requested recalls are generally reserved for “urgent situations” or for FDA use to request recalls.55 As stated earlier, human tissue and medical devices are recalled by a different process than are drugs. With either of these products (i.e., human tissue or medical devices), the FDA has the authority to order a recall. In the case studies, the recall of drugs is discussed to compare the differences between a drug or medical devices recall with that of human tissue. A class I recall is deﬁned as a “situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.”56 2.2.4.3 Class II Firm-Initiated Recall Class II ﬁrm-initiated recalls are voluntarily conducted by the pharmaceutical company. A ﬁrminitiated recall can be initiated as a result of preventative or detective measures. The aim of a class II recall is similar in intent to a class I recall — that is, to remove product from the market. A class II recall is deﬁned as a “situation in which use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.”57

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2.2.4.4 Class III Firm-Initiated Recall Class III ﬁrm-initiated recalls are similar to class II recalls in that they are conducted voluntarily. It can also be initiated as a result of preventative or detective means, and its aim is similar — to remove product from the market. A class III recall is deﬁned as a “situation in which use of, or exposure to, a violative product is not likely to cause adverse health consequences.”58 Allowing problem products to enter interstate commerce is not considered an act without future potential regulatory consequences for a ﬁrm. As a result, the FDA may seek to enforce other regulatory sanctions against a ﬁrm than was required to conduct a recall of regulated product it released for sale into interstate commerce.

2.2.5 COMMUNICATION The goal of a regulated product recall is to communicate the intent to remove the product from the marketplace and from all who received it. Whether a ﬁrm conducting a recall has effectively communicated its intent to recipients of the product is a serious issue to be determined by the FDA during and at the conclusion of the recall. Firms sometimes face several obstacles to communicating recall information. Firms must have effective methods for dealing with the negatively perceived recall information. In most instances, publicity about the recall of a product diminishes the ﬁrm’s reputation in the public’s eye. The situation is made more difﬁcult when ﬁrms experience a lack of cooperation from third parties who entered into nondisclosure contracts and are legally bound not to disclose the ultimate recipients of the product, when the consumer documentation is not maintained, or when it involves doctor/patient privilege. All of these issues impact the effectiveness of the recall communication. Additionally, products may be distributed to foreign countries that lack the internal processes to notify, collect, and return products, and multilingual communication is yet another complication. When a ﬁrm fails to communicate a recall of regulated product effectively and in a timely manner or when a ﬁrm has not been able to obtain the cooperation of third parties, the FDA may assist the ﬁrm in its efforts to provide access to the information. In any event, the FDA publicly announces recalls of all regulated products on its website. How the recipients of recalled products ﬁrst learn of the recall can further impact a ﬁrm’s consumer protection credibility, particularly if ﬁrst notice of a recall is obtained from a public announcement by the FDA.

2.3 RECALL EFFECTIVENESS MONITORING A ﬁrm recalling product has the responsibility to determine the effectiveness of its ability to contact all consignees. To ensure that ﬁrms are contacting everyone who received its recalled product, the FDA may monitor the effectiveness of the recall through inspections or audit checks and may make recommendations if it ﬁnds that the recall effort is inadequate. Limited inspection of a facility59 may occur to determine if the ﬁrm has kept its recall commitment made to the FDA. Primarily, the FDA is looking to determine if the company has contacted all levels of consignees, identiﬁed the root cause for the recall, and put in place measures to ensure it does not recur. FDA’s audit checks are performed and completed via personal visits, telephone calls, or letters to the lowest level of recipients of the recalled product. The scope of a recall is indicated by one of ﬁve categories: For level A, 100% of the total number of consignees are contacted; level B, greater than 10% but less than 100%; Level C, 10%; level D, 2%; and level E, no effectiveness checks. If the company selects level A, it is responsible for ensuring that 100% of the consignees are contacted. If a company selects level D, for example, but the FDA believes that level is not adequate, the agency will recommend that the ﬁrm increase its level of audit checks for the recall.

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2.4 STRATEGY Recalls are unusual circumstances for ﬁrms, and each recall requires a particular strategy to ensure that the product is promptly removed from the market. The FDA will review and/or recommend a ﬁrm’s recall strategy and will develop a strategy for its own audit program based on its hazard evaluation. The product distribution, type or use of the product, market availability, need for publicity, depth of the recall, level of effectiveness, audit checks, and other recall factors impact the recall strategy.

2.5 PUBLIC NOTIFICATION The recalling ﬁrm has a responsibility to notify both recipients and distributors of the recall. The FDA, through its weekly Enforcement Report, notiﬁes the public of all classes of recalls regardless of age or status. It reports recall status such as “completed” or “ongoing” from the date it began until completed. The FDA decides when it is appropriate to remove public notiﬁcation of a recall. Other notiﬁcation information may be sent directly by the FDA or recalling ﬁrm to professionals, healthcare administrators, and healthcare associations to alert them of health hazard situations.

2.6 STATUS REPORTS Status Reports are provided to the FDA periodically during the recall. The frequency of the Status Report may be determined by the class of the recall (i.e., I, II, or III). Generally, Status Reports are prepared and sent on at least a monthly basis to the district ofﬁce that serves the recalling ﬁrm. Each district ofﬁce of the FDA has a Recall Coordinator, who receives reviews and may contact recalling ﬁrms for clariﬁcation or to request additional information regarding the recalled products. Status Reports submitted to the FDA must contain the following basic information: • •

•

•

Number of consignees notiﬁed of the recall and date and method of notiﬁcation Number of consignees responding to the recall communication and quantity of product on hand at the time it was received, as well as the number of consignees not responding (if needed, the identity of nonresponding consignees may be requested by the FDA) Number of products returned or corrected by each consignee contacted and the quantity of products accounted for, as well as the number and results of effectiveness checks that were made Estimated time frame for completion of the recall

Status Reports are discontinued when the recall is terminated by the FDA.

2.7 TERMINATION Termination of a recall is an FDA decision. Firms may recommend termination; however, the ultimate decision to terminate remains with the FDA. A recall is considered terminated when the FDA believes all reasonable efforts have been made to remove recalled product from interstate commerce consistent with the recall strategy and returned product is either destroyed or reconditioned according to the degree of hazard.

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2.8 REGULATED PRODUCT WITHDRAWALS A recall involves removal of a lot or batch of related lots of regulated product, but new lots or batches of the recalled product will be available to the public in the future. Regulated product withdrawals, unlike recalls, involve complete removal and future unavailability of products. Table 2.3 shows regulated drug products withdrawn from the market from 1996 to 2001 for safety-based reasons.

2.9 FDA RECALL FACTS Figure 2.1 illustrates the recalls of drugs and mislabeled products between 1990 and 1995. Figure 2.2 shows the human drug recalls for the same time period that involved prescription and over-thecounter (OTC) products, and Figure 2.3 breaks down the recalls from 1990 to 1995 according to class. The Center for Drug Evaluation and Research (CDER) regularly publishes a list of primary defects found in drugs; a summary of the defects for ﬁscal 2001 is shown in Figure 2.4. In FY2002, MedWatch reported 24,936 defects for products regulated by all of the FDA’s centers. Of these, 67% were handled by the CDER and Center for Biologics Evaluation and Research (CBER) and entered into the Adverse Event Report System. During FY2002, none of the reported outcomes was congenital; 7 people died, 7 were disabled, 44% were hospitalized, and 26% required intervention; and 61% of the cases were life threatening (Figure 2.5). Of the various FDA centers, the CDER received 67% of the reports in FY2002 (Figure 2.6). These reports were received via telephone, fax, Internet, and mail, and 34% of the reports submitted to MedWatch are via the Internet. Most reports of product problems to the FDA are made by pharmacists; the three leading reporting sources in 2001 were hospital pharmacists (42%), retail pharmacists (18%), and other (21%) (Figure 2.7).

2.10 CASE STUDIES United States v. K-N Enterprises, Inc., N.D. ILL., 1978, 461 F. Supp. 988 United States v. C.E.B. Products, Inc., N.D. ILL., 1974 380 F. Supp. 664

RECALL EXHIBITS Documents Used in a Recall Item

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Title

Page

1

Recall communication

58

2

Return postcard

59

3

Envelope

59

4

MedWatch FDA-3500A

60

5

Vaccine Adverse Event Reporting System (VAERS)

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TABLE 2.3 Safety-Based Drug Withdrawals (1997–2001)60 Drug

Use

Risks

Date Approved

Manufacturer

2001 Baycol® (cerivastatin)

Cholesterol control

Rhabdomyolysis, severe damage to muscle that is sometimes fatal; particular risk when drug is used at a high dose or with the drug gemﬁbrozil

1997

Bayer Pharmaceutical Division; West Haven, CT

Raplon® (rapacuronium bromide)

Injectable anesthesia drug administered as a muscle relaxant for breathing tube placement and surgery

Bronchospasm, an inability to breathe normally that can lead to permanent injury or death

1999

Organon, Inc.; West Orange, NJ

2000 Lotronex® (alosetron)

Treatment for irritable bowel syndrome in women

Intestinal damage resulting from reduced blood ﬂow to the intestine (ischemic colitis) and severely obstructed or ruptured bowels (complications of severe constipation)

2000

Glaxo Wellcome, Inc. (now GlaxoSmithKline); Research Triangle Park, NC

Propulsid® (cisapride)

Treatment for nighttime heartburn

Fatal heart rhythm abnormalities

1993

Janssen Pharmaceutical, Inc.; Titusville, NJ

Phenylpropanolamine

Decongestant used in many prescription and over-the-counter cough and cold medications

Hemorrhagic stroke (bleeding in the brain)

Rezulin® (troglitazone)

Treatment for type 2 diabetes

Severe liver toxicity

—a

—a

1997

Parke-Davis/Warner Lambert; Morris Plains, NJ

1988

Janssen Pharmaceutical Inc. (Manufacturer identiﬁed in printed version of January-February 2002 FDA Consumer was incorrect.)

1999 Hismanal® (astemizole)

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Antihistamine

Fatal heart rhythm abnormalities when used with other drugs or at too high a dose

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TABLE 2.3 (cont.) Safety-Based Drug Withdrawals (1997–2001)60 Drug

Use

Risks

Date Approved

Manufacturer

1999 (cont.) Raxar® (grepaﬂoxacin)

Antibiotic

Fatal heart rhythm abnormalities

1997

Glaxo Wellcome, Inc. (now GlaxoSmithKline); Research Triangle Park, NC

1998 Posicor® (mibefradil)

Treatment for high blood pressure and chronic stable angina

Dangerous interactions with other drugs

1997

Roche Laboratories; Nutley, NJ

Duract® (bromfenac)

Pain reliever

Severe liver damage

1997

Wyeth-Ayerst Laboratories; Philadelphia, PA

Seldane® (terfenadine) and Seldane®-D

Antihistamine

Fatal heart rhythm abnormalities

1985

Hoechst Marion Roussel; Kansas City, MO Baker Norton Pharmaceuticals; Miami, FL

1997 Pondimin® (fenﬂuramine)

Treatment for obesity

Heart valve abnormalities

1973

Wyeth-Ayerst Laboratories; Philadelphia, PA

Redux® (dexfenﬂuramine)

Treatment for obesity

Heart valve abnormalities

1996

Wyeth-Ayerst Laboratories; Philadelphia, PA

a

Phenylpropanolamine was in use prior to 1962, when an amendment to food and drug laws required a review of the effectiveness of this and other drugs while they remained on the market. It was deferred from ﬁnal approval because of safety concerns about a possible association between phenylpropanolamine use and an increased risk of stroke. Based on previous case reports of stroke and data from a recent safety study, the FDA is proposing to remove phenylpropanolamine from the market.

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56

81 69

64

68 51

48

46

48 38

33 4

2

90

2

91

0

33 0

0

92 93 Fiscal Year

No. of Products Involved Class I Mislabeling Incidents

48

94

95

Mislabeling Incidents

Number of Recalls

FIGURE 2.1 Recalls and mislabeling (FY90–FY95) (www.fda.gov/cder).61

581 451 313

304

254

191 92

90

91

102

93

73

70

92 93 Fiscal Year

60

94

95

OTC

Rx

Number of Recalls

FIGURE 2.2 Human drug recalls (FY90–FY95) (www.fda.gov/cder).62

390 303 202

187

169 139

142

133 116

5

4

6

90

91

92 93 Fiscal Year

Class I

5

Class II

117 74

97 5

0

94

95

Class III

FIGURE 2.3 Prescription drug recalls (FY90–FY95) (www.fda.gov/cder).63 Lack of Effect 12%

Adulterated 5%

Contamination 11%

Tampering 5%

Drug Claims 1%

Reconstitution 2%

Deterioration 8%

Visual Change 11% Labeling 12%

Packaging 33%

FIGURE 2.4 Reasons for recalls (FY2001) (www.fda.gov/cder).64

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Congenital 0%

Died 7%

Life-Threatening 16%

Disabled 7%

Intervention 26% Hospitalization 44%

FIGURE 2.5 Recall occurrences and effects (FY2002) (www.fda.gov/cder).65

Phone 1% Mail 34%

CBER 7% CDER 67%

Fax 31%

DQRS 11% CVM 0%

Internet 34%

CFSAN 3% CDRH 12%

FIGURE 2.6 (Left) Recall reporting sources, and (right) percentage of recalls by each FDA Center (FY2002) (www.fda.gov/cder).66

Other 21% Pharmacist (Hospital) 42% Consumer 8% Physician 7% Nurse 3% Pharm Tech 1%

Pharmacist (Retail) 18%

FIGURE 2.7 Recall reporters (FY2001) (www.fda.gov/cder).67

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RECALL COMMUNICATIONS: SAMPLE DRUG RECALL LETTER [Date] [Company Name] [Company Address] Re: List 1234, Cyanocobalamin Injection Lot No. 4321 URGENT: Drug Recall — Nonsterile Injectable

Recent tests show that the above lot number of this product is not sterile and, therefore, represents a potential public health hazard; consequently, we are recalling this lot from the market. Other lot numbers are not involved. Please examine your stocks immediately to determine if you have any of lot 4321 on hand. If so, discontinue dispensing the lot and promptly return via parcel post to our New York City plant, ATTENTION: Returned Goods. [Note: If a subrecall is indicated in a particular recall situation, the following paragraph should be added. If you have distributed any of lot 4321, please immediately contact your accounts, advise them of the recall situation, and have them return their outstanding recalled stocks to you. Return these stocks as indicated above.] You will be reimbursed by check or credit memo for the returned goods and postage. Please return the enclosed card immediately providing the requested information. This recall is being made with the knowledge of the Food and Drug Administration. The FDA has classiﬁed this recall as class _____ [if classiﬁed]. We appreciate your assistance. [Company President]

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RECALL COMMUNICATIONS: SAMPLE RETURN POSTCARD USED TO NOTIFY FIRM OF STOCK ON HAND TO BE RETURNED PLEASE FILL OUT AND RETURN Date ___________ We do not have any stock of List 1234 Cyanocobalamin, Injection Lot No. 4321 on hand. We have requested our accounts to return their stocks of this merchandise to us.

❏

❏

We are returning ____ bottles of List 1234, Lot No. 4321. Name __________________________________________________________________ Address_________________________________________________________________ City________________________ State ____________ Zip Code _________________

REVERSE SIDE

RECALL COMMUNICATIONS: SAMPLE RECALL ENVELOPE

[Recalling Company Name] [Address]

[Name] [Address]

[red print]

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URGENT: Drug Recall

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MEDWATCH VOLUNTARY REGULATED PRODUCT REPORT FORM FDA-3500A

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VACCINE ADVERSE EVENT REPORTING SYSTEM

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SUMMARY A. Statutory authority to recall: Food, Drug, and Cosmetic Act of 1938; Code of Federal Regulations 21 CFR Part 7 et seq.; Safe Medical Device Act of 1990; National Childhood Vaccine Injury Act of 1986 of the Public Health Service Act, 42 USC 262; and human tissue under 21 CFR 1270.43. B. Recall type and class: Types of recalls — FDA-requested, ﬁrm-initiated, and mandatory for medical devices under the Safe Medical Device Act, Section 518(e); vaccines under the National Childhood Vaccine Injury Act of 1986 of the Public Health Service Act, 42 USC 262; and human tissue under 21 CFR 1270.43. Classes of recalls — Class I, deﬁned as a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences of death; class II, deﬁned as a situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote; class III, deﬁned as a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences. C. Communication: Communication must effectively remove violative product by giving proper notice to recipients of such products. D. Recall effectiveness monitoring: The FDA monitors recall effectiveness by follow-up inspection or audit checks or makes recommendations if it ﬁnds the recall is ineffective. E. Strategy: Each recall is different and requires a different strategy to resolve the problem. F. Public Notiﬁcation: The ﬁrm has the responsibility to notify the public of the recall, and the FDA does so via the weekly Enforcement Report. Once a recall has been placed in a weekly Enforcement Report, the FDA decides when it will be removed. G. Status Reports: Recall Status Reports must be provided periodically to update the FDA on the progress of the recall. H. Termination: Termination of a recall is determined by the FDA. I.

Regulated product withdrawal: Regulated product withdrawals result in complete removal of the product from the market and it will not be available in the future.

J. Recall facts: Recalls occur because products are adulterated or misbranded. The problems with products can occur due to manufacturing/testing method deﬁciencies, contamination, inconsistent potency, labeling or packaging mix-ups, other product speciﬁcation problems, dissolution, noncompliance with National Institute on Drug Abuse (NIDA) monographs, or bioequivalence/abbreviated new drug application (ANDA) discrepancies.

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PRACTICUM Review Title 21 CFR 7–7.85 (see CFR 7.40–7.59, below). This practicum involves a review of 21 CFR 7–7.85 and participation in the management of a sample recall. After completing the reading and recall example, the professional teams should reacquaint themselves with the adulteration and misbranding standards required for a recall and the enforcement provisions.

Title 21 CFR 7 SUBPART C — RECALLS (INCLUDING PRODUCT) Section 7.40

Recall policy

(a) Recall is an effective method of removing or correcting consumer products that are in violation of laws administered by the Food and Drug Administration. Recall is a voluntary action that takes place because manufacturers and distributors carry out their responsibility to protect the public health and well-being from products that present a risk of injury or gross deception or are otherwise defective. This section and Sections 7.41 through 7.59 recognize the voluntary nature of recall by providing guidance so that responsible ﬁrms may effectively discharge their recall responsibilities. These sections also recognize that recall is an alternative to a Food and Drug Administrationinitiated court action for removing or correcting violative, distributed products by setting forth speciﬁc recall procedures for the Food and Drug Administration to monitor recalls and assess the adequacy of a ﬁrm’s efforts in recall. (b) Recall may be undertaken voluntarily and at any time by manufacturers and distributors, or at the request of the Food and Drug Administration. A request by the Food and Drug Administration that a ﬁrm recall a product is reserved for urgent situations and is to be directed to the ﬁrm that has primary responsibility for the manufacture and marketing of the product that is to be recalled. (c) Recall is generally more appropriate and affords better protection for consumers than seizure, when many lots of product have been widely distributed. Seizure, multiple seizure, or other court action is indicated when a ﬁrm refuses to undertake a recall requested by the Food and Drug Administration, or where the agency has reason to believe that a recall would not be effective, determines that a recall is ineffective, or discovers that a violation is continuing. 43 FR 26218, June 16, 1978, as amended at 65 FR 56476, Sept. 19, 2000. Section 7.41

Health hazard evaluation and recall classification

(a) An evaluation of the health hazard presented by a product being recalled or considered for recall will be conducted by an ad hoc committee of Food and Drug Administration scientists and will take into account, but need not be limited to, the following factors: (1) Whether any disease or injuries have already occurred from the use of the product. (2) Whether any existing conditions could contribute to a clinical situation that could expose humans or animals to a health hazard. Any conclusion shall be supported as completely as possible by scientiﬁc documentation and/or statements that the conclusion is the opinion of the individual(s) making the health hazard determination. (3) Assessment of hazard to various segments of the population, e.g., children, surgical patients, pets, livestock, etc., who are expected to be exposed to the product being considered, with particular attention paid to the hazard to those individuals who may be at greatest risk.

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(4) Assessment of the degree of seriousness of the health hazard to which the populations at risk would be exposed. (5) Assessment of the likelihood of occurrence of the hazard. (6) Assessment of the consequences (immediate or long-range) of occurrence of the hazard. (b) On the basis of this determination, the Food and Drug Administration will assign the recall a classiﬁcation, i.e., class I, class II, or class III, to indicate the relative degree of health hazard of the product being recalled or considered for recall. Section 7.42

Recall strategy

(a) General. (1) A recall strategy that takes into account the following factors will be developed by the agency for a Food and Drug Administration-requested recall and by the recalling ﬁrm for a ﬁrm-initiated recall to suit the individual circumstances of the particular recall: (i) Results of health hazard evaluation. (ii) Ease in identifying the product. (iii) Degree to which the product’s deﬁciency is obvious to the consumer or user. (iv) Degree to which the product remains unused in the market-place. (v) Continued availability of essential products. (2) The Food and Drug Administration will review the adequacy of a proposed recall strategy developed by a recalling ﬁrm and recommend changes as appropriate. A recalling ﬁrm should conduct the recall in accordance with an approved recall strategy but need not delay initiation of a recall pending review of its recall strategy. (b) Elements of a recall strategy. A recall strategy will address the following elements regarding the conduct of the recall: (1) Depth of recall. Depending on the product’s degree of hazard and extent of distribution, the recall strategy will specify the level in the distribution chain to which the recall is to extend, as follows: (i) Consumer or user level, which may vary with product, including any intermediate wholesale or retail level; or (ii) Retail level, including any intermediate wholesale level; or (iii) Wholesale level. (2) Public warning. The purpose of a public warning is to alert the public that a product being recalled presents a serious hazard to health. It is reserved for urgent situations where other means for preventing use of the recalled product appear inadequate. The Food and Drug Administration in consultation with the recalling ﬁrm will ordinarily issue such publicity. The recalling ﬁrm that decides to issue its own public warning is requested to submit its proposed public warning and plan for distribution of the warning for review and comment by the Food and Drug Administration. The recall strategy will specify whether a public warning is needed and whether it will issue as: (i) General public warning through the general news media, either national or local as appropriate, or (ii) Public warning through specialized news media, e.g., professional or trade press, or to speciﬁc segments of the population such as physicians, hospitals, etc. (3) Effectiveness checks. The purpose of effectiveness checks is to verify that all consignees at the recall depth speciﬁed by the strategy have received notiﬁcation about the recall and have taken appropriate action. The method for contacting consignees may be accomplished by personal visits, telephone calls, letters, or a combination thereof. A guide entitled “Methods for Conducting

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Recall Effectiveness Checks” that describes the use of these different methods is available upon request from the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. The recalling ﬁrm will ordinarily be responsible for conducting effectiveness checks, but the Food and Drug Administration will assist in this task where necessary and appropriate. The recall strategy will specify the method(s) to be used for and the level of effectiveness checks that will be conducted, as follows: (i) Level A—100 percent of the total number of consignees to be contacted; (ii) Level B—Some percentage of the total number of consignees to be contacted, which percentage is to be determined on a case-by-case basis, but is greater that 10 percent and less than 100 percent of the total number of consignees; (iii) Level C—10 percent of the total number of consignees to be contacted; (iv) Level D—2 percent of the total number of consignees to be contacted; or (v) Level E—No effectiveness checks. 43 FR 26218, June 16, 1978, as amended at 46 FR 8455, Jan. 27, 1981; 59 FR 14363, Mar. 28, 1994; 68 FR 24879, May 9, 2003. Section 7.45

Food and Drug Administration-requested recall

(a) The Commissioner of Food and Drugs or designee may request a ﬁrm to initiate a recall when the following determinations have been made: (1) That a product that has been distributed presents a risk of illness or injury or gross consumer deception. (2) That the ﬁrm has not initiated a recall of the product. (3) That an agency action is necessary to protect the public health and welfare. (b) The Commissioner or his designee will notify the ﬁrm of this determination and of the need to begin immediately a recall of the product. Such notiﬁcation will be by letter or telegram to a responsible ofﬁcial of the ﬁrm, but may be preceded by oral communication or by a visit from an authorized representative of the local Food and Drug Administration district ofﬁce, with formal, written conﬁrmation from the Commissioner or his designee afterward. The notiﬁcation will specify the violation, the health hazard classiﬁcation of the violative product, the recall strategy, and other appropriate instructions for conducting the recall. (c) Upon receipt of a request to recall, the ﬁrm may be asked to provide the Food and Drug Administration any or all of the information listed in Section 7.46(a). The ﬁrm, upon agreeing to the recall request, may also provide other information relevant to the agency’s determination of the need for the recall or how the recall should be conducted. 43 FR 26218, June 16, 1978, as amended at 69 FR 17290, Apr. 2, 2004. Section 7.46

Firm-initiated recall

(a) A ﬁrm may decide of its own volition and under any circumstances to remove or correct a distributed product. A ﬁrm that does so because it believes the product to be violative is requested to notify immediately the appropriate Food and Drug Administration district ofﬁce listed in Section 5.115 of this chapter. Such removal or correction will be considered a recall only if the Food and Drug Administration regards the product as involving a violation that is subject to legal action, e.g., seizure. In such cases, the ﬁrm will be asked to provide the Food and Drug Administration the following information: (1) Identity of the product involved. (2) Reason for the removal or correction and the date and circumstances under which the product deﬁciency or possible deﬁciency was discovered.

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(3) Evaluation of the risk associated with the deﬁciency or possible deﬁciency. (4) Total amount of such products produced and/or the timespan of the production. (5) Total amount of such products estimated to be in distribution channels. (6) Distribution information, including the number of direct accounts and, where necessary, the identity of the direct accounts. (7) A copy of the ﬁrm’s recall communication if any has issued, or a proposed communication if none has issued. (8) Proposed strategy for conducting the recall. (9) Name and telephone number of the ﬁrm ofﬁcial who should be contacted concerning the recall. (b) The Food and Drug Administration will review the information submitted, advise the ﬁrm of the assigned recall classiﬁcation, recommend any appropriate changes in the ﬁrm’s strategy for the recall, and advise the ﬁrm that its recall will be placed in the weekly FDA Enforcement Report. Pending this review, the ﬁrm need not delay initiation of its product removal or correction. (c) A ﬁrm may decide to recall a product when informed by the Food and Drug Administration that the agency has determined that the product in question violates the law, but the agency has not speciﬁcally requested a recall. The ﬁrm’s action also is considered a ﬁrm-initiated recall and is subject to paragraphs (a) and (b) of this section. (d) A ﬁrm that initiates a removal or correction of its product which the ﬁrm believes is a market withdrawal should consult with the appropriate Food and Drug Administration district ofﬁce when the reason for the removal or correction is not obvious or clearly understood but where it is apparent, e.g., because of complaints or adverse reactions regarding the product, that the product is deﬁcient in some respect. In such cases, the Food and Drug Administration will assist the ﬁrm in determining the exact nature of the problem. Section 7.49

Recall communications

(a) General. A recalling ﬁrm is responsible for promptly notifying each of its affected direct accounts about the recall. The format, content, and extent of a recall communication should be commensurate with the hazard of the product being recalled and the strategy developed for that recall. In general terms, the purpose of a recall communication is to convey: (1) That the product in question is subject to a recall. (2) That further distribution or use of any remaining product should cease immediately. (3) Where appropriate, that the direct account should in turn notify its customers who received the product about the recall. (4) Instructions regarding what to do with the product. (b) Implementation. A recall communication can be accomplished by telegrams, mailgrams, or ﬁrst class letters conspicuously marked, preferably in bold red type, on the letter and the envelope: “drug [or food, biologic, etc.] recall [or correction]”. The letter and the envelope should be also marked: “urgent” for class I and class II recalls and, when appropriate, for class III recalls. Telephone calls or other personal contacts should ordinarily be conﬁrmed by one of the above methods and/or documented in an appropriate manner. (c) Contents. (1) A recall communication should be written in accordance with the following guidelines: (i) Be brief and to the point; (ii) Identify clearly the product, size, lot number(s), code(s) or serial number(s) and any other pertinent descriptive information to enable accurate and immediate identiﬁcation of the product;

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(iii) Explain concisely the reason for the recall and the hazard involved, if any; (iv) Provide speciﬁc instructions on what should be done with respect to the recalled products; and (v) Provide a ready means for the recipient of the communication to report to the recalling ﬁrm whether it has any of the product, e.g., by sending a postage-paid, self-addressed postcard or by allowing the recipient to place a collect call to the recalling ﬁrm. (2) The recall communication should not contain irrelevant qualiﬁcations, promotional materials, or any other statement that may detract from the message. Where necessary, followup communications should be sent to those who fail to respond to the initial recall communication. (d) Responsibility of recipient. Consignees that receive a recall communication should immediately carry out the instructions set forth by the recalling ﬁrm and, where necessary, extend the recall to its consignees in accordance with paragraphs (b) and (c) of this section. Section 7.50

Public notification of recall

The Food and Drug Administration will promptly make available to the public in the weekly FDA Enforcement Report a descriptive listing of each new recall according to its classiﬁcation, whether it was Food and Drug Administration-requested or ﬁrm-initiated, and the speciﬁc action being taken by the recalling ﬁrm. The Food and Drug Administration will intentionally delay public notiﬁcation of recalls of certain drugs and devices where the agency determines that public notiﬁcation may cause unnecessary and harmful anxiety in patients and that initial consultation between patients and their physicians is essential. The report will not include a ﬁrm’s product removals or corrections which the agency determines to be market withdrawals or stock recoveries. The report, which also includes other Food and Drug Administration regulatory actions, e.g., seizures that were effected and injunctions and prosecutions that were ﬁled, is available upon request from the Ofﬁce of Public Affairs (HFI-1), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

Section 7.53

Recall status reports

(a) The recalling ﬁrm is requested to submit periodic recall status reports to the appropriate Food and Drug Administration district ofﬁce so that the agency may assess the progress of the recall. The frequency of such reports will be determined by the relative urgency of the recall and will be speciﬁed by the Food and Drug Administration in each recall case; generally the reporting interval will be between 2 and 4 weeks. (b) Unless otherwise speciﬁed or inappropriate in a given recall case, the recall status report should contain the following information: (1) Number of consignees notiﬁed of the recall, and date and method of notiﬁcation. (2) Number of consignees responding to the recall communication and quantity of products on hand at the time it was received. (3) Number of consignees that did not respond (if needed, the identity of nonresponding consignees may be requested by the Food and Drug Administration). (4) Number of products returned or corrected by each consignee contacted and the quantity of products accounted for. (5) Number and results of effectiveness checks that were made. (6) Estimated time frames for completion of the recall. (c) Recall status reports are to be discontinued when the recall is terminated by the Food and Drug Administration.

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Section 7.55

Termination of a recall

(a) A recall will be terminated when the Food and Drug Administration determines that all reasonable efforts have been made to remove or correct the product in accordance with the recall strategy, and when it is reasonable to assume that the product subject to the recall has been removed and proper disposition or correction has been made commensurate with the degree of hazard of the recalled product. Written notiﬁcation that a recall is terminated will be issued by the appropriate Food and Drug Administration district ofﬁce to the recalling ﬁrm. (b) A recalling ﬁrm may request termination of its recall by submitting a written request to the appropriate Food and Drug Administration district ofﬁce stating that the recall is effective in accordance with the criteria set forth in paragraph (a) of this section, and by accompanying the request with the most current recall status report and a description of the disposition of the recalled product. Section 7.59

General industry guidance

A recall can be disruptive of a ﬁrm’s operation and business, but there are several steps a prudent ﬁrm can take in advance to minimize this disruptive effect. Notwithstanding similar speciﬁc requirements for certain products in other parts of this chapter, the following is provided by the Food and Drug Administration as guidance for a ﬁrm’s consideration: (a) Prepare and maintain a current written contingency plan for use in initiating and effecting a recall in accordance with Sections 7.40 through 7.49, 7.53, and 7.55. (b) Use sufﬁcient coding of regulated products to make possible positive lot identiﬁcation and to facilitate effective recall of all violative lots. (c) Maintain such product distribution records as are necessary to facilitate location of products that are being recalled. Such records should be maintained for a period of time that exceeds the shelf life and expected use of the product and is at least the length of time speciﬁed in other applicable regulations concerning records retention.

Company Z Recall Company Z has had product problems, but the root cause of these product problems has never been effectively addressed. Employee turnover in the ﬁrm is at 37%. The document control system in the ﬁrm is nonexistent. The following are recent product problems and FDA issues experienced at Company Z: • • •

Product 123 has failed stability tests. Product 456 has failed potency tests for the sixth time this year. Product 789 has resulted in a lawsuit because the medical device disassembled and lodged in the sleeping patient’s mouth, and the patient swallowed a part of the device. The part had to be removed via surgery.

FDA Prior Inspections of Company Z • •

•

1991: FDA 483 issued for nonexistent stability program and lack of failure investigation and root cause analysis. 1993: FDA 483 issued for noncompliant stability program, retesting in violation of the United States v. Bar decision; potency proﬁles of ANDA and NDA products inconsistent with approved applications; ineffective recall of product. 1996: FDA 483 and warning letter issued because stability, potency, and strength of product did not comply with approved application.

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When the president of the company resigned, the new president found that another warning letter had been issued because the stability program was still ineffective. The new president, a former regulatory affairs professional, implemented plans to revamp the compliance program in coordination with the quality assurance department; however, past releases of drug product and medical devices were adulterated because of instability and potency problems. In 2003, the recall of products 123 and 456 and the dental drill device (product 789) were investigated, summarized as follows:

Company Z Product Recalls Lots Affected

123

1

Stability

Class 1

2

Potency

Class 1

3

Adulterated

Class 1

6

Adulterated

Class 1

A462

Adulterated

Class II

G452

Subpotent (distributed internationally)

Class II

981

Malfunctioned

Class III

542

Malfunctioned; subject of lawsuit

Class III

190

Missing instructions

Class III

456

789

Problem

Health Hazard

Product

Select teams for the following Company Z and FDA personnel: •

Company Z personnel Regulatory Affairs Quality Assurance Clinical Affairs Product Safety and Surveillance Information Systems Sales and Marketing Quality Control Medical Affairs Legal Affairs and Manufacturing

•

FDA personnel Center for Drug Evaluation and Research Center for Devices and Radiological Health Ofﬁce of Regulatory Affairs Ofﬁce of Criminal Investigation Ofﬁce of Division Compliance Management and Operations Medical Products Quality Assurance Health Hazard Committee District Personnel (Safety Ofﬁcer conducting inspections) District Recall Coordinator

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The assignment of the Company Z team is to prepare standard operating procedures for the manufacture and release of their products. The team must then follow the recall procedure developed to determine if the products discussed here should be recalled. If a product should be recalled, the team should prepare all documents to support information submitted to the public and to the FDA. The FDA team should review the Exhibits section of this chapter to determine their various responsibilities and to be sure that documents received from Company Z meet industry standards and the company’s internal policies and procedures to protect the public from unsafe products. The FDA team must then write an assessment of the effectiveness of Company Z’s recalls. Upon completion of this exercise, it is recommended that participants conduct a “lessons learned” meeting to review the processes, policies, procedures, events, and issues that were involved. At the least, recall participants should discuss their ﬁndings and lessons learned and should think about ways in which the industry and the FDA could improve the process.

ENDNOTES 22. Title 21 CFR 7.41(h). 23. Title 21 CFR 7.41(g). 24. Title 21 CFR 1.3(b): Label means container of any article; a requirement is made by or under authority of this Act that any word, statement, or other information appearing on the label shall not be considered to be complied with unless such word, statement, or other information also appears on the outside container or wrapper, if any there be, of the retail package of such article, or is easily legible through the outside container or wrapper. 25. Title 21 CFR 1.3(a): Labeling means all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article. 26. Title 21 CFR 7 et seq. 27. Federal Food, Drug, and Cosmetic Act of 1938, Section 201[321](b): The term interstate commerce means: (1) commerce between any State or Territory and any place outside thereof, and (2) commerce within the District of Columbia or within any other Territory not organized with a legislative body. 28. Ibid., at Section 501[351](a)(1). 29. Ibid., at Section 501[351](a)(2)(A). 30. Ibid., at Section 501[351](a)(2)(B). 31. Ibid., at Section 501[351](a)(3). 32. Ibid. at Section 501[351](a)(4)(A). 33. Ibid., at Section 501[351](a)(d)(1). 34. Ibid., at Section 501[351](a)(d)(1). 35. P.L. 102-282, Section 502[352] et seq. 36. Ibid. at Section 502[352](a). 37. Ibid. at Section 502[352](b). 38. Ibid. at Section 502[352](c). 39. Title 21 CFR 7.46. 40. Title 21 CFR 7.45. 41. Safe Medical Device Act of 1990, Pub. L. Section 520[360](j). 42. The National Childhood Vaccine Injury Act of 1986, The Public Health Service Act (PHS Act) 42 USC 262. 43. Title 21 CFR Part 1270. 44. Title 21 CFR 211.166 et seq. 45. Title 21 CFR 211.167 et seq. 46. Title 21 CFR 211.168 et seq. 47. Title 21 CFR 211.312 et seq. 48. Ibid. 49. Title 21 CFR 211.198 et seq. 50. Title 21 CFR 211.165, 170, 192, 204, 208; Title 21 CFR 820.90 et seq. 51. Title 21 CFR 210–211. et seq.

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52. Title 21 CFR 211.100; procedures are required to be current and updated annually. 53. See Exhibits section for copy of MedWatch FDA-3500a form used to report drug and medical device product problems. 54. Ibid. 55. Compliance Policy Guide Section 400.900 — Class I Recalls of Prescription Drugs (CPG 7132.01); DHHS–FDA Ofﬁce of Regulatory Affairs, Ofﬁce of Enforcement, Division of Compliance Policy August 1996. 56. Title 21 CFR 7.3. 57. Ibid. 58. Ibid. 59. Title 21 CFR 7.53. 60. Meadows, M., Why drugs get pulled off the market, FDA Consumer, January–February, 2002. 61. http://www.fda.gov/cder/graphics/recalls.gif. 62. Ibid. 63. Ibid. 64. http://www.fda.gov/cder/Ofﬁces/CRMS/dqrs2002/sld016.htm. 65. http://www.fda.gov.cder/Ofﬁces/CRMS/dqrs2002/sld002.htm. 66. Ibid. 67. http://www.fda.gov/cder/Ofﬁces/ODS/AnnRep2002/default.htm.

OTHER RESOURCES U.S. FEDERAL GOVERNMENT LAWS, REGULATIONS, AND GUIDES CONCERNING PROTECTION OF HUMAN SUBJECTS: JOURNAL ARTICLES Berg, J. W. 1996. Legal and ethical complexities of consent with cognitively impaired research subjects: Proposed guidelines. Journal of Law and Medical Ethics 24(1):18–35. Biros, M. H., R. J. Lewis, C. M. Olson, J. W. Runge, R. O. Cummins, and N. Fost. 1995. Informed consent in emergency research: Consensus statement from the Coalition Conference of Acute Resuscitation and Critical Care Researchers. JAMA 273(16):1283–1287. See comments in JAMA, 273(16), 1299–300, 1995; JAMA, 273(16), 1300–1302, 1995; JAMA, 274(15), 1196, 1995. Biros, M. H., J. W. Runge, R. J. Lewis, and C. Doherty. 1998. Emergency medicine and the development of the Food and Drug Administration’s ﬁnal rule on informed consent and waiver of informed consent in emergency research circumstances. Academy of Emergency Medicine 5(4):359–368. Centers for Disease Control and Prevention, Agency for Toxic Substances and Disease Registry. 1995. Policy on the inclusion of women and racial and ethnic minorities in externally awarded research; notice. Federal Register 60(179):47947–47951. de Jong, J., and N. Reatig. 1998. SAMHSA philosophy and statement of ethical principles. Ethics and Behavior 8(4):339–343. Food and Drug Administration. 1990. Informed consent for human drugs and biologics: Determination that informed consent is not feasible; interim rule and opportunity for public comment. Federal Register 55(246):52814–52817. Food and Drug Administration. 1993. Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs; notice. Federal Register 58(139):39406–39416. Food and Drug Administration. 1995. Protection of human subjects; informed consent; proposed rule. Federal Register 60(183):49086–49103. Food and Drug Administration. 1996a. Addendum to the “Points To Consider in Human Somatic Cell and Gene Therapy” (1991). Human Gene Therapy 7(9):1181–1190. Food and Drug Administration. 1996b. Protection of human subjects: Informed consent and waiver of informed consent requirements in certain emergency research; ﬁnal rules. Federal Register 61(192):51498–51531 Food and Drug Administration. 1998a. Information sheets: Guidance for institutional review boards and clinical investigators. Rockville, MD: U.S. Food and Drug Administration (available at http://www.fda.gov/oc/oha/IRB/toc.html).

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Food and Drug Administration. 1998b. Protection of human subjects: Categories of research that may be reviewed by the institutional review board (IRB) through an expedited review procedure. Federal Register 63(216);60353–60356. Government Printing Ofﬁce. 1998a. Institutional review boards, 21 CFR Section 56. Government Printing Ofﬁce. 1998b. Investigational device exemptions, 21 CFR Section 812. Government Printing Ofﬁce. 1998c. Investigational new drug application, 21 CFR Section 312. Government Printing Ofﬁce. 1998d. Protection of human subjects, 21 CFR Section 50. National Human Genome Research Institute. 1996. NHGRI–DOE guidance on human subjects issues in largescale DNA sequencing. Bethesda, MD: National Human Genome Research Institute (http://www.nhgri. nih.gov/Grant_info/Funding/Statements/RFA/human_subjects.html). National Human Genome Research Institute. 1998. The use of human subjects in large-scale DNA sequencing. Bethesda, MD: National Human Genome Research Institute (http://www.genome.gov/10000921). National Institutes of Health. 1990a. Recombinant DNA research: Actions under guidelines; notice: E. Points to consider for protocols for the transfer of recombinant DNA into the genome of human subjects. Federal Register 55(41):7443–7447. National Institutes of Health. 1990b. Recombinant DNA research: Actions under guidelines; notice. Federal Register 55(177):37565–37567. National Institutes of Health. 1996a. Recombinant DNA research: Notice of intent to propose amendments to the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) regarding enhanced mechanisms for NIH oversight of recombinant DNA activities. Federal Register 61(131):35774–35777. National Institutes of Health. 1996b. Waiver of informed consent requirements in certain emergency research. Federal Register 61(192):53531–53533. National Institutes of Health. 1996c. Recombinant DNA research: Proposed actions under the guidelines; notice. Federal Register 61(227):59726–59742. National Institutes of Health. 1997. Recombinant DNA research: Proposed actions under the guidelines; notice. Federal Register 62(31):7108–7123. Ofﬁce of Science and Technology Policy. 1991. Federal policy for the protection of human subjects; ﬁnal rule. Federal Register 56(117):28003–28023. Public Health Service. 1995. Action related to emergency research activity. Federal Register 60(143):38353–38354. Public Health Service. 1996. Draft Public Health Service guideline on infectious disease: Issues in xenotransplantation (August 1996); notice. Federal Register 61(185):49919–49932. Wilson, D. J. 1993. NIH guidelines for research involving recombinant DNA molecules. Accountability in Research 3(2–3):177–185.

U.S. FEDERAL GOVERNMENT LAWS, REGULATIONS, AND GUIDES CONCERNING PROTECTION OF HUMAN SUBJECTS: BOOKS Department of Energy (DOE). 1992. Protecting human research subjects at the Department of Energy: Human subjects handbook [loose-leaf]. Washington, D.C.: U.S. Department of Energy, Ofﬁce of Health and Environmental Research. Revised in 1996; see DOE (1996). Department of Energy (DOE). 1996. DOE human subjects research handbook: Protecting human research subjects [microﬁlm], 2nd ed. Washington, D.C.: U.S. Department of Energy, Ofﬁce of Health and Environmental Research. English A. 1995. State minor consent statutes: A summary. Cincinnati, OH: Children’s Hospital Medical Center, Division of Adolescent Medicine, National Center for Youth Law for the Center for Continuing Education in Adolescent Health, p. 7. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1979. The Belmont report: Ethical principles and guidelines for the protections of human subjects. Bethesda, MD: National Institutes of Health, Ofﬁce of Human Subjects Research, 8 pages (reprinted in numerous books and on Internet websites).

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3 Civil Actions Civil actions are legal actions that the Food and Drug Administration (FDA) takes against a ﬁrm. The civil actions discussed in this chapter are seizure and injunction. A specialized form of injunction, the consent decree, is also discussed. When the FDA initiates civil actions it is represented in court by the U.S. Department of Justice, and the federal district court system has jurisdiction over any and all FDA-initiated actions. These actions initially are heard at the federal district court level and can potentially reach the U.S. Supreme Court. Actions initiated by the FDA through its administrative authority are referred to as Administrative Enforcement, and the FDA also has the authority to seek both civil and criminal actions against an industry participant. The type of action that the FDA takes against an industry participant will depend on the degree of the conduct it seeks to stop: The more willful the conduct, the more likely either civil or criminal actions will be sought rather than administrative.

3.1 SEIZURE 3.1.1 STATUTORY AUTHORITY The FDA’s statutory authority to seize an industry participant’s regulated products is found in the Food, Drug, and Cosmetic Act of 1938 (FD&C Act) 21 USC 334. The FDA can initiate three types of seizure against an industry participant: lot, multiple, or mass. If either seizure type is initiated against an industry participant, further action over the regulated product may result in a court order of condemnation, destruction, claim of possession by the industry participant, libel, or forfeiture of the regulated goods seized.

3.1.2 JURISDICTION Jurisdiction to seize violative goods rests with the federal district court (FD&C Act, 21 USC 304 et seq.) or states through embargo. The FDA initiates the seizure by ﬁling a Complaint and Seizure Warrant with the court where the goods are located. State embargoes are requested only when there is assurance the seizure will be approved by the FDA or when speciﬁc FDA criteria have been met. In the case of counterfeit drugs and the equipment used to manufacture them, the FDA can seize the materials immediately and then ﬁle a complaint later (see 21 USC 334(a)(2) and 372(e)(5)). In the case of medical devices, 21 USC 334(g) provides for administrative detention of devices. Whenever possible, the FDA will use state embargoes instead of administrative detention because the latter approach may require a greater number of personnel.

3.1.3 PURPOSE

OF

SEIZURE

Seizure is a civil action that is intended to remove adulterated or misbranded goods from interstate commerce and accessibility to consumers. When violative goods are seized, they are taken into custody by a U.S. Marshal through in rem jurisdiction. Depending upon the quantity of goods

75

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seized, they may be either actually or constructively taken. If goods are actually taken into custody, they would be removed by the U.S. Marshal from the industry participant’s warehouse, location, and control. Goods constructively taken are separated from inventory, locked away, quarantined, or in some manner sequestered to ensure that the quantity of goods seized is not diverted while in the possession of the industry participant pending further FDA action. Before seizure, the industry participant involved is not entitled to a hearing until the FDA ﬁles a Complaint for Forfeiture, and the district courts may not review any matter until the complaint is ﬁled (Parke, Davis & Co. v. Califano, 564 F.2d 1200 (6th Cir. 1977)).

3.1.4 SEIZURES: LOT, MULTIPLE,

AND

MASS

Lot seizures generally involve one lot of product located in one location that is or has become adulterated or misbranded during interstate commerce. Multiple seizures involve more than one action to arrest goods located in different jurisdictions; these seizures are intended to prevent industry participants from shipping unapproved, adulterated, or misbranded regulated products manufactured at different facilities. Mass seizures involve a warehouse full of product manufactured at one location and deemed adulterated or misbranded.

3.1.5 DISPOSITION

OF

SEIZED (ARRESTED) GOODS

When the FDA seizes goods, the United States is named as plaintiff on the complaint ﬁled with the court, and the goods are named as the defendant. The intent of seizure is to prevent the true owner, who placed product into interstate commerce, from distributing or selling the goods regardless of the money invested to develop, ship, or sell the goods. When goods are seized, the arrested goods may be disposed of in one of ﬁve ways: • • • • •

Disposition of a seizure action by trial Consent decree permitting export Consent decree permitting reconditioning Consent decree ordering destruction Consent (default) decree of destruction

A seizure action by trial is a means used by the ﬁrm/claimant to respond to the claims made by the FDA that the product is violative. To argue against the seizure, the ﬁrm/claimant must prove that the product is not adulterated or misbranded within the meaning of the FD&C Act. To support its case, the FDA produces evidence gathered through facility inspections, such as the FDA 483 (Notice of Observations), warning letters, samples, laboratory results of the samples collected, expert testimony, and testimony of Compliance Ofﬁcers who conducted the inspections. To obtain a consent decree permitting export, the ﬁrm/claimant would have to prove that there was no reason to believe that the product was violative at its shipment, receipt in U.S. Customs, or release by U.S. Customs or that the imported product was adulterated or misbranded when received by the claimant. When the federal district court is satisﬁed that the import and export provisions of the FD&C Act are met, the goods may be released for exportation or destroyed. If products are released for exportation to another country, the ﬁrm must show that the goods are within speciﬁcations for the foreign country purchaser, no conﬂict with their laws exist, the goods are labeled outside the shipping package “FOR EXPORT ONLY,” and such goods will not be sold domestically.68 After entry of a decree of condemnation, the goods may be destroyed or sold as the court determines. If the goods are sold, the money collected (less legal fees, costs, and charges) is paid into the U.S. Treasury.69 A consent decree ordering destruction is generally ordered by the court if it is not economically or scientiﬁcally feasible to recondition seized goods. If the court decides to order destruction, the product must be destroyed as required by the National Environmental Policy Act (NEPA). If it is

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economical or scientiﬁcally feasible to do so, the seized goods may be reconditioned. The ﬁrm must take into consideration the cost of supervision by the FDA; the following rates are used to bill a ﬁrm during the recondition process: • • • • •

266% of General Service grade 11, step 4 (GS 11/4) (per-hour rate) Analytical time — 266% of General Service grade 12, step 4 (GS 12/4) (per-hour rate) Per diem — speciﬁc daily rates paid to employees (41 CFR 301); in high-cost areas, per diem is higher Travel — current rate per mile (plus tolls) Miscellaneous expenses — actual cost; all charges are multiples of 1 hour, disregarding fractions of less than 1/2 hour (e.g., 1 to 1 hour, 29 minutes: 1 hour charged; 1 hour, 30 minutes to 2 hours: 2 hours charged).70

The default decree of destruction is the last of the ﬁve methods for disposing of seized goods. This occurs when no one claims the goods and the court orders destruction. In this instance, the government and the U.S. Marshals Service bear the cost of proper destruction. Alternatively, the product may be donated to charitable organizations or may be given to animals if it will have no effect on the human population. When a default decree is entered, the article is disposed of by a U.S. Marshal. This disposal may take various forms: • •

•

•

Constructive destruction — The article is destroyed by using it for a constructive purpose, such as donating misbranded but wholesome food to charity. Sale — If the article may be legally sold, the U.S. Marshals Service may sell it to recover costs. Products in violation of current laws normally would not be offered for sale after seizure. Conversion — Human food may often be converted to animal food rather than destroyed. If conversion is the method of destruction chosen by the U.S. Marshal, the product is physically treated to prevent its diversion to human food. Unless a recent precedent for conversion of a product to animal food is on ﬁle, the Center for Veterinary Medicine must approve of the reconditioning process. Destruction — The article may be destroyed by burning, burial, or dumping. The method of destruction must be appropriate under NEPA, and the article must not be able to be retrieved.

Of the four possible dispositions of seized goods, it is the responsibility of the FDA district in the territory where the goods are located to monitor activity of the ﬁrm to ensure that proper conclusion of the seizure action occurs.

3.1.6 PENAL BOND After entry of a decree, a ﬁrm who claims the goods is required to post a penal bond. The bond paid to the court is usually twice the retail value of the goods seized. The purpose of the penal bond is to ensure that the claimant complies with the conditions of the decree and performs the reconditioning in a satisfactory manner according to the FDA. If the penal bond is too low, it may be proﬁtable for the claimant to sell the product without bringing it into compliance after securing release from the U.S. Marshal. Forfeiture of the entire penal bond can occur in two instances: (1) part of the seized goods disappears, or (2) the terms and conditions of the decree are not kept. If either occurs, the government may request the court to forfeiture the entire penal bond deposited with the court. If the FDA district ofﬁce is considering criminal charges against the decreed ﬁrm or when additional analysis of the product subject to condemnation is necessary, the FDA will obtain ample and adequate reserve samples for court use. For analytical testing purposes, the claimant may obtain samples with a court order (Figure 3.1).

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100

96

80 60

60

56 43

40

32

0

30

16

20 91

15

93

92

OC Approved

94

19 19

95

FDA Referred

FIGURE 3.1 Investigations.71

3.1.7 SEIZURE VIOLATIONS A ﬁrm whose product has been seized has several options: • • •

The ﬁrm may claim the product. The ﬁrm may choose not to claim the product, and the courts will enter a default decree and destroy or donate seized product. The ﬁrm may claim the product and seek to destroy or recondition it, if reconditioning is possible.

If the ﬁrm chooses to recondition the seized product and fails, this would be considered seizure violation. When a ﬁrm violates seizure, it subjects itself to either civil or criminal contempt charges for failure to abide by the agreed reconditioning order of the court. Seizure violations and contempt charges are discussed further in Section 3.2 of this chapter.

3.1.8 CASE STUDIES United States v. Chase Laboratories United States v. Parke Davis

SEIZURE EXHIBITS Following are examples of a complaint for forfeiture, seizure claim, answer, consent agreement, and bond used in federal district courts. Exhibit 3.1: Seizure Document Examples Item

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Title

Page

1

Complaint for Forfeiture

2

Seizure Claim

79 80

3

Seizure Answer

81

4

Seizure Consent Agreement

83

5

Seizure Bond

87

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Exhibit 3.2: Complaint for Forfeiture United States District Court ___________District of ________ ________Division United States of America ) ) No._________ Plaintiff, ) ) v. ) Honorable Magistrate____________________ ) Undetermined quantities ) of an article of drug, ) labeled in part: ) [name of drug] ) ) and ) ) All other prescription drugs ) Manufactured by [company name] ) ) Defendants. ) ___________________________x Complaint for Forfeiture To the Honorable Judge of the United States District Court for the ________________ District of ___________________. NOW COMES the United States of America by ________________United States Attorney for the ___________________ District of ___________________ and shows to the Court: 1. This complaint is ﬁled by the United States of America and requests seizure and condemnation of articles of drug, as described in the caption, in accordance with the Federal Food, Drug, and Cosmetic Act (the “Act”), 21 USC 301 et seq. 2. This Court has jurisdiction under 28 USC 1345 and 21 USC 334. 3. There are at [city, state] in the possession of [company name and address], or elsewhere within the jurisdiction of this Court, articles of drug as described in the caption, which articles were manufactured from components shipped in interstate commerce. 4. The articles of drug are adulterated while held for sale after shipment of one or more of their components in interstate commerce within the meaning of the Act, 21 USC 351(a)(2)(B), in that they are drugs and the methods used in, and the facilities and controls used for, their manufacture, processing, packing, and holding do not conform to and are not operated and administered in conformity with current good manufacturing practices to assure that such drugs meet the requirements of the Act as to safety and have the identity and strength and meet the quality and purity characteristics that they purport and are represented to possess.

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5. By reason of the foregoing, the articles are held illegally within the jurisdiction of this Court and are liable to seizure and condemnation. We request that process issue against the articles; that all persons having any interest in the articles be cited to appear herein and answer the allegations of the Complaint; that this Court decree the condemnation of the articles and grant plaintiff the costs of this proceeding against the claimant of the articles; that the articles be disposed of as this Court may direct pursuant to the provisions of the Act; and that plaintiff have such other and further relief as the case may require. Respectfully submitted, By:_________________________________ [Name] Assistant United States Attorney [Address, City, State, Zip Code] [Telephone number]

Exhibit 3.3: Seizure Claim United States District Court ___________District of ________ ________Division United States of America ) ) No._________ Plaintiff, ) ) v. ) Honorable Magistrate____________________ ) [Company/individual name] ) ) Defendants. ) ___________________________x Claim [Name of company] pursuant to the provisions of the Rule C(6) of the Supplemental Rules for Certain Admiralty and Maritime Claims of the Federal Rules of Civil Procedure, intervenes in this proceeding in its own interest as owner and claimant of the articles identiﬁed in the [date] United States Marshal’s Warrant of Seizure and Monition, attached as Exhibit “Z.” [Name of company] claims the articles, states its right to defend this action, states that it is the true and bona ﬁde sole owner of the articles, and states that no other person is the owner of these articles. [Name of individual] states that s/he is the [title] of [name of company], the owner of the goods, and is duly authorized to make this claim, demand restitution of the goods, and defend this action. WHEREFORE, [name of company] respectfully requests that this Court grant it the right to defend this action.

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Respectfully submitted, By:_________________________________ [Name] Attorneys for Claimant [Name of Company] State of _________________________) County of ________________________) I, [name of individual] being the [title] of [name of company] claimant in the above-entitled action, being just and duly sworn, say that I have read the foregoing claim and that it is true and correct. ____________________________________ [Name of individual] Subscribed and sworn to Before me this ___ day of ______________, 200__.

Exhibit 3.4: Seizure Answer United States District Court ___________District of ________ ________Division United States of America ) ) No._________ Plaintiff, ) ) v. ) Honorable Magistrate____________________ ) [Company/individual name] ) ) Defendants. ) ___________________________x

The claimant, [name of company], for its answer to the complaint for forfeiture, states: 1. This complaint is ﬁled by the United States of America and requests seizure and condemnation of articles of drug, as described in the caption, in accordance with the Federal Food, Drug, and Cosmetic Act (“Act”), 21 USC 301 et seq. ANSWER: The Claimant admits that the government seeks seizure and condemnation of articles of drug, but denies that the government is entitled to that relief.

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2. This Court has jurisdiction under 28 USC 334 and 21 USC 334. ANSWER: Admitted. 3. There are at [city, state, of company], in the possession of [name of company], [address of company], or elsewhere within the jurisdiction of this Court, articles of drug as described in the caption, which articles were manufactured from components shipped in interstate commerce. ANSWER: Admitted. 4. The articles of drug are adulterated while held for sale after shipment of one or more of their components in interstate commerce within the meaning of the Act, 21 USC 351(a)(2)(B), in that they are drugs and the methods used in, and the facilities and controls used for, their manufacture, processing, packing, and holding do not conform to and are not operated and administered in conformity with current good manufacturing practices to assure that such drugs meet the requirements of the Act as to safety and have the identity and strength and meet the quality and purity characteristics that they purport and are represented to possess. ANSWER: The claimant denies each and every allegation contained in paragraph 4 and demands strict proof thereof. 5. By reason of the foregoing, the articles are held illegally within the jurisdiction of this Court and are liable to seizure and condemnation. We request that process issue against the articles; that all persons having any interest in the articles be cited to appear herein and answer the allegations of the complaint, that this Court decree the condemnation of the articles and grant plaintiff the cost of this proceeding against the claimant of the articles; that the articles be disposed of as this Court may direct pursuant to the provisions of the act; and that plaintiff have such other and further relief as the case may require. ANSWER: Claimant denies each and every allegation contained in paragraph 5 and demands strict proof thereof. Respectfully submitted, ____________________________________ [Name of attorney] Attorneys for Claimant [Name of company]

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Exhibit 3.5: Seizure Consent Agreement United States District Court ___________District of ________ ________Division United States of America ) ) No._________ Plaintiff, ) ) v. ) Honorable Magistrate____________________ ) [Company/individual name] ) ) [list drugs] ) ) Defendants. ) ___________________________x Consent Agreement On [date of complaint], a Complaint for Forfeiture against the above-described articles was ﬁled in this Court on behalf of the United States of America by [name], United States Attorney, and [Name], Assistant United States Attorney, for this District. The Complaint alleges that the articles proceeded against are drugs which, while held for sale after shipment of one or more of their components in interstate commerce, are adulterated within the meaning of the Federal Food, Drug, and Cosmetic Act (the “Act”), 21 USC 351(a)(2)(B), in that the methods used in, and the facilities and controls used for, their manufacture, processing, packing, and holding do not conform to and are not operated and administered in conformity with, the current good manufacturing practice (CGMP) requirements prescribed at 21 CFR 210 and 211 to assure that such drugs meet the requirements of the Act as to safety and have the identity and strength and meet the quality and purity characteristics that they purport and are represented to possess. Pursuant to a warrant for arrest issued by this Court, the United States Marshal for this District seized said articles on [date of seizure]. Thereafter, [name of company] (Claimant), intervened and ﬁled a Claim to said articles and ﬁled an Answer to the Complaint. Claimant avers that it is the true and bona ﬁde owner of the seized articles of drug and that no other person has an interest in them or any of them. Further, Claimant agrees to indemnify and hold the plaintiff harmless should any person hereafter ﬁle or seek to ﬁle a claim to any of the seized articles and or seek to obtain any of said articles. Claimant now herewith enters into an agreement adjudging the articles under seizure to be adulterated within the meaning of Act 21 USC 351(a)(2)(B), as alleged in the complaint, and condemning such articles. Whereupon, the Court being fully advised in the premises, it is on motion of the parties hereto ORDERED, ADJUDGED, and DECREED, that the articles under seizure are drugs which, while held for sale after shipment of one or more of their components in interstate commerce, are adulterated within the meaning of 21 U.S.C 351(a)(2)(B), as alleged in the Complaint, and are therefore hereby condemned pursuant to 21 USC 334(a); and it is further

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ORDERED, ADJUDGED, and DECREED, pursuant to 21 USC 334(e), that the United States of America shall recover from the Claimant court costs, fees, storage costs, and other proper expenses, to wit, the sum of [insert $ amount] and such additional expenses as may hereinafter be incurred and taxed. Claimant having petitioned this Court that the articles identiﬁed in Exhibit No. [#] annexed to this Decree be released to it pursuant to 21 USC 334(d), for purposes of attempting to bring them into compliance with the Act by using them for research and testing purposes only, and the United States having agreed thereto, it is further I. ORDERED, ADJUDGED, and DECREED that the United States Marshal for this District shall release from his custody to the custody of the Claimant the articles identiﬁed in Exhibit No. [#], if Claimant demonstrates to the satisfaction of the U.S. Food and Drug Administration that these articles were prepared for research and testing purposes only, are kept and maintained by the Claimant for research and development purposes only, and are neither intended to be nor will be used for further human or animal use. Claimant shall maintain accurate, complete, and current records pertaining to the disposition of such articles. Upon request of an FDA representative at reasonable time, Claimant shall make such records available for inspection and copying, and it is further II. ORDERED, ADJUDGED, and DECREED that the United States Marshal for this District shall release the remaining articles under seizure from his custody to the custody of the Claimant for the purpose of attempting to bring said articles into compliance with the Federal Food, Drug, and Cosmetic Act if Claimant, within twenty (20) days from the date of this Decree: (a) pays in full the aforementioned court costs, fees, and storage and other proper expenses of the proceeding herein, and (b) executes and ﬁles with the Clerk of this Court a good and sufﬁcient penal bond in the amount of [insert $ amount; usually twice the value of the seized goods] approved by this Court, payable to the United States of America, and conditioned on the Claimant’s abiding by and performing all the terms and conditions of this Decree and of such further orders and decrees as may be entered in this proceeding, and it is further ORDERED, ADJUDGED and DECREED that: 1. After the ﬁling of the bond with this Court, the Claimant shall give written notice to the ______________ District Ofﬁce, U.S. Food and Drug Administration, Department of Health and Human Services [insert address], that the Claimant, at its own expense, is prepared to attempt to bring said articles into compliance with the Federal Food, Drug, and Cosmetic Act under supervision of a duly authorized FDA representative. The written notice shall include the proposed plan for bring the articles into compliance. This plan shall include provisions to bring said articles and the facility at which said articles were manufactured into substantial compliance with all deviations from the CGMP regulations addressed in the most recent FDA 483 issued to the Claimant including, but not limited to, the deviations related to process validation and inadequately trained employees. The plan shall also include provisions for full compendia testing of all products by an independent laboratory and providing adequate assurances that none of the articles is adulterated with [material noted and found on FDA 483]. 2. The Claimant shall at all times, until said articles have been released by the FDA representative, retain intact the entire lot of goods comprising said articles for examination or inspection by the FDA representatives and shall maintain the records or other proof necessary to establish the identity of said lot to the satisfaction of said representative. 3. The Claimant shall not commence attempting to bring said articles into compliance until it has received written authorization to do so from the FDA representative. Such written authorization shall not be unreasonably delayed or withheld with each submitted plan. The submitted plan shall be approved, modiﬁed, or rejected within 14 calendar days of submission by the Claimant.

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4. The Claimant shall at no time and under no circumstances whatsoever ship, sell, offer for sale, or otherwise dispose of any of said articles until the FDA representative has had free access thereto in order to take any samples or make any tests or examinations that are deemed necessary, and said duly authorized representative has in writing releases for such articles for shipment, sale, or other disposition. Such sampling and testing, if desired by the FDA, shall not be unreasonably delayed, and written release shall not be unreasonably delayed or withheld. Notwithstanding paragraph II.2 of this Decree, the FDA agrees to selectively provide written release product by product or batch by batch as soon as all reconditioning requirements for a batch or product are completed. 5. Within ninety (90) days of the ﬁling of the bond, Claimant shall complete its attempt to bring said articles into compliance under the supervision of a FDA representative. 6. The Claimant shall abide by the written decisions of the FDA representative, which decisions shall be ﬁnal. If Claimant breaches any conditions stated in this Decree, or in any subsequent decree or order in this proceeding, Claimant shall return said articles immediately to the United States Marshal for this District at Claimant’s expense for disposal at Claimant’s expense or shall otherwise dispose of said articles at Claimant’s expense, pursuant to an order of this Court. 7. The claimant shall not sell or dispose of said articles or any part of them in a manner contrary to the provisions of the Federal Food, Drug, and Cosmetic Act or any other Federal law, or the laws of any State or Territory (as deﬁned in said Act), in which they are sold or disposed of. 8. Claimant shall compensate the United States of America for the cost of supervision at the rate of [insert $ amount] per hour and fraction thereof per FDA representative for each hour actually employed in the supervision of the reconditioning process, as salary or wage; where laboratory work is necessary, at the rate of [insert $ amount] per hour and fraction thereof per person for such laboratory work; and where subsistence expenses are incurred, at a rate not to exceed [insert $ amount] per day per person for subsistence expenses. Claimant shall also compensate the United States of America for necessary traveling expenses and for any other necessary expense which may be incurred in connection with the supervisory responsibilities of the FDA. The FDA agrees to closely monitor such expenses and shall notify the Claimant in writing if such expenses were to exceed [insert $ amount]. 9. If requested by the FDA representative, Claimant shall furnish to said representative duplicate copies of invoices of sale of the released articles or shall furnish such other evidence of disposition as said representative may request. The FDA representative shall notify the Claimant, in writing, when the conditions of this Decree have been met. The United States Attorney for this District, on being advised by the FDA representative that the conditions of this Decree have been performed, shall transmit such information to the Clerk of this Court, whereupon the bond given in this proceeding shall be canceled and discharged; and it is further ORDERED, ADJUDGED, and DECREED that if the claimant does not avail itself of the opportunity to repossess the condemned articles in this manner aforesaid, the United States Marshal for this District shall retain custody of said articles pending the issuance of an order by this Court regarding their disposition at Claimant’s expense; and it is further III. ORDERED, ADJUDGED, and DECREED that Claimant shall cease manufacturing, processing, packing, labeling, holding, and distributing all prescription and over-the-counter drugs unless and until: A. Claimant demonstrates to the satisfaction of the FDA that the methods, facilities, and controls for manufacturing, processing, packing, labeling, and holding the drugs are established, operated, and administered in conformity with FDA’s CGMP regulations for ﬁnished pharmaceuticals, 21 CFR 210 and 211.

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B. Claimant demonstrates its CGMP compliance to the satisfaction of the FDA through the conduct of audits of all the claimant’s procedures, practices, and records or [name of defendant] certiﬁes to the FDA that the methods, facilities, and controls for manufacturing, processing, packing, labeling, and holding drugs are established, operated, and administered in conformity with 21 CFR 210 and 211, at which time the FDA will evaluate the certiﬁcation through inspections of the Claimant’s facility. The cost of such inspections shall be borne by the Claimant. If and when the FDA determines the Claimant has demonstrated its substantial CGMP compliance, the FDA shall promptly notify the Claimant in writing, and C. Anything above to the contrary notwithstanding, upon prior oral agreement by the __________ District Ofﬁce of the FDA, subsequently conﬁrmed by Claimant in writing, Claimant shall be permitted to commence the manufacture, processing, packing, labeling, and holding, but not shipment or distribution, of prescription and over-the-counter drugs at such time(s) as may be agreed between Claimant and the FDA’s __________ District Ofﬁce. It is expressly understood that this provision is included in this Agreement to facilitate the FDA inspection of Claimant’s facility contemplated in Article III at a time when the facility is partially in production. Lots manufactured pursuant to this paragraph may be shipped and or distributed in accordance with Claimant’s normal release procedures and requirements after the FDA has provided the written certiﬁcation of CGMP compliance contemplated in paragraph III.B; and it is further IV. ORDERED, ADJUDGED, and DECREED that following any notiﬁcation by the FDA to Claimant of the FDA’s determination that Claimant is in substantial CGMP compliance, Claimant shall not commit or perform or do or cause to be done, directly or indirectly, any of the following acts: a. Violating 21 USC 331(a) by introducing or delivering for introduction into interstate commerce any drugs that are adulterated within the meaning of 21 USC 351(a)(2)(B), including but not limited to any drugs as to which there is any failure to comply with any regulation in 21 CFR 210 and 211 or b. Violating 21 USC 331(k) by manufacturing, processing, packing, labeling, holding, or doing any other act with respect to drugs while they are held for sale after shipment of one or more of their components in interstate commerce, which act results in the drugs being adulterated within the meaning of 21 USC 351(a)(2)(B), including but not limited to any drugs as to which there is any failure to comply with any regulation in 21 CFR 210 and 211; it is further V. ORDERED, ADJUDGED, and DECREED that this Court expressly retains jurisdiction and issues such further decrees and orders as may be necessary to proper disposition of this proceeding, and that should the Claimant fail to abide by and perform all the terms and conditions of this decree or of such further order or decree as may be entered in this proceeding or of the bond, then said bond, on motion of the United States of America in this proceeding, shall be forfeited in its entirety and judgment entered thereon, and any articles remaining in the custody of the United States Marshal shall be forfeited and disposed of pursuant to further Order of this Court at Claimant’s expense. Dated this ____day of ______________, 200__ Signed by United States Attorney, Assistant United States Attorney, Claimant, and representative of company

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Exhibit 3.6: Seizure Bond United States District Court ___________District of ________ ________Division United States of America ) ) Civil No._______ Plaintiff, ) ) v. ) Honorable Magistrate____________________ ) [Company/individual name] ) ) Defendants. ) ___________________________x Bond KNOW ALL MEN BY THESE PRESENTS that _________________________ as Principal, and _________________________, a corporation duly organized under the laws of the State of _________________________, and having a place of business at _________________________, as Surety are held and ﬁrmly bound into the United States of American in the sum of _________________________ dollars ($__________), for payment of which to the United States of America they bind themselves, their representatives, successors, and assigns, jointly and severally, ﬁrmly by these presents. WHEREAS, on ______________, 200__, a decree was entered in the above-described proceeding, a copy of which Decree is hereto annexed, marked Exhibit “A” and made a part hereof: NOW, THEREFORE, the condition of this obligation is such that if the said Principal shall abide by and perform all the terms and conditions of said Decree and of such further Orders and Decrees as may be entered by the above-designated Court in this proceeding, then this obligation shall become null and void; otherwise, it shall remain in full force and effect. And the said Principal and Surety covenant and agree that, by entering into and furnishing this Bond, they submit themselves and each of them to the jurisdiction of the above-designated Court and irrevocably appoint the Clerk of said Court as their agent upon whom any papers affecting their liability on said Bond may be served, that their liability on and under said Bond may be enforced on motion made in and to said Court without the necessity of an independent action, and that said motion on notice thereof may be served on the said Clerk of said Court. Signed with out hands and seal this _____ day of ________________, 200__. ______________________________________ Principal By: ___________________________________ ___________________________________

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Surety by:________________________________ Attest: ___________________________ Secretary Bond Approved: _____________________________, ______________, 200__.

SUMMARY A. Statutory authority: The FDA has authority to seize product via FD&C Act, 21 USC 334. B. Jurisdiction: Jurisdiction to seize violative goods rests with the federal district court (FD&C Act, 21 USC 304). C. Purpose of seizures: Seizure is a civil action against the goods and is intended to remove adulterated or misbranded goods from interstate commerce. D. Lot, multiple, and mass seizures: Lot seizures involve one lot of product, multiple seizures involve the arrest of goods in different states or locations within a state, and mass seizures involve full warehouse arrest of violative products. E. Arrested goods disposition: When the FDA seizes products, the plaintiff is the United States of America and the goods are the defendant. Once goods are arrested, they may be destroyed. F. Seizure violation: Firms subject to seizure have several options regarding the disposition of those goods.

READING REFERENCE SECTION Read United States v. Chase Laboratories and United States v. Parke Davis. • • •

•

Read the FD&C Act seizure standards in Appendix 1. Identify the basis the FDA used to seize products from Chase Laboratories and Parke Davis. After reading each case, review the material read and document a clear and concise history of compliance issues each ﬁrm experienced. Building on knowledge gained thus far determine how each ﬁrm could have remedied the compliance issues found. After completing your case review and analysis, research current information on each ﬁrm. Using all available resources, determine if these ﬁrms have subsequently experienced compliance issues, and discuss what type of issues or problems each ﬁrm has experienced. Compare and contrast the areas of the federal regulation to which each company is subject and determine if any future potential seizures or other prohibited acts could be asserted against these ﬁrms today.

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DISCUSSION QUESTIONS Reference the FDA Administrative Procedures Act, 21 CFR 10 and 12 et seq. 1. Distinguish between the two FDA administrative standards and the application used to seize the products of Chase Laboratories and Parke Davis. 2. Identify the type of seizure applied to each instance; determine if a different seizure type could be used and explain why. 3. Based on the reading, determine what the history of compliance achievement was for each company before, during, and after the FDA seized the ﬁrms’ products. 4. Based on your ﬁndings in question 3, do you believe the FDA acted: • Correctly • Expeditiously • Too slowly 5. For each instance above, explain your answer using the FD&C Act, amendments thereto, and the Code of Federal Regulations as standards. 6. State what you would recommend for companies that conduct themselves as Chase Laboratories and Parke Davis did. 7. Identify other FDA Administrative Enforcement actions taken against both companies and the personnel and company ofﬁcials involved, if any. 8. Based on your ﬁndings, what other FDA Administrative Enforcement actions do you believe could or should have been taken against both companies, their employees, or others? 9. Do you believe the prior compliance notice to the two companies was adequate and fair? If not, why not? 10. Conduct research to ﬁnd out if either company is still in business. If they are, research their current compliance posture since the court decision by visiting the FDA website. If they are not in business, ﬁnd out what happened to them 10 years after the court decision. Record your ﬁndings for each of the 10 years. 11. If the company is in business, based on your research and your opinion, determine whether the company will achieve full compliance within the next 2 years. Explain in detail your reasoning.

3.2 INJUNCTIONS 3.2.1 STATUTORY AUTHORITY The FDA’s statutory authority to enjoin an industry participant through the federal courts is found in the FD&C Act, 21 USC 332. The FDA can initiate, through the Department of Justice, three types of injunctions: temporary restraining order,72 preliminary injunction,73 and permanent injunction. All three injunction types are civil actions intended to stop the industry participant from continuing to place violative regulated product into interstate commerce. Depending upon the seriousness of the regulated product problem, the injunction can also be used as a means to correct the problem with the product through an FDA-supervised reconditioning of the product if feasible.

3.2.2 JURISDICTION Federal district courts take jurisdiction to enjoin industry participants who violate the Federal Food, Drug, and Cosmetic Act, Pub. L. No. 75-717, 52 Stat. 1040 (1938), as amended by 21 USC 301 et seq. (1988) through 302 of the Act and 21 USC 332. Generally, in nonfood and drug equity

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injunctions, action in federal courts is governed by Federal Rules of Civil Procedure, Rule 65. The private litigant seeking injunction would have to prove and overcome a four-prong test: (1) likelihood of success on the merits; (2) irreparable injury if the injunction is not granted; (3) if harm to one party would outweigh not granting it, when balancing the hardship equities between injunction and not enjoining; and (4) if no adequate remedy exists at law. When the FDA seeks injunction of an industry participant, overcoming the test is not required for the court to decide to enjoin. The FD&C Act speciﬁcally authorizes the federal courts to take jurisdiction and decide whether or not to issue an injunction by statute of the United States to enforce and implement congressional policy. This is decidedly different from weighing claims of two private litigants. The one factor the FDA and Department of Justice must prove is the possibility of future violation by the defendant if the defendant is not stopped. Because the FDA has collected evidence of the ﬁrm’s prior compliance practices, proving potential future violation or establishing the defendant as a repeat violator may be easily accomplished.

3.2.3 CIVIL ACTION PENALTIES

AND

FINES

The FD&C Act and amendments thereto carry the civil action penalties and ﬁnes assessed violators; ﬁve of the amendments enforced by the DHHS/FDA carry civil action penalties and ﬁnes to be paid by the ﬁrm and or individual(s) who have violated provisions of the law. If a ﬁrm or individual violates any of these laws, resulting in injunction, then the industry participant may also be subject to the following statutory civil penalties and ﬁnes: •

•

•

•

The Mammography Quality Standards Act of 199274 provided that the Secretary may assess civil money penalties in an amount not to exceed $10,000 for failure to obtain a certiﬁcate as required by this law; for each failure by a facility to substantially comply with or each day on which a facility fails to substantially comply with the standards established or the requirements described in this law; for each failure to notify a patient of risk and each violation; or for each aiding and abetting in a violation of, any provision of, or regulation promulgated under, this section by an owner, operator, or any employee of a facility required to have a certiﬁcate. The Safe Medical Devices Act (SMDA)75 of 1990 gave the FDA authority to impose administrative civil penalties for violation of the FD&C Act. The FDA may impose a penalty of up to $15,000 for a single violation and up to $1,000,000 for all violations adjudicated in a single action. In determining the amount of the penalty, the FDA may consider the seriousness of the violation, the violator’s ability to pay, any history of prior violations, the effect of the penalty on the violator’s ability to continue business, and other concerns relevant to the case.76 The Prescription Drug Marketing Act of 198777 applies to sample drug distribution and failure to make reports about distributions. A penalty as high as $1,000,000 may be imposed for the illegal sale of drug samples and failure to make certain reports. The National Childhood Vaccine Safety (NCVS) Act of 198678 provides for violation of biological product recall, recordkeeping, and reporting requirements. Reportable events under this Act are shown in Table 3.1. Any vaccine manufacturer who intentionally destroys, alters, falsiﬁes, or conceals any record or report required under this law is in violation of the NCVS Act and will be (1) subject to a civil penalty of up to $100,000 per occurrence, or (2) ﬁned $50,000 or imprisoned for not more than 1 year, or both. Such penalty shall apply to the person who intentionally destroyed, altered, falsiﬁed, or concealed such record or report; to the person who directed that such record or report be destroyed, altered, falsiﬁed, or concealed; and to the vaccine manufacturer for which such person is an agent, employee, or representative. Each act of destruction, alteration, falsiﬁcation, or concealment is treated as a separate occurrence.79

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TABLE 3.1 Table of Reportable Events Following Vaccination Vaccine/Toxoid Tetanus in any combination: DTaP, DTP, DTP–HiB, DT, Td, TT

Pertussis in any combination: DTaP, DTP-HiB, P

Measles, mumps, and rubella in any combination: MMR, MR, R

Rubella in any combination: MMR, MR, R

Inactivated polio (IPV)

Hepatitis B

Hemophilus inﬂuenzae type b (polysaccharide)

Event

Onset Interval

Anaphylaxis or anaphylactic shock

7 days

Brachial neuritis

28 days

Any sequela (including death) of above events

No limit

Events described in manufacturer’s package insert as contraindications to additional doses of vaccine

See package insert

Anaphylaxis or anaphylactic shock

7 days

Encephalopathy (or encephalitis)

7 days

Any sequela (including death) of above events

No limit

Events described in manufacturer’s package insert as contraindications to additional doses of vaccine

See package insert

Anaphylaxis or anaphylactic shock

7 days

Encephalopathy (or encephalitis)

15 days

Any sequela (including death) of above events

No limit

Events described in manufacturer’s package insert as contraindications to additional doses of vaccine

See package insert

Chronic arthritis

42 days

Any sequela (including death) of above events

No limit

Events described in manufacturer’s package insert as contraindications to additional doses of vaccine

See package insert

Anaphylaxis or anaphylactic shock

7 days

Any sequela (including death) of above events

No limit

Events described in manufacturer’s package insert as contraindications to additional doses of vaccine

See package insert

Anaphylaxis or anaphylactic shock

7 days

Any sequela (including death) of above events

No limit

Events described in manufacturer’s package insert as contraindications to additional doses of vaccine

See package insert

Early-onset HIB disease

7 days

Any sequela (including death) of above events

No limit

Events described in manufacturer’s package insert as contraindications to additional doses of vaccine

See package insert

Hemophilus inﬂuenzae type b (conjugate)

Events described in manufacturer’s package insert as contraindications to additional doses of vaccine

See package insert

Varicella

Events described in manufacturer’s package insert as contraindications to additional doses of vaccine

See package insert

Rotavirus

Events described in manufacturer’s package insert as contraindications to additional doses of vaccine

See package insert

Pneumococcal conjugate

Events described in manufacturer’s package insert as contraindications to additional doses of vaccine

See package insert

Note: The Reportable Events Table (RET) reﬂects what is reportable by law (42 USC 300aa-25) to the Vaccine Adverse Event Reporting System (VAERS) including conditions found in the manufacturer’s package insert. In addition, individuals are encouraged to report any clinically signiﬁcant or unexpected events (even if uncertain as to whether or not the vaccine caused the event) for any vaccine, whether or not it is listed on the RET. Manufacturers are also required by regulation (21 CFR 600.80) to report to the VAERS program all adverse events made known to them for any vaccine.80

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TABLE 3.2 FD&C Act Penalties Section

Conduct

Penalty

303 [333]

(a)(1) Any person who violates a provision of Section 301 shall be

Imprisoned for not more than one year or ﬁned or both (imprisonment and ﬁned

Not more than $1000

Any person committing a violation after a conviction has become ﬁnal, or commits such a violation with the intent to defraud or mislead, such person shall be

Imprisoned for not more than three years, or both imprisoned and ﬁned

Or ﬁned not more than $10,000

Any manufacturer or distributor who violates section 301(t) because of a failure to make a report required by Section 503(d)(3)(E) shall be subject to

—

A civil penalty of not more than $100,000.

301(t)

•

Amount

Radiation Control for Health and Safety Act of 1968, Section (b)(1) of the amended act, states that any person who violates provisions of the law shall be subject to a civil penalty of not more than $1000. For purposes of this subsection, any such violation shall, with respect to each electronic product involved or with respect to each act or omission made unlawful under this law, constitute a separate violation, except that the maximum civil penalty imposed on any person under this subsection for any related series of violations shall not exceed $300,000.

Civil penalties imposed on a ﬁrm or individual are determined by the area of industry and the speciﬁc law violated. For instance, using these ﬁve laws as an example, drug manufacturers may be subject to civil penalties under the Prescription Drug Marketing Act of 1987, biologic manufacturers under the National Childhood Vaccine Safety Act of 1986, and medical device ﬁrms under the Safe Medical Device Act of 1990, Radiation Control for Human Safety Act of 1968, and Mammography Quality Standards of 1992. While the speciﬁc industries regulated by the FDA are liable for civil penalties under certain laws, all regulated ﬁrms, however, are subject to civil penalties via the FD&C Act generally. Two such civil penalty provisions under the Act are illustrated in Table 3.2. The discussion in Chapter 1 regarding the FD&C Act provides additional examples of civil penalties that may be assessed industry participants.

3.2.4 CONTEST INJUNCTION

OR

OPT

FOR

CONSENT DECREE

A ﬁrm is enjoined by a federal court decision; the next step for an enjoined entity may be to go to trial to contest enjoinment or to enter into a consent decree. Litigating, as compared to entering into a consent decree, is more expensive, time consuming, and potentially more harmful to a ﬁrm’s reputation. Firms or individuals subject to injunction are required to have had adequate prior notice of the prohibited conduct unless the problem is a ﬁrst-time event that presents emergency health risks requiring immediate action. The collection of prior compliance failures of a ﬁrm, the responsible individual named on the FDA 483 Notice of Observations, warning letters, and other correspondence will serve as evidence used by the FDA to factually document the ﬁrm’s past record or an individual’s past conduct. The weight of this evidence prompts most ﬁrms to choose consent decree rather than litigation; however, contesting the injunction via litigation is available to the industry defendant.

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16 14 12 10 8 6 4 2 0

14 11 7

7

6

7

6

4 2

91

92

93

OC Approved

94

1

95

FDA Referred

FIGURE 3.2 FDA-enjoined companies (FY91–FY95).

As industry participants, it is important to understand what can be enjoined. In short, anything that violates laws enforced by the FDA may be enjoined. Injunction is reserved for industry participants who after repeated citations have failed to correct conduct that is regulated by the FDA. The conduct that can be enjoined includes conduct that has been documented in previously issued FDA 483 Notice of Observations; in warning letters from the FDA resulting from facility inspections; in applications submitted for review or approval; or in approved marketed product submissions and responses from a ﬁrm’s senior management responsible for operations of the company. In short, what can be enjoined is any gross deviation from: • • •

Current good manufacturing practices, which may include any or all of 21 CFR 210 and 211 Good clinical practices, which may include any or all of 21 CFR 56, 58, or 312 Good laboratory practices, which may include any or all of 21 CFR 50

When enjoined, the FDA can require that the ﬁrm stop the manufacture, shipment, or sale of the product or recall all violative product shipped. Anyone involved in conduct prohibited by the FD&C Act can be enjoined. Between 1991 and 1995, the FDA enjoined 38 companies (see Figure 3.2).

3.2.5 CASE STUDY: SCHERING-PLOUGH CORPORATION PERMANENT INJUNCTION* United States of America, Plaintiff v. Schering-Plough Corporation, and Schering-Plough Products, LLC, corporations, and Richard J. Kogan, and Steven C. Chellevold, Individuals, Defendants Consent Decree of Permanent Injunction The United States of America, plaintiff, having ﬁled a Complaint for Injunction against ScheringPlough Corporation and Schering-Plough Products, LLC, a subsidiary of Schering-Plough Corporation; and Richard J. Kogan, Chief Executive Ofﬁcer and Chairman of the Board, Schering-Plough Corporation, and Steven C. Chellevold, Senior Vice President, Worldwide Technical Operations, * As ﬁled at 8:30 a.m., 5/20/02, William T. Walsh, Clerk C. 02-2397(JAP), and published on the FDA/CDER website (www.gov.fda/cder).

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Schering-Plough Corporation, and Vice President, Schering-Plough Products, LLC, individuals (hereinafter, collectively, “Defendants”), and Defendants having appeared and having consented to entry of this Decree, without contest, solely for the purpose of settling this case, without admitting or denying the allegations of the Complaint and disclaiming any liability in connection herewith, and before any testimony has been taken, and the United States of America having consented to this Decree: IT IS HEREBY ORDERED, ADJUDGED, AND DECREED as follows: 1. This Court has jurisdiction over the subject matter herein, and has personal jurisdiction over all parties to this action pursuant to 21 USC 332(a) and 28 USC 1331, 1337, and 1345. 2. Venue is proper in this District under 28 USC 1391(b) and (c). 3. The Complaint for Injunction states a cause of action against the Defendants under the Federal Food, Drug, and Cosmetic Act (“FDC Act”), 21 USC 301 et seq. 4. Except as provided in paragraph 7, Defendants, and each and all of their subsidiaries, ofﬁcers, agents, employees, representatives, successors, assigns, and attorneys, and those persons in active concert or participation with any of the Defendants, are permanently enjoined under 21 USC 332(a) from directly or indirectly doing or causing the manufacture, processing, packing, and distribution of any article of human or veterinary drug (as deﬁned by 21 USC 321(g) (hereinafter, collectively, “drug(s)”) at Defendants’ facilities located at 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, and 1011 Morris Avenue, Union, New Jersey 07083 (hereinafter, “New Jersey facilities”), and at State Road No. 686, Km 0.5, Manati, Puerto Rico 00674-0486, and State Road No. 183, Pridco Industrial Park, Las Piedras, Puerto Rico 00771 (hereinafter, “Puerto Rico facilities”), unless and until, for Defendants’ New Jersey and Puerto Rico facilities, Subparagraph (A) has been satisﬁed, for the Manati facility subparagraphs (B) to (E) have been satisﬁed, and for the Las Piedras and New Jersey facilities subparagraph (F) has been satisﬁed. New Jersey and Puerto Rico Facilities A. For Defendants’ New Jersey and Puerto Rico facilities, Defendants have selected and retained one or more expert consultants (hereinafter, “expert consultant(s)”) who are qualiﬁed by education, training, and experience to inspect and to determine whether the methods, procedures, and controls used to manufacture, process, pack, and hold drug(s) at Defendants’ New Jersey and Puerto Rico facilities are in compliance with the requirements of 21 USC 351(a)(2)(B), the current good manufacturing practice (“CGMP”) regulations set forth at 21 CFR 210 and 211, and 21 USC 355 (b)(1)(B) to (D). Each such expert consultant shall be retained at Defendants’ expense and shall be without personal or ﬁnancial ties (other than consulting agreements between the parties or indirect ownership of Schering-Plough Corporation or Schering-Plough Products, LLC, or their subsidiaries (e.g., through diversiﬁed mutual funds or pension funds) to Defendants, Defendants’ subsidiaries, or their immediate families. Manati Facility B. For Defendants’ Manati facility, Defendants have caused their expert consultant(s) to inspect the facility in accordance with the CGMP Protocol for the facility, concurred with in writing by FDA on March 6, 2002 (the “March 6 CGMP Protocol”), which identiﬁes speciﬁc systems and processes that FDA believes require review by the expert consultant(s) for compliance with CGMP. C. Defendants have caused their expert consultant(s) to concurrently provide to Defendants and FDA a ﬁnal detailed written report of all results of the expert consultant(s)’s evaluation of whether the Manati facility complies with all the requirements of the March 6 CGMP Protocol;

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D. (i) Defendants’ expert consultant(s) has found that the Manati facility is in compliance with the requirements of the March 6 CGMP Protocol; (ii) Defendants’ expert consultant(s) has certiﬁed such compliance in writing to Defendants; and (iii) Defendants have sent a copy of the written certiﬁcation to FDA. Defendants’ expert consultant(s) may certify the Manati facility in its entirety or on a building-by-building basis or it may certify the part(s) of the facility used to manufacture sterile drug(s) separately from the part(s) of the facility used to manufacture nonsterile drug(s), provided that, in the professional opinion of Defendants’ expert consultant(s), it is appropriate to do so. Beginning sixty (60) days after receipt of the expert consultant(s)’s written report submitted pursuant to paragraph 4(c), Defendants shall submit reports to FDA describing: (a) the status of the implementation of the corrective actions identiﬁed in the expert consultant(s)’s written report, and (b) the impact on current production and marketed drug(s) of the deﬁciencies noted in the expert consultant(s)’s written report. Defendants shall submit such status reports every 60 (sixty) days until the date of the ﬁrst yearly inspection of the Manati facility has commenced pursuant to paragraph 26. Defendants shall cause the expert consultant(s) conducting this ﬁrst yearly inspection of the Manati facility to take into account the expert consultant(s)’s initial report and the Defendants’ subsequent status reports; and E. The drug product(s) or active pharmaceutical ingredient(s) (hereinafter, “API(s)”) manufactured by Defendants at the Manati facility meets the requirements of clause (i) or (ii) or, in the case of the active pharmaceutical ingredients alclometasone dipropionate, netilmicin sulfate, and isepamicin sulfate, such API meets the requirements of clause (iii) of this subparagraph: i. FDA has received a written certiﬁcation from Defendants’ expert consultant(s) that the production equipment and processes that are used to manufacture the drug product(s) have been, respectively, qualiﬁed and validated, in accordance with paragraphs 9–13; or ii. FDA has received a ﬁnal written certiﬁcation by Defendants’ expert consultant(s) that: (a) a product quality review was performed in accordance with the product quality review protocol and the ﬁrst, second, and third addenda were concurred with in writing by FDA on February 14, 2002; April 25, 2002; May 15, 2002; and May 16, 2002 (the “product quality review protocol”), under which the review of a drug product(s) is sufﬁcient to cover its API(s); and (b) the manufacturing process is in control and produces a drug product(s) that consistently meets all applicable approved speciﬁcations described in the product quality review protocol through the labeled expiration period of the drug product(s); or iii. With respect to the APIs alclometasone dipropionate, netilmicin sulfate, and isepamicin sulfate, FDA has received a ﬁnal written certiﬁcation by Defendants’ expert consultant that: (a) a product quality review was performed in accordance with the product quality assessment protocol for the designated Manati active pharmaceutical ingredients concurred with in writing by FDA; and (b) the process for the API is in control and produces APIs that consistently meet approved speciﬁcations through retest or expiration date. Las Piedras and New Jersey Facilities F. The drug product(s) manufactured by Defendants at the Las Piedras and New Jersey facilities meets the requirements of either paragraph 4(E)(i) or 4(E)(ii). Puerto Rico and New Jersey Facilities 5. For Defendants’ Puerto Rico and New Jersey facilities: A. Within ninety (90) days of the entry of this Decree, Defendants shall submit to FDA: (i) a written comprehensive CGMP workplan for each of Defendants’ Puerto Rico and New Jersey facilities designed to ensure that the methods, facilities, and controls used to manufacture drug(s) at each of these facilities are and will be continuously maintained, in compliance with 21 USC 351(a)(2)(B),

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21 CFR 210 and 211, and 21 USC 355(b)(1)(B) to (D) (except for equipment qualiﬁcation and process validation, which are subject to paragraphs 9 to 13 rather than this paragraph); and (ii) a timetable for completion of each signiﬁcant step in the CGMP workplan for each facility. Defendants shall obtain written FDA concurrence of the CGMP workplans and timetables. The FDA shall respond to Defendants within sixty (60) days of the receipt of any CGMP workplan and timetable or revised CGMP workplan or timetable. B. Defendants shall promptly notify FDA in writing as and when Defendants complete each step identiﬁed in the CGMP workplans for which a deadline has been established in the timetables submitted to FDA pursuant to paragraph 5(A)(ii). C. Until Defendants’ expert consultant(s) has certiﬁed that the CGMP workplan described in paragraph 5(A) for a facility has been fully and satisfactorily completed, Defendants shall cause an expert consultant(s) to review each report of an investigation of an out-of-speciﬁcation (OOS) laboratory test result for a batch of any drug(s), and any Material Review Board (“MRB”) investigation (as deﬁned by Defendants), relating to the manufacture of any batch of any drug(s) at such facility, and shall cause the expert consultant(s) to certify in writing prior to the release of such batch whether Defendants’ investigation complies with the requirements of 21 CFR 211.192. Defendants may not release for distribution any batch of a drug(s) associated with an OOS laboratory test result or MRB investigation (as deﬁned by Defendants) until Defendants’ expert consultant(s) has certiﬁed in writing that the investigation complies with all requirements of the foregoing regulation. D. Defendants’ expert consultant(s) shall conduct monthly audits of Defendants’ log(s) of all variances to ensure that any variance(s) that may adversely affect the safety, identity, strength, quality, or purity of a batch of drug(s) has been investigated by Defendants’ MRB. If Defendants’ expert consultant(s) identiﬁes a variance that may adversely affect the safety, identity, strength, quality, or purity of a batch of drug(s) that has not been investigated by Defendants’ MRB, Defendants shall immediately designate the variance as requiring review by Defendants’ MRB, and the certiﬁcation requirements of this paragraph shall apply. E. After review by the MRB, if Defendants’ expert consultant(s) does not certify that Defendants’ investigation complied with all requirements of 21 CFR 211.192, and the batch has been released for distribution, Defendants shall immediately notify FDA in writing, and shall immediately recall the batch unless FDA determines in its sole and unreviewable discretion that a recall is not required. The requirements of this paragraph do not affect Defendants’ obligations to send product defect reports to FDA as required by 21 CFR 314.81 and 510.300, or to take any other action required by law or regulation. 6. Defendants represent that, as of the date of entry of this Decree, they have voluntarily discontinued manufacturing the following drug products at Defendants’ Puerto Rico and New Jersey facilities. Defendants shall not resume the manufacture of any of these drug products at their Puerto Rico or New Jersey facilities unless and until: (A) Defendants have fully and satisfactorily completed the CGMP workplan for the applicable facility as evidenced by certiﬁcation by Defendants’ expert consultant(s); (B) Defendants have provided FDA with thirty (30) days’ prior written notice of their intention to resume the manufacture of such drug products; and (C) the drug(s) meets the requirements of paragraphs 10 to 13 of this Decree.

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Product Aclovate cream, 15 gm, 45 gm, 60 gm Aclovate ointment, 15 gm, 45 gm, 60 gm A&D Personal Care Lotion Celestone tablets, 100s and 21s Coricidin night time tablets: Coricidin high blood pressure Coricidin night time cold/ﬂu tablets, 24s Correctol, 50 tablets, 24s Correctol caplets/bisacodyl: Correctol caplets, 30s Diprolene gel (samples), 18 × 1.8 gm Diprosone lotion, 20 ml and 60 ml Doral tablets (IVAX), 15 mg, and 7.5 mg, bulk Estinyl tablets: Estinyl, 0.02 mg, 100s Estinyl, 0.02 mg, 250s Estinyl, 0.05 mg, 100s Estinyl, 0.05 mg, 250s Etrafon tablets: Etrafon, 2/10 mg, 100s Etrafon, 2/10 mg, hospital unit dose Etrafon, 2/25 mg, 100s Etrafon, 2/25 mg, hospital unit dose Etrafon, 4/25 mg, 100s Etrafon, 4/25 mg, hospital unit dose Fulvicin P/G (griseofulvin) (human) tablets: Fulvicin P/G, 125 mg, 100s Fulvicin P/G, 165 mg, 100s Fulvicin P/G, 250 mg, 100s Fulvicin P/G 330 mg, 100s Griseofulvin P/G, 125 mg, 100s Gyne-Lotrimin 3-day combination pack (cream and inserts): Gyne-Lotrimin 3-day combination pack Gyne-Lotrimin 3-day combination pack, with electronic article surveillance tag Gyne-Lotrimin 3-day inserts: Gyne-Lotrimin 3-day inserts, 200 mg Gyne-Lotrimin 3-day inserts, 200 mg, with electronic article surveillance tag Gyne-Lotrimin 7-day insert Intron A, powder, 3 MIU, 1 ml/vial Lotrimin lotion: Lotrimin creamy lotion, 20 ml (OTC) Lotrimin lotion, 30 ml (human Rx) Lotrimin solution (human Rx), 10 ml bottle, 30 ml bottle Lotrisone cream (samples), 18 × 1.8 gm Metricorten tablets, 1 mg, 100s Metricorten tablets, 2.5 mg, 30s Miradon tablets, 50 mg, 100s Naqua tablets, 4 mg, 100s Optimine tablets, 1 mg, 100s Oreton methyl tablets, 10 mg, 100s Oreton methyl tablets, 10 mg, bulk Oreton methyl tablets, 25 mg, 100s

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Manufacturing Site New New New New New

Jersey Jersey Jersey Jersey Jersey

New New New New New New

Jersey Jersey Jersey Jersey Jersey Jersey

New Jersey

New Jersey

New Jersey New Jersey

New Jersey

New Jersey New Jersey New Jersey

New New New New New New New New

Jersey Jersey Jersey Jersey Jersey Jersey Jersey Jersey

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FDA Administrative Enforcement Manual Oreton methyl buccal tablets, 10 mg × 100s, 30s Permitil oral concentrate, 5 mg, 4 oz Permitil tablets: Permitil tablets, 2.5 mg, 100s Permitil tablets, 5 mg, 100s Permitil tablets, 10 mg, 1000s Polaramine tablets, 2 mg, 100s Polaramine Repetab tablets and cores, 4 mg, 100s; 6 mg, 100s Polaramine syrup, 16 oz Proglycem oral suspension, 30 ml Proventil Repetab tablets, 4 mg, 100s, 500s, Hospital Unit Dose, 18 × 2 samples Proventil syrup, 16 oz Proventil/Albuterol tablets: Proventil tablets, 2 mg, 100s Proventil tablets, 2 mg, 500s Proventil tablets, 4 mg, 100s Proventil tablets, 4 mg, 500s Albuterol tablets, 2 mg, 100s Albuterol tablets, 2 mg, 500s Albuterol tablets, 4 mg, 100s Albuterol tablets 4 mg, 500s Sodium sulamyd ophthalmic, solution and ointment: Solution, 10% 25 × 5 ml Solution, 10% 25 × 15 ml Solution, 30%, 15 ml Ointment, 1/8 oz Trilafon concentrate, 4 oz Trilafon tablets/Perphenazine: Perphenazine tablets, 2 mg, 100 Warrick Perphenazine tablets, 4 mg, 100 Warrick Perphenazine tablets, 8 mg, 100 Warrick Perphenazine tablets, 16 mg, 100 Warrick Trilafon tablets, 2 mg, 100s Trilafon tablets, 4 mg, 100s Trilafon tablets, 8 mg, 100s Trilafon tablets, 16 mg, 100s Valisone lotion, 20 ml and 60 ml Vancenase aqueous nasal spray, 42 mcg, 25 gm, pump Vanceril double strength aerosol, 12.2 gm, and convenience package, 3 × 5.4 gm Ventolin syrup (Proventil syrup): Ventolin syrup, 16 oz Ventolin syrup 72 × 1 oz Afrin allergy 4-hr nasal spray, 15 ml Afrin menthol saline nasal spray, 15 ml, 30 ml, 45 ml Afrin menthol saline nasal spray, 45 ml with coupon Azium IV solution Betasone aqueous suspension, 5 ml Celestone phosphate injection, 2.5 mg/3 ml Diprosone cream, 15 gm and 45 gm Diprosone ointment, 15 gm and 45 gm Garacin piglet injection, 250 ml, 250 ml Durvet Garamycin cream, 15 gm Garamycin ophthalmic ointment

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New Jersey New Jersey New Jersey

New Jersey New Jersey New Jersey New Jersey New Jersey New Jersey

New Jersey

New Jersey

New Jersey New Jersey

New Jersey New Jersey New Jersey New Jersey

Manati Manati Manati Manati Manati Manati Manati Manati Manati Manati

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Garamycin ophthalmic solution 3 mg/ml Garamycin topical ointment Gentocin sterile solution (injection): 100 mg, 100 ml, 250 ml 50 mg, 50 ml, 100 ml Lotrimin cream (human Rx) 15 gm, 30 gm and 45 gm Clotrimazole cream, 1%, 15 gm, 30 gm, 45 gm, 2 × 45 gm Metimyd ophthalmic ointment, 1/8 oz Metimyd ophthalmic suspension, 5 ml Netromycin injection solution/Netromycin disc: Netromycin injection, 10 × 1.5 ml Ocuclear ophthalmic solution, 30 ml Otobiotic otic solution, 15 ml Solganal suspension, 50 mg/ml Trilafon injection 5 mg, 1 ml Ampul × 100 Valisone cream: Valisone cream, 0.1%, 15 gm Valisone cream, 0.1% 45 gm Valisone cream, 0.1%, 110 gm Valisone cream, 0.1% 430 gm jar (government) Valisone cream, 0.01%, 15 gm Valisone cream, 0.01% 60 gm Valisone ointment, 15 gm, 45 gm, 110 gm Vancenase aqueous nasal spray, 84 mcg Normodyne/Labetalol tablets: Normodyne tablets, 100 mg, 100s Normodyne tablets, 100 mg, 500s Normodyne tablets, 100 mg, 1000s Normodyne tablets, 100 mg, hospital unit dose Normodyne tablets, 200 mg, 100s Normodyne tablets, 200 mg, 500s Normodyne tablets, 200 mg, 1000s Normodyne tablets, 200 mg, hospital unit dose Normodyne tablets, 300 mg, 100s Normodyne tablets, 300 mg, 500s Normodyne tablets, 300 mg, hospital unit dose Labetalol tablets, 100 mg, 100s Labetalol tablets, 100 mg, 500s Labetalol tablets, 100 mg, 1000s Labetalol tablets, 200 mg, 100s Labetalol tablets, 200 mg, 500s Labetalol tablets, 200 mg, 1000s Labetalol tablets, 300 mg, 100s Labetalol tablets, 300 mg, 500s Theo-Dur extended release tablets (Key Pharmaceuticals) (except for 100 mg and 200 mg bulk packages for shipment to Japan): 100 mg, 100s 100 mg, 500s 100 mg, 1000s 100 mg, 5000s 100 mg, hospital unit dose 200 mg, 100s 200 mg, 500s 200 mg, 1000s

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Manati Manati Manati

Manati Manati Manati Manati Manati Manati Manati Manati Manati

Manati Manati Las Piedras

Las Piedras

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200 mg, 5000s 200 mg, hospital unit dose 300 mg, 100s 300 mg, 500s 300 mg, 1000s 300 mg, 5000s 300 mg, hospital unit dose 450 mg, 100s 450 mg, hospital unit dose Theophylline extended release tablets 100 mg, 100s 100 mg, 500s 200 mg, 100s 200 mg, 500s 200 mg, 1000s 300 mg, 100s 300 mg, 500s 300 mg, 1000s 450 mg, 60s Institution 450 mg, 100s Uni-Dur/Frivent Theophylline: Uni-Dur extended release tablets 400 mg and 600 mg, 100s

Las Piedras

Las Piedras

Exclusions 7.A. Manufacturing, processing, packing, holding, and distributing the following drugs, all of which have been identiﬁed by FDA as being medically necessary, shall be exempt from the requirements of paragraphs 4(B)–(F): • • • • • • • • • • • •

Albuterol aerosol inhalers Rebetron Ribavarin capsules Celestone Soluspan injection Garamycin injection Hyperstat injection Normodyne injection Integrilin IV injection Ethamolin injection 5% Sterile bacteriostatic water for injection, USP containing 0.9% benzyl alcohol for use with Intron Sterile bacteriostatic water for injection, USP containing benzyl alcohol for use with Etanercept Sterile water for injection for use with Etanercept.

B. Manufacturing, processing, packing, holding, and distributing investigational new human and animal drugs at Defendants’ Las Piedras and New Jersey facilities shall be exempt from the requirements of paragraphs 4(E) and (F), 5(C)–5(E), and 9–13. Defendants may manufacture, process, pack, hold, and distribute no more than ﬁve (5) batches of Ampligen from its Manati facility for use in clinical trials. C. Manufacturing, processing, packing, holding, and distributing quantities of a drug(s) that is necessary to support or prepare an application, as deﬁned in paragraph 28, or to support the

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development of a nonprescription drug(s) subject to 21 CFR Part 330, shall be exempt from paragraphs 4, 5(C)–5(E), and 9–13. Such drug(s), however, shall not be commercially distributed unless the drug(s) otherwise complies with this Decree. D. Manufacturing, processing, packing, holding, and distributing a drug(s) for the sole purpose of conducting nonclinical laboratory studies or other research and testing that does not involve exposure of human subjects shall be exempt from the requirements of this Decree. E. Manufacturing, processing, packing, holding, and distributing a drug(s) for the purposes of performing qualiﬁcation of equipment, validation of drug(s) manufacturing processes, or conducting stability studies shall be exempt from paragraphs 4, 5(C)–5(E), 6, and 9–13. Except for a drug(s) approved by FDA after the date of entry of this Decree, as provided in paragraph 42, such drug(s) shall not be commercially distributed unless it meets the requirements of paragraph 4, and, when applicable, paragraph 5(C)–5(E). F. Assembling Intron Multidose Pen, Rebetron Pen, PEG-Intron Pen, and PEG-Rebetron Pen, and packaging, labeling, testing, releasing, holding, and distributing these and any other drug(s) (including, but not limited to, Intron and PEG-Intron, as single ingredient drug(s) or as components of Rebetron or PEG-Rebetron, respectively) at Defendants’ Puerto Rico and New Jersey facilities, provided that the drug(s) was not otherwise manufactured or processed at any of Defendants’ New Jersey and Puerto Rico facilities, are exempt from the requirements of paragraphs 4(E) and 4(F), 8(A), and 9–13. G. APIs manufactured, processed, packed, and held at Defendants’ New Jersey and Puerto Rico facilities, when used as components of a drug(s) manufactured by Defendants and when not commercially distributed as APIs, are exempt from the requirements of paragraphs 4(E) and 4(F). APIs used to manufacture a drug(s) listed in paragraph 7(A) are exempt from the requirements of paragraph 4(B)–(F). Notwithstanding the foregoing, Batch numbers 2-ALOX-6001 and 2-ALOX6002 of the API alclometasone dipropionate and Batch number 2-NLMN-6903 of the API netilmicin sulfate manufactured, processed, packed, held at, and distributed from, Defendants’ Manati facility, are exempt from the requirements of paragraph 4(E) and (F) provided they are distributed by Defendants prior to June 30, 2002. Defendants may continue to manufacture, process, pack, and hold additional batches of alclometasone dipropionate, netilmicin sulfate, and isepamicin sulfate, at Defendants’ own risk, but may not commercially distribute such batches unless the requirements of paragraph 4(E)(iii) or paragraphs 9–13 are satisﬁed. H. Manufacturing, processing, packing, holding, distributing for export, and exporting any drug(s) or biological product(s) in compliance with 21 USC 381(e) or 382 and 21 CFR 312.110, or 42 USC 262(h), as appropriate, or exporting any drug(s) that is eligible for commercial distribution in domestic commerce under the terms of this Decree or that is an export-only version of such a drug(s), are not prohibited by this Decree. 8.A. For each batch of the drug(s) listed in paragraph 7(A), the manufacture of which has commenced after the date of entry of this Decree, and that is not the subject of a validation certiﬁcation under paragraphs 9–13, Defendants’ expert consultant(s) shall, prior to release of a batch for distribution, complete a record review of the complete batch production and control record for each batch approved for release by Defendants and certify in writing whether, based upon the expert consultant(s)’s review (which shall, when applicable, rely in part upon a review and certiﬁcation of an OOS result or MRB investigation that was the subject of a review and certiﬁcation pursuant to paragraphs 5(C) or 5(D)), no deviations occurred during the manufacture of the batch that, in the expert consultant(s)’s professional opinion, would, during its labeled expiration period, adversely affect the safety, identity, strength, quality, or purity of the batch or cause the batch to fail to meet any and all applicable approved speciﬁcations established in its application. In the absence of such a written certiﬁcation, Defendants shall not distribute the batch. Defendants shall

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continue to have their expert consultant(s) perform the batch-by-batch reviews required by this paragraph for each drug(s) listed in paragraph 7(A) until FDA has received from Defendants a copy of Defendants’ expert consultant(s)’s ﬁnal written validation certiﬁcation for such drug(s) under paragraphs 11 or 13. The foregoing requirements shall not apply to the assembly of Rebetron but shall apply to all other manufacturing, processing, and control steps associated with the ribavirin component of Rebetron. B. FDA shall have the sole and unreviewable discretion to add any drug(s) to, and the discretion to delete any drug(s) from, paragraph 7(A), either on its own initiative, after consultation with Defendants, or after consideration of a written request from the Defendants. Defendants may not discontinue manufacturing and distributing any drug(s) listed in or added to paragraph 7(A), without FDA’s prior written approval unless the cessation of manufacture and distribution is not within Defendants’ control, the drug(s) is manufactured for another company under contract and the contract has expired, has been terminated or not renewed in accordance with the contract’s terms, or has been terminated or breached by the other party, and Defendants provide written notice to FDA within ﬁve (5) business days of such discontinuation, or Defendants have provided written notice to FDA at least twelve (12) months prior to discontinuing the manufacture or distribution of the drug(s). C. If any drug(s) listed in paragraph 7(A) is deemed by FDA, after consultation with Defendants, to be no longer medically necessary, FDA shall notify Defendants in writing. If this notiﬁcation occurs before the drug(s) has been certiﬁed to FDA as validated by Defendants’ expert consultant(s) (as described in paragraphs 9–13), Defendants shall immediately cease manufacturing the drug(s) unless and until the drug(s) meets the requirements of paragraphs 4(E) or 4(F), or unless FDA agrees, in its sole and unreviewable discretion, that Defendants may continue to manufacture the drug(s). If any drug(s) is added to paragraph 7(A) that has not yet been certiﬁed as validated in accordance with paragraphs 9–13, the batch-by-batch review and certiﬁcation requirements of subparagraph (A) of this paragraph shall apply. Additional Requirements 9.A. Defendants shall conduct and have certiﬁed by their expert consultant(s) adequate validation studies, conducted pursuant to paragraphs 10–13, for: (a) each drug product formulation, dosage form, strength, and packaging conﬁguration identiﬁed in the timetable and list (submitted to and concurred with by FDA on May 2, 2002) of drug(s) that they intend to distribute under paragraphs 4(E)(ii) and 7(A); and (b) each API(s) manufactured by Defendants at their New Jersey or Puerto Rico facilities and identiﬁed in the list and timetable that Defendants have agreed to, and shall, submit to FDA in writing for FDA concurrence within sixty (60) days after entry of this Decree. B. As and when Defendants have fully and successfully complied with the requirements of paragraphs 9(A) and 10–13 for a particular drug(s) or API(s), the certiﬁcation requirements of paragraphs 9(A) and 10–13 shall no longer apply to the drug(s) or API(s), unless FDA determines, after consultation with Defendants, that the certiﬁcation was not adequate. 10. In certifying the validation of a drug product(s) or API(s) under paragraphs 4(E)(i), 4(F) (excluding 4(E)(ii)), and 9–13, Defendants’ expert consultant(s) shall, using the criteria described in subparagraphs (A)–(E) of this paragraph, review the protocols and reports provided by Defendants, as well as any other information Defendants’ expert consultant(s) deems to be appropriate and necessary to evaluate the adequacy of Defendants’ validation protocols and reports: A. whether the process validation protocol clearly states how the validation study was to be conducted, including test parameters, relevant characteristics of the drug(s) or API(s), production equipment used, and decision points on what constitutes acceptable test results;

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B. whether the process validation protocol was adhered to during its execution (and if not, what deviations occurred and whether the deviations may have adversely affected the validation study); C. whether the drug(s) or API(s) is being manufactured in conformity with the equipment operating principles, analytical methods, and formulations described in the current chemistry, manufacturing, and control (CMC) section of FDA-approved application(s) or, if applicable, in the most recent submission to Defendants’ Drug Master File (DMF) for an API; D. whether the equipment used in the New Jersey and Puerto Rico facilities to manufacture the drug(s) or API, including equipment used to process components, ﬁll product, and in the case of sterile drug(s) also process containers and closures, is qualiﬁed and is of appropriate design for each of its intended uses. This analysis shall include whether adequate controls exist to ensure that such equipment is operating within speciﬁcations and are sufﬁcient to ensure the safety, identity, strength, quality, and purity of the drug(s) or API(s); and E. whether the results of the validation study show that the current process used to manufacture the drug product(s) or API(s) is validated and that, in Defendants’ expert consultant(s)’s professional opinion, there is reasonable assurance that the drug(s) or API(s) will consistently meet all applicable speciﬁcations established in its approved application(s) and, if applicable, Defendants’ DMF for an API, or, for a drug(s) or API(s) that does not require an FDA-approved application, that the drug(s) or API(s) meets all applicable speciﬁcations established in ofﬁcial compendia, applicable OTC monographs, and by Defendants, when the drug(s) or API(s) is manufactured pursuant to its validated process. 11. A. As the validation of each drug product(s) or API(s) listed in the timetables concurred with by FDA under paragraph 9(A) is completed, Defendants shall notify Defendants’ expert consultant(s). Defendants’ expert consultant(s) shall promptly determine whether the current production equipment and manufacturing processes used to manufacture the drug(s) or API(s) have been, respectively, qualiﬁed and validated in accordance with the requirements of paragraphs 9 and 10. If Defendants’ expert consultant(s) ﬁnds that the equipment qualiﬁcation and process validation for the drug(s) or API(s) is adequate, Defendants’ expert consultant(s) shall so certify in writing to Defendants. Defendants shall promptly provide FDA with a copy of the certiﬁcation. B. If Defendants’ expert consultant(s) is unable to certify that a manufacturing process validation or equipment qualiﬁcation for a particular drug product(s) or API(s) is adequate, Defendants’ expert consultant shall, contemporaneously, provide a complete and detailed written report to the Senior Vice President, Worldwide Quality, Schering-Plough Corporation, and to FDA, identifying all reasons and results found during the review that are the basis for not certifying the validation of the manufacturing process or qualiﬁcation of the equipment under review (hereinafter, “negative report”). If at any time Defendants become aware that they are or will be unable to validate a drug(s) or API(s) in accordance with paragraphs 9–13, Defendants shall promptly notify FDA in writing. 12. Within thirty (30) days of receiving a negative report, if any, Defendants shall send to FDA a written proposed plan to correct all deviations found by Defendants’ expert consultant(s) along with a proposed timetable to complete the corrections. The proposed timetable shall be subject to FDA concurrence in writing. FDA shall concur with or identify any objections it may have to the timetable in writing to Defendants within ﬁfteen (15) business days of its receipt. 13. After all of the ﬁndings identiﬁed by Defendants’ expert consultant(s) pursuant to paragraph 11 have been adequately corrected for a particular drug product(s) or API(s) to the satisfaction of Defendants’ expert consultant(s), Defendants’ expert consultant(s) shall provide Defendants with a written certiﬁcation that the production equipment and the manufacturing process currently used

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for the drug(s) or API(s) is qualiﬁed and validated, respectively, in accordance with paragraphs 9–12. Defendants shall promptly provide a copy of the written certiﬁcation to FDA. Product Recalls 14. Upon entry of this Decree, Defendants shall immediately recall all lots of Theophylline and Proventil Repetabs that are still within their labeled expiration periods from all of their United States wholesale consignees and all other United States direct consignees for destruction. Disgorgement and Other Monetary Provisions 15. Schering-Plough Corporation and Schering-Plough Products, LLC (the owner of the Puerto Rico facilities) agree to pay equitable disgorgement to the United States Treasury in the total amount of ﬁve hundred million dollars ($500,000,000.00), as follows: Schering-Plough Corporation agrees to pay one hundred seventy-ﬁve million dollars ($175,000,000.00) to the United States Treasury no later than ten (10) days after the date of entry of this Decree. Schering-Plough Products, LLC agrees to pay seventy-ﬁve million dollars ($75,000,000.00) to the United States Treasury no later than ten (10) days after the date of entry of this Decree. With respect to the remaining two hundred ﬁfty million dollars ($250,000,000.00), one hundred seventy-ﬁve million dollars ($175,000,000.00) shall be paid by Schering-Plough Corporation and seventy-ﬁve million dollars ($75,000,000.00) shall be paid by Schering-Plough Products, LLC, to the United States Treasury no later than three hundred sixty-ﬁve (365) days after the date of entry of this Decree. 16.A. In the event that FDA or Defendants’ expert consultant(s) determines that Defendants have failed to: (a) submit to FDA a CGMP workplan in accordance with the time frame speciﬁed in paragraph 5(A) or satisfactorily complete a step within a time frame established in such a CGMP workplan; (b) submit a drug(s) or API(s) validation timetable in accordance with the time frame speciﬁed in paragraph 9(A) or validate any drug(s) or API(s) within a time frame established in such timetable; (c) submit a proposed plan and timetable for required corrections in accordance with the time frame speciﬁed in paragraphs 12 or 18(D); or (d) submit a copy of the expert consultant(s)’s management report or inspection report in accordance with, respectively, paragraphs 23 and 25(D); and the Defendants are continuing to distribute drugs from the affected New Jersey and/or Puerto Rico facilities after the deadlines set forth above in this paragraph, FDA shall have the sole and unreviewable discretion to order Defendant Schering-Plough Corporation (for the New Jersey facilities) and Schering-Plough Products, LLC (for the Puerto Rico facilities) to pay to the United States Treasury a portion of the proceeds from the sales of such products in the amount of ﬁfteen thousand dollars ($15,000.00) for each business day that Defendants have failed to perform any of the acts described in clauses (a) through (d) of this subparagraph. B. Payments under this paragraph shall be assessed by FDA on a quarterly basis. Total payments incurred by the corporate Defendants for business days in the calendar year 2002 during which corporate Defendants failed to perform any of the acts described in clauses (a) through (d) of subparagraph 16(A), or incurred under this paragraph by reason of paragraph 17(C), 18(C), and/or 18(E), shall not exceed twenty-ﬁve million dollars ($25,000,000). Total payments incurred by the corporate Defendants for business days in the calendar years 2003, 2004, and 2005 for the failure to perform any of the acts described in clauses (a) through (d) of Subparagraph 16(A), or incurred under this paragraph by reason of paragraph 17(C), 18(C), and/or 18(E), shall not exceed ﬁfty million dollars ($50,000,000) in any one calendar year. No payments shall be incurred by the corporate Defendants under this paragraph for Defendants’ failure(s) to perform any of the acts described in clauses (a) through (d) of subparagraph 16(A), or incurred under this paragraph by reason of paragraph 17(C), 18(C), and/or 18(E), after calendar year 2005 except by mutual agreement of the parties. Although the corporate Defendants may incur only the foregoing maximum amounts in any calendar year, nothing shall prevent FDA from assessing, and corporate Defendants

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from being obligated to pay, more than the foregoing maximum amounts in any calendar year for payments incurred in any prior year(s) or in more than a single calendar year. Payments under this paragraph shall be due and owing thirty (30) days after the date of FDA’s order to Defendants. No payment shall be due or owing under this paragraph for the failure to validate any drug(s) or API(s), or for the failure to complete a CGMP workplan step for a drug(s) or API(s) that is not commercially distributed by Defendants. Total payments incurred by Defendants under this paragraph or made pursuant to this paragraph shall not exceed one hundred seventy-ﬁve million dollars ($175,000,000) in the aggregate. 17.A. If any drug(s) or API(s) that is scheduled to be validated under paragraph 9(A) has not been certiﬁed in writing by Defendants’ expert consultant(s) as having been validated as of the date on which the last validation in that timetable is scheduled to be completed (hereinafter, “last validation date”), payments under paragraph 16 shall stop on the last validation date, and FDA shall have the sole and unreviewable discretion to order Defendant Schering-Plough Corporation (for the New Jersey facilities), and Defendant Schering-Plough Products, LLC (for the Puerto Rico facilities) to pay the United States Treasury twenty-four and six-tenths percent (24.6%) of all net sales of each uncertiﬁed drug(s) and/or API(s), excluding any drug(s) or API(s) that complies with paragraph 7(H), accruing from the last validation date and continuing until such drug(s) and/or API(s) has been certiﬁed as validated by Defendants’ expert consultant(s). The amount(s) paid under this paragraph shall be determined by a Certiﬁed Public Accountant on a quarterly basis beginning ninety (90) days after the last validation date and ending on the date that the drug(s) or API(s) is certiﬁed by Defendants’ expert consultant. Defendants shall cause the Certiﬁed Public Accountant to send a determination to FDA in writing within forty-ﬁve (45) days of the end of each quarter. Payments under this paragraph shall be due and owing thirty (30) days after the date of FDA’s order to Defendants. No payment shall be due or owing with respect to any drug(s) or API(s) that is not commercially distributed by Defendants. B. The Certiﬁed Public Accountant shall: apply Generally Accepted Accounting Principles, be paid by Defendants, and be found acceptable to Defendants and FDA. Defendants shall cooperate in full with the accountant and shall provide all records reasonably requested by the accountant to make the determinations described in this paragraph. Defendants agree, in the event of a dispute with FDA over any determinations regarding the amounts due and owing under this paragraph, to provide all records reasonably requested, by the accountant or by FDA, to FDA. The accountant and FDA shall treat any such records as conﬁdential proprietary business records and shall not disclose them to any third party. C. Notwithstanding paragraphs 16 and subparagraph (A) of this paragraph, if Defendants’ expert consultant(s) has failed to certify, to FDA’s satisfaction, that a drug(s) and/or API(s) (excluding drug(s) listed in paragraph 7(A)) has been validated within six (6) calendar months of the date that the drug(s) or API(s) is scheduled to be validated in the applicable timetable, Defendants shall immediately upon the expiration of such six-month period cease manufacturing and distributing such drug(s) or API(s) until Defendants’ expert consultant(s) has certiﬁed to FDA’s satisfaction that the drug(s) or API(s) is validated. FDA may, in its sole and unreviewable discretion, agree that manufacture and distribution of a drug(s) or API(s) may continue after the foregoing six (6) month period subject to payments described in paragraph 16 or 17(A), as applicable, provided however that no payment shall be required with respect to a drug(s) listed in paragraph 7(A) upon expiration of the twelve (12) month notiﬁcation period to FDA described in paragraph 8(B), provided that Defendants have complied with paragraph 8(B). Any request by Defendants that FDA exercise its discretion to permit Defendants to continue manufacture and distribution of an uncertiﬁed drug(s) or API(s) must be in writing and must be received by FDA no later than sixty (60) days prior to the scheduled certiﬁcation date for the drug(s) or API(s) unless FDA agrees in writing to a shorter time period.

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D. Defendants Schering-Plough Corporation and Schering-Plough Products, LLC, shall be jointly and severally liable for any and all amounts due and owing under this Decree. E. Interest on the second payments described in paragraph 15 and on all other payments that are not made by Schering-Plough Corporation or Schering-Plough Products, LLC, within the time frames established in paragraphs 16 through 19 shall begin to accrue on the day following the date on which payment is due as established in paragraphs 15 through 19, at a rate equal to the weekly average one-year constant maturity Treasury yield, as published by the Board of Governors of the Federal Reserve System. 18. The remedies provided in paragraphs 15 through 17 shall be in addition to and not in lieu of any action(s) taken under this Decree. A. The parties shall make a good faith attempt to promptly identify and resolve any issue relating to this Decree, using written communication and, when appropriate, meetings, in order to facilitate compliance with this Decree. FDA and Defendants shall each designate a primary Decree administrator who shall be responsible for implementing this provision. B. For purposes of paragraphs 16 and 17, if Defendants’ expert consultant(s) certiﬁes in writing that a validation study has been satisfactorily completed and the validation study was completed on or before the date in the timetable(s) described in paragraph 9(A) or if Defendants notify FDA that a step identiﬁed in a CGMP workplan has been satisfactorily completed on or before the date in the CGMP workplan timetable described in paragraph 5(A), it shall, for the purposes of calculating payments under this Decree, be assumed that the validation study or CGMP workplan step was satisfactorily completed by the timetable date, unless and until FDA notiﬁes Defendants to the contrary under subparagraph (C) of this paragraph. C. If at any time Defendants’ expert consultant(s) or FDA notiﬁes Defendants in writing that a validation certiﬁcation of a drug(s) or API(s) was not completed by the scheduled date in the timetable submitted pursuant to paragraph 9(A), or that a validation certiﬁcation of a drug(s) or API(s) was not adequate, or that a CGMP workplan step was not satisfactorily completed by the applicable timetable date in the timetable submitted pursuant to paragraph 5(A), payment shall be due and owing as described in paragraph(s) 16 and/or 17, as applicable, for each drug(s) and/or API(s) and each CGMP workplan step, commencing on the date Defendants’ expert consultant or FDA notiﬁed Defendants of the failure to meet such scheduled date(s), whichever is earlier, and ending on and including (for validation studies) the completion date recertiﬁed to by Defendants’ expert consultant(s) or (for a CGMP workplan step) the date on which Defendants’ expert consultant certiﬁes that the step has been completed. This process shall continue, and payments under paragraphs 16 and/or 17, as applicable, shall continue until FDA agrees in writing that the drug(s) or API(s) has been satisfactorily validated and/or the CGMP workplan step(s) has been satisfactorily completed. D. When making any such determination(s), FDA shall identify in writing the speciﬁc deﬁciencies on which it is relying. Within thirty (30) days of receiving such notiﬁcation, Defendants shall submit to FDA a written plan and timetable to correct the speciﬁed deﬁciencies. The plan and timetable shall be subject to FDA’s written concurrence. FDA shall respond to the submission within thirty (30) days. E. If Defendants’ expert consultant(s) is unable to certify the validation of an API(s) or if FDA should ﬁnd that a certiﬁcation of an API(s) is not adequate, Defendants’ expert consultant shall determine whether any prior certiﬁcation by Defendants’ expert consultant(s) of any drug(s) that contained such API(s) as an ingredient is, in the expert consultant(s)’s professional opinion, no longer valid. If Defendants’ expert consultant(s) or FDA, either as an initial matter or after review of Defendants’ expert consultant(s) opinion, determines that the API(s) certiﬁcation is not adequate and that, as a result, the validation of the drug(s) containing the API(s) is not adequate, payments

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under paragraph 16 and/or 17, as applicable, shall be due and owing from the date that the drug(s) was certiﬁed as validated by Defendants’ expert consultant(s) and shall continue until the date that the drug(s) is certiﬁed by Defendants’ expert consultant(s). If more than six (6) calendar months have passed since the drug(s) (other than those drug(s) listed in paragraph 7(A)) was initially certiﬁed by Defendants’ expert consultant, Defendants shall immediately, upon notice from Defendants’ expert consultant(s) or written notice from FDA that a drug(s) certiﬁcation is not adequate, discontinue manufacturing the drug(s) unless FDA, in its sole and unreviewable discretion, invokes, in writing, the post-six (6) month payment provision described in paragraph 17(C). 19. Defendants Schering-Plough Corporation and Schering-Plough Products, LLC shall reimburse the United States Treasury within ten (10) days of the date of entry of this Decree for the costs of conducting and reporting FDA’s prior inspections of Defendants’ New Jersey and Puerto Rico facilities that followed FDA’s issuance of warning letters to the respective facilities, at the rates applicable at the time of the inspections. The total cost associated with conducting and reporting these inspections is four hundred seventy-one thousand ﬁve hundred dollars ($471,500.00). 20. All FDA orders to Defendants issued under paragraphs 16, 17, and 18 shall be signed by the Director, Ofﬁce of Compliance, Center for Drug Evaluation and Research. 21. The parties acknowledge that the payment(s) made under paragraphs 15 through 19, 34, and 35 are not a ﬁne, penalty, forfeiture, or payment in lieu thereof. Defendants do not admit any violation of the law that is or may be a ground for the imposition of any ﬁne, penalty, forfeiture, or payment in lieu thereof. Management Controls 22. Within sixty (60) days after the date of entry of this Decree and for a period of no less than thirty-six (36) months after the date of entry of this Decree, Defendants shall assign no fewer than four individuals reporting directly to the Senior Vice President, Worldwide Quality, Schering-Plough Corporation, who are qualiﬁed by education, training, and experience to perform the functions described in this paragraph, to provide full-time on-site coverage, at least one individual per site, at each of Defendants’ New Jersey and Puerto Rico facilities. These individuals shall have fulltime responsibility for monitoring whether employees in the New Jersey and Puerto Rico facilities are properly performing their functions and the facility and personnel are operating in compliance with the CGMP workplans, Defendants’ approved standard operating procedures (“SOPs”), 21 USC 351(a)(2)(B), 21 CFR Parts 210 and 211, 21 USC 355(b)(1)(B)–(D), and this Decree. Each month these individuals shall report ﬁndings in writing directly and concurrently to the Chief Executive Ofﬁcer, the Senior Vice President, Worldwide Quality, and the Senior Vice President, Technical Operations, Schering-Plough Corporation. The Chief Executive Ofﬁcer shall take the action necessary to ensure that all adverse ﬁndings included in these reports are promptly and appropriately addressed by the appropriate personnel in the relevant facilities. 23. Defendants shall retain an expert consultant(s) to prepare a detailed written report on the adequacy of management controls of the manufacturing and laboratory operations at Defendants’ New Jersey and Puerto Rico facilities. The report shall be delivered to the Chief Executive Ofﬁcer within one hundred twenty (120) days after the date of entry of this Decree. This written report shall: A. describe Defendants’ current organizational structure and the speciﬁc responsibilities of each of Defendants’ organizational units that are involved in manufacturing drug(s) and API(s) at Defendants’ New Jersey and Puerto Rico facilities; B. assess the role and personnel resources of Defendants’ quality assurance and quality control units at Defendants’ New Jersey and Puerto Rico facilities, including the units’ roles in detecting and correcting all deﬁciencies and noncompliance with the CGMP workplans, Defendants’ SOPs, 21 USC 351(a)(2)(B), 21 CFR Parts 210 and 211, 21 USC 355(b)(1)(B)–(D), and this Decree; and

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C. evaluate whether personnel responsible for directing and performing the manufacture and quality control of drug(s) at Defendants’ New Jersey and Puerto Rico facilities are adequate in number and qualiﬁcations (education, training, and experience, or a combination thereof) to ensure compliance with the CGMP Workplans, Defendants’ SOPs, 21 USC 351(a)(2)(B), 21 CFR Parts 210 and 211, 21 USC 355(b)(1)(B)–(D), and this Decree. 24. The Chief Executive Ofﬁcer, Schering-Plough Corporation, shall, within forty-ﬁve (45) days of receipt of the expert consultant(s)’s report under paragraph 22, submit to FDA a copy of the report together with a description of the actions Defendants propose to take in response to the report and a proposed timetable for completing those actions. The timetable shall be subject to FDA written concurrence. FDA shall provide its written response to Defendants within forty-ﬁve (45) days. Yearly Inspections by an Expert Consultant(s) 25.A. Defendants shall retain an expert consultant(s) to inspect Defendants’ New Jersey and Puerto Rico facilities, no less frequently than the schedule set forth in paragraph 26, to ensure that the methods, facilities, and controls used to manufacture drug(s) are designed to remain, in compliance with the CGMP workplans, Defendants’ SOPs, 21 USC 351(a)(2)(B), 21 CFR Parts 210 and 211, 21 USC 355(b)(1)(B)–(D), and this Decree. As part of these inspections, the expert consultant(s) shall assess the steps that Defendants have taken and need to take to ensure that Defendants’ New Jersey and Puerto Rico facilities are in compliance with the requirements described in the preceding sentence. B. Qualiﬁcation of equipment and validation of manufacturing processes shall be subject to paragraphs 9–13 rather than this paragraph, except that, after Defendants’ expert consultant has certiﬁed that the equipment used to manufacture a drug(s) or API(s) has been qualiﬁed and its manufacturing process has been validated in accordance with paragraphs 9–13, any and all subsequent qualiﬁcation of equipment and process validation of the drug(s) or API(s) shall be subject to this paragraph. C. Defendants’ expert consultant(s) shall prepare written reports of the inspections required by this paragraph that set forth their inspectional ﬁndings, the progress made by Defendants, and the state of compliance with the CGMP workplans, Defendants’ SOPs, 21 USC 351(a)(2)(B), 21 CFR Parts 210 and 211, 21 USC 355(b)(1)(B)–(D), and this Decree, and shall submit these reports to the Chief Executive Ofﬁcer, Schering-Plough Corporation, no later than forty-ﬁve (45) days after the date on which the inspection is completed. D. Within sixty (60) days of receiving a copy of the expert consultant(s)’s inspection report, the Chief Executive Ofﬁcer, Schering-Plough Corporation, shall submit to FDA a copy of that report, together with a description of the actions the Chief Executive Ofﬁcer proposes to take in response to the report, and a proposed timetable for completing those actions. The proposed timetable shall be subject to FDA concurrence. FDA shall concur with or reject the proposed timetable in writing within forty-ﬁve (45) days of receipt thereof. 26. The inspections required in paragraph 25 shall commence at Defendants’ Manati facility within six (6) months of the date of entry of this Decree. The inspections of Defendants’ Las Piedras and New Jersey facilities shall commence within six (6) calendar months of the date of FDA written concurrence with the CGMP workplan submitted to FDA pursuant to paragraph 5(A) for the applicable facility. These inspections shall thereafter be conducted at each of the four facilities no less frequently than once a year per facility for a period of no less than three (3) years from those dates, for a total of four (4) inspections at each of the four facilities. 27. Defendants may, for good cause shown in writing to FDA, no later than sixty (60) days prior to the expiration of a timetable concurred in by FDA pursuant to this Decree, unless FDA agrees in writing to a shorter time period, request FDA to concur with a reasonable revision of any timetable

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previously concurred with by FDA. FDA shall concur, or not concur, with such request, in writing, within thirty (30) days. To the extent that any timetable is revised in accordance with this paragraph, the revised timetable shall control for purposes of determining whether any payment(s) may be required under paragraph 16, 17, or 18, and for purposes of calculating the amount of such payment(s). General Provisions 28. For purposes of this Decree, unless stated otherwise, any reference to an “application” shall be construed to include a new drug(s) application (NDA), supplemental NDA, abbreviated NDA, supplemental abbreviated NDA, new animal drug(s) application (NADA), supplemental NADA, abbreviated NADA, supplemental abbreviated NADA, biologics license application (BLA), or supplemental BLA; and any reference to qualiﬁcation or validation shall be construed to include requaliﬁcation or revalidation, as applicable. 29.A. If at any time after this Decree has been entered, FDA determines that, with respect to Defendants’ New Jersey or Puerto Rico facilities, and with respect to any drug(s) or API(s) manufactured at Defendants’ New Jersey and Puerto Rico facilities, Defendants have failed to fully comply with or have violated 21 USC 351(a)(2)(B), 21 CFR Parts 210 and 211, or 21 USC 355(b)(1)(B) and (C), or any provision of this Decree; or that any report, plan, written procedure, or equipment qualiﬁcation, or drug(s) or API(s) validation study prepared or submitted by Defendants pursuant to this Decree, or any measure or action implemented by Defendants to comply with this Decree, is inadequate to fully comply with the foregoing statutory and regulatory provisions, or any provision of this Decree, FDA may (except with regard to timetables concurred with by FDA pursuant to this Decree, which shall be presumed, rebuttably, to be appropriate), as and when it deems necessary, after consultation with Defendants, order Defendants in writing to take appropriate corrective action(s) within speciﬁed time frames, including but not limited to, immediately taking one or more of the following actions with respect to any of Defendants’ New Jersey and Puerto Rico facilities or with respect to any drug(s) and/or API(s) manufactured at these facilities: i. revise, modify, or expand any report(s) or plan(s) prepared pursuant to this Decree; ii. submit additional reports or information to FDA; iii. submit any supplement to an existing application to FDA; iv. cease manufacturing, processing, packing, holding, and/or distributing any drug(s) and/or API(s); v. recall any drug(s) and/or API(s) as and when FDA deems necessary and in accordance with procedures identiﬁed by FDA; and/or vi. take any other corrective action(s) as FDA, in its discretion, deems necessary to bring any of Defendants’ Puerto Rico and New Jersey facilities and any of Defendants’ drug(s) and/or APIs that they manufacture at these facilities into compliance with the statutory and regulatory provisions described in this paragraph. B. Any order issued pursuant to this paragraph shall issue from either FDA’s New Jersey District Director or its San Juan District Director, as appropriate, and shall specify the deﬁciencies or violations giving rise to the order. 30. Unless a different time frame is speciﬁed by FDA in its order, within ten (10) business days after receiving an order pursuant to paragraph 29, Defendants shall notify FDA in writing that either: (1) Defendants are undertaking or have undertaken the action(s), in which event Defendants also shall describe the speciﬁc action(s) taken or proposed to be taken and a proposed schedule for completing the action; or (2) Defendants do not agree with FDA’s order. If Defendants notify FDA that they do not agree with FDA’s order, Defendants shall fully explain in writing the basis

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for their disagreement; in so doing, Defendants also may propose speciﬁc alternative actions and speciﬁc time frames for achieving FDA’s objectives. Defendants need not comply with the order until FDA has issued a ﬁnal decision pursuant to paragraph 31. 31. If FDA afﬁrms or modiﬁes its order, FDA shall identify in its order that it is FDA’s ﬁnal order. Defendants shall, upon receipt of FDA’s ﬁnal order, immediately implement the ﬁnal order. If Defendants so choose, they may bring the matter before this Court on an expedited basis; however, Defendants shall continue to diligently and in good faith implement FDA’s ﬁnal order, unless and until the Court issues an order to the contrary. 32. Consistent with this Decree, after Defendants send FDA a copy of Defendants’ expert consultant(s)’s certiﬁcation for Defendants’ Manati facility, or any part thereof, pursuant to paragraph 4(D), and from the date of entry of this Decree with respect to Defendants’ Las Piedras and New Jersey facilities, Defendants and each and all of their subsidiaries, ofﬁcers, agents, employees, representatives, successors, assigns, and attorneys, and those persons in active concert or participation with any of the Defendants shall, with respect to such facilities, be permanently enjoined under 21 USC 332(a) from directly or indirectly doing or causing any and all of the following: introducing or delivering for introduction into interstate commerce, in violation of 21 USC 331(a) or 331(d), any article of human or veterinary drug(s), as deﬁned by 21 USC 321(g), that is adulterated within the meaning of 21 USC 351(a)(2)(B) or is an unapproved new human or veterinary drug within the meaning of 21 USC 355 or 360b, respectively, and from adulterating any article of human or veterinary drug(s) while such drug(s) is held for sale after shipment of one or more of its components in interstate commerce, in violation of 21 USC 331(k). 33. All communications required to be sent by Defendants to FDA under this Decree shall be prominently marked “Decree Correspondence.” Those communications that pertain in whole or in part to the New Jersey facilities shall be sent to the Director, FDA New Jersey District Ofﬁce, HFR-CE300, 10 Waterview Boulevard, Parsippany, New Jersey 07054. Those communications that pertain in whole or in part to the Puerto Rico facilities shall be sent to the Director, FDA San Juan District Ofﬁce, HFR-SE500, 466 FDZ Juncos Avenue, San Juan, Puerto Rico 00901-3223. All notiﬁcations and other communication required to be sent by FDA to Defendants under this Decree shall be marked “Decree Correspondence” and shall be sent to Senior Vice President for GMP Compliance Task Force, Schering-Plough Corporation, K-1-4 Ex9, 2000 Galloping Hill Road, Kenilworth, New Jersey 07033. 34. Defendants shall reimburse FDA for the costs of all FDA inspections, examinations, analytical work, and review work that FDA deems necessary to evaluate Defendants’ compliance with any part of this Decree with respect to a drug(s) and API(s) manufactured at Defendants’ New Jersey and Puerto Rico facilities at the standard rates prevailing at the time the activities are accomplished. As of the date that this Decree is signed by the parties, these rates are: $65.14 per hour and fraction thereof per representative for inspection work, $78.07 per hour or fraction thereof per representative for analytical or review work, $0.345 per mile for travel expenses by automobile, government rate or the equivalent for travel by air, and the published government per diem rate or the equivalent for the areas in which the inspections are performed per day per representative for subsistence expenses, where necessary. FDA shall submit a reasonably detailed bill of costs to Defendants at the address speciﬁed in paragraph 33. In the event that the standard rates applicable to FDA supervision of court-ordered compliance are modiﬁed, these rates shall be increased or decreased without further order of the Court. 35.A. FDA shall be permitted to take, without prior notice and at any time, any and all actions necessary to ensure continuing compliance with the provisions of this Decree, including, but not limited to, conducting inspections of the New Jersey and Puerto Rico facilities, taking photographs, collecting samples of any drug(s), and copying records. Such inspections shall include, but not be

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limited to, any drug(s), API(s), and equipment therein, ﬁnished and unﬁnished materials, containers, labeling, records (including but not limited to all computer hardware and software, computer printouts, raw data, and laboratory data generated in connection with, and/or in support of, Defendants’ expert consultant(s)’s reports required by this Decree), ﬁles, papers, written procedures, and process controls. B. The costs of all such inspections, record reviews, and sample analyses shall be borne by Defendants at the rates speciﬁed in paragraph 34. The inspections described in this Decree shall be permitted upon presentation of a copy of this Decree and appropriate credentials. The inspection authority described in this paragraph shall be separate and apart from, and in addition to, statutory authority to make inspections under the FDC Act. 36. Within ﬁfteen (15) days after the date of entry of this Decree, Defendants shall deliver copies of this Decree to each of its ofﬁcers, those employees in a supervisory or managerial position, and all other persons who are in active concert or participation with Defendants with respect to the manufacture of drug(s) at each of the facilities located in New Jersey and Puerto Rico. Within thirty (30) days of the date of entry of this Decree, Defendants shall conduct a training session(s) for all supervisors and managers at Defendants’ Puerto Rico and New Jersey facilities who are involved in the manufacture of drug(s) to fully explain the terms and requirements of this Decree. Within ten (10) days after the date of entry of this Decree, Defendants shall prominently post a copy of this Decree in the employee common areas in the New Jersey and Puerto Rico facilities so that it is fully accessible to all employees who are involved in such activities. Defendants shall ensure that the Decree remains prominently posted in the employee common areas for a period of no less than thirty-six (36) months. If any person begins employment in a supervisory or managerial position at Defendants’ New Jersey or Puerto Rico facilities involving the activities described, at a time subsequent to the periods described Defendants shall, within ten (10) days of the commencement of such employment, deliver a copy of this Decree to such person and provide adequate training to the person regarding the terms and requirements of this Decree. 37. Within forty (40) days after the date of entry of this Decree, Defendants shall provide to the District Directors of the New Jersey and San Juan District Ofﬁces afﬁdavits stating the fact and manner of their compliance with paragraph 36, identifying the names and positions of all persons receiving copies of the Decree pursuant to the ﬁrst sentence of paragraph 36 and all supervisors and managers to whom training on the terms and requirements of this Decree was provided. Thereafter, within ten (10) days of receiving a request from FDA for any information or documentation that FDA deems necessary to evaluate compliance with paragraph 36, Defendants shall provide such information or documentation to FDA. 38.A. Defendants shall notify FDA in writing within ten (10) business days of any decision to discontinue manufacturing any drug(s) or API(s) at the New Jersey or Puerto Rico facilities. However, drug(s) listed in paragraph 7(A) shall be subject to the notiﬁcation requirements described in that paragraph. B. Defendants shall notify FDA in writing at least ﬁfteen (15) business days before any of the following events, if the event may affect Defendants’ obligations arising out of this Decree: i. reorganization, bankruptcy, dissolution, or assignment or sale resulting in the emergence of a successor; ii. the creation or dissolution of subsidiaries; or iii. any other change of the corporate structure or function of Defendants. 39. Defendants shall serve a copy of this Decree on any prospective purchaser or assignee at least thirty (30) business days prior to such an assignment or change in ownership. Defendants shall

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furnish FDA with an afﬁdavit of compliance with this paragraph sworn to by the Chief Executive Ofﬁcer no later than ﬁfteen (15) business days prior to such assignment of change in ownership. 40. Whenever this Decree requires an expert consultant(s) to certify to a matter, and the expert consultant(s) is unable to make that certiﬁcation, the expert consultant(s) shall so notify Defendants and state the reasons therefor in writing. Defendants shall immediately send a copy of the expert consultant(s)’s written notiﬁcation to FDA. After Defendants have addressed the matters identiﬁed in the expert(s)’ notiﬁcation, the same expert consultant(s) shall determine whether the certiﬁcation can be made. This process shall continue until the certiﬁcation is made. 41. All destruction of any drug(s) pursuant to this Decree shall be conducted at Defendants’ expense and in a manner that complies with the requirements of the National Environmental Policy Act of 1969. 42. FDA review of Defendants’ new drug application(s) for any human drug(s) shall be in accordance with 21 USC 355(b)(4)(F). The process validation and equipment qualiﬁcation certiﬁcation requirements of paragraphs 4(E), 4(F), and 9–13 shall not apply to applications approved by FDA after the date of entry of this Decree. These requirements will be addressed by FDA in accordance with its new drug(s) pre-approval inspection program. 43. All decisions conferred upon FDA in this Decree shall be vested in the sole discretion of FDA. Defendants shall abide by the decisions of FDA, and FDA’s decision shall be ﬁnal. FDA’s decisions under this Decree shall be reviewed by this Court under the standard set forth in 5 USC 706(2)(A). Any matter brought before this Court shall be based exclusively on the written record before FDA at the time the decision was made. No discovery shall be taken by either party. 44. Defendants’ obligations under this Decree do not modify or absolve Defendants from any obligation to comply with the FDC Act and its regulations, any application, or any other federal statute or regulation. Nothing in this Decree shall affect FDA’s authority to suspend or revoke any of Defendants’ applications pursuant to 21 USC 355(e). 45. This Decree does not in any way limit any administrative, civil, or criminal action that may be deemed appropriate to be taken by any agency or department of the United States. 46. The obligations under this Decree of each individual named herein shall apply only to the extent of his authority, responsibilities, and conduct within Schering-Plough Corporation or any of its divisions, subsidiaries, or afﬁliates. 47. The execution and entry of this Decree shall not be construed by FDA to mean that Defendants are not responsible government contractors. Except as provided in this Decree, FDA has taken no action to prohibit distribution in United States or foreign commerce of any drug(s) or API(s) manufactured at Defendants’ New Jersey and Puerto Rico facilities. 48. All protocols, workplans, and timetables concurred with in writing by FDA shall be deemed to be incorporated by reference in this Decree and fully enforceable in the same manner as any other provision of this Decree. 49. If, during any ﬁve-year period after the date of entry of this Decree, FDA has not notiﬁed Defendants that there has been a signiﬁcant violation of FDA law and regulations or this Decree during such ﬁve year period, Defendants may petition the Court to dissolve this Decree, and FDA will not oppose the petition. 50. This Court shall retain jurisdiction over this action and the parties hereto for the purpose of enforcing and modifying this Decree and for the purpose of granting such additional relief as may be necessary and appropriate. If any Defendant violates this Decree and is found in civil or criminal contempt thereof, that Defendant shall, in addition to other remedies, reimburse the United States

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for its attorney’s fees, investigational expenses, and court costs relating to contempt proceedings related to that Defendant. This case is closed. Dated this _____ day of May, 2002. UNITED STATES DISTRICT JUDGE We hereby consent to the entry of this Decree: FOR DEFENDANTS: RICHARD J. KOGAN, on behalf of Schering-Plough Corporation and Schering-Plough Products, LLC PETER BARTON HUTT Covington & Burling 1201 Pennsylvania Avenue, NW Washington, D.C. 20004-2401 Attorney for Schering-Plough Corporation and Schering-Plough Products, LLC RICHARD J. KOGAN, in his individual capacity RICHARD KINGHAM Covington & Burling 1201 Pennsylvania Avenue, NW Washington, D.C. 20004-2401 Attorney for Mr. Kogan STEVEN C. CHELLEVOLD PETER O. SAFIR Kleinfeld, Kaplan and Becker 1140 Nineteenth Street, N.W. Washington, D.C. 20036-6601 Attorney for Mr. Chellevold FOR PLAINTIFF: ROBERT MCCALLUM Assistant Attorney General Civil Division U.S. Department of Justice GERALD C. KELL Senior Trial Counsel Ofﬁce of Consumer Litigation Civil Division U.S. Department of Justice P.O. Box 386 Washington, D.C. 20044 CHRISTOPHER J. CHRISTIE United States Attorney

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MICHAEL A. CHAGARES Assistant U.S. Attorney Chief, Civil Division 970 Broad Street, Suite 700 Newark, New Jersey 07102 Of Counsel: DANIEL E. TROY Chief Counsel ERIC M. BLUMBERG Deputy Chief Counsel for Litigation Food and Drug Administration 5600 Fishers Lane, Rm. 6-69 Rockville, Maryland 20857 CARL I. TURNER Associate Chief Counsel Food and Drug Administration 5600 Fishers Lane, Rm. 6-82 Rockville, Maryland 20857

When the FDA seeks an injunction, among its constitutional notice provisions is the requirement that the full names and addresses of the business and each individual to be enjoined are documented on the complaint caption. Placing the names and addresses of all parties in the complaint serves two purposes: (1) It facilitates serving the process personally to individuals at the place of business or at a residence,82 and (2) it gives the ﬁrm and individuals notice of a cause of action against them and the conduct that is prohibited. Once a ﬁrm or individual is enjoined, the FDA may seek “additional or concurrent action such as recall, publicity, multiple seizures, or embargo by cooperating with state ofﬁcials or criminal prosecution.”83 When the Department of Justice ﬁles a federal court injunction consent decree complaint, it is referred to as a complaint for forfeiture: In the United States District Court For the District of Maryland United States of America, Plaintiff, v. So many cartons, more or less, of an article of food labeled in part “____________________,” Defendant.

) ) ) ) ) ) ) ) ) ) )

No._______________

On _________, 19__, a Complaint for Forfeiture against the above-described article was ﬁled on behalf of the United States of America. The Complaint alleges that the article proceeded against

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is a food which was adulterated when introduced into and while in interstate commerce and is adulterated while held for sale after shipment in interstate commerce within the meaning of the Federal Food, Drug, and Cosmetic Act, 21 USC 342(a)(3) in that it consisted in part of a ﬁlthy substance by reason of the presence therein of insects. Pursuant to warrant for arrest in rem issued by this Court, the United States Marshal for this District seized the article on _________, 19__. It appearing that process was duly issued herein and returned according to law, that notice of the seizure of the above-described article was given according to law, and that no persons have appeared or interposed a claim before the return day named in the process; Now, therefore, on motion of ________________, United States Attorney for the District of Maryland, by _______________, Assistant United States Attorney, for a Default Decree of Condemnation and Destruction, the Court being fully advised of the premises, it is ORDERED, ADJUDGED, AND DECREED that the default of all persons be and the same are entered herein; and it is further: ORDERED, ADJUDGED, AND DECREED that the seized article is a food (or device, drug, etc.) which was adulterated (or misbranded) when introduced into interstate commerce (or while in interstate commerce, or is adulterated while held for sale after shipment in interstate commerce) within the meaning of 21 USC 342(a)(3), (or appropriate charge) in that it consists in part of a ﬁlthy substance by reason of the presence therein of insects [or enter appropriate statement] and is therefore hereby condemned and forfeited to the United States pursuant to 21 USC 334(a); and it is further: ORDERED, ADJUDGED, AND DECREED, pursuant to 21 USC 334(d), that the United States Marshal in and for the District of Maryland destroy the condemned article and make return to this Court. Destruction shall be in a manner that complies with the requirements of the National Environmental Policy Act of 1969. Dated this _____ day of _________, 19__. UNITED STATES DISTRICT JUDGE

3.2.6 CONSENT DECREE

AND ITS

RESOLUTION

Once a ﬁrm or individual is enjoined, a consent decree may be used for a ﬁrm to enter into an agreement with the Department of Justice and FDA to remedy a compliance issue. A consent decree is a negotiated agreement that a ﬁrm enters into after a federal district court ﬁnds that the evidence presented supports a ﬁnding that FD&C Act provisions were violated and there is a likelihood that, without intervention, the problems will continue. The agreement is a written and signed document explaining how the ﬁrm will resolve past violative conduct and is referred to as a consent decree of permanent injunction. The ﬁrm entering a consent decree of permanent injunction may be subject to prohibitory, mandatory actions and ﬁnes or penalties. 3.2.6.1 Prohibitory Actions Prohibitory actions are intended to stop the ﬁrm from its continued path of violation “until or unless” the stated actions are remedied. One such remedy could be to submit satisfactory proof to the FDA that it can manufacture product that is not adulterated or mislabeled and that the ﬁrm has corrected situations noted on the FDA 483 Notice of Observations, or in warning letters.

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3.2.6.2 Mandatory Actions Mandatory actions order the ﬁrm to take afﬁrmative action to remedy certain conditions. It may require it to hire an expert to certify the ﬁrm’s ability to manufacture product consistent with the FD&C Act; to modify the quality assurance function to allow it to operate independently; to develop an effective quality assurance/quality control function with trained, competent personnel; to conduct periodic audits of the quality assurance program to ensure that personnel are performing assigned quality control functions properly; to establish, implement, and adhere to adequate written procedures for the receipt, identiﬁcation, storage, handling, sampling, and examination or testing of raw materials and in-process and ﬁnished goods; and to establish, implement, and adhere to compliant methods, facilities, and controls for the manufacture, process, packing, and storing of drugs at plant facilities in conformance with current good manufacturing practice provisions (21 CFR 210 and 211). Labels and labeling review, approval, and control records prior to release of a batch must be established, implemented, and adhered to in a compliant manner consistent with 21 CFR 201 and 21 CFR 211 et seq. Also, personnel should receive the necessary training consistent with current good manufacturing practices, good clinical practices, and good laboratory practices and on a continuing basis to ensure that these functions are performed in a compliant manner. 3.2.6.3 Fines and Penalties Fines and penalties assessed ﬁrms or individuals entering into a consent decree may require payment periodically over the time it takes the ﬁrm to complete its consent-decreed workplan requirements. The ﬁnes and penalties are determined by the areas that were proved to be violated. To resolve consent decree conditions, the ﬁrm must show that it can operate in control; its ability to do so must be certiﬁed by an expert consultant and, when compliance is achieved, it must be maintained.

3.2.7 REQUIREMENTS AFTER

THE

CONSENT DECREE

As with preinjunction compliance requirements, the FDA has similar authority to reinspect ﬁrms after the consent decree. The post-consent decree is issued when the ﬁrm has reported workplan corrective action and has been successfully certiﬁed by an expert consultant. During reinspections, FDA Compliance Ofﬁcers rely heavily upon the reports, validations, and certiﬁcations attesting to the ability of the ﬁrm to make product free of previous compliance problems. The FDA expects that substantial compliance achieved after certiﬁcation is maintained for at least 3 years and beyond. When a ﬁrm fails to maintain substantial compliance, it regresses into a noncompliant state and fails to meet the terms and conditions of the consent degree. In such instances, various administrative, civil, and or criminal sanctions could be initiated against the ﬁrm by the FDA. For instance, the FDA can take the following actions: 1. Reinstatement of decree — Motion to petition the Court to reinstate the “unless and until” provisions of the existing decree, based on the fact that defendants regressed from an in-compliance state (as certiﬁed in formal notice) to an out-of-compliance state. The effect of this action is to again close the ﬁrm until corrections have been made and veriﬁed. If the decree allows for a recall, upon request by FDA, this, too, may be considered. 2. Seizure 3. Civil contempt — A civil contempt is an action to force compliance, requesting the court to impose a penalty upon the defendant for continued noncompliance. The penalty may be monetary or conﬁnement of individual defendant(s) for each day or for each violative act until the terms of the decree are met. 4. Criminal contempt — A criminal contempt action is not to coerce compliance but to punish prior behavior. The penalty does not depend upon future actions.

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5. Prosecution 6. Civil money penalties (e.g., medical devices) 7. Administrative sanctions, such as withdrawal of applications.85

3.2.8 BACKGROUND

FOR

CASE STUDY

The case study presented involves a consent-decreed company and is intended to: (1) show the dynamics of internal and external issues faced by these companies, (2) allow the reader to apply information provided in this chapter to a sample case to understand the effect of Administrative Enforcement provisions on industry participants, and (3) allow the reader to appreciate the effort exerted and required to resolve consent decree compliance issues. Understanding the dynamics of internal and external issues and how they interact is critical to determining whether or not existing management and personnel can work together to meet the court-ordered requirements and the company continues operation, successfully resolving the decreed issues and receiving back the performance or penal bond it deposited with the government. Regulatory affairs and quality assurance and control personnel are under extreme pressure to move the company toward full compliance. In some instances, internal pressures to become substantially compliant have existed before, during, and after being decreed. Whether or not regulatory affairs and quality assurance personnel belief that senior management will support a compliance program to overcome their problems will have a direct impact on the employee turnover rate in these particular departments. Alternatively, if senior management believes that the ﬁrm’s regulatory affairs and quality assurance personnel are ineffective, after an injunction decree personnel in these departments are likely to be replaced with new hires. Existing and newly hired regulatory affairs and quality assurance personnel in a decreed company are also under pressure to train the ﬁrm’s staff with regard to the prohibitory consent decree requirements and new ways of working in a compliant-controlled environment to avoid the past problems. This same group must communicate with long-term personnel in other departments who may have contributed to the situation that led to the company’s injunction. Additionally, regulatory affairs and quality assurance personnel must implement new processes and decreed workplan requirements with a sometimes resistant staff. External expert consultants generally required under mandatory consent decree provisions are hired by the ﬁrm to report, monitor, audit, and certify corrected processes to management and the FDA on a periodic basis. The consultants are for the most part judging the ability of the regulatory affairs and quality assurance staff’s performance and their ability to implement required compliance mandates. If a consultant cannot certify correction of a mandatory provision, the consultant must state why in written follow-up reports issued to the ﬁrm and the FDA. The inability to certify that problems have been corrected subjects the ﬁrm to additional ﬁnes and penalties. An inability to certify corrective actions that are generally assigned to regulatory assurance and quality assurance staffs to implement can further lower the morale of this group of employees. Consultants introduce another source of pressure on the company and its personnel because these entities are in a position to directly impact a decreed company’s ability to get back to the business of manufacturing products or conducting clinical trials. The expert’s decision affects whether or not a company will have to pay daily or periodic ﬁnes and penalties if workplan arrangements are not met and whether batchby-batch release of product can occur. Senior executive management responsible for paying the ﬁnes and penalties, expert consultant fees, and personnel salaries, as well as loss of proﬁts, are concerned about the ﬁnancial stability of the company and whether the investment will result in meeting the consent decree agreement. Shareholders are concerned about the value of their investments in the ﬁrm. The public who consumed the products manufactured by a consent-decreed company are concerned about whether they can continue to trust the product or should look for an alternative. The FDA may be concerned about the ability of the company to continue manufacturing other products without problems while it tends to correcting the issues addressed in the workplan.

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By focusing on the dynamics of a consent decree, the case studies discussed in this chapter explore the various possible agreements, ﬁnes, penalties, and solutions. (In Chapter 5, additional case studies are provided for other consent-decreed ﬁrms.) Each company faces different negotiated requirements. What must be resolved has been documented in past FDA 483 Notice of Observations, warning letters, and other correspondence from the FDA. It is important to understand that each company has a different set of regulatory issues to overcome to ensure that it operates within FD&C Act mandates and maintains and incrementally improves compliant processes. Examining the case study issues is best served by a program implementation case study structured analysis. By separating the issues into parts, the problems and glaring holes in a program are discovered before implementation either occurs or is completed. An introduction to this concept is provided before the reader begins to examine issues involving the review of an actual consent decree.

3.2.9 PROGRAM IMPLEMENTATION CASE STUDY A program implementation case study approach can be used to examine the issues faced by an enjoined company. Breaking down issues allows the reviewer to develop probable and/or suggested solutions to a complaint for permanent injunction without overlooking other interrelated parts neither highlighted nor mentioned in the injunction. The statements made herein have no import or relevance to any speciﬁc complaint for permanent injunction or its terms or conditions, directly or indirectly. This is purely an analytical approach for examining Administrative Enforcement and compliance provisions of the FDA. A program implementation case study analysis has two broad aspects: (1) overview of the problem, and (2) a hypothetical model solution. The ﬁrst part of the case study analysis includes six steps to examine in detail the Administrative Enforcement and compliance issues. The second part of the approach, for our purposes, suggests a solution based on the hypothetical set of facts presented in the case study. It is important to note that this approach is merely a suggestion; it is not the only approach that can be used and it is not intended for addressing speciﬁc issues of a particular company. The hypothetical solutions contained in this case study are based on hypothetical facts. To effectively resolve regulatory issues for any company using this process, it is imperative that actual facts, evidence, and situations be reviewed, discussed, and understood by educated, skilled, and competent regulatory affairs or quality assurance consultants or personnel who can recommend methods to resolve speciﬁc regulatory issues. The goal of this basic analytical approach is to obtain viable probable solutions to compliance problems by objectively examining the issues. 3.2.9.1 Overview of the Problem Provisions of the FD&C Act of 1938 and amendments thereto regulate industry participants’ business activities involving drugs and medical device products; the FDA is authorized through the Act to assert a claim for injunction against any ﬁrm or individual who violates the act by placing adulterated or misbranded goods into interstate commerce. The U.S. federal courts are authorized to take jurisdiction over actions in the name of the United States ﬁled by the U.S. Department of Justice (DOJ) on behalf of the FDA, which may enter a complaint for permanent injunction, resulting in the industry participant, DOJ, and FDA entering into a consent decree agreement. The purpose of a consent decree is to negotiate a plan that will enable an industry participant to correct acts the FD&C Act deﬁnes as prohibitive. While under a consent decree, the ﬁrm must refrain from continuing the prohibited conduct. The hypothetical drug company in our example is regulated by the FD&C Act, the Safe Medical Devices Act of 1990, Medical Device Quality Standards (MDQSs), and Title 21 CFR 210, 211, 820 et seq. The company’s combination drug/medical device asthmatic inhaler pump product has failed in the market due to problems with low potency and the dose-delivery system. The low potency is an adulterated product problem, and the failure of the inhalation dispensing pump to deliver full doses of product relates to MDQSs.

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3.2.9.2 Prior Notice Information The company received approval to market the combination product in 1996 from both the Center for Drug Evaluation and Research (CDER) and the Center for Devices and Radiological Health (CDRH). In 1998, the company’s raw material supplier closed, and choosing a new supplier of raw materials required new validation studies. A major manufacturing change report was sent to the FDA to give notice of the change and to obtain approval. The FDA approved the changes. In 2001, design changes were made to address product complaints made by healthcare administrators via the MedWatch system. Patients complained that they did not receive relief with one dose, so they took a small second dose which did relieve the asthmatic episode. Healthcare administrators also complained that the product did not properly dose patients in a hospital setting, and that 95% of patients required redosing to obtain a therapeutic effect. In 2002, a ﬁrm-initiated recall occurred, due to four deaths being associated with the product. The FDA had ordered two class I recalls in the preceding year. Yearly facility inspections from 1997 to 2001 had revealed OOS, potency, identity, and overall quality and manufacturing problems. The company had failed to submit annual product review reports and to report adverse events. The Division of Drug Marketing and Advertising issued a cease-and-desist order to the company for mislabeled ingredients, as the active ingredient was labeled as natural when it was actually synthetic. In 2002, an FDA 483 Notice of Observations, and a warning letter were issued. The company’s chief executive ofﬁcer (CEO) responded, agreeing to correct the problems. Later that same year, the CEO resigned and a new CEO was named; the senior executive for quality assurance also resigned and a new person was hired to ﬁll the position. Two years later, in 2004, a follow-up for cause inspection resulted in seizure and an injunction due to problems with CGMPs. 3.2.9.3 Analysis Problem Analysis Participants who voluntarily enter into the industry submit applications for approval and receive approval to market or distribute regulated product subject to the FD&C Act of 1938 and amendments thereto. Products manufactured or distributed are required to meet standards of the Act and compendia requirements of strength, purity, identity, and potency and must be packed, held, and stored in a facility absent objectionable conditions. Methods, processes, equipment, and facilities are required under Title 21 CFR 210, 211, and 820 to be qualiﬁed, calibrated, and validated to ensure that products are manufactured consistent with the Chemistry, Manufacturing, and Control sections of approved applications. If at any time in the manufacturing process a product’s strength, purity, identity, or potency is affected, Title 21 CFR 210, 211, and 820 and CGMPs require all noncomformances to be investigated and root cause analyses conducted to resolve a potential product problem before it is released into interstate commerce. Regulated product released into interstate commerce that has product problems may be subject to recall, and a ﬁrm or individual may be enjoined by the FDA consistent with the Act’s provisions. Industry participants may voluntarily suspend or be forced to stop manufacturing and distribution of product to allow an opportunity to investigate, review, and validate methods, processes, and equipment to correct the CGMP compliance problems. Problem Definition The problem deﬁnition for the industry is deﬁned in the FD&C Act of 1938, Chapter III, Prohibited Acts; the Safe Medical Device Act of 1990; and Title 21 CFR 200–820 et seq., Possible Solutions Develop, document, implement, train in, and adhere to compliant and incrementally improve compliant controlled processes.

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Selection of Solution The selection of possible solutions is dependent on the area of industry (in this case, drugs and medical devices) requiring compliance improvement (achieved, for example, through Administrative Enforcement, CGMPs, GCPs, GLPs, or advertising and promotional literature). Our hypothetical company studied and received approval to market a combination drug and medical device product. The product developed CGMP issues, resulting in the FDA seeking an injunction and potentially entering a complaint for permanent injunction. Recall that when the ﬁrm changed suppliers of its active ingredient raw material, major manufacturing change validation studies were conducted and a report was prepared, which was sent to the FDA and approved; however, postmarketing experience revealed problems with potency variation despite consistent raw material assays. In the years preceding approval, quality assurance had rejected two lots from the original supplier for dark specks. After the FDA ordered a recall of multiple lots, root cause analysis methods were established. An informal Material Review Board consisting of quality assurance personnel investigated all incidents reported, but the board failed to close its investigation and summarize its ﬁndings in a timely manner. When an informal inspection of the supplier’s facilities prompted by the rejected active raw material occurred, the drug company’s auditors discovered that water for injection (WFI) monitoring, facility cleaning, and change-over procedures were not compliant. The supplier’s quality assurance manager informed auditors that lots of the same active ingredient were manufactured using dedicated equipment, but some lots had been returned from other customers for the dark specks. To solve the problem, our company had several options to consider: • •

•

Formalize a supplier audit and develop a supplier–vendor certiﬁcation program for documented procedures. Expand Material Review Board participation and responsibility and document formal policies and procedures, being sure to include other critical personnel in the review, decision-making, and conclusion processes, to ensure conduct of root cause analyses with prompt closure periods for incidents having product impact. Conduct quarterly batch record reviews of all lots (released and rejected) to ensure application compliance with CMC batch record and method validation sections of the approved combination application. Document the process, report ﬁndings to the Material Review Board, obtain certiﬁcation from expert consultants, and provide this information to the FDA.

Implementation Obtain the staff to carry out supplier audits, participate in Material Review Board functions, and conduct quarterly batch record reviews. Write policies and procedures for each area to be implemented, and train all personnel involved in the processes in compliant procedures. Possible Outcomes and Evaluation of Outcomes The medical device ﬁrm or individual(s) enjoined by FDA will or will not overcome the decreed arrangements. Possible outcomes include the following: • • •

The ﬁrm may satisfactorily overcome both the drug potency and delivery system problems. The ﬁrm may resolve the drug potency problem but not the delivery system problem. The ﬁrm may resolve the delivery system problem but not the drug potency problem.

Anything less than satisfaction of both problems (i.e., potency and delivery system) will result in failing the consent decree’s mandatory requirements. Failure to meet the mandatory requirements may subject the ﬁrm to being charged with civil or criminal contempt of the agreement.

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3.2.9.4 CGMP Workplan To Resolve Injunction In this case study, the company is enjoined by the FDA for placing an adulterated combination drug/medical device product into interstate commerce that has been found by the U.S. District Court to have violated the Federal Food, Drug, and Cosmetic Act of 1938, the Safe Medical Devices Act of 1990, Medical Device Quality Standards, and Title 21 CFR 210, 211, 820 et seq. The company’s prohibitive and mandatory consent decree provisions, ﬁnes, and penalties are as follows: • •

• •

Prohibited provisions — Stop manufacture, distribution, and shipment of the violative medical device product. Mandatory provisions — Hire an expert consultant to monitor, audit, report, and certify the ability of the company to validate the process and method of manufacturing the drug/medical device product in compliance with CGMPs in an approved CGMP workplan. Train staff in the quality assurance and control departments. Allow the quality function to operate independently of manufacturing to ensure that released product meets FD&C Act, Safe Medical Device, and MDQS requirements. No product may be introduced into interstate commerce unless and until the method and process are validated and the product has been certiﬁed by an expert consultant. The report of the expert consultant must be issued to the company and FDA. No product may be released within 20 days of issuance of the report on validation success. If the expert consultant is unable to certify validation of released product, the product must be recalled. Fines — FDA imposes Safe Medical Devices Act of 199084 administrative civil penalties of $1000 per instance for violation of the Federal Food, Drug, and Cosmetic Act. Penalties — FDA imposes a penalty of up to $15,000 for a single violation and up to $1,000,000 for all violations adjudicated in a single action.

Analysis of the company’s compliance issues requires that the CGMP workplan include a review of Title 21 CFR 210, 211, and 820 to identify the areas needing improvement. Table 3.3 shows the applicable sections, the areas mentioned as being out of control, and those not mentioned. In our hypothetical company, the decree overview revealed compliance problems with 10 areas of Title 21. These areas are shown in the third column, “Decree Mentions.” However, because of the incorporation by reference within statutes, there are nine more regulatory areas that the company must address to fully resolve its compliance problems. These areas are shown in the fourth column, “Decree Does Not Mention.” Finally, several statutes also call for ensuring that the ﬁrm complies with other regulated areas. For instance, Title 21 CFR 211.198 (Product Complaints) states that the ﬁrm must also comply with postmarketing requirements in Title 21 CFR 310.305. Title 21 CFR 310 et seq. is part of the new drug application (NDA) section of FDA regulations, not CGMPs. To address events not speciﬁcally mentioned in the decree, the FDA states, “Obligations under this decree do not modify or absolve defendants from any obligation to comply with the FDC Act and its regulations, any application, or any other federal statute or regulation.”85 When reviewing and applying the program implementation case study to an actual consent decree company, incorporating the above CGMP workplan analysis would be helpful to identify what has not been speciﬁcally provided for in the agreement but is required to be in compliance. 3.2.9.5 Suggested Solution The company’s compliance problems fall into three broad categories that encompass the above workplan regulations: • • •

Quality Investigation Reporting

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TABLE 3.3 Company X CGMP Workplan Out of Compliance Title 21 Section

Compliance Area

Decree Mentions

Decree Does Not Mention

201.5

Adequate directions for use (201.128)

X

201.50

Statement of identity (210.10)

X

210.1

Status of CGMP regulations

211.22

Responsibility of quality control unit

211.113

Control of microbiological contamination

211.137

Expiration dating (211.166, 201.17)

211.165

Testing and release for distribution (211.194(a)(2))

211.166

Stability testing

X

211.170

Reserve samples (211.137, 211.192)

X

211.180

General requirements (211.137, 211,192, 211.198, 211.204, 211.208)

X

211.186

Master production and control records (211.192)

X

211.188

Batch production and control records (211.192, 211.134)

211.192

Production record review

211.194

Laboratory records (211.160(b)(4), 211.166)

211.198

Product complaint (211,137, 211.192, 310.305)

314.80

Postmarketing reporting adverse experiences (314.50)

X

314.81

Other postmarketing reports (201.23)

X

314.98

Postmarketing reports (314.94, 314.80)

X

820

Medical device quality systems

X

X X X X X

X X X X

Quality, for purposes of our drug/medical device combination product, includes the CGMP requirements of Title 21 CFR 210, 211, and 820. Important components of quality systems include the rigorousness of the quality unit’s implementation of compliant systems and adherence to procedures, along with development of meaningful related recordkeeping. Additionally, investigation, reporting, and continuous improvement changes are necessary preventative and detection measures of a quality system. The quality improvements necessary to overcome the decreed requirements in this case are discussed individually then collectively to reveal the larger picture necessary for achieving compliance success. The desired end result of any quality system is a controlled process and a product that meets all of its intended and customer needs consistent with FD&C Act provisions. Several quality models are recognized: • • •

Total Quality Management (TQM), by Deming Quality System Design, by Crosby Metrics, by Juran

Because promotion of any one model is not the purpose of this exercise, applying any effective quality system model to the compliance issues here may be applicable; therefore, only the major points of each of these three approaches are presented.

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Deming’s TQM model proposes the following: • • • • • • • • • • • • • • •

Create consistency of purpose. Eliminate fear. Adopt a new philosophy about quality. Eliminate or break down barriers. Stop dependence on mass inspection. Implement vigorous education and training. End the practice of awarding businesses. Remove barriers to employee pride of workmanship. Implement modern methods of supervision. Base quality on the price tag. Eliminate work standards that rely on numeric quotas. Seek never-ending improvements Find problems and resolve them. Seek new levels of productivity after improving methods. Implement modern methods of training staff.

Aspects of Crosby’s Quality System Design include the following: • • • • • • • • • • • • •

Do it over again. Develop quality awareness. Identify the cost of poor quality. Appoint a management committee. Develop zero defects planning. Educate employees. Implement zero-defects kickoff days. Establish quality improvement teams. Set up measures. Set quality goals. Practice error-cause removal. Give recognition to accomplishments. Undertake corrective action programs.

Juran’s Metrics quality system consists of: • • •

Quality planning Quality control Quality improvement

Essentially, all quality and regulatory compliance systems and programs have basic underlying elements consisting of controlled input, processes, and outputs. Remembering this concept will take your grasp of quality and compliance understanding far. Because the FDA’s regulatory mandates are paramount, we will start our discussion there and combine elements of the three quality system models in our suggested solution. 3.2.9.6 Nonconformance The nonconformance of the delivery system has resulted in product complaints from patients and healthcare administrators and requires analysis of the root causes of these problems. A typical analysis of nonconformance may include the diagram shown in Figure 3.3. We know that there

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Nonconformance Adequate Directions for Use Microbiological Contamination Product Impact ?

Expiration Dating

Yes

Investigation Process to Find Root Cause

No

General Requirements

Document Incident, Close and Report

Product Complaints

End or Closure

FIGURE 3.3 Nonconformance ﬂow diagram.

Investigation Process Initiation

Justification – Yes, or No

Yes Accept Deviation Must

No

Reject

Destroy—follow US-NEPA regulations

Be Recorded

Material Review Board Resolution Recommendation

FIGURE 3.4 Investigation ﬂow diagram.

was product impact with the combination product, as it was adulterated (low potency) and failed to pump a full dose in a single administration (defective design). An investigation of the company’s compliance problems should address all ﬁve of the issues shown in Figure 3.3. Our inquiry begins with an investigation process. An investigation systematically examines the details of a problem to determine a root cause. In this case, we must perform a detailed review of the application information that was submitted to gain approval, batch by batch, to obtain a valid justiﬁcation for ﬁnding or not ﬁnding product impact. Six areas are to be investigated, as shown in Figure 3.4 and Table 3.4. A decision regarding justiﬁcation is reached when the company determines whether or not events that occurred during manufacture of the product caused an impact on its intended and approved uses. If no impact is found, the investigation stops here. The decision to stop an investigation requires that an incident report be written. The information from the justiﬁcation and incident reports are used in annual reporting documents and are submitted to the FDA. If an impact is found, a deviation has occurred. Deviations are events inconsistent with policies and procedures that directly impact the product and its intended and approved uses (refer to Figure 3.4 and Table 3.5). The last aspect of this company’s compliance problems involves the establishment of a Material Review Board (MRB), as the company does not currently have one. Philosophies differ with regard to MRB makeup, role, and function in relation to its authority over quality control functions. In this case, we will assume that the quality assurance and quality control functions are of equal authority and that the MRB has authority over these functions and makes the ﬁnal decision regarding all product quality issues (see Figure 3.5 and Table 3.6).

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TABLE 3.4 Investigation To Find Root Cause Problem

Compliance Exposure

Document/Process Review

Resolution

Low potency

FD&C Act (adulterated product)

CMC validation, master, and batch records

Eliminate discrepancy errors, develop policy for vendor/supplier certiﬁcation program.

Delivery dose

Medical device quality system

Device design, validation, qualiﬁcation, and calibration records

Redesign and validate; incrementally improve device over time.

Batch production and control

CGMP (out-of-speciﬁcation product failure; United States v. Barr)

CMC validation, master, and batch records; change control and personnel training

Revise production and control documents; submit supplement; retrain qualiﬁed staff.

Product complaints (returns and salvage product)

CGMP

Dosage and administration, expiration dating, stability testing, reserve samples, laboratory records, adverse events, and training

Resolve inconsistent data; validate; submit major/minor manufacturing change; implement 3-, 6-, 9-, 12-month stability testing program; train qualiﬁed staff.

Validation method

CGMP

CMC section of application, master control records raw active material speciﬁcations

Bring process into conformance with approved application.

Statement of identity

CGMP

CMC section of application

Bring process into conformance with application.

TABLE 3.5 Find Root Cause of Deviations Problem

Compliance Exposure

Document/Process Review

Identity, strength, and purity

FD&C Act (adulterated product) and CGMP problems

USP Secretary FDA drug identiﬁcation Active ingredient Assay speciﬁcation Supplier audit/certiﬁcation and change control information

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Resolution Audit supplier processes, conﬁrm dedicated manufacturing practices, implement certiﬁcation of vendor/suppliers, and certify suppliers. Set internal accept/reject criteria for all raw materials and make them known to suppliers. Develop internal policies and procedures for raw material acceptance testing and train all personnel involved with process. Visit these processes, policies, and procedures periodically for update and improvement.

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Investigation Process

Justification

Yes

Deviation must be recorded and justified

No

Material Review Reject Recommendation

FIGURE 3.5 Material Review Board investigation and recommendation ﬂow diagram.

TABLE 3.6 Material Review Board: Find Root Cause Problem

Compliance Exposure

Document/Process Review

Resolution

Product quality problems exist; no current Material Review Board function in place.

FD&C Act adulterated and CGMP problems

Review and recommend corrective action on all product impact problems to reduce or eliminate failures.

Develop internal policies and procedures for MRB function, train all personnel involved with process. Visit these processes, policies and procedures periodically for update and improvement.

3.2.9.7 Summary of Consent Decree Solutions Company X’s product problems resulting in consent decree are resolvable. The problems it has experienced can be resolved via implementation of the following compliance programs: • • • • •

Material quality system and Material Review Board Materials system Production system Packaging and labeling system Laboratory control system

The programs are primary systems of control that are connected to subsystems and related to other primary systems outside of CGMP requirements. The primary systems feed subsystems with data or information; however, related non-CGMP primary systems may rely on, provide, or share input or output source material used in the respective systems as checks and balances or to ensure that functions are operating in a state of control. Finally, a discussion on the resources needed to implement the systems is included in this summary. Material Quality System and Material Review Board (CGMP Area of Control: 21 CFR 211, Subparts B, E, F, G, H, I, and K) The material quality system addresses overall compliance with CGMPs and internal policies, procedures, and speciﬁcations. The company’s quality systems in this example would extend to contract manufacturers, suppliers and vendors of raw materials, and suppliers of container closure systems and components used in ﬁnished and in-process pharmaceuticals. An effective material quality system requires the knowledge and experience of personnel in the quality assurance and

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quality control functions. These control units must be free to decide to release or reject ﬁnished pharmaceuticals. The MRB function is to be implemented with complete policies and procedures in place. Its role is to oversee and make ﬁnal recommendations on all matters affecting product quality. The quality control unit (quality assurance and quality control) has primary responsibility for reviews and approvals of change control, reprocessing batch releases, annual record reviews, validations, protocols, and reports. When discrepancies occur that affect product quality, reports should immediately be provided to the MRB for review and recommendations. The quality control unit also oversees other quality material system measures and activities implemented to control ﬁnished products and components (including water or gases) that are incorporated into ﬁnished products, containers, and closures. These measures and activities also include validation of computerized inventory control processes, drug storage, distribution controls, and records. Speciﬁcally, all of the following areas must be addressed:86 • • • • •

• • •

Validation/revalidation of computers, manufacturing processes, and laboratory methods must be conducted. Change control instances must be documented, evaluated, and approved and the need for revalidation assessed. Complaint reviews from every source must be documented, evaluated, and investigated in a timely manner, including corrective action where appropriate. Product reviews for annual reporting should include information from appropriate batches reviewed; manufacture trends must be consistent with Title 21 CFR 211.180(e). Discrepancy failures involving manufacturing, testing, and reporting are documented, evaluated, investigated, and resolved in a timely manner, including taking corrective action where appropriate. Reprocess/rework evaluation and review approval are conducted with assessment of the impact on validation and stability. Raw, rejected, and pending materials are quarantined from all other materials. A qualiﬁed staff is hired and trained.

Materials System The company’s materials system is primary and directly receives and feeds data and information to the material quality system. Written policies and procedures for this area cite the need for proper preparation, training, and implementation to control the areas covered. The materials system is also a primary system that extends beyond CGMPs into non-CGMP systems (GLP, GCP, and advertising and promotional literature). The quality and materials standards set in the materials systems are enforced throughout the company to ensure consistency and controlled processes. This system speciﬁcally covers the following areas:87 • • • • • • • • • • • •

First-in/ﬁrst-out use of components, containers, and closures. Containers and closures that are not additive, reactive, or absorptive to the drug product Identiﬁcation of components, containers, and closures Inventory of components, containers, and closures Storage conditions Storage under quarantine until material is tested or examined and released Representative samples collected, tested, or examined using appropriate means At least one speciﬁc identity test conducted on each lot of each component Quarantine of rejected materials Water and process gas supply, design, maintenance, validation, and operation Visual identiﬁcation conducted on each lot of containers and closures Testing or validation of supplier’s test results for components, containers, and closures

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•

• • • • •

Rejection of any component, container, or closure not meeting acceptance requirements, with full investigation of the company’s procedures for veriﬁcation of the source of components Appropriate retesting/reexamination of components, containers, and closures Control systems for implementing changes in the materials handling operations Qualiﬁcation, validation, and security of computerized or automated processes Finished product distribution records by lot Documented investigation into any unexpected discrepancy

Production System The company’s product system is primary and directly receives and feeds data and information to the non-CGMP inventory system. Written policies and procedures for this area require preparation, training, and implementation to control the following covered areas:88 • • • • • • • • • • • • • • • •

Formulation and manufacturing of not less than 100% Validation and veriﬁcation of cleaning, sterilization, and depyrogenation of containers and closures Calculation and documentation of actual yields and percentages of theoretical yields Contemporaneous and complete batch production documentation Established time limits for completion of phases of production Implementation and documentation of in-process controls, tests, and examinations Justiﬁcation and consistency of in-process speciﬁcations and drug product ﬁnal speciﬁcations Identiﬁcation of equipment with containers and, where appropriate, phase of manufacturing and/or status Adequate procedure and practice for charge-in of components Control system for implementing changes in processes Document investigation of all unexpected discrepancies Revalidation of any changes Batch production and control records Master production and control records Equipment cleaning and use log(s) Prevention of objectionable microorganisms in nonsterile drug products

Packaging and Labeling System The company’s packaging and labeling system is primary and directly receives and feeds data and information to the non-CGMP inventory system. Written policies and procedures for this area require preparation, training, and implementation to control the following covered areas:89 • • • • • • • • • • • •

Acceptance, and identiﬁcation operations for packaging and labeling materials Control systems for implementation of changes in packaging and labeling operations Adequate storage for labels and labeling for approved and returned materials Control of labels of similar size, shape, and color for various products Gang printing of labels not done unless the size, shape, or color are differentiated Control of ﬁlled unlabeled containers that are later labeled under multiple private labels Adequate proofreading of incoming labels Physical and spatial separation between different labeling and packaging lines Adequate expiration dates on label(s) Conformance to tamper-evident packaging requirements Validation of packaging and labeling operations, including validation and security of computerized processes Documented investigation into any unexpected discrepancy

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Laboratory Control System The company’s laboratory control system is primary and directly receives and feeds data and information to non-GCP systems. Written policies and procedures for this area require preparation, training, and implementation to control the following covered areas:90 • • • • • • • • • • • • • • • • •

Adequacy of equipment and facility for intended use Calibration and maintenance programs for analytical instruments and equipment Validation and security of computerized or automated processes Reference standards having source, purity, and assay tests to establish equivalency to current ofﬁcial reference standards System suitability checks on chromatographic systems Speciﬁcations, standards, and representative sampling plans Adherence to the written methods of analysis Validation and veriﬁcation of analytical methods Control system for implementing changes in laboratory operations Required testing performed on correct samples Documented investigation into any unexpected discrepancy Complete analytical records from all tests and summaries of results Quality and retention of raw data (chromatograms and spectra) Correlation of result summaries to raw data; presence of unused data Adherence to adequate out-of-speciﬁcation procedure, which includes timely completion of the investigation Adequate reserve samples; documentation of reserve sample examination Stability testing program, including demonstration of stability indicating capability of the test methods

Resources Needed To Implement Systems and Controls Adequate human resources are required to implement all systems and controls to bring this company into full compliance. With a primary focus on the quality control units (quality assurance and quality control), it is suggested that, for every product manufactured by the company, adequate qualiﬁed personnel are hired at a ratio of six people per product, with four and two persons hired in the quality assurance and quality control units, respectively. The estimated costs for this company to achieve full compliance and overcome the consent decree are shown in Table 3.7. This was a lot of information to grasp in one reading. It is suggested that time be taken to review the steps again before tackling WLF v. Henney. Also, remember that this is but one way to review compliance issues. Developing your own or streamlining this one may work for your purposes.

ENDNOTES 68. 69. 70. 71. 72.

FD&C Act, Part 801, Chapter VIII, 381. Ibid. at 304(d)(1). http://www.fda.gov.cder.org; FDA Ofﬁce of Regulatory Affairs Manual, Chapter 5. http://www.fda.gov.cder/graphics/seizure.gif. FDA Regulatory Procedures Manual 2004, Chapter 6: Judicial Actions, Injunction Temporary Restraining Order 6-2-3 A. 73. Ibid., Preliminary Injunction. 74. Mammography Quality Standards Act of 1992 (PHS Act, Section 34(h)(2), Pub. L. No. 102-539, 106 Stat. 3547 (1992); 42 USC 263b(h)(2), Civil Money Penalties. 75. Safe Medical Devices Act of 1990, FD&C Act Section 303(f), Pub. L. No. 101-104, Stat. 4511 (1990), 21 USC 333(f) authorizes civil penalties for most of the provisions of the FD&C Act that apply to medical devices.

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TABLE 3.7 Company X Estimated Costs To Overcome Consent Decree91 Compliance or Resource Area

Implementation Requirements

Estimated Cost

Material quality system and material review board

9 months total: 3 months to assess weaknesses, 3 months to write policies and procedures, and 3 months to train, reassess, and certify to FDA

$150,000.00 for expert consultant working with personnel; personnel salaries are not included

Material system

3 months for assessment, writing policies and procedures, training, reassessment, and certiﬁcation to FDA

$100,000.00 for expert consultant working with personnel; personnel salaries are not included

Production system

6 months for assessment, writing policies and procedures, training, reassessment, and certiﬁcation to FDA

$150,000.00 for expert consultant working with personnel; personnel salaries are not included

Packaging and labeling system

6 months for assessment, writing policies and procedures, training, reassessment, and certiﬁcation to FDA

$175,000.00 for expert consultant working with personnel; personnel salaries are not included

Laboratory control system

6 months for assessment, writing policies and procedures, training, reassessment, and certiﬁcation to FDA

$150,000.00 for expert consultant working with personnel; personnel salaries are not included

Human resources

180 personnel in the Quality Control units for the 30 marketed products

$11.7 million annual payroll

Estimated cost for Company X to achieve full compliance over the next 3 to 9 months

$12,425,000.00

Note: Company X’s asthma pump netted an annual income of $12 billion this year. The cost of achieving compliance is less than 10% of the projected annual income for this product. With full compliance, the increase in these proﬁts is projected to be 15% of the previous year’s performance.

76. http://fda.gov/cder/fuse15; DHHS Public Health Service, Food and Drug Administration Center for Devices and Radiological Health, Medical Device Reporting — User Facility Reporting, Fall 1995. 77. Prescription Drug Marketing Act of 1987 (PDMA), Pub. L. No. 100-293, 102 Stat. 95 (987), Pub. L. No. 102-353, 106 Stat. 941 (1992); 21 USC 301. 78. National Childhood Vaccine Safety Act of 1986, PHS Act Section 2128(b)(1), 42 USC 300aa–328, Pub. L. No. 99-660, 100 Stat. 3751 (1986); 42 USC 262(d)(2)(B) — Civil Penalties and Fines. 79. www.fda.gov/cder/vares/eventtab.htm; National Vaccine Safety Act, 21 USC 360pp (1988) — Civil Penalties. 80. www.fda.gov/cder/vares/eventtab.htm. 81. http://www.fda.gov/cder/graphics/injunction.gif. 82. http://www.fda.gov/cder/graphics/injunction.gif; Regulatory Procedures Manual 2004, Chapter 6: Injunction Recommendations, Business and/or Individuals To Be Enjoined. 83. http://www.fda.gov/cder/graphics/injunction.gif; Regulatory Procedures Manual 2004, Chapter 6: Injunction Recommendations, General Considerations. 84. www.fda.gov/ora/compliance. 85. Schering-Plough Consent Decree, paragraph 44. 86. http://www.fda.gov/ora/cpgm/7356_002/7356-002FINAL.pdf; FDA Compliance Program Guidance Manual Program. 87. Ibid.

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Ibid. Ibid. Ibid. www.fda.gov/cder; Schering-Plough Consent Decree.

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Actions: Debarment, 4 Criminal Disqualification, and Application Compliance and Integrity Debarment or disqualiﬁcation of individuals, ﬁrms, or Institutional Review Boards presents serious consequences for the people involved as well as the pre- and postmarket approved products. By studying the Generic Drug Enforcement Act of 1992, national and international practitioners, educators, and law and pharmacy students will gain a better understanding of the causes and impact of debarment and what is prohibited and enforced under the Act. This chapter discusses debarment, disqualiﬁcation, and application compliance and integrity.

4.1 STATUTORY AUTHORITY The FDA’s statutory authority to debar an industry participant is found in the Food, Drug, and Cosmetic (FD&C) Act, Title 21 USC 335(a), and the Generic Drug Enforcement Act (GDEA) of 1992, Pub. L. 102-282. Authority to mandate clinical testing of new drugs was authorized under the Kefauver–Harris Amendments to the Act in 1962. Additionally, on June 18, 1991, the Federal Policy for the Protection of Human Subjects, Notices and Rules, was published in the Federal Register (28002–28032) and disclosed requirements that Institutional Review Boards (IRBs) and Clinical Investigators must follow for the protection of human participants. Disqualiﬁcation of Institutional Review Boards and Clinical Investigators is regulated under 21 CFR Parts 50 and 56.121 and 45 CFR Part 46. For Clinical Investigators, a process involving an administrative regulatory hearing under 21 CFR 312.70 for misconduct in clinical trials involving humans may be heard predicated on violation of 21 CFR Parts 50 and 56 and 45 CFR Part 46 (Federal Policy). Enactment of the GDEA was predicated on the Generic Drug Scandal of 1989. Also in 1991, the FDA developed a Compliance Policy Guide (CPG; 7150-09) to disclose its policy on fraud, untrue statements of material facts, bribery, and illegal gratuities. This CPG is referred to as an application integrity policy (AIP). An AIP is the approach used by the FDA to assess the validity of scientiﬁc data submitted with applications or the continued marketing of regulated products when the application is suspected of containing false safety and/or efﬁcacy data.

4.2 JURISDICTION The district courts of the United States and the U.S. courts of the Territories have jurisdiction, for cause shown, to restrain violations, debar or disqualify individuals and ﬁrms for most sections of the FD&C Act, 21 USC 301, Chapter III (Prohibited Acts). The FDA may also use its administrative tribunal authority to decide debarment or disqualiﬁcation issues.

133

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4.3 DEBARMENT Debarment is an action taken by the FDA against individuals, corporations, partnerships, or associations that prevents them from providing any services (regulated and nonregulated) and prohibits others in the industry from using their services. The GDEA was enacted because Congress found that “there was substantial evidence that signiﬁcant corruption occurred in the FDA’s process of approving drugs under abbreviated drug applications, there is a need to establish procedures designed to restore and to ensure the integrity of the abbreviated drug application approval process and to protect the public health, and there is a need to establish procedures to bar individuals who have been convicted of crimes pertaining to the regulation of drug products from working for companies that manufacture or distribute such products.”92

4.3.1 GENERIC DRUG ENFORCEMENT ACT

OF

1992

The GDEA amended the FD&C Act (Sections 306 to 308), May 13, 1992. It authorized the FDA to debar an individual, corporation, partnership, or association convicted of certain crimes or found to have engaged in certain types of conduct from providing any services to a drug product applicant. The GDEA also authorizes the FDA to debar a ﬁrm convicted of certain crimes from obtaining or participating in certain subsequent drug approvals. This debarment extends to persons working for applicants of human, animal, and biological drug products. Applicants for drug product approval are required to certify in all applications submitted after June 1, 1992, that they have not, did not, and will not use the services of a debarred individual or ﬁrm in any capacity in connection with the application. Section 306(k) of the GDEA further requires that applicants for approval of certain generic drugs provide information concerning criminal convictions of individuals and ﬁrms involved in the applications. If an applicant knowingly uses a debarred individual’s services, that applicant may be ﬁned up to $1 million. If a debarred individual works for an applicant, the individual may be ﬁned up to $250,000. The signiﬁcant impact of this law on the careers of individuals and continued operations of ﬁrms is apparent from the language of the Act, the extent of FDA enforcement authority provided under this act, and the heavy ﬁnes to which industry participants can be subjected; however, little has been written about this subject outside of the legal ﬁeld. Within the industry, this topic is rarely discussed, and training courses are not provided to personnel regarding the impact of debarment on either the individual or the ﬁrm. In the remainder of this section, we will explore who may be debarred through action or inaction; mandatory and permissive debarment; the criminal mental state that must be proven to convict a defendant of committing debarring actions; the people, services, and afﬁliated persons who are subject to debarment; the convictions that industry participants may be subject to in a debarment action; federal crimes pertaining to FDA regulations; the effects of debarment on individuals and ﬁrms; periods for which defendants can be debarred; the possibility of debarment reversal; and methods that may be available to terminate debarment.

4.3.2 WHO MAY BE DEBARRED The GDEA authorizes debarment of persons who have committed statutory crimes. The word “person” includes individuals, corporations, partnerships, and associations. As with any industry, consultants, contractors, and general and speciﬁc service or product providers who are indirectly and directly involved in the business come under the FDA’s jurisdiction and are all thereby subject to debarment. For instance, in addition to their employees, most industry companies hire third parties to perform certain duties pertaining to their business. Table 4.1 shows the external service or product providers that may be used by ﬁrms for FDA-regulated areas, along with selected relevant CFR sections, the potential services or products provided by these third parties, and the reasons why each could be subject to debarment. Table 4.1 also shows that the number of individuals or entities who may be debarred was expanded by 15. The idea is, if a third party provides either

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TABLE 4.1 Who May Be Debarred Through Services or Products Provided by Industry FDA Regulatory Area

Code of Federal Regulation(s)

Potential Industry Service/Product Provider

Potential Debarment Reason

CGMP93

21 CFR 211.1XX (Validation)

Validation of product or equipment ﬁrms

Collected, evaluated, monitored, and reported data or data are incorporated by reference in an application for validation of product or equipment

CGMP

21 CFR 211.1XX (Environmental Controls)

Environmental control ﬁrms

Collected, evaluated, and monitored or reported data about environmental controls

21 CFR 211.1XX

Computer software/hardware ﬁrms

Collected, evaluated, and reported data via computer software/hardware

21 CFR 211.1XX

Container closure system ﬁrms

Collected and reported data about container closure system

21 CFR 211.1XX

Raw material ﬁrms

Collected, monitored, and reported data or data incorporated by reference in an application about raw material

21 CFR 211.25

Quality assurance/control ﬁrms

Collected and reported quality information

GCP94

21 CFR 312.XX (Transfer of Obligation)

Contract research organizations

Collected, evaluated, monitored, and reported data about transfer of obligation duties for a clinical trial

GLP95

21 CFR Part 56 (IRB)

Registered IRBs

Evaluated and monitored data about a clinical trial

Non-Drug-Industry Supplier Areas Subject to Debarment FDA Regulatory Area

Code of Federal Regulation(s)

Potential Industry Service/Product Provider

Potential Debarment Reason

Sales and storage of test animals

21 CFR Part 58 (Animals)

Animal storage and supply entities

Monitored and reported data about animal storage and supply conditions reported in a clinical trial

Advertising and promotional literature

21 CFR Part 201 et seq.

Label-making companies, promotional advertising companies, and entities

Information used in label making or advertising involved an application

21 CFR Part 20X (Reminder Advertisements)

Advertising

Reminder advertisement involved information about a regulated product

21 CFR 7.46 (Recalls)

Third-party fulﬁllment entities

Collected and monitored recalled product information for a product

All third parties involved with application pending or approved

Collected, analyzed, monitored, reported, and evaluated information in an application

Administrative enforcement

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TABLE 4.2 Examples of Debarring Direct/Indirect Actions Direct

Indirect

Falsifying test results

Signing off on reports without reading and understanding content

Signing to release product with known out-of-speciﬁcation results

Existence of environmental conditions that are contrary to the approved application

Using raw material with known contaminants

Not checking suspicious test results or methods

Making advertising claims that are unfounded

Accepting validation results that are illogical for equipment standards

Using laboratory animals with known or suspected illnesses

Refunding or resupplying product complaint items without thorough investigation

Enrolling clinical trial patients with known and undisclosed illnesses

Collecting adverse events without reporting quarterly, annually, or at anytime

Removing or inserting documents into records to show efﬁcacy when results were not fully tested to assure the results are accurate

Signing off on logs without questioning errors or results that are out of speciﬁcation for the product, line, equipment or environment

services or products to any FDA-regulated industry and commits a crime as identiﬁed by the GDEA, it may be subject to debarment. The cost of debarment to the person is not only economic but also damaging to that person’s professional reputation; therefore, before any person may be debarred by the FDA, one of the violations discussed below must be found in either an FDA administrative hearing or a federal district court. The actions of the defendant may be considered to have been directly or indirectly conducted.

4.3.3 DEBARMENT

FOR

DIRECT

OR INDIRECT

CONDUCT

Defendants actively commit a crime if they are directly involved, performed, wrote, or in some deliberate conscious physical way caused the act to occur. Under the GDEA, a person may be indirectly involved if he or she had actual knowledge of the act or commanded, aided, or abetted the felonious action of another without either notifying an ofﬁcer or personnel of the FDA or internal company ofﬁcial to prevent the act’s commission. The ways in which defendants directly or indirectly commit a crime are too numerous to list. Table 4.2 provides a description of what may be considered direct vs. indirect conduct. Direct conduct requires some overt act on the part of the defendant to cause the conduct or action. The conduct must be in furtherance of the event to reach a result more probable or certain to occur than not. This implies that there must be some sort of planning on the part of the defendant and/or known reliance on the part of the subsequent person who receives the information or data down the line from the defendant who acts directly. An indirect action or conduct requires some negligence on the part of the defendant. To be negligent, there must to be a duty to do something that was not done by the defendant. The duty owed by the defendant must fall below some minimum standard. The duty could involve the need to stop, correct, or inquire about an event or thing. Because there are so many ways a defendant can act directly or indirectly in the pharmaceutical healthcare industry, it is improbable that all such actions can be illustrated or even listed. Direct action requires an overt act that is intended and deliberate; no mistakes were made nor did an accident occur. An indirect act might involve a negligent mistake; the consequences were unplanned and no overt action was taken. Whether a defendant who is subject to debarment acts

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directly or indirectly, the conduct must reach a misdemeanor under federal law or a felony under state law for conduct relating to the development or approval, including the process for development or approval, of any drug product or otherwise relating to the regulation of drug products under the Act.96 Defendants may be debarred if a misdemeanor or felony is committed. A misdemeanor is a lower offense than felonies and generally is punishable by ﬁne or imprisonment other than in a penitentiary. Under federal law and most state laws, any offense other than a felony is classiﬁed as a misdemeanor.97 A felony is a more serious crime than those designated misdemeanors — for example, aggravated assault (felony) vs. simple assault (misdemeanor). Under federal law and many state statutes, any offense punishable by death or imprisonment for more than a year is a felony.98 Many state penal or criminal codes deﬁne felony status crimes, and certain states also have various classes of felonies (e.g., class A, B, C), each usually having a sentence of less than one year.

4.3.4 DEBARMENT TYPES: MANDATORY

AND

PERMISSIVE

Mandatory and permissive debarments are the two types recognized by the GDEA. Both are intended to prohibit individuals, corporations, partnerships, and associations convicted of a crime from involvement in the development, approval, or process for the development or approval of an abbreviated new drug product or for other purposes. Any person may be subject to mandatory and/or permissive debarment. After May 13, 1992, an entity convicted of a felony under federal law for conduct relating to the development or approval or any abbreviated new drug application (ANDA) may be debarred.99 If convicted of a felony under federal law for conduct (1) relating to the development or approval, including the process for development or approval, of any drug product, or (2) otherwise relating to the regulation of any drug product, the individual shall be debarred.100 Permissive debarment may be sought through the FDA Secretary’s own initiative or by petition. If action is taken against a corporation, partnership, or association, it is debarred from submitting an ANDA,101 and when action is taken against an individual that person would be disbarred from providing services in any capacity to a person that has an approved or pending drug product application.102 A corporation may be permissibly debarred if its conviction involves the development, approval, or process of approval of any ANDA; if it has committed a felony under federal law, a misdemeanor under federal law, or a felony under state law; or if it has participated in a conspiracy or aided or abetted a criminal offense that undermines the process for the regulation of drugs.103 An individual may be permissibly debarred if convicted of a misdemeanor under federal law or a felony under state law for conduct relating to the development, approval, or process of approval of any drug product or otherwise relating to the regulation of drug products; conspiracy to commit, aid, or abet criminal offense; or a felony.104

4.3.5 CRIMINAL MENTAL STATE REQUIRED TO CONVICT Because a criminal mental state is an element or part of a crime, GDEA requires that it be proven that the debarred person is aware of his criminal state of mind and knowingly committed a crime. His mental state, along with other aspects of a crime, must be proven in order to ﬁnd a person guilty. In legal terminology, the other parts of a crime are known as actus rea (an action or act), and the mental state is mens rea, referring, in a criminal case, to a guilty mind or wrongful purpose, criminal intent, guilty knowledge, and willfulness. Both the actus rea and mens rea vary depending on the type of felony crime. A person acted knowingly at the time of the act “with respect to a material element of an offense when (1) if the element involves the nature of his conduct or the attendant circumstances, he is aware that his conduct is of that nature or that such circumstances exist, and (2) if the element involves a result of his conduct, he is aware that it is practically certain that his conduct will cause such a result.”105 Persons who act knowingly are deemed to be aware that they know the actions are wrongful.

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4.3.6 SCOPE

OF

DEBARMENT

The Act prohibits a debarred individual from providing services in any capacity to a person that has an approved or pending drug product application.106 The FDA has interpreted “services in any capacity” to mean any service provided to the drug applicant, regardless of whether or not it is related to drug regulation. That means a debarred individual may not provide even non-drug-related services to a drug product applicant without violating debarment; such services might include working as a landscaper, computer software supplier, accountant, telephone repair person, janitor, interior decorator, or landlord.107

4.3.7 PEOPLE, SERVICES, AND THOSE AFFILIATED WHO MAY BE AFFECTED BY DEBARMENT

OR

Reference to people or persons under the Act includes individuals, corporations, partnerships, and associations, and the scope of services includes all those connected with the preparation, ﬁling, and submission of an application, which may include the collection, monitoring, evaluation, analysis, or reporting of data or information that appears or is speciﬁcally incorporated by reference in the application.108 Some persons involved with this process may include: • • • •

Employees of the applicant Certain contractors and their employees Certain subcontractors and their employees Clinical investigators

Persons contributing data and information contained in a drug master ﬁle (DMF) or public master ﬁle (PMF) are incorporated by reference in the application.109 An afﬁliated person for whom an applicant for approval of an ANDA should provide conviction information includes any individual, partnership, corporation, or association, including employees thereof, involved with development of submission of data that (1) are used to obtain approval of an application and (2) relate to the manufacturing, processing, or testing of the active ingredient(s) of the ﬁnished dosage form(s).110 Some examples of afﬁliated persons follow:111 • •

•

•

Clinical investigators, nurses, technicians, and other parties involved with the development or submission of data related to clinical studies: These are all afﬁliated persons. Current good manufacturing practice (CGMP) recordkeepers: Because the FDA reviews CGMP records when determining whether to grant or continue approval of a drug product, persons who develop and record CGMP data related to the manufacturing, processing, or testing of the active ingredient(s) or the ﬁnished dosage form(s) are afﬁliated persons. Commercial manufacturing facility workers: Such persons are afﬁliated persons if they are involved in the development or submission of records or data that are used to obtain and maintain approval of an application or relate to the manufacturing, processing, or testing of the active ingredient(s) or the ﬁnished dosage form(s). For example, persons recording and generating data solely for the approved commercial product are afﬁliated persons because the FDA reviews such records in determining whether to grant or continue approval of a drug product. Persons working on drug master ﬁles (DMFs) or public master ﬁles (PMFs): Persons recording and generating data for DMFs or PMSs that are relied on to support approval and that relate to, for example, the manufacturing, processing, or testing of the active ingredient(s) or ﬁnished dosage form(s) come within the deﬁnition of afﬁliated persons.

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•

139

Secretaries: If the secretary merely transcribes data, the secretary is not regarded as an afﬁliated person within the intended deﬁnition of the Act. In the rare instances that the secretary may develop data used to obtain approval, that secretary is an afﬁliated person. Janitors, packers, production crew, and assemblypersons: As long as these persons do not develop or submit data, they are not afﬁliated persons.

4.3.8 DEBARMENT CRIMES Crimes reaching the level of debarment are considered based on federal and state deﬁnitions of misdemeanor or felonious conduct. The GDEA does not attempt to deﬁne each and every type of crime an industry participant can commit, neither could this publication contain such a detailed list; however, the Act does describe some crimes that all industry participants should be aware of, and they should familiarize themselves with the deﬁnition of what it may take to be found guilty of such conduct. While it is not possible to list all potential crimes or conduct that could be prohibited by the GDEA, keep in mind that determining whether or not an act threatens to undermine the process for the regulation of drugs112 is a key issue for administrative enforcement of the Act. An important point to make at this time is that this discussion is not intended to serve as legal advice, assistance, or counseling; the following information is intended to be illustrative of the language in the GDEA only and the impact that enforcement may have on an industry participant. The Act speciﬁcally identiﬁes the following felonies:113 •

• • • •

Conspiracy to commit, or aiding or abetting • Bribery • Payment of illegal gratuities • Fraud • Perjury • False statement • Racketeering • Blackmail • Extortion Falsiﬁcation or destruction of records Interference with an investigation Obstruction of an investigation Prosecution of any criminal offense

To convict, there must be a demonstrated pattern of conduct sufﬁcient to ﬁnd reason to believe that the individual may have violated provisions under this Act relating to drug products.114

4.3.9 306(K)(2) CONVICTION INFORMATION REQUIREMENTS In instances where an ANDA is involved, the GDEA requires that “the applicant list any and all crimes convicted within the past ﬁve years of the applicant and afﬁliated persons responsible for the development or submission of such application.”115 What constitutes a conviction means the difference between the FDA reviewing or refusing to review an ANDA; therefore, it is important to understand what it takes to be convicted under the Act. Under the Act, a conviction is:116 • • •

When a judgment of conviction has been entered against the person by a federal or state court, regardless of whether there is an appeal pending. When a plea of guilty or nolo contendere by the person has been accepted by a federal or state court. When the person has entered into participation in a ﬁrst-offender, deferred adjudication, or other similar arrangement of program where judgment of conviction has been withheld.

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TABLE 4.3 Debarment Periods117 Section 306 (a)(1) Corporations, partnerships, and associations

Mandatory or Permissive

Period

Mandatory

Less than 1 year or more than 10 years

(a)(2) Individual

Permissive

Permanent

(b)(2) Any person

Permissive

Not more than 5 years

(a)(1) Subsequent debarring actions of corporations, partnerships, or associations

Mandatory

Permanent

4.3.10

DEBARMENT EFFECTS

A person subject to debarment may be affected in several ways depending upon the option the FDA uses. Many debarred persons suffer the fate of refusal to ﬁle an application, a clinical hold, or a Notice of Initiation of Disqualiﬁcation Proceedings and Opportunity To Explain (Clinical Investigators are discussed below). What can the FDA refuse to ﬁle? Any application subject to debarment. Speciﬁcally, the FDA may refuse to ﬁle any application submitted after June 1, 1992, that requires certiﬁcation, including:118 • • • • • • •

New drug applications (NDAs) Abbreviated new drug applications (ANDAs) New animal drug applications (NADAs) Abbreviated new animal drug applications (ANADAs) Export applications for certain unapproved products Biological license applications (BLAs) and product license applications (PLAs) Supplements to certain drug product applications

4.3.11

DEBARMENT PERIODS

Debarment periods are as short as less than one year, as long as 10 years, or permanent (see Table 4.3). The likelihood of continuing a career or continuing operations is remote, whether a person or company has been debarred for less than one year or permanently. Within the Act, the Secretary takes into consideration several factors before deciding the length of debarment as well as whether the debarment period terms will run concurrently or consecutively in the case of a person debarred for multiple offenses. See Tables 4.4 and 4.5 for examples of FDA postings of debarred individuals and companies.

4.3.12

DEBARRING PERIOD CONSIDERATION FACTORS

The FDA Secretary may consider several factors when determining the period of debarment for any person. The GDEA allows for shortening or lengthening the period dependent upon the conduct of the defendant. The factors that may be considered include: (1) the nature and seriousness of the offense; (2) the nature and extent of management participation in the offense; (3) whether corporate policies and practices encouraged the offense, including whether inadequate institutional controls contributed to the offense; (4) the nature and extent of voluntary steps taken to mitigate the impact on the public of any offense involved, including the recall or discontinuation of distribution of suspect drugs, full cooperation with any investigation, relinquishing of proﬁts on drug approvals fraudulently obtained, and any other actions taken to substantially limit potential or actual adverse effects to the public health; (5) the extent to which changes in ownership, management, or operations

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TABLE 4.4 Debarred Firms Name of Firm None as of this date

Effective Date

End/Term of Debarment

FR DATE.txt (MM/DD/YY)

VOLUME PAGE.pdf

—

—

—

—

have corrected the causes of the offense so that it will not occur in the future; (6) whether the person to be debarred is able to present adequate evidence that the current production of drugs subject to abbreviated drug applications and all pending abbreviated drug applications are free of fraud or material false statements; (7) and prior convictions under this Act or under other Acts involving matters within the jurisdiction of the FDA.119 Of these areas that the Secretary can consider when determining debarment periods, item 2 is one that may cause ﬁrms the most concern because it is the one area they can immediately control by implementing policies and practices that are compliant with regulations, which if they are followed can prohibit debarring acts and conduct that could lead to debarment. However, policies, procedures, and practices that may expose individuals and ﬁrms to debarment are seldom addressed in industry. Companies that have implemented policies, practices, and procedures are usually named as defendants before controls are put in place. Once debarred, both individuals and ﬁrms seek ways and methods to have the order terminated. Provisions exist under the GDEA; however, obtaining a termination order is difﬁcult.

4.3.13

TERMINATING DEBARMENT

Any person not permanently debarred may apply for debarment termination. Requests to terminate debarment are generally made in 6 months. Terminations are granted when:120 • •

The debarring term is served or reversed. There is a change in ownership; management or operations have fully corrected the causes of the offense involved and provided reasonable assurances that the offense will not occur in the future; and sufﬁcient audits, conducted by the FDA or by independent experts acceptable to the FDA, demonstrate that the pending applications and development of drugs being tested before the submission of an application are free of fraud or material false statements.

No termination shall take effect earlier than the expiration of 1 year from the date of debarment. With respect to individuals:121,122 • •

If the crime that serves as the basis for the debarment was under permissive criteria, it may be reversed and the order of debarment withdrawn. If such termination serves the interests of justice and adequately protects the integrity of the drug approval process, then the order may be reversed.

4.3.14

SUSPENSION AUTHORITY FOR ANDA PRODUCT DISTRIBUTION

The GDEA authorized additional actions against ﬁrms submitting ANDAs via its suspension authority. Under the GDEA, the FDA can suspend authority of a generic drug manufacturer to distribute drugs if a generic manufacturing ﬁrm (1) “has bribed or attempted to bribe, has paid or attempted to pay an illegal gratuity, or has induced or attempted to induce another person to bribe or pay an illegal gratuity to any ofﬁcer, employee, or agent of the DHHS or to any other federal, state, or local ofﬁcial in connection with any abbreviated drug application or has conspired to

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TABLE 4.5 Debarred Individuals FR DATE.txt (MM/DD/YY)

VOLUME PAGE.pdf

Permanent^

03/08/1993

58FR12967

FR correction

04/26/1993

58FR21983

Permanent^

04/06/1993

58FR17896

04/12/1993

Permanent^

04/12/1993

58FR19128

04/12/1993

Permanent^

04/12/1993

58FR19129

04/21/1993

Permanent^

04/21/1993

58FR21469

Name of Person

Effective Date

Chang, Charles Y.

03/08/1993

Mannan, Muhammad Z.

04/06/1993

Rivers, Jacob H. Vegesna, Raju Finelli, Gena R.

End/Term of Debarment

Kalidindi, Sanyasi Raju

04/21/1993

Permanent^

04/21/1993

58FR21470

Azeem, Mohammed

04/26/1993

Permanent^

04/26/1993

58FR21982

FR correction

05/05/1993

58FR26814

Schetlick, Gloria H.

04/26/1993

Permanent^

04/26/1993

58FR21983

Colton, Steven F.

06/17/1993

Permanent^*

06/17/1993

58FR33446

Sturm, Jan T.

06/22/1993

Permanent^

06/22/1993

58FR33941

FR correction

07/06/1993

58FR36252

06/30/1993

Permanent^

06/30/1993

58FR35006

Fogari, Robert A.

07/08/1993

Permanent^*

07/08/1993

58FR36691

Rodriquez, Juan Manuel

07/26/1993

Permanent^

07/26/1993

58FR39819

Shulman, Robert NMI

08/27/1993

Permanent^

08/27/1993

58FR45340

Prasad, Kumar

Shah, Dilip

08/31/1993

Permanent^*

08/31/1993

58FR45899

Desai, Kanubhai C.

10/06/1993

Permanent^

10/06/1993

58FR52111

Matkari, Rajaram K.

10/20/1993

Permanent^*

10/20/1993

58FR54156

06/13/2000

Withdrawn++

06/13/2000

65FR37154

Dicola, Charles G.

11/05/1993

Permanent^*

11/05/1993

58FR59044

Hossain, Liaquat

11/05/1993

Permanent^*

11/05/1993

58FR59046

Pai, Daphne (aka Lau, Daphne)

11/05/1993

Permanent^*

11/05/1993

58FR59048

Bansal, Padam C.

11/29/1993

Permanent^*

11/29/1993

58FR62674

03/11/1997

Special termination+

03/11/1997

62FR11212

Donnelly, Mary

11/29/1993

Permanent^

11/29/1993

58FR62675

Perkal, Mark B.

11/29/1993

Permanent^

11/29/1993

58FR62676

09/11/1998

Special termination+

09/11/1998

63FR48733

12/23/1993

Permanent^*

12/23/1993

58FR68147

Long, Susan M. Bae, Kun Chae

12/30/1993

Permanent^*

12/30/1993

58FR69368

Brancato, David J.

01/06/1994

Permanent^*

01/06/1994

59FR00751

Shah, Satish R.

08/01/1994

Permanent^*

08/01/1994

59FR38983

Patel, Ashok

11/08/1994

Permanent^*

11/08/1994

59FR55670

Kletch, Walter S.

11/29/1994

Permanent^*

11/29/1994

59FR60989

Ryan, Patrick T.

11/29/1994

Shah, Atul Mendell, Arnold S.

© 2005 by CRC Press LLC

Permanent^

11/29/1994

59FR60992

FR correction

01/17/1995

60FR03451

12/05/1994

Permanent^*

12/05/1994

59FR62399

03/11/1997

Special termination+

03/11/1997

62FR11212

12/21/1994

Permanent^*

12/21/1994

59FR65773

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TABLE 4.5 (cont.) Debarred Individuals Name of Person

Effective Date

End/Term of Debarment

FR DATE.txt (MM/DD/YY)

VOLUME PAGE.pdf

Quamruzzaman, Abu

11/18/1993

Permanent^#

12/30/1994

59FR67709

Morris, Andrew

05/16/1994

Permanent^#

01/11/1995

60FR02767

Shainfeld, Frederick Jay

03/10/1995

Permanent^#

02/28/1996

61FR07521

Copanos, John D.

03/11/1996

Permanent^*

03/11/1996

61FR09711

FR correction

04/18/1996

61FR16975

Permanent^*

03/22/1996

61FR11846 62FR03297

Bushlow, John W. Chatterji, Dulal C.

03/22/1996 11/01/1995

Permanent^#

01/22/1997

06/11/1998

Special termination+

06/11/1998

63FR32013

Mays, Gary D.

01/24/1997

5 years%

01/24/1997

62FR03703

Garﬁnkel, Barry D.

04/02/1997

Permanent^*

04/02/1997

162FR1573

Elbert, Robert

04/03/1997

Permanent^*

04/03/1997

62FR15902

Sacher, Robert E.

08/11/1997

Permanent^

08/11/1997

62FR42998

Islam, Amirul

08/27/1997

Permanent^#

08/27/1997

62FR45423

Banks, Norma D.

08/28/1997

Permanent^

08/28/1997

62FR45667

Herman, Hedviga

10/17/1997

Permanent^

10/17/1997

62FR54117

Rana, Nandlal

10/20/1997

Permanent^

10/20/1997

62FR54462

Anthony, James Michael

11/07/1997

Permanent^

11/07/1997

62FR60249

Feuer, Scott

06/02/1998

5 years%

06/10/1998

63FR31789

Kostas, Constantine I.

06/25/1998

Permanent^*

06/10/1998

63FR34652

Girdhari, Premchand

01/21/2000

Permanent^*

01/21/2000

65FR03454

Elsharaiha, Rami

09/29/2000

Permanent^

09/29/2000

65FR58555

Marcus, Jay

09/29/2000

5 years%

09/29/2000

65FR58556

Uddin, Mohammad

09/29/2000

Permanent^

09/29/2000

65FR58557

Petrik, Craig H.

04/30/2002

Permanent^

04/30/2002

67FR21255

Fiddes, Robert A.

11/06/2002

20 years%

11/06/2002

67FR67628

Hernandez, Delﬁna

11/06/2002

5 years%

11/06/2002

67FR67629

Lai, Yee-Ling

11/13/2002

5 years%

11/13/2002

67FR68877

Notations: ^

Mandatory debarment (Section 306(a))

%

Permissive debarment (Section 306(b))

*

Hearing requested and denied

#

Acquiesced to debarment

+

Special termination of debarment (Sections 306(d)(4)(C) and (d)(4)(D))

++

Order to withdraw order of debarment (debarment terminated) (Section 306(d)(3)(B)(i))

aka

Also known as

NMI No middle initial known to be used This public list is compiled in accordance with 21 USC 335a(e) from notices published in the Federal Register. Firm or individual names appearing for the ﬁrst time in an FR notice of debarment are added to the end of the list. Subsequent FR debarment notices concerning the same ﬁrm or person are posted after the ﬁrst listing of the ﬁrm or individual.

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commit or has aided or abetted such action”123 or (2) “has knowingly made or caused to be made a pattern or practice of false statements of misrepresentations with respect to material facts relating to any abbreviated drug application, or the production of any drug subject to an abbreviated drug application, to any ofﬁcer, employee, or agent of the DHHS or has conspired to … commit prohibited acts.”124

4.4 DISQUALIFICATIONS Disqualiﬁcation from activities in the healthcare industry is reserved for two speciﬁc participants: Institutional Review Boards (IRBs) and Clinical Investigators. The FDA can disqualify these two participants from further involvement with clinical trials when for-cause issues are presented during an inspection or the FDA receives notiﬁcation from external sources questioning the practices of these entities. The duties and responsibilities of IRBs and Clinical Investigators are to generally ensure the rights, safety, and protection of humans and animals in clinical trials; however, each must also fulﬁll speciﬁc regulatory duties. Failure to fulﬁll these duties will cause them to be disqualiﬁed. Our discussion of IRBs and Clinical Investigators will take the following path: •

•

IRB responsibilities a. Regulatory responsibilities of IRB to human clinical trial patients and Clinical Investigators b. Regulatory sanctions IRBs may face in a disqualiﬁcation action c. Impact of IRB disqualiﬁcation Clinical Investigator responsibilities a. Regulatory responsibilities of Clinical Investigators to human clinical trial patients, sponsors, and IRBs b. Regulatory sanctions Clinical Investigators may face in a disqualiﬁcation action c. Impact of Clinical Investigator disqualiﬁcation

4.4.1 IRB RESPONSIBILITIES Four broad regulatory responsibilities are required of all IRBs. Operations of the IRB are required to be outlined in written policies and procedures. The policies and procedures must be compliant, followed, and used to ensure the protection of human subjects. The IRB is responsible for:125 • •

• •

Conducting its initial and continuing review of research and for reporting its ﬁndings and actions to the investigator and the institution. Determining which projects require review more often than annually and which projects require veriﬁcation from sources other than the investigator that no material changes have occurred since the previous IRB review. Ensuring prompt reporting to the IRB of changes in research activity. Ensuring that changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to the human subjects.

4.4.1.1

Regulatory Responsibilities of IRB to Human Clinical Trial Patients and Clinical Investigators

The IRB responsibility to ensure human clinical trial patient safety is managed by controls it puts in place with regard to informed consent and policy and procedure documents. IRBs must notify Clinical Investigators of changes in the study protocol and ensure that informed consent documents are without exculpatory language. The degree and extent to which an IRB performs these and other

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statutory responsibilities will determine whether the IRB continues to operate or becomes subject to disqualiﬁcation by the FDA. 4.4.1.2

Regulatory Sanctions IRBs May Face in a Disqualification Action

Whenever the IRB or the institution has failed to take adequate steps to correct a noncompliance found through an FDA inspection, both may be disqualiﬁed. An administrative hearing begins the disqualiﬁcation process for an IRB. If at the hearing it is found that (1) the IRB has refused or repeatedly failed to comply with any of the regulations, and (2) the noncompliance adversely affects the rights or welfare of the human subjects in a clinical investigation, then the FDA may disqualify the IRB. Other parties with business relationships with the disqualiﬁed IRB as well as the IRB and parent institution will receive a notice of disqualiﬁcation. In addition, sponsors and Clinical Investigators may also be sent a notice of the disqualiﬁcation, and the Agency may elect to publish a notice of its action in the Federal Register. 4.4.1.3

Impact of IRB Disqualification

The FDA will not approve an application for a research permit for a clinical investigation that is to be under the review of a disqualiﬁed IRB or that is to be conducted at a disqualiﬁed institution, and it may refuse to consider, in support of a marketing permit, the data from a clinical investigation that was reviewed by a disqualiﬁed IRB as conducted at a disqualiﬁed institution, unless the IRB or the parent institution is reinstated. The IRB may be either disqualiﬁed or subject to other regulatory actions in addition to disqualiﬁcation. For instance, if during an inspection, apparent noncompliant operation of an IRB is observed by an FDA investigator, an oral or written summary of observations to an appropriate representative of the IRB will be given. The FDA may thereafter send a letter describing the noncompliance to the IRB and to the parent institution. The Agency will require a written response within a time period speciﬁed by the FDA describing the corrective actions that will be taken by the IRB, the institution, or both to achieve compliance with these regulations. In reliance upon the response of the IRB or institution, the FDA may schedule a reinspection to conﬁrm the adequacy of corrective actions. In addition, until the IRB or the parent institution takes appropriate corrective action, the Agency may: • • • •

Withhold approval of new studies subject to the requirements of this part that are conducted at the institution or reviewed by the IRB. Direct that no new subjects be added to ongoing studies subject to this part. Terminate ongoing studies subject to this part when doing so would not endanger the subjects. When the apparent noncompliance creates a signiﬁcant threat to the rights and welfare of human subjects, notify relevant state and federal regulatory agencies and other parties with a direct interest in the Agency’s action of the deﬁciencies in the operation of the IRB.

In this instance, the parent institution is responsible for the operation of an IRB, and the FDA will ordinarily direct any administrative action against the parent institution. However, depending on the evidence of responsibility for deﬁciencies determined during the investigation, the Agency may restrict its administrative actions to the IRB or to a component of the parent institution determined to be responsible for formal designation of the IRB.

4.4.2 CLINICAL INVESTIGATOR RESPONSIBILITIES Clinical Investigators must ensure the rights and welfare of human subjects, must keep IRBs and sponsors informed about risks to patients that are either unexpected or occur as a result of aberrations, and must not make any changes not approved by the IRB and sponsor.

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4.4.2.1

Regulatory Responsibilities of Clinical Investigators

Clinical Investigators are responsible for protecting the rights, safety, and welfare of human subjects in the studies they conduct, They must notify the IRB of changes in the research activity or unanticipated problems involving risks to human subjects or others and not make any unapproved changes following the signed investigator’s statement, must ensure that an investigational drug is administered only to study patients, must ensure that subinvestigators are supervised, and must prepare and maintain for 2 years case histories, informed consents, and records disclosing the disposition of the investigational study drug. 4.4.2.2

Regulatory Sanctions Clinical Investigators May Face in a Disqualification Action

Upon inspection or notiﬁcation of questionable clinical trial practices that may result in harm to a human trial subject and with no hope of correcting the problem, the FDA may seek Administrative Enforcement disqualiﬁcation action against a Clinical Investigator. Inﬂicting harm to humans, submitting false information repeatedly, or deliberately doing these act(s) are all bases for initiating disqualiﬁcation. Disqualiﬁcation of a Clinical Investigator begins with an inspection ﬁnding objectionable conditions, followed by issuance of a Notice of Initiation of Disqualiﬁcation Proceedings and Opportunity To Explain (NIDPOE) letter, an opportunity to give a written response, and then an administrative regulatory hearing to make a ﬁnal decision on the fate of the Clinical Investigator’s continued involvement in the proceedings. 4.4.2.3

Impact of Clinical Investigator Disqualification

If a Clinical Investigator is disqualiﬁed, the FDA may take several actions to protect trial subjects. It may shut down the sites operated by the disqualiﬁed investigator, prohibit any investigational drug to be issued to that investigator or site, or impose a clinical hold. The clinical hold may be complete or partial. Delay or suspension of all clinical work under an investigational new drug application (INDA) is considered a complete clinical hold. Delay or suspension of only part of the clinical work under an INDA is considered a partial clinical hold. A partial clinical hold could, for example, be imposed to delay or suspend one of several protocols in an IND, a part of a protocol, or a speciﬁc study site in a multisite investigation. When an IRB or Clinical Investigator has been disqualiﬁed, reinstatement is possible after a period of time has elapsed and evidence presented that a repeat occurrence will not happen. However, in either disqualiﬁcation instance, the FDA has both the authority and means to make public the disqualiﬁcation causes and action. This is a difﬁcult issue for the IRB and Clinical Investigator to overcome. Table 4.6 provides a recent list of FDA disqualiﬁed industry participants.

4.5 APPLICATIONS: COMPLIANCE AND VALIDITY ISSUES 4.5.1 APPLICATION COMPLIANCE Sponsors in the healthcare industry may submit a new drug or medical device application to the FDA center responsible for its review and approval. Such applications require various types of data. For instance, a new drug application (NDA) submitted to the Center for Drug Evaluation and Research (CDER) has 19 sections, as listed on Form 356h, Application To Market a New Drug, Biologic, or Antibiotic for Human Use: • • • •

Table of contents Labeling Summary Chemistry

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• • • • • • • • • • • • • • •

147

Nonclinical pharmacology and toxicology Human pharmacokinetics and bioavailability/bioequivalence Clinical microbiology Clinical Safety update report Statistical Case report tabulations Case report forms Patent information Patent certiﬁcation Establishment description Debarment certiﬁcation Field copy certiﬁcation User fee cover sheet Other

In either paper or electronic form, the fourth section of the applications addresses the chemistry, manufacturing, and control (CMC) of the new drug. The CMC section contains information on: • • • • • • •

Drug substance Drug product Investigational formulations Environmental assessment Methods validation Batch records (listed separately) Publication (listed separately)

The section on drug substance alone has nine parts: description and characterization, manufacturer, synthesis/method of manufacture, process controls, reference standard, speciﬁcations and analytical procedures, microbiology, container and closure systems, and stability. Of the 19 sections of the FDA 356h form, the CMC section contains the most important information for determining and assessing whether the approved application and the distributed product are made according to the ﬁled and approved application’s compliance standards. The released product must meet all strength, purity, potency, identity, and safety requirements. Few companies incorporate a compliance program in their application that requires reviews using all of the CMC sections (e.g., drug substance, methods validation, batch records) to compare the results of batches of released product. Generally, instead, companies rely on excerpted portions of the CMC batch records section within the quality assurance and control functions. Without consistent, repetitive regulatory scrutiny of the CMC portions of approved applications to ensure that effective application compliance programs are in place and in control, it is likely that, over time, out-of-speciﬁcation (OOS) results may creep into the processes, which may begin to run out of control and lead to the decline of current good manufacturing practices (CGMPs) and application compliance difﬁculties. Difﬁculties with meeting application compliance are also encountered when companies fail to implement rigorous investigation and meaningful quality audit programs. When the release of a product that meets the low end of a range of acceptance criteria is coupled with other problems such as a lack of CMC periodic application compliance reviews, lack of rigorous investigations, or lack of quality-based audit programs, these problems become intertwined, and examination of these combined problems can reveal how companies may slowly begin to operate out of control. Product released at low potency ranges of acceptance tends to fail expiry while in the market, and low potency or adulterated product requires a recall of those goods. For a time, before initiating

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TABLE 4.6 Disqualified/Totally Restricted List Name/Address

Center

Type

Action Date

WILLIAM A ABRUZZI JR, MD WAPPINGERS FALS, NY ALLAN R ALLBRITTON GONZALES, LA WILBERT S ARONOW, MD OMAHA, NE BRADY L ALLEN, MD DALLAS, TX CHAOVANEE AROONSAKUL, MD CHICAGO, IL HOWARD BALIN, MD PHILADELPHIA, PA VINCENT J BARATTA, MD N LINDENHURST, NY SHELDON R BENDER, MD PHILADELPHIA, PA CARL E BLUNCK JR, MD PLAQUEMINE, LA RICHARD L BORISON, MD AUGUSTA, GA CHETWYND E BOWLING, MD PHILADELPHIA, PA PAUL W BOYLES, MD CARY, NC WALTER C BRUSCHI, MD LEAVENWORTH, KS WALTER J BUSHNELL, MD DENVER, CO EDUARDO CARO ACEVEDO, MD BAYAMON, PR THOMAS N CARTER, MD BETHESDA, MD CHARLES CARTER, MD ORLANDO, FL WALTER A CARUSO, MD MT KISCO, NY LEO CASS, MD CAMBRIDGE, MA JOSEPH R CATALDO, MD ALEXANDRIA, VA ABRAHAM A CHAPLAN, MD ENGLEWOOD, NJ JOHN H CLOSE, MD MIAMI, FL HERBERT W COPELAN, MD PHILADELPHIA, PA DANIEL L CRANE, MD NEW YORK, NY AUBREY P CULLEN, MD HOUSTON, TX

CDER

D

31-AUG-1966

Through hearing process

CVM

D

24-JAN-1997

By consent agreement

CDER

R

8-OCT-1982

Total

CDER

D

11-DEC-1990

By consent agreement

CDER

D

16-OCT-1991

Through hearing process

CDER

D

19-MAR-1975

Through hearing process

CDER

D

13-NOV-1985

Through hearing process

CDER

D

17-FEB-1969

Through hearing process

CDER

D

07-JUL-1979

Through hearing process

CDER

D

10-NOV-1998

By consent agreement

CDER

D

13-NOV-1980

Through hearing process

CDER

D

13-APR-1995

Through hearing process

CDER

R

28-JUN-1983

Total

CDER

D

16-SEP-1988

By consent agreement

CDER

D

30-JUL-2002

Through hearing process

CDER

D

10-JUN-1980

By consent agreement

CDER

DR

CDER

R

31-AUG-1966 (reinstated 29-JUL-1969) 28- JUL-1988

CDER

D

15-DEC-1965

Through hearing process

CDER

R

14-APR-1982

Total

CDER

D

28-FEB-1979

Through hearing process

CDER

D

19-JUL-1978

Through hearing process

CDER

DR

Through hearing process

CDER

D

19-JUL-1966 (reinstated 19-AUG-1966) 27-JUN-1984

CDER

R

08-JUN-1987

© 2005 by CRC Press LLC

Comments

Through hearing process Total

By consent agreement Total

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TABLE 4.6 (cont.) Disqualified/Totally Restricted List Name/Address

Center

Type

Action Date

FRED C DALTON, MD MINEOLA, NY PHILLIP L DAY, MD SAN ANTONIO, TX BRUCE I DIAMOND, PHD AUGUSTA, GA WILLIAM L DOSS JR, MD DETROIT, MI DAVID M DRESSLER, MD NEW BRITAIN, CT EDWIN DUNLOP, MD ATTLEBORO, MA SAMUEL I FEURST, MD VICKSBURG, MS ROBERT A FIDDES, MD WHITTIER, CA ROBERT FOGARI, MD JERSEY CITY, NJ ROBERT A FOX JR, MD BRANFORD, CT WILLIAM C FRANKLIN, MD HOUSTON, TX EDWARD C FRONING, MD SAN MATEO, CA RONALD R FULLER NEWARK, OH MIGUEL H GAMARRA, MD CORAL GABLES, FL FLOYD K GARETZ, MD MINNEAPOLIS, MN BARRY D GARFINKEL, MD MINNEAPOLIS, MN JOHN M GOODING, DO PANAMA CITY, FL ROBERT A GATENBY, MD PHILADELPHIA, PA LARRIAN GILLESPIE, MD LOS ANGELES, CA EUGENE O GRECU, MD SACRAMENTO, CA BERNARD K GUERIN, MD RENO, NV JAMES A HALIKAS MINNEAPOLIS, MN DWIGHT J HOTCHKISS JR, MD FLEMINGTON, NJ J T JOHN JR, MD NASHVILLE, TN KHEM L KHOOBLALL, MD PARMA, OH

CDER

D

03-JAN-1979

Through hearing process

CDER

D

28-AUG-1975

Through hearing process

CDER

D

10-FEB-1999

By consent agreement

CDER

D

14-JUN-1979

Through hearing process

CDER

D

14-MAR-1984

By consent agreement

CDER

DR

CDER

D

16-FEB-1970 (reinstated 24-DEC-1970) 02-OCT-1984

CDER

D

01-JUN-1999

Through hearing process

CDER

R

24-APR-1985

Total

CDER

D

15-FEB-1989

By consent agreement

CDER

D

09-NOV-1982

By consent agreement

CDER

D

10-APR-1976

Through hearing process

CVM

D

29-JAN-1988

Through hearing process

CDER

D

31-MAY-1983

By consent agreement

CDER

D

23-NOV-1982

By consent agreement

CDER

R

14-MAY-1994

Total

CDER

R

07-NOV-1986

Total

CDER

D

15-NOV-1988

By consent agreement

CDER

D

02-FEB-1989

By consent agreement

CDER

D

25-MAR-1999

Through hearing process

CDER

D

13-NOV-1984

By consent agreement

CDER

D

15-JAN-2001

Through hearing process

CDER

D

25-JUN-1984

Through hearing process

CDER

D

04-NOV-1983

By consent agreement

CDER

D

17-JUL-1998

By consent agreement

© 2005 by CRC Press LLC

Comments

Through hearing process By consent agreement

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TABLE 4.6 (cont.) Disqualified/Totally Restricted List Name/Address

Center

Type

Action Date

RONALD KLEBER, MD MARIETTA, GA ALBERT M KLIGMAN, MD CONSHOHOCKEN, PA NATHAN S KLINE, MD NEW YORK, NY RICHARD B KNAPP, MD MORGANTOWN, WV PAUL KORNBLITH, MD BRONX, NY CONSTANTINE I KOSTAS, MD LYNNFIELD, MA MORTON L KURLAND, MD RANCHO MIRAGE, CA LEON C LAHAYE, MD LAFAYETTE, LA TIMOTHY A LAMPHIER, MD PALM SPRINGS, CA ANTHONY LAPOLLA, MD CAMARILLO, CA HARVEY M LEVIN, MD PHILADELPHIA, PA ROBERT A LEVINSON, MD NEWARK, NJ ELLIN LIEBERMAN, MD SOUTH PASADENA, CA LEO LOWE, MD NEW YORK, NY ELBERT MCCRACKEN, MD STUTTGART, AR GORDON MCHARDY, MD NEW ORLEANS, LA KEITH M MINTON, DO TAMPA, FL GEORGE MOSKOWITZ, MD CHARLESTOWN, SC FELIPE P NOVO, MD TEWKSBURY, MA JULIO A ORTIZ, MD HUMACAO, PR E A PAULK JR, MD ATLANTA, GA BARRY R PAULL, MD BRYAN, TX ROGER C POISSON, MD MONTREAL PQ, NG CAREY L QUARLES, PHD WELLINGTON, CO LUTHER M REAGAN, PHD HEBRON, MD

CDER

D

06-AUG-1981

Through hearing process

CDER

DR

Through hearing process

CDER

D

19-JUL-1966 (reinstated 19-AUG-1966) 13-NOV-1980

CDER

D

04-NOV-1982

By consent agreement

CBER

D

25-NOV-1991

By consent agreement

CDER

D

07-OCT-1986

By consent agreement

CDER

D

06-NOV-1978

Through hearing process

CDRH

D

18-JUN-2002

Through hearing process

CDER

D

14-FEB-1979

Through hearing process

CDER

D

05-MAY-1969

Through hearing process

CDER

D

01-FEB-1980

Through hearing process

CDER

D

31-MAR-1988

By consent agreement

CBER

D

04-OCT-1993

By consent agreement

CDER

D

18-OCT-1966

Through hearing process

CDER

D

03-MAY-1977

Through hearing process

CDER

DR

Through hearing process

CDER

D

13-JUN-1968 (reinstated 27-JAN-1969) 26-JAN-1993

By consent agreement

CDER

DR

CDER

D

31-JAN-1983 (reinstated 31-JAN-1986) 04-NOV-1980

By consent agreement for 3 years Through hearing process

CDER

D

03-DEC-1980

Through hearing process

CDER

D

08-JAN-1990

Through hearing process

CDER

R

21-NOV-1991

Total

CDER

D

28-MAY-1991

By consent agreement

CVM

D

29-JUL-2002

Through hearing process

CVM

D

01-NOV-1991

By consent agreement

© 2005 by CRC Press LLC

Comments

Through hearing process

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TABLE 4.6 (cont.) Disqualified/Totally Restricted List Name/Address

Center

Type

Action Date

ARNOLD RITTER, DO PHOENIX, AZ KATHLEEN E ROBERTS, MD SAN FRANCISCO, CA WILLIAM S ROBERTS, MD CHARLOTTE, NC BENNETT ROBIN, MD SILVER SPRING, MD C J ROSENTHAL, MD BROOKLYN, NY STANLEY F ROTH MIAMI SHORES, FL JEROME ROTSTEIN, MD BRONX,WHITE PLAINS, NY NOEL M ROWAN, MD READING, PA WALLACE RUBIN, MD NEW ORLEANS, LA W M SAMS JR, MD BIRMINGHAM, AL MANUEL SANGUILLY, MD TARRYTOWN, NY FRANCOIS SAVERY, MD LONG BEACH, CA JAMES J SCHEINER, MD FAIRFAX, VA JEROME J SCHNEYER, MD SOUTHFIELD, MI DUANE SHERWIN, MD SEATTLE, WA SHERIDAN W SHIRLEY, MD BIRMINGHAM, AL PHYLLIS F SHROFF, MD PARADISE VALLEY, AZ HARRY SHUBIN, MD PHILADELPHIA, PA LEONARD SLAZINSKI, MD SARASOTA, FL LYMAN SMITH, MD ELGIN, IL RONALD C SMITH, MD LOS ANGELES, CA JOSEPH H SOBATKA, MD PHOENIX, AZ ALEXANDER S SPIERS, MD TAMPA, FL SAMUEL SPLITTER, MD HAMPSTEAD, NY PETER P STEELE, MD DENVER, CO

CDER

D

28-FEB-1980

Through hearing process

CDER

D

24-NOV-1964

Through hearing process

CBER

D

09-JUL-1991

By consent agreement

CDER

D

19-JUN-1964

Through hearing process

CDER

D

21-JAN-1998

By consent agreement

CDER

D

03-AUG-1982

By consent agreement

CDER

D

03-DEC-1975

Through hearing process

CDER

D

10-JUN-1985

By consent agreement

CDER

D

13-MAR-1970

Through hearing process

CDER

D

23-OCT-1997

By consent agreement

CDER

D

23-NOV-1982

By consent agreement

CDER

D

06-OCT-1978

Through hearing process

CDER

D

31-JUL-1979

Through hearing process

CDER

D

16-APR-1978

Through hearing process

CDER

D

09-JUL-1982

By consent agreement

CDER

R

30-JAN-1984

Total

CDER

R

26-APR-1983

Total

CDER

D

16-MAR-1970

Through hearing process

CBER

D

16-AUG-1991

By consent agreement

CDER

DR

CDER

D

17-MAR-1975 (reinstated 08-JUN-1983) 01-AUG-1979

Through hearing process

CDER

D

21-SEP-1970

Through hearing process

CDER

DR

CDER

D

14-DEC-1987 (reinstated 24-DEC-1990) 29-JUL-1968

CDER

D

02-APR-1986

© 2005 by CRC Press LLC

Comments

Through hearing process

By consent agreement, for 3 years Through hearing process Through hearing process

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TABLE 4.6 (cont.) Disqualified/Totally Restricted List Name/Address

Center

Type

Action Date

Comments

MARC J STRAUS, MD VALHALLA, NY RICHARD A STREB, MD GONZALES, LA DAVID O TABER, MD EL PASO, TX STEVEN K TEPLICK, MD LITTLE ROCK, AR ANAND TEWARI, MD NEW HAVEN, CT MARIO P VALDEZ, MD TUCSON, AZ HUIBERT M VRIESENDORP, MD MARSHFIELD, WI WILLIAM T WALLENS, MD ROSWELL PARK, NY JEROME WEISS, MD NEW YORK, NY JOSEPH L WILLIAMS LAS VEGAS, NV DAVID T WONG, MD WITCHITA, KS ROBERT E YOUNG, MD COLUMBUS, OH

CDER

D

18-MAY-1982

By consent agreement

CDER

D

03-JAN-1997

By consent agreement

CDER

R

17-JUN-1982

Total

CDER

D

08-MAR-1994

Through hearing process

CBER

D

26-OCT-1993

By consent agreement

CDER

R

03-FEB-1994

Total

CBER

D

31-DEC-2001

Through hearing process

CDER

D

22-AUG-1983

By consent agreement

CDER

D

31-DEC-1984

By consent agreement

CDER

D

10-SEP-1999

CDER

R

09-JUL-1982

By consent agreement, for 3 years Total

CDER

D

15-OCT-1982

By consent agreement

Note: D, Disqualiﬁed or totally restricted Clinical Investigators who are not eligible to receive investigational products; DR, reinstated; R, restricted. CBER, Center for Biologics Evaluation and Research; CDER, Center for Drug Evaluation and Research; CDRH, Center for Devices and Radiological Health; CVM, Center for Veterinary Medicine.

Administrative Enforcement actions, the FDA will issue clinical holds, NIDPOEs, multiple FDA 483 Notice of Observations forms, warning letters, and other correspondence.

4.5.2 APPLICATION INTEGRITY POLICY On September 10, 1991, the FDA published notice of their application integrity policy (AIP) in an article formally entitled, “Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities: Final Policy” (Federal Register, 56 FR 46191). The AIP described the FDA’s approach regarding the review of applications that may be affected by wrongful acts that raise signiﬁcant questions regarding data reliability. This section highlights eight areas involving the AIP: • • • • • • • •

Applications involved in AIP reviews Deferral of scientiﬁc review Pattern or practice Untrue statement of material fact Validity assessment Wrongful act Invoking AIP Revoking AIP

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4.5.2.1

153

Applications Involved in AIP Reviews

Interpretation of the term “application” by the AIP is quite expansive. The term includes “any application, petition, amendment, supplement, or other submission made by an applicant to an Agency review process in support of the approval or marketing of a regulated product.… References to data in an application include all data and other information submitted in or in relation to, or incorporated by reference in the application” (56 FR 46191, at 46199). For our purposes, an application includes any submission of any type to the FDA, such as pending and approved applications or petitions, amendments, supplements, supplemental amendments, premarket notiﬁcations (510(k)s), annual reports, investigational new drug applications, investigational new animal drug applications, and investigational device exemptions (IDEs) upon which the application is based. An application also includes a drug, device, or food master ﬁle; correspondence; and any submission by any person to support the approval or marketing of a regulated product. 4.5.2.2

Deferral of Scientific Review

If the FDA suspects that false scientiﬁc information is contained in the application, it may defer its scientiﬁc review. A deferral of scientiﬁc review indicates that the Center’s review unit will not expend scientiﬁc review resources on an application until the Center is satisﬁed that the data and information in the application are reliable. To defer its review, it must ﬁnd a pattern or practice of false information contained in an approved or pending application. In this case, a pattern is the occurrence of more than one instance of errors or acts involving subject matter important to the evaluation of an application. The term “practice” includes an act or process of doing something affecting subject matter important to the evaluation of an application. A practice can be one or more acts or processes. A pattern or practice can occur in one or more applications. 4.5.2.3

Untrue Statement or Material Fact

An untrue statement of material fact is a false statement, misstatement, or omission of a fact. A determination that an untrue statement is material is necessary for purposes of invoking the AIP. The Center should make a written determination, which may involve discussions with the FDA’s Ofﬁce of the Chief Counsel (OCC). 4.5.2.4

Validity Assessment

The AIP and its accompanying preamble in the Federal Register notice (56 FR 46191) frequently refer to the validity assessment, which involves the FDA’s determination of the scope and extent of an applicant’s suspected wrongful acts, an Agency inspection of the ﬁrm, and an Agency review of the applicant’s audit. The Agency may assess the validity of any applications called into question by the wrongful acts, in addition to those directly affected. An Agency inspection may be initiated before scientiﬁc review of an application is deferred. 4.5.2.5

Wrongful Acts

A wrongful act is any act that may subvert the integrity of the review process. A wrongful act includes, but is not limited to, submitting a fraudulent application, offering or promising a bribe or illegal gratuity, or making an untrue statement of material fact. A wrongful act also includes submitting data that are otherwise unreliable due to, for example, a pattern of errors whether caused by incompetence, negligence, or a practice such as inadequate standard operating procedures or a systemwide failure to ensure the integrity of data submissions. A wrongful act may be evidenced in a document, including informal documents such as correspondence or memoranda, or verbally, such as in telephone conversations or in one-on-one meetings. Regardless of the means, each suspected incident of a wrongful act should be reported and investigated to determine whether it raises signiﬁcant questions regarding data integrity and reliability with respect to a regulated product (56 FR 46191, at 46192).

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4.5.2.6

Invoking and Revoking AIP

Invoking AIP means that the FDA will apply the application integrity policy to one or more applications by deferring substantive scientiﬁc review pending a validity assessment of data and information in all of the affected applications. Revoking AIP means that the FDA will resume substantive scientiﬁc review of all of an applicant’s pending applications that have been subject to the application integrity policy. Following are examples of letters sent to applicants when the FDA invokes or revokes AIP. Model Letter to Applicant When the Center Invokes the AIP [Date] [Responsible person, Title] [Firm name] [Firm address] Dear [Responsible person]: The Center for [applicable center] has determined that [ﬁrm name] submitted [select one or more] a fraudulent application with the Agency, or made untrue statements of material fact, or gave or promised bribes or gratuities to an Agency ofﬁcial. These ﬁndings are more fully described in the letter dated [date], indicating our intention to withdraw approval of the [select one] NDA/ANDA/PLA/BLA for [product] and/or an FDA 483 Notice of Observations form issued to [ﬁrm] on [date]. These ﬁndings raise signiﬁcant questions regarding the reliability of data in all [or identify the subset of] applications (pending and approved) that [ﬁrm] has ﬁled with the Agency. In accordance with FDA policy, the Agency will assess the validity of the data and information in all of [ﬁrm’s] affected applications. This assessment will take priority over substantive scientiﬁc data review until questions regarding data integrity are resolved. This means that the Agency will defer substantive scientiﬁc review (including review of data and labeling) of any pending application or of any new application or supplemental application ﬁled after the date of this letter. The Agency may continue or resume substantive review of an application prior to completion of the validity assessment in special circumstances where such an action is clearly in the interest of public health. The Agency’s policies regarding validity assessments and corrective actions that companies may take are described more fully in the Agency’s policy entitled “Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities: Final Policy,” which was published in the Federal Register of Tuesday, September 10, 1991. Guidance for ﬁrms (regarding audits) and the Agency in conducting validity assessments is also contained in a document entitled “Points To Consider for Internal Reviews and Corrective Action Operating Plans,” the availability of which was announced in the same issue of the Federal Register. Enclosed are copies of both documents. Staff of the local FDA district ofﬁce is available to meet with you to discuss resolution of the data integrity and reliability questions raised in the above-mentioned applications. To arrange a meeting with the district ofﬁce, please write to or call: [District Director’s name, title] [District name] U.S. Food and Drug Administration [Address] [Phone]

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To discuss the Agency’s ﬁnding that a validity assessment is warranted, please contact: U.S. Food and Drug Administration [Center name] Division of [Division name] [Applicable branch, mail stop] [Address] [Phone] Alternatively, you may withdraw the application based on [applicable Center regulation]. A listing that identiﬁes all the ﬁrm’s currently approved and pending applications ﬁled with the Agency, including those applications for which the Agency invoked the AIP, is enclosed. Please inform the Agency of the action you intend to take with regard to each of the applications within ten (10) days of the date of issuance of this letter. Sincerely, [Center Director’s name] [Title] [Center name] U.S. Food and Drug Administration [Address] Enclosures cc: (Note: Do not copy lawyers without a current written statement from the ﬁrm requesting the Agency to copy their lawyer on all correspondence. Also, AIP contact persons need to provide mail codes for all in their Center (area) who should be copied on letters from other centers that invoke the AIP.) Model Letter to Applicant When the Center Revokes the AIP [Date] [Responsible person, Title] [Firm name] [Firm address] Dear [Responsible person]: The Center for [applicable center] advised [ﬁrm] in a letter dated [date] that the Agency deferred substantive review of all [or identify the subset] approved and/or pending applications submitted by [ﬁrm] until questions regarding the reliability of the data were resolved. Since that date, [ﬁrm] has advised the FDA that it conducted an internal review to identify and correct the circumstances that gave rise to the submission of fraudulent applications or untrue statements of material fact which caused the Agency to question the validity and reliability of data in the applications. Furthermore, [ﬁrm] has submitted to the [Center] and substantially executed a Corrective Action Operating Plan (Plan) applicable to all of [ﬁrm’s] products that contain adequate safeguards and procedures designed to preclude future wrongful acts and noncompliance with regulatory requirements. The FDA’s local district ofﬁce [or applicable Center investigating unit] has conducted a validity assessment inspection of your ﬁrm and has determined that [ﬁrm] appears to have implemented the commitments made in the Plan. Therefore, I have directed my staff to resume substantive scientiﬁc review of the affected applications. For an application that was withdrawn by the ﬁrm and that was not included in the validity assessment, the ﬁrm has committed to not reﬁle or reactivate that application until the Agency is satisﬁed with the reliability of the data/information. If the validity assessment

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found that the data in the withdrawn application were unreliable, the applicant who wishes to replace the data should submit a new application according to the AIP (56 FR 46191, at 46200). Resumption of substantive scientiﬁc review by the FDA of [ﬁrm’s] applications is not to be construed as approval of any conditions that may be found in the future. Please be advised that the FDA expects [ﬁrm] to adhere to the commitments made in its Corrective Action Operating Plan, and the Agency will monitor your ﬁrm’s operations to verify continued compliance. Should it be determined at any time in the future that [ﬁrm] has failed to comply with its commitments, the FDA will not hesitate to take appropriate action. If you have any questions, you may contact [Center representative] at [telephone]. Sincerely yours, [Center Director’s name] [Title] [Center name] U.S. Food and Drug Administration [Address] cc: (Note: Do not copy lawyers without a current written statement from the ﬁrm requesting the Agency to copy their lawyer on all correspondence. Also, AIP contact persons need to provide mail codes for all in their Center (area) who should be copied on letters from other centers that invoke the AIP.)

4.5.3 CORRECTIVE ACTIONS The corrective actions an applicant will be expected to take will depend upon the facts and circumstances of each case, the nature of the wrongful acts, the nature of the data under consideration, and the requirements of the particular review process. Applicants who engage in wrongful acts ordinarily will need to take the following corrective actions to establish the reliability of data submitted to the FDA in support of pending applications and to support the integrity of products on the market: 1. Cooperate fully with FDA and other federal investigations to determine the cause and scope of any wrongful acts and to assess the effects of the acts on the safety, effectiveness, or quality of products. 2. Identify all individuals who were or may have been associated with or involved in the wrongful acts and ensure that they are removed from any substantive authority on matters under the jurisdiction of FDA. 3. Conduct a credible internal review designed to identify all instances of wrongful acts associated with applications submitted to the FDA, including any discrepancies between manufacturing conditions identiﬁed in approved applications and manufacturing conditions during actual production. The internal review is intended to supplement the FDA’s ongoing, comprehensive investigation to identify all instances of wrongful acts. The internal review should involve an outside consultant or a team of consultants who are qualiﬁed by training and experience to conduct such a review. All oral or written reports related to the review that are provided by the consultant to the applicant should be made available simultaneously to FDA for independent veriﬁcation. 4. Commit, in writing, to developing and implementing a corrective action operating plan to assure the safety, effectiveness, and quality of their products. This commitment ordinarily will be in the form of a consent decree or agreement, signed by the president, chief executive ofﬁcer, or other ofﬁcial most responsible for the applicant’s operations and submitted to the FDA. The corrective action operating plan will, as appropriate, address procedures and controls to preclude future instances of wrongful acts and noncompliance

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TABLE 4.7 Enforcement Statistics Fiscal Year 2002 0

Prosecutionsa

1

Civil money penalty

13

Seizures

15

Consent decrees of permanent injunctions (ﬁled)

317

Convictions (OCI)

755

Warning letters Number of FDA 483 forms issued Recalls Inspections Import refusals

7180 5025 18,572 32,654

Asset forfeitures (OCI)

$18,300,000

Fines and restitution (OCI)

$24,027,549

a

Does not include Ofﬁce of Criminal Investigations (OCI) data.

Source: FDA Enforcement, 2003.

with regulatory requirements for approved applications, as well as procedures and controls to preclude any recurrences of other violations which may have been found (e.g., a comprehensive ethics program). The FDA will reinspect the applicant to determine that the internal review has been satisfactorily completed and that the applicant’s written corrective action operating plan has been satisfactorily implemented. Such inspections should disclose positive evidence (e.g., effective management controls, standard operating procedures, and corroborating documentation) that the applicant’s data are reliable and that the applicant can be expected to manufacture products in compliance with current good manufacturing practices and application requirements. In addition, the FDA may request an applicant to commit in writing to retest any product (including, in the case of drugs, bioequivalence and bioavailability retesting), as the FDA deems appropriate. An applicant also may be requested under existing regulatory procedures to recall products affected by the wrongful acts or otherwise lacking adequate assurance of safety, effectiveness, or quality.126 In FY2002, civil action ﬁnes and restitution netted $24,027,549. A glance of other FDA Administrative Enforcement actions is provided in Table 4.7. From 1993 until 2002, the Ofﬁce of Criminal Investigations initiated proceedings against criminal actions that resulted in the arrests and convictions shown in Figure 4.1.

4.6 CASE STUDIES Recently, the FDA published a list of several companies that are subject to application integrity (see Table 4.8). Included in the list are the Central Files containing the information that resulted in the AIP for that particular ﬁrm. It is recommended that independent research be conducted by the reader to review this material in depth. Additionally, the FDA has published several articles in the 2003 FDA Enforcement publication. Read the articles below, and relying upon the knowledge you have gained thus far regarding FDA Administrative Enforcement, assess the events described in the articles to determine whether the FDA acted within or outside of its authority. Ascertain whether all possible avenues of legal actions have been exhausted and whether any are missing.

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FIGURE 4.1 FDA criminal arrests and convictions FY1993–FY2002.

FDA NEWS RELEASE ADDRESSING ADMINISTRATIVE ENFORCEMENT AND THE CRIMINAL ACTIONS AND PENALTIES PAID BY THOSE WHO VIOLATED THE LAW FOR IMMEDIATE RELEASE P03-47 June 20, 2003

Media Inquiries: 301-827-6242 Consumer Inquiries: 888-INFO-FDA

Federal Investigation Leads to Guilty Plea in Healthcare Crime Food and Drug Administration Ofﬁce of Criminal Investigations (FDA OCI) ofﬁcials today joined representatives of the U.S. Attorney’s Ofﬁce for the District of Delaware, the Department of Health and Human Services (DHHS), and the Defense Criminal Investigative Service (DCIS) in announcing that AstraZeneca Pharmaceuticals LP has pleaded guilty to a large-scale healthcare crime and agreed to pay $355 million to resolve the associated criminal charges and civil liabilities. The massive conspiracy, uncovered by FDA, OCI, DHHS, and DCIS investigators, involved illegitimate pricing and marketing of Zoladex, an AstraZeneca drug for the treatment of prostate cancer. The various schemes used by the ﬁrm caused multimillion dollar losses to federally and state-funded insurance programs and individual patients. “FDA will not tolerate criminal conduct that exploits patients, plunders the national treasury, and adds to the cost of health care,” said FDA Commissioner Mark B. McClellan, M.D., Ph.D. “Today’s announcement sends a strong message that the FDA will enforce the laws and take vigorous actions against those who defraud consumers and abuse the health care system.” The agreement announced today included the following main provisions: • AstraZeneca pleaded guilty to criminal conspiracy to violate the Prescription Drug Marketing Act by causing Medicare, Medicaid, and other federal providers to be overcharged for Zoladex that had been provided as free samples to urologists. As part of the plea agreement, the company agreed to pay a $63,872,156 criminal ﬁne.

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TABLE 4.8 Firms Subject to Application Integrity Center for Drug Evaluation and Research (CDER) Firm

Location

Central File No./FACTS No.

Remarks

Biochimica Opos SpA

Agrate Brianza, Italy

9611856/3002806473

—

Biopharmaceutics, Inc.*

Bellport, NY

2434267/2434267

—

Solopak Pharmaceuticals, Inc.

Elk Grove Village, IL

51450942 (Tonne Rd.)/1450942 51423737 (Chase St.)/3000719798

—

Franklin Park, IL

51419209/1419209

One ﬁrm removed from this list April 2003 Superpharm Corp.*

Bayshore, NY

2434256/2434256

—

Center for Biologics Evaluation and Research (CBER) Sclavo, S.p.a.*

Siena, Italy

9610932/1000300459

—

Center for Devices and Radiological Health (CDRH) Bionike, Inc.

South San Francisco, CA

No CFN/1000162526

—

Bioplasty, Inc.*

Minneapolis, MN

B2125840/2125840

—

Endotec, Inc.

South Orange, NJ

FEI: 3002400750

—

FEI: 3001697474

—

One ﬁrm removed from this list April 2003 Micro Detect, Inc.

Tustin, CA

Sherman Pharmaceutical, Inc.

Abita Springs, LA

2310787/2310787

—

Syntron

Carlsbad, CA

2025760/96782

—

Center for Food Safety and Applied Nutrition (CFSAN) None Center for Veterinary Medicine (CVM) None Note: The names of the ﬁrms listed here are those that were notiﬁed that the FDA is deferring substantive scientiﬁc review of one or more of the ﬁrm’s applications and/or is proceeding to withdraw the approved applications. The asterisk (*) indicates that, to the Agency’s knowledge, the ﬁrm is out of business. This table includes the company’s Central File Number and identiﬁcation number in the FDA’s electronic Field Accomplishment and Compliance Tracking System (FACTS), or the FACTS Federal Establishment Identiﬁcation (FEI) Number.

• AstraZeneca also agreed to settle its civil liabilities and to resolve allegations that its fraudulent drug pricing schemes and sales and marketing misconduct had caused false and fraudulent claims to be ﬁled with federal and state healthcare programs. • The agreed payments are $266,127,844 to the U.S. government for claims ﬁled with the Medicare, TriCare, Department of Defense, and Railroad Retirement Board Medicare programs, and a total of $24,900,000 to the U.S. and state governments for claims involving state Medicaid programs.

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The FDA Ofﬁce of Criminal Investigations began their investigation of AstraZeneca pricing and marketing practices after a private individual ﬁled a civil False Claims Act suit. The broadly based investigation, which involved also the Ofﬁce of the Inspector General for the DHHS, the DCIS, and the Federal Bureau of Investigation, discovered that AstraZeneca employees were using several illegal methods to stimulate the demand for Zoladex by enabling prescribers to reap illicit proﬁts. In one of these schemes, AstraZeneca provided thousands of free samples of Zoladex to physicians knowing that they would charge their patients and insurance programs for the samples. Another illegal inducement used by the ﬁrm involved inﬂating the price of Zoladex reported to Medicare as the basis for reimbursement while deeply discounting the actual price charged to the physicians. AstraZeneca also misreported and underpaid the Medicaid rebates it owed to the states for the use of Zoladex. The investigation, which is continuing, also resulted in charges against three physicians of conspiring with AstraZeneca to bill patients and third party payers for free Zoladex samples. Two of the prescribers have pleaded guilty. Source: www.fda.gov/bbs/topics/news/2003/NEW00915.html.

OFFICE

OF

CRIMINAL INVESTIGATIONS

In ﬁscal year 2002, the efforts of FDA’s Ofﬁce of Criminal Investigations (OCI) resulted in 372 arrests and 317 convictions for violations of the Federal Food, Drug, and Cosmetic Act and related statutes. Additionally, these criminal investigations resulted in $24,027,549.00 in ﬁnes/restitution and $18,300,000.00 in forfeitures. Center for Devices and Radiological Health Unapproved Device Promoted for Carpal Tunnel Syndrome: Defendants Ordered To Pay $211,102.30 in Restitution On January 4, 2000, FDA’s Ofﬁce of Criminal Investigations (OCI) Special Prosecutions Staff received information that a ﬁrm called Para Tech Industries (Para Tech), located in Dayton, Ohio, was shipping unapproved medical devices into interstate commerce. Para Tech was shipping these devices to various chiropractic clinics in the New York regional area. The information was uncovered in a health fraud investigation conducted by the Federal Bureau of Investigation (FBI). The device in question was the CTD Mark I promoted for use in the treatment of Carpal Tunnel Syndrome without FDA approval. In January of 2002, OCI conducted numerous interviews in Dayton, Ohio, of witnesses in this investigation. The witnesses were primarily former employees of Para Tech. The subjects of the investigation were Paul F. Fulk, President of Para Tech, and Earnie S. Philbot, Vice President of Para Tech. Fulk was also the President and Chief Executive Ofﬁcer of Therasys, Inc. Philbot was the Vice President, Secretary, and Treasurer of Therasys, Inc. The company, Therasys, Inc., is a related company incorporated in the State of Florida. Para Tech was incorporated in the State of Ohio. Based on information developed through interviews of former Para Tech employees, Fulk and Philbot were indicted on February 16, 2000, by a grand jury in White Plains, New York.127 Both individuals and both entities were indicted on the following charges: • Count 1: Conspiracy To Defraud the FDA [18 USC 371]. • Counts 2 through 18: Shipments of Adulterated Devices into Interstate Commerce [21 USC 331(a), 333, and 352; 18 USC 2].

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• Counts 19 through 35: Mail Fraud (Shipping Adulterated Medical Devices Through the U.S. Mail and/or Other Commercial Carrier) [18 USC 1341 and 2]. On February 23, 2000, Fulk and Philbot surrendered to U.S. Marshals in White Plains, New York. They appeared before U.S. Magistrate Judge George Yanthis in the Southern District of New York and pled “Not Guilty” to all of the above-mentioned charges. Fulk also pled “Not Guilty” on behalf of Para Tech and Therasys, Inc. On April 12, 2000, attorneys for Fulk, Philbot, Para Tech Industries, and Therasys, Inc., met with prosecutors and agents at the U.S. Attorney’s Ofﬁce in White Plains, New York. During the meeting, the prosecutor presented the defense attorneys with all of the evidence developed against their respective clients. Subsequently, on June 29, 2000, Fulk and Philbot signed plea agreements. Fulk was convicted of violating 18 USC 371 and 1505, Conspiring To Obstruct the Proceedings of the FDA. Fulk admitted to being the leader and organizer in the aforementioned criminal activity. Philbot was convicted of the same charges as Fulk, but he did not admit to being the leader or organizer. The FDA proceedings that the defendants obstructed were FDA inspections conducted by the FDA’s Cincinnati District Ofﬁce in December of 1994 and December of 1995. During those inspections, Fulk and Philbot provided false and misleading information during those inspections. On March 3, 2002, Chief Justice Walter Herbert Rice of the Southern District of Ohio in Dayton, Ohio, sentenced Fulk, Philbot, Para Tech, and Therasys, Inc., to the following: • Fulk was sentenced to 12 months’ incarceration with work release and 3 years supervised probation. • Philbot was sentenced to 3 years’ probation and 6 months of home conﬁnement (ﬁrst 3 months to be electronically monitored). • Para Tech and Therasys, Inc., were each ordered to pay a total of $211,102.30 in restitution to 24 chiropractors who bought the CTD-Mark I devices believing that it was an FDA-approved device. Magnet Promoted To Cure Cancer: Investigation Discloses That Cancer Victims Invested $675,000 for Fraudulent Magnetic Device This case originated on January 18, 1996, upon referral from the Tennessee Health Related Board, which contacted FDA following a physician’s complaint. The physician stated that James Gary Davidson of the Macrotech Corporation, Paris, Tennessee, was claiming to have developed a “curative” cancer treatment based on a device utilizing magnets. FDA’s Ofﬁce of Criminal Investigations (OCI), FDA’s Nashville Branch, Internal Revenue Service Criminal Investigation, U.S. Postal Inspection Service, and the Federal Bureau of Investigation conducted a joint investigation. The primary false representation made to cancer victims and their families was that a magnetic ring device, through which the patients were passed, was capable of exploding or imploding cancer cells and thereby curing cancer. Investments in the amount of $675,000 in the purported medical technology were made by cancer patients, their families, and others. Treatments with essentially the same device were also falsely represented to be cures or highly effective treatments for multiple sclerosis, arthritis, muscular dystrophy, Alzheimer’s, emphysema, coronary heart disease, and AIDS, among others. James Gary Davidson falsely represented himself as having a doctorate degree in nuclear physics from Karl Marx University in Leipzig, Germany, and as being a former Central

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Intelligence Agency agent. Davidson had previously been convicted in 1994 of felony securities fraud violations in Illinois in connection with defrauding investors in a fuel scheme. On March 4, 2002, Davidson was convicted of one count of mail fraud and one count of money laundering. Davidson admitted that he devised a scheme to defraud and obtain money by false pretenses from various persons interested in a cancer treatment, knowing full well these representations were false when he made them. Davidson also admitted that he misrepresented his education and background by falsely stating he obtained a doctorate degree in physics and stating he had worked for the Central Intelligence Agency. As part of his scheme, Davidson led individuals to believe they were free of, or had been “cleared” of cancer. On September 13, 2002, James Davidson was sentenced in the U.S. District Court to 7 years and 4 months of incarceration. During the proceedings, Davidson paid restitution to a number of named victims totaling $675,000. In sentencing Davidson, the Judge stated that Davidson’s crime was exceptionally cruel because, although his claims were unbelievable, his victims were desperate people looking for hope. Physician Sentenced for Use of Silicon and Mineral Oil Injections: Mexican Physician Convicted for Fraud, Ordered To Pay $17,000 in Restitution The FDA’s Ofﬁce of Criminal Investigations (OCI) and the Federal Bureau of Investigation (FBI) in McAllen, Texas, initiated an investigation into the use of silicon and mineral oil injections for cosmetic purposes by a Mexican physician practicing medicine in the United States. The investigation disclosed that Dr. Rosa Nunez, a licensed physician only in Mexico, was traveling from Mexico to the United States to perform cosmetic procedures on a number of women. Nunez was performing injections for fuller lips, buttocks, and calves. As a result of the injections, many of the women experienced disﬁguration at the injection site and swollen ankles that had hardened. As part of the investigation, several undercover meetings were set up between a female FBI agent and Nunez. During these meetings, Nunez agreed to inject the calves and lips of the undercover agent and her friend with silicon. Nunez was charging between $3000 and $5000 for these treatments. Incident to a meeting at a hotel room, Nunez and her two assistants were arrested and several vials of a biopolymer (silicon) solution were seized along with two large unmarked bottles which analysis conﬁrmed to contain mineral oil. This case went to trial and the witnesses/victims and both of Nunez’s assistants testiﬁed that Nunez was using the biopolymer (silicon) in the lips but injecting the bottles identiﬁed as mineral oil into the calves and buttocks. A witness from the FDA’s Forensic Chemistry Center testiﬁed to the identity of the substances, and a witness from the FDA’s Center for Devices and Radiological Health (CDRH) testiﬁed that the use of mineral oil and silicon in this way is not approved by the FDA for cosmetic purposes and that the injection of these substances was considered to be adulterated devices. At the conclusion of the trial Nunez was convicted of 18 USC 1343 (Wire Fraud) and 18 USC 371 (Conspiracy). On October 15, 2002, Nunez was sentenced in McAllen, Texas, to serve 22 months’ incarceration in a federal correctional institution and ordered to pay $17,000 in restitution to her victims. One of Nunez’s assistants, Maria Flores, was convicted of one count of violating 21 USC 331(a) (Introduction into Interstate Commerce of an Adulterated Device).

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Physician Submits False Information to FDA: Physician Falsely Presents Himself as Qualiﬁed To Interpret Mammograms This investigation was initiated based on a referral from the FDA’s Los Angeles District Ofﬁce. The district received information from the Los Angeles County Department of Health Services, Radiation Management. The Los Angeles County Department of Health Services, Radiation Management (LA Radiation Management) are FDA contract inspectors utilized to certify mammography facilities under the Mammography Quality Standards Act, 42 USC 262. An inspection conducted at Medical Diagnostic, Inc., Huntington Park, California, by the LA Radiation Management identiﬁed quality assurance issues and suspected fraudulent documentation submitted to substantiate that a physician, Terry Alan Dichter, M.D., was qualiﬁed to continue to interpret mammography by his education, background, and experience. The information provided by Dichter to the LA Radiation Management included a list of mammography cases he purportedly interpreted, a letter of veriﬁcation with signature of Dichter’s former employer for that number of mammography cases interpreted, and copies of University of Southern California (USC) School of Medicine certiﬁcates for purported continuing medical education courses attended. The investigation revealed that the list of mammography cases interpreted and the USC School of Medicine continuing medical education certiﬁcates were fraudulent. A forensic document examination of the letter of veriﬁcation and signature by the U.S. Secret Service determined that Dichter authored the fraudulent document and signature. On December 29, 2000, Dichter’s California Medical License was revoked. On October 24, 2001, Dichter agreed to waive indictment and was convicted of a one-count Information that charged him with violation of 18 USC 1001 (False Statements). The speciﬁc charge involved Dichter knowingly providing false written statements to support the false claims he made to FDA relative to his education, experience, and background. On January 14, 2002, Dichter appeared in U.S. District Court, Los Angeles, California, and was arraigned on the one-count Information. Dichter was released on a $10,000 appearance bond. On June 11, 2002, in the Central District of California, Dichter was sentenced to 10 months’ incarceration, 5 months in a Bureau of Prison facility and 5 months of home detention with electronic monitoring, and 36 months of supervised release following the completion of his term. Center for Drug Evaluation and Research128 Five Sentenced in Methamphetamine Case: Investigation Uncovers Conspiracy To Possess Methamphetamine with the Intent To Distribute The FDA’s Ofﬁce of Criminal Investigations (OCI) initiated an investigation into the purchase of pharmaceuticals by Northland Providers, a closed-door pharmacy opened and ﬁnanced by Peter Fenton, Tom Fenton, and Jim Bottineau. The partners, upon receiving the pharmaceuticals, would transfer them to their wholesale business, Lakeside Medical Supply, for sale to secondary wholesalers in Michigan and Nevada. The parties collaborated with Candi Creamer and Robert Christy. The scope of this investigation included historical witness interviews and information gained from industry sources, trash covers, pen register/toll record/trap and trace analyses, and physical surveillance, which provided probable cause for the Title III in captioned investigation from December 1998 to February 1999. Agents executed search warrants

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simultaneously in 5 states, and 31 forfeiture seizure warrants, executed in Minnesota and California, led to the seizure of approximately $1 million in cash, $350,000 in vehicles, approximately $850,000 in pharmaceutical inventory, and bond default of $100,000. On October 6, 1999, Peter Fenton was convicted of four felony charges in the District of Minnesota, including conspiracy to commit mail fraud and wire fraud, money laundering, felon in possession of a ﬁrearm, and conspiracy to possess methamphetamine with the intent to distribute. On November 18, 1999, Candi Creamer was convicted of two felony charges, including conspiracy to commit mail and wire fraud and money laundering. On February 4, 2000, Robert Christy was convicted of one felony count of possession of methamphetamine with intent to distribute and distribution of methamphetamine to Peter Fenton and Candi Creamer. Sentencing was as follows: • On August 23, 2000, Peter Fenton was sentenced to 87 months’ incarceration and victim restitution of $4,750,000. • On August 24, 2000, Candi Creamer was sentenced to 30 months’ incarceration. • On August 25, 2000, Robert Christy was sentenced to 30 months’ incarceration. • On August 28, 2001, James Bottineau was sentenced to 27 months’ incarceration and victim restitution in the amount of $4,750,000. • On September 30, 2002, Tom Fenton was sentenced to 24 months’ incarceration and victim restitution of $513,432.12. The sentencing of Tom Fenton concluded the investigation. Unapproved Drug Promoted for Treatment of Cancer: “Cancer” Drug Found To Contain Fungal Contaminants This case involved manufacturing and distribution of an unapproved drug, LK-200, by Private Biologicals Corporation (PBC), Woburn, Massachusetts. LK-200 is an injectable drug that was purported to treat cancer and to help ease the pain for patients suffering from cancer. It has not been approved for use in the United States. PBC was manufacturing LK-200 in its research facility in Woburn, Massachusetts, and was distributing it to cancer patients in the United States and the Bahamas. Between 1993 and 1995, both Tom Rodgers and T. Ronald Theodore solicited approximately $2 million from numerous investors by claiming that they had invented a promising new drug for treating cancer. Investors were told that, because the drug had not been approved by the FDA, PBC would manufacture the LK-200 overseas using a highly proprietary method of production. Theodore was also holding himself out as an “ M.D.” to investors, employees, and doctors, when he did not have a college degree or a medical degree from a recognized medical school, nor was he licensed to practice medicine in the United States. In reality, the LK-200 was not a result of any discovery by Theodore but instead was a new name for a preparation that was identiﬁed in the 1970s for use in cancer research and which was produced through well-known and widely published techniques. Theodore was manufacturing the LK-200 and packaging it with disregard for good manufacturing practices as required. PBC, in manufacturing the LK-200, maintained a continuous cell culture and made no attempt to control mutation in the cell line being used. As a result, a series of mutations in the cell line occurred while PBC was making the LK-200, with no method in place to determine whether those mutations affected the safety or potency of the product.

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PBC also failed to maintain proper sterility controls in the ﬁnal packaging for the product, which was shipped in syringes for injection into end-stage cancer patients. In 1995, retained samples were sent for laboratory testing for contamination. Ten of 62 samples tested showed a growth of fungal contaminants. On May 4, 2000, Tom Rodgers appeared in U.S. District Court, Boston, Massachusetts, and was convicted of three FDA misdemeanor charges as follows: 21 USC 331(p) (Unregistered Drug Manufacturing Facility), 21 USC 331(d) (Unapproved New Drug), and 21 USC 331(a) (Adulteration). Rodgers received a sentence of 1 year of supervised probation and a $10,000 ﬁne. On February 12, 2001, defendant T. Ronald Theodore went to trial in U.S. District Court, Boston, Massachusetts. On March 1, 2002, the jury returned a verdict of guilty on all counts as follows: • 9 felony counts of 18 USC 1341 (Mail Fraud) • 1 misdemeanor count each of 21 USC 331(p) (Unregistered Drug Manufacturing Facility) • 1 count of 21 USC 331(d) (Unapproved New Drug) • 1 count of 21 USC 331(a) (Adulteration) On March 1, 2002, Theodore was sentenced to 121 months’ incarceration followed by 3 years’ probation and was ordered to pay $1.5 million in restitution to his victims. Illegal Sale of Pediatric Vaccines: Search Warrant Uncovers Records Conﬁrming Five-Year Illegal Sales of Pediatric Vaccines The FDA’s Ofﬁce of Criminal Investigations (OCI) received information from the State of Wisconsin, Department of Regulation and Licensing, Division of Enforcement (Attorney Arthur Thexton). The initial information indicated that Roger J. Moraga, d/b/a The Clinic Pharmacy of Muskego, Wisconsin, was illegally selling various prescription drugs (pediatric vaccines) to client pediatricians in the greater Milwaukee area. The OCI, in conjunction with the New Berlin Police Department and the Wauwatosa, Wisconsin, Police Department, conducted numerous witness interviews and surveillances which eventually led to a State of Wisconsin Search Warrant being executed at Moragas’s Muskego, Wisconsin, residence on April 19, 2000. Evidence seized consisted of prescription drugs (pediatric vaccines), product sales records, and ﬁnancial business records of the Clinic Pharmacy, as well as yearly ﬁlings of federal income tax returns. Review of those records conﬁrmed 5-year sales of $661,993.00 worth of prescription drugs (pediatric vaccines) to numerous pediatricians. A Moraga proffer statement and corresponding polygraph examination, in conjunction with attorney deliberations, led to an October 25, 2001, ﬁling of a Criminal Information in the Eastern District of Wisconsin, Milwaukee, Wisconsin, charging Moraga with one count of violating 21 USC 331(t) (Introduction into Interstate Commerce of Misbranded Drugs) and one count of violating 26 USC 7201 (Filing False Income Tax Returns). On May 9, 2002, defendant Roger J. Moraga appeared before a U.S. District Court Judge, Eastern District of Wisconsin, at which time he was convicted and sentenced to 21 months’ incarceration. Moraga surrendered to federal prison authorities on September 3, 2002. Tampering with Prescription Drug: OCI Investigation Discloses Nurse Ordered Morphine for Deceased Patient The FDA’s Ofﬁce of Criminal Investigations (OCI) initiated this investigation based upon allegations concerning suspected tampering of the prescription drug Roxanol (morphine sulfate), at the Minnesota Veteran’s Nursing Home (MVH), Minneapolis, Minnesota.

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Speciﬁcally, the MVH alleged that they had found 6 bottles of Roxanol that they believed were tampered with. Subsequent investigation revealed that Thomas Maloney, a pool nurse from a nursing service, the Nurse Connection, was present on or about the time of each alleged tampering. An ongoing OCI/CGI investigation determined that Maloney was a suspect in the theft of prescription drugs and tampering. Speciﬁcally, Maloney had placed an order to an offsite pharmacy for morphine for a deceased patient while Maloney was employed at the Park Care Baptist Care Center, Minneapolis, Minnesota. Also, Maloney had placed an order for morphine for another deceased patient while employed at Maranatha Care Center, Brooklyn Center, Minnesota. Obviously, the patients never received the morphine, and on both occasions the morphine was never recovered. Based on the information, a criminal complaint was drafted alleging that on three occasions Maloney obtained controlled substances (Roxanol and Tylenol 3) by misrepresentation in violation of 21 USC 843(a)(3). Maloney was subsequently arrested. On September 10, 2001, a Federal Grand Jury in the District of Minnesota handed down a six-count indictment against Maloney charging Maloney with violations of 18 USC 1035 and 21 USC 843(a)(3). On November 5, 2001, Maloney was convicted of one count of making false statements in healthcare matters in violation of 18 USC 1035 and one count of obtaining a controlled substance through fraud in violation of 21 USC 843(a)(3). On February 21, 2002, Maloney was sentenced to 12 months’ incarceration. Prescription Drug Marketing Act The Prescription Drug Marketing Act, which was signed by the President on April 22, 1988, was enacted to ensure that prescription drug products purchased by consumers would be safe and effective and to avoid an unacceptable risk of counterfeit, adulterated, misbranded, subpotent, or expired drugs being sold to the American public. Congress decided that legislation was necessary because there were insufﬁcient safeguards in the prescription drug distribution system to prevent the introduction and retail sale of substandard, ineffective, or counterfeit drugs and that a wholesale drug diversion submarket had developed that prevented effective control over, or even routine knowledge of, the true sources of drugs. (Refer to The Prescription Drug Marketing Act, “Report to Congress,” Department of Health and Human Services, U.S. Food and Drug Administration, June 2001.) Illegal Sale of Prescription Drugs: OCI Investigation Results in Convictions for Selling Prescription Drug Samples In June 2000, the FDA’s Center for Drug Evaluation and Research (CDER) was alerted of a possible drug diversion at AstraZeneca Pharmaceutical Company. Jeffrey S. Pague was allegedly stealing drug samples from various physicians’ ofﬁces and selling the stolen product to multiple pharmacies. CDER referred this information to the FDA’s Ofﬁce of Criminal Investigations (OCI). Following his receipt of a target letter from the U.S. Attorney’s Ofﬁce, Pague admitted to improperly diverting and selling samples of the prescription drug Prilosec. Pague cooperated with the government’s investigation concerning additional suspects involved in the trading/selling of prescription drug samples. During the investigation, investigators determined that Anthony Manos, M.D., a physician practicing in West Chester, Pennsylvania, sold approximately 10,000 samples of Prilosec to Pague. On January 10, 2002, Jeffery Pague appeared in U.S. District Court for the Eastern District of Pennsylvania and was convicted of one felony count of trading and selling prescription

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drug samples in violation of 21 USC 331(t) and 333(b)(1)(B). On April 12, 2002, Pague was sentenced to serve 3 years of supervised probation, attend Narcotics Anonymous meetings during the probation period, perform 250 hours of community service, and pay a ﬁne of $15,000. On February 12, 2002, Anthony Manos, M.D., appeared in U.S. District Court for the Eastern District of Pennsylvania and was convicted of one felony count of trading and selling prescription drug samples in violation of 21 USC 331(t) and 333(b)(1)(B). On May 8, 2002, Manos was sentenced to 6 months of home conﬁnement (electronic monitoring) and 3 years’ supervised probation and to pay a ﬁne of $10,000. Pharmaceutical Diversion Scheme: Pharmacist Involved in the Purchase and Sale of Physician Samples and Misbranded Prescription Drugs The Los Angeles Field Ofﬁce of the FDA’s Ofﬁce of Criminal Investigations (OCI) initiated this investigation as part of an undercover “sting” investigation. Preliminary information regarding a criminal conspiracy to divert pharmaceuticals was forwarded to the Kansas City Field Ofﬁce for follow up. Ronald Shaffer, a pharmacist, recruited Sheryl Monbarren to manage the day-to-day operation of an illicit business that obtained prescription pharmaceuticals in Alabama and California, “laundered” them through a storefront warehouse in Colorado, and eventually sold the drugs to wholesalers nationwide. Shaffer remained behind the scenes in the operation but received a major cut of the proﬁts. Shaffer’s take of the proﬁts was paid to a shell company operated in his wife’s name. Donald Wyatt was recruited by Shafer and Monbarren to set up a closed-door pharmacy in Mobile, Alabama, called Professional IV Services. That entity certiﬁed in written contracts with pharmaceutical manufacturers that all prescription pharmaceutical products purchased from the manufacturers at prices substantially below wholesale would be sold only to nursing-home patients. However, at the direction of Monbarren, the drugs were shipped to a Colorado co-conspirator, Ralph Kopald. Ralph Kopald operated a Fort Collins, Colorado, warehouse known as Arjay Distributors. Kopald received the drugs from Professional IV Services and other closed-door pharmacy operators and immediately shipped the drugs to wholesale operations designated by Ronald Shaffer and Sheryl Monbarren. By trans-shipping through the Colorado operation rather than directly from the pharmacy, Shaffer and Monbarren made certain the pharmacy owners did not become aware of the ultimate buyer. This eliminated the possibility that the closed-door operator would cut Shaffer and Monbarren out of the business. It also gave the wholesale customer plausible deniability in that the wholesaler could deny knowledge of the fraudulent means used to obtain discounted pharmaceuticals. Wyatt, Kopald, and Shaffer were sentenced for their part in the operation in 2000. On February 11, 2002, Sheryl Monbarren was convicted of a violation of 18 USC 1341 (Mail Fraud) and 18 USC 2 (Aiding and Abetting). She received a 10-month sentence, with 5 months’ incarceration and 5 months of home detention. On September 30, 2002, Monbarren was sentenced in the U.S. District Court for the Central District of California, Los Angeles, California, for her part in the pharmaceutical diversion scheme. Monbarren’s sentencing capped an investigation of the diversion market that began in 1996. This investigation was a joint effort of OCI’s Kansas City Field Ofﬁce and the FBI’s Denver Division.

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Conspiracy To Buy and Sell Prescription Samples The FDA’s Ofﬁce of Criminal Investigations (OCI) initiated this investigation when investigators received information from U.S. Attorney’s Ofﬁce (USAO) for the District of New Jersey (DNJ), the State of New Jersey, Division of Criminal Justice, Ofﬁce of the Attorney General (NJAG), and the Avon by the Sea Police Department (AVON PD), Avon, New Jersey. This information indicated that a pharmacist, Michael Stavitski, was involved in the purchase and sale of physician samples and misbranded prescription drugs. These diverted prescription samples and prescription drugs were being sold in zip-lock bags. Nicholas Denucci, a Schering-Plough Pharmaceutical Sales Representative, had on numerous occasions sold prescription samples to Stavitski. As a result of his participation in the conspiracy to buy and sell prescription samples, Denucci made a proﬁt of $40,000.00. Stavitski purchased prescription samples from Denucci and a medical doctor. Stavitski then sold these samples to the public as prescription drugs at the Avon Pharmacy. As a result of his participation in the conspiracy to buy and sell prescription samples, Stavitski received approximately $5000 to $10,000 in revenues from the sale of these prescription samples at the Avon Pharmacy. On September 25, 2001, Nichols Denucci surrendered and appeared in front of the District Court of New Jersey. Denucci was convicted of one count of violating 18 USC 371: Conspiracy to defraud the United States and the FDA by knowingly and willfully buying and selling prescription samples in violation of 21 USC 331(t), 353(c)(1), 353(d)(1), 353(d)(2)(A), and 333(b)(1)(B). On January 14, 2002, Denucci was sentenced in the District of New Jersey, Newark, New Jersey, for his participation in a conspiracy to buy and sell prescription samples. Denucci was sentenced and ordered by the court to the following: 6 months of house arrest and 4 years’ probation; to pay the U.S. Government a ﬁne of $40,000.00; to be subject to an occupational restriction regarding employment in the pharmaceutical industry; and to provide full ﬁnancial disclosure, to include tax returns. On September 28, 2001, Stavitski, owner/operator/pharmacist of the Avon Pharmacy, Avon, New Jersey; the Wall Pharmacy, Wall, New Jersey, the Belmar Hometown Pharmacy, Belmar, New Jersey; and the Spring Lake Heights Super Pharmacy, Spring Lake Heights, New Jersey, surrendered. Stavitski was convicted of one count of violating 18 USC 371: Conspiracy to defraud the United States and the FDA by knowingly and willfully buying and selling prescription samples in violation of 21 USC 331(t), 353(c)(1), 353(d)(1), 353(d)(2)(A), and 333(b)(1)(B). On March 25, 2002, Stavitski was sentenced in the District of New Jersey, Newark, New Jersey, for his participation in a conspiracy to buy and sell prescription samples. Stavitski was sentenced and ordered by the court to 3 years’ probation and a ﬁne of $10,000. Pharmacist Convicted of Stealing Prescription Drugs: OCI Investigation Discloses Pharmacy Technician Stealing Prescription Drugs The FDA’s Ofﬁce of Criminal Investigations (OCI) initiated this investigation following receipt of information from the U.S. Veterans Administration, Ofﬁce of the Inspector General (VA OIG). The VA OIG and the OCI’s Boston Resident Ofﬁce conducted a joint investigation into Stephan Basden, a pharmacy technician at the Veterans Administration Medical Center, Bedford, Massachusetts. The investigation revealed that Stephan Basden was stealing prescription drugs from the Virginia facility. On December 5, 2001, Stephan Basden appeared before a U.S. District Court Judge and was convicted of one count of

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violating 21 USC 331(k) (Causing the Misbranding of a Drug) and one count of violating 21 USC 844(a) (Possession of a Controlled Substance). On March 18, 2002, Stephan Basden appeared in U.S. District Court to be sentenced on the above-described charges. Basden was placed on probation for a period of one year. Pharmacist Substitutes Brand Drugs with Compounded Substitutes The Texas Attorney General’s Ofﬁce, Medicaid Fraud Control Unit (MFCU), Austin, Texas, requested FDA/OCI assistance in this investigation. Richard Daniel, a registered pharmacist, and the owner and operator of Trinity Pharmacy, Carrollton, Texas, was convicted of billing Medicaid for name-brand drugs while providing patients with compounded substitutes. On August 23, 2001, Richard Daniel, Registered Pharmacist, appeared before the District Court in the Eastern District of Texas, Sherman, Texas. Daniel was convicted of a violation of 21 USC 331(i)(3) and 333(a) (Introduction or Delivery of Counterfeit Drugs) and 21 USC 331(k) and 333(a)(1) (Introduction or Delivery of Misbranded Drugs). Daniel agreed to pay approximately $148,000 to the Medicaid program for civil recovery, which resulted in his billing the Medicaid program for compounded drugs that he had substituted for trade-name or generic prescriptions. Clinical Investigator Sentenced: FDA Inspection Discloses Falsiﬁcation of Documents and Health Care Fraud The FDA’s Ofﬁce of Criminal Investigations (OCI) initiated this case following a referral from the FDA’s San Francisco District Ofﬁce alleging fraud in relation to clinical investigations conducted by Dr. William H. Ziering. FDA conducted a regulatory inspection and investigation of Dr. Ziering and the Central California Research Institute (CCRI) in April and May 1995. This investigation focused on ﬁve investigational new drug (IND) studies. The results of this investigation revealed falsiﬁcation of documents and statements and possible healthcare fraud. This was a joint investigation with the Department of Health and Human Services, Ofﬁce of the Inspector General, and the Department of Justice, MediCal Fraud Unit, and the State of California. On May 25, 2000, a Federal Grand Jury in the Eastern District of California returned a one-count indictment charging Ziering with Mail Fraud (18 USC 1341) and Aiding and Abetting (18 USC 2). The speciﬁc charge involved a Rhone Poulenc Rorer Pharmaceuticals, Inc. (RPR) study of pediatric patients with spring grass seasonal allergic rhinitis. Ziering provided a letter to RPR verifying that he had personally examined study subjects as required by the study protocol, when in fact he had not actually examined all of the research subjects. On August 25, 2000, a Federal Grand Jury in the Eastern District of California returned a 14-count superseding indictment charging Ziering with 14 counts of mail fraud concerning fraudulent Medicare and MediCal billing and clinical research practices. On August 30, 2000, Ziering appeared in the U.S. District Court, Eastern District of California, and was arraigned on 14 counts of mail fraud. On January 11, 2002, in the Eastern District of California, Ziering was convicted of one felony count of Mail Fraud (18 USC 1341) and Aiding and Abetting (18 USC 2). Further agreements made by Ziering included the following: • voluntary surrender of his medical license, with the stipulation that he not seek reinstatement of his medical license at any time; • permanent exclusion as a provider from the Medicare and Medicaid/MediCal programs;

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• permanent exclusion from participation in any manner in any drug studies, intended or required for submission to FDA; • restitution of $21,660; and • waiver of right to appeal. On June 3, 2002, in the Eastern District of California, Ziering was sentenced to 6 months’ incarceration and 24 months’ supervised release following the completion of his term. Manipulation of Clinical Trials This investigation involved the manipulation/falsiﬁcation of clinical trials for psoriasis and cutaneous T-cell lymphoma. These clinical trials were being sponsored by BioCryst Pharmaceuticals, Inc., Birmingham, Alabama. Based on the investigation and the indictment, Snyder and Peugeot conspired to make false statements that were ultimately mailed to the Center for Drug Evaluation and Research (Snyder and Peugeot were convicted in Federal Court on all charges listed in the indictment). On May 21, 2002, the U.S. Court of Appeals for the 11th Circuit afﬁrmed the conviction of Harry Snyder and Renee Peugeot stemming from their falsiﬁcation of data in connection with a clinical trial designed to study the effectiveness of the drug on psoriasis and cutaneous T-cell lymphoma. Snyder and Peugeot, husband and wife, were convicted of violating 18 USC 371 (Conspiracy), 18 USC 1341 (Mail Fraud), and 18 USC 1001 (Providing False Statements to the FDA). At sentencing, the trial court refused the government’s request to base the sentence on the $34.5 million loss sustained by investors (the sponsor, BioCryst, was a publicly held company) as a result of the defendants’ release of fraudulent data indicating that the drug was effective. The court instead based the sentence on the perceived gain of the defendants, approximately $250,000. In reversing the trial court’s sentencing determination and remanding the case for resentencing, the court held that the trial court should have used loss as the measure of the fraud and improperly used gain as a proxy for loss. Prison Sentence for Illegal Promotion of Dietary Supplements: Dietary Supplements Promoted as Cure for Cancer, Alzheimer’s, Multiple Sclerosis, Parkinson’s Disease, Lupus, Rheumatoid Arthritis, Diabetes, and Heart Disease The FDA’s Ofﬁce of Criminal Investigations (OCI) initiated this investigation based upon a referral from FDA’s San Francisco District Ofﬁce. The information was originally provided by the California State Food and Drug Branch (CAFDB). Since approximately 1992, various local, state, and federal law enforcement agencies have conducted investigations involving different fraud issues (Welfare, Food Stamps, MediCal, investment schemes) against Doris Ekker and Eddy Jo Ekker. In 1996, Diane Eckert Kunick, in conjunction with her parents, Doris and Eddy Jo Ekker, formed New Gaia Products (hereafter referred to as NGP), a company which purportedly manufactured, sold, and distributed dietary supplements, including, but not limited to, colloidal gold, colloidal silver, and colloidal titanium, to customers nationwide. According to the CAFDB, Diane Eckert Kunick had also distributed corresponding NGP promotional literature that identiﬁed speciﬁc medical claims relative to the NGP products, including, but not limited to, cures for cancer, rheumatoid arthritis, and heart disease. Eckert Kunick introduced unapproved new drugs between November 1998 and May 2000 through NGP distribution. The unapproved new drugs distributed included the following NGP products: “GaiaCol,” “Gaia CU 29,” “AquaGaia,” “GaiaGold,” “GaiaDHEA,” “GaiaTI 22,” and “GaiaCleanse.” The products were marketed as treatments or cures for many illnesses, including cancer, Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, lupus, rheumatoid arthritis, diabetes, and heart disease.

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In July 2000, federal search warrants were executed at locations identiﬁed as NGP manufacturing and distribution sites within Southern California and Southern Nevada in conjunction with law enforcement personnel from the Los Angeles Field Ofﬁce of the OCI, U.S. Postal Inspection Service, CAFDB, and Kern County Sheriff Department. On April 8, 2002, Diane Eckert Kunick appeared in U.S. District Court, Eastern District of California, Fresno, California, and was convicted of violating 21 USC 331(d) and 333(a)(1) (Introduction of Unapproved New Drug into Interstate Commerce). On July 1, 2002, Diane Eckert Kunick received a sentence of 4 months’ incarceration in the community correctional center. False Claim of Tampering Results in Prison Sentence: Investigation Discloses Father Falsely Claimed His Son Was Injured by “Fruitopia” Soft Drink On November 27, 2000, the FDA’s Baltimore District Ofﬁce notiﬁed the FDA’s Ofﬁce of Criminal Investigations (OCI) of the receipt of a possible tampering complaint that may have resulted in an injury to a 3-year-old boy. A hospital emergency room physician reported that the child’s father, Larry Wellington, brought his son in on November 26, 2000, for treatment after he had consumed a “Fruitopia” soft drink which caused him to vomit and complain of a burning sensation in his mouth. Wellington advised that he tried the product himself and felt his mouth burn as well. Testing by the FDA’s Forensic Chemistry Center conﬁrmed that the product in the Fruitopia bottle was a substance used to freshen toilets of traveling buses and airplanes. The investigation revealed that Wellington supplemented his income by working part time at a bus company which used this same formaldehyde- and methanol-based toilet freshener to reduce odors on bus toilets. Drivers and cleaners at the company stored small quantities of the toilet freshener in used soda bottles, including used Fruitopia bottles. Wellington told emergency personnel, doctors, and repeated to FDA investigators his story that the bottle had been unopened, that he had cracked open the tamper-resistant bottle cap, that his son had consumed the liquid, and that his son had experienced abdominal pain and vomiting. Responding emergency personnel stated that the child had not been injured or vomited. On February 25, 2002, Wellington was indicted by a grand jury for making a false claim of consumer product tampering in violation of 18 USC 1365(c)(1) and making false statements to the FDA in violation of 18 USC 1001: 18 U.S.C 1365(c)(1): Whoever knowingly communicates false information that a consumer product has been tainted, if such product or the results of such communication affect interstate or foreign commerce, and if such tainting, had it occurred, would create a risk of death or bodily injury to another person, shall be ﬁned not more than $25,000 or imprisoned not more than ﬁve years, or both. On March 25, 2002, Wellington entered a plea of not guilty. On May 29 through June 4, 2002, a jury trial was held in the U.S. District Court, Greenbelt, Maryland. A mistrial was declared after the jury reported an inability to render a unanimous verdict. On June 12, 2002, a superceding indictment was obtained charging Wellington with one count of communicating false information regarding tampering of a consumer product (18 USC 1365(c)(1)), two counts of false statements (18 USC 1001), and one count of obstruction of an FDA investigation (18 USC 1505). The retrial was held in U.S. District Court in Greenbelt, Maryland, August 27–30, 2002. On August 30, 2002, the jury returned a verdict of guilty on all four counts. On November 25, 2002, Wellington was sentenced

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to 27 months’ incarceration and supervised release for 3 years following his prison sentence. This case was investigated by the FDA’s Baltimore District Ofﬁce and the FDA Ofﬁce of Criminal Investigations. Pharmaceutical Drug Diversion: Defendant Falsely Claimed Firm Was Eligible for Preferential Drug Pricing This investigation was initiated based on information provided by the Federal Bureau of Investigation, Kalamazoo, Michigan. This was a pharmaceutical drug diversion investigation involving Requirements, Inc., Alpharetta, Georgia, and Cypress Resources, Inc., North Las Vegas, Nevada. Cypress Resources, Inc., placed orders for pharmaceuticals manufactured by Pharmacia & Upjohn Corporation, Kalamazoo, Michigan, through Requirements, Inc. Cypress Resources, Inc., falsely represented to Requirements, Inc., and Pharmacia & Upjohn Corporation that it was servicing government and Indian reservation hospitals, which qualiﬁed Cypress Resources, Inc., for preferential drug pricing. Storrs is the former owner of Cypress Resources, Inc., and was originally indicted on 62 counts of mail and wire fraud. On August 12, 2002, Bruce Storrs was convicted of one count of wire fraud (18 USC 1343) in the Federal Court in the Western District of Michigan. OCI and New York City Investigate Medicaid Fraud In April 2001, the FDA’s Ofﬁce of Criminal Investigations (OCI) jointly initiated an investigation with the New York City Human Resources Administration Bureau of Fraud Investigations. The Bureau of Fraud Investigations stated that a conﬁdential informant came forward with information about twin brothers, Anthony Garcia and Robert Garcia, who were engaged in the diversion of prescription drugs. The subjects were alleged to have obtained valid Medicaid numbers and/or cards and then used those to obtain pharmaceuticals from different pharmacies. The Garcia brothers were also alleged to have forged prescription slips to obtain the pharmaceuticals. The conﬁdential informant stated that these individuals operated throughout the New York City area. During the course of this investigation, the conﬁdential informant introduced an investigator from the Bureau of Fraud Investigations in an undercover capacity. The undercover investigator would “rent” to the subjects a controlled Medicaid card. The usage of this card would then be tracked to learn the type of medications and the locations where the medications were obtained. Multiple undercover operations of this type were completed from April 2001 to July 2001. Also during these operations, three additional subjects were identiﬁed as part of this diversion scheme. The new subjects were Luis Merced, William Merced, and Roger Herb. On January 23, 2002, subjects Anthony Garcia and Roger Herb were arrested as they were attempting to purchase prescription medications using forged prescriptions. Anthony Garcia was charged with violation of New York State PL 178.15 (Criminal Diversion of Prescription Drugs, 2nd Degree), PL 170.25 (Criminal Possession of Forged Instrument), and PL 110/155.25 (Petit Larceny). Roger Herb was charged with violation of New York State PL 170.25 (Criminal Possession of a Forged Instrument, 2nd Degree) and PL 110/155.25 (Petit Larceny). On this same date, the subjects Anthony Garcia, Robert Garcia, Luis Merced, and William Merced were all indicted by a grand jury in violation of New York State PL 170.10 (Forgery, 2nd Degree) and PL 170.25 (Criminal Possession of a Forged Instrument, 2nd Degree). On January 24, 2002, Roger Herb was indicted by a grand jury on violation of New York State PL 170.25 (Criminal Possession of a Forged Instrument, 2nd Degree) and PL 110/155.25 (Petit Larceny).

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Convictions and sentencing were as follows: • On April 10, 2002, Anthony Garcia was convicted of PL 170.25 and PL 170.10 and later sentenced to 28 to 84 months’ incarceration in State Prison. • On April 10, 2002, Robert Garcia was convicted of PL 170.10 and sentenced to 18 to 36 months’ incarceration in State Prison. • On April 10, 2002, Luis Merced was convicted of PL 170.10 and sentenced to 18 to 36 months’ incarceration in State Prison. • On April 10, 2002, William Merced was convicted of PL 170.10 and sentenced to 18 to 36 months’ incarceration in State Prison. • On April 17, 2002, Roger Herb was convicted of PL 170.25 and sentenced to 12 months’ incarceration in State Prison. The defendants in this case refused to cooperate with OCI or other law enforcement agencies. OCI Investigation Discloses Illegal Drug Sales: OCI Aids Local Police in Undercover Investigation of Local Drug Ring The FDA’s Ofﬁce of Criminal Investigations (OCI) initiated this investigation based on information provided in September 2001 from Sgt. Michael Riley, Task Force Commander, Northeast Merrimack Valley Drug Task Force. Sgt. Riley advised that the Merrimack Valley Drug Task Force had an undercover ofﬁcer who was preparing to conduct a series of undercover purchases of “rave”-type drugs from local drug dealers. Riley requested that OCI provide background information to the task force and assist in the investigation. OCI agents subsequently met with members of the task force and provided numerous brieﬁngs on several drugs including Ketamine, OxyContin, and Ecstasy. An undercover task force ofﬁcer made numerous undercover purchases of illegal drugs from over 17 local drug dealers, six of which included purchases of various prescription drugs, FDA unapproved drugs, and controlled substances. In December 2001, Sgt. Riley advised OCI that he was seeking to conduct a “sweep” of those individuals identiﬁed in the investigation and requested OCI assistance in conducting the arrests and performing post-arrest interviews. On December 19, 2001, as a result of successful undercover purchases, three individuals, Susanna Snodgrass, Naomi Mills, and Deanna Rogers, were arrested on criminal complaint warrants obtained from the Newburyport, Massachusetts, District Court. Snodgrass, Mills, and Rogers were charged with violating Massachusetts Penal Code 94C 40 (Conspiracy To Distribute a Controlled Substance). Rogers was charged with distributing the prescription drug Trazadone, Mills was charged with distributing Ecstasy, and Snodgrass was charged with distributing the prescription drug Diazapam. On December 28, 2001, three additional individuals, B. Kira Fiatrone, Mary Ryan, and a juvenile, were arrested by members of the Merrimack Drug Task Force and OCI on criminal complaints obtained in Newburyport, Massachusetts, District Court, based on several successful undercover purchases of Ketamine from each of the individuals. Ryan was charged with two counts of violating Massachusetts Penal Code 94C 31 (Possession of a Controlled Substance [Ketamine]) and one count of possession of a controlled substance (Ecstasy). The juvenile was charged with violating Massachusetts Penal Code 94C 40 (Conspiracy To Distribute a Controlled Substance [Ketamine]). Fiatrone was charged with one count of violating Massachusetts Penal Code 94C 32(a) (Distribution of a Controlled Substance [Ketamine] in a School Zone) and one count of violating Massachusetts Penal Code 94C 40 (Conspiracy To Distribute a Controlled Substance [Ketamine]).

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Convictions and sentencing were as follows: • On February, 6, 2002, defendant Kira Fiatrone pled guilty to one count of violating Massachusetts Penal Code 94C 40 in Newburyport District Court. Fiatrone was sentenced to 12 months’ probation. • On May 1, 2002, defendant Mary Ryan pled guilty to two counts of violating Massachusetts Penal Code 94C 31 (Possession of a Controlled Substance [Ketamine]) and one count of possession of a controlled substance (Ecstasy) in Newburyport District Court. Ryan was sentenced to 6 months’ incarceration, suspended, and 18 months’ probation. • On May 15, 2002, defendant Susanna Snodgrass appeared in Newburyport District Court where the Newburyport District Attorney’s Ofﬁce ﬁled a nolo pros against defendant Snodgrass. • On July 31, 2002, at the Newburyport District Court, defendant Deanna Rogers pled guilty to one count of Massachusetts General Law 94C 40 (Distribution of a Controlled Substance [Ketamine]). Subsequent to accepting Roger’s plea, the Judge sentenced Rogers to 18 months’ incarceration with 8 months to serve and the balance suspended with 2 years’ probation upon release. • On October 3, 2002, at the Newburyport District Court, subject Naomi Mills pled guilty to one count of Massachusetts General Law 94C 40 (Distribution of a Controlled Substance [Ecstasy]). Subsequent to accepting the guilty plea, the Judge sentenced Mills to 18 months’ incarceration with 14 days to be served and the balance suspended, with 2 years’ probation upon release. The juvenile case was removed from the adult criminal court system to the Newburyport Juvenile Court where the disposition of the case remains sealed. Illegal Compounding of Name-Brand Drugs: FDA’s Forensic Chemistry Center Analyzes Compounded Drugs and Finds Drugs Are Ineffective This investigation was initiated based on information that James Spalding, Owner, The Medicine Shoppe, Cambridge City, Indiana, was counterfeiting tradename drugs. On June 27, 1997, and July 29, 1997, the Ofﬁce of Criminal Investigations (OCI), Drug Enforcement Administration (DEA), and Richmond Police Department (RPD) executed State of Indiana search warrants at The Medicine Shoppe. On both occasions, numerous bottles of illegal compounded drugs and containers of bulk raw powders, used to compound/manufacture prescription drugs (controlled and non controlled), were seized. During the course of this investigation numerous interviews were conducted of patients who received illegally compounded/manufactured prescription drugs and their physicians, who had not authorized the compounding/manufacturing of these drugs. Numerous laboratory analyses of these drugs were conducted by the FDA’s Forensic Chemistry Center (FCC). The FCC determined that these prescription drugs were ineffective. On December 19, 2001, the Federal Grand Jury, U.S. District Court, Southern District of Indiana, Indianapolis, Indiana, returned a 13-count indictment charging Spalding as follows: • Ten counts of violating Title 21 USC 841(a)(1): Manufacturing a Schedule II controlled substance without a prescription calling for the compounding of said substance for a legitimate medical purpose. • Two counts of violating Title 21 USC 331(k), 351(b), 352(a), and 333(a)(2): Misbranding/adulterating drugs which were held for sale. • One count of violating Title 18 USC 1347 (Healthcare Fraud).

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On July 15, 2002, Spalding was convicted in U.S. District Court, Southern District of Indiana, of the following: • Three counts of violating 21 USC 841(a)(1): Manufacturing a schedule II controlled substance without a prescription calling for the compounding of said substance for a legitimate medical purpose. • Two counts of violating 21 USC 331(k), 351(b), 352(a), and 333(a)(2): Misbranding/adulterating drugs which were held for sale. • One count of violating 18 USC 1347 (Healthcare Fraud); Spalding had defrauded the Indiana Medicaid program of $114,210.50. On December 11, 2002, Spalding appeared in U.S. District Court, Southern District of Indiana, and was sentenced to serve 48 months’ incarceration, 3 years’ supervised probation upon release, 200 hours of community service, and restitution in the amount of $114,210.50. Pharmacist Sentenced for Dilution of Chemotherapy Drugs: Pharmacist Diluted Numerous Chemotherapy Drugs; Some Drugs Found To Contain Less Than 10% of Prescribed Dose United States v. Robert Courtney et al. (D. Mo.). On February 26, 2002, Robert Ray Courtney, of Kansas City, Missouri, and Courtney Pharmacy, Inc., d/b/a Research Medical Tower Pharmacy, pleaded guilty to eight counts of tampering with consumer products, as well as six counts of adulterating and six counts of misbranding a drug. Courtney is the former owner, president, and chief executive of Courtney Pharmacy, Inc. In entering their guilty pleas, Courtney and his corporation admitted that, on eight occasions in 2001, the defendants prepared intravenous drug mixtures that did not contain the prescribed amounts of the chemotherapy drugs Taxol or Gemzar. In addition, on six occasions in 2001, the defendants adulterated and misbranded drugs by preparing intravenous drug mixtures that did not contain the amounts of Taxol or Gemzar that were ordered by the treating physician and for which those mixtures were labeled. Between March and August of 2001, Courtney, among other things, diluted numerous chemotherapy drugs that were ordered from his pharmacy and misrepresented the strength of those drugs to physicians. More than 50 patients were originally identiﬁed as having been victims of this scheme; it eventually was determined that more than 4000 patients may have had their prescriptions diluted over a 10-year period. In many cases, patients received drugs that were less than 10% of the prescribed strength; several of those patients died. As part of the plea agreement, Courtney acknowledged that, in addition to the tampering, adulteration, and misbranding of Taxol and Gemzar identiﬁed in the indictment, he and his corporation diluted and tampered with additional Taxol and Gemzar preparations. Through the plea agreement, Courtney and his corporation acknowledged that they also diluted and tampered the drugs Platinol and Paraplatin; that they conspired to trafﬁc in stolen drugs, including Taxol and Gemzar, which they purchased and dispensed to pharmacy customers; and that they caused the ﬁling of false Medicare claims by not disclosing the dilution to the physician. On December 5, 2002, Robert Courtney, was sentenced to 30 years in prison and required to pay a $25,000 ﬁne as well as $10.4 million in restitution because of his sale of diluted drugs. In a related matter, on January 10, Walter J. Accurso consented to the ﬁling of a complaint alleging that he violated the Federal Food, Drug, and Cosmetic Act during the years 2000 and 2001 by causing the misbranding of various drugs. The drugs included Paraplatin,

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Lupron, Zofran, Taxol, Gemzar, Zocor, and Lipitor. Accurso acknowledged that he acquired the drugs knowing they had been stolen from a hospital; he then sold them at a discount to various pharmacists. Accurso paid a $25,000 civil judgment and forfeited to the United States an additional $8650 in cash proceeds. In addition, Stuart Smith (a hospital employee) and Gary Ravis (a pharmacist) pled to related charges, based on the sale of drugs stolen from a hospital. Ravis entered a plea to one count of receipt of stolen property; he received a probationary sentence, a $250,000 ﬁne, and 2500 hours of community service. Smith likewise entered a plea to a charge of the unlawful sale of drugs, and he received a sentence of 6 months’ in-home detention, was ordered to pay $50,000 in restitution to the hospital and a $25,000 ﬁne, and to perform 1000 hours of community service. A former pharmaceutical sales representative, Aran Paraghamian, also entered a plea to one count of interstate transportation of stolen property and received a sentence of 3 years’ probation, a ﬁne of $60,000, and 600 hours of community service for participation in this scheme. Illegal Internet Sales of Prescription Drugs: Investigation by OCI, Local Police, and Romanian and Australian Police Uncover Illegal Sale of Prescription Drugs Via the Internet This case originated on September 15, 1999, based on information received from Detective Shane Fulmer, Chilton County Sheriff’s Ofﬁce, Clanton, Alabama, in conjunction with the Investigative Analysis Branch (IAB), HQ, FDA/OCI. Detective Fulmer reported that credible information was received which indicated that Anita Yates, who resided in Clanton, Alabama, was selling pharmaceuticals via the Internet. According to the information, Yates owned and operated a business by the name of Norfolk Men’s Clinic. This clinic was the location where the prescription drug orders were processed and distributed. It was further determined that Yates and an Australian citizen identiﬁed as Anton Pusztai were operating an Internet website by the name of Viagra.au.com. With this website, a customer could order via the Internet Viagra, Celebrex, Xenical, Propecia, and Claritin-D. A joint investigation was conducted with the Chilton County Sheriff’s Department with the assistance of the Alabama Board of Medical Examiners. During September 1999, several FDA/OCI ofﬁces made undercover purchases through the aforementioned website resulting in the receipt of Viagra that was being distributed from Clanton, Alabama. Based on the undercover purchases, a search warrant was executed, not only on the business but also Yates’ residence. During the search, numerous prescription drug orders and empty prescription bottles along with several cases of prescription drugs were seized. During the course of the investigation, investigators determined that customers were ordering the prescription drugs via the Internet which resulted in Yates and Pusztai generating ﬁctitious prescriptions and having those prescription presented to Dr. Eiland, a local physician in Clanton, Alabama. Dr. Eiland would rewrite the prescriptions and present them to a local pharmacy to be ﬁlled. Once the prescriptions were ﬁlled, they would be picked up by employees of Norfolk Men’s Clinic, repackaged into plastic-type envelopes, and mailed via Federal Express to the customer. Based on the evidence seized from the residence and business, it was determined that Yates and Pusztai were obtaining wholesale supplies of pharmaceuticals from All International, Inc., which was owned and operated by Yvan Degomme. Degomme was sending wholesale volumes of prescription drugs to Yates and Pusztai even though they did not have a wholesale, pharmacy, and/or medical license. Subsequent to the initial search, Yates and Pusztai moved their operation to

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Weirton, West Virginia, where they continued to generate bogus prescriptions and have those prescriptions ﬁlled by their own established pharmacy. On July 27, 2000, Yates, Pusztai, Eiland, All International, Inc., and Yvan Degomme were indicted by a Federal Grand Jury. The charges consisted of money laundering, mail fraud, obstruction of justice, conspiracy, and violating the Federal Food, Drug, and Cosmetic (FD&C) Act. On August 6, 2000, search warrants were executed at the business site in Clanton, Alabama, and two locations in Weirton, West Virginia. During the search, numerous prescription drug orders bearing the names of foreign physicians along with numerous cases of prescription drugs were seized. Subsequent to these searches, coordination was conducted with the Bucharest Organized Crime Division, Bucharest, Romania; the Australian Federal Police; and the Therapeutic Goods Administration. With their assistance, the foreign physicians were interviewed, which resulted in conﬁrming the fact the physicians were not involved in this Internet operation. On November 9, 2001, representatives for the corporation of All International, Inc., appeared before Judge DeMent at which time the company pled guilty to one count of violating Title 18 USC 1505 (Obstructing Justice). The company admitted to misleading FDA/OCI on how many shipments of prescription drugs were sent to Yates and Pusztai. Degomme pled guilty to ﬁve counts of violating Title 21 USC 331(k). On February 16, 2002, Yates and Pusztai were convicted in Federal Court for mail fraud, money laundering, conspiracy, and violating the FD&C act. Degomme was sentenced to 12 months’ probation and ﬁned $1500. Eiland was acquitted of all charges. He was earlier sanctioned by the Alabama Board of Medical Examiners, when he was ﬁned $5000 and suspended for 90 days. On June 5, 2002, All International, Inc., the company was ﬁned $125,000. The company agreed as part of the plea agreement to relinquish all wholesale licenses. On June 18, 2002, Pusztai, being earlier found guilty of one count of conspiracy, one count of conspiracy to commit money laundering, 10 counts of mail fraud, 10 counts of misbranding, and one count of Operation of an Unregistered Drug Facility, was sentenced to 188 months’ incarceration and 36 months’ supervised probation and was ordered to forfeit $373,000 in assets that were frozen when the case was indicted. Yates was sentenced to 78 months’ incarceration and 36 months’ probation and was ordered to forfeit $373,000 in assets. The assets were forfeited as a joint forfeiture agreement between Pusztai and Yates. As a result of the forfeiture, the following agencies shared in the assets: Chilton County Sheriff’s Ofﬁce, Clanton, Alabama; Alabama Board of Medical Examiners; and Weirton Drug Task Force, Weirton, West Virginia. Smuggling of Prescription Drugs: U.S. Customs Detains Defendant Attempting To Smuggle $140,000 Worth of Prescription Drugs Manufactured in Canada into U.S. On July 25, 2001, the U.S. Customs Service (USCS) advised OCI that Christopher Gervasi was detained at the Rainbow International Bridge, Niagara Falls, New York, after he attempted to smuggle over $140,000 worth of Canadian manufactured prescription drugs into the United States. On that same evening, Gervasi was arrested for violations of 18 USC 1001 (Making a False Statement to a Federal Ofﬁcer) and was held overnight at the Erie County Holding Center. On July 26, 2001, Gervasi made an initial appearance in U.S. Magistrate’s Court in the Western District of New York (WDNY) in Buffalo. He was released on a $1000 signature bond. Further investigation conducted with the Royal

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Canadian Mounted Police (RCMP), the Federal Bureau of Investigation, and the USCS disclosed that Canadian and American organized crime were involved in the illegal smuggling of the above described prescription drugs; however, Gervasi refused to cooperate regarding this investigation. On July 18, 2002, Gervasi pled guilty as charged in Federal District Court WDNY in Buffalo. On October 4, 2002, he was sentenced to 3 years’ probation with the stipulation that he continue with periodic drug/alcohol testing. Center for Food Safety and Applied Nutrition Counterfeit Similac Infant Formula: Numerous Consumer Complaints Lead to Discovery of Counterfeit Infant Formula In February 1995, the FDA’s Ofﬁce of Criminal Investigations (OCI) initiated an investigation into the counterfeiting of Similac brand infant formula after FDA’s San Francisco District Ofﬁce and Ross Products received numerous consumer complaints. Ross Products Division is the maker of Similac brand infant formula. Ross was able to examine product being returned by some of the complainants and immediately determined that the Similac in question was actually counterfeit. All of the counterfeit Similac was isolated to Safeway stores in the San Francisco Bay area. An investigation by OCI revealed the counterfeit Similac had been purchased by Safeway through a secondary grocery wholesaler in Palm Springs, California, who had purchased the counterfeit Similac from Mohamad Mostafa Wholesale in Orange County, California. The OCI investigation revealed that Mohamad Mostafa, the owner and operator of Mohamad Mostafa Wholesale, was an infant formula diverter who hired Ivy Ong to help him procure items that Mostafa would need to produce the counterfeit product. Through Ong, Mostafa was able to obtain cans, scoops, can sealers, and an ink-jet printer that was used for printing lot numbers on the bottom of the cans. In addition, Ong was able to ﬁnd a source to supply a generic powdered infant formula for Mostafa. Mostafa entered into a $1 million contract with this source for 500,000 pounds of generic powdered infant formula. Mostafa told Ong that the infant formula was going to be exported to the Middle East. Mostafa even had several hundred labels printed in Arabic as part of his cover story and scheme, and he had 50,000 counterfeit Similac labels printed by a printer in Maryland. Mostafa was able to get an initial shipment of 8000 pounds of the powdered infant formula delivered to a warehouse in Santa Ana, California. There he had day laborers package it into cans for distribution. Had this initial contract been fulﬁlled, Mostafa would have realized illegal proceeds and proﬁts in excess of $4.3 million. OCI was able to halt this counterfeiting operation as an additional 38,000 pounds of the formula was being readied for delivery to Mostafa. Following the execution of numerous search warrants served by the OCI, Ong was arrested in February 1995. In August 1995, Ong was convicted of three counts of Title 21 USC 331(k) (Misbranding a Food After Shipment in Interstate Commerce). In August 2000, Ong was sentenced in federal court to 4 months’ home detention followed by 1 year of supervised release. An arrest warrant was issued for Mostafa, who ﬂed the United States and remained a fugitive for 6 years. Investigation and information regarding Mostafa’s whereabouts surfaced in Australia, Jordan, South Korea, and Malaysia. Finally, in June 2000, a grand jury in Santa Ana, California, returned an indictment charging Mohamad Mostafa with one count of Title 18 USC 371 (Conspiracy); one count of Title 21 USC 331(k) (Misbranding Food While Held for Sale after Shipment in Interstate Commerce); and two counts of Title 18 USC 2320 (Trafﬁcking in Counterfeit Goods).

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Mostafa remained in fugitive status until October 2001, when he was arrested following the events of September 11, 2001. The Royal Canadian Mounted Police took Mostafa into custody at Fort McMurray, Alberta, Canada, on Canadian immigration violations. Mostafa waived extradition and was brought to the United States in March 2002. In August 2002, after a 3-day bench trial, a U.S. District Court Judge, Central District of California, Santa Ana, California, found Mohamad Mostafa guilty of all four counts related to the June 2000 indictment. On December 16, 2002, Mostafa was sentenced to 3 years, 8 months of incarceration followed by 3 years’ probation.

COURT UPDATES

AND

OTHER ENFORCEMENT ACTIVITIES

Thompson et al. v. Western States Medical Center Pharmacy, 535 U.S. 357; 122 S.Ct. 1497; 152 L.Ed. 2d 563 (2002) (U.S. Supreme Court). On February 26, 2002, the U.S. Supreme Court heard oral arguments in this case involving the Ninth Circuit’s decision that provisions of the Federal Food, Drug, and Cosmetic Act (FDCA) concerning drug compounding violate the First Amendment. Deputy Solicitor General Edwin Kneedler presented arguments for the government. The statutory provisions at issue, which were enacted in 1997 as part of the Food and Drug Administration Modernization Act, exempt compounded drugs from the Act’s new drug approval, adequate directions for use, and good manufacturing practice requirements if speciﬁed conditions are met. The conditions that the Ninth Circuit found to be unconstitutional provide that, in order to qualify for the exemption, the compounded drug may not be based on a solicited prescription, and the pharmacy, pharmacist, or physician may not advertise or promote the compounding of a particular drug, class of drug, or drug type. The Ninth Circuit concluded that the conditions at issue may not be severed from the remainder of the statutory section and held it invalid in its entirety. Pending a decision by the Supreme Court on the First Amendment question, the statutory provision at issue remained in effect outside the Ninth Circuit. Thompson et al. v. Western States Medical Center Pharmacy, 535 U.S. 357, 122 S. Ct. 1497, 152 L. Ed 2nd 563 (2002). (U.S. Supreme Court). On April 29, 2002, the U.S. Supreme Court afﬁrmed a decision of the U.S. Court of Appeals for the Ninth Circuit that invalidated a provision of the Federal Food, Drug, and Cosmetic Act (FDCA). That provision exempted compounded drugs from certain of the FDCA’s requirements if speciﬁed conditions were met. The provision was enacted in 1997 as part of the Food and Drug Administration Modernization Act. The statute provided that, in order to qualify for the exemption, the compounded drug could not be based on a solicited prescription, and the pharmacy, pharmacist, or physician could not advertise or promote the compounding of a particular drug, class of drug, or drug type. The Supreme Court held that these provisions violate the First Amendment. The Court applied the test for the constitutionality of commercial speech. The Court agreed that the government has substantial interests both in preserving the FDCA’s new drug approval process and in permitting the practice of compounding. The Court also recognized the need for a distinction between compounded drugs produced on a small scale and drugs produced and sold on a large scale. The Court concluded that, even if it is assumed that drugs cannot be sold on a large scale without advertising, the provisions failed the fourth prong of the commercial speech test in that they are “more extensive than necessary.” The Court pointed to several non-speech-related means of distinguishing between permissible compounding and large-scale manufacturing and stated that there was no explanation of how the provisions restrictions on advertising achieve those interests. United States v. Philip Morris Incorporated (D.D.C.). The Department of Justice brought this suit against the major cigarette manufacturers alleging that the manufacturers engaged in a conspiracy to defraud the American public and seeking disgorgement of proﬁts and injunctive relief, including a public education campaign. The parties have been engaged in extensive document discovery, which has included a substantial amount of FDA’s tobacco- and nicotine-related documents. Defendants

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ﬁled two motions to compel documents listed on the government’s privilege log, both of which included FDA documents. On January 10 and 14, 2002, the Special Master issued a Report and Recommendation on each motion, respectively. He recommended that each motion be granted in part and denied in part by sustaining certain privilege claims, overruling others, and ordering production of certain documents after additional redactions. In the Matter of the Search of 16475 Miller Road (S.D. Ohio). On December 26, 2001, Judge James L. Graham denied a motion for return of property ﬁled by “Ovimmune” following a search warrant that OCI executed in July 2001. The search warrant was premised on allegations that Ovimmune was producing and distributing unapproved drugs in interstate commerce, speciﬁcally, eggs containing hyperimmune egg yolks, as treatment for various diseases and infections in humans. Ovimmune sought return of its property contending, among other things, that the egg product in question was a food or dietary supplement rather than a drug. The Court, in denying the motion, held that the evidence failed to establish that the afﬁdavit contained material omissions or falsehoods and that a determination of whether the eggs were foods or drugs was not ripe for review. United States v. Gonzalez Alvarez, 277 F.3d 73 (1st Cir. 2002). On January 17, 2002, the U.S. Court of Appeals for the First Circuit reversed the sentencing ﬁndings made in one of many milk adulteration cases that were brought in Puerto Rico. The defendant pleaded guilty to conspiracy and causing the delivery of adulterated food into interstate commerce with the intent to defraud and mislead. The government appealed the sentence imposed by the district court on two grounds: that the loss calculated for purposes of the sentencing guidelines was incorrect, for two reasons, and that the defendant violated a position of public trust, thus warranting a sentence enhancement. In agreeing with the government and reversing the sentencing decision, the Court held that when a product is not being sold lawfully, it has a value of zero for purposes of calculating loss under the sentencing guidelines and that the defendant was not entitled to credit for the price that the milk was sold to consumers. The court also held that because the adulterated milk was added to milk silos, defendants should be held accountable for that loss and not merely the value of the milk in the tanker trucks. The court further held that a sentence enhancement for abuse of public trust should have been applied since the defendant was licensed by a governmental agency designed to protect the quality of the milk supply, giving the defendant a duty to ensure his milk was safe for public consumption. United States v. Haryash Gugnani, 1768 F. Supp. 2d 538 (D. Md. 2002). On January 8, 2002, Judge Alexander Williams denied a petition ﬁled by defendants pursuant to the Hyde Amendment seeking reimbursement of attorneys’ fees and expenses after they successfully defended criminal charges that were brought in an FDA case. The court, in denying the petition, held that the underlying prosecution was not frivolous, vexatious, or brought in bad faith. The prosecution stemmed from allegations that defendants knowingly submitted false statements to FDA and knowingly caused adulterated and misbranded products to be introduced into interstate commerce. St. Louis University v. United States, 182 F. Supp. 2d 538 (D. Md.2002). On January 25, 2002, U.S. District Judge J. Frederick Motz entered partial summary judgment against the United States and entered summary judgment for American Cyanamid Co. (Cyanamid) in these actions. St. Louis University (SLU) sued the United States for contribution to its tort liability judgment after a St. Louis jury awarded $16 million to a child, Danny Callahan, who had become paralyzed shortly after receiving the oral polio vaccine but almost immediately after receiving improper treatment at a hospital associated with SLU for a bacterial infection. SLU instituted a similar contribution action in Missouri against Cyanamid, the manufacturer of the vaccine, which action was dismissed. In April 1999, Judge Motz entered summary judgment in favor of the United States against SLU. Cyanamid ﬁled a declaratory action against SLU, and the Court also entered summary judgment in favor of Cyanamid. SLU appealed both rulings and the Fourth Circuit reversed and remanded

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for further proceedings. On remand, SLU ﬁled a motion for partial summary judgment against the United States alleging that the government was negligent in releasing polio vaccine that violated the applicable regulations and that its negligence was at least one of the proximate causes of Callahan’s paralysis. Cyanamid ﬁled a motion for summary judgment in its declaratory judgment action. Using the same reasoning he used in a prior multidistrict litigation case involving the oral polio vaccine, Judge Motz held that the United States had a duty to protect the public from vaccine that was derived from seeds that did not comply with the regulations, even when the speciﬁc lots of vaccine derived from those seeds met the regulatory standards. Judge Motz held that the United States breached its duty by approving noncompliant seeds in violation of its regulations. He further concluded that the government’s wrongful approval of the seed was the proximate cause of Callahan’s injuries, because if the government had not approved the seed, Callahan never would have been administered a dose of oral polio vaccine and therefore would not have contracted polio. The extent of the United States’ liability, in light of SLU’s malpractice, can be determined only after development of a full factual record. With respect to Cyanamid, however, Judge Motz held that the manufacturer could not be liable for contribution because SLU could not prove that the oral polio vaccine was defective and that such defect resulted in Callahan’s injuries. Judge Motz stated that the duty owed by Cyanamid was to produce a vaccine that was safe; Cyanamid did not bear the same responsibility for the regulatory process as the government. Because SLU could not prove that a defect in the vaccine resulted in Callahan’s injuries, Judge Motz granted summary judgment for Cyanamid. United States v. Travia, 180 F. Supp. 2d 115 (D. D.C. 2001). On November 30, 2001, Chief Judge Thomas F. Hogan reversed a Magistrate Judge’s ruling that dismissed criminal charges brought against individuals who sold balloons ﬁlled with nitrous oxide in the parking lot at a rock concert. The Magistrate Judge had dismissed the charges of unlawful distribution of misbranded drugs after deciding, among other things, that the Federal Food, Drug, and Cosmetic Act (FDCA) did not apply to the individual defendants because the FDCA only regulated medical practitioners, manufacturers, and other commercial entities that distribute drugs. The court held that private individuals may be criminally prosecuted under the FDCA. He stated that the plain language of the FDCA extends its coverage to “any person” who violates the Act and noted that “person” is deﬁned to include an “individual.” The court also rejected defendants’ arguments that labeling provides the exclusive evidence of a seller’s intent for the use of a product and, in the absence of labeling, the nitrous oxide could not meet the Act’s deﬁnition of a “drug.” The court held that the nitrous oxide sold by defendants met the deﬁnition of a “drug” in the FDCA, because the circumstances surrounding its sale in the parking lot at the rock concert demonstrated the seller’s intent that the product was to be used to affect the structure or any function of the body. Finally, the court rejected defendants’ arguments that the FDCA was unconstitutionally vague, because it failed to give defendants sufﬁcient notice that their behavior was proscribed and because it impermissibly delegated to FDA Congress’ authority to decide what behavior is illegal. The court held that the FDCA provided sufﬁcient notice that the defendants’ behavior was prohibited, and he found that the nondelegation doctrine was not violated because Congress provided clear proscriptions in the Act that can be consistently followed by FDA when enforcing the Act. Mylan Pharmaceuticals, Inc. v. Thompson, 268 F.3d 1323 (Fed. Cir. 2001). On December 14, 2001, Judge Stamp of the U.S. District Court for the Northern District of West Virginia dismissed the above case without prejudice at the request of all parties. Mylan had initiated this case with a motion for a preliminary injunction and temporary restraining order (TRO), challenging FDA’s approval of a competitor’s ANDA for generic 30-milligram extended release nifedipine. On April 18, 2001, Judge Stamp denied Mylan’s motion, and Mylan appealed. After brieﬁng but before oral argument, Mylan moved to dismiss the appeal and later requested that the parties stipulate to the dismissal of the case.

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aaiPharma Inc. v. Thompson, 296 F.3d 227 (4th Cir. 2002). On July 10, 2002, the Fourth Circuit upheld the district court’s denial of a motion for a temporary restraining order (TRO) originally brought by aaiPharma in an effort to enjoin FDA from approving generic forms of Prozac. aaiPharma challenged FDA’s interpretation of the FDCA that permits FDA to rely exclusively on the pioneer drug company’s representations about whether certain patents cover its product without making any independent inquiry or independent determination, even if a party challenges those representations. In this case, aaiPharma, a third party claiming to hold a patent that covered Prozac and all generic forms of the drug, asked Eli Lilly, the company that held the patent on Prozac, to submit aaiPharma’s patent to FDA to be listed in the Orange Book as covering Prozac. Lilly declined. aaiPharma then notiﬁed FDA of its claim. FDA wrote to Lilly to conﬁrm its position and, when Lilly did so, refused aaiPharma’s request to make an independent judgment. On the eve of the expiration of Lilly’s exclusivity rights to Prozac, aaiPharma sought to enjoin FDA from approving generic versions of the drug. The district court denied aaiPharma’s motion and subsequently dismissed its claim on the merits. The district court had found that the statute unambiguously provided FDA with a strictly ministerial role in listing patents in the Orange Book, and the Agency could not disregard Lilly’s representations about the scope of the patent. On appeal, the Fourth Circuit afﬁrmed the decision. Although it declined to ﬁnd the statute unambiguous, it held that FDA’s regulation interpreting the statute as giving it a solely ministerial role in Orange Book listings is not arbitrary and capricious. The court found that FDA’s explanation that it did not have the resources and expertise to make independent patent determinations satisﬁed the requirement of reasoned Agency decision making. The court reached that holding despite the result that left aaiPharma with no relief for its grievance. The court held that only Congress could address that situation. Brubaker Amusement Co. v. United States, 304 F.3d 1349 (Fed. Cir. 2002). On June 15, 2002, the Federal Circuit afﬁrmed summary judgment for the United States in a consolidated appeal regarding FDA’s tobacco vending machine regulation. More than 500 vending machine owners and operators ﬁled claims in the Court of Federal Claims seeking compensation for “takings” of their cigarette vending machine businesses caused by FDA’s tobacco regulations and SAMHSA’s block grant program. The SAMHSA claim had already been dismissed, and the Federal Circuit afﬁrmed. The Supreme Court denied plaintiffs’ petition for certiorari on February 20, 2001. On the FDA claim, the Court of Federal Claims decided that ﬁve judges should each hear one case to serve as lead cases. On August 3, 2000, the government moved to dismiss the FDA count in the ﬁve lead cases on three alternate grounds. Each trial court judge dismissed the claim or granted summary judgment for the government. The Federal Circuit discussed only one ground of the government’s motion and held that, because the vending machine regulation was never in effect or enforced, it did not effectuate a taking. It explained that a takings challenge to a statute or regulation may be facial or “ as applied.” In these cases, plaintiffs did not assert a facial challenge; had they done so, it would be moot after FDA v. Brown & Williamson, 120 S. Ct. 1291 (2000), in which the Supreme Court held that FDA’s tobacco rulemaking was not authorized by Congress. With respect to an “ as applied” challenge, the regulation would had to have been effective to be a taking. Here, the district court in Brown & Williamson stayed the vending machine regulation before its effective date, and plaintiffs failed to show any evidence that FDA enforced that regulation. The court further held it was not error to deny discovery where plaintiffs failed to ﬁle an afﬁdavit or any evidence in support of its enforcement claim. United States v. Boston Scientiﬁc Corp. (D. Mass. 2002). On February 19, 2002, Magistrate Judge Cohen issued an Order denying Defendant Boston Scientiﬁc Corporation’s (“ BSC’s”) motion to compel production of both FDA and Patent and Trademark Ofﬁce (“ PTO”) documents in an action brought by the Federal Trade Commission (“ FTC”). The FTC brought this action against BSC, a manufacturer of intravascular ultrasound (“ IVUS”) devices, after BSC violated a 1995 consent decree with the FTC. After the case had been bifurcated and the court had determined liability, the defendant requested that the government produce documents referring or relating to any ﬁlings with the FDA by any manufacturer of an IVUS device or component thereof, including premarket

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notiﬁcations (“510(k)s”) and premarket approval applications (“PMAs”). When the government objected on grounds of relevance, burden, privilege, and conﬁdentiality, BSC moved to compel production. The government’s opposition to the motion to compel included a declaration from CDRH describing the contents of PMAs and 510(k)s, the trade secret and conﬁdential commercial nature of those documents, and the type of information relating to PMAs and 510(k)s that is available on FDA’s website. In denying the defendant’s motion to compel, the court determined that the documents requested by BSC were not relevant to the penalty phase of the proceedings. To the extent that the information sought was “marginally relevant,” the court held that BSC failed to establish a case for shifting the burden to the government to expend its resources to conduct a search of public documents. In addition, the court determined that neither the FTC nor the Attorney General had any authority to demand that FDA and PTO search for the requested documents, “much less turn over to BSC documents maintained as conﬁdential by those agencies.” United States v. Harry Snyder and Renee Peugeot, 291 F.3d 1291 (11th Cir. 2002). On May 21, 2002, the U.S. Court of Appeals for the 11th Circuit afﬁrmed the convictions of Harry Snyder and Renee Peugeot stemming from their falsiﬁcation of data in connection with a clinical trial designed to study the effectiveness of a drug. Snyder and Peugeot, husband and wife, were convicted of conspiracy, mail fraud, and making false statements to FDA. At sentencing, the trial court refused the government’s request to base the sentence on the $34.5 million loss sustained by the investors as a result of the defendants’ release of fraudulent data indicating that the drug was effective. The court, instead, based the sentence on the perceived gain to the defendants of approximately $250,000. In reversing the trial court’s sentence and remanding the case for resentencing, the 11th Circuit held that the trial court had improperly used gain as a proxy for loss, while it should have used loss as the measure of the fraud. Association of American Physicians and Surgeons, Inc., et al., v. United States Food and Drug Administration et al., 226 F. Supp. 2d 204 (D.D.C. No. 00 02898). On October 25, 2002, U.S. District Judge Henry H. Kennedy, Jr., denied the government’s motion to dismiss in a lawsuit challenging FDA’s authority to promulgate “Regulations Requiring Manufacturers To Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients,” 63 Fed. Reg. 66,632 (1998) (“the pediatric rule”). The pediatric rule requires that manufacturers submitting certain applications to FDA to, in some circumstances, evaluate the safety and effectiveness of their products in children. The rule contains provisions under which manufacturers may obtain from FDA a full waiver or a deferral of this requirement. Plaintiffs are the American Association of Physicians and Surgeons, the Consumer Enterprise Institute, and Consumer Alert. The government moved to dismiss on the grounds that plaintiffs lack standing and that the case is not ripe for adjudication. Plaintiffs claimed representational standing as associations to sue on behalf of their members. The court found that the members of the plaintiff organizations had suffered “injury in fact” as a result of the pediatric rule, because the rule will delay the approval of drugs by requiring pediatric testing of drug products. The court stated that the unavailability of safe, effective drugs that may treat or cure particular ailments can inﬂict as much harm on patients as the consumption of potentially unsafe drugs. The court found that the purposes of the three plaintiff organizations are germane to the goals of the litigation and further found that plaintiffs’ members fall within the “zone of interests” to be protected by the FDCA. Finally, the court rejected the government’s arguments that the challenge is not yet ripe for judicial review. United States v. Alejandro Holch (S.D. Fla. 2002). On February 8, 2002, Alejandro Holch and Sports Telemarketing, Inc., a company of which Holch is president, were each sentenced to 1 year of probation and given a $5000 ﬁne for their role in introducing misbranded prescription drugs into interstate commerce. Holch and Sports Telemarketing had pleaded guilty to one count of introducing misbranded drugs into interstate commerce in violation of 21 USC 331(a) and 333(a)(1). As part of the plea agreement, Holch also agreed to testify on behalf of the government in a related case in which a urologist, a pharmacist, and two telemarketers have been indicted on similar charges.

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R.J. Reynolds Tobacco Co. v. FTC (D.D.C. 2002). R.J. Reynolds Tobacco Co. (RJR) brought this action against the Federal Trade Commission (FTC) under the Freedom of Information Act (FOIA) seeking the production of certain documents relating to an expert evaluation of an RJR cigarette campaign. FTC had claimed the documents were privileged. On December 5, 2001, RJR issued a subpoena to FDA seeking related documents that FTC had provided to FDA in connection with FDA’s tobacco rulemaking. FDA moved to quash the subpoena on several grounds, including that some of the documents were privileged and had already been requested (and either produced or treated as privileged) in United States v. Philip Morris, the pending case between the Department of Justice and the cigarette manufacturers. On April 2, 2002, Judge Gladys Kessler, the same judge presiding over the DOJ case, granted FDA’s motion to quash. United States v. Hanafy, 302 F.3d 485 (5th Cir. 2002). On August 15, 2002, the U.S. Court of Appeals for the Fifth Circuit afﬁrmed the trial court’s dismissal of all charges in this criminal case. The defendants, Ibrahim Elsayed Hanafy, Mohamed M. Mokbel, Samer Samad Quassas, and Adel Hisham Saadat, had obtained cans of infant formula by various means, repackaged the cans into shipping trays that bore the trademark of the formula’s manufacturer, and resold it to wholesale distributors. The defendants mixed cans with different batch codes and expiration dates in the same shipping tray and did not indicate that the cans had been repackaged. The jury found the defendants guilty of a total of 99 counts, including one count of conspiracy, nine counts of trafﬁcking in counterfeit goods, six counts of introducing misbranded food into interstate commerce, one count of interstate transportation of stolen property, 32 counts of money laundering, and 50 counts of engaging in monetary transactions with criminally derived property. Responding to a motion ﬁled by the dependants, the trial court overturned the jury’s verdict as to all counts. The Court of Appeals afﬁrmed. With respect to the misbranding charge, the Court of Appeals held that the printed matter on the shipping trays was not “labeling” within the meaning of the Federal Food, Drug, and Cosmetic Act, because the printed matter did not provide “substantial information” about or “explain” the articles. With respect to the counterfeit charge, the court held that afﬁxing a trademark to shipping trays that contain the genuine product associated with the mark does not violate the law. Court Updates and Other Enforcement Activities: Debarment List Persons may be debarred from working for the drug industry if they are convicted of committing crimes related to drug products regulated by the Food and Drug Administration. During FY2002, one notice was published in the Federal Register concerning a person debarred pursuant to Sections 306(a) and (b) of the Federal Food, Drug, and Cosmetic Act (21 USC 335(a) and (b)): Name of Person

Effective Date

End/Term of Debarment

FR Date.txt (MM/DD/YY)

Volume/Page

Petrik, Craig H.

04/30/2002

Permanent^

04/30/2002

67FR21255

Permanent ^* Permanent ^# Firm: None (as of the latest Federal Register date on this list). Symbolic notations: ^ Mandatory Debarment (Sec. 306(a)) % Permissive Debarment (Sec. 306(b)) * Hearing requested and denied. # Acquiesced to Debarment. + Special Termination of Debarment (Sec. 306(d)(4)(C) and (D)) A complete debarment list is available on the Internet at http://www.fda.gov/ora/compliance_ref/debar/default.htm.

The debarment list is compiled in accordance with 21 USC 335a(e) from notices published in the Federal Register (FR). The name of the ﬁrm or individual appearing in the FR for the ﬁrst time is

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added to the end of the list. Subsequently published FR debarment notices concerning the same ﬁrm or person are posted after the listing of the ﬁrm or individual. Disqualified/Totally Restricted List for Clinical Investigators The Food and Drug Administration regulates scientiﬁc studies that are designed to develop evidence to support the safety and effectiveness of investigational drugs (human and animal), biological products, and medical devices. Physicians and other qualiﬁed experts (“Clinical Investigators”) who conduct these studies are required to comply with applicable statutes and regulations intended to ensure the integrity of clinical data on which product approvals are based and to help protect the rights, safety, and welfare of human subjects. The list provided below contains the names of Clinical Investigators who have been disqualiﬁed or “totally restricted” in FY2002. FDA may disqualify a Clinical Investigator if the Clinical Investigator has repeatedly or deliberately failed to comply with applicable regulatory requirements or the Clinical Investigator has repeatedly or deliberately submitted false information to the sponsor or, if applicable, to FDA. A disqualiﬁed Clinical Investigator is not eligible to receive investigational drugs, biologics, or devices. In the past, the phrase “totally restricted” was also used to refer to Clinical Investigators who had been disqualiﬁed. Where an investigator has been reinstated, it is so noted. It is important to underscore the difference between “totally restricted” Clinical Investigators and “restricted” Clinical Investigators. “Totally restricted” investigators are ineligible to receive investigational products (absent reinstatement). “Restricted” investigators, on the other hand, are still eligible to receive investigational products, provided they conduct regulated studies in accordance with the restrictions speciﬁed in their agreement with FDA and all applicable regulatory requirements. The Food and Drug Administration maintains separate lists for all Clinical Investigators who have agreed to certain restrictions with respect to their conduct of FDA-regulated studies and Clinical Investigators who have provided adequate assurances with respect to their future (http://www.fda.gov/ora/compliance_ref/bimo/dis_res_assur.htm). These lists are updated regularly. For further information about these lists, contact Jim McCormack, Food and Drug Administration, Ofﬁce of Enforcement, 5600 Fishers Lane, HFC-230, Rockville, MD 20857; phone: 301-827-0425, e-mail [email protected]; fax: 301-827-0482. FDA also makes available a separate list of ﬁrms or persons debarred pursuant to the debarment provisions of the Federal Food, Drug, and Cosmetic Act (http://www.fda.gov/ora/compliance_ref/debar/default.htm). In addition, the DHHS, Public Health Service, Ofﬁce of Research Integrity, Administrative Actions Listing is located at http://silk.nih.gov/public/[email protected].

Disqualified/Totally Restricted List Name Address

Center

Type

Action

Comments

Eduardo Caro Acevedo, MD Bayamon, PR

CDER

D

July 30, 2002

Through hearing process

Leon C. LaHaye, M.D. Lafayette, LA

CDRH

D

June 18, 2002

Through hearing process

Carey L. Quarles, Ph.D. Wellington, CO

CVM

D

July 29, 2002

Through hearing process

Huibert M. Vriesendorp, M.D. Marshﬁeld, WI

CBER

D

December 31, 2001

Through hearing process

Note: D = disqualiﬁed or totally restricted Clinical Investigators who are not eligible to receive investigational products; CDER, Center for Drug Evaluation and Research; CDRH, Center for Devices and Radiological Health; CVM, Center for Veterinary Medicine; CBER, Center for Biologics Evaluation and Research.

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SUMMARY A. Statutory authority: FDA’s authority to seek criminal action can be found in the FD&C Act (refer to Appendix 1). B. Jurisdiction: The federal court system has jurisdiction over FDA-initiated criminal actions. C. Debarment: Debarment of individuals or ﬁrms may be permissive or permanent. Permissive debarment carries options for rehabilitation and possible reinstatement of privilege to work within the industries regulated by the FDA. D. Disqualiﬁcation (Institutional Review Board and Clinical Investigator): Disqualiﬁcation of Institutional Review Board and Clinical Investigators may also be permanent or temporary. E. Application compliance and integrity: Application compliance means that the ﬁrm that manufactures the product does so consistent with the approved application; that is, the product meets all safety and efﬁcacy or immunology standards documented in ﬁled applications, USP/NF, or other recognized standards. The application integrity test is applied to applications that the FDA has received from a sponsor that it believes contains suspicious or fraudulent data or information. In such instances, the FDA will stop its review, notify the sponsor who submitted the application of its ﬁndings, and demand clariﬁcation before considering continuing its review.

READING REFERENCE SECTION Read the information provided in this chapter on clinical investigations, FDA inspections of Clinical Investigators, and FDA Institutional Review Board inspections. The following article is presented to highlight how the FDA applies criminal provisions.

PRACTICUM Refer to the reference exhibits and models and FDA criminal actions provided in this chapter, then apply your knowledge to the FDA article by Linda Bren, “Investigators Report Infant Formula Case.” This is a food case; however, it highlights the means that some will take to counterfeit products to proﬁt from the country’s most vulnerable citizens: babies. When reading this and other cases presented in this chapter, consider whether or not it is the government’s role to ferret out unethical proﬁt motives, whether or not adequate government controls exist to effectively prevent or at least deter such acts, and what is your role? Prepare a written report and participate in discussions on these topics. Article for practicum: Bren, L., Investigators’ reports: Counterfeit baby formula lands fugitive in jail, FDA Consumer, March–April, 2003.

Investigators’ Reports: Counterfeit Baby Formula Lands Fugitive in Jail By Linda Bren After more than six years of living on the run from FDA investigators, Mohamad S. Mostafa may have thought he had escaped prosecution for selling counterfeit baby formula. But he was wrong. Agents from the FDA, with the help of the Royal Canadian Mounted Police, ﬁnally got their man.

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Mostafa ran his grocery business — M&M Wholesale — out of an ofﬁce in Stanton, Calif., with warehouses in nearby Santa Ana and Tustin. He made a few dollars selling some legitimate products, investigators say, but his cash cow was counterfeit infant formula. Mostafa’s illegal operation began when he hired an associate, Ivy Ong, to ﬁnd a source of inexpensive bulk powdered infant formula. Ong complied, and in December 1994 Mostafa arranged to buy 500,000 pounds of the formula, marked “for export only,” from a legitimate company. The formula could not be sold legally in the United States because it did not contain the correct levels of some nutrients required by federal law. Selling the formula in the United States for about three times what he paid for it, Mostafa stood to net illegal proﬁts in excess of $4 million, according to Jud Bohrer, special agent in charge of the Los Angeles ﬁeld ofﬁce of the FDA’s Ofﬁce of Criminal Investigations (OCI). Mostafa did not export the formula. Instead, he hired laborers to pack the powder in cans similar in size and appearance to those used to package Similac — a higher quality infant formula made by Abbott Laboratories’ Ross Products Division in Columbus, Ohio. Posing as a company representative of Ross Products, Mostafa ordered 50,000 labels bearing the registered trade name Similac from a printing company in Beltsville, Md. Mostafa’s employees glued the labels onto the one-pound cans of illicit formula, according to investigators. In January 1995, Mostafa sold more than 3500 cases of the counterfeit formula to wholesale grocers in California. The formula eventually lined the shelves of retail stores throughout the state. FDA agents were alerted to the scam in February 1995 after numerous parents who were familiar with the real Similac product complained to Ross Laboratories and to the FDA. The powdered product looked different and the enclosed measuring scoop was a different color than the one packed with the genuine Similac. No serious illnesses were reported, but some babies got upset stomachs and vomited after consuming the fake product, investigators say. “Mostafa was in this country illegally, all the while engaging in this lucrative criminal activity that jeopardized the health and safety of thousands of infants,” says Bohrer. OCI agents in Los Angeles traced the fake formula to a grocery wholesaler in Palm Springs, Calif., who identiﬁed Mostafa as the seller. In February 1995, the agents located Mostafa’s warehouses and secretly watched employees dismantling and loading canning and labeling equipment into a rented truck. Later, agents seized 38,000 pounds of counterfeit powdered formula, cans, and Similac labels from the truck, a warehouse, and a gold BMW belonging to a friend of Mostafa’s. More than 6000 cans of the counterfeit formula were also seized from California retail and wholesale outlets. After hearing about the FDA seizure, Mostafa ﬂed the country, according to testimony provided by Ong, who was charged as a co-conspirator. Ong was arrested in February 1995, and in August he pleaded guilty to three counts of misbranding a food. He was sentenced to four months of electronic home detention and one year of supervised release. The Royal Canadian Mounted Police were on heightened alert following the terrorist attacks of Sept. 11, 2001, when they checked out the applications of several Middle Eastern men who had applied for asylum in Canada. Mostafa was one of the men. Mounties arrested Mostafa in Fort McMurray, Alberta, after they discovered that he had multiple identiﬁcation cards and that a fugitive warrant had been issued for him in the United States. In October 2001, U.S. Marshals brought Mostafa back to California and jailed him in Santa Ana County until trial. On August 8, 2002, Mostafa was convicted of conspiracy, misbranding food shipped in interstate commerce, and two counts of trafﬁcking in counterfeit goods. On December 16, 2002, he was sentenced in U.S. District Court to 44 months in prison and three years of supervised release.

Source: http://www.fda/gov/fdac/departs/2003/203_irs.html.

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ENDNOTES 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128.

Generic Drug Enforcement Act (GDEA); Pub. L. 102-282(c)(1) and (3). Current good manufacturing practices (Title 21 CFR 210–211). Good clinical practices (Title 21 CFR 312 et seq.). Good laboratory practices (Title 21 CFR 56). Pub. L. 102-282, 106 Stat. 150, 306(B)(i)(1) — Individuals. Black’s Law Dictionary, West Publishing Co., St. Paul, MN, 1983, p. 517. 18 USC 1. Pub. L. 102-282, 306(a)(1) — Mandatory Debarment — Corporations, Partnerships and Associations. Pub. L. 102-282, 306(a)(2) — Mandatory Debarment — Individuals. Pub. L. 102-282, 306(b)(1) — Permissive Debarment. Ibid. Ibid., at (A)(i), (ii), and (iii). Ibid., at (B)(i)(I) and (II). Model Penal Code 2.202. GDEA 306(a)(2) and (b)(1). Guidance for Industry: Submitting Debarment Certiﬁcation Statements, U.S. DHHS–FDA, September 1998 (draft — not for implementation). Ibid., at p. 2. Ibid., at p. 3. Ibid., at p. 7. Ibid., at p. 8. Pub. L. 102-282, 106 Stat. 150, 306(2)(A)(ii). Pub. L. 102-282, 106 Stat. 150, 306(2)(B)(ii)(I). Ibid. Ibid., (k)(2). Ibid., (k)(I)(1) — Convictions Ibid., (k)(I) — Certiﬁcation. Ibid., (c)(2)(A). Ibid., (2)(c)(3) — Considerations. Ibid., (3)(d)(3)(A) — Corporations. Ibid., (3)(d)(B) — Individuals. Ibid., at (B)(ii). Ibid., at (B)(f)(i) — Temporary Denial of Approval. Ibid., at (B)(f)(ii). Title 21 CFR 56.108 — Function and operations. http://www.fda.gov/ora/compliance_rf/cpg/cpggenl/cpg120-100html. Investigations Operational Manual, January 1998, Section 980 et seq.; Grand Jury Investigations, Regulatory Procedures Manual, p. 224. FDA/Ofﬁce of Public Affairs, February 22, 2003 (http://www.fda.gov/ora/frequent/default.htm).

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5 Case Studies 5.1 PROGRAM IMPLEMENTATION It is recommended that the program implementation case study procedure provided in Section 3.2.9 of Chapter 3 be applied to the cases presented in this chapter, which are intended to assist with an understanding of the variations in how the Food and Drug Administration (FDA) has enforced technical terms of the regulations in the past and how this history can be applied to industry participants today with regard to Administrative Enforcement issues. The program implementation case study method will help determine the extent of the compliance program needed and whether or not the proposed implementation complies with the intent of the Food, Drug, and Cosmetics (FD&C) Act; amendments to the act; and Title 21 CFR 210–211 et seq. This case study review method is also useful when a concern exists with regard to implementation problems or compliance program gaps. When reading the various case studies included here, keep in mind that the FDA does not absolve industry participants from compliance in all areas, especially those documented in correspondence that serves as prior notice of violations. Documents provided here for actual civil and criminal cases give us an opportunity to determine what has happened over time in speciﬁc companies. Any past or current FDA 483 Notices of Observations, warning letters, and consent decrees for these companies are included here to allow us to perform a detailed review and analysis. Initially, a general approach is warranted to get an idea of the extent of the problem. When examining a company’s compliance program, it is important to identify the area that is out of control: current good manufacturing practices (CGMPs), good clinical practices (GCPs), good laboratory practices (GLPs), or the company’s advertising and promotional literature. A detailed evaluation of that particular area is the next task and involves a review of speciﬁc aspects of the FD&C Act and Code of Federal Regulations relevant to that area. Developing a full understanding of the extent of the compliance program required and the resources (both human and monetary) necessary to achieve it is recommended not only to achieve compliance but also to maintain it for those companies whose operations have been out of control for a long time. A requirement for good program implementation case study review is the investment of sufﬁcient time to analyze the full depth and breadth of the data available to develop realistic solutions. The cases provided in this chapter involve Abbott, Schering-Plough, Parkedale Pharmaceutical, Wyeth-Ayerst, Warner-Lambert, and various other companies and are intended to illustrate the different ways in which the FDA may apply Administrative Enforcement regulations.

5.2 FDA 483 FORMS, RECALLS, CORRECTIONS, AND MARKET WITHDRAWALS 5.2.1 ABBOTT LABORATORIES, INC., FDA 483 NOTICE

OF

OBSERVATIONS

Review Chapter 1 (Department of Health and Human Services, Food and Drug Administration: Authority and Responsibility), Sections 1.7 and 1.8; FDA forms 482 (Notice of Inspections) and 483 (Notice of Observations). Reference Title 21 CFR 210–211 et seq. and FD&C Act of 1938 189

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501(a)(2)(B). Your review of these items will enhance your understanding of the FDA’s authority and reasoning regarding the Abbott Laboratories FDA 483 Notice of Observations issued on October 15, 2002. The FDA 483 was issued because of alleged adulteration issues in Abbott’s manufacturing facility. As you read the document, refer to the CFR sections mentioned that have allegedly been violated. ___________________________________________________ DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Food and Drug Administration Dallas District 4040 North Central Expressway Dallas, Texas 75204-3145 October 15, 2002 Ref: 2003-DAL-WL-01 Certiﬁed Mail — Return Receipt Requested Mr. Miles White Chairman and Chief Executive Ofﬁcer Abbott Laboratories, Inc. 100 Abbott Park Road Abbott Park, IL 60064-3500 WARNING LETTER

Dear Mr. White: During an inspection of your drug manufacturing facility located in Austin, Texas, conducted August 19–28, 2002, our investigators documented deviations from the Current Good Manufacturing Practice regulations (Title 21, Code of Federal Regulations, Parts 210 and 211). These deviations cause your drug product(s) to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act. At the conclusion of the inspection, an FDA 483 (Notice of Inspectional Observations) was issued to and discussed with Mr. Ronald Kirkpatrick, Site Director. A copy of the FDA 483 is attached, and it identiﬁes many production and operational deﬁciencies causing the drug products manufactured by your ﬁrm to be adulterated. The deviations include the following: 1. Failure of the Quality Assurance Unit to follow written procedures, which require oversight and review responsibilities [21 CFR 211.22(d)]. For example, the following procedures are not being followed: • Al-00, Corporate Regulatory and Quality Science Policy • BQA0035, Global Quality System Overview • GN.l0-05, HPD Quality Policy, QA Functions and Responsibilities 2. Failure to assure that automated equipment will perform a function satisfactorily during the manufacturing process for your drug products [21 CFR 211.68]. For example, the [redacted] process control computer monitoring system that is used to monitor various production and processing operations (e.g., operation conditions, equipment and component status, historical trending of collected data) is not validated to the current corporate standards. The following equipment and support utilities are not validated:

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• • • • • • • • • •

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Continuous Sterilizer Solution Preparation Equipment/Process HVAC Lifecare Rotary Fillers [redacted] Part Fill Autoﬁllers [redacted] Irrigation Filler [redacted] ADD-Vantage Autoﬁllers [redacted] PVC Compounding Bag Fabrication Seal Thickness Measurement System Reverse Osmosis Water Puriﬁcation System and Water for Injection System

3. Failure to avert contamination in separate or deﬁned areas designed to prevent contamination from occurring during manufacturing and processing operations [21 CFR 211.42(c)(5)]. For example, • The controlling and monitoring of the movement and ingress of personnel, including maintenance personnel, components, and ancillary materials, such as tools necessary for equipment repairs/adjustments into the [redacted] ﬁlling areas are not being performed. • BMFGl413, General Good Employee Practices, states: Do not bring in or use rusty racks, tools, furniture, etc. in the clean areas. However, • Rust was observed on the metal support backing of at least four stools in the [redacted] critical ﬁlling zones. • Rust was observed covering the overall surface of a stainless steel rack used to transport equipment parts into and out of the critical [redacted] ﬁlling zones. • Rust and corrosion was observed on the base and impeller blades on active air sampler, equipment no. [redacted], which was observed in use in the critical manufacturing areas. • Stools used by operators in the [redacted] ﬁlling zones were observed with worn conditions (e.g., cover worn to the point the interior foam padding was no longer conﬁned by the plastic/vinyl cover). The following is a summary list of the areas in [redacted] rooms with rust buildup: • Rotary Station Nos. [redacted] • Irrigation Filling Station Nos. [redacted] • Part Fill Station Nos. [redacted] • Manual Fill Station [redacted] and recirculating air unit • Auto Filler Nos. [redacted] 4. Failure to restrict access by unauthorized personnel from entering areas designated as limited access areas [21 CFR 211.28(c)]. For example, • The ingress and egress of maintenance personnel into the [redacted] ﬁlling areas was not restricted to nonprocessing times of operation. 5. Failure to have adequate systems to control contaminants in areas where air contamination occurs during production [21 CFR 211.46(c)]. For example, • There are numerous HEPA ﬁlter metal grills that have a build up of rust-like material and discoloration (e.g., Rotary [redacted] Irrigation Filling, Part Fill Filling, and Manual Filling). Two HEPA ﬁlter grills are bent and reveal a buildup of mold-like and other unknown material and these grills are located immediately above the [redacted] ﬁlling zone. 6. Failure to follow written production and process control procedures [21 CFR 211.100(b)]. For example, BMFG1413, General Good Employee Practices, states: Do not bring in or use rusty racks, tools, furniture, etc. in the clean areas. However,

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• Rust was observed on the metal support backing of at least four stools in the [redacted] critical ﬁlling zones. • Rust was observed covering the overall surface of a stainless steel rack used to transport equipment parts into and out of the critical [redacted] ﬁlling zones. • Rust and corrosion was observed on the base and impeller blades on active air sampler, equipment no. [redacted] which was observed in use in the critical manufacturing areas. • Stools used by operators in the [redacted] ﬁlling zones were observed with worn conditions (e.g., cover worn to the point the interior foam padding was no longer conﬁned by the plastic/vinyl cover). 7. Failure to establish and follow written procedures for the cleaning and maintenance of equipment used in the manufacture, processing, packing, or holding of a drug product [2l CFR 211.67(b)]. For example, • There are no established written procedures currently in place indicating/detailing speciﬁc requirements with regard to controlling and monitoring the movement and ingress of personnel, including maintenance personnel, components, and ancillary materials, such as tools necessary for equipment repairs and/or adjustments, into the [redacted] ﬁlling areas. 8. Failure to thoroughly review the failure of a batch or any of its components to meet any of its speciﬁcations [21 CFR 211.192]. For example, • BQA0014, Handling of Product Complaints and WIP Shipment Complaints, does not describe the level of investigation to be performed when product complaints describing particulate matter in injectable products are received. • A number of complaints for particulates were received, but no attempt to determine the source was made. • Environmental monitoring results are not routinely evaluated when complaints for metallic particles or other particulates are conﬁrmed by analysis. • Retention samples are not routinely analyzed or evaluated as part of the complaint investigation. 9. Failure to establish and follow adequate procedures describing the handling of complaints related to drug products [21 CFR 211.198]. For example, • BQA0014 Handling of Product Complaints and WIP Shipment Complaints does not describe the level of investigation to perform when product complaints describing particulate matter in injectable products are received. • The investigation of PER #100361029, lot #74087-JT, determined and/or conﬁrmed metallic particles and synthetic ﬁbers near the port. However, there was no attempt to determine the source of the particulates at the manufacturing site, there was no review of environmental monitoring data obtained during manufacturing and ﬁlling operations for the referenced lot, nor was any batch record review conducted. • The investigation of PER #100449835, lot #78125-JT, documented the presence of brown ﬂoater in solution. Lab analysis identiﬁed this as fragments of brown paper, possibly from corrugated paper. No attempt was made to ascertain the source of these fragments at the manufacturing site. A review of retained samples was requested but was not performed nor was the batch record reviewed. • Elemental analysis of metallic particulate referenced in PER #100484617, lot #74729JT, showed copper, tin, and chlorine, possibly indicative of an alloy coating. However, no attempt was made to ascertain the source of the particle at the manufacturing site.

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• This appears to be a persistent problem. In a previous inspection, after a complaint was received regarding mold in the product, the presence of mold was conﬁrmed by analysis. The investigation did not indicate any review or evaluation of environmental monitoring data as a result of the conﬁrmation that there was mold growth on the caps or any attempt to ascertain the source of the mold. 10. Failure to establish scientiﬁcally sound and appropriate sampling plans designed to ensure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity [21 CFR 211.160(b)]. For example, • BBQA0009, Particulate Counting via the [redacted], and P-0452, [redacted] Test Method for LVI and Irrigating Solutions Using [redacted], are unclear regarding the number of ﬁnished product units required to be tested for visible and subvisible particulates. P-0452 indicates that no less than [redacted] units per lot are to be tested. Management indicated that lot sizes vary between [redacted] and [redacted] ﬁnished product units and that the routine is to test [redacted] units per lot, regardless of lot size. This sampling plan does not conform to statistically valid or scientiﬁcally sound sampling principles. 11. Failure to maintain records so that data therein could be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product speciﬁcations, manufacturing, or control procedures [21 CFR 211.180(e)]. For example, • Monitoring for nonviable particulates performed 10/26/01 in room 2217 (Part Fill ﬁlling area) recorded counts over the action limit in the [redacted] area. There was no deviation report, investigation, or measure undertaken in response to this event. The above identiﬁcation of violations is not intended to be an all-inclusive list of deﬁciencies at your facility. It is your responsibility to assure adherence with each requirement of the Good Manufacturing Practice Regulations. We are aware of your ﬁrm’s agreement to correct various deﬁciencies documented during the inspection and on the FDA 483. We have also received your ﬁrm’s written responses dated September 11, 12, and 30, 2002, and have considered the information provided during your meeting with us on October 11, 2002. However, the response and information do not adequately address the deviations listed above. For example, the failure to validate the [redacted] monitoring systems has an impact on whether the production and process control system is validated. We believe that because the [redacted] monitoring systems have not been validated to current standards, the validation of the production and process control system is in question. For this reason, we continue to ﬁnd the proposed timeline to complete validation of the [redacted] monitoring systems to be unacceptable. The [redacted] monitoring systems should not be in use unless they have been completely validated to current standards. The proposed correction to your sampling plans is not acceptable in that it does not conform to statistically valid and scientiﬁcally sound sampling principles. We ﬁnd the investigational approach for handling product complaints to be incomplete in that it fails to include steps necessary to determine the root cause or prevent future occurrences of similar product defects. In light of the seriousness of the above-listed deviations and the inadequacies of your responses to date, we have determined that the issuance of this letter should not be delayed. You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action without further informal notice. Possible actions include seizure and/or injunction.

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Please notify this ofﬁce in writing, within 15 working days of receipt of this letter, of the speciﬁc steps you have taken to correct the noted violations and to prevent their recurrence. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. Your reply should be sent to the Food and Drug Administration, Dallas District Ofﬁce, Attention: Brenda C. Baumert, Compliance Ofﬁcer, at the above letterhead address. Sincerely, /s/ Sylvia Yates for Michael A. Chappell District Director

5.2.2 ABBOTT LABORATORIES, INC., RECALLS Review Chapter 2 (Recalls: Corrections and Withdrawals), Sections 2.1 and 2.2. Reference Title 21 CFR Part 7 et seq. Read the FDA News issued on August 30, 2002 (below). Determine, based on the materials reviewed, aspects of this Abbott Laboratories recall of gonorrhea test kits that may impact their ability to conduct an effective recall. Ascertain whether Abbott Laboratories could effectively perform its Status Report duties of a recall under the scenario stated in the FDA News. _______________________________ U.S. Food and Drug Administration FDA News

FOR IMMEDIATE RELEASE P02-30 August 30, 2002

Media Inquiries: 301-827-6242 Consumer Inquiries: 888-INFO-FDA

Gonorrhea Test Kits Recalled by Abbott Laboratories The Food and Drug Administration (FDA) today announced that Abbott Laboratories, Inc., has initiated a worldwide recall of 32 lots of laboratory kits used to diagnose gonorrhea. The kits have been shown to be unreliable because they may give false negative results. These test kits were distributed to hospitals and laboratories from January 11 to June 24, 2002. Gonorrhea is a serious, highly contagious sexually transmitted disease that affects both men and women. Women primarily suffer severe consequences from infection that is not detected and treated. Untreated gonorrhea in women can cause pelvic inﬂammatory disease that can lead to sterility. In pregnant women, infection can potentially cause abortion, premature delivery, or infection in the baby. If undetected and untreated in men, it can cause an infection of the urethra that makes urination painful and difﬁcult. In both sexes, infection can spread through the bloodstream and infect the joints, skin, bones, tendons, and other parts of the body. FDA is alerting the public to this recall to help protect the public health, said FDA Deputy Commissioner Lester M. Crawford. We want to make sure laboratories that have purchased these test kits, physicians who have ordered these tests, and people tested for gonorrhea since January receive this information so they can act upon it. People who have had a negative gonorrhea test since January 11 may wish to ask their physician if they should be retested for gonorrhea. Abbott notiﬁed its customers (clinical laboratories) to discontinue use of all test kits and to destroy any remaining product. Abbott also advised the laboratories to contact the health care providers served by their facility and have them determine if their patients need to be retested. The physician should offer a retest to the patients whose test results were negative and who were not

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already treated. Repeat testing should be performed on a fresh specimen and not on retained specimens. Abbott Labs will reimburse expenses associated with repeat testing. Abbott voluntarily recalled 32 lots of its gonorrhea test kits after learning through routine internal testing that certain lots did not meet speciﬁcations and, as a result, could report positive test results as negative. Upon further testing, Abbott determined that only 16 of these 32 lots did not meet internal release criteria. Abbott is continuing to investigate the cause of the problem. The 16 lots that failed to meet speciﬁcation when tested by Abbott are 84073M400; 84075M400; 84142M300; 84146M300; 85487M200; 87007M400; 87103M400; 87243M100; 87377M200; 87899M200; 87905M200; 88097M300; 88105M300; 88107M300; 88439M200; and 88439M201. Patients who received a negative test result with test kits from these lots may need to be retested. Approximately 750,000 tests are affected. Consumers or laboratories with questions can contact Abbott Laboratories at 1-800-527-1869. Physicians with questions on this recall should contact Abbott Laboratories at 1-866-233-0471.

5.2.3 ABBOTT LABORATORIES FIRM-INITIATED RECALL OF HIV P24 ANTIGEN TEST KIT Review Chapter 3 (Civil Actions) and apply it to Abbott Laboratories’ regulatory issues; focus your attention on the root cause analysis. Reference Title 21 CFR Part 7.46 et seq. (recall standards) and FD&C Act 501 (adulteration). Review Chapter 4 (Criminal Actions: Debarment, Disqualiﬁcation, and Application Compliance and Integrity). According to FDA information, on February 13, 2001, Abbott Laboratories initiated a recall of their HIV Type 1 testing kit because it did not meet established product speciﬁcations. Apply your knowledge and the review material to this matter. Date Recall Initiated: February 13, 2001 Product/Lot Number/Expiration Date: Antibody to Human Immunodeﬁciency Virus Type 1 (HIVAG-1 Monoclonal HIV p24 Antigen Test Kit) 71843M101 4/19/2001 Manufacturer: Abbott Laboratories, Inc. Abbott Park, Illinois Reason: Abbott Laboratories is recalling the above-mentioned lot of HIVAG-1 Monoclonal HIV p24 Antigen Test Kit as a result of the product not meeting established product speciﬁcations. The test kit is used in the in vitro detection of HIV-1 p24 antigen and is intended as a screening test for donated blood and plasma as well as an aid in the diagnosis and prevention of HIV-1 infection. Abbott Laboratories became aware that the Antibody to HIV-1 (Rabbit) component of the test kit does not meet the label claim for volume. The label of the component states that 27 mL of ﬂuid is in the vial; however, the vials contain approximately 21 mL. The failure to deliver the Antibody to HIV-1 (Rabbit) component of the test kit to the reaction well could result in a false negative test. The recall notiﬁcation instructs establishments that currently have in inventory the recalled product to discontinue use and discard the product.

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5.2.4 ABBOTT LABORATORIES, INC., WARNING LETTER ___________________________________________________ DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Food and Drug Administration 1401 Rockville Pike Rockville, MD 20852-1448 March 19, 1999 CBER-99-015 By Facsimile and Certiﬁed Mail — Return Receipt Requested Miles D. White Chief Executive Ofﬁcer Abbott Laboratories 100 Abbott Park Road Abbott Park, Illinois 60064-3500 WARNING LETTER

Dear Mr. White: This letter concerns Abbott Laboratories’ (Abbott) Dear Abbokinase Customer letter pertaining to the supply of Abbokinase which Abbott disseminated via Western Union Mailgram on March 16, 1999. The Food and Drug Administration (FDA) has reviewed this letter, which constitutes labeling within the meaning of the Federal Food, Drug, and Cosmetic Act (the Act), 21 USC 321(m). We have concluded that the letter violates the Act and applicable regulations as set forth below. Because your March 16, 1999, Dear Abbokinase Customer letter is labeled as deﬁned in 21 USC 321(m), you were required to include the full prescribing information for the product [21 CFR 201.100]. Since the approved product labeling for Abbokinase was not included with the letter, the product is misbranded within the meaning of 21 USC 352(f). In view of the current compliance status of your product, the inclusion of the approved product labeling with the letter was critically important. Among other important prescribing information, the approved labeling contains an amended warning statement, with agreed-upon, bolded risk assessment information for physicians to consider in deciding whether to use Abbokinase for particular patients. As you are well aware, this information was added to the labeling for Abbokinase to reﬂect the signiﬁcant, numerous deviations from Current Good Manufacturing Practices (CGMPs) observed during FDA’s recent inspections of Abbott and its supplier of human neonatal kidney (HNK) cells. In addition, the Dear Abbokinase Customer letter contains representations and suggestions that are false or misleading within the meaning of 21 USC 352(a), particularly in the absence of the product labeling, which contains the warning statement referenced above. The FDA objects to the following representations and suggestions of the safety of your product in your letter: a. Your letter states that Abbott has expanded its manufacturing procedures to include additional testing and validation…. This sentence is misleading. Rather than expanding its procedures, Abbott, in fact, initiated efforts to rectify deﬁciencies in its manufacturing procedures in order to correct the numerous, signiﬁcant deviations from CGMPs observed during FDA’s inspection of Abbott last fall.

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b. Your letter states that Abbott has always employed a viral inactivation process (heat treatment) to help ensure that Abbokinase is free of viral contamination. This claim is false or misleading, particularly in light of the letter’s claim of full validation of the viral inactivation process, because it suggests that no viruses remain in the product after viral inactivation and hence there is no risk associated with the use of this product. In fact, a heat treatment viral inactivation process does not remove any virus present in the product and therefore does not render the product free of viruses. Rather, such a process renders some or all of those viruses that may be present in the product inactive. c. Your letter states, further, that during a process characterization study … the detection of reovirus was found during Abbott’s initial in-process control study to test for the presence of viruses, not during process characterization. Abbott implemented this inprocess control testing in response to an FDA 483 observation which noted that no such procedures for testing in-process product for the presence of adventitious agents were in place nor had ever been performed. Stating that reovirus was detected during process characterization incorrectly suggests to the reader that the testing was routine and had always been in place, rather than an action recently employed to correct a manufacturing deﬁciency. d. With regard to reovirus, your letter states, … and all test results have been negative, in both cells and ﬁnished product. The reovirus was detected in three lots of in-process product (unprocessed bulk harvest). The statement in your letter is misleading because only two lots of HNK cells have been tested for reovirus to date. In addition, while Abbott has informed FDA that those lots of ﬁnal product currently on the market and lots pending at the Center for Biologics Evaluation and Research (CBER) were tested and found to be negative for reovirus, the polymerase chain reaction (PCR) test used by Abbott has not been validated. The foregoing constitute the most signiﬁcant violations and are not intended to be an all-inclusive list of the deﬁcient language in your labeling. In light of the above-mentioned violations, FDA requests that you provide all recipients of the original letter with amended correspondence that includes as part of the text the full warning statement as it now appears in the approved labeling, along with a copy of the full prescribing information, as well as corrections to the statements in the letter that fully address the points outlined above. The amended correspondence should be prominently marked and worded to enable a physician to immediately recognize that the letter is a corrected version and not simply a duplicate copy of the March 16th letter with the approved labeling. In addition, we request that you post the amended correspondence on your company’s website. Please submit in writing, within ﬁve (5) working days of receipt of this letter, your responses to the violations identiﬁed in this letter, including your corrective action plan. Failure to promptly correct these deviations may result in regulatory action, such as seizure or injunction, without further notice. Your reply should be sent to the Food and Drug Administration, Center for Biologics Evaluation and Research, 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, Attention: Division of Case Management, HFM-610. If you have questions regarding this letter, you may contact me at (301) 827-6190. Sincerely, Steven A. Masiello Acting Director, Ofﬁce of Compliance and Biologics Quality Center for Biologics Evaluation and Research

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5.2.5 SCHERING CORPORATION RECALL OF INTERFERON POWDER FOR INJECTION, INTRON A

ALFA-2B

(RECOMBINANT),

Review Chapter 1 (Department of Health and Human Services, Food and Drug Administration: Authority and Responsibility), Sections 1.7 and 1.8; Chapter 3 (Civil Actions); FDA forms 482 (Notice of Inspections) and 483 (Notice of Observations). Reference Title 21 CFR 210/211 et seq. and FD&C Act of 1938, 501(a)(2)(B). Schering Corporation initiated a recall October 22, 2001, because its Interferon alfa-2b (recombinant) product was subpotent. Date Recall Initiated: October 22, 2001 Product/Lot Number/Expiration Date: PAK-3 Carton Lot No.

Interferon Vial Lot No.

Expiration Date

9-CO-3 9-CO-6 0-CO-10 0-CO-11 1-CO-11

8-IFB-005 8-IFB-006 8-IFB-006 8-IFB-007 9-IFB-001

10/20/01 11/04/01 11/04/01 11/23/01 08/02/02

Manufacturer: Schering Corporation Kenilworth, NJ Reason: Lots 8-IFB-005, 8-IFB-006, and 8-IFB-007 were found to be subpotent, after assaying as 87–89% at 30 days following reconstitution with sterile Bacteriostatic Water for Injection. Lot 9-IFB-001 was withdrawn as a precautionary measure because of the potential that this batch would not meet the product quality speciﬁcation for assay prior to its expiration date. All of the lots are within the product quality speciﬁcation for assay when tested immediately upon reconstitution.

5.2.6 WYETH-AYERST FIRM-INITIATED RECALL HAEMOPHILUS B CONJUGATE VACCINE

OF

According to FDA information, the ﬁrm-initiated recall of Haemophilus b Conjugate Vaccine (HibTITER) occurred August 30, 2000, because it was shipped inappropriately with a freeze indicator. Apply your knowledge to this recall. Date Recall Initiated: August 30, 2000 Lot Number/Expiration Date/Control Number: 613803A 1/2002 Shipper Control #471-912 Manufacturer: Wyeth-Ayerst Pharmaceutical Radnor, PA

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Reason: Wyeth-Ayerst Pharmaceutical became aware that ﬁve cartons (each containing 80 multidose vials) of HibTITER Haemophilus b Conjugate Vaccine, Lot 613803A, were shipped inappropriately in that the product was shipped by airfreight without a documented freeze indicator. Wyeth-Ayerst Pharmaceutical has initiated a recall of vials in question from Lot 613803A and is arranging for replacement of the subject vaccine. The ﬁrm is not recommending revaccination of children who have previously received vaccine from Lot 613803A.

5.2.7 WYETH-AYERST WITHDRAWAL OF ROTAVIRUS VACCINE, LIVE, ORAL, TETRAVALENT (ROTASHIELD) Deﬁne intussusception. Determine if, through the New Drug Application process, the issues subsequently identiﬁed with the product could have been known earlier. Based on your knowledge of the New Drug Application process and the FD&C Act of 1938 and amendments thereto, was the FDA correct in (a) approving the product, and (b) withdrawing its approval? Withdrawal Date: October 15, 1999 Lot Number/Expiration Date: All marketed lots Manufacturer: Wyeth Laboratories Incorporated A Wyeth-Ayerst Company Marietta, PA 17547 Marketed by: Wyeth-Lederle Vaccines and Pediatrics Wyeth-Ayerst Laboratories Philadelphia, PA 19101 Reason: On July 16, 1999, Wyeth-Lederle Vaccines temporarily suspended further distribution and administration of RotaShield until more data on the potential association between vaccine administration and intussusception became available. The action was taken in consultation with the Food and Drug Administration following a recommendation from the Centers for Disease Control and Prevention to postpone administration because of reports to the Vaccine Adverse Event Reporting System (VAERS) of a possible association between the use of RotaShield and the development of intussusception. At that time it was hoped that conclusive data would become available before the 1999–2000 rotavirus season. Evaluation of the additional cases of intussusception reported to VAERS, as well as preliminary date from ongoing epidemiological studies conducted by CDC, suggest a temporal association between the use of RotaShield and the development of intussusception. Additional studies are planned or in progress to better understand this relationship. Available data do not indicate an ongoing risk to children given RotaShield in the past. These data will be publicly discussed at the upcoming Advisory Committee on Immunization Practices meeting on October 22, 1999.

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5.3 MASS SEIZURE ACTIONS Review Chapter 3 (Civil Actions), Section 3.1 (Seizure). For the products below, determine the type of seizure applied and why. Discuss whether the seizure was appropriate and if other regulatory sanctions could apply. Relying on your knowledge, determine what type of internal compliance problems these ﬁrms could be experiencing. Develop hypothetical solutions to these issues using the Program Implementation approach. PRODUCT: Disopyramide Phosphate 100-mg Extended Release Capsules and other quantities of in-process and ﬁnished solid-dosage form drugs (tablets and capsules only) (93-605-588 et al.) Charge: Adulterated—The methods used in, and the facilities and controls used for, the articles’ manufacture, processing, packing, and holding do not conform to and are not operated or administered in conformity with current good manufacturing practice requirements. Firms: KV Pharmaceutical Company at seven different locations in St. Louis, Missouri, and, at Highland Packaging Company, St. Louis, Missouri Filed: April 20, 1993; U.S. District Court for the Eastern District of Missouri, Eastern Division; Civil Nos. 4:93CV00919 and 4:93CV00918; FDC Nos. 66706 and 66709 Seized: April 21, 1993 — Goods valued at $28 million and $3 million PRODUCT: Prescription and over-the-counter drugs (93-707-651) Charge: Adulterated — The methods used in, and the facilities and controls used for, the articles’ manufacture, processing, packing, and holding do not conform to and are not operated and administered in conformity with current good manufacturing practice requirements. Firm: Ambix Laboratories, East Rutherford, New Jersey Filed: July 28, 1993; U.S. District Court for the District of New Jersey; Civil No. 93-3340(HLS); FDC No. 66733 Seized: July 29, 1993 — Goods valued at approximately $750,000 PRODUCT: Cathy’s Extra Strength Guarana Capsules and Cathy’s Herbal Cellulite Treatment and accompanying labeling (93-700-038 et al.) Charges: New drug — No approved applications are in effect for such drugs. Misbranded — The articles’ labels fail to bear adequate directions for use. Firm: Bill’s Wholesale, Inc., and Bill’s Health Foods, Inc.; Albany, Georgia Filed: May 13, 1993; U.S. District Court for the Middle District of Georgia; Civil No. 93-56-ALBAMER; FDC No. 66699. Seized: May 28, 1993 — Goods valued at approximately $65,000 PRODUCT: Prostazinc tablets (93-556-601). Charges: New drug — The article is an unapproved new drug. Misbranded — The article’s labeling is false and misleading; fails to contain all required words, statements, and other information; and fails to bear adequate directions for use. Firm: Food Health Services & Ideas, Miami, Florida. Filed: March 23, 1993; U.S. District Court for the Southern District of Florida; Civil No. 93-0521CIV-ATKINS; FDC No. 66656. Seized: March 24, 1993 — Goods valued at approximately $50,000.

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DEFENDANT: Muhammed Z. Mannan, former manager of the research and development department, Superpharm Corporation, Bayshore, New York Charge: A federal jury found Mr. Mannan to be guilty of submitting false information to the FDA in support of Superpharm’s generic drug applications. He was sentenced to serve four months in a halfway house. Disposition: January 27, 1992 — Federal jury trial; May 1, 1992 — Sentencing, U.S. District Court for the District of Maryland, Criminal No. Har-91-0132; FDC No. 66537 Other Cases: United States v. Olson, 1947, 161 F.2d 669, certiorari denied 68 S.Ct. 79, 332 U.S. 768, 92 L.Ed. 353 United States v. Capon Water, D.C. Pa., 1929, 30 F.2d 300

5.4 INJUNCTION ACTIONS PRODUCT: Thyroid Tablets et al. (92-633-613) Against: Richlyn Laboratories, Inc., a corporation, and Richard S. Weinberg, an individual; Philadelphia, Pennsylvania. Charge: The defendants are permanently enjoined from the interstate shipment of any drug that is misbranded because its labeling is false or misleading. They are further enjoined from the interstate shipment of drugs that are adulterated because the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or labeling are not in conformity with current good manufacturing practice regulations. Further, the defendants must comply with the speciﬁc terms and obligations in the order of permanent injunction. Filed: September 21, 1992 — Restraining Order; October 1, 1992 — Order for Preliminary Injunction signed; May 25, 1993 — Order for Permanent Injunction, U.S. District Court for the Eastern District of Pennsylvania; Civil No. 92-CV-5464; INJ No. 1296. PRODUCT: Drug products (91-613-667) Against: Able Laboratories, Inc., a corporation, and Murty Vepuri and Paul Manning, individuals; South Plainﬁeld, New Jersey Charge: Adulterated — The methods used in, or the facilities or controls used for, the manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice regulations. Filed: November 6, 1991 — U.S. District Court for the District of New Jersey; March 2, 1992 — Agreed Order of Permanent Injunction, signed by both parties and the District Court Judge Contempt: May 25, 1993 — U.S. District Court for the District of New Jersey Action: New Jersey, Civil No. 91-4916 (AJL); INJ Nos. 1268 and 1268A; Stipulated Order, amending the Agreed Order of Permanent Injunction Disposition: The Stipulated Order limits the individual defendants’ activities at the ﬁrm, sets ﬁnancial penalties for violations of the agreed order, and names the manner in which the ﬁrm will be notiﬁed if a partial or complete shutdown is required. As a separate part of the overall settlement, A.L. Laboratories, the owner of Able Laboratories, paid to the U.S. Treasury a total of $45,611, the costs for prosecuting the contempt action.

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5.5 CONSENT DECREES 5.5.1 WARNER-LAMBERT CONSENT DECREE _______________________________ U.S. Food and Drug Administration FDA News

FOR IMMEDIATE RELEASE P93-34 August 16, 1993

Media Inquiries: (301) 443-3285 Consumer Inquiries: 888-INFO-FDA

The Food and Drug Administration today announced that the Warner-Lambert Co. has agreed to correct problems with manufacturing and testing practices associated with its drug products, and to bring its facilities into compliance with Current Good Manufacturing Practice regulations (CGMPs). In a consent decree agreed to by FDA and Warner-Lambert, a U.S. District Court Judge in New Jersey entered a permanent injunction against the company and its ofﬁcers. The decree requires the company to hire independent experts to evaluate manufacturing records and data for its products and to submit written certiﬁcations to FDA that drug products distributed from its six facilities in the United States, including two in Puerto Rico, meet the applicable manufacturing standards. The decree resulted from a series of plant inspections by FDA, recalls by Warner-Lambert, and meetings between the agency and Warner-Lambert ofﬁcials. Since December l992, 14 WarnerLambert drugs have been recalled for failure to comply with CGMPs and product quality standards; however, none of the recalled products posed a critical health risk. Patients must have conﬁdence that the drugs they take are properly made, said FDA Commissioner David A. Kessler, M.D. We will continue to work closely with Warner-Lambert to ensure that its products meet the appropriate standards. The decree allows several Warner-Lambert drug products that are considered medically necessary and not otherwise available to continue to be manufactured and distributed, provided that certain conditions are met. These products include: Celontin, Chloramphenicol injection, Choledyl, Dilantin, Humatin, Ketalar, Loestrin 1/20, Lopid, Milontin, Nardil, Nipent, Nitrostat, and Zarontin. The consent decree does not affect review of pending new drug applications. Likewise, certain investigational drugs will continue to be available. Manufacture of the company’s other prescription drug products has been suspended pending completion of laboratory and product certiﬁcations. However, the company will be permitted to ship prescription and over-the-counter products in inventory from certain plants while the laboratory and product certiﬁcations are completed. Under the consent decree, Warner-Lambert has agreed to the following measures: • • • •

An independent expert will certify that each laboratory at each of the facilities complies with the GMPs. All laboratory personnel will be trained so as to be fully qualiﬁed to perform their assigned duties. Outside experts will certify that manufacturing processes are in compliance with GMPs. Expert certiﬁcations or compliance plans to correct deﬁciencies will be reviewed and approved by FDA for medically necessary products that are not otherwise available.

To ensure compliance, FDA will continue to conduct inspections of Warner-Lambert plants and examine records relating to manufacturing and testing methods. According to the decree, FDA has authority to require the company to recall any product that does not meet standards. The agency may also require Warner- Lambert to stop manufacturing and distributing any product that fails to

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comply with GMPs or is not in accordance with the approved application. The decree further requires Warner-Lambert to pay damages resulting from violations of the injunction and the agency’s costs associated with this continuing oversight. The six plants covered under the injunction are located in Morris Plains, N.J.; Lititz, Pa.; Rochester and Holland, Mich.; and Vega Baja and Fajardo, Puerto Rico. FDA is one of eight Public Health Service agencies within HHS.

5.5.2 PARKEDALE PHARMACEUTICALS, INC., CONSENT DECREE NOTIFICATION LETTER 1 ___________________________________________________ DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Food and Drug Administration Detroit District 1560 East Jefferson Avenue Detroit, MI 48207-3179 Telephone: 313-226-6260 March 10, 2000 Jefferson J. Gregory, R.Ph., J.D. President, Chief Executive Ofﬁcer Parkedale Pharmaceuticals, Inc. 870 Parkedale Road Rochester, MI 48307-1740 Re: Consent Decree of Permanent Injunction, United States v. Warner-Lambert Company, Civil Action No. 43-3525, dated August 16, 1993 Dear Mr. Gregory: From October 4 through 13, 1999, the Food and Drug Administration (FDA) conducted an inspection of Parkedale Pharmaceuticals, Inc. (Parkedale), located at 870 Parkedale Road, Rochester, Michigan. Based upon FDA’s review of the inspection, the records collected during the inspection, and your written response to the observations, we have concluded that the methods, facilities, and controls used by Parkedale in the manufacture, processing, and packing of Inﬂuenza Virus Vaccine are not established, operated, and administered in compliance with Current Good Manufacturing Practice (CGMP) regulations set forth at 21 CFR Parts 210 and 211 and thus are adulterated within the meaning of 21 USC Section 351(a)(2)(B). As acknowledged in your letter dated February 26, 1998, to Mr. Douglas Ellsworth, FDA District Director, New Jersey District, Parkedale is a successor corporation under the referenced Consent Decree of Permanent Injunction (Consent Decree). In accordance with paragraph XVI of the Consent Decree, FDA hereby notiﬁes Parkedale that it must cease and discontinue manufacturing, processing, packing, labeling, and distributing all lots of Inﬂuenza Virus Vaccine pending performance, and FDA review and acceptance, of certain actions described in detail below. As you know, this is the third letter issued to Parkedale by FDA pursuant to paragraph XVI of the Consent Decree that has included deﬁciencies in the manufacture of Inﬂuenza Virus Vaccine. The ﬁrst letter, dated August 14, 1998, resulted from the observations noted during FDA’s March 23 to April 16, 1998, inspection, and discussed widespread deviations from CGMP. Some of the deﬁciencies noted were similar to those found during the current inspection, including inadequate cleaning validation and inadequate procedures for environmental monitoring in areas where Inﬂuenza

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Virus Vaccine is manufactured. The second letter, dated August 25, 1999, resulted from the observations noted during FDA’s inspection of May 3 to 13, 1999, and discussed numerous signiﬁcant CGMP deﬁciencies in the manufacture of Inﬂuenza Virus Vaccine, including in-process testing for bioburden and potency, container/closure integrity, sterile media ﬁlls, and environmental controls. Again, some of the signiﬁcant GMP deﬁciencies noted were similar to those found during the current inspection. While we acknowledge your efforts in the past to correct the deﬁciencies cited by FDA, we have concluded that your overall corrective action plan is unacceptable and incomplete, and that Parkedale must correct the signiﬁcant CGMP deﬁciencies disclosed by the current FDA inspection before it may continue the production and distribution of Inﬂuenza Virus Vaccine. Aseptic Processing FDA’s current inspection of Parkedale revealed numerous signiﬁcant deﬁciencies in the aseptic processing of Inﬂuenza Virus Vaccine. The investigators documented that the manufacturing process is not adequately validated and does not demonstrate a stepwise reduction in bioburden. Rather, numerous monovalent strain lots of the B/Yamanashi component that demonstrated low levels of bioburden following inactivation with formaldehyde subsequently became contaminated with high levels of bioburden later in the manufacturing process. For example, eight monovalent strain lots contained over 100 colony-forming units (cfu) per milliliter (mL) of contaminating organisms immediately prior to the ﬁnal ﬁltration steps with [redacted] ﬁlters. These lots of in-process product were used to formulate ﬁnished product lots of Inﬂuenza Virus Vaccine. The lots of vaccine passed ﬁnal product sterility tests and were distributed. In addition, FDA discovered that the [redacted] ﬁlters used to render the product sterile have never been validated for bacterial retention using in-process product or an appropriate surrogate. In your September 3, 1999, letter to FDA you stated, Parkedale qualiﬁed the ﬁltration process in terms of bacterial retention. The study utilized [redacted] as the challenge organisms for the [redacted] ﬁlter. However, our investigators documented that Parkedale has never performed microbial retention studies and the qualiﬁcation study referenced was performed by one of the ﬁlter manufacturers. The ﬁlter manufacturer did not use Parkedale’s Inﬂuenza Virus Vaccine or in-process product or an appropriate surrogate to conduct the referenced study. FDA is concerned because Parkedale failed to recognize, investigate, and take appropriate corrective action in response to elevated levels of bioburden. We note that your September 3, 1999, letter to FDA reported an alert limit of [redacted] cfu/mL and action limit of [redacted], exceeding the alert limit on three consecutive bioburden samples for post- and preﬁltration product pools. However, monovalent strain lots that exceeded the newly established bioburden limits were used to formulate trivalent vaccine after your September 3, 1999, commitment. We also note your November 15, 1999, letter to FDA in which you further modiﬁed the alert and action limits for these in-process products. Your letter states that an investigation will be initiated in the event that the action limit is exceeded; however, you failed to explain the actions to be taken. For example, it is unclear whether monovalent strain lots that exceed the action limit will be quarantined and/or excluded from production. FDA is also concerned about Parkedale’s reliance upon the [redacted] ﬁltration step to provide sterility assurance for ﬁnal vaccine product manufactured using monovalent strain lots contaminated with high levels of bioburden, without ever having validated the ﬁltration step. While we acknowledge your promises of improvements in control of the environment in the [redacted] column room, you have not adequately addressed the [redacted] columns as sources of bioburden. For example, the [redacted] and the [redacted] are reused repeatedly and only changed between strains or if the ﬂow rate decreases to a certain level. The sanitization of the [redacted] media and [redacted] has not been adequately validated and the number of uses of the [redacted] column has still not been established. You state in Parkedale’s November 15, 1999, letter that the [redacted] column sanitization validation will be completed during the 1999/2000 Fluogen manufacturing season, and you acknowledge that formal qualiﬁcation of the [redacted] ﬁltration columns has not previously been completed. This response is unacceptable to FDA.

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Further, FDA investigators documented nine instances where environmental monitoring of viable particulates in the [redacted] column room exceeded the action limit and no action was taken. Instead of taking corrective action, the excursions were accepted by the quality assurance (QA) unit based on the subsequent ﬁltration steps and the fact that the ﬁnished vaccine products passed sterility testing. It is our view that review of ﬁnal product sterility testing results does not constitute adequate corrective action. Parkedale increased neither the number of sampling sites nor the frequency of sampling. Additional cleaning was not performed and the source of the environmental contamination was not investigated. Potency Testing The current FDA inspection revealed that the standard operating procedure (SOP) titled Inﬂuenza Virus Vaccine (SOP 1200, Version 4), which provides procedures for the evaluation of in-process, ﬁnished product, and stability [redacted] potency testing data for Inﬂuenza Virus, is not always followed in that retesting and re-reading of test results have occurred. In addition, this procedure is inadequate because it does not include any references to the internal formulation guidelines or targets used as part of Parkedale’s formulation strategy. For example, the investigators documented that vaccine lot number 02979 was tested numerous times for potency in July and August 1999, after the initial tests failed to meet the internal guidelines for all three components. Subsequently, Parkedale lowered the guideline for the B/Yamanashi component to [redacted] (mcg) (from [redacted]) in late September 1999, released the lot, and selectively reported only some of the testing data in its October 8, 1999, letter to FDA. FDA is concerned that Parkedale continues the practice of extensive retesting for potency when the initial test results are below the internal guidelines/targets. We are also concerned that decisions regarding the extensive retesting appear to have been made with the knowledge of the quality control unit and management personnel. Paragraph XVI Notification Based on the above observations, FDA has concluded that the conditions under which Inﬂuenza Virus Vaccine is manufactured do not comply with CGMP. Under the terms of paragraphs XVI and XVII of the Consent Decree, Parkedale must immediately cease operations with respect to Inﬂuenza Virus Vaccine until it receives written notiﬁcation from FDA that Parkedale appears to be in compliance with 21 USC Section 351(a)(2)(B) and 21 CFR Parts 210 and 211. FDA will not issue such notiﬁcation unless and until Parkedale completes the following actions: 1. Parkedale shall within 30 days of receipt of this letter, submit an outline of all critical steps, and the test methods used to evaluate those critical steps, in the manufacturing process of Inﬂuenza Virus Vaccine. FDA will review the critical process steps submitted and provide comments. Contemporaneous with FDA’s review, Parkedale shall continue to establish and implement manufacturing process validation protocols within a time frame acceptable to FDA. 2. Parkedale shall perform microbial retention validation studies of all [redacted] ﬁlters using in-process Inﬂuenza Virus Vaccine product. The challenge organism(s) should be small enough to challenge the retentivity of the ﬁlter and simulate the smallest microorganism that may occur in production. 3. Parkedale shall: • establish bioburden speciﬁcations for in-process products based on historical data and scientiﬁc judgment; • quarantine in-process products that fail to meet the established bioburden speciﬁcation; and • establish procedures for investigating bioburden failures and determining the ﬁnal disposition of in-process products that fail to meet bioburden speciﬁcations.

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4. Parkedale shall immediately revise and implement the environmental monitoring program for critical and controlled environments to include investigations and speciﬁc corrective actions to be taken when action levels are exceeded. 5. Parkedale shall: • immediately revise its potency testing and laboratory investigation procedures so that excessive retesting and re-reading are prohibited; • retrain all laboratory and quality assurance personnel on the revised potency testing and laboratory investigation procedures; and • implement the revised procedures. Following conformance with the terms of item 1 and completion of items 2 through 5 above, Parkedale may resume manufacturing, processing, packing, and labeling, but not distribution, of Inﬂuenza Virus Vaccine. A responsible corporate ofﬁcer shall certify conformance and completion of items 1 through 5 in writing to FDA prior to resumption of these operations. In addition to items 1 through 5, Parkedale must take the following actions within 120 calendar days of this notiﬁcation with submissions to the agency on a quarterly basis thereafter: 6. Parkedale shall perform adequate validation studies of the puriﬁcation processes for Inﬂuenza Virus Vaccine performed in buildings 46 and 8, and based on those ﬁndings, revise speciﬁcations referenced in the batch production records and procedures. Parkedale shall establish the acceptable number of uses of the [redacted] and [redacted] used in the [redacted] and [redacted] columns based on the results of these studies. 7. Parkedale shall: • establish and implement a cleaning validation program that includes all aspects of the Inﬂuenza Virus Vaccine manufacturing process; and • validate the sanitization of [redacted] and [redacted] used in the [redacted] and [redacted] columns. 8. Parkedale shall conduct proper media ﬁlls. Media ﬁlls will be conducted appropriately and correctly according to current guidelines, in that all media-ﬁlled vials will be incubated and examined; all positive vials will be recorded; production activities will be simulated; and records of reconciliation will be accurate. Following completion of items 2 through 8 and prior to any distribution of ﬁnished Inﬂuenza Virus Vaccine, FDA will verify satisfactory completion of the above corrective actions and substantial compliance with CGMPs. In accordance with paragraph XVII of the Decree, FDA will issue to Parkedale written notiﬁcation permitting resumption of all operations, including distribution, upon FDA’s determination that Parkedale is in substantial compliance. Correspondence FDA has reviewed Parkedale’s letters dated August 26 and September 3 and 13, 1999, which respond to FDA’s letter dated August 25, 1999, and provide a quality master plan outline, a summary of the status of corrective actions, process validation protocols for Fluogen and Aplisol, and a summary of the WFI system enhancements. We are also in receipt of your letters dated August 31; September 16, 28, and 29; October 7; November 4; and December 6, 1999, which contain the monthly potency data for the 1999–2000 Fluogen lots, the revised Fluogen formulation strategy, and the revised stability protocol for commercial lots of Fluogen manufactured for the 1999–2000 season. Additionally, we have reviewed your November 15, 1999, response to the Form FDA 483 issued at the close of the inspection on October 13, 1999. As stated earlier in this letter, we have concluded that your overall corrective action plan is unacceptable and incomplete, and our comments and requests for further information and clariﬁcation are detailed below.

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November 15, 1999, Letter In your November 15, 1999, response you acknowledge that the bioburden data collected by Parkedale does not adequately demonstrate the step-wise reduction of bioburden during the manufacturing process for Inﬂuenza Virus Vaccine. While we generally agree that enhanced environmental controls and continued bioburden monitoring of in-process product are important, we have the following comments: You state that the [redacted] column room will be environmentally monitored [redacted] during operational activity. Thereafter, the [redacted] column room will be environmentally monitored [redacted] during operation activity. This revision of the frequency of monitoring appears to require substantially less environmental monitoring of the [redacted] column room than is described in SOP Number 3110, Version 2.0, titled Environmental Microbiological Monitoring Program — Buildings 8, 43, & 46. Version 2.0 of this procedure requires [redacted]. Please explain the rationale for decreasing the environmental monitoring of the [redacted] column room. You state repeatedly that a Notice of Event (NOE) and an investigation will be initiated when action levels are exceeded in the environmental monitoring program and the in-process product bioburden monitoring program. This response is unacceptable because you fail to provide immediate, speciﬁc corrective actions that will be taken. September 3, 1999, Letter Observation 1.A — You state that all Fluogen bulk vaccine tanks are outﬁtted with vent ﬁlters that are integrity tested before and after use, and that these ﬁlters are left open during bulk vaccine storage because of the temperature changes associated with these transfers. Please explain how vent ﬁlters are left open without compromising the sterility of the bulk vaccine. You state that the data contained in your letter dated July 9, 1999, support your decision to remove the nitrogen blanket from the bulk storage tanks. We note that the scope of the experiment was limited to the effect of the nitrogen purge on the potency of the B/Yamanashi strain stored at two different temperatures during a four-week test period. Please comment. Observation 1F — You state that, based on the data submitted in your July 9, 1999, letter to the FDA, you have determined that neither the free formaldehyde nor the oxygen head space concentration had an impact on potency. However, the data presented in Attachment 3 of the July 9, 1999, letter do not appear to be correlated to potency values for each lot. In fact, the potency of eight of the lots listed in Attachment 3 fell below the release speciﬁcation by the nine-month stability measurement. Please comment. Observation 1L — As discussed earlier in this document, we disagree with your statement that Parkedale has evidence to support the progressive reduction of bacterial load with each manufacturing step. Also, the proposed bioburden speciﬁcations (alert and action limits) are unacceptable, as discussed during the September 23, 1999, meeting between the FDA and Parkedale. Observation 21B — Your response is unacceptable because it does not address the issue of sampling being representative of water usage. Water should not be sampled after ﬂushing of the drop points unless the drop points are always ﬂushed prior to the water being drawn for use in routine manufacturing. September 13, 1999, Letter The retrospective validation report and the prospective validation protocol are inadequate for process validation purposes. In addition to Observations 8 and 9 of the Form FDA 483 issued on October 13, 1999, the agency’s speciﬁc comments are outlined below. Issues related to Tuberculin process validation will be addressed by the agency under separate cover.

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Influenza Virus Vaccine Process Validation

There were numerous deviations during manufacture of the ﬁnal drug product for lots used for the retrospective analysis. All deviations encountered during a retrospective analysis should be extensively investigated for potential impact on the validity of the process. Our speciﬁc comments include the following: 1. Several of the batches analyzed retrospectively (02288F, 02298F, and 02888F) had attribute failures (defects in ﬁnal containers). These lots were [redacted] manually reworked and deemed satisfactory. There is no mention of an investigation into these failures including corrective action taken to prevent recurrence, and a detailed description of the rework procedure was not included. 2. Batch 02988F exceeded the initial [redacted] inspection reject rate of [redacted]. The acceptance of the lot was based partially on the nature of product to have temporary high rejection rates. There is no explanation of this statement and an investigation report including corrective actions taken to prevent recurrence was not included. 3. Batch 02198 failed USP sterility. It appears that a double retest was performed which also failed. An investigation concluded that the ﬁrst and second failures were a result of faulty aseptic technique. The ﬁrst and second tests were invalidated. A third test was performed, passed, and identiﬁed as a satisfactory double volume initial test for the batch. The batch was released by the Quality Review Board. An investigation report was not included. The investigation report should contain the following information: • The evidence for invalidating the initial failing result (9/21/98) and allowing the ﬁrst double retest to proceed; and • The evidence for invalidating the second failing result (9/25/98), ﬁrst double retest, and allowing the double volume retest to proceed on 10/2/98. 4. The retrospective analysis did not include any of the manufacturing steps prior to the monovalent intermediates. While it is acknowledged that there may be some variation from strain to strain, this analysis should be extended to include all steps in the manufacture of the bulk drug substance. 5. Retrospective analyses are particularly useful in correlating operating parameters (e.g., time, temperature) to successful or unsuccessful outcomes for any given process step. The retrospective validation report does not identify the operating parameters and expected outcomes for each step in the manufacturing process. The retrospective analysis should be extended to include identiﬁcation of the critical operating parameters and outcomes. 6. A prospective or concurrent process validation study should be designed to evaluate the process at its limits of operation; therefore, operating parameters (e.g., time, temperature) should be clearly identiﬁed in the protocol and their limits challenged during the execution of the study. Validation studies should also include the evaluation of additional process parameters (e.g., potency, and bioburden) than would normally be measured during routine production in order to adequately assess and validate the process. The validation protocol should outline all process parameters that are to be measured for each step with appropriate acceptance criteria. Please revise your validation protocol accordingly. Parkedale must immediately comply with this notiﬁcation. Failure to do so will result in FDA’s consideration of assessing liquidated damages against Parkedale as provided for in paragraphs XX and XXI of the Consent Decree. You are further instructed to inform FDA of the status of Parkedale’s actions taken in compliance with this notiﬁcation. A responsible corporate ofﬁcer shall certify receipt of this notiﬁcation in writing to FDA within 5 working days. Copies of your responses should be sent concurrently to my attention and to Mr. Steven A. Masiello, Director, Ofﬁce of

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Compliance and Biologics Quality, Center for Biologics Evaluation and Research, 1401 Rockville Pike, Suite 200N, Rockville, Maryland 20852-1448, Attention: Division of Case Management, HFM-610. This letter constitutes notice of a signiﬁcant failure to comply with 21 USC Section 351(a)(2)(B) and 21 CFR Parts 210 and 211 under paragraph XXII of the Consent Decree. Sincerely, Raymond V. Mlecko Director Detroit District Ofﬁce

5.5.3 PARKEDALE PHARMACEUTICALS, INC., CONSENT DECREE NOTIFICATION LETTER 2 ___________________________________________________ DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

Food and Drug Administration Detroit District 1560 East Jefferson Avenue Detroit, MI 48207-3179 Telephone: 313-226-6260 September 27, 2000 Jefferson J. Gregory, R.Ph., J.D. President, Chief Executive Ofﬁcer Parkedale Pharmaceuticals, Inc. 870 Parkedale Road Rochester, MI 48307-1740 Re: Consent Decree of Permanent Injunction, United States v. Warner-Lambert Company, Civil Action No. 93-3525, entered August 17, 1993, in the U.S. District Court for the District of New Jersey (Consent Decree) Dear Mr. Gregory: The Food and Drug Administration (FDA) has reviewed Parkedale’s letter dated July 11, 2000, which responds to FDA’s letter of June 6, 2000. FDA has also reviewed Parkedale’s July 11 and July 24, 2000, responses to the FDA 483 form issued at the close of the limited FDA inspection of the Inﬂuenza Virus Vaccine operation conducted June 26 to 29, 2000. As you know, this inspection was performed pursuant to FDA’s March 10, 2000, paragraph XVI notiﬁcation in order to verify satisfactory completion of items two through eight of the March 10, 2000, letter and compliance with CGMPs. Based upon FDA’s review of the inspection, the records collected during the inspection, and your written responses to the observations, we have concluded that the methods, facilities, and controls used by Parkedale in the manufacture, processing, and packing of Inﬂuenza Virus Vaccine are not established, operated, and administered in compliance with 21 USC Section 351(a)(2)(B) and 21 CFR Parts 210 and 211 (CGMP). Therefore, in accordance with paragraph XVI of the Consent Decree, FDA hereby notiﬁes Parkedale that it must again cease and discontinue manufacturing, processing, packing, labeling, and distributing Inﬂuenza Virus Vaccine.

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FDA’s June 2000 inspection of Parkedale revealed continuing CGMP deﬁciencies in production and process controls for Inﬂuenza Virus Vaccine. During the inspection, the investigators discovered that [redacted] monovalent strain lots of A/New Caledonia had been rejected due to egg safety test failures. The egg safety test is performed to verify that inactivation of viable inﬂuenza virus has been accomplished. FDA has serious concerns regarding Parkedale’s investigation and the actions taken in response to these egg safety test failures. Our concerns are outlined below. For some of these lots, Parkedale created a retest protocol to retest each lot at the point [redacted] past the completion of the previous test and to continue testing at [redacted] intervals until the sample meets the speciﬁcations of the test. FDA strongly objects to Parkedale’s retest protocol and the documented rationale that, … generally at [redacted] when the egg safety test was repeated on the same sample, the results were then within speciﬁcation. This is believed to be due to a slow kill rate of the virus for the particular samples. It is our view that Parkedale’s practice constitutes testing the monovalent strain lots into compliance, a practice that undermines the principles of process validation and good manufacturing practice, and could possibly result in the presence of live inﬂuenza virus in the in-process monovalent concentrate. In response to the egg safety test failures, Parkedale changed the inactivation time for the A/New Caledonia strain from [redacted] days. FDA has serious concerns regarding Parkedale’s initial failure to establish the inactivation time for this new strain of inﬂuenza virus. The kinetics for viral inactivation for every new strain should be studied and established prior to production and not in response to egg safety test failures. In addition to changing the inactivation time, Parkedale also changed the method of mixing from a [redacted] of the solution bottle to a mixing step using a [redacted] mixer. It is unclear, however, whether the change was adequately validated. FDA reminds you once again that changes in manufacturing must be reported to CBER pursuant to 21 CFR 601.12. Finally, FDA has discovered that at least one of the rejected lots, 46578, that failed the egg safety test was incorporated into monovalent concentrate lot 47115 and submitted to CBER for lot release. We interpret the submission of this monovalent concentrate to mean that Parkedale intends to market the trivalent vaccine formulated with this lot. For the reasons discussed in numbers 1 and 2 above, FDA questions the suitability and safety of monovalent concentrates prepared using strain lots that failed the egg safety test. The ﬁnal disposition of the remaining [redacted] monovalent strain lots that failed the egg safety test and were recommended for rejection by Parkedale’s Cross Functional Investigation (CFI) Team is unknown. The investigators also documented that the pooling laboratory, a classiﬁed area used to pool monovalent concentrates and formulate trivalent vaccine, had been quarantined due to mold contamination in the environment. The environmental monitoring results revealed that multiple plate exposures from the upper surface of the pooling tank were contaminated with mold. Each test result exceeded the action limit established for mold ([redacted], respectively), which was identiﬁed as [redacted]. Because of the mold contamination, [redacted] lots of monovalent concentrate [redacted] were quarantined in accordance with the established procedures. Given the circumstances, which included multiple excursions so severe as to warrant quarantine of the classiﬁed area and the products, FDA was surprised to discover that the [redacted] lots had been submitted to CBER for lot release in June 2000, when your July 24, 2000, letter characterized the lots as in quarantine pending ﬁnal disposition by Quality Assurance. Our review of Parkedale’s SOP 3010 Deviation Investigation Procedure, version 7.0, and SOP 3110 Environmental Microbiological Monitoring Program — Buildings 8, 43, & 46, version 4.0 indicates that these environmental monitoring results clearly exceeded the action limit, and the corresponding products should have been rejected. FDA is also concerned about decisions made by Parkedale’s management with respect to other monovalent strain lots that were characterized as rejected due to environmental monitoring excursions in your July 11, 2000, letter. For example, our investigators obtained records of a Quality Review Board meeting on February 20, 2000, in which numerous rejected lots were recommended

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for further processing based on product bioburden results, ﬁnal ﬁltration through a [redacted]micron ﬁlter, and a reﬁltration operation. FDA is not aware of an approved reprocessing procedure that includes reﬁltration of monovalent strain lots. Regarding your process validation efforts with respect to the reuse of [redacted] in the [redacted] columns, FDA acknowledges your statement that historical data were not available to provide the relevant background information. Inspectional information reveals that the concurrent validation study to evaluate the reuse of [redacted] was initiated on or about May 20, 2000, with the ﬁrst data recorded on May 22, 2000. The protocol collected by the investigators, however, indicates that Parkedale has not established acceptance criteria for [redacted] used in the study. Rather, the protocol states that, [t]he [redacted] concentration acceptance limits will be determined after a thorough review of the collected data from pooled fraction samples. Further, the protocol states that, [e]valuation of collected data … will determine whether [redacted] acceptance limits are required. These ﬁndings call into question the scientiﬁc basis of the study and are of concern to FDA. Regarding the microbial retention validation studies of all [redacted] micron ﬁlters used in the manufacture of Inﬂuenza Virus Vaccine, we acknowledge the revised schematic of the ﬁltration process and the clariﬁcation that Step 1 (pre-ﬁltration) was not part of the [redacted] study. FDA continues to have concern regarding the practice of switching the [redacted] ﬁlters numerous times during the preﬁltration process due to clogging. We acknowledge Parkedale’s revision to the batch record that now limits the number of ﬁlter switches to [redacted]. Parkedale states the criteria for changing ﬁlters is based on observations of decreased ﬁltrate rate, however, you also state in your July 11, 2000, letter that the ﬂow rate is not controlled except with pressure. Therefore, it is unclear how the decreased ﬁltrate rate is observed or measured. Additionally, Parkedale has not explained how the ﬁlters are switched without compromising the sterility and integrity of the product. Based on these concerns, FDA has concluded that the ﬁltration step intended to render the product sterile has not been adequately validated. Based on our review of Parkedale’s letters dated July 11 and 24, 2000, and the deviations documented during the inspection, FDA does not accept your April 13, 2000, certiﬁcation that Parkedale has conformed with and has satisfactorily completed items one through ﬁve contained in FDA’s March 10, 2000, Paragraph XVI notiﬁcation. This decision reﬂects the agency’s determination that Parkedale continues to have systemic CGMP problems that have not been satisfactorily addressed. Paragraph XVI Notification FDA has concluded that the methods, facilities, and controls used in the manufacturing, processing, packing, and labeling of Inﬂuenza Virus Vaccine are not established, operated, and administered in compliance with 21 USC Section 351(a)(2(B) and 21 CFR Parts 210 and 211, and as a result the product is adulterated. Under the terms of paragraphs XVI and XVII of the Consent Decree, FDA hereby notiﬁes you that Parkedale must immediately cease manufacturing, processing, packing, labeling, and distributing Inﬂuenza Virus Vaccine until it receives written notiﬁcation from FDA that Parkedale appears to be in compliance with 21 USC Section 351(a)(2)(B) and 21 CFR Parts 210 and 211. Additionally, FDA has concluded that the safety, purity, potency, identity, and quality of in-process Inﬂuenza Virus Vaccine in your inventory cannot be assured. We recommend, therefore, that you initiate appropriate steps for the proper disposition of the inventory. Prior to Parkedale’s resumption of any operations, FDA must verify compliance with current good manufacturing practice. In accordance with paragraph XVII of the Decree, the cessation of operations must continue until Parkedale receives written notiﬁcation from FDA permitting Parkedale to resume all Inﬂuenza Virus Vaccine operations, including distribution, upon FDA’s determination that Parkedale is in compliance with CGMPs. We advise you that both of the biologics license application supplements recently submitted by Parkedale, regarding changes to the heating, ventilation, and air conditioning system (STN

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103783-5001) and an alternate buffer for use in selected manufacturing steps (STN 103783-5000), are being reviewed in accordance with FDA’s established procedures. Parkedale must immediately comply with this notiﬁcation. Failure to do so will result in FDA’s consideration of assessing liquidated damages against Parkedale as provided for in paragraphs XX and XXI of the Consent Decree. You are further instructed to inform FDA of the status of Parkedale’s actions taken in compliance with this notiﬁcation, including the disposition of Parkedale’s inventory. A responsible corporate ofﬁcer shall certify receipt of this notiﬁcation in writing to FDA within ﬁve business days. Copies of your responses should be sent concurrently to my attention and to Mr. Steven A. Masiello, Director, Ofﬁce of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, 1401 Rockville Pike, Suite 200N, Rockville, Maryland 20852-1448, Attention: Division of Case Management, HFM-610. This letter constitutes notice of a signiﬁcant failure to comply with 21 USC Section 351(a)(2)(B) and 21 CFR Parts 210 and 211 under paragraph XXII of the Consent Decree. If you have questions about this notiﬁcation or wish to request a meeting with FDA, please contact Mr. Masiello at (301) 827-6190. Sincerely, Raymond V. Mlecko Director Detroit District Ofﬁce

5.6 CRIMINAL INDICTMENTS, PROCESS, AND FDA PROCEDURES DEFENDANT: Duramed Pharmaceuticals, Inc., Cincinnati, Ohio Information: Duramed pled guilty to two misdemeanor counts of shipping an unapproved new drug and one misdemeanor count of shipping an adulterated drug in interstate commerce. The three counts relate to abbreviated new drug applications ﬁled with FDA in mid-1986 for Prochlorperazine Maleate 10 mg Tablets and Propranolol HCl/Hydrochlorothiazide 80/25 mg Tablets. As part of the plea Duramed agreed to pay a $500,000 ﬁne over a three-year period and signed a Consent Decree of Permanent Injunction. Under the Consent Decree, the ﬁrm agreed not to violate certain applicable laws, to continue to cooperate with any further government investigation, and to cooperate with FDA during future inspections of the ﬁrm’s facilities or products. Filed: Information — May 11, 1993; Plea Agreement — May 24, 1993; Criminal No. HAR-930207, FDC No. 66101; May 24, 1993 — Consent. Decree of Permanent Injunction, Civil No. HAR93-1515, INJ 1328, U.S. District Court for the District of Maryland Disposition: Prosecution DEFENDANT: Mohammed F. Azeem, former Vice President of Technical Services, Superpharm Corporation, Bayshore, New York Charge: Mr. Azeem was convicted by a Federal jury of three felony counts of making false statements to FDA in connection with generic drug applications. He was sentenced to three years’ imprisonment on each of three felony counts, the sentences to run concurrently. In 1990, Mr. Azeem was convicted, sentenced to, and served six months in prison for making unlawful payments to FDA ofﬁcials. Disposition: January 27, 1992 — Federal jury trial; May 1, 1992 — Sentencing, U.S. District Court for the District of Maryland; Criminal No. Har-91-0132, FDC No. 66537

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DEFENDANT: Vitarine Pharmaceuticals, Inc., Springﬁeld Gardens, New York, and St. Croix, Virgin Islands Charges and Disposition: Vitarine, a manufacturer of generic drug products, has pleaded guilty to four counts of shipping adulterated drugs in interstate commerce and has been ﬁned $2,000,000. The drugs were adulterated in that falsiﬁcations had been made by corporate ofﬁcers in applications to FDA for drug approvals and in manufacturing process production records. Vitarine cooperated fully in the investigation and voluntarily ceased distribution of all involved drugs. Filed: April 13, 1992 — U.S. District Court for the District of Maryland; Criminal No. HAR-920117; FDC No. 65710 DEFENDANTS: Five former ofﬁcers of Halsey Drug Company, Inc., Brooklyn, New York: Jay Marcus, former President and Chief Executive Ofﬁcer; Hedviga Herman, former Vice President of Manufacturing; Frederick Shainfeld, former Senior Vice President of Technical and Regulatory Affairs; Amirul Islam, former Vice President of Technical Services; and Muhammad Uddin, former Assistant Vice President of Research and Development Charges: The Indictment charges the individuals with conspiring to defraud FDA by, among other things, deviating from the FDA-approved manufacturing processes for several drug products by adding unapproved ingredients, failing to report these deviations in batch production records, and failing to seek prior approval from FDA. The indictment also charged the defendants with shipping adulterated and unapproved drugs in interstate commerce, false statements to FDA, and obstruction of an FDA inspection. Filed: July 12, 1993; U.S. District Court for the District of Maryland; Criminal No. HAR-93-0286; FDC No. 65985 DEFENDANT: Halsey Drug Company, Inc., Brooklyn, New York Charges: The ﬁrm entered a guilty plea to a ﬁve-count Information charging the company with causing the adulteration of quinidine gluconate, a prescription heart medication. The drug was adulterated because it was not manufactured according to its FDA-approved formula, and it contained unapproved inactive ingredients. The company was sentenced to a $2.5 million ﬁne. Filed: July 8, 1993 — Information; July 16, 1993 — Guilty plea, U.S. District Court for the District of Maryland; Criminal No. HAR-93-0286; FDC No. 65985 PRODUCT: Latex Examination Gloves (90-552-584) Firm: Scitech Medical Products, Inc., New Hyde Park, New York Charge: Adulterated — Product contains holes. Mislabeled — Labeling fails to bear name and place of business of manufacturer, packer or distributor. Filed: November 28, 1989, U.S. District Court for the Western District of Missouri; Civil No. 891108-CV-W-3, FDC No. 65776 DEFENDANT: John W. Bushlow, former Vice President for Manufacturing and General Manager of St. Croix, V.I. facility, Vitarine Pharmaceuticals, Inc., Springﬁeld Gardens, New York, and St. Croix, Virgin Islands Charges and Disposition: Mr. Bushlow pled guilty to one count of fraudulent failure to establish and maintain records of drug manufacture, was sentenced, and is currently serving a sentence of four months in prison and four months in a halfway house, without parole. Filed: September 6, 1991 — Guilty plea; February 21, 1992 — Sentencing, U.S. District Court for the District of Maryland; Criminal No. HAR-91-0330, FDC No. 66528

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DEFENDANT: Steven Colton, former Vice President and Director of Research and Development, Vitarine Pharmaceuticals, Inc., Springﬁeld Gardens, New York, and St. Croix, Virgin Islands Charges and Disposition: Dr. Colton was convicted of three counts of providing false and fraudulent information to the Food and Drug Administration in order to obtain approval of various Vitarine products. He is currently serving a 27-month sentence without parole in a federal prison. Filed: September 6, 1991 — Sentencing, U.S. District Court for the District of Maryland; Criminal No. HAR-91-0125R, FDC No. 66529. Other Cases: United States v. Industrial Laboratories Co., CA10 (Colo.) 1972, 452 F.2d 908 United States v. Dotterwich, U.S.N.Y. 1943, 64 S.Ct. 134, 320 U.S. 277, 88 L.Ed. 48 rehearing denied 64 S.Ct. 367, 320 U.S. 815, 88 L.Ed. 492 United States v. Abbot Laboratories, Ca. 4 (N.C.) 1974, 505 F.2d. 565, certiorari denied 95 S.Ct., 1424, 420 U.S. 990, 43 L.Ed. 2d 671. United States v. Arlene (Tex.), 1991, 947 F.2d 139, certiorari denied 112 S.Ct. 1480, 503 U.S. 939, 117 L.Ed.2d 623

5.7 FDA PROSECUTION The FDA establishes procedures and policies for the review of its prosecution recommendations, including referrals for criminal investigation. It has ﬁve different procedures, depending upon the case at issue and the mental state of the defendant. These standards are developed to eliminate unnecessary review and to expedite their case review process. Absent gross, ﬂagrant, or intentional violations, fraud, or danger to health, FDA complaints are generally required to show a continuous or repeated course of violative conduct. To be a repeat, there must be at least two or more inspections, or counts, from separate violative acts at different points in time. The FDA will ordinarily exercise its prosecutorial criminal sanctions against a person only when a prior warning or other type of notice can be shown — for example, a FDA 483, warning letter, or recall. Because FDA civil and criminal lawsuits are handled by the U.S. Attorney in the Department of Justice, it must establish evidence supporting its complaint using a background of warnings or other types of notice that will demonstrate to the U.S. Attorney, the judge, and the jury that there has been a continuous course of violative conduct, along with a history of repeated failures to effectively correct problems.

5.7.1 OFFICE

OF

CRIMINAL INVESTIGATIONS

Food and Drug Administration criminal investigations are the responsibility of the Ofﬁce of Criminal Investigations (OCI). OCI works expeditiously if the district ofﬁce or Center believes that a criminal investigation is necessary. In cooperation, with the FDA’s OCI department, those familiar with the ﬁrm are responsible for completing the Regulatory Procedures Manual Referrals for Criminal Investigations Section 305 notice. The FD&C Act Section 305 has two provisions for notice: (1) criminal prosecution after, and (2) criminal prosecution before.

5.7.2 CRIMINAL PROSECUTION

AFTER

SECTION 305 NOTICE

The U.S. Constitution Fourth Amendment and the FD&C Act Section 305 provide individuals subject to criminal investigation notice and an opportunity to respond.129 During the process, the following are steps taken within the FDA: 1. When a district does not have direct reference authority to issue a Section 305 notice, the district will submit a detailed request for instructions to the appropriate center(s) for

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review. The citation request should include: (a) the names and responsibilities of each individual and the charges to be presented in the notice; (b) the full background history of notiﬁcation of the persons to receive a notice; and (c) facts supporting the proposed charges, including assurance of interstate documentation. All pertinent evidence (e.g., work sheets, labels, and inspection reports) should be submitted with the recommendation. The center may request the interstate documentation if a special need to review it exists.130 2. If the district or the center identiﬁes an issue requiring consultation with the Ofﬁce of Enforcement (OE), OCI, Ofﬁce of the Chief Counsel (OCC), or an ad hoc committee, the component identifying the issue will obtain prompt resolution as early in the review process as possible. 3. If, following the meeting held in response to the Section 305 notice, there is no signiﬁcant change in the facts, as set forth in the district’s request to issue the 305 notice, the district will notify the center, which will forward the district’s 305 citation request package promptly to the Division of Compliance Management and Operations (DCMO) (HFC210), in the OE. Concurrently, a ﬁnal Summary and Recommendation (S&R) will be sent by the district to DCMO, with copies to the Center and to the Records Section (HFA-224). If there is a signiﬁcant change in the facts or strength of the proposed case, the district will submit the prosecution recommendation package to the appropriate center solely to determine whether prosecution remains warranted in view of the new information. If prosecution is warranted, the center will promptly forward to DCMO the prosecution S&R and the center’s approval memo presenting the basis for its decision in light of the new information. Note: When a district has evidence sufﬁcient to meet the requirements for direct reference authority to issue a Section 305 notice (i.e., direct reference cite authority), the procedures in item 1 above do not apply. After the Section 305 process has been completed and — if no new information is presented that affects the basis for the direct reference authority — the district should promptly submit its prosecution S&R directly to DCMO for a limited review. The district should concurrently send a copy of the S&R to the center and HFA-224. If the response to the Section 305 notice reveals new information affecting the basis for the direct reference cite authority, the district must obtain center review and concurrence concerning that aspect of the recommendation before submitting it to DCMO. 4. DCMO will perform a limited review to determine whether the proposed prosecution conforms to agency policy and enforcement strategies and objectives. If DCMO concurs with the prosecution recommendation, it will forward all relevant materials to the CC (GCF-1), along with a memo concerning the issues it has considered and that DCMO believes the CC should review. 5. The CC will review the recommendation and, if it agrees that prosecution is supportable, prepare a referral letter and form of Information or Indictment.

5.7.3 CRIMINAL PROSECUTION

WITHOUT

SECTION 305 NOTICE

If the FDA has concern over the character of the individuals subject to prosecution then FD&C Act Section 305 will be enforced without notice. Codiﬁed in 21 CFR 7.84, no Section 305 hearing is required in lawsuits brought under Title 18 of the USC, as opposed to cases brought under the FD&C Act or in cases that are exempt under 21 CFR 7.84(a)(2) and (3). These regulatory provisions exist to prevent the loss of evidence due to alteration or destruction and to prevent ﬂight to avoid prosecution. Additionally, a Section 305 notice is usually provided when the agency is recommending

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further regulatory or legal investigations. If a criminal referral is not preceded by a Section 305 notice, the FDA policy and procedures described below are used against individuals subject to criminal investigation: • • •

The FDA will determine whether to issue a Section 305 notice or whether an ad hoc committee is needed to decide the issue. The FDA will prepare a memo reﬂecting its views on the relevant issues. The pertinent unit of the FDA will forward its memo to other internal ofﬁcials. Internal ofﬁcials will forward all relevant materials that support prosecution and will prepare a referral letter and form of Information or Indictment.

5.7.4 CONTEMPT

OF

COURT

AND

VIOLATION

OF

PROBATION

The district will prepare a document outlining the facts that establish the violative conduct and forward it and a copy of the pertinent court order to internal ofﬁcials. The FDA units responsible will have 10 working days each to comment on the proposed action. If no disagreement exists among responsible FDA authorities, all supporting evidence is sent to the next level for logging and prompt forwarding to internal legal ofﬁcials for review. If FDA legal ofﬁcials agree that the action is supportable, a referral letter will be prepared.

5.7.5 DEVELOPMENT

OF

FELONY VIOLATION

If facts support potential felony charges, the FDA can use either Title 18 of the USC or Title 21, Section 333(a)(2). A primary problem associated with these cases is determining the investigational endpoint, as these instances are resolved internally. The following matters, among others, should be considered in these situations: • • • • • • • • •

Scope of the investigation Status of current investigation, including identiﬁcation of targets and of potential cooperating individuals Strategy and timing in completing the investigation Agency compliance policy in the area at issue Preliminary evidence that violations are intentional (i.e., felonious) Identiﬁcation of inspectional or investigational problems Use of criminal search warrants Need for or wisdom of a Section 305 notice citation Recommendation for grand jury investigation

The process continues to include the following: • • • •

Referrals for Criminal Investigation Direct Reference to the Ofﬁce of Chief Counsel Information and Indictments Grand Jury Investigations and Secrecy

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5.8 DEBARMENT 5.8.1 EXAMPLE 1 Notices, Federal Register, March 11, 1997 (Volume 62, Number 47): 11212–11213 (wais.access. gpo.gov; [DOCID:fr11mr97-116]). DEPARTMENT OF HEALTH AND HUMAN SERVICES Docket No. 93N-0252 Atul Shah: Grant of Special Termination; Final Order Terminating Debarment Agency: Food and Drug Administration, Health and Human Services Action: Notice Summary: The Food and Drug Administration (FDA) is issuing a ﬁnal order under the Federal Food, Drug, and Cosmetic Act (the Act) granting special termination of the debarment of Dr. Atul Shah, 20 Hampton Hollow Dr., Perrineville, NJ 08535. FDA bases this order on a ﬁnding that Dr. Shah has provided substantial assistance in the investigations or prosecutions of offenses relating to a matter under FDA’s jurisdiction, and that special termination of Dr. Shah’s debarment serves the interest of justice and does not threaten the integrity of the drug approval process. Effective Date: March 11, 1997 Addresses: Submit written comments to the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Dr., Rm. 1-23, Rockville, MD 20857. Comments should be identiﬁed with the docket number found in brackets in the heading of this document. For Further Information Contact: Diane Sullivan-Ford, Center for Drug Evaluation and Research (HFD-7), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-2041. Supplementary Information: In a Federal Register notice dated December 5, 1994 (59 FR 62399), Dr. Atul Shah, the former Director of Analytical Research and Development at Par Pharmaceutical, Inc. (Par), was permanently debarred from providing services in any capacity to a person with an approved or pending drug product application (21 USC 335a(c)(1)(B) and (c)(2)(A)(ii) and 21 USC 321(dd)). The debarment was based on FDA’s ﬁnding that Dr. Shah was convicted of a felony under Federal law for conduct relating to the development or approval of any drug product or otherwise relating to the regulation of a drug product (21 USC 335a(a)(2)). On March 30, 1995, Dr. Shah applied for special termination of debarment, under Section 306(d)(4) of the act (21 USC 335a(d)(4)), as amended by the Generic Drug Enforcement Act. Under Section 306(d)(4)(c) and (d)(4)(D) of the act, FDA may limit the period of debarment of a permanently debarred individual if the agency ﬁnds that: (1) The debarred individual has provided substantial assistance in the investigation or prosecution of offenses described in Section 306(a) or (b) of the Act or relating to a matter under FDA’s jurisdiction; (2) termination of the debarment serves the interest of justice; and (3) termination of the debarment does not threaten the integrity of the drug approval process. Special termination of Dr. Shah’s debarment is discretionary with FDA. FDA considers a determination by the Department of Justice concerning the substantial assistance of a debarred individual conclusive in most cases. At Dr. Shah’s sentencing, the Assistant U.S. Attorney prosecuting Dr. Shah, recommended a reduced sentence based on Dr. Shah’s substantial assistance to the Government in its investigation. Accordingly, FDA ﬁnds that Dr. Shah provided substantial assistance as required by Section 306(d)(4)(c) of the Act. The additional requisite showings (i.e., that termination of debarment serves the interest of justice and poses no threat to the integrity of the drug approval process) are difﬁcult standards to satisfy. In determining whether

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these have been met, the agency weighs the signiﬁcance of all favorable and unfavorable factors in light of the remedial, public health-related purposes underlying debarment. Termination of debarment will not be granted unless, weighing all favorable and unfavorable information, there is a high level of assurance that the conduct that formed the basis for the debarment has not recurred and will not recur, and that the individual will not otherwise pose a threat to the integrity of the drug approval process. Based on a thorough analysis of the available evidence, Dr. Atul Shah has demonstrated that termination of his debarment serves the interest of justice and will not pose a threat to the integrity of the drug approval process. Under Section 306(d)(4)(D) of the act, the period of debarment of an individual who qualiﬁes for special termination may be limited to less than permanent but no less than 1 year. Dr. Shah’s period of debarment, which commenced on December 5, 1994, has lasted more than 1 year. Accordingly, the Deputy Commissioner for Operations, under Section 306(d)(4) of the Act and under authority delegated to him (21 CFR 5.20), ﬁnds that Dr. Atul Shah’s application for special termination of debarment should be granted, and that the period of debarment should terminate immediately, thereby allowing him to provide services in any capacity to a person with an approved or pending drug product application. The Deputy Commissioner for Operations further ﬁnds that, because the agency is granting Dr. Shah’s application, an informal hearing under Section 306(d)(4)(c) of the Act is unnecessary. As a result of the foregoing ﬁndings, Dr. Atul Shah’s debarment is terminated, effective [insert date of publication in the Federal Register] (21 USC 335a(d)(4)(c) and (d)(4)(D)). Dated: February 27, 1997 Michael A. Friedman, Deputy Commissioner for Operations. [FR Doc. 97-6066 Filed 3-10-97; 8:45 a.m.]

5.8.2 EXAMPLE 2 Notices, Federal Register, March 11, 1996 (Volume 61, Number 48): 9711–9713 (wais.access.gpo. gov; [DOCID:fr11mr96-91]). DEPARTMENT OF HEALTH AND HUMAN SERVICES [Docket No. 94N-0033] John D. Copanos: Denial of Hearing; Final Debarment Order Agency: Food and Drug Administration, Health and Human Services Action: Notice Summary: The Food and Drug Administration (FDA) denies John D. Copanos’ request for a hearing and issues a ﬁnal order under Section 306(a) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 USC 335a(a)) permanently debarring John D. Copanos, 6504 Montrose Ave., Baltimore, MD 21212, from providing services in any capacity to a person who has an approved or pending drug product application. FDA bases this order on its ﬁnding that Mr. Copanos was convicted of a felony under Federal law for conduct relating to the regulation of a drug product under the act. Effective Date: March 11, 1996 Addresses: Application for termination of debarment to the Dockets Management Branch (HFA305), Food and Drug Administration, 12420 Parklawn Dr., Rm. 1-23, Rockville, MD 20857. For Further Information Contact: Christine F. Rogers, Center for Drug Evaluation and Research (HFD-7), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-2041.

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Supplementary Information: I. Background John D. Copanos was the owner and president of John D. Copanos and Sons, Inc., and Kanasco, Ltd., when, on November 13, 1989, he agreed to plead guilty to one count of distributing misbranded drugs with intent to mislead, a Federal felony offense under Sections 301(a) of the Act (21 USC 331(a)) and 303(a)(2)(previously 303(b)) of the Act (21 USC 333(a)(2)) (previously 21 USC 333(b)), and one count of causing the adulteration of drugs with intent to mislead, a Federal felony offense under Sections 301(k) and 303(a)(2) of the Act. On February 16, 1990, the U.S. District Court for the District of Maryland accepted Mr. Copanos’ plea of guilty and entered judgment against him for these felonies. The bases for these convictions were as follows. Mr. Copanos distributed a drug that was misbranded because its labeling failed to bear adequate directions for use and because it failed to warn of the presence of phenylalanine, a component of aspartame. In fact, adequate testing had not been conducted to determine the effect of aspartame on the stability, potency, and effectiveness of this drug. This drug was also misbranded because it failed to reveal the presence and amount of phenylalanine. In addition, Mr. Copanos pled guilty to causing the adulteration of a drug with intent to mislead by failing to comply with current good manufacturing practice. In a notice published in the Federal Register of November 9, 1994 (59 FR 55846), FDA offered Mr. Copanos an opportunity for a hearing on the Agency’s proposal to issue an order under Section 306(a) of the Act debarring Mr. Copanos from providing services in any capacity to a person that has an approved or pending drug product application. FDA based the proposal to debar Mr. Copanos on its ﬁnding that he had been convicted of felonies under Federal law for conduct relating to the regulation of a drug product. In the Federal Register notice of November 9, 1994, FDA informed Mr. Copanos that his request for a hearing could not rest upon mere allegations or denials but must present speciﬁc facts showing that there was a genuine and substantial issue of fact requiring a hearing. FDA also informed Mr. Copanos that, if it conclusively appeared from the face of the information and factual analyses in his request for a hearing that there was no genuine and substantial issue of fact which precluded the order of debarment, FDA would enter summary judgment against him and deny his request for a hearing. In a letter dated December 8, 1994, Mr. Copanos requested a hearing, and in a letter dated January 6, 1995, Mr. Copanos submitted arguments and information in support of his hearing request. In his request for a hearing, Mr. Copanos does not dispute that he was convicted of a felony under Federal law as alleged by FDA. However, Mr. Copanos argues that: (1) He did not receive proper notice; (2) he is entitled to a hearing to contest or explain the facts underlying his plea; (3) some factual statements in the agency’s proposal are inaccurate; (4) the agency’s reliance on portions of the indictment is inappropriate; and (5) the agency’s proposal to debar him is unconstitutional. The Deputy Commissioner for Operations has considered Mr. Copanos’ arguments and concludes that they are unpersuasive and fail to raise a genuine and substantial issue of fact requiring a hearing. Moreover, the legal arguments that Mr. Copanos offers do not create the bases for a hearing (see 21 CFR 12.24(b)(1)). Mr. Copanos’ arguments are discussed below. II. Mr. Copanos’ Arguments in Support of a Hearing A. Notice: Mr. Copanos objects to being notiﬁed of his proposed debarment through publication in the Federal Register. It is the policy of the agency to send a notice of proposed debarment by certiﬁed mail. If certiﬁed mail delivery is unsuccessful, the agency attempts to deliver the notice to the individual personally. If this attempt fails also, notice is given through publication in the Federal Register. FDA attempted to serve Mr. Copanos by certiﬁed mail but was unable to do so. In September 1994, FDA’s Baltimore District Ofﬁce learned that Mr. Copanos was out of the

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country. Agents from FDA’s Baltimore District Ofﬁce visited Mr. Copanos’ home weekly to determine if he had returned. FDA’s Ofﬁce of Criminal Investigations arranged with U.S. Customs to be notiﬁed if Mr. Copanos returned to the country. When Mr. Copanos did not return to the country, the debarment notice was published in the Federal Register on November 9, 1994. Mr. Copanos requested a hearing on his proposed debarment and made arguments in support of that request. Thus, it is clear that Mr. Copanos received actual notice of the agency’s proposed action and has not been deprived of any procedural rights by virtue of publication of the debarment notice in the Federal Register. B. Facts Underlying the Plea: Mr. Copanos makes the following statements relating to the facts underlying his plea: He states that he held a management position and did not personally misbrand or manufacture adulterated drugs, that none of the drugs or products involved were put into commerce, and that the ﬁrst count of the plea related to a facility that was not under his full control at the time. Mr. Copanos also states that the agency’s proposal sets forth areas of indictment information and factual statements of allegations rather than actual proof. Mr. Copanos is correct that the agency’s proposal contained some inaccuracies. Although Mr. Copanos pled guilty to counts four and six of the indictment against him, he did not plead guilty to all the particulars listed in the indictment. In its debarment proposal, the agency mistakenly referred to parts of the indictment to which Mr. Copanos did not plead. The agency very much regrets this error. However, this misplaced reliance does not raise a genuine and substantial issue of fact requiring a hearing. The act requires FDA to mandatorily debar an individual who has been convicted of certain Federal felonies. The only relevant factual issue is whether Mr. Copanos was, in fact, convicted. Mr. Copanos does not dispute that he pled guilty to two Federal felony counts for actions that relate to the regulation of a drug product. Section 306(l) of the Act includes in its deﬁnition of a conviction, a guilty plea. Accordingly, Mr. Copanos’ statements regarding the factual circumstances underlying his plea fail to raise a genuine and substantial issue of fact justifying a hearing. C. Ex Post Facto Argument: Mr. Copanos argues that the ex post facto clause of the U.S. Constitution prohibits application of Section 306(a)(2) of the Act to him because this section was not in effect at the time of Mr. Copanos’ criminal conduct. The Generic Drug Enforcement Act (GDEA) of 1992, including Section 306(a)(2), was enacted on May 13, 1992, and Mr. Copanos was convicted on February 16, 1990. An ex post facto law is one that reaches back to punish acts that occurred before enactment of the law or that adds a new punishment to one that was in effect when the crime was committed. (Ex Parte Garland, 4 Wall. 333, 377, 18 L. Ed. 366 (1866); Collins v. Youngblood, 497 U.S. 37 (1990).) Mr. Copanos’ claim that application of the mandatory debarment provisions of the Act is prohibited by the ex post facto clause is unpersuasive, because the intent of debarment is remedial, not punitive. Congress created the GDEA in response to ﬁndings of fraud and corruption in the generic drug industry. Both the language of the GDEA and its legislative history reveal that the purpose of the debarment provisions set forth in the GDEA is to restore and ensure the integrity of the abbreviated new drug application (ANDA) approval process and to protect the public health. (See Section 1, Pub. L. 102-282, GDEA of 1992.) In a suit challenging a debarment order issued by FDA (58 FR 69368, December 30, 1993), the constitutionality of the debarment provision was upheld against a similar challenge under the ex post facto clause. The reviewing court afﬁrmed the remedial character of debarment: Without question, the GDEA serves compelling governmental interests unrelated to punishment. The punitive effects of the GDEA are merely incidental to its overriding purpose to safeguard the integrity of the generic drug industry while protecting the public health. (Bae v. Shalala, 44 F.3d 489, 493 (7th Cir. 1995).) Because the intent of the GDEA is remedial rather than punitive, Mr. Copanos’ argument that the GDEA violates the ex post facto clause must fail. (See id. at 496–497.)

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D. Miscellaneous Arguments: Mr. Copanos argues that his debarment would be an unconstitutional taking of the right to earn a living in the United States. It appears that Mr. Copanos is referring to a taking of property under the Fifth Amendment. Mr. Copanos further states that he has sold his company, including all of its approved applications and that to debar him now would be a malicious act on the part of the agency. Mr. Copanos also argues that he should not be debarred because his guilty plea was made at an emotional and stressful time. None of these arguments raises a genuine and substantial issue of fact requiring resolution at a hearing. Mr. Copanos has not established that his debarment affects any property interest protected by the Fifth Amendment. The expectation of employment is not recognized as a protected property interest under the Fifth Amendment. (Hoopa Valley Tribe v. Christie, 812 F.2d 1097, 1102 (9th Cir. 1986); Chang v. United States, 859 F.2d 893, 896-97 (Fed. Cir. 1988).) Loss of potential proﬁt is not a sufﬁcient basis for a takings claim. (Andrus v. Allard, 444 U.S. 51, 66 (1979).) To have a protected property interest, one must have a legitimate claim of entitlement to that interest. (Erikson v. United States, 67 F.3d 858 (9th Cir. 1995).) One who voluntarily enters a pervasively regulated industry, such as the pharmaceutical industry, and then violates its regulations cannot successfully claim that he has a protected property interest when he is no longer entitled to the beneﬁts of that industry. (Id.) Mr. Copanos does not dispute that he was convicted as alleged by FDA. Under Section 306(l)(1)(B) of the Act, a conviction includes a guilty plea. The facts underlying Mr. Copanos’ conviction are not at issue. Moreover, the act does not permit consideration of factors such as emotional stress; rather, the act is clear that an individual shall be debarred if convicted of a felony under Federal law for conduct relating to the regulation of any drug product. (See Section 306(a)(2)(B) of the Act.) Mr. Copanos has been convicted of such a felony. Accordingly, the Deputy Commissioner for Operations denies Mr. Copanos’ request for a hearing. III. Findings and Order Therefore, the Deputy Commissioner for Operations, under Section 306(a) of the Act and under authority delegated to him (21 CFR 5.20), ﬁnds that John D. Copanos has been convicted of felonies under Federal law for conduct relating to the regulation of a drug product (21 USC 335a(a)(2)(B)). As a result of the foregoing ﬁndings, John D. Copanos is permanently debarred from providing services in any capacity to a person with an approved or pending drug product application (page 9713) under Section 505, 507, 512, or 802 of the Act (21 USC 355, 357, 360b, or 382), or under Section 351 of the Public Health Service Act (42 USC 262), effective [insert date of publication in the Federal Register] (21 USC 335a(c)(1)(B) and (c)(2)(A)(ii)). Any person with an approved or pending drug product application who knowingly uses the services of Mr. Copanos, in any capacity, during his period of debarment will be subject to a civil money penalty (Section 307(a)(6) of the Act (21 USC 335b(a)(6))). If Mr. Copanos, during his period of debarment, provides services in any capacity to a person with an approved or pending drug product application, he will be subject to a civil penalty (Section 307(a)(7) of the Act). In addition, FDA will not accept or review any ANDA or abbreviated antibiotic drug application submitted by or with Mr. Copanos’ assistance during his period of debarment. Mr. Copanos may ﬁle an application to attempt to terminate his debarment pursuant to Section 306(d)(4)(A) of the Act. Any such application would be reviewed under the criteria and processes set forth in Section 306(d)(4)(c) and (d)(4)(D) of the Act. Such an application should be identiﬁed with Docket No. 94N-0033 and sent to the Dockets Management Branch (address above). All such submissions are to be ﬁled in four copies. The public availability of information in these submissions is governed by 21 CFR 10.20(j). Publicly available submissions may be seen in the Dockets Management Branch between 9 a.m. and 4 p.m., Monday through Friday. Dated: February 22, 1996

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CASE STUDY EXHIBITS EXHIBIT 5.1: 24-HOUR ALERT [Company] [Address] [Telephone number] 24-HOUR ALERT FORMAT Telephone or electronically mail the preliminary information listed below to the Center recall unit and Ofﬁce of Enforcement, DCMO Recall Operations Staff (HFC-210). State: “24-Hour Alert to Recall Situation.” 1. Product 2. Code/Lot Numbers 3. Recalling Firm/Manufacturer 4. Reason for Recall 5. District Awareness Date/Recall Initiation Date _______________________________________________________________________________

EXHIBIT 5.2: RECOMMENDATION

FOR

RECALL — NUMBER FORMAT

Electronically mail Recommendations for Recall (RRs) to the appropriate Center recall unit with information copy to OE/DCMO (HFC-210) and FDA Press Relations Staff (HFI-20 and HFI-21). RRs for the CDRH should also be sent to the Ofﬁce of Science and Technology (HFZ-100) and the Ofﬁce of Health and Industry Programs (HFZ-200). Flag: “Recommendation for Firm-Initiated Recall or Recommendation for FDA-Requested Recall.” 1. Product a. For each product, provide (as applicable): name; type (e.g., tablet, sugar coated); strength; sizes; form; route of administration; shipping or unit package; and a brief description of the product and its use. If a drug product, indicate prescription or over-the-counter. If product labeling does not indicate how the product is to be used and the health hazard is dependent on use, consult the ﬁrm’s catalog, the Red Book, or similar sources for the information. If after consulting with the Center it is determined that the product must be examined physically for health hazard evaluation, ship an appropriate sample to the designated unit via the most expeditious and practical means available. Notify center of time and how sent, and estimated time of arrival. b. For each product, provide: brand name; name, address, and type of responsible ﬁrm on label; number and description of private labels. A complete copy of all labeling (including product inserts or information sheets) must be sent to the appropriate Center by an expeditious method, such as FAX, Federal Express, U.S. Postal Service, etc., depending on the circumstances involved. 2. Code: List all lot and/or serial numbers, catalog numbers, product numbers, packer or manufacturer numbers, etc., that appear on the product or its labeling. 3. Recalling Firm/Manufacturer: Provide complete name and address of the recalling ﬁrm and identify the type of ﬁrm, (e.g., manufacturer, importer, broker, repacker, own label distributor). Provide complete name and address of the manufacturer if different from the recalling ﬁrm. Also,

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identify ﬁrms that processed or handled the product or supplied components that might have been responsible for the problem. Indicate which ﬁrm appears to be responsible for the violation. 4. Reason for Recall Recommendation: Provide detailed information as to how the product is defective and violates the FD&C Act or related statutes: a. Include any analytical ﬁndings in qualitative and/or quantitative terms, indicating whether the analysis was done by the ﬁrm or the FDA and which laboratory was involved. b. Provide inspectional (e.g., GMP) or other evidence where appropriate. c. List in chronological order any complaints, injuries, or associated problems with the product. Include any Medical Device Reports (MDRs) that have been submitted. If the ﬁrm was advised of FDA ﬁndings and the problem was discussed with representatives of the ﬁrm, report their reactions and plans. If the ﬁrm advised the FDA of the problem, report and explain the ﬁrm’s own analytical results and how the ﬁrm learned of the need for recall. Explain all State involvement in the recall, including sample collection or analysis, recall agreement or initiation, recall monitoring, and product disposition. For Drug Efﬁcacy Study Implementation (DESI)-related recalls, use the following terminology: Federal Register, publication (date), Drug Efﬁcacy Study Implementation. In cases where a veterinary drug product is being recalled due to subpotency of active ingredients prior to labeled expiration date provide the following information: a. The ﬁrm’s stability testing plan (including analytical methodology) which established the labeled expiration date. b. Speciﬁc batch numbers in the stability studies and assay values that are the basis of the ﬁrm’s recall. c. Potency speciﬁcations that the ﬁrm uses for recall purposes. d. Final assay values for the active ingredients that were the basis of the initial release of the batch. It should also be noted whether information regarding stability data on ﬁle with the ﬁrm and the Quality Control procedures used by the ﬁrm to determine the potency of the active ingredients is available in the Establishment Inspection Report (EIR). 5. Volume of Product in Commerce: Provide the total volume of product distributed. Provide estimate of amount and availability of stocks remaining on the market at all levels. (Indicate whether these are ﬁrm or FDA estimates.) Include product expiration dates or shelf life expectancy. (Note: If the recommendation is for an FDA Requested Recall, ensure that there is, in fact, product remaining in commerce.) 6. Distribution Pattern: Indicate the areas of distribution, the number of direct accounts, the approximate percentage of each type of consignee, and the percentage of product sent to each type of consignee. List foreign countries and U.S. Government military and/or civilian units/agencies to which product has been distributed. If various labels are involved, describe any differences in distribution pattern. Where there has been any Defense Personnel Support Center (DPSC), Department of Veterans Affairs (DVA), or other government agency sales/distribution, the consignee list should be submitted separately through the District Recall and Emergency (R&E) Coordinator to the OE/DCMO. Indicate whether these were direct or contract sales. If contract sales, report the contract number, contract date, and implementation date. 7. Firm’s Recall Strategy: Describe the ﬁrm’s planned procedure. Comment on the adequacy of this strategy from the district’s viewpoint, and evaluate the ﬁrm’s ability to effect recall. Sections 7.42 and 7.46 of 21 CFR, Part 7 (Enforcement Policy), Subpart C, set forth information to be obtained from the ﬁrm that will be evaluated by the Center. The ﬁrm’s strategy should include the

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ﬁrm’s intended course of action when an account that distributed the recall product is found to be out of business. Include date recall was initiated, if already underway. 8. Firm Ofﬁcial: Name, title, location, and telephone number of the ﬁrm ofﬁcial who should be contacted concerning the recall. In case of potential class I or FDA requested recalls, this information should also be provided for the ﬁrm’s chief executive ofﬁcer. 9. District Audit Program: State what actions have already been taken (FDA inspections, sample collections, etc.). Provide speciﬁc recommendations for headquarters action where indicated. Provide details of any publicity issued or to be issued by the FDA, ﬁrm, state, or local government. Provide the district’s proposed program for monitoring the recall. Include a timetable for followup visits or ﬁrm contacts for reviewing the recall status and the level and type of audit checks the district believes will satisfactorily verify the recall’s effectiveness. 10. Recommending Ofﬁcial: Name and title of district recommending ofﬁcial. _______________________________________________________________________________

EXHIBIT 5.3: RECOMMENDATION FOR RECALL — NUMBER AND TERMINATION FORMAT Flag: “Recommendation for Recall Classiﬁcation and Termination” 1. Product: See Exhibit 5.2. 2. Codes: See Exhibit 5.2. 3. Recalling Firm/Manufacturer: See Exhibit 5.2. 4. Reason for Recall Recommendation: See Exhibit 5.2. 5. Volume of Product in Commerce, Quantity Recovered, and Disposition: Provide total volume of product distributed and under the recalling ﬁrm’s control. Provide quantity of product recovered or corrected by the recalling ﬁrm. If no or little product was found in the market, explain why (e.g., expired, short shelf life, rapid turnover). Provide veriﬁcation of disposition or correction of recalled product. 6. Distribution: See Exhibit 5.2. 7. Firm’s Recall Strategy: Describe the level of distribution to which the recall was extended. Provide complete description of the ﬁrm’s recall notiﬁcation and/or correction efforts, any effectiveness checks accomplished, or other means the ﬁrm has to document the recall effectiveness. Provide district conclusion as to the adequacy of the ﬁrm’s actions. If known, indicate steps the ﬁrm has taken to prevent similar occurrences. 8. District Audit Program: Describe actions taken by the FDA (e.g., inspections, sample collections). Provide details of any publicity issued. Provide results of any FDA audit checks or auditing of records at the ﬁrm. List any legal action planned or underway. State that the district considers the recall to be completed and closed, and request Center concurrence with the recall termination. _______________________________________________________________________________

EXHIBIT 5.4: RECALL NOTIFICATION FORMAT The monitoring district will transmit the Recall Notiﬁcation (RN) by BANYAN mail to OE/DCMO, HFC-210. OE/DCMO staff will place the RN into the Field Initial Notiﬁcation of Recall (FINOR) computer system. Access to FINOR is FDA wide. The system may be searched for recall data using multiple ﬁelds and key words and includes full document review. (Instructions for FINOR use have been issued separately.)

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Flag: “Initial Notiﬁcation of Class (I, II, or III) ‘FDA-Requested,’ ‘Firm Initiated,’ or ‘FDA Ordered’ Recall.” Include FDA’s audit check level. List: A. Recall Number B. Program Assignment Code (PAC) C. Product Code (seven-digit number) D. County E. JD/TA F. CF Number G. Reason 1. Product: a. For each product, provide (as applicable): name; type; strength; sizes; form; route of administration; shipping or unit package; and brief description of the product and its use. If a drug product, indicate prescription or over-the-counter. b. For each product, provide: brand name; name and address and type of responsible ﬁrm on label; number of and a description of private labels. 2. Code: List all lot and/or serial numbers, catalog numbers, product numbers, packer or manufacturer numbers, etc., which appear on the product or its labeling. 3. Recalling Firm/Manufacturer: Provide complete name and address of the recalling ﬁrm and identify the type of ﬁrm (e.g., manufacturer, importer, broker, repacker, own label distributor). Provide complete name and address of manufacturer if different from recalling ﬁrm. Also, identify ﬁrms that processed or handled the product or supplied components that might have been responsible for the problem. Indicate which ﬁrm appears to be responsible for the violation. 4. Reason for Recall Recommendation: Provide detailed information as to how the product is defective and violates the FD&C Act or related acts. a. Include any analytical ﬁndings in qualitative and/or quantitative terms, indicating whether the analysis was done by the ﬁrm or FDA and which laboratory was involved. b. Provide inspectional (GMP) or other evidence where appropriate. c. List in chronological order any complaints, injuries, or deaths associated with the product. If the ﬁrm was advised of FDA ﬁndings and the problem was discussed with representatives of the ﬁrm, report their reactions and plans. If the ﬁrm advised the FDA of the problem, report and explain the ﬁrm’s own analytical results and how the ﬁrm learned of the need for a recall. For Drug Efﬁcacy Study Implementation (DESI)-related recalls, use the following terminology: Federal Register, publication (date), Drug Efﬁcacy Study Implementation. 5. Volume of Product in Commerce: Give total volume of product distributed. Provide an estimate of the amount and availability of stocks remaining on the market. (Indicate whether these are ﬁrm or FDA estimates.) 6. Distribution Pattern: Indicate the areas of distribution, the number of direct accounts, the approximate percentage of each type of consignee, and the percentage of product sent to each type of consignee. List foreign countries and U.S. Government military and/or civilian units/agencies to which the product has been distributed. If various labels are involved, describe any differences in distribution pattern. Where there has been Department of Defense (DOD), Department of Veterans Affairs (DVA), or other government sales/distribution, the consignees list should be submitted separately through the district Recall Coordinator to OE/DCMO. Indicate whether these were direct or contract sales. For contract sales, report the contract number, contract date, and implementation date.

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7. Firm’s Recall Strategy: Describe the ﬁrm’s complete recall strategy. Include the dates and kind of all recall alerts and notiﬁcations to consignees, plans for follow-up contacts and effectiveness checks, and procedures for product removal or correction. 8. Firm Ofﬁcial: Provide the name, title, location, and telephone number of the ﬁrm ofﬁcial who should be contacted concerning the recall. 9. District Audit Program: Provide the recall status, estimated date for completion of the recall, and the extent of audit checks to be accomplished. _______________________________________________________________________________

EXHIBIT 5.5: RECALL TERMINATION RECOMMENDATION/SUMMARY

OF

RECALL FORMAT

For class I recalls and safety alerts, submit the following information as a Recall Termination Recommendation to the Center recall unit for concurrence. For class II and III recalls, prepare the following and submit it to the District Director as a Summary of Recall for his/her concurrence. The original and four copies of a Recall Termination Recommendation are sent to the Center Recall Unit (CRU). Upon concurrence, the CRU will ﬁle the original and forward copies to: Records Section (HFA-224), ORA/OE/DCMO (HFC-210), and the monitoring district. The monitoring district will distribute the Summary of Recall similarly and include a copy to the CRU. Flag: “(Summary of Recall) or (Recall Termination Recommendation), Class (I, II, or III), Level (A, B, C, D, or E), (FDA Requested) or (Firm Initiated).” Recalling Firm: Date Prepared: Section I. Recall Data 1. 2. 3. 4. 5. 6.

Recall number Product involved Quantity recovered or number of units corrected Disposition of returns and held stock (when, where, and how) Samples collected Date recall completed

Section II. Verification of Effectiveness (If applicable; if none is required, so state.) 7. Date and method of notiﬁcation and number of consignees notiﬁed of the recall (by type of consignee, if available) 8. Number of consignees responding to the recall communication 9. Number, type, and results of effectiveness checks made 10. Any other available information about the ﬁrm’s actions that may aid in the evaluation of the recall Section III. Results of FDA Audit Program 11. Number of audit checks (by type of consignee) and how they were conducted (e.g., telephone or visit) 12. Breakdown of check results. 13. Description of any delays encountered in the recall progress

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Section IV. Analysis of Recall 14. Nature of violation/problem (evaluated in terms of GMPs, where applicable) 15. Action ﬁrm is taking to prevent similar occurrences (district evaluation) 16. District follow-up conducted (inspectional); summary of injury/illness or product defect complaints 17. District review of total recall effort (review of submitted recall status reports, effectiveness checks, etc.) 18. Legal action (Compliance Branch agreement) Recommended/prepared by: [Name and Title] [Date] Concurrence: ___ Disapproved: ___* District: [Name and Title] [Date] OR Center: [Name and Title] [Date] Concurrence should be by (1) Center Division Director or equivalent, if class I; (2) District Director or designee, if class II or III. * If disapproved, Center must provide further instructions for follow-up to the monitoring district. _______________________________________________________________________________

EXHIBIT 5.6: GUIDANCE

TO

HEALTH HAZARD EVALUATION COMMITTEES

The Food and Drug Administration’s recall policy (21 CFR Part 7) requires the conduct of an evaluation of the health hazard (actual or potential) presented by a product being recalled or considered for recall. The regulations (21 CFR 7.41(a)) specify the factors to be considered, among others, by the Health Hazard Evaluation Committee in making the health hazard evaluation. The purpose of the health hazard evaluation, in general, is to identify and document: • • • •

the population at risk, conditions that may exacerbate or attenuate the risk of its occurrence, the risk associated with the product under conditions of use (as labeled), and the likelihood of the risk occurring in the future.

The purpose of these guidelines is to assist the Committee in the identiﬁcation and documentation of the various factors listed in 21 CFR 7.41(a) that are to be considered in making the health hazard evaluation and to determine what additional data and information should be collected and evaluated during the recall, to either conﬁrm or revise the health hazard evaluation. The questions listed below are not all inclusive nor are they relevant to all recall situations. They are intended to focus attention on factors related to the signiﬁcance of health hazards likely to be associated with a product being recalled or considered for recall.

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7.41(a)(1) — Whether any disease or injuries have already occurred from the use of the product: 1. What is the name of the product (trade and generic) and what are its indications for use, where applicable? 2. What deaths, diseases, injuries, or other adverse reactions have already occurred in association with use of the product? 3. What documentation is there to support the association of the deaths, diseases, injuries, or other adverse reactions with the use of the product? 4. Was the product used in conformance with its labeled directions for use? (The Health Hazard Evaluation Committee should review product labeling for sufﬁciency in light of injuries.) If not, did the deaths, diseases, injuries, or other speciﬁc adverse reactions result from product misuse? 5. If the product was used according to its labeled directions, were the associated diseases, injuries, deaths, or other speciﬁc adverse reactions due to (a) product malfunction, (b) product formulation, (c) product quality (including potency, contamination, etc.), (d) product design, (e) inadequate directions for use, or (f) other known or unknown causes? Specify. 7.41(a)(2) — Whether any existing conditions could contribute to a clinical situation that could expose humans or animals to a health hazard. Any conclusion shall be supported as completely as possible by scientiﬁc documentation and/or statements that the conclusion is the opinion of the individual(s) making the health hazard determination. 1. Name the speciﬁc clinical conditions (e.g., diabetes, heart problems) which, if they exist, might render a person or animal more susceptible to experiencing a health hazard on exposure to the product. 2. How would these clinical conditions contribute to or change the risk of exposure to the products? 3. Could these clinical conditions mask or otherwise disguise the risk of exposure to the product? 4. What other products being used to treat these clinical conditions could contribute to or, conversely, lessen the risk of exposure to the product? 7.41(a)(3) — Assessment of hazard to various segments of the population (e.g., children, surgical patients, pets, livestock) expected to be exposed to the product being considered, with particular attention paid to the hazard to those individuals who may be at greatest risk. 1. What is the universe of users by segment of population and what is the relative frequency of use of each, if known; for example, what percentage of the product is used by infants or children? 2. Which segment of the population exposed to the products is at greatest risk of a health hazard? Is the risk higher for any other segment of the population than for normals? 3. Are any of the following high-risk groups likely to be exposed to the product? a. Infants b. Children c. Elderly d. Pregnant women e. Surgical patients f. Others (specify) 4. For each of the high-risk groups identiﬁed, what is the anticipated frequency of exposure to the product?

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5. In what setting is the product generally used (e.g., hospital, home)? 6. How frequently is the product used (e.g., daily, weekly) and what is the duration of use (e.g., one time only, for a month, over a lifetime)? 7. What percentage of the population at greatest risk is now under close medical supervision? Could everyone in this population be easily brought under observation? In practice, would all users be brought under medical supervision if this is needed? 8. What actions or medical interventions could reasonably be expected to decrease the likelihood of occurrence of the health hazard? For example, could patient monitoring detect the product defect before it causes any untoward health consequences and could patient monitoring entirely prevent medical injury? 7.41(a)(4) — Assessment of the degree of seriousness of the health hazard to which the population at risk would be exposed. 1. Are the health hazards likely to be acute (lasting several days to a few weeks) or chronic (lasting weeks to months)? 2. Describe the degree of seriousness of the health hazard if it did occur and which speciﬁc segment of the population might be at risk. Express in terms of the following: a. Life threatening (death could occur) b. Severe (permanent signiﬁcant disability) c. Moderate (transient but signiﬁcant disability; permanent minor disability) d. Limited (transient minor disability; annoying complaints) e. None (no disability or physical complaints anticipated) 7.41(a)(5) — Assessment of the likelihood of occurrence of the hazard. 1. How frequently have deaths, diseases, injuries, or other adverse reactions already occurred? How does the frequency of occurrence relate to the total extent of product exposure (e.g., number of devices implanted, number of prescriptions). How has this frequency been documented? 2. If deaths, diseases, injuries, or other adverse reactions have not already occurred, estimate the likelihood of occurrence in each segment of the population at risk. 7.41(a)(6) — Assessment of the consequences (immediate or long range) of occurrence of the hazard. 1. What are the immediate consequences of the health hazard? 2. What are the long-range consequences of the health hazard? 3. If the product being recalled or considered for recall is used to treat a medical condition, are alternate forms of therapy available? Summary of Health Hazard Evaluation On the basis of the answers to the questions listed above and any others that relate to the associated risk, state the likelihood of the health hazard occurring following exposure to the product being recalled or considered for recall and the likelihood of exposure to a defective product in all users of the product. In addition, to aid in the health hazard re-evaluation, recommend what additional data and information should be collected and evaluated during the progress of the recall to conﬁrm or revise the initial health hazard evaluation. Include in the recommendation speciﬁc data and information that should be collected, how and by whom these should be collected and evaluated, and how frequently the health hazard should be re-evaluated. _______________________________________________________________________________

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EXHIBIT 5.7: RECALLS OF RADIATION-EMITTING ELECTRONIC PRODUCTS UNDER SUBCHAPTER C (ELECTRONIC PRODUCT RADIATION CONTROL) OF CHAPTER V OF THE FD&C ACT (“THE ACT”), FORMERLY THE RADIATION CONTROL FOR HEALTH AND SAFETY ACT OF 1968 (RCHSA) Subchapter C contains the mandated recall provisions written into Chapter V of the Food, Drug, and Cosmetic Act (Section 535(a)). The law requires a manufacturer, when he learns that a product he manufactures is either defective or not in compliance with a published performance standard, to notify the Secretary of Health and Human Services (delegated to CDRH Director) and to notify the ﬁrst purchaser (and known subsequent transferees) of the defect(s) or noncompliance(s). Subchapter C is speciﬁc as to the method of notiﬁcation and procedure and also contains repair, replace, or refund provisions. Differences in procedures may be encountered when dealing with recalls of radiation-emitting vs. non-radiation-emitting medical devices. For most medical devices, the recall procedures for electrical and mechanical problems generally follow the pattern outlined in this chapter for general recalls; however, both medical and non-medical electronic products follow a different procedure when recalled under Subchapter C for radiation defects or deviations from a radiation safety standard. For example, consider a piece of diagnostic x-ray equipment that displays a mechanical problem not covered by Subchapter C (e.g., instability that causes the unit to fall over). Such a recall would be conducted under the standard recall procedure of recommendation by the ﬁeld, evaluation and classiﬁcation by the Center, and the standard recall notiﬁcation, monitoring, and termination procedures in the ﬁeld. On the other hand, if that same piece of equipment displays a radiation-related defect or noncompliance with the diagnostic x-ray standard (21 CFR 1020.30), the recall would fall under Subchapter C and would follow the procedure outlined below. (Note: The Health Hazard Evaluation Committee does not review recalls involving noncompliance with a standard because the signiﬁcance of the hazard was considered when the standard was introduced.) Recalls Conducted Under Subchapter C of the Act 1. Center for Devices and Radiological Health (CDRH) Learns of Defect or Noncompliance A manufacturer who discovers a radiation-related defect or noncompliance is required by Subchapter C to immediately notify CDRH and submit a proposed corrective action plan (CAP). CDRH may also learn of defects or noncompliances from various other sources, including establishment inspection, results from FDA ﬁeld and laboratory testing, and review of reports required to be submitted by the manufacturer. CDRH will inform the manufacturer in writing of the defect or noncompliance and request the ﬁrm to propose a CAP as required by Subchapter C. In some cases, special ﬁeld testing may be necessary in order to deﬁne the precise defect or noncompliance. These tests will be arranged by CDRH. 2. Opportunity To Refute Declaration or To Request Exemption from Notification Requirements As provided by Subchapter C, a manufacturer has the opportunity to refute a defect or noncompliance declaration (Section 535(a)(2)). The manufacturer is usually given 14 days to refute the Center’s declaration or to request exemption from notiﬁcation based on evidence that the defect or noncompliance is not such as to create a signiﬁcant risk of injury, including genetic injury, to any person. The burden of proof lies with the manufacturer. If the refutation is accepted, or if the exemption is granted, the manufacturer is then exempt from the notiﬁcation requirements and is relieved of responsibility to repair, replace, or refund.

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3. Proposal of Corrective Action Plan by Manufacturer If no request for exemption has been ﬁled or if the exemption request was denied, the manufacturer must then submit proposals to CDRH for user notiﬁcation and correction of defective or noncompliant product(s). The notiﬁcation to users is required to be by certiﬁed mail to the ﬁrst purchaser (or subsequent transferees, if known) and must be mailed within 14 days after CDRH approval. CDRH requires that return receipts be maintained for recall audit purposes. Manufacturers are also required to provide CDRH with copies of all notices, bulletins, and other communications to dealers, distributors, purchasers, or other transferees which they have issued as required by Section 535(d). These notiﬁcations to users are required to contain instructions for interim safe operation of the product until such time as corrections can be made. 4. Correction Action Plan (CAP) Review Upon receipt of the manufacturer’s proposed CAP, the Center will review that document for thoroughness and technical accuracy. The following are elements of a typical approved CAP: a. Product description (including all model and serial numbers used) and the total number of units of this product that are involved b. Consignee list (foreign and domestic) c. Description of the defect (including all reports, documents, memos, etc., of meetings, technical reviews, etc., which pertain to the analysis of the problem and the development of a ﬁx) d. Proposed steps to be taken to correct the product in the ﬁeld and steps taken to prevent future occurrences e. Proposed effectiveness checks to be conducted f. Proposed date of completion and appropriate interim dates for design, fabrication, and implementation of the correction g. Any and all injury/death investigations or reports h. Pertinent complaints on ﬁle Some additional requirements may be included in a CAP if necessary. For example, a CAP may require that the recalling ﬁrm obtain a signed statement from their purchaser stating that corrections have been made or it may require that copies of service or work orders be held for FDA review. In the event that the proposal is insufﬁcient, the Center will request the additional data needed. When sufﬁcient information has been submitted to the Center for review, the plan is evaluated and approved if it appears to be adequate. 5. Mechanics of Conducting Recall CDRH will assign a recall number and issue a classiﬁcation memo to the district and the press ofﬁce (HFC-21) when the CAP and an approval letter are signed and issued to the recalling ﬁrm. CDRH will send copies of the CAP approval letter, the corrective action plan, and the letter of noncompliance with the classiﬁcation memo. The home district will then promptly obtain from the ﬁrm by telephone or a visit any other information required for the Enforcement Report and the Initial Recall Notiﬁcation message to the ﬁeld. This will not affect the way the district processes recalls for x-ray assemblers and suntan lamp recalls. The home district ofﬁce will still continue to submit a Recommendation for Recall for cases generated in the ﬁeld. The districts will approve the corrective action plans for these cases and submit a copy of the district approval letter with the Recommendation for Recall to CDRH for issuance of a recall number. The timeliness of audit check issuance will depend on the progress of the CAP and may be determined by recall status reports received from the ﬁrm. Audit checks should be issued when the recall is approximately 25% complete and continue throughout completion of the recall. At the

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point when the recalling ﬁrm indicates by way of their status reports to the district that they have completed the recall action at 25% of their consignees, the ﬁeld will issue a request for a portion of the required audit checks to the affected districts. Upon receipt of the completed audit check reports from the districts, the home district Recall Coordinator will evaluate the audit checks to determine if the recall is effectively ongoing. If apparently effective, the balance of the audit checks need not be requested until the recall is complete, or nearly so. Center consultation is available, if needed, in determining the effectiveness of the recall at the 25% complete mark. The recalling ﬁrm must, in its CAP, provide a target date for completing the recall. The time span is typically six months to one year. If the ﬁrm does not or is not likely to complete the recall within the speciﬁed time, a warning letter should be issued to the ﬁrm. The ﬁrm may request a time extension to complete the recall. All such requests must be approved by CDRH. If a request for extension is denied, the home district will send the ﬁrm a warning letter when the target completion date expires. The home district will document unsatisfactory results of a CAP and/or other violations of Subchapter C by inspection and ﬁeld testing. Bimonthly recall status reports will be sent to the Center recall unit and OE/DCMO by the home district. At the conclusion of the recall, the home district will conduct a termination (close-out) inspection at the recalling ﬁrm, terminate the recall appropriately according to classiﬁcation, and prepare a recall termination letter to the ﬁrm (see Exhibits 5.14 and 5.15). 6. Time Frames The time frames associated with electronic product recalls are considerably different than for general FD&C recalls. At the time the Center identiﬁes a problem, the manufacturer is often unaware that any problem exists. Opportunity is provided to the manufacturer to examine and possibly refute the Agency’s evidence, to request exemption, or to locate all products and formulate a CAP. The time between declaration of noncompliance and CDRH approval of the CAP varies widely, depending upon the product, the nature of the problem, and the thoroughness of the proposed correction. _______________________________________________________________________________

EXHIBIT 5.8: RECALLS

OF

MEDICAL DEVICES UNDER SECTION 518(E)

April 19, 1993 Ofﬁce of Compliance, CDRH Interim Guidance Regarding Mandatory Recalls Under Section 518(e) of the Federal Food, Drug, and Cosmetic Act Directors, Investigations Branch Directors, Compliance Branch Info: All Recall Coordinators Background On November 28, 1990, the President signed into law the Safe Medical Devices Act (SMDA), which was intended to improve the Medical Device Amendments of 1976. The new law includes provisions designed to expand and strengthen FDA’s authority to ensure that devices entering the market are safe and effective. The SMDA, by streamlining procedures and augmenting FDA’s authority, reﬁnes premarket controls and adds postmarketing controls relating to medical devices introduced into interstate commerce.

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One of these provisions is Section 518(e), the so-called mandatory recall authority. Actually, Section 518(e) requires a two-step process that (1) orders a ﬁrm to immediately cease distribution of a defective device and to notify users to cease using it, and (2) either vacates the order or amends the order to require the product’s recall. In the ﬁrst step, if FDA ﬁnds there is a reasonable probability that a device intended for human use would cause serious, adverse health consequences or death, the FDA orders the manufacturer, importer, distributor, retailer, or any appropriate person to immediately cease distribution of the device and to immediately notify health professionals and device user facilities of the FDA’s order and to instruct such professionals and facilities to cease use of the device. Reasonable probability means that it is more likely than not that an event will occur. Serious adverse health consequence means any signiﬁcant adverse consequence, including those which may be either life threatening or involve permanent or long-term injury but excluding non-lifethreatening injuries that are temporary and reasonably reversible. Injuries attributable to a device that are treatable and reversible by standard medical techniques, proximate in time to the injury, meet this latter deﬁnition. After giving the party subject to the order in step 1 an opportunity for an informal hearing, the FDA either vacates the order or amends it to include a recall of the device. The informal hearing must be held not later than 10 days after the date of issuance of the order, in accordance with the procedures set out in Section 201(y) of the Act and 21 CFR Part 16. Failure to request a hearing will generally result in an amended order requiring recall. The party subject to the order may also request, by written submission, review of an order without an informal hearing. The FDA has already found this new authority useful in securing removal from the market of several devices that met the criteria set forth in Section 518(e): 1. Enteral feeding pumps were defective, resulting in overfeeding and underfeeding. 2. Temporomandibular joint (TMJ) implants were made of a material that, when used in load-bearing situations such as TMJ applications, resulted in breakdown of the material. Large cell tumors resulted from fragments of the material, bone degeneration occurred, and patients were severely affected. 3. Cold sterilizing solution and disinfecting solutions were labeled and promoted as sterilants for use on reused medical devices such as laparoscopes, endoscopes, and other invasive devices. Laboratory tests by the FDA indicated that the products were ineffective as sterilants, thereby subjecting patients to devices that may have been improperly sterilized or disinfected. 4. A safety-lift used to lift patients, for example, from wheelchairs into baths experienced latch failures that resulted in patients being dropped and killed or injured. 5. A high-frequency jet ventilator was marketed for high-risk neonates but had defects in hardware and software that resulted in unreliability. Deaths and injuries were reported. This case was the ﬁrst to involve a hearing. Interim Procedures These procedures are interim pending ﬁnal publication of regulations implementing Section 518(e). Because the provisions of Section 518(e) were effective upon passage of the statute, these interim procedures have been developed. Actions under Section 518(e) may be initiated by the Center or recommended by the ﬁeld. Factors to be considered when deciding to recommend a 518(e) action include: •

Does the hazard meet the criteria for a class I recall situation (i.e., is there is a strong likelihood that the use of, or exposure to, a violative product will cause serious, adverse health consequences, or death)?

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•

•

Are other administrative or enforcement actions more appropriate to address the problem? Seizure or detention may be a lesser agency burden and may address the health risk situation more effectively. GMP issues alone will not support the contention that use of the device will cause serious adverse health consequences.

If the district ofﬁce believes this threshold has been met, a recommendation should be submitted to the Ofﬁce of Compliance (OC), HFZ-300. Before the district submits a 518(e) recommendation, the ﬁrm should be fully apprised of the district’s concerns and should have been given an opportunity to initiate corrective action (i.e., recall). The 518(e) recommendation should be in an organized Recall Recommendation format and be ﬂagged: “Recommendation for 518(e) Action.” It should include the following: 1. The product labeling, and product advertising and/or newsletters to consumers, if pertinent. 2. The basis for determining that 518(e) criteria have been met, such as: a. Any sample analysis that documents that the device does, or may, present a serious health hazard. b. Any testing done that substantiates device failure (e.g., ﬁrm’s in-house and/or FDA testing, independent studies). c. The number of known injuries and/or deaths as documented in the ﬁrm’s ﬁles. Complete documentation of those events should be provided to support the 518(e) criteria. The ﬁrm’s complaint, litigation, and service ﬁles are valuable in obtaining this information. d. A summary of complaints and description of those complaints (e.g., 20 complaints of electrical shortage, 15 complaints of shock, 13 complaints due to overinfusion, 30 complaints of underinfusion). To say that there are 300 complaints may indicate a problem but does not necessarily indicate a serious health issue. Provide copies of signiﬁcant or representative medical device complaints or service records, if available, and any signiﬁcant correspondence with customers. e. The Establishment Inspection Report (EIR), if inspectional ﬁndings support the problem, especially if testing is inadequate. f. Any pertinent manufacturing or recall history. g. Date of the last visit to the ﬁrm, reason for the visit, and any subsequent correspondence or communications. Is a limited update inspection needed or is some other mechanism available to determine whether the hazard condition still exists? Be clear on the ﬁrm’s regulatory history, conditions of approval of the device, etc., so the ﬁrm will not later argue that it did not have advance notice of the problems. It presents problems in demonstrating that the case represents a serious health risk if the case review has taken months. h. Any other pertinent information to document that the device presents a hazard consistent with 518(e) criteria. 3. Because a hearing may take place quickly, include one extra copy of all information for the Ofﬁce of the Chief Counsel (OCC). All written materials that the FDA will rely on for support at the hearing (for example, the EIR) must be turned over to the opposing side at least one day before the informal hearing. Do not delay other regulatory actions (e.g., seizure) pending the 518(e) review. In addition, do not stop collecting data, as the issue can still potentially result in a trial, seizure, Congressional hearing, etc. The OC will convene a Health Hazard Evaluation (HHE) Committee to evaluate the information in the recommendation. If the HHE concludes that a 518(e) action is warranted, the OC, with Chief

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Counsel concurrence, will prepare the order for the signature of the director of the OC. The order will be faxed to the ﬁrm and the district. If the ﬁrm cannot receive facsimile transmissions, the order will be hand delivered by the district. In either situation, the district should seek an immediate determination from the ﬁrm as to its actions. If the order is not complied with, any product encountered should be administratively detained in accordance with the instructions in the Regulatory Procedures Manual (page 136, Administrative Detentions) and appropriate regulations found in 21 CFR 800.55. The ﬁrm is to provide periodic status reports to the district. The frequency of such reports will be speciﬁed in the order. Communications developed by the ﬁrm to implement the order must be submitted to the CDRH for review and approval prior to distribution. The Center will work with the district and ﬁrm so that users comply with the order in a medically safe manner. The ﬁrm may need to immediately replace defective devices with equivalent devices, including those of a competitor. The Center will review all emergency or urgent need requests to permit continued use of the device on a case-by-case basis. For some medical conditions, no alternative to the device subject to the order is available. In those cases, continued use of the device is permitted provided certain safety precautions are followed. Informal Hearing The person receiving the order may, within the timeframe speciﬁed in the order, submit a written request to the FDA for a regulatory hearing. The request must be addressed to the agency employee identiﬁed in the order. Ordinarily, the FDA requires that the person named in the order submit the hearing request within 3 days of receipt of the order. When necessary, however, the FDA may require that the hearing request be submitted in less than 3 days. The informal hearing is conducted as a regulatory hearing under 21 CFR Part 16. Following the hearing, the Hearing Ofﬁcer issues a decision to vacate the original cease-and-desist order, modify the order, or amend the order to require recall of the product. An ordered recall should begin on the date of the amended order to recall and, generally, should be at mid-stage in six weeks and completed no later than three months from initiation of the recall. The Ofﬁce of Standards and Regulations (OSR), CDRH, makes arrangements for informal hearings, including a conference room and stenographer. The hearings are held in the Washington, D.C., area. The Center identiﬁes a Hearing Ofﬁcer. The hearing will be held not later than 10 days after issuance of the order, unless both the person named in the order and FDA agree that the hearing will be held at a later date. Such an agreement is unlikely because of the hazard presented by the device. As soon as the OC determines that a 518(e) action is appropriate, the ﬁeld fact witnesses should immediately prepare for possible testimony in anticipation of the informal hearing. Each should prepare a narrative memo of ﬁndings of facts pertaining to the device (e.g., inspectional or analytical ﬁndings). The OCC must have the narrative memo three days before the hearing and follows up with a telephone call to the CSO involved. The Center also gathers documentary support and locates expert witnesses to testify at the hearing. Expert identiﬁcation and preparation are difﬁcult and time consuming. Field ofﬁces are alert to potential experts and are able to provide their names to the CDRH. A pre-meeting of FDA participants and the CC is held one to two days prior to the informal hearing, to discuss the issues and prepare our strategy for the hearing. If a hearing is to be public, it will be announced on the public calendar. If the FDA wants the hearing to be closed to the public, it must state one of the reasons contained in 21 CFR 16.60. If the company wants the hearing to be closed to the public, the company must state its reason under 21 CFR 16.60 in its request for a hearing. The Hearing Ofﬁcer will make the ﬁnal determination as to whether a hearing is to be open to the public or closed. If the person named in the order does not request a hearing within the timeframe speciﬁed in the order, the right to a hearing will be deemed waived. In such cases, the FDA is free to amend the order to require a recall as it deems appropriate.

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The person named in an order may, in lieu of requesting a hearing, submit a written request to the FDA asking that the order be modiﬁed or vacated. The written request must be addressed to the agency employee identiﬁed in the order and must be submitted within the timeframe speciﬁed in the order. The agency ofﬁcial who issued the cease distribution and notiﬁcation order must provide the requestor written notiﬁcation of the agency decision to afﬁrm, modify, or vacate the order within a reasonable time after completing the review of the request. If the person named in a cease distribution and notiﬁcation order does not request a regulatory hearing or submit a request for agency review of the order, or if, after conducting a regulatory hearing or completing agency review of a cease distribution and notiﬁcation order, the FDA determines that the order should be amended to include a mandatory recall of the device with respect to which the order was issued, the FDA will amend the order. The amended order will contain the requirements of the mandatory recall and the form of patient notiﬁcation, if required. The statute does not permit the FDA to require the recall of devices in the possession of patients or individuals; however, the FDA may require the ﬁrm to notify patients, if necessary. Patient notiﬁcation should be used only where the device is in a home-healthcare setting and notiﬁcation to doctors would not be sufﬁcient. Patient notiﬁcation should be evaluated on a case-by-case basis, depending on the type of product being recalled. If a signiﬁcant number of individuals at risk cannot be identiﬁed, the FDA may use any technique at its disposal to notify such individuals (refer to Section 705(b) [Publicity] of the Act). Similarly, an amended order cannot include recall of a device from user facilities if the FDA determines that the risk of recalling it from the facilities presents a greater health risk than the health risk of not recalling the device, unless the device can be replaced with an equivalent device by the recalling ﬁrm (including a competitor’s product equivalent to the device). _______________________________________________________________________________

EXHIBIT 5.9: MANDATORY RECALLS OF HUMAN TISSUE INTENDED FOR TRANSPLANTATION If, following issuance of an Order for Retention, Recall, and/or Destruction pursuant to the regulation at 21 CFR 1270, a ﬁrm initiates a recall of human tissue intended for transplantation, the Ofﬁce of Compliance, CBER, has determined the following to be appropriate. 1. A recall recommendation should be generated by the ﬁeld and forwarded to CBER for evaluation. It is not necessary for the district ofﬁce to send copies of documents already submitted to HFM-650 in support of the original recall order; however, the ﬁrm’s recall letter and complete distribution information should be forwarded with the recall recommendation. 2. Considering the authority provided by the regulation to issue a recall order prior to a Health Hazard Evaluation, it has been determined that assignment of class I, II, or III under 21 CFR Part 7 is unnecessary; however, CBER will perform a health hazard evaluation based on information regarding the donor population, extent of processing the tissue, viral marker testing, and donor suitability. 3. CBER will assign a recall (“B”) number to the FDA ordered recall action. 4. The recall action will be published in the FDA Enforcement Report in a section entitled “Human Tissue Mandatory Recall,” which will be inserted under the “Biologics” heading before the “class I” heading.” CBER’s review and processing of tissue recalls is consistent with 21 CFR Part 7 with the exception of classiﬁcation. _______________________________________________________________________________

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EXHIBIT 5.10: SAMPLE DRUG RECALL LETTER [Date] Control Division [Company Name] [Address] URGENT: Drug Recall

Noncompliant adulterated or misbranded product Re: [Product Name], [Lot No.], [Descriptive Information] Recent tests show that the above lot number of this product is [not sterile, subpotent, misbranded, etc.] and, therefore, represents a potential public health hazard. Consequently, we are recalling this lot from the market. Other lot numbers are [are not] involved. Please examine your stocks immediately to determine if you have any Lot [No.] on hand. If so, discontinue dispensing or administering the lot and promptly return, via Parcel Post, to our plant. Mark package “ATTENTION: Returned Goods.” [Note: If a subrecall is indicated in a particular recall situation, the following paragraph should be added: If you have distributed any of Lot [No.], please immediately contact your accounts, advise them of the recall situation, and have them return their outstanding recalled stocks to you. Return these stocks as indicated above.] You will be reimbursed by check or credit memo for the returned goods and postage. Please return the enclosed card immediately providing the requested information. This recall is being made with the knowledge of the Food and Drug Administration. The FDA has classiﬁed this recall as class [I, II or III]. We appreciate your assistance. [Signed] _______________________________________________________________________________

EXHIBIT 5.11: SAMPLE RECALL POSTCARD

PLEASE FILL OUT AND RETURN Date ___________ We do not have any stock of Lot [No.], product on hand.

❏

We have asked our accounts to return their stocks of this merchandise to us.

❏

We are returning ____ [units] of Lot [No.]. Name __________________________________________________________________ Address ________________________________________________________________ City________________________ State ____________ Zip Code _________________

_______________________________________________________________________________

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EXHIBIT 5.12: SAMPLE RECALL ENVELOPE [Recalling Company Name] [Address]

[Name] [Address]

URGENT: Drug Recall

_______________________________________________________________________________

EXHIBIT 5.13: SAMPLE DISTRICT DIRECTOR RECALL NOTIFICATION LETTER [Date] [Name] [Company] [Address] Re: Recall No. D-000-9 Dear [Name]: We agree with your ﬁrm’s decision to recall [Product], Code Nos. [numbers], due to [reason for recall]. We have reviewed your action and conclude that it meets the formal deﬁnition of a Recall. This is signiﬁcant, as your action is an alternative to a Food and Drug Administration legal action to remove your defective product from the market. This recall will be reported in an upcoming issue of the weekly FDA Enforcement Report. In conducting your recall, it is suggested that you follow the FDA’s Enforcement Policy for Recalls (including Product Corrections) in the Guidelines on Policy, Procedures, and Industry Responsibilities issued June 16, 1978. Enclosed is a copy of this Enforcement Policy as well as a copy of the FDA’s Methods for Conducting Recall Effectiveness Checks. This recall has been classiﬁed by the FDA as a class [I, II, or III] recall. This means [insert deﬁnition]. Our evaluation indicates that this recall should be conducted to the [consumer or user, retail, wholesale, etc.] level, and that level [provide] effectiveness checks should be conducted by your ﬁrm. Level [provide] effectiveness checks are [deﬁne].

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In addition to your recall efforts, it is equally important to promptly handle, store, and inventory the merchandise in such a manner as to ensure its separation from acceptable materials so it will not be used or shipped inadvertently. Our past experience in similar situations has shown that the longer a defective product is held between the initiation and termination of a recall, the greater the chance of its accidental misuse. We, therefore, urge you to immediately begin making plans to destroy the product or recondition it to bring it into compliance with the law. Either method should be done under the supervision of an investigator from this ofﬁce. [Note: The paragraph above may be modiﬁed to reﬂect concern about appropriate disposition of toxic materials.] We request that you advise us within ten days of the steps you have taken or will take to ensure that the recalled merchandise is properly inventoried and maintained to prevent unintended use or shipment and that you provide your proposed method of disposition of the returned goods. In addition, we request that you submit to our [City] district ofﬁce a recall status report at [monthly or biweekly] intervals. These recall status reports should contain the following information: (1) Number of consignees notiﬁed of the recall and date and method of notiﬁcation (2) Number of consignees responding to the recall communication and quantity of products on hand at the time it was received (3) Number of consignees that did not respond (4) Number of products returned or corrected by each consignee contacted and the quantity of products accounted for (5) Number and results of effectiveness checks that were made (6) Estimated time frames for completion of the recall These periodic status reports should be addressed to [district determines who receives ﬁrm’s responses]. Our judgment regarding the effectiveness of your recall will largely be based upon your implementation of the enclosed recall guidelines. Please be advised that failure to conduct an effective recall could result in seizure of the violative product or other legal sanctions under the Federal Food, Drug, and Cosmetic Act [list other acts, as appropriate]. Your response to this letter should be addressed to: [District Director’s name and address]. Your cooperation in this matter is obviously important for the protection of the general public. Sincerely yours, [Signed] [Name] District Director [District] Enclosures _______________________________________________________________________________

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EXHIBIT 5.14: SAMPLE RECALL TERMINATION LETTER [Date] [Name] [Company] [Address] Dear [Name]: The Food and Drug Administration has completed their audit of your ﬁrm’s actions concerning the recall of [Product], [Lot Nos.], [Recall Nos.]. We conclude that the recall has been completed and there has been proper disposition of the recalled articles; therefore, the FDA considers the recall terminated. This letter is not intended to imply that the FDA will not recommend civil or criminal legal action related to this matter, nor does it relieve you or your ﬁrm from the responsibility of taking all necessary steps to ensure compliance with the Federal Food, Drug, and Cosmetic Act (or other acts as appropriate) in the future. Sincerely, [Signed] [Name] District Director [District] _______________________________________________________________________________

EXHIBIT 5.15: SAMPLE COMBINED RECALL NOTIFICATION/TERMINATION LETTER [Date] [Name] [Company] [Address] Re: Recall No. Z-000-5 Dear [Name]: This is to advise you that the Food and Drug Administration agrees with your decision to [retrieve from the market to the retail, user, hospital, consumer, etc., level, or conduct a ﬁeld correction of] [Product], [Lot Nos.], due to [reason for action taken]. We have reviewed your action and conclude that it meets the FDA deﬁnition of a class [I, II, or III] recall. This is a situation in which [appropriate classiﬁcation deﬁnition] from Section 7.3(m) of Title 21 CFR applies. This recall [will be or has been] reported in [upcoming or speciﬁc issue] of the weekly FDA Enforcement Report. [Note: When appropriate, a statement on the Center’s suggested effectiveness check level and the ﬁrm’s satisfactory completion of same may be added at this point.] Information provided to the FDA indicates that the [recall has been completed and there has been proper disposition of the recalled product or corrective action has been completed); therefore, the FDA considers the recall terminated.

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This letter is not intended to imply that the FDA will not recommend civil or criminal legal action related to this matter, nor does it relieve you or your ﬁrm from the responsibility of taking all necessary steps to ensure compliance with the Federal Food, Drug, and Cosmetic Act (or other acts as appropriate) in the future. Sincerely, [Signed] [Name] District Director [District]

ENDNOTES 129. FDA Compliance Policy Guide, PB915499, Section 160.400. 130. Ibid., at 160.500; Investigations Operational Manual, January 1998, Subchapter 980 et seq.

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Appendix 1. FD&C Act of 1938 CHAPTER III. PROHIBITED ACTS AND PENALTIES SEIZURE Section 304. [334] (a)(1) Any article of food, drug, or cosmetic that is adulterated or misbranded when introduced into or while in interstate commerce or while held for sale (whether or not the ﬁrst sale) after shipment in interstate commerce, or which may not, under the provisions of section 404 or 505, be introduced into interstate commerce, shall be liable to be proceeded against while in interstate commerce, or at any time thereafter, on libel of information and condemned in any district court of the United States or United States court of a Territory within the jurisdiction of which the article is found. No libel for condemnation shall be instituted under this Act, for any alleged misbranding if there is pending in any court a libel for condemnation proceeding under this Act based upon the same alleged misbranding, and not more than one such proceeding shall be instituted if no such proceeding is so pending, except that such limitations shall not apply (A) when such misbranding has been the basis of a prior judgment in favor of the United States, in a criminal, injunction, or libel for condemnation proceeding under this Act, or (B) when the Secretary has probable cause to believe from facts found, without hearing, by him or any ofﬁcer or employee of the Department that the misbranded article is dangerous to health, or that the labeling of the misbranded article is fraudulent, or would be in a material respect misleading to the injury or damage of the purchaser or consumer. In any case where the number of libel for condemnation proceedings is limited as above provided the proceeding pending or instituted shall, on application of the claimant, seasonably made, be removed for trial to any district agreed upon by stipulation between the parties, or, in case of failure to so stipulate within a reasonable time, the claimant may apply to the court of the district in which the seizure has been made, and such court (after giving the United States attorney for such district reasonable notice and opportunity to be heard) shall by order, unless good cause to the contrary is shown, specify a district of reasonable proximity to the claimant’s principal place of business, to which the case shall be removed for trial. (2) The following shall be liable to be proceeded against at any time on libel of information and condemned in any district court of the United States or United States court of a Territory within the jurisdiction of which they are found: (A) Any drug that is a counterfeit drug, (B) Any container of a counterfeit drug, (C) Any punch, die, plate, stone, labeling, container, or other thing used or designed for use in making a counterfeit drug or drugs, and (D) Any adulterated or misbranded device. (3)(A) Except as provided in subparagraph (B), no libel for condemnation may be instituted under paragraph (1) or (2) against any food which – (i) is misbranded under section 403(a)(2) because of its advertising, and (ii) is being held for sale to the ultimate consumer in an establishment other than an establishment owned or operated by a manufacturer, packer, or distributor of the food.

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(B) A libel for condemnation may be instituted under paragraph (1) or (2) against a food described in subparagraph (A) if – (i)(I) the food’s advertising which resulted in the food being misbranded under section 403(a)(2) was disseminated in the establishment in which the food is being held for sale to the ultimate consumer, (II) such advertising was disseminated by, or under the direction of, the owner or operator of such establishment, or (III) all or part of the cost of such advertising was paid by such owner or operator; and (ii) the owner or operator of such establishment used such advertising in the establishment to promote the sale of the food. (b) The article, equipment, or other thing proceeded against shall be liable to seizure by process pursuant to the libel, and the procedure in cases under this section shall conform, as nearly as may be, to the procedure in admiralty; except that on demand of either party any issue of fact joined in any such case shall be tried by jury. When libel for condemnation proceedings under this section, involving the same claimant and the same issues of adulteration or misbranding, are pending in two or more jurisdictions, such pending proceedings, upon application of the claimant seasonably made to the court of one such jurisdiction, shall be consolidated for trial by order of such court, and tried in (1) any district selected by the claimant where one of such proceedings is pending; or (2) a district agreed upon by stipulation between the parties. If no order for consolidation is so made within a reasonable time, the claimant may apply to the court of one such jurisdiction and such court (after giving the United States attorney for such district reasonable notice and opportunity to be heard) shall by order, unless good cause to the contrary is shown, specify a district of reasonable proximity to the claimant’s principal place of business, in which all such pending proceedings shall be consolidated for trial and tried. Such order of consolidation shall not apply so as to require the removal of any case the date for trial of which has been ﬁxed. The court granting such order shall give prompt notiﬁcation thereof to the other courts having jurisdiction of the cases covered thereby. (c) The court at any time after seizure up to a reasonable time before trial shall by order allow any party to a condemnation proceeding, his attorney or agent, to obtain a representative sample of the article seized and a true copy of the analysis, if any, on which the proceeding is based and the identifying marks or numbers, if any, of the packages from which the samples analyzed were obtained. (d)(1) Any food, drug, device, or cosmetic condemned under this section shall, after entry of the decree, be disposed of by destruction or sale as the court may, in accordance with the provisions of this section, direct and the proceeds thereof, if sold, less the legal costs and charges, shall be paid into the Treasury of the United States; but such article shall not be sold under such decree contrary to the provisions of this Act or the laws of the jurisdiction in which sold. After entry of the decree and upon the payment of the costs of such proceedings and the execution of a good and sufﬁcient bond conditioned that such article shall not be sold or disposed of contrary to the provisions of this Act or the laws of any State or Territory in which sold, the court may by order direct that such article be delivered to the owner thereof to be destroyed or brought into compliance with the provisions of this Act, under the supervision of an ofﬁcer or employee duly designated by the Secretary, and the expenses of such supervision shall be paid by the person obtaining release of the article under bond. If the article was imported into the United States and the person seeking its release establishes (A) that the adulteration, misbranding, or violation did not occur after the article was imported, and (B) that he had no cause for believing that it was adulterated, misbranded, or in violation before it was released from customs custody, the court may permit the article to be delivered to the owner for exportation in lieu of destruction upon a showing by the owner that all

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of the conditions of section 801(e) can and will be met. The provisions of this sentence shall not apply where condemnation is based upon violation of section 402(a)(1), (2), or (6), section 501(a)(3), section 502(j), or section 601(a) or (d). Where such exportation is made to the original foreign supplier, then paragraphs (1) and (2) of section 801(e) and the preceding sentence shall not be applicable; and in all cases of exportation the bond shall be conditioned that the article shall not be sold or disposed of until the applicable conditions of section 801(e) have been met. Any article condemned by reason of its being an article which may not, under section 404 or 505, be introduced into interstate commerce, shall be disposed of by destruction. (2) The provisions of paragraph (1) of this subsection shall, to the extent deemed appropriate by the court, apply to any equipment or other thing which is not otherwise within the scope of such paragraph and which is referred to in paragraph (2) of subsection (a). (3) Whenever in any proceeding under this section, involving paragraph (2) of subsection (a), the condemnation of any equipment or thing (other than a drug) is decreed, the court shall allow the claim of any claimant, to the extent of such claimant’s interest, for remission or mitigation of such forfeiture if such claimant proves to the satisfaction of the court (i) that he has not committed or caused to be committed any prohibited act referred to in such paragraph (2) and has no interest in any drug referred to therein, (ii) that he has an interest in such equipment or other thing as owner or lien or otherwise, acquired by him in good faith, and (iii) that he at no time had any knowledge or reason to believe that such equipment or other thing was being or would be used in, or to facilitate, the violation of laws of the United States relating to counterfeit drugs. (e) When a decree of condemnation is entered against the article, court costs and fees, and storage and other proper expenses, shall be awarded against the person, if any, intervening as claimant of the article. (f) In the case of removal for trial of any case as provided by subsection (a) or (b) – (1) The clerk of the court from which removal is made shall promptly transmit to the court in which the case is to be tried all records in the case necessary in order that such court may exercise jurisdiction. (2) The court to which such case was removed shall have the powers and be subject to the duties, for purposes of such case, which the court from which removal was made would have had, or to which such court would have been subject, if such case had not been removed. (g)(1) If during an inspection conducted under section 704 of a facility or a vehicle, a device which the ofﬁcer or employee making the inspection has reason to believe is adulterated or misbranded is found in such facility or vehicle, such ofﬁcer or employee may order the device detained (in accordance with regulations prescribed by the Secretary) for a reasonable period which may not exceed twenty days unless the Secretary determines that a period of detention greater than twenty days is required to institute an action under subsection (a) or section 302, in which case he may authorize a detention period of not to exceed thirty days. Regulations of the Secretary prescribed under this paragraph shall require that before a device may be ordered detained under this paragraph the Secretary or an ofﬁcer or employee designated by the Secretary approve such order. A detention order under this paragraph may require the labeling or marking of a device during the period of its detention for the purpose of identifying the device as detained. Any person who would be entitled to claim a device if it were seized under subsection (a) may appeal to the Secretary a detention of such device under this paragraph. Within ﬁve days of the date an appeal of a detention is ﬁled with the Secretary, the Secretary shall after affording opportunity for an informal hearing by order conﬁrm the detention or revoke it. (2)(A) Except as authorized by subparagraph (B), a device subject to a detention order issued under paragraph (1) shall not be moved by any person from the place at which it is ordered detained until –

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(i) released by the Secretary, or (ii) the expiration of the detention period applicable to such order, whichever occurs ﬁrst. (B) A device subject to a detention order under paragraph (1) may be moved – (i) in accordance with regulations prescribed by the Secretary, and (ii) if not in ﬁnal form for shipment, at the discretion of the manufacturer of the device for the purpose of completing the work required to put it in such form.

HEARING BEFORE REPORT

OF

CRIMINAL VIOLATION

Section 305. [335] Before any violation of this Act is reported by the Secretary to any United States attorney for institution of a criminal proceeding, the person against whom such proceeding is contemplated shall be given appropriate notice and an opportunity to present his views, either orally or in writing, with regard to such contemplated proceeding.

DEBARMENT, TEMPORARY DENIAL

OF

APPROVAL,

AND

SUSPENSION

Section 306. [335a] (a) MANDATORY DEBARMENT — (1) CORPORATIONS, PARTNERSHIPS, AND ASSOCIATIONS — If the Secretary ﬁnds that a person other than an individual has been convicted, after the date of enactment of this section, of a felony under Federal law for conduct relating to the development or approval, including the process for development or approval, of any abbreviated drug application, the Secretary shall debar such person from submitting, or assisting in the submission of, any such application. (2) INDIVIDUALS — If the Secretary ﬁnds that an individual has been convicted of a felony under Federal law for conduct – (A) relating to the development or approval, including the process for development or approval, of any drug product, or (B) otherwise relating to the regulation of any drug product under this Act, the Secretary shall debar such individual from providing services in any capacity to a person that has an approved or pending drug product application. (b) PERMISSIVE DEBARMENT — (1) IN GENERAL — The Secretary, on the Secretary’s own initiative or in response to a petition, may, in accordance with paragraph (2), debar – (A) a person other than an individual from submitting or assisting in the submission of any abbreviated drug application, or (B) an individual from providing services in any capacity to a person that has an approved or pending drug product application. (2) PERSONS SUBJECT TO PERMISSIVE DEBARMENT — The following persons are subject to debarment under paragraph (1): (A) CORPORATIONS, PARTNERSHIPS, AND ASSOCIATIONS — Any person other than an individual that the Secretary ﬁnds has been convicted – (i) for conduct that – (I) relates to the development or approval, including the process for the development or approval, of any abbreviated drug application; and (II) is a felony under Federal law (if the person was convicted before the date of enactment of this section), a misdemeanor under Federal law, or a felony under State law, or

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(ii) of a conspiracy to commit, or aiding or abetting, a criminal offense described in clause (i) or a felony described in subsection (a)(1), if the Secretary ﬁnds that the type of conduct which served as the basis for such conviction undermines the process for the regulation of drugs. (B) INDIVIDUALS — (i) Any individual whom the Secretary ﬁnds has been convicted of – (I) a misdemeanor under Federal law or a felony under State law for conduct relating to the development or approval, including the process for development or approval, of any drug product or otherwise relating to the regulation of drug products under this Act, or (II) a conspiracy to commit, or aiding or abetting, such criminal offense or a felony described in subsection (a)(2), if the Secretary ﬁnds that the type of conduct which served as the basis for such conviction undermines the process for the regulation of drugs. (ii) Any individual whom the Secretary ﬁnds has been convicted of – (I) a felony which is not described in subsection (a)(2) or clause (i) of this subparagraph and which involves bribery, payment of illegal gratuities, fraud, perjury, false statement, racketeering, blackmail, extortion, falsiﬁcation or destruction of records, or interference with, obstruction of an investigation into, or prosecution of, any criminal offense, or (II) a conspiracy to commit, or aiding or abetting, such felony, if the Secretary ﬁnds, on the basis of the conviction of such individual and other information, that such individual has demonstrated a pattern of conduct sufﬁcient to ﬁnd that there is reason to believe that such individual may violate requirements under this Act relating to drug products. (iii) Any individual whom the Secretary ﬁnds materially participated in acts that were the basis for a conviction for an offense described in subsection (a) or in clause (i) or (ii) for which a conviction was obtained, if the Secretary ﬁnds, on the basis of such participation and other information, that such individual has demonstrated a pattern of conduct sufﬁcient to ﬁnd that there is reason to believe that such individual may violate requirements under this Act relating to drug products. (iv) Any high managerial agent whom the Secretary ﬁnds – (I) worked for, or worked as a consultant for, the same person as another individual during the period in which such other individual took actions for which a felony conviction was obtained and which resulted in the debarment under subsection (a)(2), or clause (i), of such other individual, (II) had actual knowledge of the actions described in subclause (I) of such other individual, or took action to avoid such actual knowledge, or failed to take action for the purpose of avoiding such actual knowledge, (III) knew that the actions described in subclause (I) were violative of law, and (IV) did not report such actions, or did not cause such actions to be reported, to an ofﬁcer, employee, or agent of the Department or to an appropriate law enforcement ofﬁcer, or failed to take other appropriate action that would have ensured that the process for the regulation of drugs was not undermined, within a reasonable time after such agent ﬁrst knew of such actions,

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if the Secretary ﬁnds that the type of conduct which served as the basis for such other individual’s conviction undermines the process for the regulation of drugs. (3) STAY OF CERTAIN ORDERS — An order of the Secretary under clause (iii) or (iv) of paragraph (2)(B) shall not take effect until 30 days after the order has been issued. (c) DEBARMENT PERIODS AND CONSIDERATIONS — (1) EFFECT OF DEBARMENT — The Secretary – (A) shall not accept or review (other than in connection with an audit under this section) any abbreviated drug application submitted by or with the assistance of a person debarred under subsection (a)(1) or (b)(2)(A) during the period such person is debarred, (B) shall, during the period of a debarment under subsection (a)(2) or (b)(2)(B), debar an individual from providing services in any capacity to a person that has an approved or pending drug product application and shall not accept or review (other than in connection with an audit under this section) an abbreviated drug application from such individual, and (C) shall, if the Secretary makes the ﬁnding described in paragraph (6) or (7) of section 307(a), assess a civil penalty in accordance with section 307. (2) DEBARMENT PERIODS — (A) IN GENERAL — The Secretary shall debar a person under subsection (a) or (b) for the following periods: (i) The period of debarment of a person (other than an individual) under subsection (a)(1) shall not be less than 1 year or more than 10 years, but if an act leading to a subsequent debarment under subsection (a) occurs within 10 years after such person has been debarred under subsection (a)(1), the period of debarment shall be permanent. (ii) The debarment of an individual under subsection (a)(2) shall be permanent. (iii) The period of debarment of any person under subsection (b)(2) shall not be more than 5 years. The Secretary may determine whether debarment periods shall run concurrently or consecutively in the case of a person debarred for multiple offenses. (B) NOTIFICATION — Upon a conviction for an offense described in subsection (a) or (b) or upon execution of an agreement with the United States to plead guilty to such an offense, the person involved may notify the Secretary that the person acquiesces to debarment and such person’s debarment shall commence upon such notiﬁcation. (3) CONSIDERATIONS — In determining the appropriateness and the period of a debarment of a person under subsection (b) and any period of debarment beyond the minimum speciﬁed in subparagraph (A)(i) of paragraph (2), the Secretary shall consider where applicable – (A) the nature and seriousness of any offense involved, (B) the nature and extent of management participation in any offense involved, whether corporate policies and practices encouraged the offense, including whether inadequate institutional controls contributed to the offense, (C) the nature and extent of voluntary steps to mitigate the impact on the public of any offense involved, including the recall or the discontinuation of the distribution of suspect drugs, full cooperation with any investigations (including the extent of disclosure to appropriate authorities of all wrongdoing), the relinquishing of proﬁts on drug approvals fraudulently obtained, and any other actions taken to substantially limit potential or actual adverse effects on the public health, (D) whether the extent to which changes in ownership, management, or operations have corrected the causes of any offense involved and provide reasonable assurances that the offense will not occur in the future,

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(E) whether the person to be debarred is able to present adequate evidence that current production of drugs subject to abbreviated drug applications and all pending abbreviated drug applications are free of fraud or material false statements, and (F) prior convictions under this Act or under other Acts involving matters within the jurisdiction of the Food and Drug Administration. (d) TERMINATION OF DEBARMENT — (1) APPLICATION — Any person that is debarred under subsection (a) (other than a person permanently debarred) or any person that is debarred under subsection (b) of this section may apply to the Secretary for termination of the debarment under this subsection. Any information submitted to the Secretary under this paragraph does not constitute an amendment or supplement to pending or approved abbreviated drug applications. (2) DEADLINE — The Secretary shall grant or deny any application respecting a debarment which is submitted under paragraph (1) within 180 days of the date the application is submitted. (3) ACTION BY THE SECRETARY — (A) CORPORATIONS — (i) CONVICTION REVERSAL — If the conviction which served as the basis for the debarment of a person under subsection (a)(1) or (b)(2)(A) is reversed, the Secretary shall withdraw the order of debarment. (ii) APPLICATION — Upon application submitted under paragraph (1), the Secretary shall terminate the debarment of a person if the Secretary ﬁnds that – (I) changes in ownership, management, or operations have fully corrected the causes of the offense involved and provide reasonable assurances that the offense will not occur in the future, and (II) sufﬁcient audits, conducted by the Food and Drug Administration or by independent experts acceptable to the Food and Drug Administration, demonstrate that pending applications and the development of drugs being tested before the submission of an application are free of fraud or material false statements. In the case of persons debarred under subsection (a)(1), such termination shall take effect no earlier than the expiration of one year from the date of the debarment. (B) INDIVIDUALS — (i) CONVICTION REVERSAL — If the conviction which served as the basis for the debarment of an individual under subsection (a)(2) or clause (i), (ii), (iii), or (iv) of subsection (b)(2)(B) is reversed, the Secretary shall withdraw the order of debarment (ii) APPLICATION — Upon application submitted under paragraph (1), the Secretary shall terminate the debarment of an individual who has been debarred under subsection (b)(2)(B) if such termination serves the interests of justice and adequately protects the integrity of the drug approval process. (4) SPECIAL TERMINATION — (A) APPLICATION — Any person that is debarred under subsection (a)(1) (other than a person permanently debarred under subsection (c)(2)(A)(i)) or any individual who is debarred under subsection (a)(2) may apply to the Secretary for special termination of debarment under this subsection. Any information submitted to the Secretary under this subparagraph does not constitute an amendment or supplement to pending or approved abbreviated drug applications.

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(B) CORPORATIONS — Upon an application submitted under subparagraph (A), the Secretary may take the action described in subparagraph (D) if the Secretary, after an informal hearing, ﬁnds that – (i) the person making the application under subparagraph (A) has demonstrated that the felony conviction which was the basis for such person’s debarment involved the commission of an offense which was not authorized, requested, commanded, performed, or recklessly tolerated by the board of directors or by a high managerial agent acting on behalf of the person within the scope of the board’s or agent’s ofﬁce or employment, (ii) all individuals who were involved in the commission of the offense or who knew or should have known of the offense have been removed from employment involving the development or approval of any drug subject to sections 505 or 507, (iii) the person fully cooperated with all investigations and promptly disclosed all wrongdoing to the appropriate authorities, and (iv) the person acted to mitigate any impact on the public of any offense involved, including the recall, or the discontinuation of the distribution, of any drug with respect to which the Secretary requested a recall or discontinuation of distribution due to concerns about the safety or efﬁcacy of the drug. (C) INDIVIDUALS — Upon an application submitted under subparagraph (A), the Secretary may take the action described in subparagraph (D) if the Secretary, after an informal hearing, ﬁnds that such individual has provided substantial assistance in the investigations or prosecutions of offenses which are described in subsection (a) or (b) or which relate to any matter under the jurisdiction of the Food and Drug Administration. (D) SECRETARIAL ACTION — The action referred to in subparagraphs (B) and (C) is – (i) in the case of a person other than an individual – (I) terminating the debarment immediately, or (II) limiting the period of debarment to less than one year, and (ii) in the case of an individual, limiting the period of debarment to less than permanent but to no less than 1 year, whichever best serves the interest of justice and protects the integrity of the drug approval process. (e) PUBLICATION AND LIST OF DEBARRED PERSONS — The Secretary shall publish in the Federal Register the name of any person debarred under subsection (a) or (b), the effective date of the debarment, and the period of the debarment. The Secretary shall also maintain and make available to the public a list, updated no less often than quarterly, of such persons, of the effective dates and minimum periods of such debarments, and of the termination of debarments. (f) TEMPORARY DENIAL OF APPROVAL — (1) IN GENERAL — The Secretary, on the Secretary’s own initiative or in response to a petition, may, in accordance with paragraph (3), refuse by order, for the period prescribed by paragraph (2), to approve any abbreviated drug application submitted by any person – (A) if such person is under an active Federal criminal investigation in connection with an action described in subparagraph (B), (B) if the Secretary ﬁnds that such person – (i) has bribed or attempted to bribe, has paid or attempted to pay an illegal gratuity, or has induced or attempted to induce another person to bribe or pay an illegal gratuity to any ofﬁcer, employee, or agent of the Department of Health and Human Services or to any other Federal, State, or local ofﬁcial in connection with any abbreviated drug application, or has conspired to commit, or aided or abetted, such actions, or

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(ii) has knowingly made or caused to be made a pattern or practice of false statements or misrepresentations with respect to material facts relating to any abbreviated drug application, or the production of any drug subject to an abbreviated drug application, to any ofﬁcer, employee, or agent of the Department of Health and Human Services, or has conspired to commit, or aided or abetted, such actions, and (C) if a signiﬁcant question has been raised regarding – (i) the integrity of the approval process with respect to such abbreviated drug application, or (ii) the reliability of data in or concerning such person’s abbreviated drug application. Such an order may be modiﬁed or terminated at any time. (2) APPLICABLE PERIOD — (A) IN GENERAL — Except as provided in subparagraph (B), a denial of approval of an application of a person under paragraph (1) shall be in effect for a period determined by the Secretary but not to exceed 18 months beginning on the date the Secretary ﬁnds that the conditions described in subparagraphs (A), (B), and (C) of paragraph (1) exist. The Secretary shall terminate such denial – (i) if the investigation with respect to which the ﬁnding was made does not result in a criminal charge against such person, if criminal charges have been brought and the charges have been dismissed, or if a judgment of acquittal has been entered, or (ii) if the Secretary determines that such ﬁnding was in error. (B) EXTENSION — If, at the end of the period described in subparagraph (A), the Secretary determines that a person has been criminally charged for an action described in subparagraph (B) of paragraph (1), the Secretary may extend the period of denial of approval of an application for a period not to exceed 18 months. The Secretary shall terminate such extension if the charges have been dismissed, if a judgment of acquittal has been entered, or if the Secretary determines that the ﬁnding described in subparagraph (A) was in error. (3) INFORMAL HEARING — Within 10 days of the date an order is issued under paragraph (1), the Secretary shall provide such person with an opportunity for an informal hearing, to be held within such 10 days, on the decision of the Secretary to refuse approval of an abbreviated drug application. Within 60 days of the date on which such hearing is held, the Secretary shall notify the person given such hearing whether the Secretary’s refusal of approval will be continued, terminated, or otherwise modiﬁed. Such notiﬁcation shall be ﬁnal agency action. (g) SUSPENSION AUTHORITY — (1) IN GENERAL — If – (A) the Secretary ﬁnds – (i) that a person has engaged in conduct described in subparagraph (B) of subsection (f)(1) in connection with 2 or more drugs under abbreviated drug applications, or (ii) that a person has engaged in ﬂagrant and repeated, material violations of good manufacturing practice or good laboratory practice in connection with the development, manufacturing, or distribution of one or more drugs approved under an abbreviated drug application during a 2-year period, and – (I) such violations may undermine the safety and efﬁcacy of such drugs, and (II) the causes of such violations have not been corrected within a reasonable period of time following notice of such violations by the Secretary, and (B) such person is under an active investigation by a Federal authority in connection with a civil or criminal action involving conduct described in subparagraph (A),

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the Secretary shall issue an order suspending the distribution of all drugs the development or approval of which was related to such conduct described in subparagraph (A) or suspending the distribution of all drugs approved under abbreviated drug applications of such person if the Secretary ﬁnds that such conduct may have affected the development or approval of a signiﬁcant number of drugs which the Secretary is unable to identify. The Secretary shall exclude a drug from such order if the Secretary determines that such conduct was not likely to have inﬂuenced the safety or efﬁcacy of such drug. (2) PUBLIC HEALTH WAIVER — The Secretary shall, on the Secretary’s own initiative or in response to a petition, waive the suspension under paragraph (1) (involving an action described in paragraph (1)(A)(i)) with respect to any drug if the Secretary ﬁnds that such waiver is necessary to protect the public health because sufﬁcient quantities of the drug would not otherwise be available. The Secretary shall act on any petition seeking action under this paragraph within 180 days of the date the petition is submitted to the Secretary. (h) TERMINATION OF SUSPENSION — The Secretary shall withdraw an order of suspension of the distribution of a drug under subsection (g) if the person with respect to whom the order was issued demonstrates in a petition to the Secretary – (1)(A) on the basis of an audit by the Food and Drug Administration or by experts acceptable to the Food and Drug Administration, or on the basis of other information, that the development, approval, manufacturing, and distribution of such drug is in substantial compliance with the applicable requirements of this Act, and (B) changes in ownership, management, or operations – (i) fully remedy the patterns or practices with respect to which the order was issued, and (ii) provide reasonable assurances that such actions will not occur in the future, or (2) the initial determination was in error. The Secretary shall act on a submission of a petition under this subsection within 180 days of the date of its submission and the Secretary may consider the petition concurrently with the suspension proceeding. Any information submitted to the Secretary under this subsection does not constitute an amendment or supplement to a pending or approved abbreviated drug application. (i) PROCEDURE — The Secretary may not take any action under subsection (a), (b), (c), (d)(3), (g), or (h) with respect to any person unless the Secretary has issued an order for such action made on the record after opportunity for an agency hearing on disputed issues of material fact. In the course of any investigation or hearing under this subsection, the Secretary may administer oaths and afﬁrmations, examine witnesses, receive evidence, and issue subpoenas requiring the attendance and testimony of witnesses and the production of evidence that relates to the matter under investigation. (j) JUDICAL REVIEW — (1) IN GENERAL — Except as provided in paragraph (2), any person that is the subject of an adverse decision under subsection (a), (b), (c), (d), (f), (g), or (h) may obtain a review of such decision by the United States Court of Appeals for the District of Columbia or for the circuit in which the person resides, by ﬁling in such court (within 60 days following the date the person is notiﬁed of the Secretary’s decision) a petition requesting that the decision be modiﬁed or set aside. (2) EXCEPTION — Any person that is the subject of an adverse decision under clause (iii) or (iv) of subsection (b)(2)(B) may obtain a review of such decision by the United States District Court for the District of Columbia or a district court of the United States for the district in which the person resides, by ﬁling in such court (within 30 days following the date the person is notiﬁed of the Secretary decision) a complaint requesting that the decision be modiﬁed or set aside. In such an action, the court shall determine the matter de novo.

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(k) CERTIFICATION — Any application for approval of a drug product shall include – (1) a certiﬁcation that the applicant did not and will not use in any capacity the services of any person debarred under subsection (a) or (b), in connection with such application, and (2) if such application is an abbreviated drug application, a list of all convictions, described in subsections (a) and (b) which occurred within the previous 5 years, of the applicant and afﬁliated persons responsible for the development or submission of such application. (l) APPLICABILITY — (1) CONVICTION — For purposes of this section, a person is considered to have been convicted of a criminal offense – (A) when a judgment of conviction has been entered against the person by a Federal or State court, regardless of whether there is an appeal pending, (B) when a plea of guilty or nolo contendere by the person has been accepted by a Federal or State court, or (C) when the person has entered into participation in a ﬁrst offender, deferred adjudication, or other similar arrangement or program where judgment of conviction has been withheld. (2) EFFECTIVE DATES — Subsection (a), subparagraph (A) of subsection (b)(2), and clauses (i) and (ii) of subsection (b)(2)(B) shall not apply to a conviction which occurred more than 5 years before the initiation of an agency action proposed to be taken under subsection (a) or (b). Clauses (iii) and (iv) of subsection (b)(2)(B) and subsections (f) and (g) shall not apply to an act or action which occurred more than 5 years before the initiation of an agency action proposed to be taken under subsection (b), (f), or (g). Clause (iv) of subsection (b)(2)(B) shall not apply to an action which occurred before June 1, 1992. Subsection (k) shall not apply to applications submitted to the Secretary before June 1, 1992.

CIVIL PENALTIES Section 307. [335b] (a) IN GENERAL — Any person that the Secretary ﬁnds – (1) knowingly made or caused to be made, to any ofﬁcer, employee, or agent of the Department of Health and Human Services, a false statement or misrepresentation of a material fact in connection with an abbreviated drug application, (2) bribed or attempted to bribe or paid or attempted to pay an illegal gratuity to any ofﬁcer, employee, or agent of the Department of Health and Human Services in connection with an abbreviated drug application, (3) destroyed, altered, removed, or secreted, or procured the destruction, alteration, removal, or secretion of, any material document or other material evidence which was the property of or in the possession of the Department of Health and Human Services for the purpose of interfering with that Department’s discharge of its responsibilities in connection with an abbreviated drug application, (4) knowingly failed to disclose, to an ofﬁcer or employee of the Department of Health and Human Services, a material fact which such person had an obligation to disclose relating to any drug subject to an abbreviated drug application, (5) knowingly obstructed an investigation of the Department of Health and Human Services into any drug subject to an abbreviated drug application, (6) is a person that has an approved or pending drug product application and has knowingly – (A) employed or retained as a consultant or contractor, or (B) otherwise used in any capacity the services of, a person who was debarred under section 306, or

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(7) is an individual debarred under section 306 and, during the period of debarment, provided services in any capacity to a person that had an approved or pending drug product application, shall be liable to the United States for a civil penalty for each such violation in an amount not to exceed $250,000 in the case of an individual and $1,000,000 in the case of any other person. (b) PROCEDURE — (1) IN GENERAL — (A) ACTION BY THE SECRETARY — A civil penalty under subsection (a) shall be assessed by the Secretary on a person by an order made on the record after an opportunity for an agency hearing on disputed issues of material fact and the amount of the penalty. In the course of any investigation or hearing under this subparagraph, the Secretary may administer oaths and afﬁrmations, examine witnesses, receive evidence, and issue subpoenas requiring the attendance and testimony of witnesses and the production of evidence that relates to the matter under investigation. (B) ACTION BY THE ATTORNEY GENERAL — In lieu of a proceeding under subparagraph (A), the Attorney General may, upon request of the Secretary, institute a civil action to recover a civil money penalty in the amount and for any of the acts set forth in subsection (a). Such an action may be instituted separately from or in connection with any other claim, civil or criminal, initiated by the Attorney General under this Act. (2) AMOUNT — In determining the amount of a civil penalty under paragraph (1), the Secretary or the court shall take into account the nature, circumstances, extent, and gravity of the act subject to penalty, the person’s ability to pay, the effect on the person’s ability to continue to do business, any history of prior, similar acts, and such other matters as justice may require. (3) LIMITATION ON ACTIONS — No action may be initiated under this section – (A) with respect to any act described in subsection (a) of this section that occurred before the date of enactment of this section, or (B) more than 6 years after the date when facts material to the act are known or reasonably should have been known by the Secretary but in no event more than 10 years after the date the act took place. (c) JUDICAL REVIEW — Any person that is the subject of an adverse decision under subsection (b)(1)(A) may obtain a review of such decision by the United States Court of Appeals for the District of Columbia or for the circuit in which the person resides, by ﬁling in such court (within 60 days following the date the person is notiﬁed of the Secretary’s decision) a petition requesting that the decision be modiﬁed or set aside. (d) RECOVERY OF PENALTIES — The Attorney General may recover any civil penalty (plus interest at the currently prevailing rates from the date the penalty became ﬁnal) assessed under subsection (b)(1)(A) in an action brought in the name of the United States. The amount of such penalty may be deducted, when the penalty has become ﬁnal, from any sums then or later owing by the United States to the person against whom the penalty has been assessed. In an action brought under this subsection, the validity, amount, and appropriateness of the penalty shall not be subject to judicial review. (e) INFORMANTS — The Secretary may award to any individual (other than an ofﬁcer or employee of the Federal Government or a person who materially participated in any conduct described in subsection (a)) who provides information leading to the imposition of a civil penalty under this section an amount not to exceed – (1) $250,000, or (2) one-half of the penalty so imposed and collected, whichever is less. The decision of the Secretary on such award shall not be reviewable.

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AUTHORITY TO WITHDRAW APPROVAL

OF

ABBREVIATED DRUG APPLICATIONS

Section 308. [335c] (a) IN GENERAL — The Secretary – (1) shall withdraw approval of an abbreviated drug application if the Secretary ﬁnds that the approval was obtained, expedited, or otherwise facilitated through bribery, payment of an illegal gratuity, or fraud or material false statement, and (2) may withdraw approval of an abbreviated drug application if the Secretary ﬁnds that the applicant has repeatedly demonstrated a lack of ability to produce the drug for which the application was submitted in accordance with the formulations or manufacturing practice set forth in the abbreviated drug application and has introduced, or attempted to introduce, such adulterated or misbranded drug into commerce. (b) PROCEDURE — The Secretary may not take any action under subsection (a) with respect to any person unless the Secretary has issued an order for such action made on the record after opportunity for an agency hearing on disputed issues of material fact. In the course of any investigation or hearing under this subsection, the Secretary may administer oaths and afﬁrmations, examine witnesses, receive evidence, and issue subpoenas requiring the attendance and testimony of witnesses and the production of evidence that relates to the matter under investigation. (c) APPLICABILITY — Subsection (a) shall apply with respect to offenses or acts regardless of when such offenses or acts occurred. (d) JUDICIAL REVIEW — Any person that is the subject of an adverse decision under subsection (a) may obtain a review of such decision by the United States Court of Appeals for the District of Columbia or for the circuit in which the person resides, by ﬁling in such court (within 60 days following the date the person is notiﬁed of the Secretary’s decision) a petition requesting that the decision be modiﬁed or set aside.

REPORT

OF

MINOR VIOLATIONS

Section 309. [336] Nothing in this Act shall be construed as requiring the Secretary to report for prosecution, or for the institution of libel or injunction proceedings, minor violations of this Act whenever he believes that the public interest will be adequately served by a suitable written notice or warning.

PROCEEDINGS

IN

NAME

OF

UNITED STATES; PROVISION

AS TO

SUBPOENAS

Section 310. [337] (a) Except as provided in subsection (b), all such proceedings for the enforcement, or to restrain violations, of this Act shall be by and in the name of the United States. Subpoenas for witnesses who are required to attend a court of the United States, in any district, may run into any other district in any proceeding under this section. (b)(1) A State may bring in its own name and within its jurisdiction proceedings for the civil enforcement, or to restrain violations, of section 401, 403(b), 403(c), 403(d), 403(e), 403(f), 403(g), 403(h), 403(i), 403(k), 403(q), or 403(r) if the food that is the subject of the proceedings is located in the State. (2) No proceeding may be commenced by a State under paragraph (1) – (A) before 30 days after the State has given notice to the Secretary that the State intends to bring such proceeding, (B) before 90 days after the State has given notice to the Secretary of such intent if the Secretary has, within such 30 days, commenced an informal or formal enforcement action pertaining to the food which would be the subject of such proceeding, or

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(C) if the Secretary is diligently prosecuting a proceeding in court pertaining to such food, has settled such proceeding, or has settled the informal or formal enforcement action pertaining to such food. In any court proceeding described in subparagraph (C), a State may intervene as a matter of right.

CHAPTER V. DRUGS AND DEVICES

SUBCHAPTER A. DRUGS

AND

ADULTERATED DRUGS

DEVICES

AND

DEVICES

Section 501. [351] A drug or device shall be deemed to be adulterated – (a)(1) If it consists in whole or in part of any ﬁlthy, putrid, or decomposed substance; or (2)(A) if it has been prepared, packed, or held under unsanitary conditions whereby it may have been contaminated with ﬁlth, or whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess; or (C) if it is a compounded positron emission tomography drug and the methods used in, or the facilities and controls used for, its compounding, processing, packing, or holding do not conform to or are not operated or administered in conformity with the positron emission tomography compounding standards and the ofﬁcial monographs of the United States Pharmacopoeia to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, that it purports or is represented to possess; or (3) if its container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health; or (4) if (A) it bears or contains, for purposes of coloring only, a color additive which is unsafe within the meaning of section 721(a), or (B) it is a color additive the intended use of which in or on drugs or devices is for purposes of coloring only and is unsafe within the meaning of section 721(a); or (5) if it is a new animal drug which is unsafe within the meaning of section 512; or (6) if it is an animal feed bearing or containing a new animal drug, and such animal feed is unsafe within the meaning of section 512. (b) If it purports to be or is represented as a drug the name of which is recognized in an ofﬁcial compendium, and its strength differs from, or its quality or purity falls below, the standard set forth in such compendium. Such determination as to strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium, except that whenever tests or methods of assay have not been prescribed in such compendium, or such tests or methods of assay as are prescribed are, in the judgment of the Secretary, insufﬁcient for the making of such determination, the Secretary shall bring such fact to the attention of the appropriate body charged with the revision of such compendium, and if such body fails within a reasonable time to prescribe tests or methods of assay which, in the judgment of the Secretary, are sufﬁcient for purposes of this paragraph, then the Secretary shall promulgate regulations prescribing appropriate tests or methods of assay in accordance with which such determination as to strength, quality, or purity shall be made. No drug deﬁned in an ofﬁcial compendium shall be deemed to be adulterated under this paragraph because it differs from the standard of strength, quality, or purity therefore set forth in such compendium, if its difference in strength, quality, or purity from such standard is plainly stated on its label. Whenever a drug is recognized in both the United States Pharmacopoeia and the Homoeopathic Pharmacopoeia of the United States it shall be subject to the requirements of

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the United States Pharmacopoeia unless it is labeled and offered for sale as a homoeopathic drug, in which case it shall be subject to the provisions of the Homoeopathic Pharmacopoeia of the United States and not to those of the United States Pharmacopoeia. (c) If it is not subject to the provisions of paragraph (b) of this section and its strength differs from, or its purity or quality falls below, that which it purports or is represented to possess. (d) If it is a drug and any substance has been (1) mixed or packed therewith so as to reduce its quality or strength or (2) substituted wholly or in part therefore. (e)(1) If it is, or purports to be or is represented as, a device which is subject to a performance standard established under section 514 unless such device is in all respects in conformity with such standard. (2) If it is declared to be, purports to be, or is represented as, a device that is in conformity with any standard recognized under section 514(c) unless such device is in all respects in conformity with such standard. (f)(1) If it is a class III device – (A)(i) which is required by a regulation promulgated under subsection (b) of section 515 to have an approval under such section of an application for premarket approval and which is not exempt from section 515 under section 520(g), and (ii)(I) for which an application for premarket approval or a notice of completion of a product development protocol was not ﬁled with the Secretary within the ninety-day period beginning on the date of the promulgation of such regulation, or (II) for which such an application was ﬁled and approval of the application has been denied, suspended, or withdrawn, or such a notice was ﬁled and has been declared not completed or the approval of the device under the protocol has been withdrawn; (B)(i) which was classiﬁed under section 513(f) into class III, which under section 515(a) is required to have in effect an approved application for premarket approval, and which is not exempt from section 515 under section 520(g), and (ii) which has an application which has been suspended or is otherwise not in effect; or (C) which was classiﬁed under section 520(l) into class III, which under such section is required to have in effect an approved application under section 515, and which has an application which has been suspended or is otherwise not in effect. (2)(A) In the case of a device classiﬁed under section 513(f) into class III and intended solely for investigational use, paragraph (1)(B) shall not apply with respect to such device during the period ending on the ninetieth day after the date of the promulgation of the regulations prescribing the procedures and conditions required by section 520(g)(2). (B) In the case of a device subject to a regulation promulgated under subsection (b) of section 515, paragraph (1) shall not apply with respect to such device during the period ending – (i) on the last day of the thirtieth calendar month beginning after the month in which the classiﬁcation of the device in class III became effective under section 513, or (ii) on the ninetieth day after the date of the promulgation of such regulation, whichever occurs later. (g) If it is a banned device. (h) If it is a device and the methods used in, or the facilities or controls used for, its manufacture, packing, storage, or installation are not in conformity with applicable requirements under section 520(f)(1) or an applicable condition prescribed by an order under section 520(f)(2).

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(i) If it is a device for which an exemption has been granted under section 520(g) for investigational use and the person who was granted such exemption or any investigator who uses such device under such exemption fails to comply with a requirement prescribed by or under such section.

MISBRANDED DRUGS

AND

DEVICES

Section 502. [352] A drug or device shall be deemed to be misbranded – (a) If its labeling is false or misleading in any particular. Health care economic information provided to a formulary committee, or other similar entity, in the course of the committee or the entity carrying out its responsibilities for the selection of drugs for managed care or other similar organizations, shall not be considered to be false or misleading under this paragraph if the health care economic information directly relates to an indication approved under section 505 or under section 351(a) of the Public Health Service Act for such drug and is based on competent and reliable scientiﬁc evidence. The requirements set forth in section 505(a) or in section 351(a) of the Public Health Service Act shall not apply to health care economic information provided to such a committee or entity in accordance with this paragraph. Information that is relevant to the substantiation of the health care economic information presented pursuant to this paragraph shall be made available to the Secretary upon request. In this paragraph, the term “health care economic information” means any analysis that identiﬁes, measures, or compares the economic consequences, including the costs of the represented health outcomes, of the use of a drug to the use of another drug, to another health care intervention, or to no intervention. (b) If in package form unless it bears a label containing (1) the name and place of business of the manufacturer, packer, or distributor; and (2) an accurate statement of the quantity of the contents in terms of weight, measure, or numerical count: Provided, That under clause (2) of this paragraph reasonable variations shall be permitted, and exemptions as to small packages shall be established, by regulations prescribed by the Secretary. (c) If any word, statement, or other information required by or under authority of this Act to appear on the label or labeling is not prominently placed thereon with such conspicuousness (as compared with other words, statements, designs, or devices, in the labeling) and in such terms as to render it likely to be read and understood by the ordinary individual under customary conditions of purchase and use. [(d) Repealed by Pub. L. 105–115, November 21, 1997.] (e)(1)(A) If it is a drug, unless its label bears, to the exclusion of any other nonproprietary name (except the applicable systematic chemical name or the chemical formula), (i) the established name (as deﬁned in subparagraph (3)) of the drug, if such there is such a name; (ii) the established name and quantity or, if determined to be appropriate by the Secretary, the proportion of each active ingredient, including the quantity, kind, and proportion of any alcohol, and also including whether active or not the established name and quantity or if determined to be appropriate by the Secretary, the proportion of any bromides, ether, chloroform, acetanilide, acetophenetidin, amidopyrine, antipyrine, atropine, hyoscine, hyoscyamine, arsenic, digitalis, digitalis glucosides, mercury, ouabain, strophanthin, strychnine, thyroid, or any derivative or preparation of any such substances, contained therein, except that the requirement for stating the quantity of the active ingredients, other than the quantity of those speciﬁcally named in this subclause, shall not apply to nonprescription drugs not intended for human use; and (iii) the established name of each inactive ingredient listed in alphabetical order on the outside container of the retail package and, if determined to be appropriate by the

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Secretary, on the immediate container, as prescribed in regulation promulgated by the Secretary, except that nothing in this subclause shall be deemed to require that any trade secret be divulged, and except that the requirements of this subclause with respect to alphabetical order shall apply only to nonprescription drugs that are not also cosmetics and that this subclause shall not apply to nonprescription drugs not intended for human use. (B) for any prescription drug the established name of such drug or ingredient, as the case may be, on such label (and on any labeling on which a name for such drug or ingredient is used) shall be printed prominently and in type at least half as large as that used thereon for any proprietary name or designation for such drug or ingredient; except, that to the extent that compliance with the requirements of subclause (ii) or (iii) of clause (A) or this clause is impracticable, exemptions shall be established by regulations promulgated by the Secretary. (2) If it is a device and it has an established name, unless its label bears, to the exclusion of any other nonproprietary name, its established name (as deﬁned in subparagraph (4)) prominently printed in type at least half as large as that used thereon for any proprietary name or designation for such device, except that to the extent compliance with the requirements of this subparagraph is impracticable, exemptions shall be established by regulations promulgated by the Secretary. (3) As used in subparagraph (1), the term “established name,” with respect to a drug or ingredient thereof, means (A) the applicable ofﬁcial name designated pursuant to section 508, or (B), if there is no such name and such drug, or such ingredient, is an article recognized in an ofﬁcial compendium, then the ofﬁcial title thereof in such compendium, or (C) if neither clause (A) nor clause (B) of this subparagraph applies, then the common or usual name, if any, of such drug or of such ingredient, except that where clause (B) of this subparagraph applies to an article recognized in the United States Pharmacopeia and in the Homoeopathic Pharmacopoeia under different ofﬁcial titles, the ofﬁcial title used in the United States Pharmacopeia shall apply unless it is labeled and offered for sale as a homoeopathic drug, in which case the ofﬁcial title used in the Homoeopathic Pharmacopoeia shall apply. (4) As used in subparagraph (2), the term “established name” with respect to a device means (A) the applicable ofﬁcial name of the device designated pursuant to section, 508, (B) if there is no such name and such device is an article recognized in an ofﬁcial compendium, then the ofﬁcial title thereof in such compendium, or (C) if neither clause (A) nor clause (B) of this subparagraph applies, then any common or usual name of such device. (f) Unless its labeling bears (1) adequate directions for use; and (2) such adequate warnings against use in those pathological conditions or by children where its use may be dangerous to health, or against unsafe dosage or methods or duration of administration or application, in such manner and form, as are necessary for the protection of users, except that where any requirement of clause (1) of this paragraph, as applied to any drug or device, is not necessary for the protection of the public health, the Secretary shall promulgate regulations exempting such drug or device from such requirement. (g) If it purports to be a drug the name of which is recognized in an ofﬁcial compendium, unless it is packaged and labeled as prescribed therein. The method of packing may be modiﬁed with the consent of the Secretary. Whenever a drug is recognized in both the United States Pharmacopoeia and the Homoeopathic Pharmacopoeia of the United States, it shall be subject to the requirements of the United States Pharmacopoeia with respect to packaging and labeling unless it is labeled and offered for sale as a homoeopathic drug, in which case it shall be subject to the provisions of the Homoeopathic Pharmacopoeia of the United States, and not those of the United States Pharmacopoeia, except that in the event of inconsistency between the requirements of this paragraph and those of paragraph (e) as to the name by which the drug or its ingredients shall be designated, the requirements of paragraph (e) shall prevail.

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(h) If it has been found by the Secretary to be a drug liable to deterioration, unless it is packaged in such form and manner, and its label bears a statement of such precautions, as the Secretary shall by regulations require as necessary for the protection of the public health. No such regulation shall be established for any drug recognized in an ofﬁcial compendium until the Secretary shall have informed the appropriate body charged with the revision of such compendium of the need for such packaging or labeling requirements and such body shall have failed within a reasonable time to prescribe such requirements. (i)(1) If it is a drug and its container is so made, formed, or ﬁlled as to be misleading; or (2) if it is an imitation of another drug; or (3) if it is offered for sale under the name of another drug. (j) If it is dangerous to health when used in the dosage or manner, or with the frequency or duration prescribed, recommended, or suggested in the labeling thereof. [(k) Repealed by Pub. L. 105–115, November 21, 1997.] [(1) Repealed by Pub. L. 105–115, November 21, 1997.] (m) If it is a color additive the intended use of which is for the purpose of coloring only, unless its packaging and labeling are in conformity with such packaging and labeling requirements applicable to such color additive, as may be contained in regulations issued under section 721. (n) In the case of any prescription drug distributed or offered for sale in any State, unless the manufacturer, packer, or distributor thereof includes in all advertisements and other descriptive printed matter issued or caused to be issued by the manufacturer, packer, or distributor with respect to that drug a true statement of (1) the established name as deﬁned in section 502(e), printed prominently and in type at least half as large as that used for any trade or brand name thereof, (2) the formula showing quantitatively each ingredient of such drug to the extent required for labels under section 502(e), and (3) such other information in brief summary relating to side effects, contraindications, and effectiveness as shall be required in regulations which shall be issued by the Secretary in accordance with the procedure speciﬁed in section 701(e) of this Act, except that (A) except in extraordinary circumstances, no regulation issued under this paragraph shall require prior approval by the Secretary of the content of any advertisement, and (B) no advertisement of a prescription drug, published after the effective date of regulations issued under this paragraph applicable to advertisements of prescription drugs, shall with respect to the matters speciﬁed in this paragraph or covered by such regulations, be subject to the provisions of sections 12 to 17 of the Federal Trade Commission Act, as amended (15 U.S.C. 52–57). This paragraph (n) shall not be applicable to any printed matter which the Secretary determines to be labeling as deﬁned in section 201(m) of this Act. Nothing in the Convention on Psychotropic Substances, signed at Vienna, Austria, on February 21, 1971, shall be construed to prevent drug price communications to consumers. (o) If it was manufactured, prepared, propagated, compounded, or processed in an establishment in any State not duly registered under section 510, if it was not included in a list required by section 510(j), if a notice or other information respecting it was not provided as required by such section or section 510(k), or if it does not bear such symbols from the uniform system for identiﬁcation of devices prescribed under section 510(e) as the Secretary by regulation requires. (p) If it is a drug and its packaging or labeling is in violation of an applicable regulation issued pursuant to section 3 or 4 of the Poison Prevention Packaging Act of 1970. (q) In the case of any restricted device distributed or offered for sale in any State, if (1) its advertising is false or misleading in any particular, or (2) it is sold, distributed, or used in violation of regulations prescribed under section 520(e). (r) In the case of any restricted device distributed or offered for sale in any State, unless the manufacturer, packer, or distributor thereof includes in all advertisements and other descriptive

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printed matter issued or caused to be issued by the manufacturer, packer, or distributor with respect to that device (1) a true statement of the device established name as deﬁned in section 502(e), printed prominently and in type at least half as large as that used for any trade or brand name thereof, and (2) a brief statement of the intended uses of the device and relevant warnings, precautions, side effects, and contraindications and, in the case of speciﬁc devices made subject to a ﬁnding by the Secretary after notice and opportunity for comment that such action is necessary to protect the public health, a full description of the components of such device or the formula showing quantitatively each ingredient of such device to the extent required in regulations which shall be issued by the Secretary after an opportunity for a hearing. Except in extraordinary circumstances, no regulation issued under this paragraph shall require prior approval by the Secretary of the content of any advertisement and no advertisement of a restricted device, published after the effective date of this paragraph shall, with respect to the matters speciﬁed in this paragraph or covered by regulations issued hereunder, be subject to the provisions of sections 12 through 15 of the Federal Trade Commission Act (15 U.S.C. 52–55). This paragraph shall not be applicable to any printed matter which the Secretary determines to be labeling as deﬁned in section 201(m). (s) If it is a device subject to a performance standard established under section 514, unless it bears such labeling as may be prescribed in such performance standard. (t) If it is a device and there was a failure or refusal (1) to comply with any requirement prescribed under section 518 respecting the device, (2) to furnish any material or information required by or under section 519 respecting the device, or (3) to comply with a requirement under section 522.

EXEMPTIONS AND CONSIDERATIONS FOR CERTAIN DRUGS, DEVICES, AND BIOLOGICAL PRODUCTS Section 503. [353] (a) The Secretary is directed to promulgate regulations exempting from any labeling or packaging requirement of this Act drugs and devices which are, in accordance with the practice of the trade, to be processed, labeled, or repacked in substantial quantities at establishments other than those where originally processed or packed, on condition that such drugs and devices are not adulterated or misbranded under the provisions of this Act upon removal from such processing, labeling, or repacking establishment. (b)(1) A drug intended for use by man which – (A) because of its toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such drug; or (B) is limited by an approved application under section 505 to use under the professional supervision of a practitioner licensed by law to administer such drug; shall be dispensed only (i) upon a written prescription of a practitioner licensed by law to administer such drug, or (ii) upon an oral prescription of such practitioner which is reduced promptly to writing and ﬁled by the pharmacist, or (iii) by reﬁlling any such written or oral prescription if such reﬁlling is authorized by the prescriber either in the original prescription or by oral order which is reduced promptly to writing and ﬁled by the pharmacist. The act of dispensing a drug contrary to the provisions of this paragraph shall be deemed to be an act which results in the drug being misbranded while held for sale. (2) Any drug dispensed by ﬁlling or refilling a written or oral prescription of a practitioner licensed by law to administer such drug shall be exempt from the requirements of section 502, except paragraphs (a), (i)(2) and (3), (k), and (l), and the packaging requirements of paragraphs (g), (h), and (p), if the drug bears a label containing the name and address of the dispenser, the serial number and date of the prescription or of its ﬁlling, the name of the prescriber, and, if stated in the prescription, the name of the patient, and the directions for use and cautionary

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statements, if any, contained in such prescription. This exemption shall not apply to any drug dispensed in the course of the conduct of a business of dispensing drugs pursuant to diagnosis by mail, or to a drug dispensed in violation of paragraph (1) of this subsection. (3) The Secretary may by regulation remove drugs subject to sections 502(d) and 505 from the requirements of paragraph (1) of this subsection when such requirements are not necessary for the protection of the public health. (4)(A) A drug which is subject to paragraph (1) shall be deemed to be misbranded if at any time prior to dispensing its label fails to bear at a minimum, the symbol “Rx only.” (B) A drug to which paragraph (1) does not apply shall be deemed to be misbranded if at any time prior to dispensing the label of the drug bears the symbol described in subparagraph (A). (5) Nothing in this subsection shall be construed to relieve any person from any requirement prescribed by or under authority of law with respect to drugs now included or which may hereafter be included within the classiﬁcations stated in section 3220 of the Internal Revenue Code (26 U.S.C. 3220) or to marihuana as deﬁned in section 3238(b) of the Internal Revenue Code (26 U.S.C. 3238(b)). (c)(1) No person may sell, purchase, or trade or offer to sell, purchase, or trade any drug sample. For purposes of this paragraph and subsection (d), the term “drug sample” means a unit of a drug, subject to subsection (b), which is not intended to be sold and is intended to promote the sale of the drug. Nothing in this paragraph shall subject an ofﬁcer or executive of a drug manufacturer or distributor to criminal liability solely because of a sale, purchase, trade, or offer to sell, purchase, or trade in violation of this paragraph by other employees of the manufacturer or distributor. (2) No person may sell, purchase, or trade, offer to sell, purchase, or trade, or counterfeit any coupon. For purposes of this paragraph, the term “coupon” means a form which may be redeemed, at no cost or at a reduced cost, for a drug which is prescribed in accordance with subsection (b). (3)(A) No person may sell, purchase, or trade, or offer to sell, purchase, or trade, any drug – (i) which is subject to subsection (b), and (ii)(I) which was purchased by a public or private hospital or other health care entity, or (II) which was donated or supplied at a reduced price to a charitable organization described in section 501(c)(3) of the Internal Revenue Code of 1954. (B) Subparagraph (A) does not apply to – (i) the purchase or other acquisition by a hospital or other health care entity which is a member of a group purchasing organization of a drug for its own use from the group purchasing organization or from other hospitals or health care entities which are members of such organization, (ii) the sale, purchase, or trade of a drug or an offer to sell, purchase, or trade a drug by an organization described in subparagraph (A)(ii)(II) to a nonproﬁt afﬁliate of the organization to the extent otherwise permitted by law, (iii) a sale, purchase, or trade of a drug or an offer to sell, purchase, or trade a drug among hospitals or other health care entities which are under common control, (iv) a sale, purchase, or trade of a drug or an offer to sell, purchase, or trade a drug for emergency medical reasons, or (v) a sale, purchase, or trade of a drug, an offer to sell, purchase, or trade a drug, or the dispensing of a drug pursuant to a prescription executed in accordance with subsection (b).

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For purposes of this paragraph, the term “entity” does not include a wholesale distributor of drugs or a retail pharmacy licensed under State law and the term “emergency medical reasons” includes transfers of a drug between health care entities or from a health care entity to a retail pharmacy undertaken to alleviate temporary shortages of the drug arising from delays in or interruptions of regular distribution schedules. (d)(1) Except as provided in paragraphs (2) and (3), no person may distribute any drug sample. For purposes of this subsection, the term “distribute” does not include the providing of a drug sample to a patient by a – (A) practitioner licensed to prescribe such drug, (B) health care professional acting at the direction and under the supervision of such a practitioner, or (C) pharmacy of a hospital or of another health care entity that is acting at the direction of such a practitioner and that received such sample pursuant to paragraph (2) or (3). (2)(A) The manufacturer or authorized distributor of record of a drug subject to subsection (b) may, in accordance with this paragraph, distribute drug samples by mail or common carrier to practitioners licensed to prescribe such drugs or, at the request of a licensed practitioner, to pharmacies of hospitals or other health care entities. Such a distribution of drug samples may only be made – (i) in response to a written request for drug samples made on a form which meets the requirements of subparagraph (B), and (ii) under a system which requires the recipient of the drug sample to execute a written receipt for the drug sample upon its delivery and the return of the receipt to the manufacturer or authorized distributor of record. (B) A written request for a drug sample required by subparagraph (A)(i) shall contain – (i) the name, address, professional designation, and signature of the practitioner making the request, (ii) the identity of the drug sample requested and the quantity requested, (iii) the name of the manufacturer of the drug sample requested, and (iv) the date of the request. (C) Each drug manufacturer or authorized distributor of record which makes distributions by mail or common carrier under this paragraph shall maintain, for a period of 3 years, the request forms submitted for such distributions and the receipts submitted for such distributions and shall maintain a record of distributions of drug samples which identiﬁes the drugs distributed and the recipients of the distributions. Forms, receipts, and records required to be maintained under this subparagraph shall be made available by the drug manufacturer or authorized distributor of record to Federal and State ofﬁcials engaged in the regulation of drugs and in the enforcement of laws applicable to drugs. (3) The manufacturer or authorized distributor of record of a drug subject to subsection (b) may, by means other than mail or common carrier, distribute drug samples only if the manufacturer or authorized distributor of record makes the distributions in accordance with subparagraph (A) and carries out the activities described in subparagraphs (B) through (F) as follows: (A) Drug samples may only be distributed – (i) to practitioners licensed to prescribe such drugs if they make a written request for the drug samples, or (ii) at the written request of such a licensed practitioner, to pharmacies of hospitals or other health care entities.

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A written request for drug samples shall be made on a form which contains the practitioner’s name, address, and professional designation, the identity of the drug sample requested, the quantity of drug samples requested, the name of the manufacturer or authorized distributor of record of the drug sample, the date of the request and signature of the practitioner making the request. (B) Drug manufacturers or authorized distributors of record shall store drug samples under conditions that will maintain their stability, integrity, and effectiveness and will assure that the drug samples will be free of contamination, deterioration, and adulteration. (C) Drug manufacturers or authorized distributors of record shall conduct, at least annually, a complete and accurate inventory of all drug samples in the possession of representatives of the manufacturer or authorized distributor of record. Drug manufacturers or authorized distributors of record shall maintain lists of the names and address of each of their representatives who distribute drug samples and of the sites where drug samples are stored. Drug manufacturers or authorized distributors of record shall maintain records for at least 3 years of all drug samples distributed, destroyed, or returned to the manufacturer or authorized distributor of record, of all inventories maintained under this subparagraph, of all thefts or signiﬁcant losses of drug samples, and of all requests made under subparagraph (A) for drug samples. Records and lists maintained under this subparagraph shall be made available by the drug manufacturer or authorized distributor of record to the Secretary upon request. (D) Drug manufacturers or authorized distributors of record shall notify the Secretary of any signiﬁcant loss of drug samples and any known theft of drug samples. (E) Drug manufacturers or authorized distributors of record shall report to the Secretary any conviction of their representatives for violations of subsection (c)(1) or a State law because of the sale, purchase, or trade of a drug sample or the offer to sell, purchase, or trade a drug sample. (F) Drug manufacturers or authorized distributors of record shall provide to the Secretary the name and telephone number of the individual responsible for responding to a request for information respecting drug samples. (e)(1)(A) Each person who is engaged in the wholesale distribution of a drug subject to subsection (b) and who is not the manufacturer or an authorized distributor of record of such drug shall, before each wholesale distribution of such drug (including each distribution to an authorized distributor of record or to a retail pharmacy), provide to the person who receives the drug a statement (in such form and containing such information as the Secretary may require) identifying each prior sale, purchase, or trade of such drug (including the date of the transaction and the names and addresses of all parties to the transaction). (B) Each manufacturer of a drug subject to subsection (b) shall maintain at its corporate ofﬁces a current list of the authorized distributors of record of such drug. (2)(A) No person may engage in the wholesale distribution in interstate commerce of drugs subject to subsection (b) in a State unless such person is licensed by the State in accordance with the guidelines issued under subparagraph (B), or has registered with the Secretary in accordance with paragraph (3). (B) The Secretary shall by regulation issue guidelines establishing minimum standards, terms, and conditions for the licensing of persons to make wholesale distributions in interstate commerce of drugs subject to subsection (b). Such guidelines shall prescribe requirements for the storage and handling of such drugs and for the establishment and maintenance of records of the distributions of such drugs.

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(3) Any person who engages in the wholesale distribution in interstate commerce of drugs that are subject to subsection (b) in a State that does not have a program that meets the guidelines established under paragraph (2)(B) shall register with the Secretary the following: (A) The person’s name and place of business. (B) The name of each establishment the person owns or operates that is engaged in the wholesale distribution of drugs in a State that does not have a program to license persons engaged in such distribution. (4) For the purposes of this subsection and subsection (d) – (A) the term “authorized distributors of record” means those distributors with whom a manufacturer has established an ongoing relationship to distribute such manufacturer’s products, and (B) the term “wholesale distribution” means distribution of drugs subject to subsection (b) to other than the consumer or patient but does not include intracompany sales and does not include distributions of drugs described in subsection (c)(3)(B). (f)(l)(A) A drug intended for use by animals other than man, other than a veterinary feed directive drug intended for use in animal feed or an animal feed bearing or containing a veterinary feed directive drug, which – (i) because of its toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary for its use, is not safe for animal use except under the professional supervision of a licensed veterinarian, or (ii) is limited by an approved application under subsection (b) of section 512 to use under the professional supervision of a licensed veterinarian, shall be dispensed only by or upon the lawful written or oral order of a licensed veterinarian in the course of the veterinarian’s professional practice. (B) For purposes of subparagraph (A), an order is lawful if the order – (i) is a prescription or other order authorized by law, (ii) is, if an oral order, promptly reduced to writing by the person lawfully ﬁlling the order, and ﬁled by that person, and (iii) is reﬁlled only if authorized in the original order or in a subsequent oral order promptly reduced to writing by the person lawfully ﬁlling the order, and ﬁled by that person. (C) The act of dispensing a drug contrary to the provisions of this paragraph shall be deemed to be an act which results in the drug being misbranded while held for sale. (2) Any drug when dispensed in accordance with paragraph (1) of this subsection – (A) shall be exempt from the requirements of section 502, except subsections (a), (g), (h), (i)(2), (i)(3), and (p) of such section, and (B) shall be exempt from the packaging requirements of subsections (g), (h), and (p) of such section, if – (i) when dispensed by a licensed veterinarian, the drug bears a label containing the name and address of the practitioner and any directions for use and cautionary statements speciﬁed by the practitioner, or (ii) when dispensed by ﬁlling the lawful order of a licensed veterinarian, the drug bears a label containing the name and address of the dispenser, the serial number and date of the order or of its ﬁlling, the name of the licensed veterinarian, and the directions for use and cautionary statements, if any, contained in such order. The preceding sentence shall not apply to any drug dispensed in the course of the conduct of a business of dispensing drugs pursuant to diagnosis by mail.

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(3) The Secretary may by regulation exempt drugs for animals other than man subject to section 512 from the requirements of paragraph (1) when such requirements are not necessary for the protection of the public health. (4) A drug which is subject to paragraph (1) shall be deemed to be misbranded if at any time prior to dispensing its label fails to bear the statement “Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.” A drug to which paragraph (1) does not apply shall be deemed to be misbranded if at any time prior to dispensing its label bears the statement speciﬁed in the preceding sentence. (g)(1) The Secretary shall designate a component of the Food and Drug Administration to regulate products that constitute a combination of a drug, device, or biological product. The Secretary shall determine the primary mode of action of the combination product. If the Secretary determines that the primary mode of action is that of – (A) a drug (other than a biological product), the persons charged with premarket review of drugs shall have primary jurisdiction, (B) a device, the persons charged with premarket review of devices shall have primary jurisdiction, or (C) a biological product, the persons charged with premarket review of biological products shall have primary jurisdiction. (2) Nothing in this subsection shall prevent the Secretary from using any agency resources of the Food and Drug Administration necessary to ensure adequate review of the safety, effectiveness, or substantial equivalence of an article. (3) The Secretary shall promulgate regulations to implement market clearance procedures in accordance with paragraphs (1) and (2) not later than 1 year after the date of enactment of this subsection. (4) As used in this subsection: (A) The term “biological product” has the meaning given the term in section 351(i) of the Public Health Service Act (42 U.S.C. 262(i)). (B) The term “market clearance” includes – (i) approval of an application under section 505, 507, 515, or 520(g), (ii) a ﬁnding of substantial equivalence under this part, and (iii) approval of a biologics license application under subsection (a) of section 351 of the Public Health Service Act (42 U.S.C. 262). Section 503A. [353a] PHARMACY COMPOUNDING — (a) IN GENERAL — Sections 501(a)(2)(B), 502(f)(l), and 505 shall not apply to a drug product if the drug product is compounded for an identiﬁed individual patient based on the unsolicited receipt of a valid prescription order or a notation, approved by the prescribing practitioner, on the prescription order that a compounded product is necessary for the identiﬁed patient, if the drug product meets the requirements of this section, and if the compounding – (1) is by – (A) a licensed pharmacist in a State licensed pharmacy or a Federal facility, or (B) a licensed physician, on the prescription order for such individual patient made by a licensed physician or other licensed practitioner authorized by State law to prescribe drugs; or (2)(A) is by a licensed pharmacist or licensed physician in limited quantities before the receipt of a valid prescription order for such individual patient; and

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(B) is based on a history of the licensed pharmacist or licensed physician receiving valid prescription orders for the compounding of the drug product, which orders have been generated solely within an established relationship between – (i) the licensed pharmacist or licensed physician; and (ii)(I) such individual patient for whom the prescription order will be provided; or (II) the physician or other licensed practitioner who will write such prescription order. (b) COMPOUNDED DRUG — (1) LICENSED PHARMACIST AND LICENSED PHYSICIAN — A drug product may be compounded under subsection (a) if the licensed pharmacist or licensed physician – (A) compounds the drug product using bulk drug substances, as deﬁned in regulations of the Secretary published at section 207.3(a)(4) of title 21 of the Code of Federal Regulations – (i) that (I) comply with the standards of an applicable United States Pharmacopoeia or National Formulary monograph, if a monograph exists, and the United States Pharmacopoeia chapter on pharmacy compounding; (II) if such a monograph does not exist, are drug substances that are components of drugs approved by the Secretary; or (III) if such a monograph does not exist and the drug substance is not a component of a drug approved by the Secretary, that appear on a list developed by the Secretary through regulations issued by the Secretary under subsection (d); (ii) that are manufactured by an establishment that is registered under section 510 (including a foreign establishment that is registered under section 510(i)); and (iii) that are accompanied by valid certiﬁcates of analysis for each bulk drug substance; (B) compounds the drug product using ingredients (other than bulk drug substances) that comply with the standards of an applicable United States Pharmacopoeia or National Formulary monograph, if a monograph exists, and the United States Pharmacopoeia chapter on pharmacy compounding; (C) does not compound a drug product that appears on a list published by the Secretary in the Federal Register of drug products that have been withdrawn or removed from the market because such drug products or components of such drug products have been found to be unsafe or not effective; and (D) does not compound regularly or in inordinate amounts (as deﬁned by the Secretary) any drug products that are essentially copies of a commercially available drug product, (2) DEFINITION — For purposes of paragraph (1)(D), the term “essentially a copy of a commercially available drug product” does not include a drug product in which there is a change, made for an identiﬁed individual patient, which produces for that patient a signiﬁcant difference, as determined by the prescribing practitioner, between the compounded drug and the comparable commercially available drug product. (3) DRUG PRODUCT — A drug product may be compounded under subsection (a) only if – (A) such drug product is not a drug product identiﬁed by the Secretary by regulation as a drug product that presents demonstrable difﬁculties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of that drug product; and (B) such drug product is compounded in a State – (i) that has entered into a memorandum of understanding with the Secretary which addresses the distribution of inordinate amounts of compounded drug products interstate

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and provides for appropriate investigation by a State agency of complaints relating to compounded drug products distributed outside such State; or (ii) that has not entered into the memorandum of understanding described in clause (i) and the licensed pharmacist, licensed pharmacy, or licensed physician distributes (or causes to be distributed) compounded drug products out of the State in which they are compounded in quantities that do not exceed 5 percent of the total prescription orders dispensed or distributed by such pharmacy or physician. The Secretary shall, in consultation with the National Association of Boards of Pharmacy, develop a standard memorandum of understanding for use by the States in complying with subparagraph (B)(i). (c) ADVERTISING AND PROMOTION — A drug may be compounded under subsection (a) only if the pharmacy, licensed pharmacist, or licensed physician does not advertise or promote the compounding of any particular drug, class of drug, or type of drug. The pharmacy, licensed pharmacist, or licensed physician may advertise and promote the compounding service provided by the licensed pharmacist or licensed physician. (d) REGULATIONS — (1) IN GENERAL — The Secretary shall issue regulations to implement this section. Before issuing regulations to implement subsections (b)(l)(A)(i)(III), (b)(1)(C), or (b)(3)(A), the Secretary shall convene and consult an advisory committee on compounding unless the Secretary determines that the issuance of such regulations before consultation is necessary to protect the public health. The advisory committee shall include representatives from the National Association of Boards of Pharmacy, the United States Pharmacopoeia, pharmacy, physician, and consumer organizations, and other experts selected by the Secretary. (2) LIMITING COMPOUNDING — The Secretary, in consultation with the United States Pharmacopoeia Convention, Incorporated, shall promulgate regulations identifying drug substances that may be used in compounding under subsection (b)(l)(A)(i)(III) for which a monograph does not exist or which are not components of drug products approved by the Secretary. The Secretary shall include in the regulation the criteria for such substances, which shall include historical use, reports in peer reviewed medical literature, or other criteria the Secretary may identify. (e) APPLICATION — This section shall not apply to – (1) compounded positron emission tomography drugs as deﬁned in section 201(ii); or (2) radiopharmaceuticals. (f) DEFINITION — As used in this section, the term “compounding” does not include mixing, reconstituting, or other such acts that are performed in accordance with directions contained in approved labeling provided by the product manufacturer and other manufacturer directions consistent with that labeling.

VETERINARY FEED DIRECTIVE DRUGS Section 504. [354] (Not included here, as our emphasis is on human drugs.)

NEW DRUGS Section 505. [355] (a) No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application ﬁled pursuant to subsection (b) or (j) is effective with respect to such drug.

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(b)(1) Any person may ﬁle with the Secretary an application with respect to any drug subject to the provisions of subsection (a). Such person shall submit to the Secretary as a part of the application (A) full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use; (B) a full list of the articles used as components of such drug; (C) a full statement of the composition of such drug; (D) a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug; (E) such samples of such drug and of the articles used as components thereof as the Secretary may require; and (F) specimens of the labeling proposed to be used for such drug. The applicant shall ﬁle with the application the patent number and the expiration date of any patent which claims the drug for which the applicant submitted the application or which claims a method of using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture, use, or sale of the drug. If an application is ﬁled under this subsection for a drug and a patent which claims such drug or a method of using such drug is issued after the ﬁling date but before approval of the application, the applicant shall amend the application to include the information required by the preceding sentence. Upon approval of the application, the Secretary shall publish information submitted under the two preceding sentences. The Secretary shall, in consultation with the Director of the National Institutes of Health and with representatives of the drug manufacturing industry, review and develop guidance, as appropriate, on the inclusion of women and minorities in clinical trials required by clause (A). (2) An application submitted under paragraph (1) for a drug for which the investigations described in clause (A) of such paragraph and relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted shall also include – (A) a certiﬁcation, in the opinion of the applicant and to the best of his knowledge, with respect to each patent which claims the drug for which such investigations were conducted or which claims a use for such drug for which the applicant is seeking approval under this subsection and for which information is required to be ﬁled under paragraph (1) or subsection (c) – (i) that such patent information has not been ﬁled, (ii) that such patent has expired, (iii) of the date on which such patent will expire, or (iv) that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted; and (B) if with respect to the drug for which investigations described in paragraph (1)(A) were conducted information was ﬁled under paragraph (1) or subsection (c) for a method of use patent which does not claim a use for which the applicant is seeking approval under this subsection, a statement that the method of use patent does not claim such a use. (3)(A) An applicant who makes a certiﬁcation described in paragraph (2)(A)(iv) shall include in the application a statement that the applicant will give the notice required by subparagraph (B) to – (i) each owner of the patent which is the subject of the certiﬁcation or the representative of such owner designated to receive such notice, and (ii) the holder of the approved application under subsection (b) for the drug which is claimed by the patent or a use of which is claimed by the patent or the representative of such holder designated to receive such notice.

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(B) The notice referred to in subparagraph (A) shall state that an application has been submitted under this subsection for the drug with respect to which the certiﬁcation is made to obtain approval to engage in the commercial manufacture, use, or sale of the drug before the expiration of the patent referred to in the certiﬁcation. Such notice shall include a detailed statement of the factual and legal basis of the applicant’s opinion that the patent is not valid or will not be infringed. (C) If an application is amended to include a certiﬁcation described in paragraph (2)(A)(iv), the notice required by subparagraph (B) shall be given when the amended application is submitted. (4)(A) The Secretary shall issue guidance for the individuals who review applications submitted under paragraph (1) or under section 351 of the Public Health Service Act, which shall relate to promptness in conducting the review, technical excellence, lack of bias and conﬂict of interest, and knowledge of regulatory and scientiﬁc standards, and which shall apply equally to all individuals who review such applications. (B) The Secretary shall meet with a sponsor of an investigation or an applicant for approval for a drug under this subsection or section 351 of the Public Health Service Act if the sponsor or applicant makes a reasonable written request for a meeting for the purpose of reaching agreement on the design and size of clinical trials intended to form the primary basis of an effectiveness claim. The sponsor or applicant shall provide information necessary for discussion and agreement on the design and size of the clinical trials. Minutes of any such meeting shall be prepared by the Secretary and made available to the sponsor or applicant upon request. (C) Any agreement regarding the parameters of the design and size of clinical trials of a new drug under this paragraph that is reached between the Secretary and a sponsor or applicant shall be reduced to writing and made part of the administrative record by the Secretary. Such agreement shall not be changed after the testing begins, except – (i) with the written agreement of the sponsor or applicant; (ii) pursuant to a decision, made in accordance with subparagraph (D) by the director of the reviewing division, that a substantial scientiﬁc issue essential to determining the safety or effectiveness of the drug has been identiﬁed after the testing has begun. (D) A decision under subparagraph (C)(ii) by the director shall be in writing and the Secretary shall provide to the sponsor or applicant an opportunity for a meeting at which the director and the sponsor or applicant will be present and at which the director will document the scientiﬁc issue involved. (E) The written decisions of the reviewing division shall be binding upon, and may not directly or indirectly be changed by, the ﬁeld or compliance division personnel unless such ﬁeld or compliance division personnel demonstrate to the reviewing division why such decision should be modiﬁed. (F) No action by the reviewing division may be delayed because of the unavailability of information from or action by ﬁeld personnel unless the reviewing division determines that a delay is necessary to assure the marketing of a safe and effective drug. (G) For purposes of this paragraph, the reviewing division is the division responsible for the review of an application for approval of a drug under this subsection or section 351 of the Public Health Service Act (including all scientiﬁc and medical matters, chemistry, manufacturing, and controls). (c)(1) Within one hundred and eighty days after the ﬁling of an application under subsection (b), or such additional period as may be agreed upon by the Secretary and the applicant, the Secretary shall either –

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(A) approve the application if he then ﬁnds that none of the grounds for denying approval speciﬁed in subsection (d) applies, or (B) give the applicant notice of an opportunity for a hearing before the Secretary under subsection (d) on the question whether such application is approvable. If the applicant elects to accept the opportunity for hearing by written request within thirty days after such notice, such hearing shall commence not more than ninety days after the expiration of such thirty days unless the Secretary and the applicant otherwise agree. Any such hearing shall thereafter be conducted on an expedited basis and the Secretary’s order thereon shall be issued within ninety days after the date ﬁxed by the Secretary for ﬁling ﬁnal briefs. (2) If the patent information described in subsection (b) could not be ﬁled with the submission of an application under subsection (b) because the application was ﬁled before the patent information was required under subsection (b) or a patent was issued after the application was approved under such subsection, the holder of an approved application shall ﬁle with the Secretary the patent number and the expiration date of any patent which claims the drug for which the application was submitted or which claims a method of using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture, use, or sale of the drug. If the holder of an approved application could not ﬁle patent information under subsection (b) because it was not required at the time the application was approved, the holder shall ﬁle such information under this subsection not later than thirty days after the enactment of this sentence; and if the holder of an approved application could not ﬁle patent information under subsection (b) because no patent had been issued when an application was ﬁled or approved, the holder shall ﬁle such information under this subsection not later than thirty days after the date the patent involved is issued. Upon the submission of patent information under this subsection, the Secretary shall publish it. (3) The approval of an application ﬁled under subsection (b) which contains a certiﬁcation required by paragraph (2) of such subsection shall be made effective on the last applicable date determined under the following: (A) If the applicant only made a certiﬁcation described in clause (i) or (ii) of subsection (b)(2)(A) or in both such clauses, the approval may be made effective immediately. (B) If the applicant made a certiﬁcation described in clause (iii) of subsection (b)(2)(A), the approval may be made effective on the date certiﬁed under clause (iii). (C) If the applicant made a certiﬁcation described in clause (iv) of subsection (b)(2)(A), the approval shall be made effective immediately unless an action is brought for infringement of a patent which is the subject of the certiﬁcation before the expiration of forty-ﬁve days from the date the notice provided under paragraph (3)(B) is received. If such an action is brought before the expiration of such days, the approval may be made effective upon the expiration of the thirty-month period beginning on the date of the receipt of the notice provided under paragraph (3)(B) or such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action, except that – (i) if before the expiration of such period the court decides that such patent is invalid or not infringed, the approval may be made effective on the date of the court decision, (ii) if before the expiration of such period the court decides that such patent has been infringed, the approval may be made effective on such date as the court orders under section 271(e)(4)(A) of title 35, United States Code or (iii) if before the expiration of such period the court grants a preliminary injunction prohibiting the applicant from engaging in the commercial manufacture or sale of the drug until the court decides the issues of patent validity and infringement and if the court decides that such patent is invalid or not infringed, the approval shall be made effective on the date of such court decision.

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In such an action, each of the parties shall reasonably cooperate in expediting the action. Until the expiration of forty-ﬁve days from the date the notice made under paragraph (3)(B) is received, no action may be brought under section 2201 of title 28 United States Code for a declaratory judgment with respect to the patent. Any action brought under such section 2201 shall be brought in the judicial district where the defendant has its principal place of business or a regular and established place of business. (D)(i) If an application (other than an abbreviated new drug application) submitted under subsection (b) for a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under subsection (b), was approved during the period beginning January 1, 1982, and ending on the date of enactment of this subsection∂, the Secretary may not make the approval of another application for a drug for which the investigations described in clause (A) of subsection (b)(1) and relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted effective before the expiration of ten years from the date of the approval of the application previously approved under subsection (b). (ii) If an application submitted under subsection (b) for a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under subsection (b), is approved after the date of the enactment of this clause, no application which refers to the drug for which the subsection (b) application was submitted and for which the investigations described in clause (A) of subsection (b)(1) and relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted may be submitted under subsection (b) before the expiration of ﬁve years from the date of the approval of the application under subsection (b), except that such an application may be submitted under subsection (b) after the expiration of four years from the date of the approval of the subsection (b) application if it contains a certiﬁcation of patent invalidity or noninfringement described in clause (iv) of subsection (b)(2)(A). The approval of such an application shall be made effective in accordance with this paragraph except that, if an action for patent infringement is commenced during the one-year period beginning forty-eight months after the date of the approval of the subsection (b) application, the thirty-month period referred to in subparagraph (C) shall be extended by such amount of time (if any) which is required for seven and onehalf years to have elapsed from the date of approval of the subsection (b) application. (iii) If an application submitted under subsection (b) for a drug, which includes an active ingredient (including any ester or salt of the active ingredient) that has been approved in another application approved under subsection (b), is approved after the date of enactment of this clause, and if such application contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the application and conducted or sponsored by the applicant, the Secretary may not make the approval of an application submitted under subsection (b) for the conditions of approval of such drug in the approved subsection (b) application effective before the expiration of three years from the date of the approval of the application under subsection (b) if the investigations described in clause (A) of subsection (b)(1) and relied upon by the applicant for approval of the application were not conducted by or for the applicant and if the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. (iv) If a supplement to an application approved under subsection (b) is approved after the date of enactment of this clause, and the supplement contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the supplement and conducted or sponsored by the person submitting the supplement, the Secretary may

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not make the approval of an application submitted under subsection (b) for a change approved in the supplement effective before the expiration of three years from the date of the approval of the supplement under subsection (b) if the investigations described in clause (A) of subsection (b)(1) and relied upon by the applicant for approval of the application were not conducted by or for the applicant and if the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. (v) If an application (or supplement to an application) submitted under subsection (b) for a drug, which includes an active ingredient (including any ester or salt of the active ingredient) that has been approved in another application under subsection (b), was approved during the period beginning January 1, 1982, and ending on the date if enactment of this clause, the Secretary may not make the approval of an application submitted under this subsection and for which the investigations described in clause (A) of subsection (b)(1) and relied upon by the applicant for approval of the application were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted and which refers to the drug for which the subsection (b) application was submitted effective before the expiration of two years from the date of enactment of this clause. (4) A drug manufactured in a pilot or other small facility may be used to demonstrate the safety and effectiveness of the drug and to obtain approval for the drug prior to manufacture of the drug in a larger facility, unless the Secretary makes a determination that a full scale production facility is necessary to ensure the safety or effectiveness of the drug. (d) If the Secretary ﬁnds, after due notice to the applicant in accordance with subsection (c) and giving him an opportunity for a hearing, in accordance with said subsection, that (1) the investigations, reports of which are required to be submitted to the Secretary pursuant to subsection (b), do not include adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof; (2) the results of such tests show that such drug is unsafe for use under such conditions or do not show that such drug is safe for use under such conditions; (3) the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity; (4) upon the basis of the information submitted to him as part of the application, or upon the basis of any other information before him with respect to such drug, he has insufﬁcient information to determine whether such drug is safe for use under such conditions; or (5) evaluated on the basis of the information submitted to him as part of the application and any other information before him with respect to such drug, there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof; or (6) the application failed to contain the patent information prescribed by subsection (b); or (7) based on a fair evaluation of all material facts, such labeling is false or misleading in any particular; he shall issue an order refusing to approve the application. If, after such notice and opportunity for hearing, the Secretary ﬁnds that clauses (1) through (6) do not apply, he shall issue an order approving the application. As used in this subsection and subsection (e), the term “substantial evidence” means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualiﬁed by scientiﬁc training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and conﬁrmatory evidence (obtained prior to or after such investigation) are sufﬁcient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence for purposes of the proceeding sentence.

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(e) The Secretary shall, after due notice and opportunity for hearing to the applicant, withdraw approval of an application with respect to any drug under this section if the Secretary ﬁnds (1) that clinical or other experience, tests, or other scientiﬁc data show that such drug is unsafe for use under the conditions of use upon the basis of which the application was approved; (2) that new evidence of clinical experience, not contained in such application or not available to the Secretary until after such application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when such application was approved, evaluated together with the evidence available to the Secretary when the application was approved, shows that such drug is not shown to be safe for use under the conditions of use upon the basis of which the application was approved; or (3) on the basis of new information before him with respect to such drug, evaluated together with the evidence available to him when the application was approved, that there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling thereof; or (4) the patent information prescribed by subsection (c) was not ﬁled within thirty days after the receipt of written notice from the Secretary specifying the failure to ﬁle such information; or (5) that the application contains any untrue statement of a material fact: Provided, That if the Secretary (or in his absence the ofﬁcer acting as Secretary) ﬁnds that there is an imminent hazard to the public health, he may suspend the approval of such application immediately, and give the applicant prompt notice of his action and afford the applicant the opportunity for an expedited hearing under this subsection; but the authority conferred by this proviso to suspend the approval of an application shall not be delegated. The Secretary may also, after due notice and opportunity for hearing to the applicant, withdraw the approval of an application submitted under subsection (b) or (j) with respect to any drug under this section if the Secretary ﬁnds (1) that the applicant has failed to establish a system for maintaining required records, or has repeatedly or deliberately failed to maintain such records or to make required reports, in accordance with a regulation or order under subsection (k) or to comply with the notice requirements of section 510(k)(2), or the applicant has refused to permit access to, or copying or veriﬁcation of, such records as required by paragraph (2) of such subsection; or (2) that on the basis of new information before him, evaluated together with the evidence before him when the application was approved, the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to assure and preserve its identity, strength, quality, and purity and were not made adequate within a reasonable time after receipt of written notice from the Secretary specifying the matter complained of; or (3) that on the basis of new information before him, evaluated together with the evidence before him when the application was approved, the labeling of such drug, based on a fair evaluation of all material facts, is false or misleading in any particular and was not corrected within a reasonable time after receipt of written notice from the Secretary specifying the matter complained of. Any order under this subsection shall state the ﬁndings upon which it is based. (f) Whenever the Secretary ﬁnds that the facts so require, he shall revoke any previous order under subsection (d) or (e) refusing, withdrawing, or suspending approval of an application and shall approve such application or reinstate such approval, as may be appropriate. (g) Orders of the Secretary issued under this section shall be served (1) in person by any ofﬁcer or employee of the department designated by the Secretary or (2) by mailing the order by registered mail or by certiﬁed mail addressed to the applicant or respondent at his last-known address in the records of the Secretary. (h) An appeal may be taken by the applicant from an order of the Secretary refusing or withdrawing approval of an application under this section. Such appeal shall be taken by ﬁling in the United States court of appeals for the circuit wherein such applicant resides or has his principal place of business, or in the United States Court of Appeals for the District of Columbia Circuit, within sixty days after the entry of such order, a written petition praying that the order of the Secretary be set

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aside. A copy of such petition shall be forthwith transmitted by the clerk of the court to the Secretary, or any ofﬁcer designated by him for that purpose, and thereupon the Secretary shall certify and ﬁle in the court the record upon which the order complained of was entered, as provided in section 2112 of title 28, United States Code. Upon the ﬁling of such petition such court shall have exclusive jurisdiction to afﬁrm or set aside such order, except that until the ﬁling of the record the Secretary may modify or set aside his order. No objection to the order of the Secretary shall be considered by the court unless such objection shall have been urged before the Secretary or unless there were reasonable grounds for failure so to do. The ﬁnding of the Secretary as to the facts, if supported by substantial evidence, shall be conclusive. If any person shall apply to the court for leave to adduce additional evidence, and shall show to the satisfaction of the court that such additional evidence is material and that there were reasonable grounds for failure to adduce such evidence in the proceeding before the Secretary, the court may order such additional evidence to be taken before the Secretary and to be adduced upon the hearing in such manner and upon such terms and conditions as to the court may seem proper. The Secretary may modify his ﬁndings as to the facts by reason of the additional evidence so taken, and he shall ﬁle with the court such modiﬁed ﬁndings which, if supported by substantial evidence, shall be conclusive, and his recommendation, if any, for the setting aside of the original order. The judgment of the court afﬁrming or setting aside any such order of the Secretary shall be ﬁnal, subject to review by the Supreme Court of the United States upon certiorari or certiﬁcation as provided in section 1254 of title 28 of the United States Code. The commencement of proceedings under this subsection shall not, unless speciﬁcally ordered by the court to the contrary, operate as a stay of the Secretary’s order. (i)(1) The Secretary shall promulgate regulations for exempting from the operation of the foregoing subsections of this section drugs intended solely for investigational use by experts qualiﬁed by scientiﬁc training and experience to investigate the safety and effectiveness of drugs. Such regulations may, within the discretion of the Secretary, among other conditions relating to the protection of the public health, provide for conditioning such exemption upon – (A) the submission to the Secretary, before any clinical testing of a new drug is undertaken, of reports, by the manufacturer or the sponsor of the investigation of such drug, or preclinical tests (including tests on animals) of such drug adequate to justify the proposed clinical testing; (B) the manufacturer or the sponsor of the investigation of a new drug proposed to be distributed to investigators for clinical testing obtaining a signed agreement from each of such investigators that patients to whom the drug is administered will be under his personal supervision, or under the supervision of investigators responsible to him, and that he will not supply such drug to any other investigator, or to clinics, for administration to human beings; and (C) the establishment and maintenance of such records, and the making of such reports to the Secretary, by the manufacturer or the sponsor of the investigation of such drug, of data (including but not limited to analytical reports by investigators) obtained as the result of such investigational use of such drug, as the Secretary ﬁnds will enable him to evaluate the safety and effectiveness of such drug in the event of the ﬁling of an application pursuant to subsection (b). (2) Subject to paragraph (3), a clinical investigation of a new drug may begin 30 days after the Secretary has received from the manufacturer or sponsor of the investigation a submission containing such information about the drug and the clinical investigation, including — (A) information on design of the investigation and adequate reports of basic information, certiﬁed by the applicant to be accurate reports, necessary to assess the safety of the drug for use in clinical investigation; and

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(B) adequate information on the chemistry and manufacturing of the drug, controls available for the drug, and primary data tabulations from animal or human studies. (3)(A) At any time, the Secretary may prohibit the sponsor of an investigation from conducting the investigation (referred to in this paragraph as a “clinical hold”) if the Secretary makes a determination described in subparagraph (B). The Secretary shall specify the basis for the clinical hold, including the speciﬁc information available to the Secretary which served as the basis for such clinical hold, and conﬁrm such determination in writing. (B) For purposes of subparagraph (A), a determination described in this subparagraph with respect to a clinical hold is that – (i) the drug involved represents an unreasonable risk to the safety of the persons who are the subjects of the clinical investigation, taking into account the qualiﬁcations of the clinical investigators, information about the drug, the design of the clinical investigation, the condition for which the drug is to be investigated, and the health status of the subjects involved; or (ii) the clinical hold should be issued for such other reasons as the Secretary may by regulation establish (including reasons established by regulation before the date of the enactment of the Food and Drug Administration Modernization Act of 1997). (C) Any written request to the Secretary from the sponsor of an investigation that a clinical hold be removed shall receive a decision, in writing and specifying the reasons therefor, within 30 days after receipt of such request. Any such request shall include sufﬁcient information to support the removal of such clinical hold. (4) Regulations under paragraph (1) shall provide that such exemption shall be conditioned upon the manufacturer, or the sponsor of the investigation, requiring that experts using such drugs for investigational purposes certify to such manufacturer or sponsor that they will inform any human beings to whom such drugs, or any controls used in connection therewith, are being administered, or their representatives, that such drugs are being used for investigational purposes and will obtain the consent of such human beings or their representatives, except where it is not feasible or it is contrary to the best interests of such human beings. Nothing in this subsection shall be construed to require any clinical investigator to submit directly to the Secretary reports on the investigational use of drugs. (j)(1) Any person may ﬁle with the Secretary an abbreviated application for the approval of a new drug. (2)(A) An abbreviated application for a new drug shall contain – (i) information to show that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the new drug have been previously approved for a drug listed under paragraph (7) (hereinafter in this subsection referred to as a “listed drug”); (ii)(I) if the listed drug referred to in clause (i) has only one active ingredient, information to show that the active ingredient of the new drug is the same as that of the listed drug; (II) if the listed drug referred to in clause (i) has more than one active ingredient, information to show that the active ingredients of the new drug are the same as those of the listed drug, or (III) if the listed drug referred to in clause (i) has more than one active ingredient and if one of the active ingredients of the new drug is different and the application is ﬁled pursuant to the approval of a petition ﬁled under subparagraph (C), information to show that the other active ingredients of the new drug are the same as the active ingredients of the listed drug, information to show that the different active ingredient is an active ingredient of a listed drug or of a drug which does not meet the requirements of section 201(p), and such other information respecting the different active ingredient with respect to which the petition was ﬁled as the Secretary may require;

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(iii) information to show that the route of administration, the dosage form, and the strength of the new drug are the same as those of the listed drug referred to in clause (i) or, if the route of administration, the dosage form, or the strength of the new drug is different and the application is ﬁled pursuant to the approval of a petition ﬁled under subparagraph (C), such information respecting the route of administration, dosage form, or strength with respect to which the petition was ﬁled as the Secretary may require; (iv) information to show that the new drug is bioequivalent to the listed drug referred to in clause (i), except that if the application is ﬁled pursuant to the approval of a petition ﬁled under subparagraph (C), information to show that the active ingredients of the new drug are of the same pharmacological or therapeutic class as those of the listed drug referred to in clause (i) and the new drug can be expected to have the same therapeutic effect as the listed drug when administered to patients for a condition of use referred to in clause (i); (v) information to show that the labeling proposed for the new drug is the same as the labeling approved for the listed drug referred to in clause (i) except for changes required because of differences approved under a petition ﬁled under subparagraph (C) or because the new drug and the listed drug are produced or distributed by different manufacturers; (vi) the items speciﬁed in clauses (B) through (F) of subsection (b)(1); (vii) a certiﬁcation, in the opinion of the applicant and to the best of his knowledge, with respect to each patent which claims the listed drug referred to in clause (i) or which claims a use for such listed drug for which the applicant is seeking approval under this subsection and for which information is required to be ﬁled under subsection (b) or (c) – (I) that such patent information has not been ﬁled, (II) that such patent has expired, (III) of the date on which such patent will expire, or (IV) that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted; and (viii) if with respect to the listed drug referred to in clause (i) information was ﬁled under subsection (b) or (c) for a method of use patent which does not claim a use for which the applicant is seeking approval under this subsection, a statement that the method of use patent does not claim such a use. The Secretary may not require that an abbreviated application contain information in addition to that required by clauses (i) through (viii). (B)(i) An applicant who makes a certiﬁcation described in subparagraph (A)(vii)(IV) shall include in the application a statement that the applicant will give the notice required by clause (ii) to – (I) each owner of the patent which is the subject of the certiﬁcation or the representative of such owner designated to receive such notice, and (II) the holder of the approved application under subsection (b) for the drug which is claimed by the patent or a use of which is claimed by the patent or the representative of such holder designated to receive such notice. (ii) The notice referred to in clause (i) shall state that an application, which contains data from bioavailability or bioequivalence studies, has been submitted under this subsection for the drug with respect to which the certiﬁcation is made to obtain approval to engage in the commercial manufacture, use, or sale of such drug before the expiration of the patent referred to in the certiﬁcation. Such notice shall include a detailed statement of the factual and legal basis of the applicant’s opinion that the patent is not valid or will not be infringed.

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(iii) If an application is amended to include a certiﬁcation described in subparagraph (A)(vii)(IV), the notice required by clause (ii) shall be given when the amended application is submitted. (C) If a person wants to submit an abbreviated application for a new drug which has a different active ingredient or whose route of administration, dosage form, or strength differ from that of a listed drug, such person shall submit a petition to the Secretary seeking permission to ﬁle such an application. The Secretary shall approve or disapprove a petition submitted under this subparagraph within ninety days of the date the petition is submitted. The Secretary shall approve such a petition unless the Secretary ﬁnds – (i) that investigations must be conducted to show the safety and effectiveness of the drug or of any of its active ingredients, the route of administration, the dosage form, or strength which differ from the listed drug; or (ii) that any drug with a different active ingredient may not be adequately evaluated for approval as safe and effective on the basis of the information required to be submitted in an abbreviated application. (3)(A) The Secretary shall issue guidance for the individuals who review applications submitted under paragraph (1), which shall relate to promptness in conducting the review, technical excellence, lack of bias and conﬂict of interest, and knowledge of regulatory and scientiﬁc standards, and which shall apply equally to all individuals who review such applications. (B) The Secretary shall meet with a sponsor of an investigation or an applicant for approval for a drug under this subsection if the sponsor or applicant makes a reasonable written request for a meeting for the purpose of reaching agreement on the design and size of bioavailability and bioequivalence studies needed for approval of such application. The sponsor or applicant shall provide information necessary for discussion and agreement on the design and size of such studies. Minutes of any such meeting shall be prepared by the Secretary and made available to the sponsor or applicant. (C) Any agreement regarding the parameters of design and size of bioavailability and bioequivalence studies of a drug under this paragraph that is reached between the Secretary and a sponsor or applicant shall be reduced to writing and made part of the administrative record by the Secretary. Such agreement shall not be changed after the testing begins, except – (i) with the written agreement of the sponsor or applicant; (ii) pursuant to a decision, made in accordance with subparagraph (D) by the director of the reviewing division, that a substantial scientiﬁc issue essential to determining the safety or effectiveness of the drug has been identiﬁed after the testing has begun. (D) A decision under subparagraph (C)(ii) by the director shall be in writing and the Secretary shall provide to the sponsor or applicant an opportunity for a meeting at which the director and the sponsor or applicant will be present and at which the director will document the scientiﬁc issue involved. (E) The written decisions of the reviewing division shall be binding upon, and may not directly or indirectly be changed by, the ﬁeld or compliance ofﬁce personnel unless such ﬁeld or compliance ofﬁce personnel demonstrate to the reviewing division why such decision should be modiﬁed. (F) No action by the reviewing division may be delayed because of the unavailability of information from or action by ﬁeld personnel unless the reviewing division determines that a delay is necessary to assure the marketing of a safe and effective drug.

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(G) For purposes of this paragraph, the reviewing division is the division responsible for the review of an application for approval of a drug under this subsection (including scientiﬁc matters, chemistry, manufacturing, and controls). (4) Subject to paragraph (5), the Secretary shall approve an application for a drug unless the Secretary ﬁnds – (A) the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug are inadequate to assure and preserve its identity, strength, quality, and purity; (B) information submitted with the application is insufﬁcient to show that each of the proposed conditions of use have been previously approved for the listed drug referred to in the application; (C)(i) if the listed drug has only one active ingredient, information submitted with the application is insufﬁcient to show that the active ingredient is the same as that of the listed drug; (ii) if the listed drug has more than one active ingredient, information submitted with the application is insufﬁcient to show that the active ingredients are the same as the active ingredients of the listed drug, or (iii) if the listed drug has more than one active ingredient and if the application is for a drug which has an active ingredient different from the listed drug, information submitted with the application is insufﬁcient to show – (I) that the other active ingredients are the same as the active ingredients of the listed drug, or (II) that the different active ingredient is an active ingredient of a listed drug or a drug which does not meet the requirements of section 201(p), or no petition to ﬁle an application for the drug with the different ingredient was approved under paragraph (2)(C); (D)(i) if the application is for a drug whose route of administration, dosage form, or strength of the drug is the same as the route of administration, dosage form, or strength of the listed drug referred to in the application, information submitted in the application is insufﬁcient to show that the route of administration, dosage form, or strength is the same as that of the listed drug, or (ii) if the application is for a drug whose route of administration, dosage form, or strength of the drug is different from that of the listed drug referred to in the application, no petition to ﬁle an application for the drug with the different route of administration, dosage form, or strength was approved under paragraph (2)(C); (E) if the application was ﬁled pursuant to the approval of a petition under paragraph (2)(C), the application did not contain the information required by the Secretary respecting the active ingredient, route of administration, dosage form, or strength which is not the same; (F) information submitted in the application is insufﬁcient to show that the drug is bioequivalent to the listed drug referred to in the application or, if the application was ﬁled pursuant to a petition approved under paragraph (2)(C), information submitted in the application is insufﬁcient to show that the active ingredients of the new drug are of the same pharmacological or therapeutic class as those of the listed drug referred to in paragraph (2)(A)(i) and that the new drug can be expected to have the same therapeutic effect as the listed drug when administered to patients for a condition of use referred to in such paragraph; (G) information submitted in the application is insufﬁcient to show that the labeling proposed for the drug is the same as the labeling approved for the listed drug referred to in the application except for changes required because of differences approved under a petition

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ﬁled under paragraph (2)(C) or because the drug and the listed drug are produced or distributed by different manufacturers; (H) information submitted in the application or any other information available to the Secretary shows that (i) the inactive ingredients of the drug are unsafe for use under the conditions prescribed, recommended, or suggested in the labeling proposed for the drug, or (ii) the composition of the drug is unsafe under such conditions because of the type or quantity of inactive ingredients included or the manner in which the inactive ingredients are included; (I) the approval under subsection (c) of the listed drug referred to in the application under this subsection has been withdrawn or suspended for grounds described in the ﬁrst sentence of subsection (e), the Secretary has published a notice of opportunity for hearing to withdraw approval of the listed drug under subsection (c) for grounds described in the ﬁrst sentence of subsection (e), the approval under this subsection of the listed drug referred to in the application under this subsection has been withdrawn or suspended under paragraph (6), or the Secretary has determined that the listed drug has been withdrawn from sale for safety or effectiveness reasons; (J) the application does not meet any other requirement of paragraph (2)(A); or (K) the application contains an untrue statement of material fact. (5)(A) Within one hundred and eighty days of the initial receipt of an application under paragraph (2) or within such additional period as may be agreed upon by the Secretary and the applicant, the Secretary shall approve or disapprove the application. (B) The approval of an application submitted under paragraph (2) shall be made effective on the last applicable date determined under the following: (i) If the applicant only made a certiﬁcation described in subclause (I) or (II) of paragraph (2)(A)(vii) or in both such subclauses, the approval may be made effective immediately. (ii) If the applicant made a certiﬁcation described in subclause (III) of paragraph (2)(A)(vii), the approval may be made effective on the date certiﬁed under subclause (III). (iii) If the applicant made a certiﬁcation described in subclause (IV) of paragraph (2)(A)(vii), the approval shall be made effective immediately unless an action is brought for infringement of a patent which is the subject of the certiﬁcation before the expiration of forty-ﬁve days from the date the notice provided under paragraph (2)(B)(i) is received. If such an action is brought before the expiration of such days, the approval shall be made effective upon the expiration of the thirty-month period beginning on the date of the receipt of the notice provided under paragraph (2)(B)(i) or such shorter or longer period as the court may order because either party to the action failed to reasonably cooperate in expediting the action, except that – (I) if before the expiration of such period the court decides that such patent is invalid or not infringed, the approval shall be made effective on the date of the court decision, (II) if before the expiration of such period the court decides that such patent has been infringed, the approval shall be made effective on such date as the court orders under section 271(e)(4)(A) of title 35, United States Code or (III) if before the expiration of such period the court grants a preliminary injunction prohibiting the applicant from engaging in the commercial manufacture or sale of the drug until the court decides the issues of patent validity and infringement and if the court decides that such patent is invalid or not infringed, the approval shall be made effective on the date of such court decision.

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In such an action, each of the parties shall reasonably cooperate in expediting the action. Until the expiration of forty-ﬁve days from the date the notice made under paragraph (2)(B)(i) is received, no action may be brought under section 2201 of title 28, United States Code, for a declaratory judgment with respect to the patent. Any action brought under section 2201 shall be brought in the judicial district where the defendant has its principal place of business or a regular and established place of business. (iv) If the application contains a certification described in subclause (IV) of paragraph (2)(A)(vii) and is for a drug for which a previous application has been submitted under this subsection continuing such a certiﬁcation, the application shall be made effective not earlier than one hundred and eighty days after – (I) the date the Secretary receives notice from the applicant under the previous application of the ﬁrst commercial marketing of the drug under the previous application, or (II) the date of a decision of a court in an action described in clause (iii) holding the patent which is the subject of the certiﬁcation to be invalid or not infringed, whichever is earlier. (C) If the Secretary decides to disapprove an application, the Secretary shall give the applicant notice of an opportunity for a hearing before the Secretary on the question of whether such application is approvable. If the applicant elects to accept the opportunity for hearing by written request within thirty days after such notice, such hearing shall commence not more than ninety days after the expiration of such thirty days unless the Secretary and the applicant otherwise agree. Any such hearing shall thereafter be conducted on an expedited basis and the Secretary’s order thereon shall be issued within ninety days after the date ﬁxed by the Secretary for ﬁling ﬁnal briefs. (D)(i) If an application (other than an abbreviated new drug application) submitted under subsection (b) for a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under subsection (b), was approved during the period beginning January 1, 1982, and ending on the date of enactment of this subsection, the Secretary may not make the approval of an application submitted under this subsection which refers to the drug for which the subsection (b) application was submitted effective before the expiration of ten years from the date of the approval of the application under subsection (b). (ii) If an application submitted under subsection (b) for a drug, no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under subsection (b), is approved after the date of enactment of this subsection, no application may be submitted under this subsection which refers to the drug for which the subsection (b) application was submitted before the expiration of ﬁve years from the date of the approval of the application under subsection (b), except that such an application may be submitted under this subsection after the expiration of four years from the date of the approval of the subsection (b) application if it contains a certiﬁcation of patent invalidity or non infringement described in subclause (IV) of paragraph (2)(A)(vii). The approval of such an application shall be made effective in accordance with subparagraph (B) except that, if an action for patent infringement is commenced during the one-year period beginning forty-eight months after the date of the approval of the subsection (b) application, the thirty-month period referred to in subparagraph (B)(iii) shall be extended by such amount of time (if any) which is required for seven and onehalf years to have elapsed from the date of approval of the subsection (b) application.

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(iii) If an application submitted under subsection (b) for a drug, which includes an active ingredient (including any ester or salt of the active ingredient) that has been approved in another application approved under subsection (b), is approved after the date of enactment of this subsection, and if such application contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the application and conducted or sponsored by the applicant, the Secretary may not make the approval of an application submitted under this subsection for the conditions of approval of such drug in the subsection (b) application effective before the expiration of three years from the date of the approval of the application under subsection (b) for such drug. (iv) If a supplement to an application approved under subsection (b) is approved after the date of enactment of this subsection, and the supplement contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the supplement and conducted or sponsored by the person submitting the supplement, the Secretary may not make the approval of an application submitted under this subsection for a change approved in the supplement effective before the expiration of three years from the date of the approval of the supplement under subsection (b). (v) If an application (or supplement to an application) submitted under subsection (b) for a drug, which includes an active ingredient (including any ester or salt of the active ingredient) that has been approved in another application under subsection (b), was approved during the period beginning January 1, 1982, and ending on the date of enactment of this subsection, the Secretary may not make the approval of an application submitted under this subsection which refers to the drug for which the subsection (b) application was submitted or which refers to a change approved in a supplement to the subsection (b) application effective before the expiration of two years from the date of enactment of this subsection. (6) If a drug approved under this subsection refers in its approved application to a drug the approval of which was withdrawn or suspended for grounds described in the ﬁrst sentence of subsection (e) or was withdrawn or suspended under this paragraph or which, as determined by the Secretary, has been withdrawn from sale for safety or effectiveness reasons, the approval of the drug under this subsection shall be withdrawn or suspended – (A) for the same period as the withdrawal or suspension under subsection (e) or this paragraph, or (B) if the listed drug has been withdrawn from sale, for the period of withdrawal from sale or, if earlier, the period ending on the date the Secretary determines that the withdrawal from sale is not for safety or effectiveness reasons. (7)(A)(i) Within sixty days of the date of enactment of this subsection, the Secretary shall publish and make available to the public – (I) a list in alphabetical order of the ofﬁcial and proprietary name of each drug which has been approved for safety and effectiveness under subsection (c) before the date of enactment of this subsection; (II) the date of approval if the drug is approved after 1981 and the number of the application which was approved; and (III) whether in vitro or in vivo bioequivalence studies, or both such studies, are required for applications ﬁled under this subsection which will refer to the drug published. (ii) Every thirty days after the publication of the ﬁrst list under clause (i) the Secretary shall revise the list to include each drug which has been approved for safety and effectiveness under subsection (c) or approved under this subsection during the thirty-day period.

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(iii) When patent information submitted under subsection (b) or (c) respecting a drug included on the list is to be published by the Secretary, the Secretary shall, in revisions made under clause (ii), include such information for such drug. (B) A drug approved for safety and effectiveness under subsection (c) or approved under this subsection shall, for purposes of this subsection, be considered to have been published under subparagraph (A) on the date of its approval or the date of enactment, whichever is later. (C) If the approval of a drug was withdrawn or suspended for grounds described in the ﬁrst sentence of subsection (e) or was withdrawn or suspended under paragraph (6) or if the Secretary determines that a drug has been withdrawn from sale for safety or effectiveness reasons, it may not be published in the list under subparagraph (A) or, if the withdrawal or suspension occurred after its publication in such list, it shall be immediately removed from such list – (i) for the same period as the withdrawal or suspension under subsection (e) or paragraph (6), or (ii) if the listed drug has been withdrawn from sale, for the period of withdrawal from sale or, if earlier, the period ending on the date the Secretary determines that the withdrawal from sale is not for safety or effectiveness reasons. A notice of the removal shall be published in the Federal Register. (8) For purposes of this subsection: (A) The term “bioavailability” means the rate and extent to which the active ingredient or therapeutic ingredient is absorbed from a drug and becomes available at the site of drug action. (B) A drug shall be considered to be bioequivalent to a listed drug if – (i) the rate and extent of absorption of the drug do not show a signiﬁcant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or (ii) the extent of absorption of the drug does not show a signiﬁcant difference from the extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses and the difference from the listed drug in the rate of absorption of the drug is intentional, is reﬂected in its proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insigniﬁcant for the drug. (9) The Secretary shall, with respect to each application submitted under this subsection, maintain a record of – (A) the name of the applicant, (B) the name of the drug covered by the application, (C) the name of each person to whom the review of the chemistry of the application was assigned and the date of such assignment, and (D) the name of each person to whom the bioequivalence review for such application was assigned and the date of such assignment. The information the Secretary is required to maintain under this paragraph with respect to an application submitted under this subsection shall be made available to the public after the approval of such application. (k)(1) In the case of any drug for which an approval of an application ﬁled under subsection (b) or (j) is in effect, the applicant shall establish and maintain such records, and make such reports to the Secretary, of data relating to clinical experience and other data or information, received or

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otherwise obtained by such applicant with respect to such drug, as the Secretary may by general regulation, or by order with respect to such application, prescribe on the basis of a ﬁnding that such records and reports are necessary in order to enable the Secretary to determine, or facilitate a determination, whether there is or may be ground for invoking subsection (e) of this section. Regulations and orders issued under this subsection and under subsection (i) shall have due regard for the professional ethics of the medical profession and the interests of patients and shall provide, where the Secretary deems it to be appropriate, for the examination, upon request, by the persons to whom such regulations or orders are applicable, of similar information received or otherwise obtained by the Secretary. (2) Every person required under this section to maintain records, and every person in charge or custody thereof, shall, upon request of an ofﬁcer or employee designated by the Secretary, permit such ofﬁcer or employee at all reasonable times to have access to and copy and verify such records. (l) Safety and effectiveness data and information which has been submitted in an application under subsection (b) for a drug and which has not previously been disclosed to the public shall be made available to the public, upon request, unless extraordinary circumstances are shown – (1) if no work is being or will be undertaken to have the application approved, (2) if the Secretary has determined that the application is not approvable and all legal appeals have been exhausted, (3) if approval of the application under subsection (c) is withdrawn and all legal appeals have been exhausted, (4) if the Secretary has determined that such drug is not a new drug, or (5) upon the effective date of the approval of the ﬁrst application under subsection (j) which refers to such drug or upon the date upon which the approval of an application under subsection (j) which refers to such drug could be made effective if such an application had been submitted. (m) For purposes of this section, the term “patent” means a patent issued by the Patent and Trademark Ofﬁce of the Department of Commerce. (n)(1) For the purpose of providing expert scientiﬁc advice and recommendations to the Secretary regarding a clinical investigation of a drug or the approval for marketing of a drug under section 505 or section 351 of the Public Health Service Act, the Secretary shall establish panels of experts or use panels of experts established before the date of enactment of the Food and Drug Administration Modernization Act of 1997, or both. (2) The Secretary may delegate the appointment and oversight authority granted under section 904 to a director of a center or successor entity within the Food and Drug Administration. (3) The Secretary shall make appointments to each panel established under paragraph (1) so that each panel shall consist of – (A) members who are qualiﬁed by training and experience to evaluate the safety and effectiveness of the drugs to be referred to the panel and who, to the extent feasible, possess skill and experience in the development, manufacture, or utilization of such drugs; (B) members with diverse expertise in such ﬁelds as clinical and administrative medicine, pharmacy, pharmacology, pharmacoeconomics, biological and physical sciences, and other related professions; (C) a representative of consumer interests, and a representative of interests of the drug manufacturing industry not directly affected by the matter to be brought before the panel; and

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(D) two or more members who are specialists or have other expertise in the particular disease or condition for which the drug under review is proposed to be indicated. Scientiﬁc, trade, and consumer organizations shall be afforded an opportunity to nominate individuals for appointment to the panels. No individual who is in the regular full-time employ of the United States and engaged in the administration of this Act may be a voting member of any panel. The Secretary shall designate one of the members of each panel to serve as chairman thereof. (4) Each member of a panel shall publicly disclose all conﬂicts of interest that member may have with the work to be undertaken by the panel. No member of a panel may vote on any matter where the member or the immediate family of such member could gain ﬁnancially from the advice given to the Secretary. The Secretary may grant a waiver of any conﬂict of interest requirement upon public disclosure of such conﬂict of interest if such waiver is necessary to afford the panel essential expertise, except that the Secretary may not grant a waiver for a member of a panel when the member’s own scientiﬁc work is involved. (5) The Secretary shall, as appropriate, provide education and training to each new panel member before such member participates in a panel’s activities, including education regarding requirements under this Act and related regulations of the Secretary, and the administrative processes and procedures related to panel meetings. (6) Panel members (other than ofﬁcers or employees of the United States), while attending meetings or conferences of a panel or otherwise engaged in its business, shall be entitled to receive compensation for each day so engaged, including travel time, at rates to be ﬁxed by the Secretary, but not to exceed the daily equivalent of the rate in effect for positions classiﬁed above grade GS-15 of the General Schedule. While serving away from their homes or regular places of business, panel members may be allowed travel expenses (including per diem in lieu of subsistence) as authorized by section 5703 of title 5, United States Code, for persons in the Government service employed intermittently. (7) The Secretary shall ensure that scientiﬁc advisory panels meet regularly and at appropriate intervals so that any matter to be reviewed by such a panel can be presented to the panel not more than 60 days after the matter is ready for such review. Meetings of the panel may be held using electronic communication to convene the meetings. (8) Within 90 days after a scientiﬁc advisory panel makes recommendations on any matter under its review, the Food and Drug Administration ofﬁcial responsible for the matter shall review the conclusions and recommendations of the panel, and notify the affected persons of the ﬁnal decision on the matter, or of the reasons that no such decision has been reached. Each such ﬁnal decision shall be documented including the rationale for the decision. Section 505A. [355a] PEDIATRIC STUDIES OF DRUGS — (a) MARKET EXCLUSIVITY FOR NEW DRUGS — If, prior to approval of an application that is submitted under section 505(b)(l), the Secretary determines that information relating to the use of a new drug in the pediatric population may produce health beneﬁts in that population, the Secretary makes a written request for pediatric studies (which shall include a timeframe for completing such studies), and such studies are completed within any such timeframe and the reports thereof submitted in accordance with subsection (d)(2) or accepted in accordance with subsection (d)(3) – (1)(A)(i) the period referred to in subsection (c)(3)(D)(ii) of section 505, and in subsection (j)(4)(D)(ii) of such section, is deemed to be ﬁve years and six months rather than ﬁve years, and the references in subsections (c)(3)(D)(ii) and (j)(4)(D)(ii) of such section to four years, to forty-eight months, and to seven and one-half years are deemed to be four and one-half years, ﬁfty-four months, and eight years, respectively; or

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(ii) the period referred to in clauses (iii) and (iv) of subsection (c)(3)(D) of such section, and in clauses (iii) and (iv) of subsection (j)(4)(D) of such section, is deemed to be three years and six months rather than three years; and (B) if the drug is designated under section 526 for a rare disease or condition, the period referred to in section 527(a) is deemed to be seven years and six months rather than seven years; and (2)(A) if the drug is the subject of — (i) a listed patent for which a certiﬁcation has been submitted under subsection (b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of section 505 and for which pediatric studies were submitted prior to the expiration of the patent (including any patent extensions; or (ii) a listed patent for which a certiﬁcation has been submitted under subsections (b)(2)(A)(iii) or (j)(2)(A)(vii)(IV) of section 505, the period during which an application may not be approved under section 505(c)(3) or section 505(j)(4)(B) shall be extended a period of six months after the date the patent expires (including any patent extensions); or (B) if the drug is the subject of a listed patent for which certiﬁcation has been submitted under subsection (b)(2)(A)(iv) or (j)(2)(A)(vii)(IV) of section 505, and in the patent infringement litigation resulting from the certiﬁcation the court determines that the patent is valid and would be infringed, the period during which an application may not be approved under section 505(c)(3) or section 505(j)(4)(B) shall be extended by a period of six months after the date the patent expires (including any patent extensions). (b) SECRETARY TO DEVELOP LIST OF DRUGS FOR WHICH ADDITIONAL PEDIATRIC INFORMATION MAY BE BENEFICIAL — Not later than 180 days after the date of enactment of the Food and Drug Administration Modernization Act of 1997, the Secretary, after consultation with experts in pediatric research shall develop, prioritize, and publish an initial list of approved drugs for which additional pediatric information may produce health beneﬁts in the pediatric population. The Secretary shall annually update the list. (c) MARKET EXCLUSIVITY FOR ALREADY-MARKETED DRUGS — If the Secretary makes a written request to the holder of an approved application under section 505(b)(l) for pediatric studies (which shall include a timeframe for completing such studies) concerning a drug identiﬁed in the list described in subsection (b), the holder agrees to the request, the studies are completed within any such timeframe, and the reports thereof are submitted in accordance with subsection (d)(2) or accepted in accordance with subsection (d)(3) – (1)(A)(i) the period referred to in subsection (c)(3)(D)(ii) of section 505, and in subsection (j)(4)(D)(ii) of such section, is deemed to be ﬁve years and six months rather than ﬁve years, and the references in subsections (c)(3)(D)(ii) and (j)(4)(D)(ii) of such section to four years, to forty-eight months, and to seven and one-half years are deemed to be four and one-half years, ﬁfty-four months, and eight years, respectively; or (ii) the period referred to in clauses (iii) and (iv) of subsection (c)(3)(D) of such section, and in clauses (iii) and (iv) of subsection (j)(4)(D) of such section, is deemed to be three years and six months rather than three years; and (B) if the drug is designated under section 526 for a rare disease or condition, the period referred to in section 527(a) is deemed to be seven years and six months rather than seven years; and (2)(A) if the drug is the subject of – (i) a listed patent for which a certiﬁcation has been submitted under subsection (b)(2)(A)(ii) or (j)(2)(A)(vii)(II) of section 505 and for which pediatric studies were submitted prior to the expiration of the patent (including any patent extensions); or

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(ii) a listed patent for which a certiﬁcation has been submitted under subsection (b)(2)(A)(iii) or (j)(2)(A)(vii)(III) of section 505, the period during which an application may not be approved under section 505(c)(3) or section 505(j)(4)(B) shall be extended by a period of six months after the date the patent expires (including any patent extensions); or (B) if the drug is the subject of a listed patent for which certiﬁcation has been submitted under subsection (b)(2)(A)(iv) or (j)(2)(A)(vii)(IV) of section 505, and in the patent infringement litigation resulting from the certiﬁcation the court determines that the patent is valid and would be infringed, the period during which an application may not be approved under section 505(c)(3) or section 505(j)(4)(B) shall be extended by a period of six months after the date the patent expires (including any patent extensions). (d) CONDUCT OF PEDIATRIC STUDIES — (1) AGREEMENT FOR STUDIES — The Secretary may, pursuant to a written request from the Secretary under subsection (a) or (c), after consultation with – (A) the sponsor of an application for an investigational new drug under section 505(i); (B) the sponsor of an application for a new drug under section 505(b)(l); or (C) the holder of an approved application for a drug under section 505(b)(l), agree with the sponsor or holder for the conduct of pediatric studies for such drug. Such agreement shall be in writing and shall include a timeframe for such studies. (2) WRITTEN PROTOCOLS TO MEET THE STUDIES REQUIREMENT — If the sponsor or holder and the Secretary agree upon written protocols for the studies, the studies requirement of subsection (a) or (c) is satisﬁed upon the completion of the studies and submission of the reports thereof in accordance with the original written request and the written agreement referred to in paragraph (1). Not later than 60 days after the submission of the report of the studies, the Secretary shall determine if such studies were or were not conducted in accordance with the original written request and the written agreement and reported in accordance with the requirements of the Secretary for ﬁling and so notify the sponsor or holder. (3) OTHER METHODS TO MEET THE STUDIES REQUIREMENT — If the sponsor or holder and the Secretary have not agreed in writing on the protocols for the studies, the studies requirement of subsection (a) or (c) is satisfied when such studies have been completed and the reports accepted by the Secretary. Not later than 90 days after the submission of the reports of the studies, the Secretary shall accept or reject such reports and so notify the sponsor or holder. The Secretary’s only responsibility in accepting or rejecting the reports shall be to determine, within the 90 days, whether the studies fairly respond to the written request, have been conducted in accordance with commonly accepted scientiﬁc principles and protocols, and have been reported in accordance with the requirements of the Secretary for ﬁling. (e) DELAY OF EFFECTIVE DATE FOR CERTAIN APPLICATION — If the Secretary determines that the acceptance or approval of an application under section 505(b)(2) or 505(j) for a new drug may occur after submission of reports of pediatric studies under this section, which were submitted prior to the expiration of the patent (including any patent extension) or the applicable period under clauses (ii) through (iv) of section 505(c)(3)(D) or clauses (ii) through (iv) of section 505(j)(4)(D), but before the Secretary has determined whether the requirements of subsection (d) have been satisﬁed, the Secretary shall delay the acceptance or approval under section 505(b)(2) or 505(j) until the determination under subsection (d) is made, but any such delay shall not exceed 90 days. In the event that requirements of this section are satisﬁed, the applicable six-month period under subsection (a) or (c) shall be deemed to have been running during the period of delay.

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(f) NOTICE OF DETERMINATIONS ON STUDIES REQUIREMENT — The Secretary shall publish a notice of any determination that the requirements of subsection (d) have been met and that submissions and approvals under subsection (b)(2) or (j) of section 505 for a drug will be subject to the provisions of this section. (g) DEFINITIONS — As used in this section, the term “pediatric studies” or “studies” means at least one clinical investigation (that, at the Secretary’s discretion, may include pharmacokinetic studies) in pediatric age groups in which a drug is anticipated to be used. (h) LIMITATIONS —A drug to which the six-month period under subsection (a) or (b) has already been applied – (1) may receive an additional six-month period under subsection (c)(l)(A)(ii) for a supplemental application if all other requirements under this section are satisﬁed, except that such a drug may not receive any additional such period under subsection (c)(2); and (2) may not receive any additional such period under subsection (c)(l)(B). (i) RELATIONSHIP TO REGULATIONS — Notwithstanding any other provision of law, if any pediatric study is required pursuant to regulations promulgated by the Secretary and such study meets the completeness, timeliness, and other requirements of this section, such study shall be deemed to satisfy the requirement for market exclusivity pursuant to this section. (j) SUNSET —A drug may not receive any six-month period under subsection (a) or (c) unless the application for the drug under section 505(b)(l) is submitted on or before January 1, 2002. After January 1, 2002, a drug shall receive a six-month period under subsection (c) if – (1) the drug was in commercial distribution as of the date of enactment of the Food and Drug Administration Modernization Act of 1997; (2) the drug was included by the Secretary on the list under subsection (b) as of January 1, 2002; (3) the Secretary determines that there is a continuing need for information relating to the use of the drug in the pediatric population and that the drug may provide health beneﬁts in that population; and (4) all requirements of this section are met. (k) REPORT —The Secretary shall conduct a study and report to Congress not later than January 1, 2001, based on the experience under the program established under this section. The study and report shall examine all relevant issues, including – (1) the effectiveness of the program in improving information about important pediatric uses for approved drugs; (2) the adequacy of the incentive provided under this section; (3) the economic impact of the program on taxpayers and consumers, including the impact of the lack of lower cost generic drugs on patients, including on lower income patients; and (4) any suggestions for modiﬁcation that the Secretary determines to be appropriate. Section 506. [356] FAST TRACK PRODUCTS — (a) DESIGNATION OF DRUG AS A FAST TRACK PRODUCT — (1) IN GENERAL — The Secretary shall, at the request of the sponsor of a new drug, facilitate the development and expedite the review of such drug if it is intended for the treatment of a serious or life-threatening condition and it demonstrates the potential to address unmet medical needs for such a condition. (In this section, such a drug is referred to as a “fast track product”).

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(2) REQUEST FOR DESIGNATION — The sponsor of a new drug may request the Secretary to designate the drug as a fast track product. A request for the designation may be made concurrently with, or at any time after, submission of an application for the investigation of the drug under section 505(i) or section 351(a)(3) of the Public Health Service Act. (3) DESIGNATION — Within 60 calendar days after the receipt of a request under paragraph (2), the Secretary shall determine whether the drug that is the subject of the request meets the criteria described in paragraph (1). If the Secretary ﬁnds that the drug meets the criteria, the Secretary shall designate the drug as a fast track product and shall take such actions as are appropriate to expedite the development and review of the application for approval of such product. (b) APPROVAL OF APPLICATION FOR A FAST TRACK PRODUCT — (1) IN GENERAL — The Secretary may approve an application for approval of a fast track product under section 505(c) or section 351 of the Public Health Service Act upon a determination that the product has an effect on a clinical endpoint or on a surrogate endpoint that is reasonably likely to predict clinical beneﬁt. (2) LIMITATION — Approval of a fast track product under this subsection may be subject to the requirements – (A) that the sponsor conduct appropriate post-approval studies to validate the surrogate endpoint or otherwise conﬁrm the effect on the clinical endpoint; and (B) that the sponsor submit copies of all promotional materials related to the fast track product during the preapproval review period and, following approval and for such period thereafter as the Secretary determines to be appropriate, at least 30 days prior to dissemination of the materials. (3) EXPEDITED WITHDRAWAL OF APPROVAL — The Secretary may withdraw approval of a fast track product using expedited procedures (as prescribed by the Secretary in regulations which shall include an opportunity for an informal hearing) if – (A) the sponsor fails to conduct any required post-approval study of the fast track drug with due diligence; (B) a post-approval study of the fast track product fails to verify clinical beneﬁt of the product; (C) other evidence demonstrates that the fast track product is not safe or effective under the conditions of use; (D) the sponsor disseminates false or misleading promotional materials with respect to the product. (c) REVIEW OF INCOMPLETE APPLICATIONS FOR APPROVAL OF A FAST TRACK PRODUCT — (1) IN GENERAL — If the Secretary determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast track product may be effective, the Secretary shall evaluate for ﬁling, and may commence review of portions of, an application for the approval of the product before the sponsor submits a complete application. The Secretary shall commence such review only if the applicant – (A) provides a schedule for submission of information necessary to make the application complete; and (B) pays any fee that may be required under section 736.

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(2) EXCEPTION — Any time period for review of human drug applications that has been agreed to by the Secretary and that has been set forth in goals identiﬁed in letters of the Secretary (relating to the use of fees collected under section 736 to expedite the drug development process and the review of human drug applications) shall not apply to an application submitted under paragraph (1) until the date on which the application is complete. (d) AWARENESS EFFORTS — The Secretary shall – (1) develop and disseminate to physicians, patient organizations, pharmaceutical and biotechnology companies, and other appropriate persons a description of the provisions of this section applicable to fast track products; and (2) establish a program to encourage the development of surrogate endpoints that are reasonably likely to predict clinical beneﬁt for serious or life-threatening conditions for which there exist signiﬁcant unmet medical needs. Section 506A [356a] MANUFACTURING CHANGES — (a) IN GENERAL — With respect to a drug for which there is in effect an approved application under section 505 or 512 or a license under section 351 of the Public Health Service Act, a change from the manufacturing process approved pursuant to such application or license may be made, and the drug as made with the change may be distributed, if – (1) the holder of the approved application or license (referred to in this section as a “holder”) has validated the effects of the change in accordance with subsection (b); and (2)(A) in the case of a major manufacturing change, the holder has complied with the requirements of subsection (c); or (B) in the case of a change that is not a major manufacturing change, the holder complies with the applicable requirements of subsection (d). (b) VALIDATION OF EFFECTS OF CHANGES — For purposes of subsection (a)(l), a drug made with a manufacturing change (whether a major manufacturing change or otherwise) may be distributed only if, before distribution of the drug as so made, the holder involved validates the effects of the change on the identity, strength, quality, purity, and potency of the drug as the identity, strength, quality, purity, and potency may relate to the safety or effectiveness of the drug. (c) MAJOR MANUFACTURING CHANGES — (1) REQUIREMENT OF SUPPLEMENTAL APPLICATION — For purposes of subsection (a)(2)(A), a drug made with a major manufacturing change may be distributed only if, before the distribution of the drug as so made, the holder involved submits to the Secretary a supplemental application for such change and the Secretary approves the application. The application shall contain such information as the Secretary determines to be appropriate, and shall include the information developed under subsection (b) by the holder in validating the effects of the change. (2) CHANGES QUALIFYING AS MAJOR CHANGES — For purposes of subsection (a)(2)(A), a major manufacturing change is a manufacturing change that is determined by the Secretary to have substantial potential to adversely affect the identity, strength, quality, purity, or potency of the drug as they may relate to the safety or effectiveness of a drug. Such a change includes a change that – (A) is made in the qualitative or quantitative formulation of the drug involved or in the speciﬁcations in the approved application or license referred to in subsection (a) for the drug (unless exempted by the Secretary by regulation or guidance from the requirements of this subsection);

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(B) is determined by the Secretary by regulation or guidance to require completion of an appropriate clinical study demonstrating equivalence of the drug to the drug as manufactured without the change; or (C) is another type of change determined by the Secretary by regulation or guidance to have a substantial potential to adversely affect the safety or effectiveness of the drug. (d) OTHER MANUFACTURING CHANGES — (1) IN GENERAL — For purposes of subsection (a)(2)(B), the Secretary may regulate drugs made with manufacturing changes that are not major manufacturing changes as follows: (A) The Secretary may in accordance with paragraph (2) authorize holders to distribute such drugs without submitting a supplemental application for such changes. (B) The Secretary may in accordance with paragraph (3) require that, prior to the distribution of such drugs, holders submit to the Secretary supplemental applications for such changes. (C) The Secretary may establish categories of such changes and designate categories to which subparagraph (A) applies and categories to which subparagraph (B) applies. (2) CHANGES NOT REQUIRING SUPPLEMENTAL APPLICATION — (A) SUBMISSION OF REPORT — A holder making a manufacturing change to which paragraph (1)(A) applies shall submit to the Secretary a report on the change, which shall contain such information as the Secretary determines to be appropriate, and which shall include the information developed under subsection (b) by the holder in validating the effects of the change. The report shall be submitted by such date as the Secretary may specify. (B) AUTHORITY REGARDING ANNUAL REPORTS — In the case of a holder that during a single year makes more than one manufacturing change to which paragraph (1)(A) applies, the Secretary may in carrying out subparagraph (A) authorize the holder to comply with such subparagraph by submitting a single report for the year that provides the information required in such subparagraph for all the changes made by the holder during the year. (3) CHANGES REQUIRING SUPPLEMENTAL APPLICATION — (A) SUBMISSION OF SUPPLEMENTAL APPLICATION — The supplemental application required under paragraph (1)(B) for a manufacturing change shall contain such information as the Secretary determines to be appropriate, which shall include the information developed under subsection (b) by the holder in validating the effects of the change. (B) AUTHORITY FOR DISTRIBUTION — In the case of a manufacturing change to which paragraph (1)(B) applies: (i) The holder involved may commence distribution of the drug involved 30 days after the Secretary receives the supplemental application under such paragraph, unless the Secretary notiﬁes the holder within such 30-day period that prior approval of the application is required before distribution may be commenced. (ii) The Secretary may designate a category of such changes for the purpose of providing that, in the case of a change that is in such category, the holder involved may commence distribution of the drug involved upon the receipt by the Secretary of a supplemental application for the change. (iii) If the Secretary disapproves the supplemental application, the Secretary may order the manufacturer to cease the distribution of the drugs that have been made with the manufacturing change.

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Section 506B. [356b] REPORTS OF POSTMARKETING STUDIES — (a) SUBMISSION — (1) IN GENERAL — A sponsor of a drug that has entered into an agreement with the Secretary to conduct a postmarketing study of a drug shall, submit to the Secretary, within 1 year after the approval of such drug and annually thereafter until the study is completed or terminated, a report of the progress of the study or the reasons for the failure of the sponsor to conduct the study. The report shall be submitted in such form as is prescribed by the Secretary in regulations issued by the Secretary. (2) AGREEMENTS PRIOR TO EFFECTIVE DATE — Any agreement entered into between the Secretary and a sponsor of a drug, prior to the date of enactment of the Food and Drug Administration Modernization Act of 1997, to conduct postmarketing study of a drug shall be subject to the requirements of paragraph (1). An initial report for such an agreement shall be submitted within 6 months after the date of the issuance of the regulations under paragraph (1). (b) CONSIDERATION OF INFORMATION AS PUBLIC INFORMATION — Any information pertaining to a report described in subsection (a) shall be considered to be public information to the extent that the information is necessary – (1) to identify the sponsor; and (2) to establish the status of a study described in subsection (a) and the reasons, if any, for any failure to carry out the study. (c) STATUS OF STUDIES AND REPORTS — The Secretary shall annually develop and publish in the Federal Register a report that provides information on the status of the postmarketing studies – (1) that sponsors have entered into agreements to conduct; and (2) for which reports have been submitted under subsection (a)(l). Section 506C. [356c] DISCONTINUANCE OF A LIFE SAVING PRODUCT — (a) IN GENERAL — A manufacturer that is the sole manufacturer of a drug – (1) that is – (A) life-supporting; (B) life-sustaining; or (C) intended for use in the prevention of a debilitating disease or condition; (2) for which an application has been approved under section 505(b) or 505(j); and (3) that is not a product that was originally derived from human tissue and was replaced by a recombinant product, shall notify the Secretary of a discontinuance of the manufacture of the drug at least 6 months prior to the date of the discontinuance. (b) REDUCTION IN NOTIFICATION PERIOD — The notiﬁcation period required under subsection (a) for a manufacturer may be reduced if the manufacturer certiﬁes to the Secretary that good cause exists for the reduction, such as a situation in which — (1) a public health problem may result from continuation of the manufacturing for the 6-month period; (2) a biomaterials shortage prevents the continuation of the manufacturing for the 6-month period; (3) a liability problem may exist for the manufacturer if the manufacturing is continued for the 6-month period;

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(4) continuation of the manufacturing for the 6-month period may cause substantial economic hardship for the manufacturer; (5) the manufacturer has ﬁled for bankruptcy under chapter 7 or 11 of title 11, United States Code; or (6) the manufacturer can continue the distribution of the drug involved for 6 months. (c) DISTRIBUTION — To the maximum extent practicable, the Secretary shall distribute information on the discontinuation of the drugs described in subsection (a) to appropriate physician and patient organizations. [Section 507. [357] Repealed by Public Law 105–115, November 21, 1997.]

AUTHORITY TO DESIGNATE OFFICIAL NAMES Section 508. [358] (a) The Secretary may designate an ofﬁcial name for any drug or device if he determines that such action is necessary or desirable in the interest of usefulness and simplicity. Any ofﬁcial name designated under this section for any drug or device shall be the only ofﬁcial name of that drug or device used in any ofﬁcial compendium published after such name has been prescribed or for any other purpose of this Act. In no event, however, shall the Secretary establish an ofﬁcial name so as to infringe a valid trademark. (b) Within a reasonable time after the effective date of this section, and at such other times as he may deem necessary, the Secretary shall cause a review to be made of the ofﬁcial names by which drugs are identiﬁed in the ofﬁcial United States Pharmacopoeia, the ofﬁcial Homoeopathic Pharmacopoeia of the United States, and the ofﬁcial National Formulary, and all supplements thereto, and at such times as he may deem necessary shall cause a review to be made of the ofﬁcial names by which devices are identiﬁed in any ofﬁcial compendium (and all supplements thereto) to determine whether revision of any of those names is necessary or desirable in the interest of usefulness and simplicity. (c) Whenever he determines after any such review that (1) any such ofﬁcial name is unduly complex or is not useful for any other reason, (2) two or more ofﬁcial names have been applied to a single drug or device, or to two or more drugs which are identical in chemical structure and pharmacological action and which are substantially identical in strength, quality, and purity, or to two or more devices which are substantially equivalent in design and purpose or (3) no ofﬁcial name has been applied to a medically useful drug or device, he shall transmit in writing to the compiler of each ofﬁcial compendium in which that drug or drugs or device are identiﬁed and recognized his request for the recommendation of a single ofﬁcial name for such drug or drugs or device which will have usefulness and simplicity. Whenever such a single ofﬁcial name has not been recommended within one hundred and eighty days after such request, or the Secretary determines that any name so recommended is not useful for any reason, he shall designate a single ofﬁcial name for such drug or drugs or device. Whenever he determines that the name so recommended is useful, he shall designate that name as the ofﬁcial name of such drug or drugs or device. Such designation shall be made as a regulation upon public notice and in accordance with the procedure set forth in section 553 of title 5, United States Code. (d) After each such review, and at such other times as the Secretary may determine to be necessary or desirable, the Secretary shall cause to be compiled, published, and publicly distributed a list which shall list all revised ofﬁcial names of drugs or devices designated under this section and shall contain such descriptive and explanatory matter as the Secretary may determine to be required for the effective use of those names. (e) Upon a request in writing by any compiler of an ofﬁcial compendium that the Secretary exercise the authority granted to him under subsection 508(a), he shall upon public notice and in accordance

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with the procedure set forth in section 553 of title 5, United States Code designate the ofﬁcial name of the drug or device for which the request is made.

NONAPPLICABILITY

TO

COSMETICS

Section 509. [359] This chapter, as amended by the Drug Amendments of 1962, shall not apply to any cosmetic unless such cosmetic is also a drug or device or component thereof.

REGISTRATION

OF

PRODUCERS

OF

DRUGS

AND

DEVICES

Section 510. [360] (a) As used in this section – (1) the term “manufacture, preparation, propagation, compounding, or processing” shall include repackaging or otherwise changing the container, wrapper, or labeling of any drug package or device package in furtherance of the distribution of the drug or device from the original place of manufacture to the person who makes ﬁnal delivery or sale to the ultimate consumer or user; and (2) the term “name” shall include in the case of a partnership the name of each partner and, in the case of a corporation, the name of each corporate ofﬁcer and director, and the State of incorporation (b) On or before December 31 of each year every person who owns or operates any establishment in any State engaged in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs or a device or devices shall register with the Secretary his name, places of business, and all such establishments. (c) Every person upon ﬁrst engaging in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs or a device or devices in any establishment which he owns or operates in any State shall immediately register with the Secretary his name, place of business, and such establishment (d) Every person duly registered in accordance with the foregoing subsections of this section shall immediately register with the Secretary any additional establishment which he owns or operates in any State and in which he begins the manufacture, preparation, propagation, compounding, or processing of a drug or drugs or a device or devices. (e) The Secretary may assign a registration number to any person or any establishment registered in accordance with this section. The Secretary may also assign a listing number to each drug or class of drugs listed under subsection (j). Any number assigned pursuant to the preceding sentence shall be the same as that assigned pursuant to the National Drug Code. The Secretary may by regulation prescribe a uniform system for the identiﬁcation of devices intended for human use and may require that persons who are required to list such devices pursuant to subsection (j) shall list such devices in accordance with such system. (f) The Secretary shall make available for inspection, to any person so requesting, any registration ﬁled pursuant to this section; except that any list submitted pursuant to paragraph (3) of subsection (j) and the information accompanying any list or notice ﬁled under paragraph (1) or (2) of that subsection shall be exempt from such inspection unless the Secretary ﬁnds that such an exemption would be inconsistent with protection of the public health. (g) The foregoing subsections of this section shall not apply to – (1) pharmacies which maintain establishments in conformance with any applicable local laws regulating the practice of pharmacy and medicine and which are regularly engaged in dispensing prescription drugs or devices, upon prescriptions of practitioners licensed to administer such drugs or devices to patients under the care of such practitioners in the course of their professional

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practice, and which do not manufacture, prepare, propagate, compound, or process drugs or devices for sale other than in the regular course of their business of dispensing or selling drugs or devices at retail; (2) practitioners licensed by law to prescribe or administer drugs or devices and who manufacture, prepare, propagate, compound, or process drugs or devices solely for use in the course of their professional practice; (3) persons who manufacture, prepare, propagate, compound, or process drugs or devices solely for use in research, teaching, or chemical analysis and not for sale; (4) any distributor who acts as a wholesale distributor of devices, and who does not manufacture, repackage, process, or relabel a device; or (5) such other classes of persons as the Secretary may by regulation exempt from the application of this section upon a ﬁnding that registration by such classes of persons in accordance with this section is not necessary for the protection of the public health. In this subsection, the term “wholesale distributor” means any person (other than the manufacturer or the initial importer) who distributes a device from the original place of manufacture to the person who makes the ﬁnal delivery or sale of the device to the ultimate consumer or user. (h) Every establishment in any State registered with the Secretary pursuant to this section shall be subject to inspection pursuant to section 704 and every such establishment engaged in the manufacture, propagation, compounding, or processing of a drug or drugs or of a device or devices classiﬁed in class II or III shall be so inspected by one or more ofﬁcers or employees duly designated by the Secretary at least once in the two-year period beginning with the date of registration of such establishment pursuant to this section and at least once in every successive two-year period thereafter. (i)(l) Any establishment within any foreign country engaged in the manufacture, preparation, propagation, compounding, or processing of a drug or a device that is imported or offered for import into the United States shall register with the Secretary the name and place of business of the establishment and the name of the United States agent for the establishment. (2) The establishment shall also provide the information required by subsection (j). (3) The Secretary is authorized to enter into cooperative arrangements with ofﬁcials of foreign countries to ensure that adequate and effective means are available for purposes of determining, from time to time, whether drugs or devices manufactured, prepared, propagated, compounded, or processed by an establishment described in paragraph (1), if imported or offered for import into the United States, shall be refused admission on any of the grounds set forth in section 801(a). (j)(1) Every person who registers with the Secretary under subsection (b), (c), or (d) shall, at the time of registration under any such subsection, ﬁle with the Secretary a list of all drugs and a list of all devices and a brief statement of the basis for believing that each device included in the list is a device rather than a drug (with each drug and device in each list listed by its established name (as deﬁned in section 502(e)) and by any proprietary name) which are being manufactured, prepared, propagated, compounded, or processed by him for commercial distribution and which he has not included in any list of drugs or devices ﬁled by him with the Secretary under this paragraph or paragraph (2) before such time of registration. Such list shall be prepared in such form and manner as the Secretary may prescribe and shall be accompanied by – (A) in the case of a drug contained in the applicable list and subject to section 505 or 512, or a device intended for human use contained in the applicable list with respect to which a performance standard has been established under section 514 or which is subject to section 515, a reference to the authority for the marketing of such drug or device and a copy of all labeling for such drug or device;

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(B) in the case of any other drug or device contained in an applicable list – (i) which drug is subject to section 503(b)(1), or which device is a restricted device, a copy of all labeling for such drug or device, a representative sampling of advertisements for such drug or device, and, upon request made by the Secretary for good cause, a copy of all advertisements for a particular drug product or device, or (ii) which drug is not subject to section 503(b)(1) or which device is not a restricted device, the label and package insert for such drug or device and a representative sampling of any other labeling for such drug or device; (C) in the case of any drug contained in an applicable list which is described in subparagraph (B), a quantitative listing of its active ingredient or ingredients, except that with respect to a particular drug product the Secretary may require the submission of a quantitative listing of all ingredients if he ﬁnds that such submission is necessary to carry out the purposes of this Act; and (D) if the registrant ﬁling a list has determined that a particular drug product or device contained in such list is not subject to section 505 or 512, or the particular device contained in such list is not subject to a performance standard established under section 514 or to section 515 or is not a restricted device a brief statement of the basis upon which the registrant made such determination if the Secretary requests such a statement with respect to that particular drug product or device. (2) Each person who registers with the Secretary under this section shall report to the Secretary once during the month of June of each year and once during the month of December of each year the following information: (A) A list of each drug or device introduced by the registrant for commercial distribution which has not been included in any list previously ﬁled by him with the Secretary under this subparagraph or paragraph (1) of this subsection. A list under this subparagraph shall list a drug or device by its established name (as deﬁned in section 502(e)), and by any proprietary name it may have and shall be accompanied by the other information required by paragraph (1). (B) If since the date the registrant last made a report under this paragraph (or if he has not made a report under this paragraph, since the effective date of this subsection) he has discontinued the manufacture, preparation, propagation, compounding, or processing for commercial distribution of a drug or device included in a list ﬁled by him under subparagraph (A) or paragraph (1); notice of such discontinuance, the date of such discontinuance, and the identity (by established name (as deﬁned in section 502(e)) and by any proprietary name) of such drug or device. (C) If since the date the registrant reported pursuant to subparagraph (B) a notice of discontinuance he has resumed the manufacture, preparation, propagation, compounding, or processing for commercial distribution of the drug or device with respect to which such notice of discontinuance was reported; notice of such resumption, the date of such resumption, the identity of such drug or device (each by established name (as deﬁned in section 502(e)) and by any proprietary name), and the other information required by paragraph (1), unless the registrant has previously reported such resumption to the Secretary pursuant to this subparagraph. (D) Any material change in any information previously submitted pursuant to this paragraph or paragraph (1). (3) The Secretary may also require each registrant under this section to submit a list of each drug product which (A) the registrant is manufacturing, preparing, propagating, compounding, or processing for commercial distribution, and (B) contains a particular ingredient. The Secretary may

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not require the submission of such a list unless he has made a ﬁnding that the submission of such a list is necessary to carry out the purposes of this Act. (k) Each person who is required to register under this section and who proposes to begin the introduction or delivery for introduction into interstate commerce for commercial distribution of a device intended for human use shall, at least ninety days before making such introduction or delivery, report to the Secretary (in such form and manner as the Secretary shall by regulation prescribe) – (1) the class in which the device is classiﬁed under section 513 or if such person determines that the device is not classiﬁed under such section, a statement of that determination and the basis for such person’s determination that the device is or is not so classiﬁed, and (2) action taken by such person to comply with requirements under section 514 or 515which are applicable to the device. (l) A report under subsection (k) is not required for a device intended for human use that is exempted from the requirements of this subsection under subsection (m) or is within a type that has been classiﬁed into class I under section 513. The exception established in the preceding sentence does not apply to any class I device that is intended for a use which is of substantial importance in preventing impairment of human health, or to any class I device that presents a potential unreasonable risk of illness or injury. (m)(1) Not later than 60 days after the date of enactment of the Food and Drug Administration Modernization Act of 1997, the Secretary shall publish in the Federal Register a list of each type of class II device that does not require a report under subsection (k) to provide reasonable assurance of safety and effectiveness. Each type of class II device identiﬁed by the Secretary as not requiring the report shall be exempt from the requirement to provide a report under subsection (k) as of the date of the publication of the list in the Federal Register. (2) Beginning on the date that is 1 day after the date of the publication of a list under this subsection, the Secretary may exempt a class II device from the requirement to submit a report subsection (k), upon the Secretary’s own initiative or a petition of an interested person, if the Secretary determines that such report is not necessary to assure the safety and effectiveness of the device. The Secretary shall publish in the Federal Register notice of the intent of the Secretary to exempt the device, or of the petition, and provide a 30-day period for public comment. Within 120 days after the issuance of the notice in the Federal Register, the Secretary shall publish an order in the Federal Register that sets forth the ﬁnal determination of the Secretary regarding the exemption of the device that was the subject of the notice. If the Secretary fails to respond to a petition within 180 days of receiving it, the petition shall be deemed to be granted. (n) The Secretary shall review the report required in subsection (k) and make a determination under section 513(f)(l) not later than 90 days after receiving the report. Section 511. ***

NEW ANIMAL DRUGS Section 512 [360] (Not included here, as our emphasis is on human drugs.)

CLASSIFICATION

OF

DEVICES INTENDED

FOR

HUMAN USE

Device Classes Section 513. [360c] (a)(1) There are established the following classes of devices intended for human use:

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(A) CLASS I, GENERAL CONTROLS — (i) A device for which the controls authorized by or under section 501, 502, 510, 516, 518, 519, or 520 or any combination of such sections are sufﬁcient to provide reasonable assurance of the safety and effectiveness of the device. (ii) A device for which insufﬁcient information exists to determine that the controls referred to in clause (i) are sufﬁcient to provide reasonable assurance of the safety and effectiveness of the device or to establish special controls to provide such assurance, but because it – (I) is not purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health, and (II) does not present a potential unreasonable risk of illness or injury, is to be regulated by the controls referred to in clause (i). (B) CLASS II, SPECIAL CONTROLS — A device which cannot be classiﬁed as a class I device because the general controls by themselves are insufﬁcient to provide reasonable assurance of the safety and effectiveness of the device, and for which there is sufﬁcient information to establish special controls to provide such assurance, including the promulgation of performance standards, postmarket surveillance, patient registries, development and dissemination of guidelines (including guidelines for the submission of clinical data in premarket notiﬁcation submissions in accordance with section 510(k)), recommendations, and other appropriate actions as the Secretary deems necessary to provide such assurance. For a device that is purported or represented to be for a use in supporting or sustaining human life, the Secretary shall examine and identify the special controls, if any, that are necessary to provide adequate assurance of safety and effectiveness and describe how such controls provide such assurance. (C) CLASS III, PREMARKET APPROVAL — A device which because – (i) it (I) cannot be classiﬁed as a class I device because insufﬁcient information exists to determine that the application of general controls are sufﬁcient to provide reasonable assurance of the safety and effectiveness of the device, and (II) cannot be classiﬁed as a class II device because insufﬁcient information exists to determine that the special controls described in subparagraph (B) would provide reasonable assurance of its safety and effectiveness, and (ii)(I) is purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health, or (II) presents a potential unreasonable risk of illness or injury, is to be subject, in accordance with section 515, to premarket approval to provide reasonable assurance of its safety and effectiveness. If there is not sufﬁcient information to establish a performance standard for a device to provide reasonable assurance of its safety and effectiveness, the Secretary may conduct such activities as may be necessary to develop or obtain such information. (2) For purposes of this section and sections 514 and 515, the safety and effectiveness of a device are to be determined – (A) with respect to the persons for whose use the device is represented or intended, (B) with respect to the conditions of use prescribed, recommended, or suggested in the labeling of the device, and

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(C) weighing any probable beneﬁt to health from the use of the device against any probable risk of injury or illness from such use. (3)(A) Except as authorized by subparagraph (B), the effectiveness of a device is, for purposes of this section and sections 514 and 515, to be determined, in accordance with regulations promulgated by the Secretary, on the basis of well-controlled investigations, including 1 or more clinical investigations where appropriate, by experts qualiﬁed by training and experience to evaluate the effectiveness of the device, from which investigations it can fairly and responsibly be concluded by qualiﬁed experts that the device will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling of the device. (B) If the Secretary determines that there exists valid scientiﬁc evidence (other than evidence derived from investigations described in subparagraph (A)) – (i) which is sufﬁcient to determine the effectiveness of a device, and (ii) from which it can fairly and responsibly be concluded by qualiﬁed experts that the device will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling of the device, then, for purposes of this section and sections 514 and 515, the Secretary may authorize the effectiveness of the device to be determined on the basis of such evidence. (C) In making a determination of a reasonable assurance of the effectiveness of a device for which an application under section 515 has been submitted, the Secretary shall consider whether the extent of data that otherwise would be required for approval of the application with respect to effectiveness can be reduced through reliance on postmarket controls. (D)(i) The Secretary, upon the written request of any person intending to submit an application under section 515, shall meet with such person to determine the type of valid scientiﬁc evidence (within the meaning of subparagraphs (A) and (B)) that will be necessary to demonstrate for purposes of approval of an application the effectiveness of a device for the conditions of use proposed by such person. The written request shall include a detailed description of the device, a detailed description of the proposed conditions of use of the device, a proposed plan for determining whether there is a reasonable assurance of effectiveness, and, if available, information regarding the expected performance from the device. Within 30 days after such meeting, the Secretary shall specify in writing the type of valid scientiﬁc evidence that will provide a reasonable assurance that a device is effective under the conditions of use proposed by such person. (ii) Any clinical data, including one or more well-controlled investigations, speciﬁed in writing by the Secretary for demonstrating a reasonable assurance of device effectiveness shall be speciﬁed as result of a determination by the Secretary that such data are necessary to establish device effectiveness. The Secretary shall consider, in consultation with the applicant, the least burdensome appropriate means of evaluating device effectiveness that would have a reasonable likelihood of resulting in approval. (iii) The determination of the Secretary with respect to the speciﬁcation of valid scientiﬁc evidence under clauses (i) and (ii) shall be binding upon the Secretary, unless such determination by the Secretary could be contrary to the public health. Classification; Classification Panels (b)(1) For purposes of — (A) determining which devices intended for human use should be subject to the requirements of general controls, performance standards, or premarket approval, and

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(B) providing notice to the manufacturers and importers of such devices to enable them to prepare for the application of such requirements to devices manufactured or imported by them, the Secretary shall classify all such devices (other than devices classiﬁed by subsection (f)) into the classes established by subsection (a). For the purpose of securing recommendations with respect to the classiﬁcation of devices, the Secretary shall establish panels of experts or use panels of experts established before the date of the enactment of this section, or both. Section 14 of the Federal Advisory Committee Act shall not apply to the duration of a panel established under this paragraph. (2) The Secretary shall appoint to each panel established under paragraph (1) persons who are qualiﬁed by training and experience to evaluate the safety and effectiveness of the devices to be referred to the panel and who, to the extent feasible, possess skill in the use of, or experience in the development, manufacture, or utilization of, such devices. The Secretary shall make appointments to each panel so that each panel shall consist of members with adequately diversiﬁed expertise in such ﬁelds as clinical and administrative medicine, engineering, biological and physical sciences, and other related professions. In addition, each panel shall include as nonvoting members a representative of consumer interests and a representative of interests of the device manufacturing industry. Scientiﬁc, trade, and consumer organizations shall be afforded an opportunity to nominate individuals for appointment to the panels. No individual who is in the regular full-time employ of the United States and engaged in the administration of this Act may be a member of any panel. The Secretary shall designate one of the members of each panel to serve as chairman thereof. (3) Panel members (other than ofﬁcers or employees of the United States), while attending meetings or conferences of a panel or otherwise engaged in its business, shall be entitled to receive compensation at rates to be ﬁxed by the Secretary, but not at rates exceeding the daily equivalent of the rate in effect for grade GS-18 of the General Schedule, for each day so engaged, including travel time; and while so serving away from their homes or regular places of business each member may be allowed travel expenses (including per diem in lieu of subsistence) as authorized by section 5703 of title 5, United States Code for persons in the Government service employed intermittently. (4) The Secretary shall furnish each panel with adequate clerical and other necessary assistance. (5) Classiﬁcation panels covering each type of device shall be scheduled to meet at such times as may be appropriate for the Secretary to meet applicable statutory deadlines. (6)(A) Any person whose device is speciﬁcally the subject of review by a classiﬁcation panel shall have — (i) the same access to data and information submitted to a classiﬁcation panel (except for data and information that are not available for public disclosure under section 552 of title 5, United States Code) as the Secretary; (ii) the opportunity to submit, for review by a classiﬁcation panel, information that is based on the data or information provided in the application submitted under section 515 by the person, which information shall be submitted to the Secretary for prompt transmittal to the classiﬁcation panel; and (iii) the same opportunity as the Secretary to participate in meetings of the panel. (B) Any meetings of a classiﬁcation panel shall provide adequate time for initial presentations and for response to any differing views by persons whose devices are speciﬁcally the subject of a classiﬁcation panel review, and shall encourage free and open participation by all interested persons.

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(7) After receiving from a classiﬁcation panel the conclusions and recommendations of the panel on a matter that the panel has reviewed, the Secretary shall review the conclusions and recommendations, shall make a ﬁnal decision on the matter in accordance with section 515(d)(2), and shall notify the affected persons of the decision in writing and, if the decision differs from the conclusions and recommendations of the panel, shall include the reasons for the difference. (8) A classiﬁcation panel under this subsection shall not be subject to the annual chartering and annual report requirements of the Federal Advisory Committee Act. Classification Panel Organization and Operation (c)(1) The Secretary shall organize the panels according to the various ﬁelds of clinical medicine and fundamental sciences in which devices intended for human use are used. The Secretary shall refer a device to be classiﬁed under this section to an appropriate panel established or authorized to be used under subsection (b) for its review and for its recommendation respecting the classiﬁcation of the device. The Secretary shall by regulation prescribe the procedure to be followed by the panels in making their reviews and recommendations. In making their reviews of devices, the panels, to the maximum extent practicable, shall provide an opportunity for interested persons to submit data and views on the classiﬁcation of the devices. (2)(A) Upon completion of a panel’s review of a device referred to it under paragraph (1), the panel shall, subject to subparagraphs (B) and (C), submit to the Secretary its recommendation for the classiﬁcation of the device. Any such recommendation shall (i) contain (I) a summary of the reasons for the recommendation, (II) a summary of the data upon which the recommendation is based, and (III) an identiﬁcation of the risks to health (if any) presented by the device with respect to which the recommendation is made, and (ii) to the extent practicable, include a recommendation for the assignment of a priority for the application of the requirements of section 514 or 515 to a device recommended to be classiﬁed in class II or class III. (B) A recommendation of a panel for the classiﬁcation of a device in class I shall include a recommendation as to whether the device should be exempted from the requirements of section 510, 519, or 520(f). (C) In the case of a device which has been referred under paragraph (1) to a panel, and which – (i) is intended to be implanted in the human body or is purported or represented to be for a use in supporting or sustaining human life, and (ii)(I) has been introduced or delivered for introduction into interstate commerce for commercial distribution before the date of enactment of this section, or (II) is within a type of device which was so introduced or delivered before such date and is substantially equivalent to another device within that type, such panel shall recommend to the Secretary that the device be classiﬁed in class III unless the panel determines that classiﬁcation of the device in such class is not necessary to provide reasonable assurance of its safety and effectiveness. If a panel does not recommend that such a device be classiﬁed in class III, it shall in its recommendation to the Secretary for the classiﬁcation of the device set forth the reasons for not recommending classiﬁcation of the device in such class. (3) The panels shall submit to the Secretary within one year of the date funds are ﬁrst appropriated for the implementation of this section their recommendations respecting all devices of a type introduced or delivered for introduction into interstate commerce for commercial distribution before the date of enactment of this section.

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Classification (d)(1) Upon receipt of a recommendation from a panel respecting a device, the Secretary shall publish in the Federal Register the panel’s recommendation and a proposed regulation classifying such device and shall provide interested persons an opportunity to submit comments on such recommendation and the proposed regulation. After reviewing such comments, the Secretary shall, subject to paragraph (2), by regulation classify such device. (2)(A) A regulation under paragraph (1) classifying a device in class I shall prescribe which, if any, of the requirements of section 510, 519, or 520(f) shall not apply to the device. A regulation which makes a requirement of section 510, 519, or 520(f) inapplicable to a device shall be accompanied by a statement of the reasons of the Secretary for making such requirement inapplicable. (B) A device described in subsection (c)(2)(C) shall be classiﬁed in class III unless the Secretary determines that classiﬁcation of the device in such class is not necessary to provide reasonable assurance of its safety and effectiveness. A proposed regulation under paragraph (1) classifying such a device in a class other than class III shall be accompanied by a full statement of the reasons of the Secretary (and supporting documentation and data) for not classifying such device in such class and an identiﬁcation of the risks to health (if any) presented by such device. (3) In the case of devices classiﬁed in class II and devices classiﬁed under this subsection in class III and described in section 515(b)(1) the Secretary may establish priorities which, in his discretion, shall be used in applying sections 514 and 515, as appropriate, to such devices. Classification Changes (e)(1) Based on new information respecting a device, the Secretary may, upon his own initiative or upon petition of an interested person, by regulation (A) change such device’s classiﬁcation, and (B) revoke, because of the change in classiﬁcation, any regulation or requirement in effect under section 514 or 515 with respect to such device. In the promulgation of such a regulation respecting a device’s classiﬁcation, the Secretary may secure from the panel to which the device was last referred pursuant to subsection (c) a recommendation respecting the proposed change in the device’s classiﬁcation and shall publish in the Federal Register any recommendation submitted to the Secretary by the panel respecting such change. A regulation under this subsection changing the classiﬁcation of a device from class III to class II may provide that such classiﬁcation shall not take effect until the effective date of a performance standard established under section 514 for such device. (2) By regulation promulgated under paragraph (1), the Secretary may change the classiﬁcation of a device from class III – (A) to class II if the Secretary determines that special controls would provide reasonable assurance of the safety and effectiveness of the device and that general controls would not provide reasonable assurance of the safety and effectiveness of the device, or (B) to class I if the Secretary determines that general controls would provide reasonable assurance of the safety and effectiveness of the device. Initial Classification and Reclassification of Certain Devices (f)(1) Any device intended for human use which was not introduced or delivered for introduction into interstate commerce for commercial distribution before the date of enactment of this section, is classiﬁed in class III unless – (A) the device –

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(i) is within a type of device (I) which was introduced or delivered for introduction into interstate commerce for commercial distribution before such date and which is to be classiﬁed pursuant to subsection (b), or (II) which was not so introduced or delivered before such date and has been classiﬁed in class I or II, and (ii) is substantially equivalent to another device within such type, or (B) the Secretary in response to a petition submitted under paragraph (2) has classiﬁed such device in class I or II. A device classiﬁed in class III under this paragraph shall be classiﬁed in that class until the effective date of an order of the Secretary under paragraph (2) or (3) classifying the device in class I or II. (2)(A) Any person who submits a report under section 510(k) for a type of device that has not been previously classiﬁed under this Act, and that is classiﬁed into class III under paragraph (1), may request, within 30 days after receiving written notice of such a classiﬁcation, the Secretary to classify the device under the criteria set forth in subparagraphs (A) through (C) of subsection (a)(l). The person may, in the request, recommend to the Secretary a classiﬁcation for the device. Any such request shall describe the device and provide detailed information and reasons for the recommended classiﬁcation. (B)(i) Not later than 60 days after the date of the submission of the request under subparagraph (A), the Secretary shall by written order classify the device involved. Such classiﬁcation shall be the initial classiﬁcation of the device for purposes of paragraph (1) and any device classiﬁed under this paragraph shall be a predicate device for determining substantial equivalence under paragraph (1). (ii) A device that remains in class III under this subparagraph shall be deemed to be adulterated within the meaning of section 501(f)(l)(B) until approved under section 515 or exempted from such approval under section 520(g). (C) Within 30 days after the issuance of an order classifying a device under this paragraph, the Secretary shall publish a notice in the Federal Register announcing such classiﬁcation. (3)(A) The Secretary may initiate the reclassiﬁcation of a device classiﬁed into class III under paragraph (1) of this subsection or the manufacturer or importer of a device classiﬁed under paragraph (1) may petition the Secretary (in such form and manner as he shall prescribe) for the issuance of an order classifying the device in class I or class II. Within thirty days of the ﬁling of such a petition, the Secretary shall notify the petitioner of any deﬁciencies in the petition which prevent the Secretary from making a decision on the petition. (B)(i) Upon determining that a petition does not contain any deﬁciency which prevents the Secretary from making a decision on the petition, the Secretary may for good cause shown refer the petition to an appropriate panel established or authorized to be used under subsection (b). A panel to which such a petition has been referred shall not later than ninety days after the referral of the petition make a recommendation to the Secretary respecting approval or denial of the petition. Any such recommendation shall contain (I) a summary of the reasons for the recommendation, (II) a summary of the data upon which the recommendation is based, and (III) an identiﬁcation of the risks to health (if any) presented by the device with respect to which the petition was ﬁled. In the case of a petition for a device which is intended to be implanted in the human body or which is purported or represented to be for a use in supporting or sustaining human life, the panel shall recommend that the petition be denied unless the panel determines that the classiﬁcation in class III of the device is not necessary to provide reasonable assurance of its safety and effectiveness. If the panel recommends that such petition be approved, it shall in its recommendation to the Secretary set forth its reasons for such recommendation.

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(ii) The requirements of paragraphs (1) and (2) of subsection (c) (relating to opportunities for submission of data and views and recommendations respecting priorities and exemptions from sections 510, 519, and 520(f)) shall apply with respect to consideration by panels of petitions submitted under subparagraph (A). (C)(i) Within ninety days from the date the Secretary receives the recommendation of a panel respecting a petition (but not later than 210 days after the ﬁling of such petition) the Secretary shall by order deny or approve the petition. If the Secretary approves the petition, the Secretary shall order the classiﬁcation of the device into class I or class II in accordance with the criteria prescribed by subsection (a)(1)(A) or (a)(1)(B). In the case of a petition for a device which is intended to be implanted in the human body or which is purported or represented to be for a use in supporting or sustaining human life, the Secretary shall deny the petition unless the Secretary determines that the classiﬁcation in class III of the device is not necessary to provide reasonable assurance of its safety and effectiveness. An order approving such petition shall be accompanied by a full statement of the reasons of the Secretary (and supporting documentation and data) for approving the petition and an identiﬁcation of the risks to health (if any) presented by the device to which such order applies. (ii) The requirements of paragraphs (1) and (2)(A) of subsection (d) (relating to publication of recommendations, opportunity for submission of comments, and exemption from sections 510, 519, and 520(f)) shall apply with respect to action by the Secretary on petitions submitted under subparagraph (A). (4) If a manufacturer reports to the Secretary under section 510(k) that a device is substantially equivalent to another device — (A) which the Secretary has classiﬁed as a class III device under subsection (b), (B) which was introduced or delivered for introduction into interstate commerce for commercial distribution before December 1, 1990, and (C) for which no ﬁnal regulation requiring premarket approval has been promulgated under section 515(b), the manufacturer shall certify to the Secretary that the manufacturer has conducted a reasonable search of all information known or otherwise available to the manufacturer respecting such other device and has included in the report under section 510(k) a summary of and a citation to all adverse safety and effectiveness data respecting such other device and respecting the device for which the section 510(k) report is being made and which has not been submitted to the Secretary under section 519. The Secretary may require the manufacturer to submit the adverse safety and effectiveness data described in the report. (5) The Secretary may not withhold a determination of the initial classiﬁcation of a device under paragraph (1) because of a failure to comply with any provision of this Act unrelated to a substantial equivalence decision, including a ﬁnding that the facility in which the device is manufactured is not in compliance with good manufacturing requirements as set forth in regulations of the Secretary under section 520(f) (other than a ﬁnding that there is a substantial likelihood that the failure to comply with such regulations will potentially present a serious risk to human health). Information (g) Within sixty days of the receipt of a written request of any person for information respecting the class in which a device has been classiﬁed or the requirements applicable to a device under this chapter, the Secretary shall provide such person a written statement of the classiﬁcation (if any) of such device and the requirements of this chapter applicable to the device.

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Definitions (h) For purposes of this section and sections 501, 510, 514, 515, 516, 519 and 520 – (1) a reference to “general controls” is a reference to the controls authorized by or under sections 501, 502, 510, 516, 518, 519, and 520, (2) a reference to “class I,” “class II,” or “class III” is a reference to a class of medical devices described in subparagraph (A), (B), or (C) of subsection (a)(1), and (3) a reference to a “panel” under section 513 is a reference to a panel established or authorized to be used under this section. (i)(1)(A) For purposes of determinations of substantial equivalence under subsection (f) and section 520(l), the term “substantially equivalent” or “substantial equivalence” means, with respect to a device being compared to a predicate device, that the device has the same intended use as the predicate device and that the Secretary by order has found that the device – (i) has the same technological characteristics as the predicate device, or (ii)(I) has different technological characteristics and the information submitted that the device is substantially equivalent to the predicate device contains information, including appropriate clinical or scientiﬁc data if deemed necessary by the Secretary or a person accredited under section 523, that demonstrates that the device is as safe and effective as a legally marketed device, and (II) does not raise different questions of safety and effectiveness than the predicate device. (B) For purposes of subparagraph (A), the term “different technological characteristics” means, with respect to a device being compared to a predicate device, that there is a signiﬁcant change in the materials, design, energy source, or other features of the device from those of the predicate device. (C) To facilitate reviews of reports submitted to the Secretary under section 510(k), the Secretary shall consider the extent to which reliance on postmarket controls may expedite the classiﬁcation of devices under subsection (f)(l) of this section. (D) Whenever the Secretary requests information to demonstrate that devices with differing technological characteristics are substantially equivalent, the Secretary shall only request information that is necessary to making substantial equivalence determinations. In making such request, the Secretary shall consider the least burdensome means of demonstrating substantial equivalence and request information accordingly. (E)(i) Any determination by the Secretary of the intended use of a device shall be based upon the proposed labeling submitted in a report for the device under section 510(k). However, when determining that a device can be found substantially equivalent to a legally marketed device, the director of the organizational unit responsible for regulating devices (in this subparagraph referred to as the “Director”) may require a statement in labeling that provides appropriate information regarding a use of the device not identiﬁed in the proposed labeling if, after providing an opportunity for consultation with the person who submitted such report, the Director determines and states in writing – (I) that there is a reasonable likelihood that the device will be used for an intended use not identiﬁed in the proposed labeling for the device; and (II) that such use could cause harm. (ii) Such determination shall – (I) be provided to the person who submitted the report within 10 days from the date of the notiﬁcation of the Director’s concerns regarding the proposed labeling;

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(II) specify the limitations on the use of the device not included in the proposed labeling; and (III) ﬁnd the device substantially equivalent if the requirements of subparagraph (A) are met and if the labeling for such device conforms to the limitations speciﬁed in subclause (II). (iii) The responsibilities of the Director under this subparagraph may not be delegated. (iv) This subparagraph has no legal effect after the expiration of the ﬁve-year period beginning on the date of the enactment of the Food and Drug Administration Modernization Act of 1997. (F) Not later than 270 days after the date of the enactment of the Food and Drug Administration Modernization Act of 1997, the Secretary shall issue guidance specifying the general principles that the Secretary will consider in determining when a speciﬁc intended use of a device is not reasonably included within a general use of such device for purposes of a determination of substantial equivalence under subsection (f) or section 520(l). (2) A device may not be found to be substantially equivalent to a predicate device that has been removed from the market at the initiative of the Secretary or that has been determined to be misbranded or adulterated by a judicial order. (3)(A) As part of a submission under section 510(k) respecting a device, the person required to ﬁle a premarket notiﬁcation under such section shall provide an adequate summary of any information respecting safety and effectiveness or state that such information will be made available upon request by any person. (B) Any summary under subparagraph (A) respecting a device shall contain detailed information regarding data concerning adverse health effects and shall be made available to the public by the Secretary within 30 days of the issuance of a determination that such device is substantially equivalent to another device.

PERFORMANCE STANDARDS Provision of Standards Section 514. [360d] (a)(1) The special controls required by section 513c(a)(1)(B) shall include performance standards for a class II device if the Secretary determines that a performance standard is necessary to provide reasonable assurance of the safety and effectiveness of the device. A class III device may also be considered a class II device for purposes of establishing a standard for the device under subsection (b) if the device has been reclassiﬁed as a class II device under a regulation under section 513(e) but such regulation provides that the reclassiﬁcation is not to take effect until the effective date of such a standard for the device. (2) A performance standard established under this section for a device – (A) shall include provisions to provide reasonable assurance of its safe and effective performance; (B) shall, where necessary to provide reasonable assurance of its safe and effective performance, include – (i) provisions respecting the construction, components, ingredients, and properties of the device and its compatibility with power systems and connections to such systems, (ii) provisions for the testing (on a sample basis or, if necessary, on an individual basis) of the device or, if it is determined that no other more practicable means are available to the Secretary to assure the conformity of the device to the standard, provisions for the testing (on a sample basis or, if necessary, on an individual basis) by the Secretary or by another person at the direction of the Secretary,

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(iii) provisions for the measurement of the performance characteristics of the device, (iv) provisions requiring that the results of each or of certain of the tests of the device required to be made under clause (ii) show that the device is in conformity with the portions of the standard for which the test or tests were required, and (v) a provision requiring that the sale and distribution of the device be restricted but only to the extent that the sale and distribution of a device may be restricted under a regulation under section 520(e); and (C) shall, where appropriate, require the use and prescribe the form and content of labeling for the proper installation, maintenance, operation, and use of the device. (3) The Secretary shall provide for periodic evaluation of performance standards established under subsection (b) to determine if such standards should be changed to reﬂect new medical, scientiﬁc, or other technological data. (4) In carrying out his duties under this section and subsection (b), the Secretary shall, to the maximum extent practicable – (A) use personnel, facilities, and other technical support available in other Federal agencies, (B) consult with other Federal agencies concerned with standard-setting and other nationally or internationally recognized standard-setting entities, and (C) invite appropriate participation, through joint or other conferences, workshops, or other means, by informed persons representative of scientiﬁc, professional, industry, or consumer organizations who in his judgment can make a signiﬁcant contribution. Establishment of a Standard (b)(1)(A) The Secretary shall publish in the Federal Register a notice of proposed rulemaking for the establishment, amendment, or revocation of any performance standard for a device. (B) A notice of proposed rulemaking for the establishment or amendment of a performance standard for a device shall – (i) set forth a ﬁnding with supporting justiﬁcation that the performance standard is appropriate and necessary to provide reasonable assurance of the safety and effectiveness of the device, (ii) set forth proposed ﬁndings with respect to the risk of illness or injury that the performance standard is intended to reduce or eliminate, (iii) invite interested persons to submit to the Secretary, within 30 days of the publication of the notice, requests for changes in the classiﬁcation of the device pursuant to section 513(e) based on new information relevant to the classiﬁcation, and (iv) invite interested persons to submit an existing performance standard for the device, including a draft or proposed performance standard, for consideration by the Secretary. (C) A notice of proposed rulemaking for the revocation of a performance standard shall set forth a ﬁnding with supporting justiﬁcation that the performance standard is no longer necessary to provide reasonable assurance of the safety and effectiveness of a device. (D) The Secretary shall provide for a comment period of not less than 60 days. (2) If, after publication of a notice in accordance with paragraph (1), the Secretary receives a request for a change in the classiﬁcation of the device, the Secretary shall, within 60 days of the publication of the notice, after consultation with the appropriate panel under section 513, either deny the request or give notice of an intent to initiate such change under section 513(e). (3)(A) After the expiration of the period for comment on a notice of proposed rulemaking published under paragraph (1) respecting a performance standard and after consideration of such

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comments and any report from an advisory committee under paragraph (5), the Secretary shall (i) promulgate a regulation establishing a performance standard and publish in the Federal Register ﬁndings on the matters referred to in paragraph (1), or (ii) publish a notice terminating the proceeding for the development of the standard together with the reasons for such termination. If a notice of termination is published, the Secretary shall (unless such notice is issued because the device is a banned device under section 516 of this title) initiate a proceeding under section 513(e) to reclassify the device subject to the proceeding terminated by such notice. (B) A regulation establishing a performance standard shall set forth the date or dates upon which the standard shall take effect, but no such regulation may take effect before one year after the date of its publication unless (i) the Secretary determines that an earlier effective date is necessary for the protection of the public health and safety, or (ii) such standard has been established for a device which, effective upon the effective date of the standard, has been reclassiﬁed from class III to class II. Such date or dates shall be established so as to minimize, consistent with the public health and safety, economic loss to, and disruption or dislocation of, domestic and international trade. (4)(A) The Secretary, upon his own initiative or upon petition of an interested person may by regulation, promulgated in accordance with the requirements of paragraphs (1), (2), and (3)(B) of this subsection, amend or revoke a performance standard. (B) The Secretary may declare a proposed amendment of a performance standard to be effective on and after its publication in the Federal Register and until the effective date of any ﬁnal action taken on such amendment if he determines that making it so effective is in the public interest. A proposed amendment of a performance standard made so effective under the preceding sentence may not prohibit, during the period in which it is so effective, the introduction or delivery for introduction into interstate commerce of a device which conforms to such standard without the change or changes provided by such proposed amendment. (5)(A) The Secretary – (i) may on his own initiative refer a proposed regulation for the establishment, amendment, or revocation of a performance standard, or (ii) shall, upon the request of an interested person which demonstrates good cause for referral and which is made before the expiration of the period for submission of comments on such proposed regulation refer such proposed regulation, to an advisory committee of experts, established pursuant to subparagraph (B), for a report and recommendation with respect to any matter involved in the proposed regulation which requires the exercise of scientiﬁc judgment. If a proposed regulation is referred under this subparagraph to an advisory committee, the Secretary shall provide the advisory committee with the data and information on which such proposed regulation is based. The advisory committee shall, within sixty days of the referral of a proposed regulation and after independent study of the data and information furnished to it by the Secretary and other data and information before it, submit to the Secretary a report and recommendation respecting such regulation, together with all underlying data and information and a statement of the reason or basis for the recommendation. A copy of such report and recommendation shall be made public by the Secretary. (B) The Secretary shall establish advisory committees (which may not be panels under section 513) to receive referrals under subparagraph (A). The Secretary shall appoint as members of any such advisory committee persons qualiﬁed in the subject matter to be referred to the committee and of appropriately diversiﬁed professional background, except that the Secretary may not appoint to such a committee any individual who is in the regular full-time

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employ of the United States and engaged in the administration of this Act. Each such committee shall include as nonvoting members a representative of consumer interests and a representative of interests of the device manufacturing industry. Members of an advisory committee who are not ofﬁcers or employees of the United States, while attending conferences or meetings of their committee or otherwise serving at the request of the Secretary, shall be entitled to receive compensation at rates to be ﬁxed by the Secretary, which rates may not exceed the daily equivalent of the rate in effect for grade GS-18 of the General Schedule, for each day (including travel time) they are so engaged; and while so serving away from their homes or regular places of business each member may be allowed travel expenses, including per diem in lieu of subsistence, as authorized by section 5703 of title 5 of the United States Code for persons in the Government service employed intermittently. The Secretary shall designate one of the members of each advisory committee to serve as chairman thereof. The Secretary shall furnish each advisory committee with clerical and other assistance, and shall by regulation prescribe the procedures to be followed by each such committee in acting on referrals made under subparagraph (A). Recognition of a Standard (c)(l)(A) In addition to establishing a performance standard under this section, the Secretary shall, by publication in the Federal Register, recognize all or part of an appropriate standard established by a nationally or internationally recognized standard development organization for which a person may submit a declaration of conformity in order to meet a premarket submission requirement or other requirement under this Act to which such standard is applicable. (B) If a person elects to use a standard recognized by the Secretary under subparagraph (A) to meet the requirements described in such subparagraph, the person shall provide a declaration of conformity to the Secretary that certiﬁes that the device is in conformity with such standard. A person may elect to use data, or information, other than data required by a standard recognized under subparagraph (A) to meet any requirement regarding devices under this Act. (2) The Secretary may withdraw such recognition of a standard through publication of a notice in the Federal Register if the Secretary determines that the standard is no longer appropriate for meeting a requirement regarding devices under this Act. (3)(A) Subject to subparagraph (B), the Secretary shall accept a declaration of conformity that a device is in conformity with a standard recognized under paragraph (1) unless the Secretary ﬁnds – (i) that the data or information submitted to support such declaration does not demonstrate that the device is in conformity with the standard identiﬁed in the declaration of conformity; or (ii) that the standard identiﬁed in the declaration of conformity is not applicable to the particular device under review. (B) The Secretary may request, at any time the data or information relied on by the person to make a declaration of conformity with respect to a standard recognized under paragraph (1). (C) A person making a declaration of conformity with respect to a standard recognized under paragraph (1) shall maintain the data and information demonstrating conformity of the device to the standard for a period of two years after the date of the classiﬁcation or approval of the device by the Secretary or a period equal to the expected design life of the device, whichever is longer.

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PREMARKET APPROVAL General Requirement Section 515. [360e] (a) A class III device – (1) which is subject to a regulation promulgated under subsection (b); or (2) which is a class III device because of section 513(f), is required to have, unless exempt under section 520(g), an approval under this section of an application for premarket approval. Regulation to Require Premarket Approval (b)(1) In the case of a class III device which – (A) was introduced or delivered for introduction into interstate commerce for commercial distribution before the date of enactment of this section; or (B) is (i) of a type so introduced or delivered, and (ii) is substantially equivalent to another device within that type, the Secretary shall by regulation, promulgated in accordance with this subsection, require that such device have an approval under this section of an application for premarket approval. (2)(A) A proceeding for the promulgation of a regulation under paragraph (1) respecting a device shall be initiated by the publication in the Federal Register of a notice of proposed rulemaking. Such notice shall contain — (i) the proposed regulation; (ii) proposed ﬁndings with respect to the degree of risk of illness or injury designed to be eliminated or reduced by requiring the device to have an approved application for premarket approval and the beneﬁt to the public from use of the device; (iii) opportunity for the submission of comments on the proposed regulation and the proposed ﬁndings; and (iv) opportunity to request a change in the classiﬁcation of the device based on new information relevant to the classiﬁcation of the device. (B) If, within ﬁfteen days after publication of a notice under subparagraph (A), the Secretary receives a request for a change in the classiﬁcation of a device, he shall, within sixty days of the publication of such notice and after consultation with the appropriate panel under section 513, by order published in the Federal Register, either deny the request for change in classiﬁcation or give notice of his intent to initiate such a change under section 513(e). (3) After the expiration of the period for comment on a proposed regulation and proposed ﬁndings published under paragraph (2) and after consideration of comments submitted on such proposed regulation and ﬁndings, the Secretary shall (A) promulgate such regulation and publish in the Federal Register ﬁndings on the matters referred to in paragraph (2)(A)(ii), or (B) publish a notice terminating the proceeding for the promulgation of the regulation together with the reasons for such termination. If a notice of termination is published, the Secretary shall (unless such notice is issued because the device is a banned device under section 516) initiate a proceeding under section 513(e) to reclassify the device subject to the proceeding terminated by such notice. (4) The Secretary, upon his own initiative or upon petition of an interested person, may by regulation amend or revoke any regulation promulgated under this subsection. A regulation to amend or revoke a regulation under this subsection shall be promulgated in accordance with the requirements prescribed by this subsection for the promulgation of the regulation to be amended or revoked.

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Application for Premarket Approval (c)(1) Any person may ﬁle with the Secretary an application for premarket approval for a class III device. Such an application for a device shall contain – (A) full reports of all information, published or known to or which should reasonably be known to the applicant, concerning investigations which have been made to show whether or not such device is safe and effective; (B) a full statement of the components, ingredients, and properties and of the principle or principles of operation, of such device; (C) a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and, when relevant, packing and installation of, such device; (D) an identifying reference to any performance standard under section 514 which would be applicable to any aspect of such device if it were a class II device, and either adequate information to show that such aspect of such device fully meets such performance standard or adequate information to justify any deviation from such standard; (E) such samples of such device and of components thereof as the Secretary may reasonably require, except that where the submission of such samples is impracticable or unduly burdensome, the requirement of this subparagraph may be met by the submission of complete information concerning the location of one or more such devices readily available for examination and testing; (F) specimens of the labeling proposed to be used for such device; and (G) such other information relevant to the subject matter of the application as the Secretary, with the concurrence of the appropriate panel under section 513, may require. (2) Upon receipt of an application meeting the requirements set forth in paragraph (1), the Secretary – (A) may on the Secretary’s own initiative, or (B) shall, upon the request of an applicant unless the Secretary ﬁnds that the information in the application which would be reviewed by a panel substantially duplicates information which has previously been reviewed by a panel appointed under section 513, refer such application to the appropriate panel under section 513 for study and for submission (within such period as he may establish) of a report and recommendation respecting approval of the application, together with all underlying data and the reasons or basis for the recommendation. Action on Application for Premarket Approval (d)(1)(A) As promptly as possible, but in no event later than one hundred and eighty days after the receipt of an application under subsection (c) (except as provided in section 520(l)(3)(D)(ii) or unless, in accordance with subparagraph (B)(i), an additional period as agreed upon by the Secretary and the applicant), the Secretary, after considering the report and recommendation submitted under paragraph (2) of such subsection, shall – (i) issue an order approving the application if he ﬁnds that none of the grounds for denying approval speciﬁed in paragraph (2) of this subsection applies; or (ii) deny approval of the application if he ﬁnds (and sets forth the basis for such ﬁnding as part of or accompanying such denial) that one or more grounds for denial speciﬁed in paragraph (2) of this subsection apply. In making the determination whether to approve or deny the application, the Secretary shall rely on the conditions of use included in the proposed labeling as the basis for determining

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whether or not there is a reasonable assurance of safety and effectiveness, if the proposed labeling is neither false nor misleading. In determining whether or not such labeling is false or misleading, the Secretary shall fairly evaluate all material facts pertinent to the proposed labeling. (B)(i) The Secretary may not enter into an agreement to extend the period in which to take action with respect to an application submitted for a device subject to a regulation promulgated under subsection (b) unless he ﬁnds that the continued availability of the device is necessary for the public health. (ii) An order approving an application for a device may require as a condition to such approval that the sale and distribution of the device be restricted but only to the extent that the sale and distribution of a device may be restricted under a regulation under section 520(e). (iii) The Secretary shall accept and review statistically valid and reliable data and any other information from investigations conducted under the authority of regulations required by section 520(g) to make a determination of whether there is a reasonable assurance of safety and effectiveness of a device subject to a pending application under this section if – (I) the data or information is derived from investigations of an earlier version of the device, the device has been modiﬁed during or after the investigations (but prior to submission of an application under subsection (c)) and such a modiﬁcation of the device does not constitute a signiﬁcant change in the design or in the basic principles of operation of the device that would invalidate the data or information; or (II) the data or information relates to a device approved under this section, is available for use under this Act, and is relevant to the design and intended use of the device for which the application is pending. (2) The Secretary shall deny approval of an application for a device if, upon the basis of the information submitted to the Secretary as part of the application and any other information before him with respect to such device, the Secretary ﬁnds that — (A) there is a lack of a showing of reasonable assurance that such device is safe under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof; (B) there is a lack of a showing of reasonable assurance that the device is effective under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof; (C) the methods used in, or the facilities or controls used for, the manufacture, processing, packing, or installation of such device do not conform to the requirements of section 520(f); (D) based on a fair evaluation of all material facts, the proposed labeling is false or misleading in any particular; or (E) such device is not shown to conform in all respects to a performance standard in effect under section 514 of this title compliance with which is a condition to approval of the application and there is a lack of adequate information to justify the deviation from such standard. Any denial of an application shall, insofar as the Secretary determines to be practicable, be accompanied by a statement informing the applicant of the measures required to place such application in approvable form (which measures may include further research by the applicant in accordance with one or more protocols prescribed by the Secretary). (3)(A)(i) The Secretary shall, upon the written request of an applicant, meet with the applicant, not later than 100 days after the receipt of an application that has been ﬁled as complete under subsection (c), to discuss the review status of the application. (ii) The Secretary shall, in writing and prior to the meeting, provide to the applicant a description of any deﬁciencies in the application that, at that point, have been identiﬁed by

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the Secretary based on an interim review of the entire application and identify the information that is required to correct those deﬁciencies. (iii) The Secretary shall notify the applicant promptly of – (I) any additional deﬁciency identiﬁed in the application, (II) any additional information required to achieve completion of the review and ﬁnal action on the application, that was not described as a deﬁciency in the written description provided by the Secretary under clause (ii). (B) The Secretary and the applicant may, by mutual consent, establish a different schedule for a meeting required under this paragraph. (4) An applicant whose application has been denied approval may, by petition ﬁled on or before the thirtieth day after the date upon which he receives notice of such denial, obtain review thereof in accordance with either paragraph (1) or (2) of subsection (g), and any interested person may obtain review, in accordance with paragraph (1) or (2) of subsection (g), of an order of the Secretary approving an application. (5) In order to provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human diseases or conditions, the Secretary shall provide review priority for devices – (A) representing breakthrough technologies, (B) for which no approved alternatives exist, (C) which offer signiﬁcant advantages over existing approved alternatives, or (D) the availability of which is in the best interest of the patients. (6)(A)(i) A supplemental application shall be required for any change to a device subject to an approved application under this subsection that affects safety or effectiveness, unless such change is a modiﬁcation in a manufacturing procedure or method of manufacturing and the holder of the approved application submits a written notice to the Secretary that describes in detail the change, summarizes the data or information supporting the change, and informs the Secretary that the change has been made under the requirements of section 520(f). (ii) The holder of an approved application who submits a notice under clause (i) with respect to a manufacturing change of a device may distribute the device 30 days after the date on which the Secretary receives the notice, unless the Secretary within such 30-day period notiﬁes the holder that the notice is not adequate and describes such further information or action that is required for acceptance of such change. If the Secretary notiﬁes the holder that a supplemental application is required, the Secretary shall review the supplement within 135 days after the receipt of the supplement. The time used by the Secretary to review the notice of the manufacturing change shall be deducted from the 135-day review period if the notice meets appropriate content requirements for premarket approval supplements. (B)(i) Subject to clause (ii), in reviewing a supplement to an approved application, for an incremental change to the design of a device that affects safety or effectiveness, the Secretary shall approve such supplement if – (I) nonclinical data demonstrate that the design modiﬁcation creates the intended additional capacity, function, or performance of the device; and (II) clinical data from the approved application and any supplement to the approved application provide a reasonable assurance of safety and effectiveness for the changed device. (ii) The Secretary may require, when necessary, additional clinical data to evaluate the design modiﬁcation of the device to provide a reasonable assurance of safety and effectiveness.

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Withdrawal and Temporary Suspension of Approval of Application (e)(1) The Secretary shall, upon obtaining, where appropriate, advice on scientiﬁc matters from a panel or panels under section 513, and after due notice and opportunity for informal hearing to the holder of an approved application for a device, issue an order withdrawing approval of the application if the Secretary ﬁnds — (A) that such device is unsafe or ineffective under the conditions of use prescribed, recommended, or suggested in the labeling thereof; (B) on the basis of new information before him with respect to such device, evaluated together with the evidence available to him when the application was approved, that there is a lack of a showing of reasonable assurance that the device is safe or effective under the conditions of use prescribed, recommended, or suggested in the labeling thereof; (C) that the application contained or was accompanied by an untrue statement of a material fact; (D) that the applicant (i) has failed to establish a system for maintaining records, or has repeatedly or deliberately failed to maintain records or to make reports, required by an applicable regulation under section 519(a), (ii) has refused to permit access to, or copying or veriﬁcation of, such records as required by section 704, or (iii) has not complied with the requirements of section 510; (E) on the basis of new information before him with respect to such device, evaluated together with the evidence before him when the application was approved, that the methods used in, or the facilities and controls used for, the manufacture, processing, packing, or installation of such device do not conform with the requirements of section 520(f) and were not brought into conformity with such requirements within a reasonable time after receipt of written notice from the Secretary of nonconformity; (F) on the basis of new information before him, evaluated together with the evidence before him when the application was approved, that the labeling of such device, based on a fair evaluation of all material facts, is false or misleading in any particular and was not corrected within a reasonable time after receipt of written notice from the Secretary of such fact; or (G) on the basis of new information before him, evaluated together with the evidence before him when the application was approved, that such device is not shown to conform in all respects to a performance standard which is in effect under section 514 compliance with which was a condition to approval of the application and that there is a lack of adequate information to justify the deviation from such standard. (2) The holder of an application subject to an order issued under paragraph (1) withdrawing approval of the application may, by petition ﬁled on or before the thirtieth day after the date upon which he receives notice of such withdrawal, obtain review thereof in accordance with either paragraph (1) or (2) of subsection (g). (3) If, after providing an opportunity for an informal hearing, the Secretary determines there is reasonable probability that the continuation of distribution of a device under an approved application would cause serious, adverse health consequences or death, the Secretary shall by order temporarily suspend the approval of the application approved under this section. If the Secretary issues such an order, the Secretary shall proceed expeditiously under paragraph (1) to withdraw such application. Product Development Protocol (f)(1) In the case of a class III device which is required to have an approval of an application submitted under subsection (c) of this section, such device shall be considered as having such an

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approval if a notice of completion of testing conducted in accordance with a product development protocol approved under paragraph (4) has been declared completed under paragraph (6). (2) Any person may submit to the Secretary a proposed product development protocol with respect to a device. Such a protocol shall be accompanied by data supporting it. If, within thirty days of the receipt of such a protocol, the Secretary determines that it appears to be appropriate to apply the requirements of this subsection to the device with respect to which the protocol is submitted, the Secretary – (A) may, at the initiative of the Secretary, refer the proposed protocol to the appropriate panel under section 513 for its recommendation respecting approval of the protocol; or (B) shall so refer such protocol upon the request of the submitter, unless the Secretary ﬁnds that the proposed protocol and accompanying data which would be reviewed by such panel substantially duplicate a product development protocol and accompanying data which have previously been reviewed by such a panel. (3) A proposed product development protocol for a device may be approved only if – (A) the Secretary determines that it is appropriate to apply the requirements of this subsection to the device in lieu of the requirement of approval of an application submitted under subsection (c); and (B) the Secretary determines that the proposed protocol provides – (i) a description of the device and the changes which may be made in the device, (ii) a description of the preclinical trials (if any) of the device and a speciﬁcation of (I) the results from such trials to be required before the commencement of clinical trials of the device, and (II) any permissible variations in preclinical trials and the results therefrom, (iii) a description of the clinical trials (if any) of the device and a speciﬁcation of (I) the results from such trials to be required before the ﬁling of a notice of completion of the requirements of the protocol, and (II) any permissible variations in such trials and the results therefrom, (iv) a description of the methods to be used in, and the facilities and controls to be used for, the manufacture, processing, and, when relevant, packing and installation of the device, (v) an identifying reference to any performance standard under section 514 to be applicable to any aspect of such device, (vi) if appropriate, specimens of the labeling proposed to be used for such device, (vii) such other information relevant to the subject matter of the protocol as the Secretary, with the concurrence of the appropriate panel or panels under section 513, may require, and (viii) a requirement for submission of progress reports and, when completed, records of the trials conducted under the protocol which records are adequate to show compliance with the protocol. (4) The Secretary shall approve or disapprove a proposed product development protocol submitted under paragraph (2) within one hundred and twenty days of its receipt unless an additional period is agreed upon by the Secretary and the person who submitted the protocol. Approval of a protocol or denial of approval of a protocol is ﬁnal agency action subject to judicial review under chapter 7 of title 5, United States Code. (5) At any time after a product development protocol for a device has been approved pursuant to paragraph (4), the person for whom the protocol was approved may submit a notice of completion –

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(A) stating (i) his determination that the requirements of the protocol have been fulﬁlled and that, to the best of his knowledge, there is no reason bearing on safety or effectiveness why the notice of completion should not become effective, and (ii) the data and other information upon which such determination was made, and (B) setting forth the results of the trials required by the protocol and all the information required by subsection (c)(1). (6)(A) The Secretary may, after providing the person who has an approved protocol and opportunity for an informal hearing and at any time prior to receipt of notice of completion of such protocol, issue a ﬁnal order to revoke such protocol if he ﬁnds that – (i) such person has failed substantially to comply with the requirements of the protocol, (ii) the results of the trials obtained under the protocol differ so substantially from the results required by the protocol that further trials cannot be justiﬁed, or (iii) the results of the trials conducted under the protocol or available new information do not demonstrate that the device tested under the protocol does not present an unreasonable risk to health and safety. (B) After the receipt of a notice of completion of an approved protocol the Secretary shall, within the ninety-day period beginning on the date such notice is received, by order either declare the protocol completed or declare it not completed. An order declaring a protocol not completed may take effect only after the Secretary has provided the person who has the protocol opportunity for an informal hearing on the order. Such an order may be issued only if the Secretary ﬁnds – (i) such person has failed substantially to comply with the requirements of the protocol, (ii) the results of the trials obtained under the protocol differ substantially from the results required by the protocol, or (iii) there is a lack of a showing of reasonable assurance of the safety and effectiveness of the device under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof. (C) A ﬁnal order issued under subparagraph (A) or (B) shall be in writing and shall contain the reasons to support the conclusions thereof. (7) At any time after a notice of completion has become effective, the Secretary may issue an order (after due notice and opportunity for an informal hearing to the person for whom the notice is effective) revoking the approval of a device provided by a notice of completion which has become effective as provided in subparagraph (B) if he ﬁnds that any of the grounds listed in subparagraphs (A) through (G) of subsection (e)(1) of this section apply. Each reference in such subparagraphs to an application shall be considered for purposes of this paragraph as a reference to a protocol and the notice of completion of such protocol, and each reference to the time when an application was approved shall be considered for purposes of this paragraph as a reference to the time when a notice of completion took effect. (8) A person who has an approved protocol subject to an order issued under paragraph (6)(A) revoking such protocol, a person who has an approved protocol with respect to which an order under paragraph (6)(B) was issued declaring that the protocol had not been completed, or a person subject to an order issued under paragraph (7) revoking the approval of a device may, by petition ﬁled on or before the thirtieth day after the date upon which he receives notice of such order, obtain review thereof in accordance with either paragraph (1) or (2) of subsection (g).

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REVIEW (g)(1) Upon petition for review of – (A) an order under subsection (d) approving or denying approval of an application or an order under subsection (e) withdrawing approval of an application, or (B) an order under subsection (f)(6)(A) revoking an approved protocol, under subsection (f)(6)(B) declaring that an approved protocol has not been completed, or under subsection (f)(7) revoking the approval of a device, the Secretary shall, unless he ﬁnds the petition to be without good cause or unless a petition for review of such order has been submitted under paragraph (2), hold a hearing, in accordance with section 554 of title 5, United States Code, on the order. The panel or panels which considered the application, protocol, or device subject to such order shall designate a member to appear and testify at any such hearing upon request of the Secretary, the petitioner, or the ofﬁcer conducting the hearing, but this requirement does not preclude any other member of the panel or panels from appearing and testifying at any such hearing. Upon completion of such hearing and after considering the record established in such hearing, the Secretary shall issue an order either afﬁrming the order subject to the hearing or reversing such order and, as appropriate, approving or denying approval of the application, reinstating the application’s approval, approving the protocol, or placing in effect a notice of completion. (2)(A) Upon petition for review of – (i) an order under subsection (d) approving or denying approval of an application or an order under subsection (e) withdrawing approval of an application, or (ii) an order under subsection (f)(6)(A) revoking an approved protocol, under subsection (f)(6)(B) declaring that an approved protocol has not been completed, or under subsection (f)(7) revoking the approval of a device, the Secretary shall refer the application or protocol subject to the order and the basis for the order to an advisory committee of experts established pursuant to subparagraph (B) for a report and recommendation with respect to the order. The advisory committee shall, after independent study of the data and information furnished to it by the Secretary and other data and information before it, submit to the Secretary a report and recommendation, together with all underlying data and information and a statement of the reasons or basis for the recommendation. A copy of such report shall be promptly supplied by the Secretary to any person who petitioned for such referral to the advisory committee. (B) The Secretary shall establish advisory committees (which may not be panels under section 513) to receive referrals under subparagraph (A). The Secretary shall appoint as members of any such advisory committee persons qualiﬁed in the subject matter to be referred to the committee and of appropriately diversiﬁed professional backgrounds, except that the Secretary may not appoint to such a committee any individual who is in the regular full-time employ of the United States and engaged in the administration of this Act. Members of an advisory committee (other than ofﬁcers or employees of the United States), while attending conferences or meetings of their committee or otherwise serving at the request of the Secretary, shall be entitled to receive compensation at rates to be ﬁxed by the Secretary, which rates may not exceed the daily equivalent for grade GS-18 of the General Schedule for each day (including travel time) they are so engaged; and while so serving away from their homes or regular places of business each member may be allowed travel expenses, including per diem in lieu of subsistence, as authorized by section 5703 of title 5 of the United States Code for persons in the Government service employed intermittently. The Secretary shall designate the chairman of an advisory committee from its members. The Secretary

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shall furnish each advisory committee with clerical and other assistance, and shall by regulation prescribe the procedures to be followed by each such committee in acting on referrals made under subparagraph (A). (C) The Secretary shall make public the report and recommendation made by an advisory committee with respect to an application and shall by order, stating the reasons therefor, either afﬁrm the order referred to the advisory committee or reverse such order and, if appropriate, approve or deny approval of the application, reinstate the application’s approval, approve the protocol, or place in effect a notice of completion. Service of Orders (h) Orders of the Secretary under this section shall be served (1) in person by any ofﬁcer or employee of the department designated by the Secretary, or (2) by mailing the order by registered mail or certiﬁed mail addressed to the applicant at his last known address in the records of the Secretary. Revision (i)(1) Before December 1, 1995, the Secretary shall by order require manufacturers of devices, which were introduced or delivered for introduction into interstate commerce for commercial distribution before May 28, 1976, and which are subject to revision of classiﬁcation under paragraph (2), to submit to the Secretary a summary of and citation to any information known or otherwise available to the manufacturer respecting such devices, including adverse safety or effectiveness information which has not been submitted under section 519. The Secretary may require the manufacturer to submit the adverse safety or effectiveness data for which a summary and citation were submitted, if such data are available to the manufacturer. (2) After the issuance of an order under paragraph (1) but before December 1, 1995, the Secretary shall publish a regulation in the Federal Register for each device – (A) which the Secretary has classiﬁed as a class III device, and (B) for which no ﬁnal regulation has been promulgated under section 515, revising the classiﬁcation of the device so that the device is classiﬁed into class I or class II, unless the regulation requires the device to remain in class III. In determining whether to revise the classiﬁcation of a device or to require a device to remain in class III, the Secretary shall apply the criteria set forth in section 513(a). Before the publication of a regulation requiring a device to remain in class III or revising its classiﬁcation, the Secretary shall publish a proposed regulation respecting the classiﬁcation of a device under this paragraph and provide reasonable opportunity for the submission of comments on any such regulation. No regulation requiring a device to remain in class III or revising its classiﬁcation may take effect before the expiration of 90 days from the date of its publication in the Federal Register as a proposed regulation. (3) The Secretary shall, as promptly as is reasonably achievable, but not later than 12 months after the effective date of the regulation requiring a device to remain in class III, establish a schedule for the promulgation of a section 515 regulation for each device which is subject to the regulation requiring the device to remain in class III.

BANNED DEVICES General Rule Section 516. [360f] (a) Whenever the Secretary ﬁnds, on the basis of all available data and information, that – (1) a device intended for human use presents substantial deception or an unreasonable and substantial risk of illness or injury; and

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(2) in the case of substantial deception or an unreasonable and substantial risk of illness or injury which the Secretary determined could be corrected or eliminated by labeling or change in labeling and with respect to which the Secretary provided written notice to the manufacturer specifying the deception or risk of illness or injury, the labeling or change in labeling to correct the deception or eliminate or reduce such risk, and the period within which such labeling or change in labeling was to be done, such labeling or change in labeling was not done within such period; he may initiate a proceeding to promulgate a regulation to make such device a banned device. Special Effective Date (b) The Secretary may declare a proposed regulation under subsection (a) to be effective upon its publication in the Federal Register and until the effective date of any ﬁnal action taken respecting such regulation if (1) he determines, on the basis of all available data and information, that the deception or risk of illness or injury associated with the use of the device which is subject to the regulation presents an unreasonable, direct, and substantial danger to the health of individuals, and (2) before the date of the publication of such regulation, the Secretary notiﬁes the manufacturer of such device that such regulation is to be made so effective. If the Secretary makes a proposed regulation so effective, he shall, as expeditiously as possible, give interested persons prompt notice of his action under this subsection, provide reasonable opportunity for an informal hearing on the proposed regulation, and either afﬁrm, modify, or revoke such proposed regulation.

JUDICIAL REVIEW Application of Section Section 517. [360g] (a) Not later than thirty days after – (1) the promulgation of a regulation under section 513 classifying a device in class I or changing the classiﬁcation of a device to class I or an order under subsection (f)(2) of such section reclassifying a device or denying a petition for reclassiﬁcation of a device, (2) the promulgation of a regulation under section 514 establishing, amending, or revoking a performance standard for a device, (3) the issuance of an order under section 514(b)(2) or 515(b)(2)(B) denying a request for reclassiﬁcation of a device, (4) the promulgation of a regulation under paragraph (3) of section 515(b) requiring a device to have an approval of a premarket application, a regulation under paragraph (4) of that section amending or revoking a regulation under paragraph (3), or an order pursuant to section 515(g)(1) or 515(g)(2)(C), (5) the promulgation of a regulation under section 516 (other than a proposed regulation made effective under subsection (b) of such section upon the regulation’s publication) making a device a banned device, (6) the issuance of an order under section 520(f)(2), (7) an order under section 520(g)(4) disapproving an application for an exemption of a device for investigational use or an order under section 520(g)(5) withdrawing such an exemption for a device, (8) an order pursuant to section 513(i), (9) a regulation under section 515(i)(2) or 520(l)(5)(B), or (10) an order under section 520(h)(4)(B),

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any person adversely affected by such regulation or order may ﬁle a petition with the United States Court of Appeals for the District of Columbia or for the circuit wherein such person resides or has his principal place of business for judicial review of such regulation or order. A copy of the petition shall be transmitted by the clerk of the court to the Secretary or other ofﬁcer designated by him for that purpose. The Secretary shall ﬁle in the court the record of the proceedings on which the Secretary based his regulation or order as provided in section 2112 of title 28, United States Code. For purposes of this section, the term “record” means all notices and other matter published in the Federal Register with respect to the regulation or order reviewed, all information submitted to the Secretary with respect to such regulation or order, proceedings of any panel or advisory committee with respect to such regulation or order, any hearing held with respect to such regulation or order, and any other information identiﬁed by the Secretary, in the administrative proceeding held with respect to such regulation or order, as being relevant to such regulation or order. Additional Data, Views, and Arguments (b) If the petitioner applies to the court for leave to adduce additional data, views, or arguments respecting the regulation or order being reviewed and shows to the satisfaction of the court that such additional data, views, or arguments are material and that there were reasonable grounds for the petitioner’s failure to adduce such data, views, or arguments in the proceedings before the Secretary, the court may order the Secretary to provide additional opportunity for the oral presentation of data, views, or arguments and for written submissions. The Secretary may modify his ﬁndings, or make new ﬁndings by reason of the additional data, views, or arguments so taken and shall ﬁle with the court such modiﬁed or new ﬁndings, and his recommendation, if any, for the modiﬁcation or setting aside of the regulation or order being reviewed, with the return of such additional data, views, or arguments. Standard for Review (c) Upon the ﬁling of the petition under subsection (a) of this section for judicial review of a regulation or order, the court shall have jurisdiction to review the regulation or order in accordance with chapter 7 of title 5, United States Code and to grant appropriate relief, including interim relief, as provided in such chapter. A regulation described in paragraph (2) or (5) of subsection (a) and an order issued after the review provided by section 515(g) shall not be afﬁrmed if it is found to be unsupported by substantial evidence on the record taken as a whole. Finality of Judgment (d) The judgment of the court afﬁrming or setting aside, in whole or in part, any regulation or order shall be ﬁnal, subject to review by the Supreme Court of the United States upon certiorari or certiﬁcation, as provided in section 1254 of title 28. Remedies (e) The remedies provided for in this section shall be in addition to and not in lieu of any other remedies provided by law. Statement of Reasons (f) To facilitate judicial review under this section or under any other provision of law of a regulation or order issued under section 513, 514, 515, 516, 518, 519, 520, or 521 each such regulation or order shall contain a statement of the reasons for its issuance and the basis, in the record of the proceedings held in connection with its issuance, for its issuance.

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NOTIFICATION

321 AND

OTHER REMEDIES

Notification Section 518. [360h] (a) If the Secretary determines that – (1) a device intended for human use which is introduced or delivered for introduction into interstate commerce for commercial distribution presents an unreasonable risk of substantial harm to the public health, and (2) notiﬁcation under this subsection is necessary to eliminate the unreasonable risk of such harm and no more practicable means is available under the provisions of this Act (other than this section) to eliminate such risk, the Secretary may issue such order as may be necessary to assure that adequate notiﬁcation is provided in an appropriate form, by the persons and means best suited under the circumstances involved, to all health professionals who prescribe or use the device and to any other person (including manufacturers, importers, distributors, retailers, and device users) who should properly receive such notiﬁcation in order to eliminate such risk. An order under this subsection shall require that the individuals subject to the risk with respect to which the order is to be issued be included in the persons to be notiﬁed of the risk unless the Secretary determines that notice to such individuals would present a greater danger to the health of such individuals than no such notiﬁcation. If the Secretary makes such a determination with respect to such individuals, the order shall require that the health professionals who prescribe or use the device provide for the notiﬁcation of the individuals whom the health professionals treated with the device of the risk presented by the device and of any action which may be taken by or on behalf of such individuals to eliminate or reduce such risk. Before issuing an order under this subsection, the Secretary shall consult with the persons who are to give notice under the order. Repair, Replacement, or Refund (b)(1)(A) If, after affording opportunity for an informal hearing, the Secretary determines that – (i) a device intended for human use which is introduced or delivered for introduction into interstate commerce for commercial distribution presents an unreasonable risk of substantial harm to the public health, (ii) there are reasonable grounds to believe that the device was not properly designed or manufactured with reference to the state of the art as it existed at the time of its design or manufacture, (iii) there are reasonable grounds to believe that the unreasonable risk was not caused by failure of a person other than a manufacturer, importer, distributor, or retailer of the device to exercise due care in the installation, maintenance, repair, or use of the device, and (iv) the notiﬁcation authorized by subsection (a) would not by itself be sufﬁcient to eliminate the unreasonable risk and action described in paragraph (2) of this subsection is necessary to eliminate such risk, the Secretary may order the manufacturer, importer, or any distributor of such device, or any combination of such persons, to submit to him within a reasonable time a plan for taking one or more of the actions described in paragraph (2). An order issued under the preceding sentence which is directed to more than one person shall specify which person may decide which action shall be taken under such plan and the person speciﬁed shall be the person who the Secretary determines bears the principal, ultimate ﬁnancial responsibility for action taken under the plan unless the Secretary cannot determine who bears such responsibility or the Secretary determines that the protection of the public health requires that such decision

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be made by a person (including a device user or health professional) other than the person he determines bears such responsibility. (B) The Secretary shall approve a plan submitted pursuant to an order issued under subparagraph (A) unless he determines (after affording opportunity for an informal hearing) that the action or actions to be taken under the plan or the manner in which such action or actions are to be taken under the plan will not assure that the unreasonable risk with respect to which such order was issued will be eliminated. If the Secretary disapproves a plan, he shall order a revised plan to be submitted to him within a reasonable time. If the Secretary determines (after affording opportunity for an informal hearing) that the revised plan is unsatisfactory or if no revised plan or no initial plan has been submitted to the Secretary within the prescribed time, the Secretary shall (i) prescribe a plan to be carried out by the person or persons to whom the order issued under subparagraph (A) was directed, or (ii) after affording an opportunity for an informal hearing, by order prescribe a plan to be carried out by a person who is a manufacturer, importer, distributor, or retailer of the device with respect to which the order was issued but to whom the order under subparagraph (A) was not directed. (2) The actions which may be taken under a plan submitted under an order issued under paragraph (1) are as follows: (A) To repair the device so that it does not present the unreasonable risk of substantial harm with respect to which the order under paragraph (1) was issued. (B) To replace the device with a like or equivalent device which is in conformity with all applicable requirements of this Act. (C) To refund the purchase price of the device (less a reasonable allowance for use if such device has been in the possession of the device user for one year or more – (i) at the time of notiﬁcation ordered under subsection (a), or (ii) at the time the device user receives actual notice of the unreasonable risk with respect to which the order was issued under paragraph (1), whichever ﬁrst occurs). (3) No charge shall be made to any person (other than a manufacturer, importer, distributor or retailer) for availing himself of any remedy, described in paragraph (2) and provided under an order issued under paragraph (1), and the person subject to the order shall reimburse each person (other than a manufacturer, importer, distributor, or retailer) who is entitled to such a remedy for any reasonable and foreseeable expenses actually incurred by such person in availing himself of such remedy. Reimbursement (c) An order issued under subsection (b) of this section with respect to a device may require any person who is a manufacturer, importer, distributor, or retailer of the device to reimburse any other person who is a manufacturer, importer, distributor, or retailer of such device for such other person’s expenses actually incurred in connection with carrying out the order if the Secretary determines such reimbursement is required for the protection of the public health. Any such requirement shall not affect any rights or obligations under any contract to which the person receiving reimbursement or the person making such reimbursement is a party. Effect on Other Liability (d) Compliance with an order issued under this section shall not relieve any person from liability under Federal or State law. In awarding damages for economic loss in an action brought for the enforcement of any such liability, the value to the plaintiff in such action of any remedy provided him under such order shall be taken into account.

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Recall Authority (e)(1) If the Secretary ﬁnds that there is a reasonable probability that a device intended for human use would cause serious, adverse health consequences or death, the Secretary shall issue an order requiring the appropriate person (including the manufacturers, importers, distributors, or retailers of the device) – (A) to immediately cease distribution of such device, and (B) to immediately notify health professionals and device user facilities of the order and to instruct such professionals and facilities to cease use of such device. The order shall provide the person subject to the order with an opportunity for an informal hearing, to be held not later than 10 days after the date of the issuance of the order, on the actions required by the order and on whether the order should be amended to require a recall of such device. If, after providing an opportunity for such a hearing, the Secretary determines that inadequate grounds exist to support the actions required by the order, the Secretary shall vacate the order. (2)(A) If, after providing an opportunity for an informal hearing under paragraph (1), the Secretary determines that the order should be amended to include a recall of the device with respect to which the order was issued, the Secretary shall, except as provided in subparagraphs (B) and (C), amend the order to require a recall. The Secretary shall specify a timetable in which the device recall will occur and shall require periodic reports to the Secretary describing the progress of the recall. (B) An amended order under subparagraph (A) – (i) shall – (I) not include recall of a device from individuals, and (II) not include recall of a device from device user facilities if the Secretary determines that the risk of recalling such device from the facilities presents a greater health risk than the health risk of not recalling the device from use, and (ii) shall provide for notice to individuals subject to the risks associated with the use of such device. In providing the notice required by clause (ii), the Secretary may use the assistance of health professionals who prescribed or used such a device for individuals. If a signiﬁcant number of such individuals cannot be identiﬁed, the Secretary shall notify such individuals pursuant to section 705(b). (3) The remedy provided by this subsection shall be in addition to remedies provided by subsections (a), (b), and (c).

RECORDS

AND

REPORTS

ON

DEVICES

General Rule Section 519. [360i] (a) Every person who is a manufacturer or importer of a device intended for human use shall establish and maintain such records, make such reports, and provide such information, as the Secretary may by regulation reasonably require to assure that such device is not adulterated or misbranded and to otherwise assure its safety and effectiveness. Regulations prescribed under the preceding sentence – (1) shall require a device manufacturer or importer to report to the Secretary whenever the manufacturer or importer receives or otherwise becomes aware of information that reasonably suggests that one of its marketed devices – (A) may have caused or contributed to a death or serious injury, or

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(B) has malfunctioned and that such device or a similar device marketed by the manufacturer or importer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur; (2) shall deﬁne the term “serious injury” to mean an injury that – (A) is life threatening, (B) results in permanent impairment of a body function or permanent damage to a body structure, or (C) necessitates medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure; (3) shall require reporting of other signiﬁcant adverse device experiences as determined by the Secretary to be necessary to be reported; (4) shall not impose requirements unduly burdensome to a device manufacturer or importer taking into account his cost of complying with such requirements and the need for the protection of the public health and the implementation of this Act; (5) which prescribe the procedure for making requests for reports or information shall require that each request made under such regulations for submission of a report or information to the Secretary state the reason or purpose for such request and identify to the fullest extent practicable such report or information; (6) which require submission of a report or information to the Secretary shall state the reason or purpose for the submission of such report or information and identify to the fullest extent practicable such report or information; (7) may not require that the identity of any patient be disclosed in records, reports, or information required under this subsection unless required for the medical welfare of an individual, to determine the safety or effectiveness of a device, or to verify a record, report, or information submitted under this Act; and (8) may not require a manufacturer or importer of a class I device to – (A) maintain for such a device records respecting information not in the possession of the manufacturer or importer, or (B) to submit for such a device to the Secretary any report or information – (i) not in the possession of the manufacturer or importer, or (ii) on a periodic basis, unless such report or information is necessary to determine if the device should be reclassiﬁed or if the device is adulterated or misbranded. In prescribing such regulations, the Secretary shall have due regard for the professional ethics of the medical profession and the interests of patients. The prohibitions of paragraph (7) of this subsection continue to apply to records, reports, and information concerning any individual who has been a patient, irrespective of whether or when he ceases to be a patient. The Secretary shall by regulation require distributors to keep records and make such records available to the Secretary upon request. Paragraphs (4) and (8) apply to distributors to the same extent and in the same manner as such paragraphs apply to manufacturers and importers. User Reports (b)(1)(A) Whenever a device user facility receives or otherwise becomes aware of information that reasonably suggests that a device has or may have caused or contributed to the death of a patient of the facility, the facility shall, as soon as practicable but not later than 10 working days after

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becoming aware of the information, report the information to the Secretary and, if the identity of the manufacturer is known, to the manufacturer of the device. In the case of deaths, the Secretary may by regulation prescribe a shorter period for the reporting of such information. (B) Whenever a device user facility receives or otherwise becomes aware of – (i) information that reasonably suggests that a device has or may have caused or contributed to the serious illness of, or serious injury to, a patient of the facility, or (ii) other signiﬁcant adverse device experiences as determined by the Secretary by regulation to be necessary to be reported, the facility shall, as soon as practicable but not later than 10 working days after becoming aware of the information, report the information to the manufacturer of the device or to the Secretary if the identity of the manufacturer is not known. (C) Each device user facility shall submit to the Secretary on an annual basis a summary of the reports made under subparagraphs (A) and (B). Such summary shall be submitted on January 1 of each year. The summary shall be in such form and contain such information from such reports as the Secretary may require and shall include – (i) sufﬁcient information to identify the facility which made the reports for which the summary is submitted, (ii) in the case of any product which was the subject of a report, the product name, serial number, and model number, (iii) the name and the address of the manufacturer of such device, and (iv) a brief description of the event reported to the manufacturer. (D) For purposes of subparagraphs (A), (B), and (C), a device user facility shall be treated as having received or otherwise become aware of information with respect to a device of that facility when medical personnel who are employed by or otherwise formally afﬁliated with the facility receive or otherwise become aware of information with respect to that device in the course of their duties. (2) The Secretary may not disclose the identity of a device user facility which makes a report under paragraph (1) except in connection with – (A) an action brought to enforce section 301(q), (B) a communication to a manufacturer of a device which is the subject of a report under paragraph (1). This paragraph does not prohibit the Secretary from disclosing the identity of a device user facility making a report under paragraph (1) or any information in such a report to employees of the Department of Health and Human Services, to the Department of Justice, or to the duly authorized committees and subcommittees of the Congress. (3) No report made under paragraph (1) by – (A) a device user facility, (B) an individual who is employed by or otherwise formally afﬁliated with such a facility, or (C) a physician who is not required to make such a report, shall be admissible into evidence or otherwise used in any civil action involving private parties unless the facility, individual, or physician who made the report had knowledge of the falsity of the information contained in the report. (4) A report made under paragraph (1) does not affect any obligation of a manufacturer who receives the report to ﬁle a report as required under subsection (a). (5) With respect to device user facilities:

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(A) The Secretary shall by regulation plan and implement a program under which the Secretary limits user reporting under paragraphs (1) through (4) to a subset of user facilities that constitutes a representative proﬁle of user reports for device deaths and serious illnesses or serious injuries. (B) During the period of planning the program under subparagraph (A), paragraphs (1) through (4) continue to apply. (C) During the period in which the Secretary is providing for a transition to the full implementation of the program, paragraphs (1) through (4) apply except to the extent that the Secretary determines otherwise. (D) On and after the date on which the program is fully implemented, paragraphs (1) through (4) do not apply to a user facility unless the facility is included in the subset referred to in subparagraph (A). (E) Not later than 2 years after the date of the enactment of the Food and Drug Administration Modernization Act of 1997, the Secretary shall submit to the Committee on Commerce of the House of Representatives, and to the Committee on Labor and Human Resources of the Senate, a report describing the plan developed by the Secretary under subparagraph (A) and the progress that has been made toward the implementation of the plan. (6) For purposes of this subsection: (A) The term “device user facility” means a hospital, ambulatory surgical facility, nursing home, or outpatient treatment facility which is not a physician’s ofﬁce. The Secretary may by regulation include an outpatient diagnostic facility which is not a physician’s ofﬁce in such term. (B) The terms “serious illness” and “serious injury” mean illness or injury, respectively, that – (i) is life threatening, (ii) results in permanent impairment of a body function or permanent damage to a body structure, or (iii) necessitates medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure. Persons Exempt (c) Subsection (a) shall not apply to – (1) any practitioner who is licensed by law to prescribe or administer devices intended for use in humans and who manufactures or imports devices solely for use in the course of his professional practice; (2) any person who manufactures or imports devices intended for use in humans solely for such person’s use in research or teaching and not for sale (including any person who uses a device under an exemption granted under section 520(g)); and (3) any other class of persons as the Secretary may by regulation exempt from subsection (a) of this section upon a ﬁnding that compliance with the requirements of such subsection by such class with respect to a device is not necessary to (A) assure that a device is not adulterated or misbranded or (B) otherwise to assure its safety and effectiveness. [(d) Repealed by Pub. L. 105–115, November 21, 1997.] Device Tracking (e)(l) The Secretary may by order require a manufacturer to adopt a method of tracking a class II or class III device –

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(A) the failure of which would be reasonably likely to have serious adverse health consequences; or (B) which is – (i) intended to be implanted in the human body for more than one year, or (ii) a life sustaining or life supporting device used outside a device user facility. (2) Any patient receiving a device subject to tracking under paragraph (1) may refuse to release, or refuse permission to release, the patient’s name, address, social security number, or other identifying information for the purpose of tracking. Reports of Removals and Corrections (f)(1) Except as provided in paragraph (2), the Secretary shall by regulation require a manufacturer or importer of a device to report promptly to the Secretary any correction or removal of a device undertaken by such manufacturer or importer if the removal or correction was undertaken – (A) to reduce a risk to health posed by the device, or (B) to remedy a violation of this Act caused by the device which may present a risk to health. A manufacturer or importer of a device who undertakes a correction or removal of a device which is not required to be reported under this paragraph shall keep a record of such correction or removal. (2) No report of the corrective action or removal of a device may be required under paragraph (1) if a report of the corrective action or removal is required and has been submitted under subsection (a). (3) For purposes of paragraphs (1) and (2), the terms “correction” and “removal” do not include routine servicing.

GENERAL PROVISIONS RESPECTING CONTROL

OF

DEVICES INTENDED

FOR

HUMAN USE

General Rule Section 520. [360j] (a) Any requirement authorized by or under section 501, 502, 510, or 519 applicable to a device intended for human use shall apply to such device until the applicability of the requirement to the device has been changed by action taken under section 513, 514, or 515 or under subsection (g) of this section, and any requirement established by or under section 501, 502, 510, or 519 which is inconsistent with a requirement imposed on such device under section 514 or 515 or under subsection (g) of this section shall not apply to such device. Custom Devices (b) Sections 514 and 515 do not apply to any device which, in order to comply with the order of an individual physician or dentist (or any other specially qualiﬁed person designated under regulations promulgated by the Secretary after an opportunity for an oral hearing) necessarily deviates from an otherwise applicable performance standard or requirement prescribed by or under section 515 if (1) the device is not generally available in ﬁnished form for purchase or for dispensing upon prescription and is not offered through labeling or advertising by the manufacturer, importer, or distributor thereof for commercial distribution, and (2) such device – (A)(i) is intended for use by an individual patient named in such order of such physician or dentist (or other specially qualiﬁed person so designated) and is to be made in a speciﬁc form for such patient, or (ii) is intended to meet the special needs of such physician or dentist (or other specially qualiﬁed person so designated) in the course of the professional practice of such physician or dentist (or other specially qualiﬁed person so designated), and

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(B) is not generally available to or generally used by other physicians or dentists (or other specially qualiﬁed persons so designated). Trade Secrets (c) Any information reported to or otherwise obtained by the Secretary or his representative under section 513, 514, 515, 516, 518, 519, or 704 or under subsection (f) or (g) of this section which is exempt from disclosure pursuant to subsection (a) of section 552 of title 5, United States Code by reason of subsection (b)(4) of such section shall be considered conﬁdential and shall not be disclosed and may not be used by the Secretary as the basis for the reclassiﬁcation of a device from class III to class II or class I or as the basis for the establishment or amendment of a performance standard under section 514 for a device reclassiﬁed from class III to class II, except (1) in accordance with subsection (h), and (2) that such information may be disclosed to other ofﬁcers or employees concerned with carrying out this Act or when relevant in any proceeding under this Act (other than section 513 or 514). Notices and Findings (d) Each notice of proposed rulemaking under section 513, 514, 515, 516, 518, or 519, or under this section, any other notice which is published in the Federal Register with respect to any other action taken under any such section and which states the reasons for such action, and each publication of ﬁndings required to be made in connection with rulemaking under any such section shall set forth – (1) the manner in which interested persons may examine data and other information on which the notice or ﬁndings is based, and (2) the period within which interested persons may present their comments on the notice or ﬁndings (including the need therefor) orally or in writing, which period shall be at least sixty days but may not exceed ninety days unless the time is extended by the Secretary by a notice published in the Federal Register stating good cause therefor. Restricted Devices (e)(1) The Secretary may by regulation require that a device be restricted to sale, distribution, or use – (A) only upon the written or oral authorization of a practitioner licensed by law to administer or use such device, or (B) upon such other conditions as the Secretary may prescribe in such regulation, if, because of its potentiality for harmful effect or the collateral measures necessary to its use, the Secretary determines that there cannot otherwise be reasonable assurance of its safety and effectiveness. No condition prescribed under subparagraph (B) may restrict the use of a device to persons with speciﬁc training or experience in its use or to persons for use in certain facilities unless the Secretary determines that such a restriction is required for the safe and effective use of the device. No such condition may exclude a person from using a device solely because the person does not have the training or experience to make him eligible for certiﬁcation by a certifying board recognized by the American Board of Medical Specialties or has not been certiﬁed by such a Board. A device subject to a regulation under this subsection is a restricted device. (2) The label of a restricted device shall bear such appropriate statements of the restrictions required by a regulation under paragraph (1) as the Secretary may in such regulation prescribe.

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Good Manufacturing Practice Requirements (f)(1)(A) The Secretary may, in accordance with subparagraph (B), prescribe regulations requiring that the methods used in, and the facilities and controls used for, the manufacture, pre-production design validation (including a process to assess the performance of a device but not including an evaluation of the safety or effectiveness of a device), packing, storage, and installation of a device conform to current good manufacturing practice, as prescribed in such regulations, to assure that the device will be safe and effective and otherwise in compliance with this Act. (B) Before the Secretary may promulgate any regulation under subparagraph (A) he shall – (i) afford the advisory committee established under paragraph (3) an opportunity to submit recommendations to him with respect to the regulation proposed to be promulgated, (ii) afford opportunity for an oral hearing; and (iii) ensure that such regulation conforms, to the extent practicable, with internationally recognized standards deﬁning quality systems, or parts of the standards, for medical devices. The Secretary shall provide the advisory committee a reasonable time to make its recommendation with respect to proposed regulations under subparagraph (A). (2)(A) Any person subject to any requirement prescribed by regulations under paragraph (1) may petition the Secretary for an exemption or variance from such requirement. Such a petition shall be submitted to the Secretary in such form and manner as he shall prescribe and shall – (i) in the case of a petition for an exemption from a requirement, set forth the basis for the petitioner’s determination that compliance with the requirement is not required to assure that the device will be safe and effective and otherwise in compliance with this Act, (ii) in the case of a petition for a variance from a requirement, set forth the methods proposed to be used in, and the facilities and controls proposed to be used for, the manufacture, packing, storage, and installation of the device in lieu of the methods, facilities, and controls prescribed by the requirement, and (iii) contain such other information as the Secretary shall prescribe. (B) The Secretary may refer to the advisory committee established under paragraph (3) any petition submitted under subparagraph (A). The advisory committee shall report its recommendations to the Secretary with respect to a petition referred to it within sixty days of the date of the petition’s referral. Within sixty days after – (i) the date the petition was submitted to the Secretary under subparagraph (A), or (ii) if the petition was referred to an advisory committee, the expiration of the sixty-day period beginning on the date the petition was referred to the advisory committee, whichever occurs later, the Secretary shall by order either deny the petition or approve it. (C) The Secretary may approve – (i) a petition for an exemption for a device from a requirement if he determines that compliance with such requirement is not required to assure that the device will be safe and effective and otherwise in compliance with this Act, and (ii) a petition for a variance for a device from a requirement if he determines that the methods to be used in, and the facilities and controls to be used for, the manufacture, packing, storage, and installation of the device in lieu of the methods, controls, and facilities prescribed by the requirement are sufﬁcient to assure that the device will be safe and effective and otherwise in compliance with this Act.

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An order of the Secretary approving a petition for a variance shall prescribe such conditions respecting the methods used in, and the facilities and controls used for, the manufacture, packing, storage, and installation of the device to be granted the variance under the petition as may be necessary to assure that the device will be safe and effective and otherwise in compliance with this Act. (D) After the issuance of an order under subparagraph (B) respecting a petition, the petitioner shall have an opportunity for an informal hearing on such order. (3) The Secretary shall establish an advisory committee for the purpose of advising and making recommendations to him with respect to regulations proposed to be promulgated under paragraph (1)(A) and the approval or disapproval of petitions submitted under paragraph (2). The advisory committee shall be composed of nine members as follows: (A) Three of the members shall be appointed from persons who are ofﬁcers or employees of any State or local government or of the Federal Government. (B) Two of the members shall be appointed from persons who are representative of interests of the device manufacturing industry; two of the members shall be appointed from persons who are representative of the interests of physicians and other health professionals; and two of the members shall be representative of the interests of the general public. Members of the advisory committee who are not ofﬁcers or employees of the United States, while attending conferences or meetings of the committee or otherwise engaged in its business, shall be entitled to receive compensation at rates to be ﬁxed by the Secretary, which rates may not exceed the daily equivalent of the rate in effect for grade GS-18 of the General Schedule, for each day (including travel time) they are so engaged; and while so serving away from their homes or regular places of business each member may be allowed travel expenses, including per diem in lieu of subsistence, as authorized by section 5703 of title 5 of the United States Code for persons in the Government service employed intermittently. The Secretary shall designate one of the members of the advisory committee to serve as its chairman. The Secretary shall furnish the advisory committee with clerical and other assistance. Section 14 of the Federal Advisory Committee Act shall not apply with respect to the duration of the advisory committee established under this paragraph. Exemption for Devices for Investigational Use (g)(1) It is the purpose of this subsection to encourage, to the extent consistent with the protection of the public health and safety and with ethical standards, the discovery and development of useful devices intended for human use and to that end to maintain optimum freedom for scientiﬁc investigators in their pursuit of that purpose. (2)(A) The Secretary shall, within the one hundred and twenty-day period beginning on the date of enactment of this section, by regulation prescribe procedures and conditions under which devices intended for human use may upon application be granted an exemption from the requirements of section 502, 510, 514, 515, 516, 519, or 721 or subsection (e) or (f) of this section or from any combination of such requirements to permit the investigational use of such devices by experts qualiﬁed by scientiﬁc training and experience to investigate the safety and effectiveness of such devices. (B) The conditions prescribed pursuant to subparagraph (A) shall include the following: (i) A requirement that an application be submitted to the Secretary before an exemption may be granted and that the application be submitted in such form and manner as the Secretary shall specify. (ii) A requirement that the person applying for an exemption for a device assure the establishment and maintenance of such records, and the making of such reports to the Secretary

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of data obtained as a result of the investigational use of the device during the exemption, as the Secretary determines will enable him to assure compliance with such conditions, review the progress of the investigation, and evaluate the safety and effectiveness of the device. (iii) Such other requirements as the Secretary may determine to be necessary for the protection of the public health and safety. (C) Procedures and conditions prescribed pursuant to subparagraph (A) for an exemption may appropriately vary depending on (i) the scope and duration of clinical testing to be conducted under such exemption, (ii) the number of human subjects that are to be involved in such testing, (iii) the need to permit changes to be made in the device subject to the exemption during testing conducted in accordance with a clinical testing plan required under paragraph (3)(A), and (iv) whether the clinical testing of such device is for the purpose of developing data to obtain approval for the commercial distribution of such device. (3) Procedures and conditions prescribed pursuant to paragraph (2)(A) shall require, as a condition to the exemption of any device to be the subject of testing involving human subjects, that the person applying for the exemption – (A) submit a plan for any proposed clinical testing of the device and a report of prior investigations of the device (including, where appropriate, tests on animals) adequate to justify the proposed clinical testing – (i) to the local institutional review committee which has been established in accordance with regulations of the Secretary to supervise clinical testing of devices in the facilities where the proposed clinical testing is to be conducted, or (ii) to the Secretary, if – (I) no such committee exists, or (II) the Secretary ﬁnds that the process of review by such committee is inadequate (whether or not the plan for such testing has been approved by such committee), for review for adequacy to justify the commencement of such testing; and, unless the plan and report are submitted to the Secretary, submit to the Secretary a summary of the plan and a report of prior investigations of the device (including, where appropriate, tests on animals); (B) promptly notify the Secretary (under such circumstances and in such manner as the Secretary prescribes) of approval by a local institutional review committee of any clinical testing plan submitted to it in accordance with subparagraph (A); (C) in the case of a device to be distributed to investigators for testing, obtain signed agreements from each of such investigators that any testing of the device involving human subjects will be under such investigator’s supervision and in accordance with subparagraph (D) and submit such agreements to the Secretary; and (D) assure that informed consent will be obtained from each human subject (or his representative) of proposed clinical testing involving such device, except where subject to such conditions as the Secretary may prescribe, the investigator conducting or supervising the proposed clinical testing of the device determines in writing that there exists a life threatening situation involving the human subject of such testing which necessitates the use of such device and it is not feasible to obtain informed consent from the subject and there is not sufﬁcient time to obtain such consent from his representative. The determination required by subparagraph (D) shall be concurred in by a licensed physician who is not involved in the testing of the human subject with respect to which such determination is made unless immediate use of the device is required to save the life of the human subject of such testing and there is not sufﬁcient time to obtain such concurrence.

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(4)(A) An application, submitted in accordance with the procedures prescribed by regulations under paragraph (2), for an exemption for a device (other than an exemption from section 516) shall be deemed approved on the thirtieth day after the submission of the application to the Secretary unless on or before such day the Secretary by order disapproves the application and notiﬁes the applicant of the disapproval of the application. (B) The Secretary may disapprove an application only if he ﬁnds that the investigation with respect to which the application is submitted does not conform to procedures and conditions prescribed under regulations under paragraph (2). Such a notiﬁcation shall contain the order of disapproval and a complete statement of the reasons for the Secretary’s disapproval of the application and afford the applicant opportunity for an informal hearing on the disapproval order. (5) The Secretary may by order withdraw an exemption granted under this subsection for a device if the Secretary determines that the conditions applicable to the device under this subsection for such exemption are not met. Such an order may be issued only after opportunity for an informal hearing, except that such an order may be issued before the provision of an opportunity for an informal hearing if the Secretary determines that the continuation of testing under the exemption with respect to which the order is to be issued will result in an unreasonable risk to the public health. (6)(A) Not later than 1 year after the date of the enactment of the Food and Drug Administration Modernization Act of 1997, the Secretary shall by regulation establish, with respect to a device for which an exemption under this subsection is in effect, procedures and conditions that, without requiring an additional approval of an application for an exemption or the approval of a supplement to such an application, permit – (i) developmental changes in the device (including manufacturing changes) that do not constitute a signiﬁcant change in design or in basic principles of operation and that are made in response to information gathered during the course of an investigation; and (ii) changes or modiﬁcations to clinical protocols that do not affect – (I) the validity of data or information resulting from the completion of an approved protocol, or the relationship of likely patient risk to beneﬁt relied upon to approve a protocol; (II) the scientiﬁc soundness of an investigational plan submitted under paragraph (3)(A); or (III) the rights, safety, or welfare of the human subjects involved in the investigation. (B) Regulations under subparagraph (A) shall provide that a change or modiﬁcation described in such subparagraph may be made if – (i) the sponsor of the investigation determines, on the basis of credible information (as deﬁned by the Secretary) that the applicable conditions under subparagraph (A) are met; and (ii) the sponsor submits to the Secretary, not later than 5 days after making the change or modiﬁcation, a notice of the change or modiﬁcation. (7)(A) In the case of a person intending to investigate the safety or effectiveness of a class III device or any implantable device, the Secretary shall ensure that the person has an opportunity, prior to submitting an application to the Secretary or to an institutional review committee, to submit to the Secretary, for review, an investigational plan (including a clinical protocol). If the applicant submits a written request for a meeting with the Secretary regarding such review, the Secretary shall, not later than 30 days after receiving the request, meet with the applicant for the purpose of reaching agreement regarding the investigational plan (including a clinical protocol).

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The written request shall include a detailed description of the device, a detailed description of the proposed conditions of use of the device, a proposed plan (including a clinical protocol) for determining whether there is a reasonable assurance of effectiveness, and, if available information regarding the expected performance from the device. (B) Any agreement regarding the parameters of an investigational plan (including a clinical protocol) that is reached between the Secretary and a sponsor or applicant shall be reduced to writing and made part of the administrative record by the Secretary. Any such agreement shall not be changed, except – (i) with the written agreement of the sponsor or applicant; or (ii) pursuant to a decision, made in accordance with subparagraph (C) by the director of the ofﬁce in which the device involved is reviewed, that a substantial scientiﬁc issue essential to determining the safety or effectiveness of the device involved has been identiﬁed. (C) A decision under subparagraph (B)(ii) by the director shall be in writing, and may be made only after the Secretary has provided to the sponsor or applicant an opportunity for a meeting at which the director and the sponsor or applicant are present and at which the director documents the scientiﬁc issue involved. Release of Information Respecting Safety and Effectiveness (h)(1) The Secretary shall promulgate regulations under which a detailed summary of information respecting the safety and effectiveness of a device which information was submitted to the Secretary and which was the basis for – (A) an order under section 515(d)(1)(A) approving an application for premarket approval for the device or denying approval of such an application or an order under section 515(e) withdrawing approval of such an application for the device, (B) an order under section 515(f)(6)(A) revoking an approved protocol for the device, an order under section 515(f)(6)(B) declaring a protocol for the device completed or not completed, or an order under section 515(f)(7) revoking the approval of the device, or (C) an order approving an application under subsection (g) for an exemption for the device from section 516 or an order disapproving, or withdrawing approval of, an application for an exemption under such subsection for the device, shall be made available to the public upon issuance of the order. Summaries of information made available pursuant to this paragraph respecting a device shall include information respecting any adverse effects on health of the device. (2) The Secretary shall promulgate regulations under which each advisory committee established under section 515(g)(2)(B) shall make available to the public a detailed summary of information respecting the safety and effectiveness of a device which information was submitted to the advisory committee and which was the basis for its recommendation to the Secretary made pursuant to section 515(g)(2)(A). A summary of information upon which such a recommendation is based shall be made available pursuant to this paragraph only after the issuance of the order with respect to which the recommendation was made and each summary shall include information respecting any adverse effect on health of the device subject to such order. (3) Except as provided in paragraph (4), any information respecting a device which is made available pursuant to paragraph (1) or (2) of this subsection (A) may not be used to establish the safety or effectiveness of another device for purposes of this Act by any person other than the person who submitted the information so made available, and (B) shall be made available subject to subsection (c) of this section.

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(4)(A) Any information contained in an application for premarket approval ﬁled with the Secretary pursuant to section 515(c) (including information from clinical and preclinical tests or studies that demonstrate the safety and effectiveness of a device, but excluding descriptions of methods of manufacture and product composition and other trade secrets) shall be available, 6 years after the application has been approved by the Secretary, for use by the Secretary in – (i) approving another device; (ii) determining whether a product development protocol has been completed, under section 515 for another device; (iii) establishing a performance standard or special control under this Act; or (iv) classifying or reclassifying another device under section 513 and subsection (1)(2). (B) The publicly available detailed summaries of information respecting the safety and effectiveness of devices required by paragraph (1)(A) shall be available for use by the Secretary as the evidentiary basis for the agency actions described in subparagraph (A). Proceedings of Advisory Panels and Committees (i) Each panel under section 513 and each advisory committee established under section 514(b)(5)(B) or 515(g) or under subsection (f) of this section shall make and maintain a transcript of any proceeding of the panel or committee. Each such panel and committee shall delete from any transcript made pursuant to this subsection information which under subsection (c) of this section is to be considered conﬁdential. Traceability (j) Except as provided in section 519(e), no regulation under this Act may impose on a type or class of device requirements for the traceability of such type or class of device unless such requirements are necessary to assure the protection of the public health. Research and Development (k) The Secretary may enter into contracts for research, testing, and demonstrations respecting devices and may obtain devices for research, testing, and demonstration purposes without regard to section 3648 and 3709 of the Revised Statutes (31 U.S.C. 529, 41 U.S.C. 5). Transitional Provisions for Devices Considered as New Drugs (l)(1) Any device intended for human use – (A) for which on the date of enactment of the Medical Device Amendments of 1976∑ (hereinafter in this subsection referred to as the “enactment date”) an approval of an application submitted under section 505(b) was in effect; (B) for which such an application was ﬁled on or before the enactment date and with respect to which application no order of approval or refusing to approve had been issued on such date under subsection (c) or (d) of such section; (C) for which on the enactment date an exemption under subsection (i) of such section was in effect; (D) which is within a type of device described in subparagraph (A), (B), or (C) and is substantially equivalent to another device within that type; (E) which the Secretary in a notice published in the Federal Register before the enactment date has declared to be a new drug subject to section 505; or

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(F) with respect to which on the enactment date an action is pending in a United States court under section 302, 303, or 304 for an alleged violation of a provision of section 301 which enforces a requirement of section 505 or for an alleged violation of section 505(a), is classiﬁed in class III unless the Secretary in response to a petition submitted under paragraph (2) has classiﬁed such device in class I or II. (2) The Secretary may initiate the reclassiﬁcation of a device classiﬁed into class III under paragraph (1) of this subsection or the manufacturer or importer of a device classiﬁed under paragraph (1) may petition the Secretary (in such form and manner as he shall prescribe) for the issuance of an order classifying the device in class I or class II. Within thirty days of the ﬁling of such a petition, the Secretary shall notify the petitioner of any deﬁciencies in the petition which prevent the Secretary from making a decision on the petition. Except as provided in paragraph (3)(D)(ii), within one hundred and eighty days after the ﬁling of a petition under this paragraph, the Secretary shall, after consultation with the appropriate panel under section 513, by order either deny the petition or order the classiﬁcation, in accordance with the criteria prescribed by section 513(a)(1)(A) or 513(a)(1)(B), of the device in class I or class II. (3)(A) In the case of a device which is described in paragraph (1)(A) and which is in class III – (i) such device shall on the enactment date be considered a device with an approved application under section 515, and (ii) the requirements applicable to such device before the enactment date under section 505 shall continue to apply to such device until changed by the Secretary as authorized by this Act. (B) In the case of a device which is described in paragraph (1)(B) and which is in class III, an application for such device shall be considered as having been ﬁled under section 515 on the enactment date. The period in which the Secretary shall act on such application in accordance with section 515(d)(1) shall be one hundred and eighty days from the enactment date (or such greater period as the Secretary and the applicant may agree upon after the Secretary has made the ﬁnding required by section 515(d)(1)(B)(i)) less the number of days in the period beginning on the date an application for such device was ﬁled under section 505 and ending on the enactment date. After the expiration of such period such device is required, unless exempt under subsection (g) of this section, to have in effect an approved application under section 515. (C) A device which is described in paragraph (1)(C) and which is in class III shall be considered a new drug until the expiration of the ninety-day period beginning on the date of the promulgation of regulations under subsection (g) of this section. After the expiration of such period such device is required, unless exempt under subsection (g), to have in effect an approved application under section 515. (D)(i) Except as provided in clauses (ii) and (iii), a device which is described in subparagraph (D), (E), or (F) of paragraph (1) and which is in class III is required, unless exempt under subsection (g) of this section, to have on and after sixty days after the enactment date in effect an approved application under section 515. (ii) If – (I) a petition is ﬁled under paragraph (2) for a device described in subparagraph (D), (E), or (F) of paragraph (1), or (II) an application for premarket approval is ﬁled under section 360e of this title for such a device, within the sixty-day period beginning on the enactment date (or within such greater period as the Secretary, after making the ﬁnding required under section 515(d)(1)(B), and the petitioner or applicant may agree upon), the Secretary shall act on such petition or application

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in accordance with paragraph (2) or section 515 except that the period within which the Secretary must act on the petition or application shall be within the one hundred and twenty-day period beginning on the date the petition or application is ﬁled. If such a petition or application is ﬁled within such sixty-day (or greater) period, clause (i) of this subparagraph shall not apply to such device before the expiration of such one hundred and twentyday period, or if such petition is denied or such application is denied approval, before the date of such denial, whichever occurs ﬁrst. (iii) In the case of a device which is described in subparagraph (E) of paragraph (1), which the Secretary in a notice published in the Federal Register after March 31, 1976, declared to be a new drug subject to section 505, and which is in class III – (I) the device shall, after eighteen months after the enactment date, have in effect an approved application under section 515 unless exempt under subsection (g) of this section, and (II) the Secretary may, during the period beginning one hundred and eighty days after the enactment date and ending eighteen months after such date, restrict the use of the device to investigational use by experts qualiﬁed by scientiﬁc training and experience to investigate the safety and effectiveness of such device, and to investigational use in accordance with the requirements applicable under regulations under subsection (g) of this section to investigational use of devices granted an exemption under such subsection. If the requirements under subsection (g) of this section are made applicable to the investigational use of such a device, they shall be made applicable in such a manner that the device shall be made reasonably available to physicians meeting appropriate qualiﬁcations prescribed by the Secretary. [(4) Repealed by Pub. L 105–115, November 21, 1997.] (5)(A) Before December 1, 1991, the Secretary shall by order require manufacturers of devices described in paragraph (1), which are subject to revision of classiﬁcation under subparagraph (B), to submit to the Secretary a summary of and citation to any information known or otherwise available to the manufacturers respecting the devices, including adverse safety or effectiveness information which has not been submitted under section 519. The Secretary may require a manufacturer to submit the adverse safety or effectiveness data for which a summary and citation were submitted, if such data are available to the manufacturer. (B) Except as provided in subparagraph (C), after the issuance of an order under subparagraph (A) but before December 1, 1992, the Secretary shall publish a regulation in the Federal Register for each device which is classiﬁed in class III under paragraph (1) revising the classiﬁcation of the device so that the device is classiﬁed into class I or class II, unless the regulation requires the device to remain in class III. In determining whether to revise the classiﬁcation of a device or to require a device to remain in class III, the Secretary shall apply the criteria set forth in section 513(a). Before the publication of a regulation requiring a device to remain in class III or revising its classiﬁcation, the Secretary shall publish a proposed regulation respecting the classiﬁcation of a device under this subparagraph and provide an opportunity for the submission of comments on any such regulation. No regulation under this subparagraph requiring a device to remain in class III or revising its classiﬁcation may take effect before the expiration of 90 days from the date of the publication in the Federal Register of the proposed regulation. (C) The Secretary may by notice published in the Federal Register extend the period prescribed by subparagraph (B) for a device for an additional period not to exceed 1 year.

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Humanitarian Device Exemption (m)(1) To the extent consistent with the protection of the public health and safety and with ethical standards, it is the purpose of this subsection to encourage the discovery and use of devices intended to beneﬁt patients in the treatment and diagnosis of diseases or conditions that affect fewer than 4,000 individuals in the United States. (2) The Secretary may grant a request for an exemption from the effectiveness requirements of sections 514 and 515 for a device for which the Secretary ﬁnds that – (A) the device is designed to treat or diagnose a disease or condition that affects fewer than 4,000 individuals in the United States, (B) the device would not be available to a person with a disease or condition referred to in subparagraph (A) unless the Secretary grants such an exemption and there is no comparable device, other than under this exemption, available to treat or diagnose such disease or condition, and (C) the device will not expose patients to an unreasonable or signiﬁcant risk of illness or injury and the probable beneﬁt to health from the use of the device outweighs the risk of injury or illness from its use, taking into account the probable risks and beneﬁts of currently available devices or alternative forms of treatment. The request shall be in the form of an application submitted to the Secretary. Not later than 75 days after the date of the receipt of the application, the Secretary shall issue an order approving or denying the application. (3) No person granted an exemption under paragraph (2) with respect to a device may sell the device for an amount that exceeds the costs of research and development, fabrication, and distribution of the device. (4) Devices granted an exemption under paragraph (2) may only be used – (A) in facilities that have established, in accordance with regulations of the Secretary, a local institutional review committee to supervise clinical testing of devices in the facilities, and (B) if, before the use of a device, an institutional review committee approves the use in the treatment or diagnosis of a disease or condition referred to in paragraph (2)(A), unless a physician determines in an emergency situation that approval from a local institutional review committee can not be obtained in time to prevent serious harm or death to a patient. In a case described in subparagraph (B) in which a physician uses a device without an approval from an institutional review committee, the physician shall, after the use of the device, notify the chairperson of the local institutional review committee of such use. Such notiﬁcation shall include the identiﬁcation of the patient involved, the date on which the device was used, and the reason for the use. (5) The Secretary may require a person granted an exemption under paragraph (2) to demonstrate continued compliance with the requirements of this subsection if the Secretary believes such demonstration to be necessary to protect the public health or if the Secretary has reason to believe that the criteria for the exemption are no longer met. (6) The Secretary may suspend or withdraw an exemption from the effectiveness requirements of sections 514 and 515 for a humanitarian device only after providing notice and an opportunity for an informal hearing.

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AND

LOCAL REQUIREMENTS RESPECTING DEVICES

General Rule Section 521. [360k] (a) Except as provided in subsection (b), no State or political subdivision of a State may establish or continue in effect with respect to a device intended for human use any requirement – (1) which is different from, or in addition to, any requirement applicable under this Act to the device, and (2) which relates to the safety or effectiveness of the device or to any other matter included in a requirement applicable to the device under this Act. Exempt Requirements (b) Upon application of a State or a political subdivision thereof, the Secretary may, by regulation promulgated after notice and opportunity for an oral hearing, exempt from subsection (a), under such conditions as may be prescribed in such regulation, a requirement of such State or political subdivision applicable to a device intended for human use if – (1) the requirement is more stringent than a requirement under this Act which would be applicable to the device if an exemption were not in effect under this subsection; or (2) the requirement – (A) is required by compelling local conditions, and (B) compliance with the requirement would not cause the device to be in violation of any applicable requirement under this Act.

POSTMARKET SURVEILLANCE Section 522. [360l] (a) IN GENERAL — The Secretary may by order require a manufacturer to conduct postmarket surveillance for any device of the manufacturer which is a class II or class III device the failure of which would be reasonably likely to have serious adverse health consequences or which is intended to be – (1) implanted in the human body for more than one year, or (2) a life sustaining or life supporting device used outside a device user facility. (b) SURVEILLANCE APPROVAL — Each manufacturer required to conduct a surveillance of a device shall, within 30 days of receiving an order from the Secretary prescribing that the manufacturer is required under this section to conduct such surveillance, submit, for the approval of the Secretary, a plan for the required surveillance. The Secretary, within 60 days of the receipt of such plan, shall determine if the person designated to conduct the surveillance has appropriate qualiﬁcations and experience to undertake such surveillance and if the plan will result in the collection of useful data that can reveal unforeseen adverse events or other information necessary to protect the public health. The Secretary, in consultation with the manufacturer, may by order require a prospective surveillance period of up to 36 months. Any determination by the Secretary that a longer period is necessary shall be made by mutual agreement between the Secretary and the manufacturer or, if no agreement can be reached, after the completion of a dispute resolution process as described in section 562. Section 523. [360m] ACCREDITED PERSONS — (a) IN GENERAL — (1) REVIEW AND CLASSIFICATION OF DEVICES — Not later than 1 year after the date of the enactment of the Food and Drug Administration Modernization Act of 1997, the Secretary

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subject to paragraph (3), accredit persons for the purpose of reviewing reports submitted under section 510(k) and making recommendations to the Secretary regarding the initial classiﬁcation of devices under section 513(f)(l). (2) REQUIREMENTS REGARDING REVIEW — (A) IN GENERAL — In making a recommendation to the Secretary under paragraph (1), an accredited person shall notify the Secretary in writing of the reasons for the recommendation. (B) TIME PERIOD FOR REVIEW — Not later than 30 days after the date on which the Secretary is notiﬁed under subparagraph (A) by an accredited person with respect to a recommendation of an initial classiﬁcation of a device, the Secretary shall make a determination with respect to the initial classiﬁcation. (C) SPECIAL RULE — The Secretary may change the initial classiﬁcation under section 513(f)(l) that is recommended under paragraph (1) by an accredited person, and in such case shall provide to such person, and the person who submitted the report under section 510(k) for the device, a statement explaining in detail the reasons for the change. (3) CERTAIN DEVICES — (A) IN GENERAL — An accredited person may not be used to perform a review of – (i) a class III device; (ii) a class II device which is intended to be permanently implantable or life sustaining or life supporting; or (iii) a class II device which requires clinical data in the report submitted under section 510(k) for the device, except that the number of class II devices to which the Secretary applies this clause for a year, less the number of such reports to which clauses (i) and (ii) apply, may not exceed 6 percent of the number that is equal to the total number of reports submitted to the Secretary under such section for such year less the number of such reports to which such clauses apply for such year. (B) ADJUSTMENT — In determining for a year the ratio described in subparagraph (A)(iii), the Secretary shall not include in the numerator class III devices that the Secretary reclassiﬁed into class II, and the Secretary shall include in the denominator class II devices for which reports under section 510(k) were not required to be submitted by reason of the operation of section 510(m). (b) ACCREDITATION — (1) PROGRAMS — The Secretary shall provide for such accreditation through programs administered by the Food and Drug Administration, other government agencies, or by other qualiﬁed nongovernmental organizations. (2) ACCREDITATION — (A) IN GENERAL — Not later than 180 days after the date of the enactment of the Food and Drug Administration Modernization Act of 1997, the Secretary shall establish and publish in the Federal Register criteria to accredit or deny accreditation to persons who request to perform the duties speciﬁed in subsection (a). The Secretary shall respond to a request for accreditation within 60 days of the receipt of the request. The accreditation of such person shall specify the particular activities under subsection (a) for which such person is accredited. (B) WITHDRAWAL OF ACCREDITATION — The Secretary may suspend or withdraw accreditation of any person accredited under this paragraph, after providing notice and an opportunity for an informal hearing, when such person is substantially not in compliance with the requirements of this section or poses a threat to public health or fails to act in a manner that is consistent with the purposes of this section.

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(C) PERFORMANCE AUDITING — To ensure that persons accredited under this section will continue to meet the standards of accreditation, the Secretary shall – (i) make onsite visits on a periodic basis to each accredited person to audit the performance of such person; and (ii) take such additional measures as the Secretary determines to be appropriate. (D) ANNUAL REPORT — The Secretary shall include in the annual report required under section 903(g) the names of all accredited persons and the particular activities under subsection (a) for which each such person is accredited and the name of each accredited person whose accreditation has been withdrawn during the year. (3) QUALIFICATIONS — An accredited person shall, at a minimum, meet the following requirements: (A) Such person may not be an employee of the Federal Government. (B) Such person shall be an independent organization which is not owned or controlled by a manufacturer, supplier, or vendor of devices and which has no organizational, material, or ﬁnancial afﬁliation with such a manufacturer, supplier, or vendor. (C) Such person shall be a legally constituted entity permitted to conduct the activities for which it seeks accreditation. (D) Such person shall not engage in the design, manufacture, promotion, or sale of devices. (E) The operations of such person shall be in accordance with generally accepted professional and ethical business practices and shall agree in writing that as a minimum it will – (i) certify that reported information accurately reﬂects data reviewed; (ii) limit work to that for which competence and capacity are available; (iii) treat information received, records, reports, and recommendations as proprietary information; (iv) promptly respond and attempt to resolve complaints regarding its activities for which it is accredited; and (v) protect against the use, in carrying out subsection (a) with respect to a device, of any ofﬁcer or employee of the person who has a ﬁnancial conﬂict of interest regarding the device, and annually make available to the public disclosures of the extent to which the person, and the ofﬁcers and employees of the person, have maintained compliance with requirements under this clause relating to ﬁnancial conﬂicts of interest. (4) SELECTION OF ACCREDITED PERSONS — The Secretary shall provide each person who chooses to use an accredited person to receive a section 510(k) report a panel of at least two or more accredited persons from which the regulated person may select one for a speciﬁc regulatory function. (5) COMPENSATION OF ACCREDITED PERSONS — Compensation for an accredited person shall be determined by agreement between the accredited person and the person who engages the services of the accredited person, and shall be paid by the person who engages such services. (c) DURATION — The authority provided by this section terminates – (1) 5 years after the date on which the Secretary notiﬁes Congress that at least; 2 persons accredited under subsection (b) are available to review at least 60 percent of the submissions under section 510(k), or (2) 4 years after the date on which the Secretary notiﬁes Congress that the Secretary has made a determination described in paragraph (2)(B) of subsection (a) for at least 35 percent of the devices that are subject to review under paragraph (1) of such subsection, whichever occurs ﬁrst.

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SUBCHAPTER B. DRUGS

FOR

RARE DISEASES

OR

CONDITIONS

RECOMMENDATIONS FOR INVESTIGATIONS OF DRUGS FOR RARE DISEASES OR CONDITIONS Section 525. [360aa] (a) The sponsor of a drug for a disease or condition which is rare in the States may request the Secretary to provide written recommendations for the non-clinical and clinical investigations which must be conducted with the drug before – (1) it may be approved for such disease or condition under section 505, or (2) if the drug is a biological product, it may be licensed for such disease or condition under section 351 of the Public Health Service Act. If the Secretary has reason to believe that a drug for which a request is made under this section is a drug for a disease or condition which is rare in the States, the Secretary shall provide the person making the request written recommendations for the nonclinical and clinical investigations which the Secretary believes, on the basis of information available to the Secretary at the time of the request under this section, would be necessary for approval of such drug for such disease or condition under section 505 or licensing of such drug for such disease or condition under section 351 of the Public Health Service Act. (b) The Secretary shall by regulation promulgate procedures for the implementation of subsection (a).

DESIGNATION

OF

DRUGS

FOR

RARE DISEASES

OR

CONDITIONS

Section 526. [360bb] (a)(1) The manufacturer or the sponsor of a drug may request the Secretary to designate the drug as a drug for a rare disease or condition. A request for designation of a drug shall be made before the submission of an application under section 505(b) for the drug, the submission of an application for certiﬁcation of the drug under section 357 of this title, or the submission of an application for licensing of the drug under section 351 of the Public Health Service Act. If the Secretary ﬁnds that a drug for which a request is submitted under this subsection is being or will be investigated for a rare disease or condition and – (A) if an application for such drug is approved under section 505, (B) if a license for such drug is issued under section 351 of the Public Health Service Act, the approval, certiﬁcation, or license would be for use for such disease or condition, the Secretary shall designate the drug as a drug for such disease or condition. A request for a designation of a drug under this subsection shall contain the consent of the applicant to notice being given by the Secretary under subsection (b) respecting the designation of the drug. (2) For purposes of paragraph (1), the term “rare disease or condition” means any disease or condition which (A) affects less than 200,000 persons in the United States, or (B) affects more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales in the United States of such drug. Determinations under the preceding sentence with respect to any drug shall be made on the basis of the facts and circumstances as of the date the request for designation of the drug under this subsection is made. (b) A designation of a drug under subsection (a) shall be subject to the condition that – (1) if an application was approved for the drug under section 505(b) or a license was issued for the drug under section 351 of the Public Health Service Act, the manufacturer of the drug will notify the Secretary of any discontinuance of the production of the drug at least one year before discontinuance, and

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(2) if an application has not been approved for the drug under section 505(b) or a license has not been issued for the drug under section 351 of the Public Health Service Act and if preclinical investigations or investigations under section 505(i) are being conducted with the drug, the manufacturer or sponsor of the drug will notify the Secretary of any decision to discontinue active pursuit of approval of an application under section 505(b) or approval of a license under section 351 of the Public Health Service Act. (c) Notice respecting the designation of a drug under subsection (a) shall be made available to the public. (d) The Secretary shall by regulation promulgate procedures for the implementation of subsection (a).

PROTECTION

FOR

DRUGS

FOR

RARE DISEASES

OR

CONDITIONS

Section 527. [360cc] (a) Except as provided in subsection (b), if the Secretary – (1) approves an application ﬁled pursuant to section 505, or (2) issues a license under section 351 of the Public Health Service Act for a drug designated under section 526 for a rare disease or condition, the Secretary may not approve another application under section 505 or issue another license under section 351 of the Public Health Service Act for such drug for such disease or condition for a person who is not the holder of such approved application, of such certiﬁcation, or of such license until the expiration of seven years from the date of the approval of the approved application, the issuance of the certiﬁcation, or the issuance of the license. Section 505(c)(2) does not apply to the refusal to approve an application under the preceding sentence. (b) If an application ﬁled pursuant to section 505 is approved for a drug designated under section 526 for a rare disease or condition, or if a license is issued under section 351 of the Public Health Service Act for such a drug, the Secretary may, during the seven-year period beginning on the date of the application approval, or of the issuance of the license, approve another application under section 355 of this title, or issue a license under section 351 of the Public Health Service Act, for such drug for such disease or condition for a person who is not the holder of such approved application, of such certiﬁcation, or of such license if – (1) the Secretary ﬁnds, after providing the holder notice and opportunity for the submission of views, that in such period the holder of the approved application, or of the license cannot assure the availability of sufﬁcient quantities of the drug to meet the needs of persons with the disease or condition for which the drug was designated; or (2) such holder provides the Secretary in writing the consent of such holder for the approval of other applications, or the issuance of other licenses before the expiration of such seven-year period.

OPEN PROTOCOLS FOR INVESTIGATIONS OF DRUGS FOR RARE DISEASES OR CONDITIONS Section 528. [360dd] If a drug is designated under section 526 as a drug for a rare disease or condition and if notice of a claimed exemption under section 505(i) or regulations issued thereunder is ﬁled for such drug, the Secretary shall encourage the sponsor of such drug to design protocols for clinical investigations of the drug which may be conducted under the exemption to permit the addition to the investigations of persons with the disease or condition who need the drug to treat the disease or condition and who cannot be satisfactorily treated by available alternative drugs.

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SUBCHAPTER C. ELECTRONIC PRODUCT RADIATION CONTROL DEFINITIONS Section 531. [360hh] As used in this subchapter – (1) the term “electronic product radiation” means – (A) any ionizing or non-ionizing electromagnetic or particulate radiation, or (B) any sonic, infrasonic, or ultrasonic wave, which is emitted from an electronic product as the result of the operation of an electronic circuit in such product; (2) the term “electronic product” means (A) any manufactured or assembled product which, when in operation, (i) contains or acts as part of an electronic circuit and (ii) emits (or in the absence of effective shielding or other controls would emit) electronic product radiation, or (B) any manufactured or assembled article which is intended for use as a component, part, or accessory of a product described in clause (A) and which when in operation emits (or in the absence of effective shielding or other controls would emit) such radiation; (3) the term “manufacturer” means any person engaged in the business of manufacturing, assembling, or importing of electronic products; (4) the term “commerce” means (A) commerce between any place in any State and any place outside thereof; and (B) commerce wholly within the District of Columbia; and (5) the term “State” includes the District of Columbia, the Commonwealth of Puerto Rico, the Northern Mariana Islands, the Virgin Islands, Guam, and American Samoa.

ELECTRONIC PRODUCT RADIATION CONTROL PROGRAM Section 532. [360ii] (a) The Secretary shall establish and carry out an electronic product radiation control program designed to protect the public health and safety from electronic product radiation. As a part of such program, he shall – (1) pursuant to section 534, develop and administer performance standards for electronic products; (2) plan, conduct, coordinate, and support research, development, training, and operational activities to minimize the emissions of and the exposure of people to, unnecessary electronic product radiation; (3) maintain liaison with and receive information from other Federal and State departments and agencies with related interests, professional organizations, industry, industry and labor associations, and other organizations on present and future potential electronic product radiation; (4) study and evaluate emissions of, and conditions of exposure to, electronic product radiation and intense magnetic ﬁelds; (5) develop, test, and evaluate the effectiveness of procedures and techniques for minimizing exposure to electronic product radiation; and (6) consult and maintain liaison with the Secretary of Commerce, the Secretary of Defense, the Secretary of Labor, the Atomic Energy Commission, and other appropriate Federal departments and agencies on (A) techniques, equipment, and programs for testing and evaluating electronic product radiation, and (B) the development of performance standards pursuant to section 534 to control such radiation emissions. (b) In carrying out the purposes of subsection (a), the Secretary is authorized to – (1)(A) collect and make available, through publications and other appropriate means, the results of, and other information concerning, research and studies relating to the nature and extent of the hazards and control of electronic product radiation; and

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(B) make such recommendations relating to such hazards and control as he considers appropriate; (2) make grants to public and private agencies, organizations, and institutions, and to individuals for the purposes stated in paragraphs (2), (4), and (5) of subsection (a); (3) contract with public or private agencies, institutions, and organizations, and with individuals, without regard to section 3324 of title 31 United States Code and Section 3709 of the Revised Statutes of the United States Code (41 U.S.C. 5); and (4) procure (by negotiation or otherwise) electronic products for research and testing purposes, and sell or otherwise dispose of such products. (c)(1) Each recipient of assistance under this subchapter pursuant to grants or contracts entered into under other than competitive bidding procedures shall keep such records as the Secretary shall prescribe, including records which fully disclose the amount and disposition by such recipient of the proceeds of such assistance, the total cost of the project or undertaking in connection with which such assistance is given or used, and the amount of that portion of the cost of the project or undertaking supplied by other sources, and such other records as will facilitate an effective audit. (2) The Secretary and the Comptroller General of the United States, or any of their duly authorized representatives, shall have access for the purpose of audit and examination to any books, documents, papers, and records of the recipients that are pertinent to the grants or contracts entered into under this subchapter under other than competitive bidding procedures.

STUDIES

BY THE

SECRETARY

Section 533. [360jj] (a) The Secretary shall conduct the following studies, and shall make a report or reports of the results of such studies to the Congress on or before January 1, 1970, and from time to time thereafter as he may ﬁnd necessary, together with such recommendations for legislation as he may deem appropriate: (1) A study of present State and Federal control of health hazards from electronic product radiation and other types of ionizing radiation, which study shall include, but not be limited to – (A) control of health hazards from radioactive materials other than materials regulated under the Atomic Energy Act of 1954; (B) any gaps and inconsistencies in present controls; (C) the need for controlling the sale of certain used electronic products, particularly antiquated X-ray equipment, without upgrading such products to meet the standards for new products or separate standards for used products; (D) measures to assure consistent and effective control of the aforementioned health hazards; (E) measures to strengthen radiological health programs of State governments; and (F) the feasibility of authorizing the Secretary to enter into arrangements with individual States or groups of States to deﬁne their respective functions and responsibilities for the control of electronic product radiation and other ionizing radiation; (2) A study to determine the necessity for the development of standards for the use of nonmedical electronic products for commercial and industrial purposes; and (3) A study of the development of practicable procedures for the detection and measurement of electronic product radiation which may be emitted from electronic products manufactured or imported prior to the effective date of any applicable standard established pursuant to this subchapter.

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(b) In carrying out these studies, the Secretary shall invite the participation of other Federal departments and agencies having related responsibilities and interests, State governments — particularly those of States which regulate radioactive materials under section 274 of the Atomic Energy Act of 1954, as amended, and interested professional, labor, and industrial organizations. Upon request from congressional committees interested in these studies, the Secretary shall keep these committees currently informed as to the progress of the studies and shall permit the committees to send observers to meetings of the study groups. (c) The Secretary or his designee shall organize the studies and the participation of the invited participants as he deems best. Any dissent from the ﬁndings and recommendations of the Secretary shall be included in the report if so requested by the dissenter.

PERFORMANCE STANDARDS

FOR

ELECTRONIC PRODUCTS

Section 534. [360kk] (a)(1) The Secretary shall by regulation prescribe performance standards for electronic products to control the emission of electronic product radiation from such products if he determines that such standards are necessary for the protection of the public health and safety. Such standards may include provisions for the testing of such products and the measurement of their electronic product radiation emissions, may require the attachment of warning signs and labels, and may require the provision of instructions for the installation, operation, and use of such products. Such standards may be prescribed from time to time whenever such determinations are made, but the ﬁrst of such standards shall be prescribed prior to January 1, 1970. In the development of such standards, the Secretary shall consult with Federal and State departments and agencies having related responsibilities or interests and with appropriate professional organizations and interested persons, including representatives of industries and labor organizations which would be affected by such standards, and shall give consideration to – (A) the latest available scientiﬁc and medical data in the ﬁeld of electronic product radiation; (B) the standards currently recommended by (i) other Federal agencies having responsibilities relating to the control and measurement of electronic product radiation, and (ii) public or private groups having an expertise in the ﬁeld of electronic product radiation; (C) the reasonableness and technical feasibility of such standards as applied to a particular electronic product; (D) the adaptability of such standards to the need for uniformity and reliability of testing and measuring procedures and equipment; and (E) in the case of a component, or accessory described in paragraph (2)(B) of section 531, the performance of such article in the manufactured or assembled product for which it is designed. (2) The Secretary may prescribe different and individual performance standards, to the extent appropriate and feasible, for different electronic products so as to recognize their different operating characteristics and uses. (3) The performance standards prescribed under this section shall not apply to any electronic product which is intended solely for export if (A) such product and the outside of any shipping container used in the export of such product are labeled or tagged to show that such product is intended for export, and (B) such product meets all the applicable requirements of the country to which such product is intended for export. (4) The Secretary may by regulation amend or revoke any performance standard prescribed under this section.

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(5) The Secretary may exempt from the provisions of this section any electronic product intended for use by departments or agencies of the United States provided such department or agency has prescribed procurement speciﬁcations governing emissions of electronic product radiation and provided further that such product is of a type used solely or predominantly by departments or agencies of the United States. (b) The provisions of subchapter II of chapter 5 of title 5 of the United States Code (relating to the administrative procedure for rulemaking), and of chapter 7 of such title (relating to judicial review), shall apply with respect to any regulation prescribing, amending, or revoking any standard prescribed under this section. (c) Each regulation prescribing, amending, or revoking a standard shall specify the date on which it shall take effect which, in the case of any regulation prescribing, or amending any standard, may not be sooner than one year or not later than two years after the date on which such regulation is issued, unless the Secretary ﬁnds, for good cause shown, that an earlier or later effective date is in the public interest and publishes in the Federal Register his reason for such ﬁnding, in which case such earlier or later date shall apply. (d)(1) In a case of actual controversy as to the validity of any regulation issued under this section prescribing, amending, or revoking a performance standard, any person who will be adversely affected by such regulation when it is effective may at any time prior to the sixtieth day after such regulation is issued ﬁle a petition with the United States court of appeals for the circuit wherein such person resides or has his principal place of business, for a judicial review of such regulation. A copy of the petition shall be forthwith transmitted by the clerk of the court to the Secretary or other ofﬁcer designated by him for that purpose. The Secretary thereupon shall ﬁle in the court the record of the proceedings on which the Secretary based the regulation, as provided in section 2112 of title 28 of the United States Code. (2) If the petitioner applies to the court for leave to adduce additional evidence, and shows to the satisfaction of the court that such additional evidence is material and that there were reasonable grounds for the failure to adduce such evidence in the proceeding before the Secretary, the court may order such additional evidence (and evidence in rebuttal thereof) to be taken before the Secretary, and to be adduced upon the hearing, in such manner and upon such terms and conditions as to the court may seem proper. The Secretary may modify his ﬁndings, or make new ﬁndings, by reason of the additional evidence so taken, and he shall ﬁle such modiﬁed or new ﬁndings, and his recommendations, if any, for the modiﬁcation or setting aside of his original regulation, with the return of such additional evidence. (3) Upon the ﬁling of the petition referred to in paragraph (1) of this subsection, the court shall have jurisdiction to review the regulation in accordance with chapter 7 of title 5 of the United States Code and to grant appropriate relief as provided in such chapter. (4) The judgment of the court afﬁrming or setting aside, in whole or in part, any such regulation of the Secretary shall be ﬁnal, subject to review by the Supreme Court of the United States upon certiorari or certiﬁcation as provided in section 1254 of title 28 of the United States Code. (5) Any action instituted under this subsection shall survive, notwithstanding any change in the person occupying the ofﬁce of Secretary or any vacancy in such ofﬁce. (6) The remedies provided for in this subsection shall be in addition to and not substitution for any other remedies provided by law. (e) A certiﬁed copy of the transcript of the record and administrative proceedings under this section shall be furnished by the Secretary to any interested party at his request, and payment of the costs thereof, and shall be admissible in any criminal, exclusion of imports, or other proceeding arising under or in respect of this subchapter irrespective of whether proceedings with respect to the regulation have previously been initiated or become ﬁnal under this section.

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(f)(1)(A) The Secretary shall establish a Technical Electronic Product Radiation Safety Standards Committee (hereafter in this part referred to as the “Committee”) which he shall consult before prescribing any standard under this section. The Committee shall be appointed by the Secretary, after consultation with public and private agencies concerned with the technical aspect of electronic product radiation safety, and shall be composed of ﬁfteen members each of whom shall be technically qualiﬁed by training and experience in one or more ﬁelds of science or engineering applicable to electronic product radiation safety, as follows: (i) Five members shall be selected from governmental agencies, including State and Federal Governments; (ii) Five members shall be selected from the affected industries after consultation with industry representatives; and (iii) Five members shall be selected from the general public, of which at least one shall be a representative of organized labor. (B) The Committee may propose electronic product radiation safety standards to the Secretary for his consideration. All proceedings of the Committee shall be recorded and the record of each such proceeding shall be available for public inspection. (2) Payments to members of the Committee who are not ofﬁcers or employees of the United States pursuant to subsection (c) of section 208 of the Public Health Service Act shall not render members of the Committee ofﬁcers or employees of the United States for any purpose. (g) The Secretary shall review and evaluate on a continuing basis testing programs carried out by industry to assure the adequacy of safeguards against hazardous electronic product radiation and to assure that electronic products comply with standards prescribed under this section. (h) Every manufacturer of an electronic product to which is applicable a standard in effect under this section shall furnish to the distributor or dealer at the time of delivery of such product, in the form of a label or tag permanently afﬁxed to such product or in such manner as approved by the Secretary, the certiﬁcation that such product conforms to all applicable standards under this section. Such certiﬁcation shall be based upon a test, in accordance with such standard, of the individual article to which it is attached or upon a testing program which is in accord with good manufacturing practice and which has not been disapproved by the Secretary (in such manner as he shall prescribe by regulation) on the grounds that it does not assure the adequacy of safeguards against hazardous electronic product radiation or that it does not assure that electronic products comply with the standards prescribed under this section.

NOTIFICATION OF DEFECTS IN AND REPAIR OR REPLACEMENT OF ELECTRONIC PRODUCTS Section 535. [360ll] (a)(1) Every manufacturer of electronic products who discovers that an electronic product produced, assembled, or imported by him has a defect which relates to the safety of use of such product by reason of the emission of electronic product radiation, or that an electronic product produced, assembled, or imported by him on or after the effective date of an applicable standard prescribed pursuant to section 534 fails to comply with such standard, shall immediately notify the Secretary of such defect or failure to comply if such product has left the place of manufacture and shall (except as authorized by paragraph (2)) with reasonable promptness furnish notiﬁcation of such defect or failure to the persons (where known to the manufacturer) speciﬁed in subsection (b) of this section. (2) If, in the opinion of such manufacturer, the defect or failure to comply is not such as to create a signiﬁcant risk of injury, including genetic injury, to any person, he may, at the time of giving notice to the Secretary of such defect or failure to comply, apply to the Secretary for an exemption from the requirement of notice to the persons speciﬁed in subsection (b). If such application states reasonable grounds for such exemption, the Secretary shall afford such manufacturer an

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opportunity to present his views and evidence in support of the application, the burden of proof being on the manufacturer. If, after such presentation, the Secretary is satisﬁed that such defect or failure to comply is not such as to create a signiﬁcant risk of injury, including genetic injury, to any person, he shall exempt such manufacturer from the requirement of notice to the persons speciﬁed in subsection (b) of this section and from the requirements of repair or replacement imposed by subsection (f) of this section. (b) The notiﬁcation (other than to the Secretary) required by paragraph (1) of subsection (a) of this section shall be accomplished – (1) by certiﬁed mail to the ﬁrst purchaser of such product for purposes other than resale, and to any subsequent transferee of such product; and (2) by certiﬁed mail or other more expeditious means to the dealers or distributors of such manufacturer to whom such product was delivered. (c) The notiﬁcations required by paragraph (1) of subsection (a) of this section shall contain a clear description of such defect or failure to comply with an applicable standard, an evaluation of the hazard reasonably related to such defect or failure to comply, and a statement of the measures to be taken to repair such defect. In the case of a notiﬁcation to a person referred to in subsection (b) of this section, the notiﬁcation shall also advise the person of his rights under subsection (f) of this section. (d) Every manufacturer of electronic products shall furnish to the Secretary a true or representative copy of all notices, bulletins, and other communications to the dealers or distributors of such manufacturer or to purchasers (or subsequent transferees) of electronic products of such manufacturer regarding any such defect in such product or any such failure to comply with a standard applicable to such product. The Secretary shall disclose to the public so much of the information contained in such notice or other information obtained under section 537 as he deems will assist in carrying out the purposes of this subchapter, but he shall not disclose any information which contains or relates to a trade secret or other matter referred to in section 1905 of title 18 United States Code unless he determines that it is necessary to carry out the purposes of this subchapter. (e) If through testing, inspection, investigation, or research carried out pursuant to this subchapter, or examination of reports submitted pursuant to section 537, or otherwise, the Secretary determines that any electronic product – (1) does not comply with an applicable standard prescribed pursuant to section 534; or (2) contains a defect which relates to the safety of use of such product by reason of the emission of electronic product radiation; he shall immediately notify the manufacturer of such product of such defect or failure to comply. The notice shall contain the ﬁndings of the Secretary and shall include all information upon which the ﬁndings are based. The Secretary shall afford such manufacturer an opportunity to present his views and evidence in support thereof, to establish that there is no failure of compliance or that the alleged defect does not exist or does not relate to safety of use of the product by reason of the emission of such radiation hazard. If after such presentation by the manufacturer the Secretary determines that such product does not comply with an applicable standard prescribed pursuant to section 534, or that it contains a defect which relates to the safety of use of such product by reason of the emission of electronic product radiation, the Secretary shall direct the manufacturer to furnish the notiﬁcation speciﬁed in subsection (c) to the persons speciﬁed in paragraphs (1) and (2) of subsection (b) (where known to the manufacturer), unless the manufacturer has applied for an exemption from the requirement of such notiﬁcation on the ground speciﬁed in paragraph (2) of subsection (a) and the Secretary is satisﬁed that such noncompliance or defect is not such as to create a signiﬁcant risk of injury, including genetic injury, to any person.

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(f) If any electronic product is found under subsection (a) or (e) to fail to comply with an applicable standard prescribed under this subchapter or to have a defect which relates to the safety of use of such product, and the notiﬁcation speciﬁed in subsection (c) is required to be furnished on account of such failure or defect, the manufacturer of such product shall (1) without charge, bring such product into conformity with such standard or remedy such defect and provide reimbursement for any expenses for transportation of such product incurred in connection with having such product brought into conformity or having such defect remedied, (2) replace such product with a like or equivalent product which complies with each applicable standard prescribed under this subchapter and which has no defect relating to the safety of its use, or (3) make a refund of the cost of such product. The manufacturer shall take the action required by this subsection in such manner, and with respect to such persons, as the Secretary by regulations shall prescribe. (g) This section shall not apply to any electronic product that was manufactured before the date of the enactment of this subchapter.

IMPORTS Section 536. [360mm] (a) Any electronic product offered for importation into the United States which fails to comply with an applicable standard prescribed under this subchapter, or to which is not afﬁxed a certiﬁcation in the form of a label or tag in conformity with section 534(h) shall be refused admission into the United States. The Secretary of the Treasury shall deliver to the Secretary of Health and Human Services, upon the latter’s request, samples of electronic products which are being imported or offered for import into the United States, giving notice thereof to the owner or consignee, who may have a hearing before the Secretary of Health and Human Services. If it appears from an examination of such samples or otherwise that any electronic product fails to comply with applicable standards prescribed pursuant to section 534, then, unless subsection (b) applies and is complied with, (1) such electronic product shall be refused admission, and (2) the Secretary of the Treasury shall cause the destruction of such electronic product unless such article is exported, under regulations prescribed by the Secretary of the Treasury, within 90 days after the date of notice of refusal of admission or within such additional time as may be permitted by such regulations. (b) If it appears to the Secretary of Health and Human Services that any electronic product refused admission pursuant to subsection (a) can be brought into compliance with applicable standards prescribed pursuant to section 534, ﬁnal determination as to admission of such electronic product may be deferred upon ﬁling of timely written application by the owner or consignee and the execution by him of a good and sufﬁcient bond providing for the payment of such liquidated damages in the event of default as the Secretary of Health and Human Services may by regulation prescribe. If such application is ﬁled and such bond is executed the Secretary of Health and Human Services may, in accordance with rules prescribed by him, permit the applicant to perform such operations with respect to such electronic product as may be speciﬁed in the notice of permission. (c) All expenses (including travel, per diem or subsistence, and salaries of ofﬁcers or employees of the United States) in connection with the destruction provided for in subsection (a) and the supervision of operations provided for in subsection (b) of this section, and all expenses in connection with the storage, cartage, or labor with respect to any electronic product refused admission pursuant to subsection (a), shall be paid by the owner or consignee, and, in event of default, shall constitute a lien against any future importations made by such owner or consignee. (d) It shall be the duty of every manufacturer offering an electronic product for importation into the United States to designate in writing an agent upon whom service of all administrative and judicial processes, notices, orders, decisions, and requirements may be made for and on behalf of said manufacturer, and to ﬁle such designation with the Secretary, which designation may from

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time to time be changed by like writing, similarly ﬁled. Service of all administrative and judicial processes, notices, orders, decisions, and requirements may be made upon said manufacturer by service upon such designated agent at his ofﬁce or usual place of residence with like effect as if made personally upon said manufacturer, and in default of such designation of such agent, service of process, notice, order, requirement, or decision in any proceeding before the Secretary or in any judicial proceeding for enforcement of this subchapter or any standards prescribed pursuant to this subchapter may be made by posting such process, notice, order, requirement, or decision in the Ofﬁce of the Secretary or in a place designated by him by regulation.

INSPECTION

AND

REPORTS

Section 537. [360nn] (a) If the Secretary ﬁnds for good cause that the methods, tests, or programs related to electronic product radiation safety in a particular factory, warehouse, or establishment in which electronic products are manufactured or held, may not be adequate or reliable, ofﬁcers or employees duly designated by the Secretary, upon presenting appropriate credentials and a written notice to the owner, operator, or agent in charge, are thereafter authorized (1) to enter, at reasonable times, any area in such factory, warehouse, or establishment in which the manufacturer’s tests (or testing programs) required by section 534(h) are carried out, and (2) to inspect, at reasonable times and within reasonable limits and in a reasonable manner, the facilities and procedures within such area which are related to electronic product radiation safety. Each such inspection shall be commenced and completed with reasonable promptness. In addition to other grounds upon which good cause may be found for purposes of this subsection, good cause will be considered to exist in any case where the manufacturer has introduced into commerce any electronic product which does not comply with an applicable standard prescribed under this part and with respect to which no exemption from the notiﬁcation requirements has been granted by the Secretary under section 535(a)(2) or 535(e). (b) Every manufacturer of electronic products shall establish and maintain such records (including testing records), make such reports, and provide such information, as the Secretary may reasonably require to enable him to determine whether such manufacturer has acted or is acting in compliance with this subchapter and standards prescribed pursuant to this subchapter and shall, upon request of an ofﬁcer or employee duly designated by the Secretary, permit such ofﬁcer or employee to inspect appropriate books, papers, records, and documents relevant to determining whether such manufacturer has acted or is acting in compliance with standards prescribed pursuant to this subchapter. (c) Every manufacturer of electronic products shall provide to the Secretary such performance data and other technical data related to safety as may be required to carry out the purposes of this subchapter. The Secretary is authorized to require the manufacturer to give such notiﬁcation of such performance and technical data at the time of original purchase to the ultimate purchaser of the electronic product, as he determines necessary to carry out the purposes of this subchapter after consulting with the affected industry. (d) Accident and investigation reports made under this subchapter by any ofﬁcer, employee, or agent of the Secretary shall be available for use in any civil, criminal, or other judicial proceeding arising out of such accident. Any such ofﬁcer, employee, or agent may be required to testify in such proceedings as to the facts developed in such investigations. Any such report shall be made available to the public in a manner which need not identify individuals. All reports on research projects, demonstration projects, and other related activities shall be public information. (e) The Secretary or his representative shall not disclose any information reported to or otherwise obtained by him, pursuant to subsection (a) or (b), which concerns any information which contains or relates to a trade secret or other matter referred to in section 1905 of title 18 of the United States Code, except that such information may be disclosed to other ofﬁcers or employees of the Department

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and of other agencies concerned with carrying out this subchapter or when relevant in any proceeding under this subchapter. Nothing in this section shall authorize the withholding of information by the Secretary, or by any ofﬁcers or employees under his control, from the duly authorized committees of the Congress. (f) The Secretary may by regulation (1) require dealers and distributors of electronic products, to which there are applicable standards prescribed under this subchapter and the retail prices of which is not less than $50, to furnish manufacturers of such products such information as may be necessary to identify and locate, for purposes of section 535, the ﬁrst purchasers of such products for purposes other than resale, and (2) require manufacturers to preserve such information. Any regulation establishing a requirement pursuant to clause (1) of the preceding sentence shall (A) authorize such dealers and distributors to elect, in lieu of immediately furnishing such information to the manufacturer, to hold and preserve such information until advised by the manufacturer or Secretary that such information is needed by the manufacturer for purposes of section 535, and (B) provide that the dealer or distributor shall, upon making such election, give prompt notice of such election (together with information identifying the notiﬁer and the product) to the manufacturer and shall, when advised by the manufacturer or Secretary, of the need therefor for the purposes of section 535, immediately furnish the manufacturer with the required information. If a dealer or distributor discontinues the dealing in or distribution of electronic products, he shall turn the information over to the manufacturer. Any manufacturer receiving information pursuant to this subsection concerning ﬁrst purchasers of products for purposes other than resale shall treat it as conﬁdential and may use it only if necessary for the purpose of notifying persons pursuant to section 535(a).

PROHIBITED ACTS Section 538. [360oo] (a) It shall be unlawful – (1) for any manufacturer to introduce, or to deliver for introduction, into commerce, or to import into the United States, any electronic product which does not comply with an applicable standard prescribed pursuant to section 534; (2) for any person to fail to furnish any notiﬁcation or other material or information required by section 535 or 537; or to fail to comply with the requirements of section 535; (3) for any person to fail or to refuse to establish or maintain records required by this subchapter or to permit access by the Secretary or any of his duly authorized representatives to, or the copying of, such records, or to permit entry or inspection, as required by or pursuant to section 537; (4) for any person to fail or to refuse to make any report required pursuant to section 537(b) or to furnish or preserve any information required pursuant to section 537(f); or (5) for any person (A) to fail to issue a certiﬁcation as required by section 534(h), or (B) to issue such a certiﬁcation when such certiﬁcation is not based upon a test or testing program meeting the requirements of section 534(h) or when the issuer, in the exercise of due care, would have reason to know that such certiﬁcation is false or misleading in a material respect. (b) The Secretary may exempt any electronic product, or class thereof, from all or part of subsection (a), upon such conditions as he may ﬁnd necessary to protect the public health or welfare, for the purpose of research, investigations, studies, demonstrations, or training, or for reasons of national security.

ENFORCEMENT Section 539. [360pp] (a) The district courts of the United States shall have jurisdiction, for cause shown, to restrain violations of section 538 and to restrain dealers and distributors of electronic products from selling or otherwise disposing of electronic products which do not conform to an

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applicable standard prescribed pursuant to section 534 except when such products are disposed of by returning them to the distributor or manufacturer from whom they were obtained. The district courts of the United States shall also have jurisdiction in accordance with section 1355 of title 28 of the United States Code to enforce the provisions of subsection (b) of this section. (b)(1) Any person who violates section 538 shall be subject to a civil penalty of not more than $1,000. For purposes of this subsection, any such violation shall with respect to each electronic product involved, or with respect to each act or omission made unlawful by section 538, constitute a separate violation, except that the maximum civil penalty imposed on any person under this subsection for any related series of violations shall not exceed $300,000. (2) Any such civil penalty may on application be remitted or mitigated by the Secretary. In determining the amount of such penalty, or whether it should be remitted or mitigated and in what amount, the appropriateness of such penalty to the size of the business of the person charged and the gravity of the violation shall be considered. The amount of such penalty, when ﬁnally determined, may be deducted from any sums owing by the United States to the person charged. (c) Actions under subsections (a) and (b) may be brought in the district court of the United States for the district wherein any act or omission or transaction constituting the violation occurred, or in such court for the district where the defendant is found or transacts business, and process in such cases may be served in any other district of which the defendant is an inhabitant or wherever the defendant may be found. (d) Nothing in this subchapter shall be construed as requiring the Secretary to report for the institution of proceedings minor violations of this subchapter whenever he believes that the public interest will be adequately served by a suitable written notice or warning. (e) Except as provided in the ﬁrst sentence of section 542, compliance with this subchapter or any regulations issued thereunder shall not relieve any person from liability at common law or under statutory law. (f) The remedies provided for in this subchapter shall be in addition to and not in substitution for any other remedies provided by law.

ANNUAL REPORT Section 540. [360qq] (a) The Secretary shall prepare and submit to the President for transmittal to the Congress on or before April 1 of each year a comprehensive report on the administration of this part for the preceding calendar year. Such report shall include – (1) a thorough appraisal (including statistical analyses, estimates, and long-term projections) of the incidence of biological injury and effects, including genetic effects, to the population resulting from exposure to electronic product radiation, with a breakdown, insofar as practicable, among the various sources of such radiation; (2) a list of Federal electronic product radiation control standards prescribed or in effect in such year, with identiﬁcation of standards newly prescribed during such year; (3) an evaluation of the degree of observance of applicable standards, including a list of enforcement actions, court decisions, and compromises of alleged violations by location and company name; (4) a summary of outstanding problems confronting the administration of this part in order of priority; (5) an analysis and evaluation of research activities completed as a result of Government and private sponsorship, and technological progress for safety achieved during such year;

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(6) a list, with a brief statement of the issues, of completed or pending judicial actions under this subchapter; (7) the extent to which technical information was disseminated to the scientiﬁc, commercial, and labor community and consumer-oriented information was made available to the public; and (8) the extent of cooperation between Government ofﬁcials and representatives of industry and other interested parties in the implementation of this subchapter including a log or summary of meetings held between Government ofﬁcials and representatives of industry and other interested parties. (b) The report required by subsection (a) shall contain such recommendations for additional legislation as the Secretary deems necessary to promote cooperation among the several States in the improvement of electronic product radiation control and to strengthen the national electronic product radiation control program.

FEDERAL–STATE COOPERATION Section 541[360rr] The Secretary is authorized (1) to accept from State and local authorities engaged in activities related to health or safety or consumer protection, on a reimbursable basis or otherwise, any assistance in the administration and enforcement of this subchapter which he may request and which they may be able and willing to provide and, if so agreed, may pay in advance or otherwise for the reasonable cost of such assistance, and (2) he may, for the purpose of conducting examinations, investigations, and inspections, commission any ofﬁcer or employee of any such authority as an ofﬁcer of the Department.

STATE STANDARDS Section 542. [360ss] Whenever any standard prescribed pursuant to section 534 with respect to an aspect of performance of an electronic product is in effect, no State or political subdivision of a State shall have any authority either to establish, or to continue in effect, any standard which is applicable to the same aspect of performance of such product and which is not identical to the Federal standard. Nothing in this subchapter shall be construed to prevent the Federal Government or the government of any State or political subdivision thereof from establishing a requirement with respect to emission of radiation from electronic products procured for its own use if such requirement imposes a more restrictive standard than that required to comply with the otherwise applicable Federal standard.

SUBCHAPTER D. DISSEMINATION

OF

TREATMENT INFORMATION

Section 551. [360aaa] REQUIREMENTS FOR DISSEMINATION OF TREATMENT INFORMATION ON DRUGS OR DEVICES — (a) IN GENERAL — Notwithstanding sections 301(d), 502(f), and 505, and section 351 of the Public Health Service Act (42 U.S.C. 262), a manufacturer may disseminate to – (1) a health care practitioner; (2) a pharmacy beneﬁt manager; (3) a health insurance issuer; (4) a group health plan; or (5) a Federal or State governmental agency; written information concerning the safety, effectiveness, or beneﬁt of a use not described in the approved labeling of a drug or device if the manufacturer meets the requirements of subsection (b).

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(b) SPECIFIC REQUIREMENTS — A manufacturer may disseminate information under subsection (a) on a new use only if – (1)(A) in the case of a drug, there is in effect for the drug an application filed under subsection (b) or (j) of section 505 or a biologics license issued under section 351 of the Public Health Service Act; or (B) in the case of a device, the device is being commercially distributed in accordance with a regulation under subsection (d) or (e) of section 513, an order under subsection (f) of such section, or the approval of an application under section 515; (2) the information meets the requirements of section 552; (3) the information to be disseminated is not derived from clinical research conducted by another manufacturer or if it was derived from research conducted by another manufacturer, the manufacturer disseminating the information has the permission of such other manufacturer to make the dissemination; (4) the manufacturer has, 60 days before such dissemination, submitted to the Secretary – (A) a copy of the information to be disseminated; and (B) any clinical trial information the manufacturer has relating to the safety or effectiveness of the new use, any reports of clinical experience pertinent to the safety of the new use, and a summary of such information; (5) the manufacturer has complied with the requirements of section 554 (relating to a supplemental application for such use); (6) the manufacturer includes along with the information to be disseminated under this subsection – (A) a prominently displayed statement that discloses – (i) that the information concerns a use of a drug or device that has not been approved or cleared by the Food and Drug Administration; (ii) if applicable, that the information is being disseminated at the expense of the manufacturer; (iii) if applicable, the name of any authors of the information who are employees of, consultants to, or have received compensation from, the manufacturer, or who have a significant ﬁnancial interest in the manufacturer; (iv) the ofﬁcial labeling for the drug or device and all updates with respect to the labeling; (v) if applicable, a statement that there are products or treatments that have been approved or cleared for the use that is the subject of the information being disseminated pursuant to subsection (a)(l); and (vi) the identiﬁcation of any person that has provided funding for the conduct of a study relating to the new use of a drug or device for which such information is being disseminated; and (B) a bibliography of other articles from a scientiﬁc reference publication or scientiﬁc or medical journal that have been previously published about the use of the drug or device covered by the information disseminated (unless the information already includes such bibliography). (c) ADDITIONAL INFORMATION — If the Secretary determines, after providing notice of such determination and an opportunity for a meeting with respect to such determination, that the information submitted by a manufacturer under subsection (b)(3)(B), with respect to the use of a drug or device for which the manufacturer intends to disseminate information, fails to provide data, analyses, or other written matter that is objective and balanced, the Secretary may require the manufacturer to disseminate –

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(1) additional objective and scientiﬁcally sound information that pertains to the safety or effectiveness of the use and is necessary to provide objectivity and balance, including any information that the manufacturer has submitted to the Secretary or, where appropriate, a summary of such information or any other information that the Secretary has authority to make available to the public; and (2) an objective statement of the Secretary, based on data or other scientiﬁcally sound information available to the Secretary, that bears on the safety or effectiveness of the new use of the drug or device. Section 552. [360aaa-1] INFORMATION AUTHORIZED TO BE DISSEMINATED — (a) AUTHORIZED INFORMATION — A manufacturer may disseminate information under section 551 on a new use only if the information – (1) is in the form of an unabridged – (A) reprint or copy of an article, peer-reviewed by experts qualiﬁed by scientiﬁc training or experience to evaluate the safety or effectiveness of the drug or device involved, which was published in a scientiﬁc or medical journal (as deﬁned in section 556(5)), which is about a clinical investigation with respect to the drug or device, and which would be considered to be scientiﬁcally sound by such experts; or (B) reference publication, described in subsection (b), that includes information about a clinical investigation with respect to the drug or device that would be considered to be scientiﬁcally sound by experts qualiﬁed by scientiﬁc training or experience to evaluate the safety or effectiveness of the drug or device that is the subject of such a clinical investigation; and (2) is not false or misleading and would not pose a signiﬁcant risk to the public health. (b) REFERENCE PUBLICATION — A reference publication referred to in subsection (a)(l)(B) is a publication that – (1) has not been written, edited, excerpted, or published speciﬁcally for, or at the request of, a manufacturer of a drug or device; (2) has not been edited or signiﬁcantly inﬂuenced by such a manufacturer; (3) is not solely distributed through such a manufacturer but is generally available in bookstores or other distribution channels where medical textbooks are sold; (4) does not focus on any particular drug or device of a manufacturer that disseminates information under section 551 and does not have a primary focus on new uses of drugs or devices that are marketed or under investigation by a manufacturer supporting the dissemination of information; and (5) presents materials that are not false or misleading. Section 553. [360aaa-2] ESTABLISHMENT OF LIST OF ARTICLES AND PUBLICATIONS DISSEMINATED AND LIST OF PROVIDERS THAT RECEIVED ARTICLES AND REFERENCE PUBLICATIONS — (a) IN GENERAL — A manufacturer may disseminate information under section 551 on a new use only if the manufacturer prepares and submits to the Secretary biannually – (1) a list containing the titles of the articles and reference publications relating to the new use of drugs or devices that were disseminated by the manufacturer to a person described in section 551(a) for the 6-month period preceding the date on which the manufacturer submits the list to the Secretary; and (2) a list that identiﬁes the categories of providers (as described in section 551(a)) that received the articles and reference publications for the 6-month period described in paragraph (1).

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(b) RECORDS — A manufacturer that disseminates information under section 551 shall keep records that may be used by the manufacturer when, pursuant to section 555, such manufacturer is required to take corrective action and shall be made available to the Secretary, upon request, for purposes of ensuring or taking corrective action pursuant to such section. Such records, at the Secretary’s discretion, may identify the recipient of information provided pursuant to section 551 or the categories of such recipients. Section 554. [360aaa-3] REQUIREMENT REGARDING SUBMISSION OF SUPPLEMENTAL APPLICATION FOR NEW USE; EXEMPTION FROM REQUIREMENT — (a) IN GENERAL — A manufacturer may disseminate information under section 551 on a new use only if – (1)(A) the manufacturer has submitted to the Secretary a supplemental application for such use; or (B) the manufacturer meets the condition described in subsection (b) or (c) (relating to a certiﬁcation that the manufacturer will submit such an application); or (2) there is in effect for the manufacturer an exemption under subsection (d) from the requirement of paragraph (1). (b) CERTIFICATION ON SUPPLEMENTAL APPLICATION; CONDITION IN CASE OF COMPLETED STUDIES — For purposes of subsection (a)(l)(B), a manufacturer may disseminate information on a new use if the manufacturer has submitted to the Secretary an application containing a certiﬁcation that – (1) the studies needed for the submission of a supplemental application for the new use have been completed; and (2) the supplemental application will be submitted to the Secretary not later than 6 months after the date of the initial dissemination of information under section 551. (c) CERTIFICATION ON SUPPLEMENTAL APPLICATION; CONDITION IN CASE OF PLANNED STUDIES — (1) IN GENERAL — For purposes of subsection (a)(l)(B), a manufacturer may disseminate information on a new use if – (A) the manufacturer has submitted to the Secretary an application containing – (i) a proposed protocol and schedule for conducting the studies needed for the submission of a supplemental application for the new use; and (ii) a certiﬁcation that the supplemental application will be submitted to the Secretary not later than 36 months after the date of the initial dissemination of information under section 551 (or, as applicable, not later than such date as the Secretary may specify pursuant to an extension under paragraph (3)); and (B) the Secretary has determined that the proposed protocol is adequate and that the schedule for completing such studies is reasonable. (2) PROGRESS REPORTS ON STUDIES — A manufacturer that submits to the Secretary an application under paragraph (1) shall submit to the Secretary periodic reports describing the status of the studies involved. (3) EXTENSION OF TIME REGARDING PLANNED STUDIES — The period of 36 months authorized in paragraph (1)(A)(ii) for the completion of studies may be extended by the Secretary if – (A) the Secretary determines that the studies needed to submit such an application cannot be completed and submitted within 36 months; or

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(B) the manufacturer involved submits to the Secretary a written request for the extension and the Secretary determines that the manufacturer has acted with due diligence to conduct the studies in a timely manner, except that an extension under this subparagraph may not be provided for more than 24 additional months. (d) EXEMPTION FROM REQUIREMENT OF SUPPLEMENTAL APPLICATION — (1) IN GENERAL — For purposes of subsection (a)(2), a manufacturer may disseminate information on a new use if – (A) the manufacturer has submitted to the Secretary an application for an exemption from meeting the requirement of subsection (a)(1); and (B)(i) the Secretary has approved the application in accordance with paragraph (2); or (ii) the application is deemed under paragraph (3)(A) to have been approved (unless such approval is terminated pursuant to paragraph (3)(B)). (2) CONDITIONS FOR APPROVAL — The Secretary may approve an application under paragraph (1) for an exemption if the Secretary makes a determination described in subparagraph (A) or (B), as follows: (A) The Secretary makes a determination that, for reasons deﬁned by the Secretary, it would be economically prohibitive with respect to such drug or device for the manufacturer to incur the costs necessary for the submission of a supplemental application. In making such determination, the Secretary shall consider (in addition to any other considerations the Secretary ﬁnds appropriate) – (i) the lack of the availability under law of any period during which the manufacturer would have exclusive marketing rights with respect to the new use involved; and (ii) the size of the population expected to beneﬁt from approval of the supplemental application. (B) The Secretary makes a determination that, for reasons deﬁned by the Secretary, it would be unethical to conduct the studies necessary for the supplemental application. In making such determination, the Secretary shall consider (in addition to any other considerations the Secretary ﬁnds appropriate) whether the new use involved is the standard of medical care for a health condition. (3) TIME FOR CONSIDERATION OF APPLICATION; DEEMED APPROVAL — (A) IN GENERAL — The Secretary shall approve or deny an application under paragraph (1) for an exemption not later than 60 days after the receipt of the application. If the Secretary does not comply with the preceding sentence, the application is deemed to be approved. (B) TERMINATION OF DEEMED APPROVAL — If pursuant to a deemed approval under subparagraph (A) a manufacturer disseminates written information under section 551 on a new use, the Secretary may at any time terminate such approval and under section 555(b)(3) order the manufacturer to cease disseminating the information. (e) REQUIREMENTS REGARDING APPLICATIONS — Applications under this section shall be submitted in the form and manner prescribed by the Secretary. Section 555. [360aaa-4] CORRECTIVE ACTIONS; CESSATION OF DISSEMINATION — (a) POSTDISSEMINATION DATA REGARDING SAFETY AND EFFECTIVENESS — (1) CORRECTIVE ACTIONS — With respect to data received by the Secretary after the dissemination of information under section 551 by a manufacturer has begun (whether received pursuant to paragraph (2) or otherwise), if the Secretary determines that the data indicate that the new use involved may not be effective or may present a signiﬁcant risk to public health, the

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Secretary shall, after consultation with the manufacturer, take such action regarding the dissemination of the information as the Secretary determines to be appropriate for the protection of the public health, which may include ordering that the manufacturer cease the dissemination of the information. (2) RESPONSIBILITIES OF MANUFACTURERS TO SUBMIT DATA — After a manufacturer disseminates information under section 551, the manufacturer shall submit to the Secretary a notiﬁcation of any additional knowledge of the manufacturer on clinical research or other data that relate to the safety or effectiveness of the new use involved. If the manufacturer is in possession of the data, the notiﬁcation shall include the data. The Secretary shall by regulation establish the scope of the responsibilities of manufacturers under this paragraph, including such limits on the responsibilities as the Secretary determines to be appropriate. (b) CESSATION OF DISSEMINATION — (1) FAILURE OF MANUFACTURER TO COMPLY WITH REQUIREMENTS — The Secretary may order a manufacturer to cease the dissemination of information pursuant to section 551 if the Secretary determines that the information being disseminated does not comply with the requirements established in this subchapter. Such an order may be issued only after the Secretary has provided notice to the manufacturer of the intent of the Secretary to issue the order and (unless paragraph (2)(B) applies) has provided an opportunity for a meeting with respect to such intent. If the failure of the manufacturer constitutes a minor violation of this subchapter, the Secretary shall delay issuing the order and provide to the manufacturer an opportunity to correct the violation. (2) SUPPLEMENTAL APPLICATIONS — The Secretary may order a manufacturer to cease the dissemination of information pursuant to section 551 if – (A) in the case of a manufacturer that has submitted a supplemental application for a new use pursuant to section 554(a)(1), the Secretary determines that the supplemental application does not contain adequate information for approval of the new use for which the application was submitted; (B) in the case of a manufacturer that has submitted a certiﬁcation under section 554(b), the manufacturer has not, within the 6-month period involved, submitted the supplemental application referred to in the certiﬁcation; or (C) in the case of a manufacturer that has submitted a certiﬁcation under section 554(c) but has not yet submitted the supplemental application referred to in the certiﬁcation, the Secretary determines, after an informal hearing, that the manufacturer is not acting with due diligence to complete the studies involved. (3) TERMINATION OF DEEMED APPROVAL OF EXEMPTION REGARDING SUPPLEMENTAL APPLICATIONS — If under section 554(d)(3) the Secretary terminates a deemed approval of an exemption, the Secretary may order the manufacturer involved to cease, disseminating the information. A manufacturer shall comply with an order under the preceding sentence not later than 60 days after the receipt of the order. (c) CORRECTIVE ACTIONS BY MANUFACTURERS — (1) IN GENERAL — In any case in which under this section the Secretary orders a manufacturer to cease disseminating information, the Secretary may order the manufacturer to take action to correct the information that has been disseminated, except as provided in paragraph (2). (2) TERMINATION OF DEEMED APPROVAL OF EXEMPTION REGARDING SUPPLEMENTAL APPLICATIONS — In the case of an order under subsection (b)(3) to cease disseminating information, the Secretary may not order the manufacturer involved to take action to correct the information that has been disseminated unless the Secretary determines that the new use described in the information would pose a signiﬁcant risk to the public health.

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Section 556. [360aaa-5] DEFINITIONS — For purposes of this subchapter: (1) The term “health care practitioner” means a physician, or other individual who is a provider of health care, who is licensed under the law of a State to prescribe drugs or devices. (2) The terms “health insurance issuer” and “group health plan” have the meaning given such terms under section 2791 of the Public Health Service Act. (3) The term “manufacturer” means a person who manufactures a drug or device, or who is licensed by such person to distribute or market the drug or device. (4) The term “new use” – (A) with respect to a drug, means a use that is not included in the labeling of the approved drug; and (B) with respect to a device, means a use that is not included in the labeling for the approved or cleared device. (5) The term “scientiﬁc or medical journal” means a scientiﬁc or medical publication – (A) that is published by an organization – (i) that has an editorial board; (ii) that utilizes experts, who have demonstrated expertise in the subject of an article under review by the organization and who are independent of the organization, to review and objectively select, reject, or provide comments about proposed articles; and (iii) that has a publicly stated policy, to which the organization adheres, of full disclosure of any conﬂict of interest or biases for all authors or contributors involved with the journal or organization; (B) whose articles are peer-reviewed and published in accordance with the regular peerreview procedures of the organization; (C) that is generally recognized to be of national scope and reputation; (D) that is indexed in the Index Medicus of the National Library of Medicine of the National Institutes of Health; and (E) that is not in the form of a special supplement that has been funded in whole or in part by one or more manufacturers. Section 557. [360aaa-6] RULES OF CONSTRUCTION — (a) UNSOLICITED REQUEST — Nothing in section 551 shall be construed as prohibiting a manufacturer from disseminating information in response to an unsolicited request from a health care practitioner. (b) DISSEMINATION OF INFORMATION ON DRUGS OR DEVICES NOT EVIDENCE OF INTENDED USE — Notwithstanding subsection (a), (f), or (o) of section 502, or any other provision of law, the dissemination of information relating to a new use of a drug or device, in accordance with section 551, shall not be construed by the Secretary as evidence of a new intended use of the drug or device that is different from the intended use of the drug or device set forth in the ofﬁcial labeling of the drug or device. Such dissemination shall not be considered by the Secretary as labeling, adulteration, or misbranding of the drug or device. (c) PATENT PROTECTION — Nothing in section 551 shall affect patent rights in any manner. (d) AUTHORIZATION FOR DISSEMINATION OF ARTICLES AND FEES FOR REPRINTS OF ARTICLES — Nothing in section 551 shall be construed as prohibiting an entity that publishes a scientiﬁc journal (as deﬁned in section 556(5)) from requiring authorization from the entity to disseminate an article published by such entity or charging fees for the purchase of reprints of published articles from such entity.

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FDA Administrative Enforcement Manual

TO

DRUGS

AND

DEVICES

Section 561. [360bbb] EXPANDED ACCESS TO UNAPPROVED THERAPIES AND DIAGNOSTICS — (a) EMERGENCY SITUATIONS — The Secretary may, under appropriate conditions determined by the Secretary, authorize the shipment of investigational drugs or investigational devices for the diagnosis, monitoring, or treatment of a serious disease or condition in emergency situations. (b) INDIVIDUAL PATIENT ACCESS TO INVESTIGATIONAL PRODUCTS INTENDED FOR SERIOUS DISEASES — Any person, acting through a physician licensed in accordance with State law, may request from a manufacturer or distributor, and any manufacturer or distributor may, after complying with the provisions of this subsection, provide to such physician an investigational drug or investigational device for the diagnosis, monitoring, or treatment of a serious disease or condition if – (1) the licensed physician determines that the person has no comparable or satisfactory alternative therapy available to diagnose, monitor, or treat the disease or condition involved, and that the probable risk to the person from the investigational drug or investigational device is not greater than the probable risk from the disease or condition; (2) the Secretary determines that there is sufﬁcient evidence of safety and effectiveness to support the use of the investigational drug or investigational device in the case described in paragraph (1); (3) the Secretary determines that provision of the investigational drug or investigational device will not interfere with the initiation, conduct, or completion of clinical investigations to support marketing approval; and (4) the sponsor, or clinical investigator, of the investigational drug or investigational device submits to the Secretary a clinical protocol consistent with the provisions of section 505(i) or 520(g), including any regulations promulgated under section 505(i) or 520(g), describing the use of the investigational drug or investigational device in a single patient or a small group of patients. (c) TREATMENT INVESTIGATIONAL NEW DRUG APPLICATIONS AND TREATMENT INVESTIGATIONAL DEVICE EXEMPTIONS — Upon submission by a sponsor or a physician of a protocol intended to provide widespread access to an investigational drug or investigational device for eligible patients (referred to in this subsection as an “expanded access protocol”), the Secretary shall permit such investigational drug or investigational device to be made available for expanded access under a treatment investigational new drug application or treatment investigational device exemption if the Secretary determines that – (1) under the treatment investigational new drug application or treatment investigational device exemption, the investigational drug or investigational device is intended for use in the diagnosis, monitoring, or treatment of a serious or immediately life-threatening disease or condition; (2) there is no comparable or satisfactory alternative therapy available to diagnose, monitor, or treat that stage of disease or condition in the population of patients to which the investigational drug or investigational device is intended to be administered; (3)(A) the investigational drug or investigational device is under investigation in a controlled clinical trial for the use described in paragraph (1) under an investigational drug application in effect under section 505(i) or investigational device exemption in effect under section 520(g); or (B) all clinical trials necessary for approval of that use of the investigational drug or investigational device have been completed;

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(4) the sponsor of the controlled clinical trials is actively pursuing marketing approval of the investigational drug or investigational device for the use described in paragraph (1) with due diligence; (5) in the case of an investigational drug or investigational device described in paragraph (3)(A), the provision of the investigational drug or investigational device will not interfere with the enrollment of patients in ongoing clinical investigations under section 505(i) or 520(g); (6) in the case of serious diseases, there is sufﬁcient evidence of safety and effectiveness to support the use described in paragraph (1); and (7) in the case of immediately life-threatening diseases, the available scientiﬁc evidence, taken as a whole, provides a reasonable basis to conclude that the investigational drug or investigational device may be effective for its intended use and would not expose patients to an unreasonable and signiﬁcant risk of illness or injury. A protocol submitted under this subsection shall be subject to the provisions of section 505(i) or 520(g), including regulations promulgated under section 505(i) or 520(g). The Secretary may inform national, State, and local medical associations and societies, voluntary health associations, and other appropriate persons about the availability of an investigational drug or investigational device under expanded access protocols submitted under this subsection. The information provided by the Secretary, in accordance with the preceding sentence, shall be the same type of information that is required by section 402(j)(3) of the Public Health Service Act. (d) TERMINATION —The Secretary may, at any time, with respect to a sponsor, physician, manufacturer, or distributor described in this section, terminate expanded access provided under this section for an investigational drug or investigational device if the requirements under this section are no longer met. (e) DEFINITIONS —In this section, the terms “investigational drug,” “investigational device,” “treatment investigational new drug application,” and “treatment investigational device exemption” shall have the meanings given the terms in regulations prescribed by the Secretary. Section 562. [360bbb-1] DISPUTE RESOLUTION — If, regarding an obligation concerning drugs or devices under this Act or section 351 of the Public Health Service Act, there is a scientiﬁc controversy between the Secretary and a person who is a sponsor, applicant, or manufacturer and no speciﬁc provision of the Act involved, including a regulation promulgated under such Act, provides a right of review of the matter in controversy, the Secretary shall, by regulation, establish a procedure under which such sponsor, applicant, or manufacturer may request a review of such controversy, including a review by an appropriate scientiﬁc advisory panel described in section 505(n) or an advisory committee described in section 515(g)(2)(B). Any such review shall take place in a timely manner. The Secretary shall promulgate such regulations within 1 year after the date of the enactment of the Food and Drug Administration Modernization Act of 1997. Section 563. [360bbb-2] CLASSIFICATION OF PRODUCTS — (a) REQUEST — A person who submits an application or submission (including a petition, notiﬁcation, and any other similar form of request) under this Act for a product, may submit a request to the Secretary respecting the classiﬁcation of the product as a drug, biological product, device, or a combination product subject to section 503(g) or respecting the component of the Food and Drug Administration that will regulate the product. In submitting the request, the person shall recommend a classiﬁcation for the product, or a component to regulate the product.

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(b) STATEMENT — Not later than 60 days after the receipt of the request described in subsection (a), the Secretary shall determine the classiﬁcation of the product under subsection (a), or the component of the Food and Drug Administration that will regulate the product, and shall provide to the person a written statement that identiﬁes such classiﬁcation or such component, and the reasons for such determination. The Secretary may not modify such statement except with the written consent of the person, or for public health reasons based on scientiﬁc evidence. (c) INACTION OF SECRETARY — If the Secretary does not provide the statement within the 60-day period described in subsection (b), the recommendation made by the person under subsection (a) shall be considered to be a ﬁnal determination by the Secretary of such classiﬁcation of the product, or the component of the Food and Drug Administration that will regulate the product, as applicable, and may not be modiﬁed by the Secretary except with the written consent of the person, or for public health reasons based on scientiﬁc evidence.

CHAPTER VIII. IMPORTS AND EXPORTS IMPORTS

AND

EXPORTS

Section 801. [381] (a) The Secretary of the Treasury shall deliver to the Secretary of Health and Human Services, upon his request, samples of food, drugs, devices, and cosmetics which are being imported or offered for import into the United States, giving notice thereof to the owner or consignee, who may appear before the Secretary of Health and Human Services and have the right to introduce testimony. The Secretary of Health and Human Services shall furnish to the Secretary of the Treasury a list of establishments registered pursuant to subsection (i) of section 510 and shall request that if any drugs or devices manufactured, prepared, propagated, compounded, or processed in an establishment not so registered are imported or offered for import into the United States, samples of such drugs or devices be delivered to the Secretary of Health and Human Services, with notice of such delivery to the owner or consignee, who may appear before the Secretary of Health and Human Services and have the right to introduce testimony. If it appears from the examination of such samples or otherwise that (1) such article has been manufactured, processed, or packed under unsanitary conditions or, in the case of a device, the methods used in, or the facilities or controls used for, the manufacture, packing, storage, or installation of the device do not conform to the requirements of section 520(f) or (2) such article is forbidden or restricted in sale in the country in which it was produced or from which it was exported, or (3) such article is adulterated, misbranded, or in violation of section 505, then such article shall be refused admission, except as provided in subsection (b) of this section. The Secretary of the Treasury shall cause the destruction of any such article refused admission unless such article is exported, under regulations prescribed by the Secretary of the Treasury, within ninety days of the date of notice of such refusal or within such additional time as may be permitted pursuant to such regulations. Clause (2) of the third sentence of this paragraph shall not be construed to prohibit the admission of narcotic drugs the importation of which is permitted under the Controlled Substances Import and Export Act. (b) Pending decision as to the admission of an article being imported or offered for import, the Secretary of the Treasury may authorize delivery of such article to the owner or consignee upon the execution by him of a good and sufﬁcient bond providing for the payment of such liquidated damages in the event of default as may be required pursuant to regulations of the Secretary of the Treasury. If it appears to the Secretary of Health and Human Services that an article included within the provisions of clause (3) of subsection (a) of this section can, by relabeling or other action, be brought into compliance with the Act or rendered other than a food, drug, device, or cosmetic, ﬁnal determination as to admission of such article may be deferred and, upon ﬁling of timely written application by the owner or consignee and the execution by him of a bond as provided in the

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preceding provisions of this subsection, the Secretary may, in accordance with regulations, authorize the applicant to perform such relabeling or other action speciﬁed in such authorization (including destruction or export of rejected articles or portions thereof, as may be speciﬁed in the Secretary’s authorization). All such relabeling or other action pursuant to such authorization shall in accordance with regulations be under the supervision of an ofﬁcer or employee of the Department of Health and Human Services designated by the Secretary, or an ofﬁcer or employee of the Department of the Treasury designated by the Secretary of the Treasury. (c) All expenses (including travel, per diem or subsistence, and salaries of ofﬁcers or employees of the United States) in connection with the destruction provided for in subsection (a) of this section and the supervision of the relabeling or other action authorized under the provisions of subsection (b) of this section, the amount of such expenses to be determined in accordance with regulations, and all expenses in connection with the storage, cartage, or labor with respect to any article refused admission under subsection (a) of this section, shall be paid by the owner or consignee and, in default of such payment, shall constitute a lien against any future importations made by such owner or consignee. (d)(1) Except as provided in paragraph (2), no drug subject to section 503(b) or composed wholly or partially of insulin which is manufactured in a State and exported may be imported into the United States unless the drug is imported by the manufacturer of the drug. (2) The Secretary may authorize the importation of a drug the importation of which is prohibited by paragraph (1) if the drug is required for emergency medical care. (3) No component of a drug, no component part or accessory of a device, or other article of device requiring further processing, which is ready or suitable for use for health-related purposes, and no food additive, color additive, or dietary supplement, including a product in bulk form, shall be excluded from importation into the United States under subsection (a) if – (A) the importer of such article of a drug or device or importer of the food additive, color additive, or dietary supplement submits a statement to the Secretary, at the time of initial importation, that such article of a drug or device, food additive, color additive, or dietary supplement is intended to be further processed by the initial owner or consignee, or incorporated by the initial owner or consignee into a drug, biological product, device, food, food additive, color additive, or dietary supplement that will be exported by such owner or consignee from the United States in accordance with section 801(e) or 802 or section 351(h) of the Public Health Service Act; (B) the initial owner or consignee responsible for such imported article maintains records that identify the use of such imported article and upon request of the Secretary submits a report that provides an accounting of the exportation or the disposition of the imported article, including portions that have been destroyed, and the manner in which such person complied with the requirements of this paragraph; and (C) any imported component, part, article, or accessory of a drug or device and any food additive, color additive, or dietary supplement not incorporated or further processed as described in subparagraph (A) is destroyed or exported by the owner or consignee. (4) The importation into the United States of blood, blood components, source plasma, or source leukocytes or of a component, accessory, or part thereof is not permitted pursuant to paragraph (3) unless the importation complies with section 351(a) of the Public Health Service Act or the Secretary permits the importation under appropriate circumstances and conditions, as determined by the Secretary. The importation of tissue or a component or part of tissue is not permitted pursuant to paragraph (3) unless the importation complies with section 361 of the Public Health Service Act.

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(e)(1) A food, drug, device, or cosmetic intended for export shall not be deemed to be adulterated or misbranded under this chapter if it – (A) accords to the speciﬁcations of the foreign purchaser, (B) is not in conﬂict with the laws of the country to which it is intended for export, (C) is labeled on the outside of the shipping package that it is intended for export, and (D) is not sold or offered for sale in domestic commerce. (2) Paragraph (1) does not apply to any device – (A) which does not comply with an applicable requirement of section 514 or 515, (B) which under section 520(g) is exempt from either such section, or (C) which is a banned device under section 516, unless, in addition to the requirements of paragraph (1), either (i) the Secretary has determined that the exportation of the device is not contrary to public health and safety and has the approval of the country to which it is intended for export or (ii) the device is eligible for export under section 802. (3) A new animal drug that requires approval under section 512 shall not be exported pursuant to paragraph (1) if such drug has been banned in the United States. (4)(A) Any person who exports a drug, animal drug, or device may request that the Secretary – (i) certify in writing that the exported drug, animal drug, or device meets the requirements of paragraph (1) or section 802; or (ii) certify in writing that the drug, animal drug, or device being exported meets the applicable requirements of this Act upon a showing that the drug or device meets the applicable requirements of this Act. The Secretary shall issue such a certiﬁcation within 20 days of the receipt of a request for such certiﬁcation. (B) If the Secretary issues a written export certiﬁcation within the 20 days prescribed by subparagraph (A), a fee for such certiﬁcation may be charged but shall not exceed $175 for each certiﬁcation. Fees collected for a ﬁscal year pursuant to this subparagraph shall be credited to the appropriation account for salaries and expenses of the Food and Drug Administration and shall be available in accordance with appropriations Acts until expended without ﬁscal year limitation. Such fees shall be collected in each ﬁscal year in an amount equal to the amount speciﬁed in appropriations Acts for such ﬁscal year and shall only be collected and available for the costs of the Food and Drug Administration. (f)(l) If a drug (other than insulin, an antibiotic drug, an animal drug, or a drug exported under section 802) being exported in accordance with subsection (e) is being exported to a country that has different or additional labeling requirements or conditions for use and such country requires the drug to be labeled in accordance with those requirements or uses, such drug may be labeled in accordance with such requirements and conditions for use in the country to which such drug is being exported if it also is labeled in accordance with the requirements of this Act. (2) If, pursuant to paragraph (1), the labeling of an exported drug includes conditions for use that have not been approved under this Act, the labeling must state that such conditions for use have not been approved under this Act. A drug exported under section 802 is exempt from this section.

EXPORTS

OF

CERTAIN UNAPPROVED PRODUCTS

Section 802. [382] (a) A drug or device – (1) which, in the case of a drug –

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(A)(i) requires approval by the Secretary under section 505 before such drug may be introduced or delivered for introduction into interstate commerce; or (ii) requires licensing by the Secretary under section 351 of the Public Health Service Act or by the Secretary of Agriculture under the Act of March 4, 1913 (known as the VirusSerum Toxin Act) before it may be introduced or delivered for introduction into interstate commerce; (B) does not have such approval or license; and (C) is not exempt from such sections or Act; and (2) which, in the case of a device – (A) does not comply with an applicable requirement under section 514 or 515; (B) under section 520(g) is exempt from either such section; or (C) is a banned device under section 516, is adulterated, misbranded, and in violation of such sections or Act unless the export of the drug or device is, except as provided in subsection (f), authorized under subsection (b), (c), (d), or (e) or section 801(e)(2). If a drug or device described in paragraphs (1) and (2) may be exported under subsection (b) and if an application for such drug or device under section 505 or 515 or section 351 of the Public Health Service Act was disapproved, the Secretary shall notify the appropriate public health ofﬁcial of the country to which such drug will be exported of such disapproval. (b)(1)(A) A drug or device described in subsection (a) may be exported to any country, if the drug or device complies with the laws of that country and has valid marketing authorization by the appropriate authority – (i) in Australia, Canada, Israel, Japan, New Zealand, Switzerland, or South Africa; or (ii) in the European Union or a country in the European Economic Area (the countries in the European Union and the European Free Trade Association) if the drug or device is marketed in that country or the drug or device is authorized for general marketing in the European Economic Area. (B) The Secretary may designate an additional country to be included in the list of countries described in clauses (i) and (ii) of subparagraph (A) if all of the following requirements are met in such country: (i) Statutory or regulatory requirements which require the review of drugs and devices for safety and effectiveness by an entity of the government of such country and which authorize the approval of only those drugs and devices which have been determined to be safe and effective by experts employed by or acting on behalf of such entity and qualiﬁed by scientiﬁc training and experience to evaluate the safety and effectiveness of drugs and devices on the basis of adequate and well-controlled investigations, including clinical investigations, conducted by experts qualiﬁed by scientiﬁc training and experience to evaluate the safety and effectiveness of drugs and devices. (ii) Statutory or regulatory requirements that the methods used in, and the facilities and controls used for – (I) the manufacture, processing, and packing of drugs in the country are adequate to preserve their identity, quality, purity, and strength; and (II) the manufacture, preproduction design validation, packing, storage, and installation of a device are adequate to assure that the device will be safe and effective. (iii) Statutory or regulatory requirements for the reporting of adverse reactions to drugs and devices and procedures to withdraw approval and remove drugs and devices found not to be safe or effective.

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(iv) Statutory or regulatory requirements that the labeling and promotion of drugs and devices must be in accordance with the approval of the drug or device. (v) The valid marketing authorization system in such country or countries is equivalent to the systems in the countries described in clauses (i) and (ii) of subparagraph (A). The Secretary shall not delegate the authority granted under this subparagraph. (C) An appropriate country ofﬁcial, manufacturer, or exporter may request the Secretary to take action under subparagraph (B) to designate an additional country or countries to be added to the list of countries described in clauses (i) and (ii) of subparagraph (A) by submitting documentation to the Secretary in support of such designation. Any person other than a country, requesting such designation shall include, along with the request, a letter from the country indicating the desire of such country to be designated. (2) A drug described in subsection (a) may be directly exported to a country which is not listed in clause (i) or (ii) of paragraph (1)(A) if – (A) the drug complies with the laws of that country and has valid marketing authorization by the responsible authority in that country; and (B) the Secretary determines that all of the following requirements are met in that country: (i) Statutory or regulatory requirements which require the review of drugs for safety and effectiveness by an entity of the government of such country and which authorize the approval of only those drugs which have been determined to be safe and effective by experts employed by or acting on behalf of such entity and qualiﬁed by scientiﬁc training and experience to evaluate the safety and effectiveness of drugs on the basis of adequate and well-controlled investigations, including clinical investigations, conducted by experts qualiﬁed by scientiﬁc training and experience to evaluate the safety and effectiveness of drugs. (ii) Statutory or regulatory requirements that the methods used in, and the facilities and controls used for the manufacture, processing, and packing of drugs in the country are adequate to preserve their identity, quality, purity, and strength. (iii) Statutory or regulatory requirements for the reporting of adverse reactions to drugs and procedures to withdraw approval and remove drugs found not to be safe or effective. (iv) Statutory or regulatory requirements that the labeling and promotion of drugs must be in accordance with the approval of the drug. (3) The exporter of a drug described in subsection (a) which would not meet the conditions for approval under this Act or conditions for approval of a country described in clause (i) or (ii) of paragraph (1XA) may petition the Secretary for authorization to export such drug to a country which is not described in clause (i) or (ii) of paragraph (1)(A) or which is not described in paragraph (2). The Secretary shall permit such export if – (A) the person exporting the drug – (i) certiﬁes that the drug would not meet the conditions for approval under this Act or the conditions for approval of a country described in clause (i) or (ii) of paragraph (1)(A); and (ii) provides the Secretary with credible scientiﬁc evidence, acceptable to the Secretary, that the drug would be safe and effective under the conditions of use in the country to which it is being exported; and (B) the appropriate health authority in the country to which the drug is being exported – (i) requests approval of the export of the drug to such country; (ii) certiﬁes that the health authority understands that the drug is not approved under this Act or in a country described in clause (i) or (ii) of paragraph (1)(A); and

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(iii) concurs that the scientiﬁc evidence provided pursuant to subparagraph (A) is credible scientiﬁc evidence that the drug would be reasonably safe and effective in such country. The Secretary shall take action on a request for export of a drug under this paragraph within 60 days of receiving such request. (c) A drug or device intended for investigational use in any country described in clause (i) or (ii) of subsection (b)(l)(A) may be exported in accordance with the laws of that country and shall be exempt from regulation under section 505(i) or 520(g). (d) A drug or device intended for formulation, ﬁlling, packaging, labeling, or further processing in anticipation of market authorization in any country described in clause (i) or (ii) of subsection (b)(l)(A) may be exported for use in accordance with the laws of that country. (e)(l) A drug or device which is used in the diagnosis, prevention, or treatment of a tropical disease or another disease not of signiﬁcant prevalence in the United States and which does not otherwise qualify for export under this section shall, upon approval of an application, be permitted to be exported if the Secretary ﬁnds that the drug or device will not expose patients in such country to an unreasonable risk of illness or injury and the probable beneﬁt to health from the use of the drug or device (under conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling of the drug or device) outweighs the risk of injury or illness from its use, taking into account the probable risks and beneﬁts of currently available drug or device treatment. (2) The holder of an approved application for the export of a drug or device under this subsection shall report to the Secretary – (A) the receipt of any credible information indicating that the drug or device is being or may have been exported from a country for which the Secretary made a ﬁnding under paragraph (1)(A) to a country for which the Secretary cannot make such a ﬁnding; and (B) the receipt of any information indicating adverse reactions to such drug. (3)(A) If the Secretary determines that – (i) a drug or device for which an application is approved under paragraph (1) does not continue to meet the requirements of such paragraph; or (ii) the holder of an approved application under paragraph (1) has not made the report required by paragraph (2), the Secretary may, after providing the holder of the application an opportunity for an informal hearing, withdraw the approved application. (3) If the Secretary determines that the holder of an approved application under paragraph (1) or an importer is exporting a drug or device from the United States to an importer and such importer is exporting the drug or device to a country for which the Secretary cannot make a ﬁnding under paragraph (1) and such export presents an imminent hazard, the Secretary shall immediately prohibit the export of the drug or device to such importer, provide the person exporting the drug or device from the United States prompt notice of the prohibition, and afford such person an opportunity for an expedited hearing. (f) A drug or device may not be exported under this section – (1) if the drug or device is not manufactured, processed, packaged, and held in substantial conformity with current good manufacturing practice requirements or does not meet international standards as certiﬁed by an international standards organization recognized by the Secretary; (2) if the drug or device is adulterated under clause (1), (2)(A), or (3) of section 501(a) or subsection (c) or (d) of section 501;

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(3) if the requirements of subparagraphs (A) through (D) of section 801(e)(l) have not been met; (4)(A) if the drug or device is the subject of a notice by the Secretary or the Secretary of Agriculture of a determination that the probability of reimportation of the exported drug or device would present an imminent hazard to the public health and safety of the United States and the only means of limiting the hazard is to prohibit the export of the drug or device; or (B) if the drug or device presents an imminent hazard to the public health of the country to which the drug or device would be exported; (5) if the labeling of the drug or device is not (A) in accordance with the requirements and conditions for use in – (i) the country in which the drug or device received valid marketing authorization under subsection (b); and (ii) the country to which the drug or device would be exported; and (B) in the language and units of measurement of the country to which the drug or device would be exported or in the language designated by such country; or (6) if the drug or device is not promoted in accordance with the labeling requirements set forth in paragraph (5). In making a ﬁnding under paragraph (4)(B), (5), or (6) the Secretary shall consult with the appropriate public health ofﬁcial in the affected country. (g) The exporter of a drug or device exported under subsection (b)(l) shall provide a simple notiﬁcation to the Secretary identifying the drug or device when the exporter ﬁrst begins to export such drug or device to any country listed in clause (i) or (ii) of subsection (b)(l)(A). When an exporter of a drug or device ﬁrst begins to export a drug or device to a country which is not listed in clause (i) or (ii) of subsection (b)(l)(A), the exporter shall provide a simple notiﬁcation to the Secretary identifying the drug or device and the country to which such drug or device is being exported. Any exporter of a drug or device shall maintain records of all drugs or devices exported and the countries to which they were exported. (h) For purposes of this section – (1) a reference to the Secretary shall in, the case of a biological product which is required to be licensed under the Act of March 4,.1913 (37 Stat. 832833) (commonly known as the VirusSerum Toxin Act) be considered to be a reference to the Secretary of Agriculture, and (2) the term “drug” includes drugs for human use as well as biologicals under section 351 of the Public Health Service Act or the Act of March 4, 1913 (37 Stat. 832–833) (commonly known as the Virus-Serum Toxin Act). (i) Insulin and antibiotic drugs may be exported without regard to the requirements in this section if the insulin and antibiotic drugs meet the requirements of section 801(e)(l).

OFFICE

OF INTERNATIONAL

RELATIONS

Section 803. [383] (a) There is established in the Department of Health and Human Services an Ofﬁce of International Relations. (b) In carrying out the functions of the ofﬁce under subsection (a), the Secretary may enter into agreements with foreign countries to facilitate commerce in devices between the United States and such countries consistent with the requirements of this Act. In such agreements, the Secretary shall encourage the mutual recognition of –

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(1) good manufacturing practice regulations promulgated under section 520(f), and (2) other regulations and testing protocols as the Secretary determines to be appropriate. (c)(l) The Secretary shall support the Ofﬁce of the United States Trade Representative, in consultation with the Secretary of Commerce, in meetings with representatives of other countries to discuss methods and approaches to reduce the burden of regulation and harmonize regulatory requirements if the Secretary determines that such harmonization continues consumer protections consistent with the purposes of this Act. (2) The Secretary shall support the Ofﬁce of the United States Trade Representative, in consultation with the Secretary of Commerce, in efforts to move toward the acceptance of mutual recognition agreements relating to the regulation of drugs, biological products, devices, foods, food additives, and color additives, and the regulation of good manufacturing practices, between the European Union and the United States. (3) The Secretary shall regularly participate in meetings with representatives of other foreign governments to discuss and reach agreement on methods and approaches to harmonize regulatory requirements. (4) The Secretary shall, not later than 180 days after the date of enactment of the Food and Drug Administration Modernization Act of 1997, make public a plan that establishes a framework for achieving mutual recognition of good manufacturing practices inspections. (5) Paragraphs (1) through (4) shall not apply with respect to products deﬁned in section 201(ff).

CHAPTER IX. MISCELLANEOUS SEPARABILITY CLAUSE Section 901. [391] If any provision of this Act is declared unconstitutional, or the applicability thereof to any person or circumstances is held invalid, the constitutionality of the remainder of the Act and the applicability thereof to other persons and circumstances shall not be affected thereby.

EFFECTIVE DATE

AND

REPEALS

Section 902. [392] (a) This Act shall take effect twelve months after the date of its enactment. The Federal Food and Drug Act of June 30, 1906, as amended (U.S.C., 1934 ed., title 21, secs. 1–15), shall remain in force until such effective date, and except as otherwise provided in this subsection, is hereby repealed effective upon such date: Provided, That the provisions of section 701 shall become effective on the enactment of this Act, and thereafter the Secretary [of Agriculture] is authorized hereby to (1) conduct hearings and to promulgate regulations which shall become effective on or after the effective date of this Act as the Secretary [of Agriculture] shall direct, and (2) designate prior to the effective date of this Act food having common or usual names and exempt such food from the requirements of clause (2) of section 403(i) for a reasonable time to permit the formulation, promulgation, and effective application of deﬁnitions and standards of identity therefore as provided by section 401: Provided further, That sections 502(j), 505, and 601(a), and all other provisions of this Act to the extent that they may relate to the enforcement of such sections, shall take effect on the date of the enactment of this Act, except that in the case of a cosmetic to which the proviso of section 601(a) relates, such cosmetic shall not, prior to the ninetieth day after such date of enactment, be deemed adulterated by reason of the failure of its label to bear the legend prescribed in such proviso: Provided further, That the Act of March 4, 1923 (U.S.C., 1945 ed., title 21, sec. 321a; 32 Stat. 1500, ch. 268), deﬁning butter and providing a standard therefore; the Act of July 24, 1919 (U.S.C., 1946 ed., title 21, sec. 321b; 41 Stat. 271, ch. 26), deﬁning

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wrapped meats as in package form; and the amendment to the Food and Drug Act, section 10A, approved August 27, 1935 (U.S.C., 1946 ed., title 21, sec. 372a [49 Stat. 871, ch. 7391), shall remain in force and effect and be applicable to the provisions of this Act. (b) Meats and meat food products shall be exempt from the provisions of this Act to the extent of the application or the extension thereto of the Meat Inspection Act, approved March 4, 1907, as amended (U.S.C. 1946 ed., title 21, secs. 71–96; 34 Stat 1260 et seq.). (c) Nothing contained in this chapter shall be construed as in any way affecting, modifying, repealing, or superseding the provisions of section 351 of Public Health Service Act (relating to viruses, serums, toxins, and analogous products applicable to man); the virus, serum, toxin, and analogous products provisions, applicable to domestic animals, of the Act of Congress approved March 4, 1913 (37 Stat. 832–833); the Filled Cheese Act of June 6, 1896 (U.S.C., 1934 ed., title 26, ch. 17, secs. 2350–2362); the Filled Milk Act of March 4, 1923 (U.S.C. 1946 ed., title 21, ch. 3, secs. 61–64); or the Import Milk Act of February 15, 1927 (U.S.C. 1946 ed., title 21, ch. 4, secs. 141–149). Section 903. [393] FOOD AND DRUG ADMINISTRATION — (a) IN GENERAL — There is established in the Department of Health and Human Services the Food and Drug Administration (hereinafter in this section referred to as the “Administration”). (b) MISSION — The Administration shall – (1) promote the public health by promptly and efﬁciently reviewing clinical research and taking appropriate action on the marketing of regulated products in a timely manner; (2) with respect to such products, protect the public health by ensuring that – (A) foods are safe, wholesome, sanitary, and properly labeled; (B) human and veterinary drugs are safe and effective; (C) there is reasonable assurance of the safety and effectiveness of devices intended for human use; (D) cosmetics are safe and properly labeled; and (E) public health and safety are protected from electronic product radiation; (3) participate through appropriate processes with representatives of other countries to reduce the burden of regulation, harmonize regulatory requirements, and achieve appropriate reciprocal arrangements; and (4) as determined to be appropriate by the Secretary, carry out paragraphs (1) through (3) in consultation with experts in science, medicine, and public health, and in cooperation with consumers, users, manufacturers, importers, packers, distributors, and retailers of regulated products. (c) INTERAGENCY COLLABORATION — The Secretary shall implement programs and policies that will foster collaboration between the Administration, the National Institutes of Health, and other science-based Federal agencies, to enhance the scientiﬁc and technical expertise available to the Secretary in the conduct of the duties of the Secretary with respect to the development, clinical investigation, evaluation, and postmarket monitoring of emerging medical therapies, including complementary therapies, and advances in nutrition and food science. (d) COMMISSIONER — (1) APPOINTMENT — There shall be in the Administration a Commissioner of Food and Drugs (hereinafter in this section referred to as the “Commissioner”) who shall be appointed by the President by and with the advice and consent of the Senate.

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(2) GENERAL POWERS — The Secretary, through the Commissioner, shall be responsible for executing this chapter and for – (A) providing overall direction to the Food and Drug Administration and establishing and implementing general policies respecting the management and operation of programs and activities of the Food and Drug Administration; (B) coordinating and overseeing the operation of all administrative entities within the Administration; (C) research relating to foods, drugs, cosmetics, and devices in carrying out this Act; (D) conducting educational and public information programs relating to the responsibilities of the Food and Drug Administration; and (E) performing such other functions as the Secretary may prescribe. (e) TECHNICAL AND SCIENTIFIC REVIEW GROUPS — The Secretary through the Commissioner of Food and Drugs may, without regard to the provisions of title 5 governing appointments in the competitive service and without regard to the provisions of chapter 51 and subchapter III of chapter 53 of such title relating to classiﬁcation and General Schedule pay rates, establish such technical and scientiﬁc review groups as are needed to carry out the functions of the Administration, including functions under the Federal Food, Drug, and Cosmetic Act, and appoint and pay the members of such groups, except that ofﬁcers and employees of the United States shall not receive additional compensation for service as members of such groups. (f) AGENCY PLAN FOR STATUTORY COMPLIANCE — (1) IN GENERAL — Not later than 1 year after the date of enactment of the Food and Drug Administration Modernization Act of 1997, the Secretary, after consultation with appropriate scientiﬁc and academic experts, health care professionals, representatives of patient and consumer advocacy groups, and the regulated industry, shall develop and publish in the Federal Register a plan bringing the Secretary into compliance with each of the obligations of the Secretary under this Act. The Secretary shall review the plan biannually and shall revise the plan as necessary, in consultation with such persons. (2) OBJECTIVES OF AGENCY PLAN — The plan required by paragraph (1) shall establish objectives and mechanisms to achieve such objectives, including objectives related to – (A) maximizing the availability and clarity of information about the process for review of applications and submissions (including petitions, notiﬁcations, and any other similar forms of request) made under this Act; (B) maximizing the availability and clarity of information for consumers and patients concerning new products; (C) implementing inspection and postmarket monitoring provisions of this Act; (D) ensuring access to the scientiﬁc and technical expertise needed by the Secretary to meet obligations described in paragraph (1); (E) establishing mechanisms, by July 1, 1999, for meeting the time periods speciﬁed in this Act for the review of all applications and submissions described in subparagraph (A) and submitted after the date of enactment of the Food and Drug Administration Modernization Act of 1997; and (F) eliminating backlogs in the review of applications and submissions described in subparagraph (A), by January 1, 2000. (g) ANNUAL REPORT — The Secretary shall annually prepare and publish in the Federal Register and solicit public comment on a report that –

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(1) provides detailed statistical information on the performance of the Secretary under the plan described in subsection (f); (2) compares such performance of the Secretary with the objectives of the plan and with the statutory obligations of the Secretary; and (3) identiﬁes any regulatory policy that has a signiﬁcant negative impact on compliance with any objective of the plan or any statutory obligation and sets forth any proposed revision to any such regulatory policy. Section 904. [394] SCIENTIFIC REVIEW GROUPS — Without regard to the provisions of title 5, United States Code, governing appointments in the competitive service and without regard to the provisions of chapter 51 and subchapter III of chapter 53 of such title relating to classiﬁcation and General Schedule pay rates, the Commissioner of Food and Drugs may – (1) establish such technical and scientiﬁc review groups as are needed to carry out the functions of the Food and Drug Administration (including functions prescribed under this Act); and (2) appoint and pay the members of such groups, except that ofﬁcers and employees of the United States shall not receive additional compensation for service as members of such groups. Section 905. [395] LOAN REPAYMENT PROGRAM — (a) IN GENERAL — (1) AUTHORITY FOR PROGRAM — Subject to paragraph (2), the Secretary shall carry out a program of entering into contracts with appropriately qualiﬁed health professionals under which such health professionals agree to conduct research, as employees of the Food and Drug Administration, in consideration of the Federal Government agreeing to repay, for each year of such service, not more than $20,000 of the principal and interest of the educational loans of such health professionals. (2) LIMITATION — The Secretary may not enter into an agreement with a health professional pursuant to paragraph (1) unless such professional – (A) has a substantial amount of educational loans relative to income; and (B) agrees to serve as an employee of the Food and Drug Administration for purposes of paragraph (1) for a period of not less than 3 years. (b) APPLICABILTY OF CERTAIN PROVISIONS — With respect to the National Health Service Corps Loan Repayment Program established in subpart III of part D of title III of the Public Health Service Act, the provisions of such subpart shall, except as inconsistent with subsection (a), apply to the program established in such subsection in the same manner and to the same extent as such provisions apply to the National Health Service Corps Loan Repayment Program. (c) AUTHORIZATION OF APPROPRIATIONS — For the purpose of carrying out this section, there are authorized to be appropriated such sums as may be necessary for each of the ﬁscal years 1994 through 1996. Section 906. PRACTICE OF MEDICINE — Nothing in this Act shall be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate health care practitionerpatient relationship. This section shall not limit any existing authority of the Secretary to establish and enforce restrictions on the sale or distribution, or in the labeling, of a device that are part of a determination of substantial equivalence, established as a condition of approval, or promulgated through regulations. Further, this section shall not change any existing prohibition on the promotion of unapproved uses of legally marketed devices.

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Section 907. CONTRACTS FOR EXPERT REVIEW — (a) IN GENERAL — (1) AUTHORITY — The Secretary may enter into a contract with any organization or any individual (who is not an employee of the Department) with relevant expertise, to review and evaluate, for the purpose of making recommendations to the Secretary on, part or all of any application or submission (including a petition, notiﬁcation, and any other similar form of request) made under this Act for the approval or classiﬁcation of an article or made under section 351(a) of the Public Health Service Act (42 U.S.C. 262(a)) with respect to a biological product. Any such contract shall be subject to the requirements of section 708 relating to the conﬁdentiality of information. (2) INCREASED EFFICIENCY AND EXPERTISE THROUGH CONTRACTS — The Secretary may use the authority granted in paragraph (1) whenever the Secretary determines that use of a contract described in paragraph (1) will improve the timeliness of the review of an application or submission described in paragraph (1), unless using such authority would reduce the quality, or unduly increase the cost, of such review. The Secretary may use such authority whenever the Secretary determines that use of such a contract will improve the quality of the review of an application or submission described in paragraph (1), unless using such authority would unduly increase the cost of such review. Such improvement in timeliness or quality may include providing the Secretary increased scientiﬁc or technical expertise that is necessary to review or evaluate new therapies and technologies. (b) REVIEW OF EXPERT REVIEW — (1) IN GENERAL — Subject to paragraph (2), the ofﬁcial of the Food and Drug Administration responsible for any matter for which expert review is used pursuant to subsection (a) shall review the recommendations of the organization or individual who conducted the expert review and shall make a ﬁnal decision regarding the matter in a timely manner. (2) LIMITATION — A ﬁnal decision by the Secretary on any such application or submission shall be made within the applicable prescribed time period for review of the matter as set forth in this Act or in the Public Health Service Act (42 U.S.C. 201 et seq.).

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Appendix 2. Drug Law History Synopsis 1906 The original Food and Drugs Act, passed by Congress on June 30 and signed by President Theodore Roosevelt, prohibits interstate commerce in misbranded and adulterated foods and drugs. The Meat Inspection Act is passed the same day. Shocking disclosures of unsanitary conditions in meatpacking plants, the use of poisonous preservatives and dyes in foods, and cure-all claims for worthless and dangerous patent medicines were the major problems leading to the enactment of these laws.

1911 In United States v. Johnson, the Supreme Court rules that the 1906 Food and Drugs Act does not prohibit false therapeutic claims but only false and misleading statements about the ingredients or identity of a drug.

1912 Congress enacts the Sherley Amendment to overcome the ruling in United States v. Johnson. It prohibits labeling medicines with false therapeutic claims intended to defraud the purchaser, a standard difﬁcult to prove.

1914 The Harrison Narcotic Act imposes upper limits on the amount of opium, opium-derived products, and cocaine allowed in products available to the public; requires prescriptions for products exceeding the allowable limit of narcotics; and mandates increased recordkeeping for physicians and pharmacists that dispense narcotics. A separate law dealing with marijuana would be enacted in 1937.

1933 The FDA recommends a complete revision of the obsolete 1906 Food and Drugs Act. The ﬁrst bill is introduced into the Senate, launching a ﬁve-year legislative battle. The FDA assembles a graphic display of shortcomings in pharmaceutical and other regulations under the 1906 act, dubbed by one reporter as the “Chamber of Horrors,” and exhibited it nationwide to help draw support for a new law.

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1937 Elixir Sulfanilamide, containing the poisonous solvent diethylene glycol, kills 107 persons, many of whom are children. This incident dramatized the need to ensure drug safety before marketing and to enact the pending food and drug law.

1938 The Federal Food, Drug, and Cosmetic Act of 1938 is passed by Congress, containing new provisions: • • • • • • •

Requiring new drugs to be shown safe before marketing, thus initiating a new system of drug regulation Eliminating the Sherley Amendment requirement to prove intent to defraud in drug misbranding cases Extending control to cosmetics and therapeutic devices Providing that safe tolerances be set for unavoidable poisonous substances Authorizing standards of identity, quality, and ﬁll-of-container for foods Authorizing factory inspections Adding the remedy of court injunctions to the previous penalties of seizures and prosecutions

Under the Wheeler–Lea Act, the Federal Trade Commission is charged to oversee advertising associated with products, including pharmaceuticals, otherwise regulated by the FDA. The FDA promulgates the policy in August that sulfanilamide and selected other dangerous drugs must be administered under the direction of a qualiﬁed expert, thus launching the requirement for prescription-only (non-narcotic) drugs.

1941 The Insulin Amendment requires the FDA to test and certify purity and potency of this life-saving drug for diabetes. Nearly 300 deaths and injuries result from distribution of sulfathiazole tablets tainted with the sedative Phenobarbital. The incident prompts the FDA to revise manufacturing and quality controls drastically — the beginning of what would later be called good manufacturing practices (GMPs).

1945 The Penicillin Amendment requires FDA testing and certiﬁcation of the safety and effectiveness of all penicillin products. Later amendments would extend this requirement to all antibiotics. In 1983, such control would be found no longer needed and abolished.

1948 Supreme Court rules in United States v. Sullivan that the FDA’s jurisdiction extends to retail distribution, thereby permitting the FDA to prohibit pharmacies from engaging in illegal sales of drugs — the most problematical being barbiturates and amphetamines.

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1951 Durham–Humphrey Amendment deﬁnes the kinds of drugs that cannot be used safely without medical supervision and restricts their sale to prescription by a licensed practitioner.

1952 In United States v. Cardiff, the Supreme Court rules that the factory inspection provision of the 1938 FDC Act is too vague to be enforced as criminal law. A nationwide investigation by the FDA reveals that chloramphenicol, a broad-spectrum antibiotic, had caused nearly 180 cases of often fatal blood diseases. Two years later, the FDA would engage the American Society of Hospital Pharmacists, the American Association of Medical Record Librarians, and later the American Medical Association in a voluntary program of drug reaction reporting.

1953 Factory Inspection Amendment clariﬁes previous law and requires the FDA to give manufacturers written reports of conditions observed during inspections and analyses of factory samples.

1955 HEW Secretary Olveta Culp Hobby appoints a committee of 14 citizens to study the adequacy of the FDA’s facilities and programs. The committee recommends a substantial expansion of the FDA staff and facilities, a new headquarters building, and more use of educational and informational programs.

1962 Thalidomide, a new sleeping pill, is found to have caused birth defects in thousands of babies born in western Europe. News reports on the role of Dr. Frances Kelsey, the FDA medical ofﬁcer, in keeping the drug off the U.S. market arouse public support for stronger drug regulation. The Kefauver–Harris Drug Amendments are passed to ensure drug efﬁcacy and greater drug safety. For the ﬁrst time, drug manufacturers are required to prove to the FDA the effectiveness of their products before marketing them. In addition, the FDA is given closer control over investigational drug studies, the FDA inspectors are granted access to additional company records, and manufacturers must demonstrate the efﬁcacy of products approved prior to 1962.

1963 The Advisory Committee on Investigational Drugs meets, the ﬁrst meeting of a committee to advise the FDA on product approval and policy on an ongoing basis.

1965 The Drug Abuse Control Amendments are enacted to deal with problems caused by abuse of depressants, stimulants, and hallucinogens.

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1966 The FDA contracts with the National Academy of Sciences/National Research Council to evaluate the effectiveness of 4000 drugs approved on the basis of safety alone between 1938 and 1962.

1968 The FDA Bureau of Drug Abuse Control and the Treasury Department’s Bureau of Narcotics are transferred to the Department of Justice to form the Bureau of Narcotics and Dangerous Drugs (BNDD), consolidating efforts to police trafﬁc in abused drugs. A reorganization of BNDD in 1973 formed the Drug Enforcement Administration. The FDA forms the Drug Efﬁcacy Study Implementation (DESI) to incorporate the recommendations of a National Academy of Sciences investigation of effectiveness of drugs marketed between 1938 and 1962. Animal Drug Amendments place all regulation of new animal drugs under one section of the Food, Drug, and Cosmetic Act (Section 512), making approval of animal drugs and medicated feeds more efﬁcient.

1970 In Upjohn v. Finch, the Court of Appeals upholds enforcement of the 1962 drug effectiveness amendments by ruling that commercial success alone does not constitute substantial evidence of drug safety and efﬁcacy. The FDA requires the ﬁrst patient package insert: Oral contraceptives must contain information for the patient about speciﬁc risks and beneﬁts. The Comprehensive Drug Abuse Prevention and Control Act replaces previous laws and categorizes drugs based on abuse and addiction potential vis-à-vis therapeutic value.

1972 The Over-the-Counter Drug Review is initiated to enhance the safety, effectiveness, and appropriate labeling of drugs sold without prescription.

1973 The U.S. Supreme Court upholds the 1962 drug effectiveness law and endorses the FDA action to control entire classes of products by regulations rather than to rely only on time-consuming litigation.

1976 The Vitamins and Minerals Amendments (“Proxmire Amendments”) stop the FDA from establishing standards limiting potency of vitamins and minerals in food supplements or regulating them as drugs based solely on potency.

1982 Tamper-resistant packaging regulations are issued by the FDA to prevent poisonings such as the deaths resulting from cyanide placed in Tylenol capsules. The Federal Anti-Tampering Act, passed in 1983, makes it a crime to tamper with packaged consumer products.

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1983 The Orphan Drug Act is passed, enabling the FDA to promote research and marketing of drugs needed for treating rare diseases.

1984 The Drug Price Competition and Patent Term Restoration Act expedites the availability of less costly generic drugs by permitting the FDA to approve applications to market generic versions of brand-name drugs without repeating the research done to prove them safe and effective. At the same time, the brand-name companies can apply for up to ﬁve years of additional patent protection for the new medicines they developed to make up for time lost while their products were going through the FDA’s approval process.

1987 The FDA revises investigational drug regulations to expand access to experimental drugs for patients with serious diseases with no alternative therapies.

1988 The Prescription Drug Marketing Act bans the diversion of prescription drugs from legitimate commercial channels. Congress ﬁnds that the resale of such drugs leads to the distribution of mislabeled, adulterated, subpotent, and counterfeit drugs to the public. The new law requires drug wholesalers to be licensed by the states, restricts reimportation from other countries, and bans the sale, trade, or purchase of drug samples and trafﬁcking or counterfeiting of redeemable drug coupons.

1991 The FDA publishes regulations to accelerate reviews of drugs for life-threatening diseases.

1992 The Generic Drug Enforcement Act imposes debarment and other penalties for illegal acts involving abbreviated drug applications. The Prescription Drug User Fee requires drug and biologics manufacturers to pay fees for product applications and supplements and other services. The act also requires the FDA to use these funds to hire more reviewers to assess applications.

1994 The FDA announces it could consider regulating nicotine in cigarettes as a drug, in response to a citizen’s petition by the Coalition on Smoking or Health. The Uruguay Round Agreements Act extends the patent terms of U.S. drugs from 17 to 20 years.

1995 The FDA declares cigarettes to be “drug delivery devices.” Restrictions are proposed on marketing and sales to reduce smoking by young people.

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1997 The Food and Drug Administration Modernization Act reauthorizes the Prescription Drug User Fee Act of 1992 and mandates the most wide-ranging reforms in agency practices since 1938. Provisions include measures to accelerate reviews of devices, advertising unapproved uses of approved drugs and devices, health claims for foods in agreement with published data by a reputable public health source, and development of good guidance practices for agency decision making.

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Appendix 3. Clinical Investigators CLINICAL INVESTIGATOR REGULATORY SANCTIONS This section focuses on the applicability of regulatory sanctions to clinical investigators participating in studies involving investigational new drugs, antibiotics, biologics, medical devices, medical foods, or food additives. (Note: Although this text refers to human subjects in the context of an investigational new drug application [IND], analogous principles apply to animal subjects in an investigational new animal drug application [INAD].) Regulations do not state that hearings will be held at FDA headquarters, and investigators may suggest another location. Hearings can be denied if investigators fail to submit any information that raises any question of fact.

THE DISQUALIFICATION PROCESS Informal Conference or Written Explanation The FDA may disqualify clinical investigators from receiving investigational drugs, biologics, and devices only when the investigator has repeatedly or deliberately violated the Agency’s regulations or has submitted false information to the sponsor in a required report. The appropriate FDA Center will send the investigator a written notice describing the noncompliance or false submission and offer the investigator an opportunity to respond to the notice at an informal conference or in writing. The Agency will specify a time period within which the investigator must respond. While the conference is informal, a transcript may be made, and the investigator may have legal representation. If the investigator offers a timely and satisfactory explanation for the noncompliance, and the Center accepts, the process is terminated and the investigator is so notiﬁed in writing. If, however, the investigator offers an explanation that the Center rejects or if the investigator fails to respond within the speciﬁed time period, FDA will offer the investigator an opportunity for an informal regulatory “Part 16” hearing under the Agency’s regulations (21 CFR Part 16) to determine whether the investigator should remain eligible to receive investigational test articles. Notice of an Opportunity for Hearing on Proposed Disqualifications The FDA initiates a Part 16 hearing when it sends the investigator a written Notice of Opportunity for Hearing. The Notice speciﬁes the allegations and other relevant information that are the subject of the hearing. If the investigator does not respond within the time period speciﬁed in the letter, FDA considers the offer to have been refused, and no informal hearing will be held. The Commissioner will then consider the information available to FDA to determine whether the investigator should be disqualiﬁed. If a hearing is requested, the Commissioner will designate a presiding ofﬁcer from the Ofﬁce of Health Affairs (OHA), and the hearing will take place at a mutually agreeable time at FDA headquarters. If agreement cannot be reached, however, the presiding ofﬁcer will designate a hearing date acceptable to FDA.

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Part 16 Hearing and Final Order on Disqualification Before the hearing, FDA gives the investigator notice of the matters to be considered at the hearing which includes a comprehensive statement of the basis for the proposal to disqualify the investigator and a general summary of the information that the Center will present. The Center and the investigator exchange written notices of any published articles or written information to be presented or relied upon at the hearing. If it seems unreasonable to expect the other party to have, or to be able to obtain, a copy of a particular document, a copy of the document is provided. The investigator or the Center may each ﬁle a motion for summary decision. Part 16 hearings are informal, and the rules of evidence do not apply. Any participant may comment upon or rebut all data, information, and views presented. The presiding ofﬁcer conducts the hearing. The hearing begins with Center staff giving a complete statement of the action that is the subject of the hearing and describing the information and reasons supporting disqualiﬁcation. They may present any oral or written information relevant to the hearing. The investigator, who may be represented by legal counsel, then may present any oral or written information relevant to the hearing. After the hearing, the OHA presiding ofﬁcer prepares a written report. This report includes a recommended decision and the reasons for the recommendation. The administrative record of the hearing includes all written material presented at the hearing and the hearing transcript. The parties are given the opportunity to review and comment on the presiding ofﬁcer’s report. The report and the comments of the parties are transmitted to the Commissioner who considers them along with the administrative record to determine whether the investigator should be disqualiﬁed. The Commissioner issues a written decision giving the basis for the action taken. Actions Upon Disqualification If the Commissioner determines that the investigator has repeatedly or deliberately failed to comply with the regulatory requirements, or has deliberately or repeatedly submitted false information to the sponsor in any required report, the Commissioner will: (1) Notify the investigator and the sponsor(s) of any investigation(s) in which the investigator has participated that the investigator is not entitled to receive investigational drugs, biologics, or devices. The notiﬁcation will include a statement explaining the basis for this determination. (2) Notify the sponsors of studies conducted under each IND, IDE, or approved application containing data reported by the investigator that the Agency will not accept the investigator’s work in support of claims of safety and efﬁcacy without validating information establishing that the study results were unaffected by the investigator’s misconduct. (3) After the investigator’s data are eliminated from consideration, determine whether the data remaining can support a conclusion that studies under the IND or IDE may continue. If the Commissioner determines that the remaining data are inadequate, the sponsor will be notiﬁed and will have an opportunity for a regulatory hearing under 21 CFR Part 16. If a danger to public health exists, however, the Commissioner will terminate the IND or IDE immediately and notify the sponsor of the determination. The sponsor will then have an opportunity for a Part 16 regulatory hearing to determine whether the IND or IDE should be reinstated. (4) After the investigator’s data are eliminated from consideration, determine whether the continued approval of the product is justiﬁed. If it is not, the Commissioner will move to withdraw approval in accordance with the applicable provisions of the Federal Food, Drug, and Cosmetic Act. The action to be taken with regard to an ongoing clinical investigation conducted by a disqualiﬁed investigator is made on a case-by-case basis. FDA considers the nature of the clinical investigation, the number of subjects involved, the risks to the subjects from discontinuation of the study, and the

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need for involvement of an acceptable investigator. If another investigator accepts responsibility for the investigation, FDA may allow an investigation to continue. If not, further use of the test article is deferred until another investigator is identiﬁed. If this deferment could create a life-threatening situation, FDA may permit a subject to continue to receive or use a test article without a further written statement from the disqualiﬁed investigator. The investigator can bring such cases to the Agency’s attention during the regulatory hearing, so that the Commissioner may consider this option. Public Disclosure of Information Regarding Disqualification A danger to the public health includes not only the subjects’ safety in any study in question, but also the safety of subjects in other studies in which the investigator is involved. The Notice of Opportunity for a Hearing letter is available under the Freedom of Information provisions but is not placed on public display. The FDA will notify other government agencies of a proposed disqualiﬁcation whenever the Agency deems such notiﬁcation to be appropriate. If the Agency notiﬁes other parties of its preliminary ﬁndings prior to ﬁnal disqualiﬁcation, FDA will provide a description of these ﬁndings, state that the Agency has yet to reach a ﬁnal decision on whether the investigator should be disqualiﬁed, and will not recommend that action be taken by the third party. If the disqualiﬁcation proceeding does not result in a disqualiﬁcation or a consent agreement, FDA will so advise those third parties that had been contacted. A copy of each notiﬁcation will be sent to the investigator. If the Agency gives notice of the disqualiﬁcation of a speciﬁc investigator to a third party, FDA will provide a copy of the ﬁnal disqualiﬁcation order, explain its legal meaning, and state that FDA is not advising or recommending that the person notiﬁed take any action upon the matter. A copy of each notiﬁcation will be sent to the investigator. The list of investigators who are ineligible to receive investigational new drugs, biologics, and devices or who have agreed to some restriction of use of investigational drugs, biologics, and devices (see below) is not considered to be a “notice” as discussed above. Reinstatement of a Disqualified Investigator Investigators who have been disqualiﬁed may be reinstated if the Commissioner determines that the investigators have presented adequate assurances that they will employ investigational drugs, biologics, and devices in compliance with FDA regulations. The Agency’s reinstatement guidelines, entitled “Procedures for Reinstating Eligibility of Disqualiﬁed Clinical Investigators To Receive Investigational Articles,” are available by writing to the Freedom of Information staff at the address given below.

CONSENT AGREEMENTS In addition to an opportunity for an informal conference or to respond in writing to Center allegations, the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, and the Center for Devices and Radiological Health offer investigators the opportunity to enter into a consent agreement whereby the investigator agrees to meet certain conditions mutually acceptable to both FDA and the investigator. This agreement obviates the need to proceed further with the disqualiﬁcation process. Consent agreements generally take one of two forms: (1) the individual agrees to refrain from further studies with FDA-regulated test articles, or (2) the individual agrees to speciﬁc restrictions in the use of investigational products, such as oversight by an individual acceptable to both the investigator and to the Agency. The consent agreement option remains available to the clinical investigator at all stages of the disqualiﬁcation process. Most actions have been settled by consent agreements.

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CRIMINAL PROSECUTIONS After a Part 16 proceeding, a ﬁnal order or entry into a consent agreement constitutes ﬁnal Agency administrative action. This, however, does not preclude institution of criminal proceedings against an investigator. Those investigators referred for criminal prosecution are generally clinical investigators who have knowingly or willingly submitted false information to a research sponsor.

ADDITIONAL INFORMATION FDA maintains a list of investigators who are ineligible to receive FDA-regulated test articles or who have agreed to some restriction of use of FDA-regulated test articles. This list is regularly updated and is not considered to be a “notice” of disqualiﬁcation (see above). The list is available to the public by writing to the following FDA ofﬁce: Freedom of Information Staff (HFI-35) Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857

INVESTIGATOR RESPONSIBILITIES 312.60 General Responsibilities of Investigators — An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation. An investigator shall, in accordance with the provisions of Part 50 of this chapter, obtain the informed consent of each human subject to whom the drug is administered, except as provided in Sections 50.23 and 50.24 of this chapter. Additional speciﬁc responsibilities of clinical investigators are set forth in this part and in Parts 50 and 56 of this chapter. 312.61 Control of the Investigational Drug — An investigator shall administer the drug only to subjects under the investigator’s personal supervision or under the supervision of a sub-investigator responsible to the investigator. The investigator shall not supply the investigational drug to any person not authorized under this part to receive it. 312.62 Investigator Recordkeeping and Record Retention — (a) Disposition of drug. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug to the sponsor, or otherwise provide for disposition of the unused supplies of the drug under Section 312.59. (b) Case histories. An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual’s hospital chart(s), and the nurses’ notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study. (c) Record retention. An investigator shall retain records required to be maintained under this part for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be ﬁled or if the application

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is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notiﬁed. 312.64 Investigator Reports — (a) Progress reports. The investigator shall furnish all reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained. The sponsor is required under Section 312.33 to submit annual reports to FDA on the progress of the clinical investigations. (b) Safety reports. An investigator shall promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the investigator shall report the adverse effect immediately. (c) Final report. An investigator shall provide the sponsor with an adequate report shortly after completion of the investigator’s participation in the investigation. (d) Financial disclosure reports. The clinical investigator shall provide the sponsor with sufﬁcient accurate ﬁnancial information to allow an applicant to submit complete and accurate certiﬁcation or disclosure statements as required under Part 54 of this chapter. The clinical investigator shall promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following the completion of the study. 312.66 Assurance of IRB Review — An investigator shall assure that an IRB that complies with the requirements set forth in Part 56 will be responsible for the initial and continuing review and approval of the proposed clinical study. The investigator shall also assure that he or she will promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others, and that he or she will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects. 312.68 Inspection of Investigator’s Records and Reports — An investigator shall upon request from any properly authorized ofﬁcer or employee of FDA, at reasonable times, permit such ofﬁcer or employee to have access to, and copy and verify, any records or reports made by the investigator pursuant to Section 312.62. The investigator is not required to divulge subject names unless the records of particular individuals require a more detailed study of the cases, or unless there is reason to believe that the records do not represent actual case studies, or do not represent actual results obtained. 312.69 Handling of Controlled Substances — If the investigational drug is subject to the Controlled Substances Act, the investigator shall take adequate precautions, including storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is limited, to prevent theft or diversion of the substance into illegal channels of distribution. 312.70 Disqualiﬁcation of a Clinical Investigator — (a) If FDA has information indicating that an investigator (including a sponsor–investigator) has repeatedly or deliberately failed to comply with the requirements of this part, Part 50, or Part 56 of this chapter, or has submitted to FDA or to the sponsor false information in any required report, the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research will furnish the investigator written notice of the matter complained of and offer the investigator an opportunity to explain the matter in writing, or, at the option of the investigator, in an informal conference. If an explanation is offered but not accepted by the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research, the investigator will be given an opportunity for a regulatory hearing under Part 16 on the question of whether the investigator is entitled to receive investigational new drugs.

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(b) After evaluating all available information, including any explanation presented by the investigator, if the Commissioner determines that the investigator has repeatedly or deliberately failed to comply with the requirements of this part, Part 50, or Part 56 of this chapter, or has deliberately or repeatedly submitted false information to FDA or to the sponsor in any required report, the Commissioner will notify the investigator and the sponsor of any investigation in which the investigator has been named as a participant that the investigator is not entitled to receive investigational drugs. The notiﬁcation will provide a statement of basis for such determination. (c) Each IND and each approved application submitted under Part 314 containing data reported by an investigator who has been determined to be ineligible to receive investigational drugs will be examined to determine whether the investigator has submitted unreliable data that are essential to the continuation of the investigation or essential to the approval of any marketing application. (d) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the data remaining are inadequate to support a conclusion that it is reasonably safe to continue the investigation, the Commissioner will notify the sponsor who shall have an opportunity for a regulatory hearing under Part 16. If a danger to the public health exists, however, the Commissioner shall terminate the IND immediately and notify the sponsor of the determination. In such case, the sponsor shall have an opportunity for a regulatory hearing before FDA under Part 16 on the question of whether the IND should be reinstated. (e) If the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the continued approval of the drug product for which the data were submitted cannot be justiﬁed, the Commissioner will proceed to withdraw approval of the drug product in accordance with the applicable provisions of the act. (f) An investigator who has been determined to be ineligible to receive investigational drugs may be reinstated as eligible when the Commissioner determines that the investigator has presented adequate assurances that the investigator will employ investigational drugs solely in compliance with the provisions of this part and of Parts 50 and 56.

FDA INSPECTIONS OF CLINICAL INVESTIGATORS BACKGROUND The FDA Bioresearch Monitoring Program involves site visits to clinical investigators, research sponsors, contract research organizations, Institutional Review Boards (IRBs), and nonclinical (animal) laboratories. All FDA product areas (i.e., drugs, biologics, medical devices, radiological products, foods, and veterinary drugs) are involved in the Bioresearch Monitoring Program. While program procedures differ slightly depending upon product type, all inspections have as their objective ensuring the quality and integrity of data and information submitted to FDA as well as the protection of human research subjects.

CLINICAL INVESTIGATOR INSPECTION PROGRAMS FDA carries out three distinct types of clinical investigator inspections: (1) study-oriented inspections; (2) investigator-oriented inspections; and (3) bioequivalence study inspections. Bioequivalence study inspections are conducted because one study may be the sole basis for a drug’s marketing approval. The bioequivalence study inspection differs from the other inspections in that it requires participation by an FDA chemist or an investigator knowledgeable about analytical evaluations. The other two types of inspections are discussed in more detail below.

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Study-Oriented Inspections FDA ﬁeld ofﬁces conduct study-oriented inspections on the basis of assignments developed by headquarters staff. Assignments are based almost exclusively on studies that are important to product evaluation, such as new drug applications and product license applications pending before the Agency. When a clinical investigator who has participated in the study being examined is selected for an inspection, an FDA investigator from the FDA District Ofﬁce will contact the clinical investigator to arrange a mutually acceptable time for the visit. Upon arrival, the FDA investigator will show FDA credentials (photo ID) and present a “Notice of Inspection” form to the clinical investigator. FDA credentials let the clinical investigator know that the FDA investigator is a duly authorized FDA representative. If, during the course of an FDA inspection, a clinical investigator has any questions that the FDA investigator has not answered, either the Director of the District Ofﬁce or the Center that initiated the inspection may be contacted. The name and telephone number of the District Director and the speciﬁc Center contact person are available from FDA investigator. The investigation consists of two basic parts. First, determining the facts surrounding the conduct of the study: • • • • • • •

Who did what The degree of delegation of authority Where speciﬁc aspects of the study were performed How and where data were recorded How test article accountability was maintained How the monitor communicated with the clinical investigator How the monitor evaluated the study’s progress.

Second, the study data are audited. The FDA investigator compares the data submitted to the Agency and/or the sponsor with all available records that might support the data. These records may come from the physician’s ofﬁce, hospital, nursing home, laboratories, or other sources. FDA may also examine patient records that predate the study to determine whether the medical condition being studied was, in fact, properly diagnosed and whether a possibly interfering medication had been given before the study began. The FDA investigator may also review records covering a reasonable period after completion of the study to determine if there was proper follow-up, and if all signs and symptoms reasonably attributable to the product’s use had been reported. Investigator-Oriented Inspections An investigator-oriented inspection may be initiated because an investigator conducted a pivotal study that merits in-depth examination because of its singular importance in product approval or its effect on medical practice. An inspection may also be initiated because representatives of the sponsor have reported to FDA that they are having difﬁculty getting case reports from the investigator or that they have some other concern with the investigator’s work. In addition, the Agency may initiate an inspection, if a subject in a study complains about protocol or subject rights violations. Investigator-oriented inspections may also be initiated because clinical investigators have participated in a large number of studies or have done work outside their specialty areas. Other reasons include safety or effectiveness ﬁndings that are inconsistent with those of other investigators studying the same test article; too many subjects with a speciﬁc disease given the locale of the investigation are claimed; or laboratory results that are outside the range of expected biological variation. Once the Agency has determined that an investigator-oriented inspection should be conducted, the procedures are essentially the same as in the study-oriented inspection except

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that the data audit goes into greater depth, covers more case reports, and may cover more than one study. If the investigator has repeatedly or deliberately violated FDA regulations or has submitted false information to the sponsor in a required report, FDA will initiate actions that may ultimately determine that the clinical investigator is not to receive investigational products in the future.

INSPECTION FINDINGS At the end of an inspection, the FDA investigator will conduct an “exit interview” with the clinical investigator. At this interview, the FDA investigator will discuss the ﬁndings from the inspection, will clarify any misunderstandings that might exist, and may issue a written Form FDA 483 (Notice of Observations) to the clinical investigator. Following the inspection, the FDA ﬁeld investigator prepares a written report and submits it to headquarters for evaluation. After the report has been evaluated, FDA headquarters usually issues a letter to the clinical investigator. The letter is generally one of three types: (1) A notice that no signiﬁcant deviations from the regulations were observed. This letter does not require any response from the clinical investigator. (2) An informational letter that identiﬁes deviations from regulations and good investigational practice. This letter may or may not require a response from the clinical investigator. If a response is requested, the letter will describe what is necessary and give a contact person for questions. (3) A “warning letter” identifying serious deviations from regulations requiring prompt correction by the clinical investigator. The letter will give a contact person for questions. In these cases, FDA may inform both the study sponsor and the reviewing IRB of the deﬁciencies. The Agency may also inform the sponsor if the clinical investigator’s procedural deﬁciencies indicate ineffective monitoring by the sponsor. In addition to issuing these letters, FDA may take other courses of action (i.e., regulatory and/or administrative sanctions).

ADDITIONAL INFORMATION A copy of the FDA Compliance Program Guidance Manual for Clinical Investigator Inspections (Program 7348.811), the document used by an FDA investigator to conduct the inspection, is available by writing to: Freedom of Information Staff (HFI-35) Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 Also see the FDA Information Sheet “Clinical Investigator Regulatory Sanctions.”

FDA INSTITUTIONAL REVIEW BOARD INSPECTIONS BACKGROUND Since 1971, FDA regulations have required that studies involving investigational new drugs and biologics performed on human subjects in institutions (including hospitals, nursing homes, mental institutions, and prisons) receive review and approval by an Institutional Review Board (IRB). Medical devices have required IRB review since 1976. FDA developed the Bioresearch Monitoring Program and began an expanded review of IRB operations in April 1977. The Bioresearch Monitoring Program, which encompasses not only IRBs but also clinical investigators, research sponsors,

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monitors, and nonclinical (animal) laboratories, is primarily intended to ensure the quality and integrity of data submitted to FDA for regulatory decisions, as well as to protect human subjects of research. For this reason, the IRB regulations note that FDA may inspect IRBs and review and copy IRB records (21 CFR 56.115(b)).

IRB REVIEW PROGRAM Under the Bioresearch Monitoring Program, FDA conducts on-site procedural reviews of IRBs. These reviews are conducted to determine whether an IRB is operating in accordance with its own written procedures as well as in compliance with current FDA regulations affecting IRBs. These regulations include 21 CFR Part 50 (Informed Consent), Part 56 (Standards for IRBs), Part 312 (Investigational New Drugs), and Part 812 (Investigational Devices). When an IRB is selected for a procedural review, an investigator from one of the Agency’s District Ofﬁces will contact a responsible individual at the institution, usually the IRB chairperson, and arrange a mutually acceptable time for the visit. When the ﬁeld investigators arrive at the institution, they will show FDA credentials (photo ID) and present a “Notice of Inspection” form to the responsible ofﬁcial. This is done simply to let those persons at the institution know that the investigators are duly authorized representatives of FDA conducting ofﬁcial business. The investigator will interview appropriate persons and obtain information about the IRB’s policies and procedures. Then, using one or more studies that are subject to FDA regulations, the investigator will examine the IRB’s performance by tracking these studies through the review process used by the IRB. The IRB procedures and membership rosters will be examined to see whether they conform to current Agency regulations. The FDA investigator may request copies of records of IRB membership, IRB procedures and guidelines, minutes of meetings at which the studies were reviewed and discussed, material on the studies submitted by the clinical investigator to the IRB, and any other materials pertaining to these studies. Copies of these materials become part of the ﬁeld investigator’s report to FDA Headquarters. After the inspection has been completed, the investigator will conduct an “exit interview” with a responsible institutional representative and/or the IRB chairperson. At this interview, the investigator will review the ﬁndings, will clarify any misunderstandings that might exist, will describe any deviations from the current regulations, and may suggest corrective actions. A written Form FDA 483 (Notice of Observations) may be left with the institution. After the investigator returns to the District Ofﬁce, a written report is prepared. This report is forwarded to FDA Headquarters for evaluation. When the evaluation is completed, a letter may be sent to the IRB chairperson or other responsible institutional ofﬁcial. If the regulations have not been followed, the letter may suggest methods to achieve compliance and ask the IRB to correct its procedures. If serious deviations were observed, a written response assuring adequate correction is usually required. A follow-up inspection may be also conducted. FDA may take administrative actions against IRBs and/or their institutions for noncompliance with the regulations (21 CFR Part 56 Subpart E).

ADDITIONAL INFORMATION A copy of the FDA Compliance Program Guidance Manual for IRB Inspections (Program 7348.809) is available to the public by writing to: Freedom of Information Staff (HFI-35) Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857

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Contact Person for Inspection Problems If, during the course of an inspection, questions arise that the FDA ﬁeld investigator has not answered, the Director of the District Ofﬁce may be contacted. The name and telephone number of the District Director are available from the ﬁeld investigator and are also provided on the Notice of Inspection (Form FDA 482).

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Appendix 4. FDA Administrative Procedures Act (FAPA) TITLE 21 (FOOD AND DRUGS) CFR 10.1–10.206 SUBCHAPTER A — GENERAL Subpart A — General Provisions Section 10.1

Scope.

(a) Part 10 governs practices and procedures for petitions, hearings, and other administrative proceedings and activities conducted by the Food and Drug Administration under the Federal Food, Drug, and Cosmetic Act, the Public Health Service Act, and other laws which the Commissioner of Food and Drugs administers. (b) If a requirement in another part of Title 21 differs from a requirement in this part, the requirements of this part apply to the extent that they do not conﬂict with the other requirements. (c) References in this part and parts 12, 13, 14, 15, and 16 to regulatory sections of the Code of Federal Regulations are to chapter I of Title 21 unless otherwise noted. (d) References in this part and parts 12, 13, 14, 15, and 16 to publication, or to the day or date of publication, or use of the phrase to publish, refer to publication in the Federal Register unless otherwise noted. [44 FR 22323, Apr. 13, 1979, as amended at 54 FR 9034, Mar. 3, 1989; 69 FR 17290, Apr. 2, 2004] Section 10.3

Deﬁnitions.

(a) The following deﬁnitions apply in this part and parts 12, 13, 14, 15, 16, and 19: Act means the Federal Food, Drug, and Cosmetic Act unless otherwise indicated. Administrative action includes every act, including the refusal or failure to act, involved in the administration of any law by the Commissioner, except that it does not include the referral of apparent violations to U.S. attorneys for the institution of civil or criminal proceedings or an act in preparation of a referral. Administrative ﬁle means the ﬁle or ﬁles containing all documents pertaining to a particular administrative action, including internal working memoranda, and recommendations. Administrative record means the documents in the administrative ﬁle of a particular administrative action on which the Commissioner relies to support the action. Agency means the Food and Drug Administration. Chief Counsel means the Chief Counsel of the Food and Drug Administration.

391

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Commissioner means the Commissioner of Food and Drugs, Food and Drug Administration, U.S. Department of Health and Human Services, or the Commissioner’s designee. Department means the U.S. Department of Health and Human Services. Division of Dockets Management means the Division of Dockets Management, Ofﬁce of Management and Operations of the Food and Drug Administration, U.S. Department of Health and Human Services, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Ex parte communication means an oral or written communication not on the public record for which reasonable prior notice to all parties is not given, but does not include requests for status reports on a matter. FDA means the Food and Drug Administration. Food and Drug Administration employee or Food and Drug Administration representative includes members of the Food and Drug Division of the ofﬁce of the General Counsel of the Department of Health and Human Services. Formal evidentiary public hearing means a hearing conducted under part 12. Interested person or any person who will be adversely affected means a person who submits a petition or comment or objection or otherwise asks to participate in an informal or formal administrative proceeding or court action. Meeting means any oral discussion, whether by telephone or in person. Ofﬁce of the Commissioner includes the ofﬁces of the Associate Commissioners but not the centers or the regional or district ofﬁces. Order means the ﬁnal agency disposition, other than the issuance of a regulation, in a proceeding concerning any matter and includes action on a new drug application, new animal drug application, or biological license. Participant means any person participating in any proceeding, including each party and any other interested person. Party means the center of the Food and Drug Administration responsible for a matter involved and every person who either has exercised a right to request or has been granted the right by the Commissioner to have a hearing under part 12 or part 16 or who has waived the right to a hearing to obtain the establishment of a Public Board of Inquiry under part 13 and as a result of whose action a hearing or a Public Board of Inquiry has been established. Person includes an individual, partnership, corporation, association, or other legal entity. Petition means a petition, application, or other document requesting the Commissioner to establish, amend, or revoke a regulation or order, or to take or not to take any other form of administrative action, under the laws administered by the Food and Drug Administration. Presiding ofﬁcer means the Commissioner or the Commissioner’s designee or an administrative law judge appointed as provided in 5 U.S.C. 3105. Proceeding and administrative proceeding means any undertaking to issue, amend, or revoke a regulation or order, or to take or refrain from taking any other form of administrative action. Public advisory committee or advisory committee means any committee, board, commission, council, conference, panel, task force, or other similar group, or any subcommittee or other subgroup of an advisory committee, that is not composed wholly of full-time employees of the Federal Government and is established or utilized by the Food and Drug Administration to obtain advice or recommendations. Public Board of Inquiry or Board means an administrative law tribunal constituted under part 13. Public hearing before a public advisory committee means a hearing conducted under part 14. Public hearing before a Public Board of Inquiry means a hearing conducted under part 13. Public hearing before the Commissioner means a hearing conducted under part 15. Regulations means an agency rule of general or particular applicability and future effect issued under a law administered by the Commissioner or relating to administrative practices and

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procedures. In accordance with section 10.90(a), each agency regulation will be published in the Federal Register and codiﬁed in the Code of Federal Regulations. Regulatory hearing before the Food and Drug Administration means a hearing conducted under part 16. Secretary means the Secretary of Health and Human Services. The laws administered by the Commissioner or the laws administered by the Food and Drug Administration means all the laws that the Commissioner is authorized to administer. (b) A term that is deﬁned in section 201 of the Federal Food, Drug, and Cosmetic Act or part 1 has the same deﬁnition in this part. (c) Words in the singular form include the plural, words in the masculine form include the feminine, and vice versa. (d) Whenever a reference is made in this part to a person in FDA, e.g., the director of a center, the reference includes all persons to whom that person has delegated the speciﬁc function involved. [44 FR 22323, Apr. 13, 1979, as amended at 46 FR 8455, Jan. 27, 1981; 50 FR 8994, Mar. 6, 1985; 54 FR 6886, Feb. 15, 1989; 54 FR 9034, Mar. 3, 1989; 59 FR 14363, Mar. 28, 1994; 69 FR 17290, Apr. 2, 2004] Section 10.10

Summaries of administrative practices and procedures.

To encourage public participation in all agency activities, the Commissioner will prepare for public distribution summaries of FDA administrative practices and procedures in readily understandable terms. Section 10.19

Waiver, suspension, or modiﬁcation of procedural requirements.

The Commissioner or a presiding ofﬁcer may, either voluntarily or at the request of a participant, waive, suspend, or modify any provision in parts 12 through 16 applicable to the conduct of a public hearing by announcement at the hearing or by notice in advance of the hearing if no participant will be prejudiced, the ends of justice will thereby be served, and the action is in accordance with law. Subpart B — General Administrative Procedures Section 10.20 Submission of documents to Division of Dockets Management; computation of time; availability for public disclosure. (a) A submission to the Division of Dockets Management of a petition, comment, objection, notice, compilation of information, or any other document is to be ﬁled in four copies except as otherwise speciﬁcally provided in a relevant Federal Register notice or in another section of this chapter. The Division of Dockets Management is the agency custodian of these documents. (b) A submission is to be signed by the person making it, or by an attorney or other authorized representative of that person. Submissions by trade associations are also subject to the requirements of section 10.105(b). (c) Information referred to or relied upon in a submission is to be included in full and may not be incorporated by reference, unless previously submitted in the same proceeding. (1) A copy of an article or other reference or source cited must be included, except where the reference or source is: (i) A reported Federal court case; (ii) A Federal law or regulation;

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(iii) An FDA document that is routinely publicly available; or (iv) A recognized medical or scientiﬁc textbook that is readily available to the agency. (2) If a part of the material submitted is in a foreign language, it must be accompanied by an English translation veriﬁed to be complete and accurate, together with the name, address, and a brief statement of the qualiﬁcations of the person making the translation. A translation of literature or other material in a foreign language is to be accompanied by copies of the original publication. (3) Where relevant information is contained in a document also containing irrelevant information, the irrelevant information is to be deleted and only the relevant information is to be submitted. (4) Under section 20.63(a) and (b), the names and other information that would identify patients or research subjects are to be deleted from any record before it is submitted to the Division of Dockets Management in order to preclude a clearly unwarranted invasion of personal privacy. (5) Defamatory, scurrilous, or intemperate matter is to be deleted from a record before it is submitted to the Division of Dockets Management. (6) The failure to comply with the requirements of this part or with section 12.80 or section 13.20 will result in rejection of the submission for ﬁling or, if it is ﬁled, in exclusion from consideration of any portion that fails to comply. If a submission fails to meet any requirement of this section and the deﬁciency becomes known to the Division of Dockets Management, the Division of Dockets Management shall not ﬁle the submission but return it with a copy of the applicable regulations indicating those provisions not complied with. A deﬁcient submission may be corrected or supplemented and subsequently ﬁled. The ofﬁce of the Division of Dockets Management does not make decisions regarding the conﬁdentiality of submitted documents. (d) The ﬁling of a submission means only that the Division of Dockets Management has identiﬁed no technical deﬁciencies in the submission. The ﬁling of a petition does not mean or imply that it meets all applicable requirements or that it contains reasonable grounds for the action requested or that the action requested is in accordance with law. (e) All submissions to the Division of Dockets Management will be considered as submitted on the date they are postmarked or, if delivered in person during regular business hours, on the date they are delivered, unless a provision in this part, an applicable Federal Register notice, or an order issued by an administrative law judge speciﬁcally states that the documents must be received by a speciﬁed date, e.g., section 10.33(g) relating to a petition for reconsideration, in which case they will be considered submitted on the date received. (f) All submissions are to be mailed or delivered in person to the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. (g) FDA ordinarily will not acknowledge or give receipt for documents, except: (1) Documents delivered in person or by certiﬁed or registered mail with a return receipt requested; and (2) Petitions for which acknowledgment of receipt of ﬁling is provided by regulation or by customary practice, e.g., section 10.30(c) relating to a citizen petition. (h) Saturdays, Sundays, and Federal legal holidays are included in computing the time allowed for the submission of documents, except that when the time for submission expires on a Saturday, Sunday, or Federal legal holiday, the period will be extended to include the next business day. (i) All submissions to the Division of Dockets Management are representations that, to the best of the knowledge, information, and belief of the person making the submission, the statements made in the submission are true and accurate. All submissions are subject to the False Reports to the Government Act (18 U.S.C. 1001) under which a willfully false statement is a criminal offense.

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(j) The availability for public examination and copying of submissions to the Division of Dockets Management is governed by the following rules: (1) Except to the extent provided in paragraphs (j)(2) and (3) of this section, the following submissions, including all supporting material, will be on public display and will be available for public examination between 9 a.m. and 4 p.m., Monday through Friday. Requests for copies of submissions will be ﬁled and handled in accordance with subpart C of part 20: (i) Petitions. (ii) Comments on petitions, on documents published in the Federal Register, and on similar public documents. (iii) Objections and requests for hearings ﬁled under part 12. (iv) Material submitted at a hearing under section 12.32(a)(2) and parts 12, 13, and 15. (v) Material placed on public display under the regulations in this chapter, e.g., agency guidance documents developed under section 10.115. (2)(i) Material prohibited from public disclosure under section 20.63 (clearly unwarranted invasion of personal privacy) and, except as provided in paragraph (j)(3) of this section, material submitted with objections and requests for hearing ﬁled under part 12, or at a hearing under part 12 or part 13, or an alternative form of public hearing before a public advisory committee or a hearing under section 12.32(a)(2) or (3), of the following types will not be on public display, will not be available for public examination, and will not be available for copying or any other form of verbatim transcription unless it is otherwise available for public disclosure under part 20: (a) Safety and effectiveness information, which includes all studies and tests of an ingredient or product on animals and humans and all studies and tests on the ingredient or product for identity, stability, purity, potency, bioavailability, performance, and usefulness. (b) A protocol for a test or study. (c) Manufacturing methods or processes, including quality control procedures. (d) Production, sales distribution, and similar information, except any compilation of information aggregated and prepared in a way that does not reveal conﬁdential information. (e) Quantitative or semiquantitative formulas. (f) Information on product design or construction. (ii) Material submitted under paragraph (j)(2) of this section is to be segregated from all other submitted material and clearly so marked. A person who does not agree that a submission is properly subject to paragraph (j)(2) may request a ruling from the Associate Commissioner for Public Affairs whose decision is ﬁnal, subject to judicial review under section 20.48. (3) Material listed in paragraph (j)(2)(i)(a) and (b) of this section may be disclosed under a protective order issued by the administrative law judge or other presiding ofﬁcer at a hearing referenced in paragraph (j)(2)(i). The administrative law judge or presiding ofﬁcer shall permit disclosure of the data only in camera and only to the extent necessary for the proper conduct of the hearing. The administrative law judge or presiding ofﬁcer shall direct to whom the information is to be made available (e.g., to parties or participants, or only to counsel for parties or participants), and persons not speciﬁcally permitted access to the data will be excluded from the in camera part of the proceeding. The administrative law judge or other presiding ofﬁcer may impose other conditions or safeguards. The limited availability of material under this paragraph does not constitute prior disclosure to the public as deﬁned in section 20.81, and no information subject to a particular order is to be submitted to or received or considered by FDA in support of a petition or other request from any other person.

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[44 FR 22323, Apr. 13, 1979, as amended at 46 FR 8455, Jan. 27, 1981; 49 FR 7363, Feb. 29, 1984; 54 FR 9034, Mar. 3, 1989; 59 FR 14363, Mar. 28, 1994; 64 FR 69190, Dec. 10, 1999; 65 FR 56477, Sept. 19, 2000; 66 FR 56035, Nov. 6, 2001; 66 FR 66742, Dec. 27, 2001; 68 FR 25285, May 12, 2003] Section 10.25

Initiation of administrative proceedings.

An administrative proceeding may be initiated in the following three ways: (a) An interested person may petition the Commissioner to issue, amend, or revoke a regulation or order, or to take or refrain from taking any other form of administrative action. A petition must be either: (1) In the form speciﬁed in other applicable FDA regulations, e.g., the form for a color additive petition in section 71.1, for a food additive petition in section 171.1, for a new drug application in section 314.50, for a new animal drug application in section 514.1, or (2) in the form for a citizen petition in section 10.30. (b) The Commissioner may initiate a proceeding to issue, amend, or revoke a regulation or order or take or refrain from taking any other form of administrative action. FDA has primary jurisdiction to make the initial determination on issues within its statutory mandate, and will request a court to dismiss, or to hold in abeyance its determination of or refer to the agency for administrative determination, any issue which has not previously been determined by the agency or which, if it has previously been determined, the agency concluded should be reconsidered and subject to a new administrative determination. The Commissioner may utilize any of the procedures established in this part in reviewing and making a determination on any matter initiated under this paragraph. (c) The Commissioner will institute a proceeding to determine whether to issue, amend, or revoke a regulation or order, or take or refrain from taking any other form of administrative action whenever any court, on its own initiative, holds in abeyance or refers any matter to the agency for an administrative determination and the Commissioner concludes that an administrative determination is feasible within agency priorities and resources. [44 FR 22323, Apr. 13, 1979, as amended at 54 FR 9034, Mar. 3, 1989] Section 10.30

Citizen petition.

(a) This section applies to any petition submitted by a person (including a person who is not a citizen of the United States) except to the extent that other sections of this chapter apply different requirements to a particular matter. (b) A petition (including any attachments) must be submitted in accordance with section 10.20 and in the following form: (Date)________________________________________ Division of Dockets Management, Food and Drug Administration, Department of Health and Human Services, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Citizen Petition The undersigned submits this petition under ___ (relevant statutory sections, if known) of the ___ (Federal Food, Drug, and Cosmetic Act or the Public Health Service Act or any other statutory provision for which authority has been delegated to the Commissioner of Food and Drugs under 21 CFR 5.10) to request the Commissioner of Food and Drugs to ___ (issue, amend, or revoke a regulation or order or take or refrain from taking any other form of administrative action).

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A. Action requested ((1) If the petition requests the Commissioner to issue, amend, or revoke a regulation, the exact wording of the existing regulation (if any) and the proposed regulation or amendment requested.) ((2) If the petition requests the Commissioner to issue, amend, or revoke an order, a copy of the exact wording of the citation to the existing order (if any) and the exact wording requested for the proposed order.) ((3) If the petition requests the Commissioner to take or refrain from taking any other form of administrative action, the speciﬁc action or relief requested.) B. Statement of grounds (A full statement, in a well organized format, of the factual and legal grounds on which the petitioner relies, including all relevant information and views on which the petitioner relies, as well as representative information known to the petitioner which is unfavorable to the petitioner’s position.) C. Environmental impact (A claim for categorical exclusion under sections 25.30, 25.31, 25.32, 25.33, or 25.34 of this chapter or an environmental assessment under section 25.40 of this chapter.) D. Economic impact (The following information is to be submitted only when requested by the Commissioner following review of the petition: A statement of the effect of requested action on: (1) Cost (and price) increases to industry, government, and consumers; (2) productivity of wage earners, businesses, or government; (3) competition; (4) supplies of important materials, products, or services; (5) employment; and (6) energy supply or demand.) E. Certiﬁcation The undersigned certiﬁes, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition. (Signature)________________________________________ (Name of petitioner)________________________________ (Mailing address)___________________________________ (Telephone number)_________________________________ (c) A petition which appears to meet the requirements of paragraph (b) of this section and section 10.20 will be ﬁled by the Division of Dockets Management, stamped with the date of ﬁling, and assigned a docket number. The docket number identiﬁes the ﬁle established by the Division of Dockets Management for all submissions relating to the petition, as provided in this part. Subsequent submissions relating to the matter must refer to the docket number and will be ﬁled in the docket ﬁle. Related petitions may be ﬁled together and given the same docket number. The Division of Dockets Management will promptly notify the petitioner in writing of the ﬁling and docket number of a petition. (d) An interested person may submit written comments to the Division of Dockets Management on a ﬁled petition, which comments become part of the docket ﬁle. The comments are to specify the docket number of the petition and may support or oppose the petition in whole or in part. A request for alternative or different administrative action must be submitted as a separate petition.

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(e)(1) The Commissioner shall, in accordance with paragraph (e)(2), rule upon each petition ﬁled under paragraph (c) of this section, taking into consideration (i) available agency resources for the category of subject matter, (ii) the priority assigned to the petition considering both the category of subject matter involved and the overall work of the agency, and (iii) time requirements established by statute. (2) Except as provided in paragraph (e)(4) of this section, the Commissioner shall furnish a response to each petitioner within 180 days of receipt of the petition. The response will either: (i) Approve the petition, in which case the Commissioner shall concurrently take appropriate action (e.g., publication of a Federal Register notice) implementing the approval; (ii) Deny the petition; or (iii) Provide a tentative response, indicating why the agency has been unable to reach a decision on the petition, e.g., because of the existence of other agency priorities, or a need for additional information. The tentative response may also indicate the likely ultimate agency response, and may specify when a ﬁnal response may be furnished. (3) The Commissioner may grant or deny such a petition, in whole or in part, and may grant such other relief or take other action as the petition warrants. The petitioner is to be notiﬁed in writing of the Commissioner’s decision. The decision will be placed in the public docket ﬁle in the ofﬁce of the Division of Dockets Management and may also be in the form of a notice published in the Federal Register. (4) The Commissioner shall furnish a response to each petitioner within 90 days of receipt of a petition ﬁled under section 505(j)(2)(C) of the act. The response will either approve or disapprove the petition. Agency action on a petition shall be governed by section 314.93 of this chapter. (f) If a petition ﬁled under paragraph (c) of this section requests the Commissioner to issue, amend, or revoke a regulation, section 10.40 or section 10.50 also apply. (g) A petitioner may supplement, amend, or withdraw a petition in writing without agency approval and without prejudice to resubmission at anytime until the Commissioner rules on the petition, unless the petition has been referred for a hearing under parts 12, 13, 14, or 15. After a ruling or referral, a petition may be supplemented, amended, or withdrawn only with the approval of the Commissioner. The Commissioner may approve withdrawal, with or without prejudice against resubmission of the petition. (h) In reviewing a petition the Commissioner may use the following procedures: (1) Conferences, meetings, discussions, and correspondence under section 10.65. (2) A hearing under parts 12, 13, 14, 15, or 16. (3) A Federal Register notice requesting information and views. (4) A proposal to issue, amend, or revoke a regulation, in accordance with section 10.40 or section 12.20. (5) Any other speciﬁc public procedure established in this chapter and expressly applicable to the matter. (i) The record of the administrative proceeding consists of the following: (1) The petition, including all information on which it relies, ﬁled by the Division of Dockets Management. (2) All comments received on the petition, including all information submitted as a part of the comments. (3) If the petition resulted in a proposal to issue, amend, or revoke a regulation, all of the documents speciﬁed in section 10.40(g).

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(4) The record, consisting of any transcripts, minutes of meetings, reports, Federal Register notices, and other documents resulting from the optional procedures speciﬁed in paragraph (h) of this section, except a transcript of a closed portion of a public advisory committee meeting. (5) The Commissioner’s decision on the petition, including all information identiﬁed or ﬁled by the Commissioner with the Division of Dockets Management as part of the record supporting the decision. (6) All documents ﬁled with the Division of Dockets Management under section 10.65(h). (7) If a petition for reconsideration or for a stay of action is ﬁled under paragraph (j) of this section, the administrative record speciﬁed in section 10.33(k) or section 10.35(h). (j) The administrative record speciﬁed in paragraph (i) of this section is the exclusive record for the Commissioner’s decision. The record of the administrative proceeding closes on the date of the Commissioner’s decision unless some other date is speciﬁed. Thereafter any interested person may submit a petition for reconsideration under section 10.33 or a petition for stay of action under section 10.35. A person who wishes to rely upon information or views not included in the administrative record shall submit them to the Commissioner with a new petition to modify the decision in accordance with this section. (k) This section does not apply to the referral of a matter to a United States attorney for the initiation of court enforcement action and related correspondence, or to requests, suggestions, and recommendations made informally in routine correspondence received by FDA. Routine correspondence does not constitute a petition within the meaning of this section unless it purports to meet the requirements of this section. Action on routine correspondence does not constitute ﬁnal administrative action subject to judicial review under section 10.45. (l) The Division of Dockets Management will maintain a chronological list of each petition ﬁled under this section and section 10.85, but not of petitions submitted elsewhere in the agency under section 10.25(a)(1), showing: (1) The docket number; (2) The date the petition was ﬁled by the Division of Dockets Management; (3) The name of the petitioner; (4) The subject matter involved; and (5) The disposition of the petition. [44 FR 22323, Apr. 13, 1979, as amended at 46 FR 8455, Jan. 27, 1981; 50 16656, Apr. 26, 1985; 54 FR 9034, Mar. 3, 1989; 57 FR 17980, Apr. 28, 1992; 59 FR 14364, Mar. 28, 1994; 62 FR 40592, July 29, 1997; 66 FR 6467, Jan. 22, 2001; 66 FR 12848, Mar. 1, 2001] Section 10.33

Administrative reconsideration of action.

(a) The Commissioner may at any time reconsider a matter, on the Commissioner’s own initiative or on the petition of an interested person. (b) An interested person may request reconsideration of part or all of a decision of the Commissioner on a petition submitted under section 10.25. Each request for reconsideration must be submitted in accordance with section 10.20 and in the following form no later than 30 days after the date of the decision involved. The Commissioner may, for good cause, permit a petition to be ﬁled after 30 days. In the case of a decision published in the Federal Register, the day of publication is the day of decision. (Date)________________________________________

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Division of Dockets Management, Food and Drug Administration, Department of Health and Human Services, Rm. 1-23, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Petition for Reconsideration [Docket No.] The undersigned submits this petition for reconsideration of the decision of the Commissioner of Food and Drugs in Docket No. __. A. Decision involved (A concise statement of the decision of the Commissioner which the petitioner wishes to have reconsidered.) B. Action requested (The decision which the petitioner requests the Commissioner to make upon reconsideration of the matter.) C. Statement of grounds (A full statement, in a well-organized format, of the factual and legal grounds upon which the petitioner relies. The grounds must demonstrate that relevant information and views contained in the administrative record were not previously or not adequately considered by the Commissioner. (No new information or views may be included in a petition for reconsideration.) (Signature)________________________________________ (Name of petitioner)________________________________________ (Mailing address)________________________________________ (Telephone number)________________________________________ (c) A petition for reconsideration relating to a petition submitted under section 10.25(a)(2) is subject to the requirements of section 10.30(c) and (d), except that it is ﬁled in the same docket ﬁle as the petition to which it relates. (d) The Commissioner shall promptly review a petition for reconsideration. The Commissioner may grant the petition when the Commissioner determines it is in the public interest and in the interest of justice. The Commissioner shall grant a petition for reconsideration in any proceeding if the Commissioner determines all of the following apply: (1) The petition demonstrates that relevant information or views contained in the administrative record were not previously or not adequately considered. (2) The petitioner’s position is not frivolous and is being pursued in good faith. (3) The petitioner has demonstrated sound public policy grounds supporting reconsideration. (4) Reconsideration is not outweighed by public health or other public interests. (e) A petition for reconsideration may not be based on information and views not contained in the administrative record on which the decision was made. An interested person who wishes to rely on information or views not included in the administrative record shall submit them with a new petition to modify the decision under section 10.25(a). (f) The decision on a petition for reconsideration is to be in writing and placed on public display as part of the docket ﬁle on the matter in the ofﬁce of the Division of Dockets Management. A determination to grant reconsideration will be published in the Federal Register if the Commissioner’s original decision was so published. Any other determination to grant or deny reconsideration may also be published in the Federal Register.

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(g) The Commissioner may consider a petition for reconsideration only before the petitioner brings legal action in the courts to review the action, except that a petition may also be considered if the Commissioner has denied a petition for stay of action and the petitioner has petitioned for judicial review of the Commissioner’s action and requested the reviewing court to grant a stay pending consideration of review. A petition for reconsideration submitted later than 30 days after the date of the decision involved will be denied as untimely unless the Commissioner permits the petition to be ﬁled after 30 days. A petition for reconsideration will be considered as submitted on the day it is received by the Division of Dockets Management. (h) The Commissioner may initiate the reconsideration of all or part of a matter at any time after it has been decided or action has been taken. If review of the matter is pending in the courts, the Commissioner may request that the court refer the matter back to the agency or hold its review in abeyance pending administrative reconsideration. The administrative record of the proceeding is to include all additional documents relating to such reconsideration. (i) After determining to reconsider a matter, the Commissioner shall review and rule on the merits of the matter under section 10.30(e). The Commissioner may reafﬁrm, modify, or overrule the prior decision, in whole or in part, and may grant such other relief or take such other action as is warranted. (j) The Commissioner’s reconsideration of a matter relating to a petition submitted under section 10.25(a)(2) is subject to section 10.30(f) through (h), (j), and (k). (k) The record of the administrative proceeding consists of the following: (1) The record of the original petition speciﬁed in section 10.30(i). (2) The petition for reconsideration, including all information on which it relies, ﬁled by the Division of Dockets Management. (3) All comments received on the petition, including all information submitted as a part of the comments. (4) The Commissioner’s decision on the petition under paragraph (f) of this section, including all information identiﬁed or ﬁled by the Commissioner with the Division of Dockets Management as part of the record supporting the decision. (5) Any Federal Register notices or other documents resulting from the petition. (6) All documents ﬁled with the Division of Dockets Management under section 10.65(h). (7) If the Commissioner reconsiders the matter, the administrative record relating to reconsideration speciﬁed in section 10.30(i). [44 FR 22323, Apr. 13, 1979, as amended at 46 FR 8455, Jan. 27, 1981; 59 FR 14364, Mar. 28, 1994; 66 FR 6467, Jan. 22, 2001; 66 FR 12848, Mar. 1, 2001] Section 10.35

Administrative stay of action.

(a) The Commissioner may at any time stay or extend the effective date of an action pending or following a decision on any matter. (b) An interested person may request the Commissioner to stay the effective date of any administrative action. A stay may be requested for a speciﬁc time period or for an indeﬁnite time period. A request for stay must be submitted in accordance with section 10.20 and in the following form no later than 30 days after the date of the decision involved. The Commissioner may, for good cause, permit a petition to be ﬁled after 30 days. In the case of a decision published in the Federal Register, the day of publication is the date of decision. (Date)________________________________________

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Division of Dockets Management, Food and Drug Administration, Department of Health and Human Services, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Petition for Stay of Action The undersigned submits this petition requesting that the Commissioner of Food and Drugs stay the effective date of the following matter. A. Decision involved (The speciﬁc administrative action being taken by the Commissioner for which a stay is requested, including the docket number or other citation to the action involved.) B. Action requested (The length of time for which the stay is requested, which may be for a speciﬁc or indeﬁnite time period.) C. Statement of grounds (A full statement, in a well-organized format, of the factual and legal grounds upon which the petitioner relies for the stay.) (Signature)________________________________________ (Name of petitioner)________________________________________ (Mailing address)________________________________________ (Telephone number)________________________________________ (c) A petition for stay of action relating to a petition submitted under section 10.25(a)(2) is subject to the requirements of section 10.30(c) and (d), except that it will be ﬁled in the same docket ﬁle as the petition to which it relates. (d) Neither the ﬁling of a petition for a stay of action nor action taken by an interested person in accordance with any other administrative procedure in this part or in any other section of this chapter, e.g., the ﬁling of a citizen petition under section 10.30 or a petition for reconsideration under section 10.33 or a request for an advisory opinion under section 10.85, will stay or otherwise delay any administrative action by the Commissioner, including enforcement action of any kind, unless one of the following applies: (1) The Commissioner determines that a stay or delay is in the public interest and stays the action. (2) A statute requires that the matter be stayed. (3) A court orders that the matter be stayed. (e) The Commissioner shall promptly review a petition for stay of action. The Commissioner may grant or deny a petition, in whole or in part; and may grant such other relief or take such other action as is warranted by the petition. The Commissioner may grant a stay in any proceeding if it is in the public interest and in the interest of justice. The Commissioner shall grant a stay in any proceeding if all of the following apply: (1) The petitioner will otherwise suffer irreparable injury. (2) The petitioner’s case is not frivolous and is being pursued in good faith. (3) The petitioner has demonstrated sound public policy grounds supporting the stay. (4) The delay resulting from the stay is not outweighted by public health or other public interests.

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(f) The Commissioner’s decision on a petition for stay of action is to be in writing and placed on public display as part of the ﬁle on the matter in the ofﬁce of the Division of Dockets Management. A determination to grant a stay will be published in the Federal Register if the Commissioner’s original decision was so published. Any other determination to grant or to deny a stay may also be published in the Federal Register. (g) A petition for a stay of action submitted later than 30 days after the date of the decision involved will be denied as untimely unless the Commissioner permits the petition to be ﬁled after 30 days. A petition for a stay of action is considered submitted on the day it is received by the Division of Dockets Management. (h) The record of the administrative proceeding consists of the following: (1) The record of the proceeding to which the petition for stay of action is directed. (2) The petition for stay of action, including all information on which it relies, ﬁled by the Division of Dockets Management. (3) All comments received on the petition, including all information submitted as a part of the comments. (4) The Commissioner’s decision on the petition under paragraph (e) of this section, including all information identiﬁed or ﬁled by the Commissioner with the Division of Dockets Management as part of the record supporting the decision. (5) Any Federal Register notices or other documents resulting from the petition. (6) All documents ﬁled with the Division of Dockets Management under section 10.65(h). [44 FR 22323, Apr. 13, 1979, as amended at 46 FR 8455, Jan. 27, 1981; 54 FR 9034, Mar. 3, 1989; 59 FR 14364, Mar. 28, 1994; 66 FR 6468, Jan. 22, 2001; 66 FR 12848, Mar. 1, 2001] Section 10.40

Promulgation of regulations for the efﬁcient enforcement of the law.

(a) The Commissioner may propose and promulgate regulations for the efﬁcient enforcement of the laws administered by FDA whenever it is necessary or appropriate to do so. The issuance, amendment, or revocation of a regulation may be initiated in any of the ways speciﬁed in section 10.25. (1) This section applies to any regulation: (i) Not subject to section 10.50 and part 12, or (ii) if it is subject to section 10.50 and part 12, to the extent that those provisions make this section applicable. (2) A regulation proposed by an interested person in a petition submitted under section 10.25(a) will be published in the Federal Register as a proposal if: (i) The petition contains facts demonstrating reasonable grounds for the proposal; and (ii) The petition substantially shows that the proposal is in the public interest and will promote the objectives of the act and the agency. (3) Two or more alternative proposed regulations may be published on the same subject to obtain comment on the different alternatives. (4) A regulation proposed by an interested person in a petition submitted under section 10.25(a) may be published together with the Commissioner’s preliminary views on the proposal and any alternative proposal. (b) Except as provided in paragraph (e) of this section, each regulation must be the subject of a notice of proposed rulemaking published in the Federal Register.

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(1) The notice will contain: (i) The name of the agency; (ii) The nature of the action, e.g., proposed rule, or notice; (iii) A summary in the ﬁrst paragraph describing the substance of the document in easily understandable terms; (iv) Relevant dates, e.g., comment closing date, and proposed effective date(s); (v) The name, business address, and phone number of an agency contact person who can provide further information to the public about the notice; (vi) An address for submitting written comments; (vii) Supplementary information about the notice in the form of a preamble that summarizes the proposal and the facts and policy underlying it, includes references to all information on which the Commissioner relies for the proposal (copies or a full list of which are a part of the docket ﬁle on the matter in the ofﬁce of the Division of Dockets Management), and cites the authority under which the regulation is proposed; (viii) Either the terms or substance of the proposed regulation or a description of the subjects and issues involved; (ix) A reference to the existence or lack of need for an environmental impact statement under section 25.52 of this chapter; and (x) The docket number of the matter, which identiﬁes the docket ﬁle established by the Division of Dockets Management for all relevant submissions. (2) The proposal will provide 60 days for comment, although the Commissioner may shorten or lengthen this time period for good cause. In no event is the time for comment to be less than 10 days. (3) After publication of the proposed rule, any interested person may request the Commissioner to extend the comment period for an additional speciﬁed period by submitting a written request to the Division of Dockets Management stating the grounds for the request. The request is submitted under section 10.35 but should be headed “REQUEST FOR EXTENSION OF COMMENT PERIOD.” (i) A request must discuss the reason comments could not feasibly be submitted within the time permitted, or that important new information will shortly be available, or that sound public policy otherwise supports an extension of the time for comment. The Commissioner may grant or deny the request or may grant an extension for a time period different from that requested. An extension may be limited to speciﬁc persons who have made and justiﬁed the request, but will ordinarily apply to all interested persons. (ii) A comment time extension of 30 days or longer will be published in the Federal Register and will be applicable to all interested persons. A comment time extension of less than 30 days will be the subject either of a letter or memorandum ﬁled with the Division of Dockets Management or of a notice published in the Federal Register. (4) A notice of proposed rulemaking will request that four copies of all comments be submitted to the Division of Dockets Management, except that individuals may submit single copies. Comments will be stamped with the date of receipt and will be numbered chronologically. (5) Persons submitting comments critical of a proposed regulation are encouraged to include their preferred alternative wording. (c) After the time for comment on a proposed regulation has expired, the Commissioner will review the entire administrative record on the matter, including all comments and, in a notice published

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in the Federal Register, will terminate the proceeding, issue a new proposal, or promulgate a ﬁnal regulation. (1) The quality and persuasiveness of the comments will be the basis for the Commissioner’s decision. The number or length of comments will not ordinarily be a signiﬁcant factor in the decision unless the number of comments is material where the degree of public interest is a legitimate factor for consideration. (2) The decision of the Commissioner on the matter will be based solely upon the administrative record. (3) A ﬁnal regulation published in the Federal Register will have a preamble stating: (i) The name of the agency, (ii) the nature of the action e.g., ﬁnal rule, notice, (iii) a summary ﬁrst paragraph describing the substance of the document in easily understandable terms, (iv) relevant dates, e.g., the rule’s effective date and comment closing date, if an opportunity for comment is provided, (v) the name, business address, and phone number of an agency contact person who can provide further information to the public about the notice, (vi) an address for the submission of written comments when they are permitted, (vii) supplementary information about the regulation in the body of the preamble that contains references to prior notices relating to the same matter and a summary of each type of comment submitted on the proposal and the Commissioner’s conclusions with respect to each. The preamble is to contain a thorough and comprehensible explanation of the reasons for the Commissioner’s decision on each issue. (4) The effective date of a ﬁnal regulation may not be less than 30 days after the date of publication in the Federal Register, except for: (i) A regulation that grants an exemption or relieves a restriction; or (ii) A regulation for which the Commissioner ﬁnds, and states in the notice good cause for an earlier effective date. (d) The provisions for notice and comment in paragraphs (b) and (c) of this section apply only to the extent required by the Administrative Procedure Act (5 U.S.C. 551, 552, and 553). As a matter of discretion, however, the Commissioner may voluntarily follow those provisions in circumstances in which they are not required by the Administrative Procedure Act. (e) The requirements of notice and public procedure in paragraph (b) of this section do not apply in the following situations: (1) When the Commissioner determines for good cause that they are impracticable, unnecessary, or contrary to the public interest. In these cases, the notice promulgating the regulation will state the reasons for the determination, and provide an opportunity for comment to determine whether the regulation should subsequently be modiﬁed or revoked. A subsequent notice based on those comments may, but need not, provide additional opportunity for public comment. (2) Food additive and color additive petitions, which are subject to the provisions of section 12.20(b)(2). (3) New animal drug regulations, which are promulgated under section 512(i) of the act. (f) In addition to the notice and public procedure required under paragraph (b) of this section, the Commissioner may also subject a proposed or ﬁnal regulation, before or after publication in the Federal Register, to the following additional procedures: (1) Conferences, meetings, discussions, and correspondence under section 10.65. (2) A hearing under parts 12, 13, 14, or 15. (3) A notice published in the Federal Register requesting information and views before the Commissioner determines whether to propose a regulation.

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(4) A draft of a proposed regulation placed on public display in the ofﬁce of the Division of Dockets Management. If this procedure is used, the Commissioner shall publish an appropriate notice in the Federal Register stating that the document is available and specifying the time within which comments on the draft proposal may be submitted orally or in writing. (5) A revised proposal published in the Federal Register, which proposal is subject to all the provisions in this section relating to proposed regulations. (6) A tentative ﬁnal regulation or tentative revised ﬁnal regulation placed on public display in the ofﬁce of the Division of Dockets Management and, if deemed desirable by the Commissioner, published in the Federal Register. If the tentative regulation is placed on display only, the Commissioner shall publish an appropriate notice in the Federal Register stating that the document is available and specifying the time within which comments may be submitted orally or in writing on the tentative ﬁnal regulation. The Commissioner shall mail a copy of the tentative ﬁnal regulation and the Federal Register notice to each person who submitted comments on the proposed regulation if one has been published. (7) A ﬁnal regulation published in the Federal Register that provides an opportunity for the submission of further comments, in accordance with paragraph (e)(1) of this section. (8) Any other public procedure established in this chapter and expressly applicable to the matter. (g) The record of the administrative proceeding consists of all of the following: (1) If the regulation was initiated by a petition, the administrative record speciﬁed in section 10.30(i). (2) If a petition for reconsideration or for a stay of action is ﬁled, the administrative record speciﬁed in sections 10.33(k) and 10.35(h). (3) The proposed rule published in the Federal Register, including all information identiﬁed or ﬁled by the Commissioner with the Division of Dockets Management on the proposal. (4) All comments received on the proposal, including all information submitted as a part of the comments. (5) The notice promulgating the ﬁnal regulation, including all information identiﬁed or ﬁled by the Commissioner with the Division of Dockets Management as part of the administrative record of the ﬁnal regulation. (6) The transcripts, minutes of meetings, reports, Federal Register notices, and other documents resulting from the procedures speciﬁed in paragraph (f) of this section, but not the transcript of a closed portion of a public advisory committee meeting. (7) All documents submitted to the Division of Dockets Management under section 10.65(h). (h) The record of the administrative proceeding closes on the date of publication of the ﬁnal regulation in the Federal Register unless some other date is speciﬁed. Thereafter, any interested person may submit a petition for reconsideration under section 10.33 or a petition for stay of action under section 10.35. A person who wishes to rely upon information or views not included in the administrative record shall submit it to the Commissioner with a new petition to modify the ﬁnal regulation. (i) The Division of Dockets Management shall maintain a chronological list of all regulations proposed and promulgated under this section and section 10.50 (which list will not include regulations resulting from petitions ﬁled and assigned a docket number under section 10.30) showing— (1) The docket number (for a petition submitted directly to a center, the list also includes the number or other designation assigned by the center, e.g., the number assigned to a food additive petition);

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(2) The name of the petitioner, if any; (3) The subject matter involved; and (4) The disposition of the petition. [44 FR 22323, Apr. 13, 1979, as amended at 52 FR 36401, Sept. 29, 1987; 54 FR 9034, Mar. 3, 1989; 56 FR 13758, Apr. 4, 1991; 62 FR 40592, July 29, 1997; 66 FR 6468, Jan. 22, 2001; 66 FR 12848, Mar. 1, 2001] Section 10.45 remedies.

Court review of ﬁnal administrative action; exhaustion of administrative

(a) This section applies to court review of ﬁnal administrative action taken by the Commissioner, including action taken under sections 10.25 through 10.40 and section 16.1(b), except action subject to section 10.50 and part 12. (b) A request that the Commissioner take or refrain from taking any form of administrative action must ﬁrst be the subject of a ﬁnal administrative decision based on a petition submitted under section 10.25(a) or, where applicable, a hearing under section 16.1(b) before any legal action is ﬁled in a court complaining of the action or failure to act. If a court action is ﬁled complaining of the action or failure to act before the submission of the decision on a petition under section 10.25(a) or, where applicable, a hearing under section 16.1(b), the Commissioner shall request dismissal of the court action or referral to the agency for an initial administrative determination on the grounds of a failure to exhaust administrative remedies, the lack of ﬁnal agency action as required by 5 U.S.C. 701 et seq., and the lack of an actual controversy as required by 28 U.S.C. 2201. (c) A request that administrative action be stayed must ﬁrst be the subject of an administrative decision based upon a petition for stay of action submitted under section 10.35 before a request is made that a court stay the action. If a court action is ﬁled requesting a stay of administrative action before the Commissioner’s decision on a petition submitted in a timely manner pursuant to section 10.35, the Commissioner shall request dismissal of the court action or referral to the agency for an initial determination on the grounds of a failure to exhaust administrative remedies, the lack of ﬁnal agency action as required by 5 U.S.C. 701 et seq., and the lack of an actual controversy as required by 28 U.S.C. 2201. If a court action is ﬁled requesting a stay of administrative action after a petition for a stay of action is denied because it was submitted after expiration of the time period provided under section 10.35, or after the time for submitting such a petition has expired, the Commissioner will request dismissal of the court action on the ground of a failure to exhaust administrative remedies. (d) Unless otherwise provided, the Commissioner’s ﬁnal decision constitutes ﬁnal agency action (reviewable in the courts under 5 U.S.C. 701 et seq. and, where appropriate, 28 U.S.C. 2201) on a petition submitted under section 10.25(a), on a petition for reconsideration submitted under section 10.33, on a petition for stay of action submitted under section 10.35, on an advisory opinion issued under section 10.85, on a matter involving administrative action which is the subject of an opportunity for a hearing under section 16.1(b) of this chapter, or on the issuance of a ﬁnal regulation published in accordance with section 10.40, except that the agency’s response to a petition ﬁled under section 505(j)(2)(C) of the act (21 U.S.C. 355(j)(2)(C)) and section 314.93 of this chapter will not constitute ﬁnal agency action until any petition for reconsideration submitted by the petitioner is acted on by the Commissioner. (1) It is the position of FDA except as otherwise provided in paragraph (d)(2) of this section, that: (i) Final agency action exhausts all administrative remedies and is ripe for preenforcement judicial review as of the date of the ﬁnal decision, unless applicable law explicitly requires that the petitioner take further action before judicial review is available;

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(ii) An interested person is affected by, and thus has standing to obtain, judicial review of ﬁnal agency action; and (iii) It is not appropriate to move to dismiss a suit for preenforcement judicial review of ﬁnal agency action on the ground that indispenable parties are not joined or that it is an unconsented suit against the United States if the defect could be cured by amending the complaint. (2) The Commissioner shall object to judicial review of a matter if: (i) The matter is committed by law to the discretion of the Commissioner, e.g., a decision to recommend or not to recommend civil or criminal enforcement action under sections 302, 303, and 304 of the act; or (ii) Review is not sought in a proper court. (e) An interested person may request judicial review of a ﬁnal decision of the Commissioner in the courts without ﬁrst petitioning the Commissioner for reconsideration or for a stay of action, except that in accordance with paragraph (c) of this section, the person shall request a stay by the Commissioner under section 10.35 before requesting a stay by the court. (f) The Commissioner shall take the position in an action for judicial review under 5 U.S.C. 701 et seq., whether or not it includes a request for a declaratory judgment under 28 U.S.C. 2201, or in any other case in which the validity of administrative action is properly challenged, that the validity of the action must be determined solely on the basis of the administrative record speciﬁed in sections 10.30(i), 10.33(k), 10.35(h), 10.40(g), and 16.80(a) or the administrative record applicable to any decision or action under the regulations referenced in section 16.1(b), and that additional information or views may not be considered. An interested person who wishes to rely upon information or views not included in the administrative record shall submit them to the Commissioner with a new petition to modify the action under section 10.25(a). (g) The Commissioner requests that all petitions for judicial review of a particular matter be ﬁled in a single U.S. District court. If petitions are ﬁled in more than one jurisdiction, the Commissioner will take appropriate action to prevent a multiplicity of suits in various jurisdictions, such as: (1) A request for transfer of one or more suits to consolidate separate actions, under 28 U.S.C. 1404(a) or 28 U.S.C. 2112(a); (2) A request that actions in all but one jurisdiction be stayed pending the conclusion of one proceeding; (3) A request that all but one action be dismissed pending the conclusion of one proceeding, with the suggestion that the other plaintiffs intervene in that one suit; or (4) A request that one of the suits be maintained as a class action in behalf of all affected persons. (h)(1) For the purpose of 28 U.S.C. 2112(a), a copy of any petition ﬁled in any U.S. Court of Appeals challenging a ﬁnal action of the Commissioner shall be sent by certiﬁed mail, return receipt requested, or by personal delivery to the Chief Counsel of FDA. The petition copy shall be timestamped by the clerk of the court when the original is ﬁled with the court. The petition copy should be addressed to: Ofﬁce of the Chief Counsel (GCF-1), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. The Chief Counsel requests that the purpose of all petitions mailed or delivered to the Ofﬁce of Chief Counsel to satisfy 28 U.S.C. 2112(a) be clearly identiﬁed in a cover letter. (2) If the Chief Counsel receives two or more petitions ﬁled in two or more U.S. Courts of Appeals for review of any agency action within 10 days of the effective date of that action for the purpose of judicial review, the Chief Counsel will notify the U.S. Judicial Panel on Multidistrict Litigation of any petitions that were received within the 10-day period, in accordance with the applicable rule of the panel.

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(3) For the purpose of determining whether a petition for review has been received within the 10-day period under paragraph (h)(2) of this section, the petition shall be considered to be received on the date of delivery, if personally delivered. If the delivery is accomplished by mail, the date of receipt shall be the date noted on the return receipt card. (i) Upon judicial review of administrative action under this section: (1) If a court determines that the administrative record is inadequate to support the action, the Commissioner shall determine whether to proceed with such action. (i) If the Commissioner decides to proceed with the action, the court will be requested to remand the matter to the agency to reopen the administrative proceeding and record, or on the Commissioner’s own initiative the administrative proceeding and record may be reopened upon receipt of the court determination. A reopened administrative proceeding will be conducted under the provisions of this part and in accordance with any directions of the court. (ii) If the Commissioner concludes that the public interest requires that the action remain in effect pending further administrative proceedings, the court will be requested not to stay the matter in the interim and the Commissioner shall expedite the further administrative proceedings. (2) If a court determines that the administrative record is adequate, but the rationale for the action must be further explained: (i) The Commissioner shall request either that further explanation be provided in writing directly to the court without further administrative proceedings, or that the administrative proceeding be reopened in accordance with paragraph (i)(1)(i) of this section; and (ii) If the Commissioner concludes that the public interest requires that the action remain in effect pending further court or administrative proceedings, the court will be requested not to stay the matter in the interim and the Commissioner shall expedite the further proceedings. [44 FR 22323, Apr. 13, 1979, as amended at 54 FR 6886, Feb. 15, 1989; 54 FR 9034, Mar. 3, 1989; 57 FR 17980, Apr. 28, 1992; 65 FR 56477, Sept. 19, 2000; 69 FR 31705, June 4, 2004] Section 10.50 Promulgation of regulations and orders after an opportunity for a formal evidentiary public hearing. (a) The Commissioner shall promulgate regulations and orders after an opportunity for a formal evidentiary public hearing under part 12 whenever all of the following apply: (1) The subject matter of the regulation or order is subject by statute to an opportunity for a formal evidentiary public hearing. (2) The person requesting the hearing has a right to an opportunity for a hearing and submits adequate justiﬁcation for the hearing as required by sections 12.20 through 12.22 and other applicable provisions in this chapter, e.g., sections 314.200, 514.200, and 601.7(a). (b) The Commissioner may order a formal evidentiary public hearing on any matter whenever it would be in the public interest to do so. (c) The provisions of the act, and other laws, that afford a person who would be adversely affected by administrative action an opportunity for a formal evidentiary public hearing as listed below. The list imparts no right to a hearing where the statutory section provides no opportunity for a hearing. (1) Section 401 on any action for the amendment or repeal of any deﬁnition and standard of identity for any dairy product (including products regulated under parts 131, 133, and 135 of this chapter) or maple syrup (regulated under section 168.140 of this chapter).

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(2) Section 403(j) on regulations for labeling of foods for special dietary uses. (3) Section 404(a) on regulations for emergency permit control. (4) Section 406 on tolerances for poisonous substances in food. (5) Section 409(c), (d), and (h) on food additive regulations. (6) Section 501(b) on tests or methods of assay for drugs described in ofﬁcial compendia. (7) [Reserved] (8) Section 502(h) on regulations designating requirements for drugs liable to deterioration. (9) Section 502(n) on prescription drug advertising regulations. (10) [Reserved] (11) Section 507(f) on regulations for antibiotic drug certiﬁcation. (12) Section 512(n)(5) on regulations for animal antibiotic drugs and certiﬁcation requirements. (13) Section 721(b) and (c) on regulations for color additive listing and certiﬁcation. (14) Section 4(a) of the Fair Packaging and Labeling Act on food, drug, device, and cosmetic labeling. (15) Section 5(c) of the Fair Packaging and Labeling Act on additional economic regulations for food, drugs, devices, and cosmetics. (16) Section 505(d) and (e) on new drug applications. (17) Section 512(d), (e) and (m) (3) and (4) on new animal drug applications. (18) Section 515(g) on device premarket approval applications and product development protocols. (19) Section 351(a) of the Public Health Service Act on a biologics license for a biological product. (20) Section 306 on debarment, debarment period and considerations, termination of debarment under section 306(d)(3), suspension, and termination of suspension. [44 FR 22323, Apr. 13, 1979, as amended at 54 FR 9034, Mar. 3, 1989; 58 FR 49190, Sept. 22, 1993; 60 FR 38626, July 27, 1995; 63 FR 26697, May 13, 1998; 64 FR 398, Jan. 5, 1999; 64 FR 56448, Oct. 20, 1999; 67 FR 4906, Feb. 1, 2002] Section 10.55

Separation of functions; ex parte communications.

(a) This section applies to any matter subject by statute to an opportunity for a formal evidentiary public hearing, as listed in section 10.50(c), and any matter subject to a hearing before a Public Board of Inquiry under part 13. (b) In the case of a matter listed in section 10.50(c)(1) through (10) and (12) through (15): (1) An interested person may meet or correspond with any FDA representative concerning a matter prior to publication of a notice announcing a formal evidentiary public hearing or a hearing before a Public Board of Inquiry on the matter; the provisions of section 10.65 apply to the meetings and correspondence; and (2) Upon publication of a notice announcing a formal evidentiary public hearing or a hearing before a Public Board of Inquiry, the following separation of functions apply: (i) The center responsible for the matter is, as a party to the hearing, responsible for all investigative functions and for presentation of the position of the center at the hearing and in any pleading or oral argument before the Commissioner. Representatives of the center may not participate or advise in any decision except as witness or counsel in public proceedings. There is to be no other communication between representatives of the center and representatives of

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the ofﬁce of the Commissioner concerning the matter before the decision of the Commissioner. The Commissioner may, however, designate representatives of a center to advise the ofﬁce of the Commissioner, or designate members of that ofﬁce to advise a center. The designation will be in writing and ﬁled with the Division of Dockets Management no later than the time speciﬁed in paragraph (b)(2) of this section for the application of separation of functions. All members of FDA other than representatives of the involved center (except those speciﬁcally designated otherwise) shall be available to advise and participate with the ofﬁce of the Commissioner in its functions relating to the hearing and the ﬁnal decision. (ii) The Chief Counsel for FDA shall designate members of the ofﬁce of General Counsel to advise and participate with the center in its functions in the hearing and members who are to advise the ofﬁce of the Commissioner in its functions related to the hearing and the ﬁnal decision. The members of the ofﬁce of General Counsel designated to advise the center may not participate or advise in any decision of the Commissioner except as counsel in public proceedings. The designation is to be in the form of a memorandum ﬁled with the Division of Dockets Management and made a part of the administrative record in the proceeding. There may be no other communication between those members of the ofﬁce of General Counsel designated to advise the ofﬁce of the Commissioner and any other persons in the ofﬁce of General Counsel or in the involved center with respect to the matter prior to the decision of the Commissioner. The Chief Counsel may assign new attorneys to advise either the center or the ofﬁce of the Commissioner at any stage of the proceedings. The Chief Counsel will ordinarily advise and participate with the ofﬁce of the Commissioner in its functions relating to the hearing and the ﬁnal decision. (iii) The ofﬁce of the Commissioner is responsible for the agency review and ﬁnal decision of the matter, with the advice and participation of anyone in FDA other than representatives of the involved center and those members of the ofﬁce of General Counsel designated to assist in the center’s functions in the hearing. (c) In a matter listed in section 10.50(c)(11) and (16) through (19), the provisions relating to separation of functions set forth in sections 314.200(f), 514.200, and 601.7(a) are applicable before publication of a notice announcing a formal evidentiary public hearing or a hearing before a Public Board of Inquiry. Following publication of the notice of hearing, the rules in paragraph (b)(2) of this section apply. (d) Except as provided in paragraph (e) of this section, between the date that separation of functions applies under paragraph (b) or (c) of this section and the date of the Commissioner’s decision on the matter, communication concerning the matter involved in the hearing will be restricted as follows: (1) No person outside the agency may have an ex parte communication with the presiding ofﬁcer or any person representing the ofﬁce of the Commissioner concerning the matter in the hearing. Neither the presiding ofﬁcer nor any person representing the ofﬁce of the Commissioner may have any ex parte communication with a person outside the agency concerning the matter in the hearing. All communications are to be public communications, as witness or counsel, under the applicable provisions of this part. (2) A participant in the hearing may submit a written communication to the ofﬁce of the Commissioner with respect to a proposal for settlement. These communications are to be in the form of pleadings, served on all other participants, and ﬁled with the Division of Dockets Management like any other pleading. (3) A written communication contrary to this section must be immediately served on all other participants and ﬁled with the Division of Dockets Management by the presiding ofﬁcer at the hearing, or by the Commissioner, depending on who received the communication. An oral communication contrary to this section must be immediately recorded in a written memorandum

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and similarly served on all other participants and ﬁled with the Division of Dockets Management. A person, including a representative of a participant in the hearing, who is involved in an oral communication contrary to this section, must, if possible, be made available for crossexamination during the hearing with respect to the substance of that conversation. Rebuttal testimony pertinent to a written or oral communication contrary to this section will be permitted. Cross-examination and rebuttal testimony will be transcribed and ﬁled with the Division of Dockets Management. (e) The prohibitions speciﬁed in paragraph (d) of this section apply to a person who knows of a notice of hearing in advance of its publication from the time the knowledge is acquired. (f) The making of a communication contrary to this section may, consistent with the interests of justice and the policy of the underlying statute, result in a decision adverse to the person knowingly making or causing the making of such a communication. [44 FR 22323, Apr. 13, 1979, as amended at 50 FR 8994, Mar. 6, 1985; 54 FR 9035, Mar. 3, 1989; 64 FR 398, Jan. 5, 1999] Section 10.60

Referral by court.

(a) This section applies when a Federal, State, or local court holds in abeyance, or refers to the Commissioner, any matter for an initial administrative determination under section 10.25(c) or section 10.45(b). (b) The Commissioner shall promptly agree or decline to accept a court referral. Whenever feasible in light of agency priorities and resources, the Commissioner shall agree to accept a referral and shall proceed to determine the matter referred. (c) In reviewing the matter, the Commissioner may use the following procedures: (1) Conferences, meetings, discussions, and correspondence under section 10.65. (2) A hearing under parts 12, 13, 14, 15, or 16. (3) A notice published in the Federal Register requesting information and views. (4) Any other public procedure established in other sections of this chapter and expressly applicable to the matter under those provisions. (d) If the Commissioner’s review of the matter results in a proposed rule, the provisions of section 10.40 or section 10.50 also apply. Section 10.65

Meetings and correspondence.

(a) In addition to public hearings and proceedings established under this part and other sections of this chapter, meetings may be held and correspondence may be exchanged between representatives of FDA and an interested person outside FDA on a matter within the jurisdiction of the laws administered by the Commissioner. Action on meetings and correspondence does not constitute ﬁnal administrative action subject to judicial review under section 10.45. (b) The Commissioner may conclude that it would be in the public interest to hold an open public meeting to discuss a matter (or class of matters) pending before FDA, in which any interested person may participate. (1) The Commissioner shall inform the public of the time and place of the meeting and of the matters to be discussed. (2) The meeting will be informal, i.e., any interested person may attend and participate in the discussion without prior notice to the agency unless the notice of the meeting speciﬁes otherwise.

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(c) Every person outside the Federal Government may request a private meeting with a representative of FDA in agency ofﬁces to discuss a matter. FDA will make reasonable efforts to accommodate such requests. (1) The person requesting a meeting may be accompanied by a reasonable number of employees, consultants, or other persons with whom there is a commercial arrangement within the meaning of section 20.81(a) of this chapter. Neither FDA nor any other person may require the attendance of a person who is not an employee of the executive branch of the Federal Government without the agreement of the person requesting the meeting. Any person may attend by mutual consent of the person requesting the meeting and FDA. (2) FDA will determine which representatives of the agency will attend the meeting. The person requesting the meeting may request, but not require or preclude, the attendance of a speciﬁc FDA employee. (3) A person who wishes to attend a private meeting, but who is not invited to attend either by the person requesting the meeting or by FDA, or who otherwise cannot attend the meeting, may request a separate meeting with FDA to discuss the same matter or an additional matter. (d) FDA employees have a responsibility to meet with all segments of the public to promote the objectives of the laws administered by the agency. In pursuing this responsibility, the following general policy applies where agency employees are invited by persons outside the Federal Government to attend or participate in meetings outside agency ofﬁces as representatives of the agency. (1) A person outside the executive branch may invite an agency representative to attend or participate in a meeting outside agency ofﬁces. The agency representative is not obligated to attend or participate, but may do so where it is in the public interest and will promote the objectives of the act. (2) The agency representative may request that the meeting be open if that would be in the public interest. The agency representative may decline to participate in a meeting held as a private meeting if that will best serve the public interest. (3) An agency representative may not knowingly participate in a meeting that is closed on the basis of gender, race, or religion. (e) An ofﬁcial transcript, recording, or memorandum summarizing the substance of any meeting described in this section will be prepared by a representative of FDA when the agency determines that such documentation will be useful. (f) FDA promptly will ﬁle in the appropriate administrative ﬁle memoranda of meetings prepared by FDA representatives and all correspondence, including any written summary of a meeting from a participant, that relate to a matter pending before the agency. (g) Representatives of FDA may initiate a meeting or correspondence on any matter concerning the laws administered by the Commissioner. Unless otherwise required by law, meetings may be public or private at FDA’s discretion. (h) A meeting of an advisory committee is subject to the requirements of part 14 of this chapter. [66 FR 6468, Jan. 22, 2001] Section 10.70

Documentation of signiﬁcant decisions in administrative ﬁle.

(a) This section applies to every signiﬁcant FDA decision on any matter under the laws administered by the Commissioner, whether it is raised formally, for example, by a petition or informally, for example, by correspondence.

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(b) FDA employees responsible for handling a matter are responsible for insuring the completeness of the administrative ﬁle relating to it. The ﬁle must contain: (1) Appropriate documentation of the basis for the decision, including relevant evaluations, reviews, memoranda, letters, opinions of consultants, minutes of meetings, and other pertinent written documents; and (2) The recommendations and decisions of individual employees, including supervisory personnel, responsible for handling the matter. (i) The recommendations and decisions are to reveal signiﬁcant controversies or differences of opinion and their resolution. (ii) An agency employee working on a matter and, consistent with the prompt completion of other assignments, an agency employee who has worked on a matter may record individual views on that matter in a written memorandum, which is to be placed in the ﬁle. (c) A written document placed in an administrative ﬁle must: (1) Relate to the factual, scientiﬁc, legal or related issues under consideration; (2) Be dated and signed by the author; (3) Be directed to the ﬁle, to appropriate supervisory personnel, and to other appropriate employees, and show all persons to whom copies were sent; (4) Avoid defamatory language, intemperate remarks, undocumented charges, or irrelevant matters (e.g., personnel complaints); (5) If it records the views, analyses, recommendations, or decisions of an agency employee in addition to the author, be given to the other employees; and (6) Once completed (i.e., typed in ﬁnal form, dated, and signed) not be altered or removed. Later additions to or revisions of the document must be made in a new document. (d) Memoranda or other documents that are prepared by agency employees and are not in the administrative ﬁle have no status or effect. (e) FDA employees working on a matter have access to the administrative ﬁle on that matter, as appropriate for the conduct of their work. FDA employees who have worked on a matter have access to the administrative ﬁle on that matter so long as attention to their assignments is not impeded. Reasonable restrictions may be placed upon access to assure proper cataloging and storage of documents, the availability of the ﬁle to others, and the completeness of the ﬁle for review. Section 10.75

Internal agency review of decisions.

(a) A decision of an FDA employee, other than the Commissioner, on a matter, is subject to review by the employee’s supervisor under the following circumstances: (1) At the request of the employee. (2) On the initiative of the supervisor. (3) At the request of an interested person outside the agency. (4) As required by delegations of authority. (b)(1) The review will be made by consultation between the employee and the supervisor or by review of the administrative ﬁle on the matter, or both. The review will ordinarily follow the established agency channels of supervision or review for that matter. (2) A sponsor, applicant, or manufacturer of a drug or device regulated under the act or the Public Health Service Act (42 U.S.C. 262), may request review of a scientiﬁc controversy by an appropriate scientiﬁc advisory panel as described in section 505(n) of the act, or an advisory

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committee as described in section 515(g)(2)(B) of the act. The reason(s) for any denial of a request for such review shall be brieﬂy set forth in writing to the requester. Persons who receive a Center denial of their request under this section may submit a request for review of the denial. The request should be sent to the Chief Mediator and Ombudsman. (c) An interested person outside the agency may request internal agency review of a decision through the established agency channels of supervision or review. Personal review of these matters by center directors or the ofﬁce of the Commissioner will occur for any of the following purposes: (1) To resolve an issue that cannot be resolved at lower levels within the agency (e.g., between two parts of a center or other component of the agency, between two centers or other components of the agency, or between the agency and an interested person outside the agency). (2) To review policy matters requiring the attention of center or agency management. (3) In unusual situations requiring an immediate review in the public interest. (4) As required by delegations of authority. (d) Internal agency review of a decision must be based on the information in the administrative ﬁle. If an interested person presents new information not in the ﬁle, the matter will be returned to the appropriate lower level in the agency for reevaluation based on the new information. [44 FR 22323, Apr. 13, 1979, as amended at 50 FR 8994, Mar. 6, 1985; 63 FR 63982, Nov. 18, 1998] Section 10.80

Dissemination of draft Federal Register notices and regulations.

(a) A representative of FDA may discuss orally or in writing with an interested person ideas and recommendations for notices or regulations. FDA welcomes assistance in developing ideas for, and in gathering the information to support, notices and regulations. (b) Notices and proposed regulations: (1) Once it is determined that a notice or proposed regulation will be prepared, the general concepts may be discussed by a representative of FDA with an interested person. Details of a draft of a notice or proposed regulation may be discussed with a person outside the executive branch only with the speciﬁc permission of the Commissioner. The permission must be in writing and ﬁled with the Division of Dockets Management. (2) A draft of a notice or proposed regulation or its preamble, or a portion of either, may be furnished to an interested person outside the executive branch only if it is made available to all interested persons by a notice published in the Federal Register. A draft of a notice or proposed regulation made available in this manner may, without the prior permission of the Commissioner, be discussed with an interested person to clarify and resolve questions raised and concerns expressed about the draft. (c) After publication of a notice or proposed regulation in the Federal Register, and before preparation of a draft of the ﬁnal notice or regulation, a representative of FDA may discuss the proposal with an interested person as provided in paragraph (b)(2) of this section. (d) Final notices and regulations: (1) Details of a draft of a ﬁnal notice or regulation may be discussed with an interested person outside the executive branch only with the speciﬁc permission of the Commissioner. The permission must be in writing and ﬁled with the Division of Dockets Management. (2) A draft of a ﬁnal notice or regulation or its preamble, or any portion of either, may be furnished to an interested person outside the executive branch only if it is made available to all interested persons by a notice published in the Federal Register, except as otherwise provided in paragraphs (g) and (j) of this section. A draft of a ﬁnal notice or regulation made available to an

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interested person in this manner may, without the prior permission of the Commissioner, be discussed as provided in paragraph (b)(2) of this section. (i) The ﬁnal notice or regulation and its preamble will be prepared solely on the basis of the administrative record. (ii) If additional technical information from a person outside the executive branch is necessary to draft the ﬁnal notice or regulation or its preamble, it will be requested by FDA in general terms and furnished directly to the Division of Dockets Management to be included as part of the administrative record. (iii) If direct discussion by FDA of a draft of a ﬁnal notice or regulation or its preamble is required with a person outside the executive branch, appropriate protective procedures will be undertaken to make certain that a full and impartial administrative record is established. Such procedures may include either: (a) The scheduling of an open public meeting under section 10.65(b) at which interested persons may participate in review of and comment on the draft document; or (b) The preparation of a tentative ﬁnal regulation or tentative revised ﬁnal regulation under section 10.40(f)(6), on which interested persons will be given an additional period of time for oral and written comment. (e) After a ﬁnal regulation is published, an FDA representative may discuss any aspect of it with an interested person. (f) In addition to the requirements of this section, the provisions of section 10.55 apply to the promulgation of a regulation subject to section 10.50 and part 12. (g) A draft of a ﬁnal food additive color additive, or new animal drug regulation may be furnished to the petitioner for comment on the technical accuracy of the regulation. Every meeting with a petitioner relating to the draft will be recorded in a written memorandum, and all memoranda and correspondence will be ﬁled with the Division of Dockets Management as part of the administrative record of the regulation under the provisions of section 10.65. (h) In accordance with 42 U.S.C 263f, the Commissioner shall consult with interested persons and with the Technical Electronic Product Radiation Safety Standards Committee (TEPRSSC) before prescribing any performance standard for an electronic product. Accordingly, the Commissioner shall publish in the Federal Register an announcement when a proposed or ﬁnal performance standard, including any amendment, is being considered for an electronic product, and any draft of any proposed or ﬁnal standard will be furnished to an interested person upon request and may be discussed in detail. (i) The provisions of section 10.65 apply to meetings and correspondence relating to draft notices and regulations. (j) The provisions of this section restricting discussion and disclosure of draft notices and regulations do not apply to situations covered by sections 20.83 through 20.89. [44 FR 22323, Apr. 13, 1979, as amended at 54 FR 9035, Mar. 3, 1989; 64 FR 398, Jan. 5, 1999] Section 10.85

Advisory opinions.

(a) An interested person may request an advisory opinion from the Commissioner on a matter of general applicability. (1) The request will be granted whenever feasible. (2) The request may be denied if:

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(i) The request contains incomplete information on which to base an informed advisory opinion; (ii) The Commissioner concludes that an advisory opinion cannot reasonably be given on the matter involved; (iii) The matter is adequately covered by a prior advisory opinion or a regulation; (iv) The request covers a particular product or ingredient or label and does not raise a policy issue of broad applicability; or (v) The Commissioner otherwise concludes that an advisory opinion would not be in the public interest. (b) A request for an advisory opinion is to be submitted in accordance with section 10.20, is subject to the provisions of section 10.30(c) through (l), and must be in the following form: (Date)________________________________________ Division of Dockets Management, Food and Drug Administration, Department of Health and Human Services, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Request for Advisory Opinion The undersigned submits this request for an advisory opinion of the Commissioner of Food and Drugs with respect to ___ (the general nature of the matter involved). A. Issues involved. (A concise statement of the issues and questions on which an opinion is requested.) B. Statement of facts and law. (A full statement of all facts and legal points relevant to the request.) The undersigned certiﬁes that, to the best of his/her knowledge and belief, this request includes all data, information, and views relevant to the matter, whether favorable or unfavorable to the position of the undersigned, which is the subject of the request. (Signature)________________________________________ (Person making request)________________________________________ (Mailing address)________________________________________ (Telephone number)________________________________________ (c) The Commissioner may respond to an oral or written request to the agency as a request for an advisory opinion, in which case the request will be ﬁled with the Division of Dockets Management and be subject to this section. (d) A statement of policy or interpretation made in the following documents, unless subsequently repudiated by the agency or overruled by a court, will constitute an advisory opinion: (1) Any portion of a Federal Register notice other than the text of a proposed or ﬁnal regulation, e.g., a notice to manufacturers or a preamble to a proposed or ﬁnal regulation. (2) Trade Correspondence (T.C. Nos. 1-431 and 1A-8A) issued by FDA between 1938 and 1946. (3) Compliance policy guides issued by FDA beginning in 1968 and codiﬁed in the Compliance Policy Guides manual.

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(4) Other documents speciﬁcally identiﬁed as advisory opinions, e.g., advisory opinions on the performance standard for diagnostic X-ray systems, issued before July 1, 1975, and ﬁled in a permanent public ﬁle for prior advisory opinions maintained by the Freedom of Information Staff (HFI-35). (e) An advisory opinion represents the formal position of FDA on a matter and except as provided in paragraph (f) of this section, obligates the agency to follow it until it is amended or revoked. The Commissioner may not recommend legal action against a person or product with respect to an action taken in conformity with an advisory opinion which has not been amended or revoked. (f) In unusual situations involving an immediate and signiﬁcant danger to health, the Commissioner may take appropriate civil enforcement action contrary to an advisory opinion before amending or revoking the opinion. This action may be taken only with the approval of the Commissioner, who may not delegate this function. Appropriate amendment or revocation of the advisory opinion involved will be expedited. (g) An advisory opinion may be amended or revoked at any time after it has been issued. Notice of amendment or revocation will be given in the same manner as notice of the advisory opinion was originally given or in the Federal Register, and will be placed on public display as part of the ﬁle on the matter in the ofﬁce of the Division of Dockets Management. The Division of Dockets Management shall maintain a separate chronological index of all advisory opinions ﬁled. The index will specify the date of the request for the advisory opinion, the date of the opinion, and identiﬁcation of the appropriate ﬁle. (h) Action undertaken or completed in conformity with an advisory opinion which has subsequently been amended or revoked is acceptable to FDA unless the Commissioner determines that substantial public interest considerations preclude continued acceptance. Whenever possible, an amended or revoked advisory opinion will state when action previously undertaken or completed does not remain acceptable, and any transition period that may be applicable. (i) An interested person may submit written comments on an advisory opinion or modiﬁed advisory opinion. Four copies of any comments are to be sent to the Division of Dockets Management for inclusion in the public ﬁle on the advisory opinion. Individuals may submit only one copy. Comments will be considered in determining whether further modiﬁcation of an advisory opinion is warranted. (j) An advisory opinion may be used in administrative or court proceedings to illustrate acceptable and unacceptable procedures or standards, but not as a legal requirement. (k) A statement made or advice provided by an FDA employee constitutes an advisory opinion only if it is issued in writing under this section. A statement or advice given by an FDA employee orally, or given in writing but not under this section or section 10.90, is an informal communication that represents the best judgment of that employee at that time but does not constitute an advisory opinion, does not necessarily represent the formal position of FDA, and does not bind or otherwise obligate or commit the agency to the views expressed. [44 FR 22323, Apr. 13, 1979, as amended at 46 FR 8455, Jan. 27, 1981; 59 FR 14364, Mar. 28, 1994; 65 FR 56477, Sept. 19, 2000] Section 10.90 Food and Drug Administration regulations, recommendations, and agreements. (a) Regulations. FDA regulations are promulgated in the Federal Register under section 10.40 or section 10.50 and codiﬁed in the Code of Federal Regulations. Regulations may contain provisions that will be enforced as legal requirements, or which are intended only as guidelines and recommendations, or both. The dissemination of draft notices and regulations is subject to section 10.80.

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(b) [Reserved] (c) Recommendations. In addition to the guidelines subject to paragraph (b) of this section, FDA often formulates and disseminates recommendations about matters which are authorized by, but do not involve direct regulatory action under, the laws administered by the Commissioner, e.g., model State and local ordinances, or personnel practices for reducing radiation exposure, issued under 42 U.S.C. 243 and 263d(b). These recommendations may, in the discretion of the Commissioner, be handled under the procedures established in paragraph (b) of this section, except that the recommendations will be included in a separate public ﬁle of recommendations established by the Division of Dockets Management and will be separated from the guidelines in the notice of availability published in the Federal Register, or be published in the Federal Register as regulations under paragraph (a) of this section. (d) Agreements. Formal agreements, memoranda of understanding, or other similar written documents executed by FDA and another person will be included in the public ﬁle on agreements established by the Freedom of Information Staff (HFI-35) under section 20.108. A document not included in the public ﬁle is deemed to be rescinded and has no force or effect whatever. [44 FR 22323, Apr. 13, 1979, as amended at 54 FR 9035, Mar. 3, 1989; 65 FR 56477, Sept. 19, 2000] Section 10.95 Participation in outside standard-setting activities. (a) General. This section applies to participation by FDA employees in standard-setting activities outside the agency. Standard-setting activities include matters such as the development of performance characteristics, testing methodology, manufacturing practices, product standards, scientiﬁc protocols, compliance criteria, ingredient speciﬁcations, labeling, or other technical or policy criteria. FDA encourages employee participation in outside standard-setting activities that are in the public interest. (b) Standard-setting activities by other Federal Government agencies: (1) An FDA employee may participate in these activities after approval of the activity under procedures speciﬁed in the current agency Staff Manual Guide. (2) Approval forms and all pertinent background information describing the activity will be included in the public ﬁle on standard-setting activities established by the Freedom of Information Staff. (3) If a member of the public is invited by FDA to present views to, or to accompany, the FDA employee at a meeting, the invitations will be extended to a representative sampling of the public, including consumer groups, industry associations, professional societies, and academic institutions. (4) An FDA employee appointed as the liaison representative to an activity shall refer all requests for information about or participation in the activity to the group or organization responsible for the activity. (c) Standard-setting activities by State and local government agencies and by United Nations organizations and other international organizations and foreign governments pursuant to treaty: (1) An FDA employee may participate in these activities after approval of the activity under procedures speciﬁed in the current agency Staff Manual Guide. (2) Approval forms and all pertinent background information describing the activity will be included in the public ﬁle on standard-setting activities established by the Freedom of Information Staff (HFI-35). (3) The availability for public disclosure of records relating to the activity will be governed by part 20.

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(4) If a member of the public is invited by FDA to present views to, or to accompany, the FDA employee at a meeting, the invitation will be extended to a representative sampling of the public, including consumer groups, industry associations, professional societies, and academic institutions. (5) An FDA employee appointed as the liaison representative to an activity shall refer all requests for information about or participation in the activity to the group or organization responsible for the activity. (d) Standard-setting activities by private groups and organizations. (1) An FDA employee may engage in these activities after approval of the activity under procedures speciﬁed in the current agency Staff Manual Guide. A request for ofﬁcial participation must be made by the group or organization in writing, must describe the scope of the activity, and must demonstrate that the minimum standards set out in paragraph (d)(5) of this section are met. Except as provided in paragraph (d)(7) of this section, a request that is granted will be the subject of a letter from the Commissioner or the center director to the organization stating— (i) Whether participation by the individual will be as a voting or nonvoting liaison representative; (ii) That participation by the individual does not connote FDA agreement with, or endorsement of, any decisions reached; and (iii) That participation by the individual precludes service as the deciding ofﬁcial on the standard involved if it should later come before FDA. The deciding ofﬁcial is the person who signs a document ruling upon the standard. (2) The letter requesting ofﬁcial FDA participation, the approval form, and the Commissioner’s or center director’s letter, together with all pertinent background information describing the activities involved, will be included in the public ﬁle on standard-setting activities established by the Freedom of Information Staff (HFI-35). (3) The availability for public disclosure of records relating to the activities will be governed by part 20. (4) An FDA employee appointed as the liaison representative to an activity shall refer all requests for information about or participation in the activity to the group or organization responsible for the activity. (5) The following minimum standards apply to an outside private standard- setting activity in which FDA employees participate: (i) The activity will be based upon consideration of sound scientiﬁc and technological information, will permit revision on the basis of new information, and will be designed to protect the public against unsafe, ineffective, or deceptive products or practices. (ii) The activity and resulting standards will not be designed for the economic beneﬁt of any company, group, or organization, will not be used for such antitrust violations as ﬁxing prices or hindering competition, and will not involve establishment of certiﬁcation or speciﬁc approval of individual products or services. (iii) The group or organization responsible for the standard-setting activity must have a procedure by which an interested person will have an opportunity to provide information and views on the activity and standards involved, without the payment of fees, and the information and views will be considered. How this is accomplished, including whether the presentation will be in person or in writing, will be decided by the group or organization responsible for the activity. (6) Membership of an FDA employee in an organization that also conducts a standard-setting activity does not invoke the provisions of this section unless the employee participates in the standard-setting activity. Participation in a standard-setting activity is subject to this section.

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(7) The Commissioner may determine in writing that, because direct involvement by FDA in a particular standard-setting activity is in the public interest and will promote the objectives of the act and the agency, the participation is exempt from the requirements of paragraph (d)(1) (ii) and/or (iii) of this section. This determination will be included in the public ﬁle on standardsetting activities established by the Freedom of Information Staff and in any relevant administrative ﬁle. The activity may include the establishment and validation of analytical methods for regulatory use, drafting uniform laws and regulations, and the development of recommendations concerning public health and preventive medicine practices by national and international organizations. (8) Because of the close daily cooperation between FDA and the associations of State and local government ofﬁcials listed below in this paragraph, and the large number of agency employees who are members of or work with these associations, participation in the activities of these associations is exempt from paragraphs (d)(1) through (7) of this section, except that a list of the committees and other groups of these associations will be included in the public ﬁle on standard-setting activities established by the Freedom of Information Staff (HFI-35): (i) American Association of Food Hygiene Veterinarians (AAFHV). (ii) American Public Health Association (APHA). (iii) Association of American Feed Control Ofﬁcials, Inc. (AAFCO). (iv) Association of Food and Drug Ofﬁcials (AFDO). (v) Association of Ofﬁcial Analytical Chemists (AOAC). (vi) Association of State and Territorial Health Ofﬁcials (ASTHO). (vii) Conference for Food Protection (CFP). (viii) Conference of State Health and Environmental Managers (COSHEM). (ix) Conference of Radiation Control Program Directors (CRCPD). (x) International Association of Milk, Food, and Environmental Sanitation, Inc. (IAMFES). (xi) Interstate Shellﬁsh Sanitation Conference (ISSC). (xii) National Association of Boards of Pharmacy (NABP). (xiii) National Association of Departments of Agriculture (NADA). (xiv) National Conference on Interstate Milk Shipments (NCIMS). (xv) National Conference of Local Environmental Health Administrators (NCLEHA). (xvi) National Conference on Weights and Measures (NCWW). (xvii) National Environmental Health Association (NEHA). (xviii) National Society of Professional Sanitarians (NSPS). [44 FR 22323, Apr. 13, 1979, as amended at 46 FR 8455, Jan. 27, 1981; 52 FR 35064, Sept. 17, 1987; 54 FR 9035, Mar. 3, 1989] Section 10.100

Public calendar.

(a) Public calendar. A public calendar will be prepared and made publicly available by FDA each week showing, to the extent feasible, signiﬁcant events of the previous week, including signiﬁcant meetings with persons outside the executive branch, that involve the representatives of FDA designated under paragraph (c) of this section. (1) Public calendar entries will include: (i) Signiﬁcant meetings with members of the judiciary, representatives of Congress, or staffs of congressional committees when the meeting relates to a pending court case, administrative hearing, or other regulatory action or decision;

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(ii) Signiﬁcant meetings, conferences, seminars, and speeches; and (iii) Social events sponsored by the regulated industry. (2) The public calendar will not include reports of meetings that would prejudice law enforcement activities (e.g., a meeting with an informant) or invade privacy (e.g., a meeting with a candidate for possible employment at FDA), meetings with members of the press, or meetings with onsite contractors. (b) Calendar entries. The calendar will specify for each entry the date, person(s), and subject matter involved. If a large number of persons are in attendance, the name of each individual need not be speciﬁed. When more than one FDA representative is in attendance, the most senior agency ofﬁcial will report the meeting on the public calendar. (c) Affected persons. The following FDA representatives are subject to the requirements of this section: (1) Commissioner of Food and Drugs. (2) Senior Associate Commissioners. (3) Deputy Commissioners. (4) Associate Commissioner for Regulatory Affairs. (5) Center Directors. (6) Chief Counsel for the Food and Drug Administration. (d) Public display. The public calendar will be placed on public display at the following locations: (1) Division of Dockets Management. (2) Ofﬁce of the Associate Commissioner for Public Affairs. (3) The FDA home page, to the extent feasible. [66 FR 6468, Jan. 22, 2001] Section 10.105

Representation by an organization.

(a) An organization may represent its members by ﬁling petitions, comments, and objections, and otherwise participating in an administrative proceeding subject to this part. (b) A petition, comment, objection, or other representation by an organization will not abridge the right of a member to take individual action of a similar type, in the member’s own name. (c) It is requested that each organization participating in FDA administrative proceedings ﬁle annually with the Division of Dockets Management a current list of all of the members of the organization. (d) The ﬁling by an organization of an objection or request for hearing under sections 12.20 through 12.22 does not provide a member a legal right with respect to the objection or request for hearing that the member may individually exercise. A member of an organization wishing to ﬁle an objection or request for hearing must do so individually. (e) In a court proceeding in which an organization participates, the Commissioner will take appropriate legal measures to have the case brought or considered as a class action or otherwise as binding upon all members of the organization except those speciﬁcally excluded by name. Regardless of whether the case is brought or considered as a class action or as otherwise binding upon all members of the organization except those speciﬁcally excluded by name, the Commissioner will take the position in any subsequent suit involving the same issues and a member of the organization that the issues are precluded from further litigation by the member under the doctrines of collateral estoppel or res judicata.

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Settlement proposals.

At any time in the course of a proceeding subject to this part, a person may propose settlement of the issues involved. A participant in a proceeding will have an opportunity to consider a proposed settlement. Unaccepted proposals of settlement and related matters, e.g., proposed stipulations not agreed to, will not be admissible in evidence in an FDA administrative proceeding. FDA will oppose the admission in evidence of settlement information in a court proceeding or in another administrative proceeding. Section 10.115

Good guidance practices.

(a) What are good guidance practices? Good guidance practices (GGPs) are FDA’s policies and procedures for developing, issuing, and using guidance documents. (b) What is a guidance document? (1) Guidance documents are documents prepared for FDA staff, applicants/sponsors, and the public that describe the agency’s interpretation of or policy on a regulatory issue. (2) Guidance documents include, but are not limited to, documents that relate to: The design, production, labeling, promotion, manufacturing, and testing of regulated products; the processing, content, and evaluation or approval of submissions; and inspection and enforcement policies. (3) Guidance documents do not include: Documents relating to internal FDA procedures, agency reports, general information documents provided to consumers or health professionals, speeches, journal articles and editorials, media interviews, press materials, warning letters, memoranda of understanding, or other communications directed to individual persons or ﬁrms. (c) What other terms have a special meaning? (1) “Level 1 guidance documents” include guidance documents that: (i) Set forth initial interpretations of statutory or regulatory requirements; (ii) Set forth changes in interpretation or policy that are of more than a minor nature; (iii) Include complex scientiﬁc issues; or (iv) Cover highly controversial issues. (2) “Level 2 guidance documents” are guidance documents that set forth existing practices or minor changes in interpretation or policy. Level 2 guidance documents include all guidance documents that are not classiﬁed as Level 1. (3) “You” refers to all affected parties outside of FDA. (d) Are you or FDA required to follow a guidance document? (1) No. Guidance documents do not establish legally enforceable rights or responsibilities. They do not legally bind the public or FDA. (2) You may choose to use an approach other than the one set forth in a guidance document. However, your alternative approach must comply with the relevant statutes and regulations. FDA is willing to discuss an alternative approach with you to ensure that it complies with the relevant statutes and regulations. (3) Although guidance documents do not legally bind FDA, they represent the agency’s current thinking. Therefore, FDA employees may depart from guidance documents only with appropriate justiﬁcation and supervisory concurrence. (e) Can FDA use means other than a guidance document to communicate new agency policy or a new regulatory approach to a broad public audience? The agency may not use documents or other means of communication that are excluded from the deﬁnition of guidance document to informally

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communicate new or different regulatory expectations to a broad public audience for the ﬁrst time. These GGPs must be followed whenever regulatory expectations that are not readily apparent from the statute or regulations are ﬁrst communicated to a broad public audience. (f) How can you participate in the development and issuance of guidance documents? (1) You can provide input on guidance documents that FDA is developing under the procedures described in paragraph (g) of this section. (2) You can suggest areas for guidance document development. Your suggestions should address why a guidance document is necessary. (3) You can submit drafts of proposed guidance documents for FDA to consider. When you do so, you should mark the document “Guidance Document Submission” and submit it to Division of Dockets Management (HFA-305), 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. (4) You can, at any time, suggest that FDA revise or withdraw an already existing guidance document. Your suggestion should address why the guidance document should be revised or withdrawn and, if applicable, how it should be revised. (5) Once a year, FDA will publish, both in the Federal Register and on the Internet, a list of possible topics for future guidance document development or revision during the next year. You can comment on this list (e.g., by suggesting alternatives or making recommendations on the topics that FDA is considering). (6) To participate in the development and issuance of guidance documents through one of the mechanisms described in paragraphs (f)(1), (f)(2), or (f)(4) of this section, you should contact the center or ofﬁce that is responsible for the regulatory activity covered by the guidance document. (7) If FDA agrees to draft or revise a guidance document, under a suggestion made under paragraphs (f)(1), (f)(2), (f)(3) or (f)(4) of this section, you can participate in the development of that guidance document under the procedures described in paragraph (g) of this section. (g) What are FDA’s procedures for developing and issuing guidance documents? (1) FDA’s procedures for the development and issuance of Level 1 guidance documents are as follows: (i) Before FDA prepares a draft of a Level 1 guidance document, FDA can seek or accept early input from individuals or groups outside the agency. For example, FDA can do this by participating in or holding public meetings and workshops. (ii) After FDA prepares a draft of a Level 1 guidance document, FDA will: (a) Publish a notice in the Federal Register announcing that the draft guidance document is available; (b) Post the draft guidance document on the Internet and make it available in hard copy; and (c) Invite your comment on the draft guidance document. Paragraph (h) of this section tells you how to submit your comments. (iii) After FDA prepares a draft of a Level 1 guidance document, FDA also can: (a) Hold public meetings or workshops; or (b) Present the draft guidance document to an advisory committee for review. (iv) After providing an opportunity for public comment on a Level 1 guidance document, FDA will: (a) Review any comments received and prepare the ﬁnal version of the guidance document that incorporates suggested changes, when appropriate;

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(b) Publish a notice in the Federal Register announcing that the guidance document is available; (c) Post the guidance document on the Internet and make it available in hard copy; and (d) Implement the guidance document. (v) After providing an opportunity for comment, FDA may decide that it should issue another draft of the guidance document. In this case, FDA will follow the steps in paragraphs (g)(1)(ii), (g)(1)(iii), and (g)(1)(iv) of this section. (2) FDA will not seek your comment before it implements a Level 1 guidance document if the agency determines that prior public participation is not feasible or appropriate. (3) FDA will use the following procedures for developing and issuing Level 1 guidance documents under the circumstances described in paragraph (g)(2) of this section: (i) After FDA prepares a guidance document, FDA will: (a) Publish a notice in the Federal Register announcing that the guidance document is available; (b) Post the guidance document on the Internet and make it available in hard copy; (c) Immediately implement the guidance document; and (d) Invite your comment when it issues or publishes the guidance document. Paragraph (h) of this section tells you how to submit your comments. (ii) If FDA receives comments on the guidance document, FDA will review those comments and revise the guidance document when appropriate. (4) FDA will use the following procedures for developing and issuing Level 2 guidance documents: (i) After it prepares a guidance document, FDA will: (a) Post the guidance document on the Internet and make it available in hard copy; (b) Immediately implement the guidance document, unless FDA indicates otherwise when the document is made available; and (c) Invite your comment on the Level 2 guidance document. Paragraph (h) of this section tells you how to submit your comments. (ii) If FDA receives comments on the guidance document, FDA will review those comments and revise the document when appropriate. If a version is revised, the new version will be placed on the Internet. (5) You can comment on any guidance document at any time. Paragraph (h) of this section tells you how to submit your comments. FDA will revise guidance documents in response to your comments when appropriate. (h) How should you submit comments on a guidance document? (1) If you choose to submit comments on any guidance document under paragraph (g) of this section, you must send them to the Division of Dockets Management (HFA-305), 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. (2) Comments should identify the docket number on the guidance document, if such a docket number exists. For documents without a docket number, the title of the guidance document should be included. (3) Comments will be available to the public in accordance with FDA’s regulations on submission of documents to the Division of Dockets Management speciﬁed in section 10.20(j).

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(i) What standard elements must FDA include in a guidance document? (1) A guidance document must: (i) Include the term “guidance,” (ii) Identify the center(s) or ofﬁce(s) issuing the document, (iii) Identify the activity to which and the people to whom the document applies, (iv) Prominently display a statement of the document’s nonbinding effect, (v) Include the date of issuance, (vi) Note if it is a revision to a previously issued guidance and identify the document that it replaces, and (vii) Contain the word “draft” if the document is a draft guidance. (2) Guidance documents must not include mandatory language such as “shall,” “must,” “required,” or “requirement,” unless FDA is using these words to describe a statutory or regulatory requirement. (3) When issuing draft guidance documents that are the product of international negotiations (e.g., guidances resulting from the International Conference on Harmonisation), FDA need not apply paragraphs (i)(1) and (i)(2) of this section. However, any ﬁnal guidance document issued according to this provision must contain the elements in paragraphs (i)(1) and (i)(2) of this section. (j) Who, within FDA, can approve issuance of guidance documents? Each center and ofﬁce must have written procedures for the approval of guidance documents. Those procedures must ensure that issuance of all documents is approved by appropriate senior FDA ofﬁcials. (k) How will FDA review and revise existing guidance documents? (1) The agency will periodically review existing guidance documents to determine whether they need to be changed or withdrawn. (2) When signiﬁcant changes are made to the statute or regulations, the agency will review and, if appropriate, revise guidance documents relating to that changed statute or regulation. (3) As discussed in paragraph (f)(3) of this section, you may at any time suggest that FDA revise a guidance document. (l) How will FDA ensure that FDA staff are following GGPs? (1) All current and new FDA employees involved in the development, issuance, or application of guidance documents will be trained regarding the agency’s GGPs. (2) FDA centers and ofﬁces will monitor the development and issuance of guidance documents to ensure that GGPs are being followed. (m) How can you get copies of FDA’s guidance documents? FDA will make copies available in hard copy and, as feasible, through the Internet. (n) How will FDA keep you informed of the guidance documents that are available? (1) FDA will maintain on the Internet a current list of all guidance documents. New documents will be added to this list within 30 days of issuance. (2) Once a year, FDA will publish in the Federal Register its comprehensive list of guidance documents. The comprehensive list will identify documents that have been added to the list or withdrawn from the list since the previous comprehensive list. (3) FDA’s guidance document lists will include the name of the guidance document, issuance and revision dates, and information on how to obtain copies of the document.

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(o) What can you do if you believe that someone at FDA is not following these GGPs? If you believe that someone at FDA did not follow the procedures in this section or that someone at FDA treated a guidance document as a binding requirement, you should contact that person’s supervisor in the center or ofﬁce that issued the guidance document. If the issue cannot be resolved, you should contact the next highest supervisor. You can also contact the center or ofﬁce ombudsman for assistance in resolving the issue. If you are unable to resolve the issue at the center or ofﬁce level or if you feel that you are not making progress by going through the chain of command, you may ask the Ofﬁce of the Chief Mediator and Ombudsman to become involved. [65 FR 56477, Sept. 19, 2000] Subpart C — Electronic Media Coverage of Public Administrative Section 10.200

Scope.

This guideline describes FDA’s policy and procedures applicable to electronic media coverage of agency public administrative proceedings. It is a guideline intended to clarify and explain FDA’s policy on the presence and operation of electronic recording equipment at such proceedings and to assure uniform and consistent application of practices and procedures throughout the agency. Section 10.203

Deﬁnitions.

(a) Public administrative proceeding as used in this guideline means any FDA proceeding which the public has a right to attend. This includes a formal evidentiary public hearing as set forth in part 12, a public hearing before a Public Board of Inquiry as set forth in part 13, a public hearing before a Public Advisory Committee as set forth in part 14, a public hearing before the Commissioner as set forth in part 15, a regulatory hearing before FDA as set forth in part 16, consumer exchange meetings, and Commissioner’s public meetings with health professionals. (b) Advance notice as used in this guideline means written or telephone notiﬁcation to FDA’s Ofﬁce of Public Affairs (Press Relations Staff) of intent to electronically record an agency public administrative proceeding. (c) Electronic recording as used in this guideline means any visual or audio recording made by videotape recording equipment or moving ﬁlm camera, and/or other electronic recording equipment. [49 FR 14726, Apr. 13, 1984, as amended at 54 FR 9035, Mar. 3, 1989] Section 10.204

General.

(a) FDA has for many years willingly committed itself to a policy of openness. In many instances FDA has sought to make the open portions of agency public administrative proceedings more accessible to public participation. Similarly, FDA has sought, wherever possible, to allow full written media access to its proceedings, so that members of the press would have the opportunity to provide ﬁrst-hand reports. However, because electronic media coverage presents certain difﬁculties that are easier to resolve with advance notice to the agency and all participants, FDA believes that codiﬁcation of its policy will facilitate and further increase media access to its public administrative proceedings. The agency intends to refer to this guideline when notices of hearing, or individual advisory committee meetings, are published in the Federal Register. Thus, all parties to a proceeding will be on notice that the proceeding may be recorded electronically and any person interested in videotaping or otherwise recording the proceeding will be notiﬁed that there are established procedures to be followed. (b) The designated presiding ofﬁcer of a public administrative proceeding retains the existing discretionary authority set forth in speciﬁc regulations pertaining to each type of administrative

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proceeding to regulate the conduct of the proceeding over which he or she presides. The responsibilities of the presiding ofﬁcer, established elsewhere in parts 10 through 16, include an obligation to be concerned with the timely conduct of a hearing, the limited availability of certain witnesses, and reducing disruptions to the proceeding which may occur. Each proceeding varies, and the presiding ofﬁcer cannot anticipate all that might occur. Discretionary authority to regulate conduct at a proceeding has traditionally been granted to presiding ofﬁcers to enable them to fulﬁll their responsibility to maintain a fair and orderly hearing conducted in an expeditious manner. (c) This guideline provides the presiding ofﬁcer with a degree of ﬂexibility in that it sets forth the agency’s policy as well as the procedures that presiding ofﬁcers should ordinarily follow, but from which they may depart in particular situations if necessary, subject to the presumption of openness of public proceedings to electronic media coverage. The presiding ofﬁcer’s discretion to establish additional procedures or to limit electronic coverage is to be exercised only in the unusual circumstances deﬁned in this guideline. Even though a presiding ofﬁcer may establish additional procedures or limits as may be required in a particular situation, he or she will be guided by the policy expressed in this guideline in establishing these conditions. The presiding ofﬁcer may also be less restrictive, taking into account such factors as the duration of a hearing and the design of the room. (d) If a portion or all of a proceeding is closed to the public because material is to be discussed that is not disclosable to the public under applicable laws, the proceeding also will be closed to electronic media coverage. (e) The agency requests advance notice of intent to record a proceeding electronically to facilitate the orderly conduct of the proceeding. Knowledge of anticipated media coverage will allow the presiding ofﬁcer to make any special arrangements required by the circumstances of the proceeding. The agency believes that this guideline establishes sufﬁciently speciﬁc criteria to promote uniformity. (f) The agency would like to allow all interested media representatives to videotape a proceeding in which they have an interest. However, should space limitations preclude a multitude of cameras, the presiding ofﬁcer may require pool sharing. In such a case, pool sharing arrangements of the resulting videotape should be made between those allowed to ﬁlm and those who were excluded. Arrangements for who is designated to present the pool and a method of distributing the resulting ﬁlm or tape may be determined by the established networks’ pooling system. However, the agency has a strong commitment to ensuring that media representatives other than the major networks also be able to obtain a copy of the tape at cost. FDA is concerned that if the network pool representative wishes to record only a short portion of a proceeding, but an excluded party wishes to record the entire proceeding, confusion will result. The agency expects the interested media representatives to negotiate a suitable agreement among themselves before commencement of the proceeding. For example, the network pool representatives might agree to record a portion of the proceeding up to a break in the proceeding, at which time, while the network representative is disassembling equipment, another media representative might set up to continue recording. If an agreement cannot be reached before the proceeding, the agency will use the time of receipt of any advance notice to determine the representation for each category of media, e.g., one network reporter, one independent reporter. The agency recommends that parties intending to videotape provide as much advance notice as possible, so that the agency may best respond to the needs of the electronic media. (g) To ensure the timely conduct of agency hearings and to prevent disruptions, equipment is to be stationary during a proceeding and should be set up and taken down when the proceeding is not in progress. As noted previously, the presiding ofﬁcer may, at his or her discretion, be less restrictive if appropriate.

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(h) The agency recognizes that electronic media representatives may desire only short footage of a proceeding, a facsimile of the proceeding, and/or interview opportunities and may be unnecessarily restricted by requirements for setting up before a proceeding and then waiting until a break in the proceeding before being permitted to take down their equipment. To accommodate this possibility, FDA’s Press Relations Staff will attempt to make arrangements to respond to such needs by, for example, requesting that the presiding ofﬁcer provide a break shortly after commencement of the proceeding to permit take down of equipment. (i) The agency is making a full commitment to allowing, whenever possible, electronic coverage of its public administrative proceedings subject to the limited restrictions established in this guideline. Section 10.205

Electronic media coverage of public administrative proceedings.

(a) A person may record electronically any open public administrative proceeding, subject to the procedures speciﬁed in this guideline. The procedures include a presumption that agency public proceedings are open to the electronic media. Whenever possible, FDA will permit all interested persons access to record agency public administrative proceedings. Restrictions other than those listed in section 10.206 will be imposed only under exceptional circumstances. (b) A videotape recording of an FDA public administrative proceeding is not an ofﬁcial record of the proceeding. The only ofﬁcial record is the written transcript of the proceeding, which is taken by the ofﬁcial reporter. Section 10.206 proceedings.

Procedures for electronic media coverage of agency public administrative

(a) To facilitate the agency’s response to media needs, a person intending to videotape an FDA public administrative proceeding should, whenever possible, provide advance notice to the Press Relations Staff (HFI-20), Ofﬁce of Public Affairs, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, in writing or by telephone (telephone 301-443-4177), at least 48 hours in advance of the proceeding. The Press Relations Staff will inform the presiding ofﬁcer that the proceeding will be attended by representatives of the electronic media, and ascertain whether any special provisions in addition to those set forth in this subpart are required by the presiding ofﬁcer. If so, the Press Relations Staff will function as a liaison between the presiding ofﬁcer and the person intending to record the proceeding in facilitating any procedures in addition to those outlined in this subpart. The presiding ofﬁcer will not deny access for failure to provide a 48-hour advance notice. Any advance notice may describe the intended length of recording if known, the amount and type of equipment to be used, and any special needs such as interviews. (b) Cameras should be completely set up before a proceeding is scheduled to begin or during a break in the proceeding and should remain standing in the area designated for electronic media equipment. Cameras may be taken down only during breaks or after the hearing is over. Roving cameras will not be permitted during the proceeding. Any artiﬁcial lighting should be unobtrusive. Microphones, like cameras, should be in place before the start of a proceeding and may be taken down as indicated in this paragraph. (c) When space in the hearing room is limited, the presiding ofﬁcer may restrict the number of cameras or the equipment present. Should such a restriction become necessary, the pool arrangements are the responsibility of the participating media. The agency encourages the network pool to make copies of the tape, ﬁlm, or other product available at cost to nonpool participants. However, if this is not possible, the agency may need to use the time of receipt of any advance notice to determine the representation for each category, e.g., one network reporter, one independent reporter, etc.

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(d) Off the record portions of a proceeding may not be videotaped. (e) Before or during the proceeding, the presiding ofﬁcer may establish other conditions speciﬁc to the proceeding for which the request is being made. These conditions may be more or less restrictive than those stated in this guideline, except that the presiding ofﬁcer shall observe the agency’s presumption of openness of its public proceedings to the electronic media. Only a substantial and clear threat to the agency’s interests in order, fairness, and timeliness authorizes the presiding ofﬁcer to impose additional restrictions. This threat must outweigh the public interest in electronic media coverage of agency proceedings. Additional restrictions shall be narrowly drawn to the particular circumstances. The following factors are listed to assist presiding ofﬁcers in determining whether the agency’s interest is sufﬁciently compelling to call for the unusual step of imposing additional restrictions. Generally this step is justiﬁed when one of the following factors is met: (1) Electronic recording would result in a substantial likelihood of disruption that clearly cannot be contained by the procedures established in paragraphs (a) through (d) of this section. (2) Electronic recording would result in a substantial likelihood of prejudicial impact on the fairness of the proceeding or the substantive discussion in a proceeding. (3) There is a substantial likelihood that a witness’ ability to testify may be impaired due to unique personal circumstances such as the age or psychological state of the witness or the particularly personal or private nature of the witness’ testimony, if the witness’ testimony were electronically recorded. (f) Before the proceeding, the Press Relations Staff will, upon request, provide written copies of any additional conditions imposed by the presiding ofﬁcer (as described in paragraph (e) of this section) to requesting members of the media. Any appeals should be made in accordance with paragraph (h) of this section. (g) The presiding ofﬁcer retains authority to restrict or discontinue videotaping or other recording of a proceeding, or parts of a proceeding, should such a decision become necessary. The presiding ofﬁcer’s responsibility to conduct the hearing includes the right and duty to remove a source of substantial disruption. In exercising his or her authority, the presiding ofﬁcer shall observe the presumption that agency public proceedings are open to the electronic media. The presiding ofﬁcer shall exercise his or her discretion to restrict or discontinue electronic coverage of a public proceeding, or portions of a public proceeding, only if he or she determines that the agency’s interest in the fair and orderly administrative process is substantially threatened. A clear and substantial threat to the integrity of agency proceedings must clearly outweigh the public interest in electronic media coverage of the proceedings before additional restrictions are imposed on the electronic media during the course of the proceedings. The factors noted in paragraph (e) of this section indicate the kind of substantial threat to the agency interests that may require imposing additional restrictions during the course of the proceedings. If additional requirements are established during the hearing, the presiding ofﬁcer shall notify immediately the Deputy Commissioner of Food and Drugs of that fact by telephone and submit a written explanation of the circumstances that necessitated such an action within 24 hours or sooner if requested by the Deputy Commissioner. In the absence or unavailability of the Deputy Commissioner, the presiding ofﬁcer shall notify the Associate Commissioner for Regulatory Affairs. (h) A decision by a presiding ofﬁcer, made either before the proceeding or during the course of a proceeding, to establish requirements in addition to the minimum standards set forth in this guideline may be appealed by any adversely affected person who intends to record the proceeding electronically. Appeals may be made in writing or by phone to the Deputy Commissioner or, in his or her absence, to the Associate Commissioner for Regulatory Affairs. The ﬁling of an appeal, whether before or during a proceeding, does not require the presiding ofﬁcer to interrupt the proceeding.

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However, the Deputy Commissioner or, in his or her absence, the Associate Commissioner for Regulatory Affairs will resolve an appeal as expeditiously as possible so as to preserve, to the extent possible, the reporters’ opportunity to record the proceedings. [49 FR 14726, Apr. 13, 1984, as amended at 54 FR 9035, Mar. 3, 1989] Authority: 5 U.S.C. 551–558, 701–706; 15 U.S.C. 1451–1461; 21 U.S.C. 141–149, 321–397, 467f, 679, 821, 1034; 28 U.S.C. 2112; 42 U.S.C. 201, 262, 263b, 264. Source: 44 FR 22323, Apr. 13, 1979, unless otherwise noted.

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Glossary Acceptance criteria Product speciﬁcations and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan that are necessary for making a decision to accept or reject a lot or batch (or any other convenient subgroups of manufactured units). Act Federal Food, Drug, and Cosmetic (FD&C) Act of 1938. Active ingredient Any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and may be present in the drug product in a modiﬁed form intended to furnish the speciﬁed activity or effect. Active moiety The molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate), of the molecule responsible for the physiological or pharmacological action of the drug substance. Actual yield The quantity that is actually produced at any appropriate phase of manufacture, processing, or packing of a particular drug product. Advertising and labeling Include the promotional material described in 21 CFR 202.1(l)(1) and (2), respectively. Agency component The Center for Biologics Evaluation and Research, the Center for Devices and Radiological Health, the Center for Drug Evaluation and Research, or alternative organizational component of the agency. Alcohol The substance known as ethanol, ethyl alcohol, or Alcohol, USP. Ambulatory surgical facility (ASF) Distinct entity that operates for the primary purpose of furnishing same-day outpatient surgical services to patients. An ASF may be either an independent entity (not a part of a provider of services or any other facility) or operated by another medical entity (under the common ownership, licensure, or control of an entity). An ASF is subject to this regulation regardless of whether it is licensed by a federal, state, municipal, or local government or regardless of whether it is accredited by a recognized accreditation organization. If an adverse event meets the criteria for reporting, the ASF must report that event regardless of the nature or location of the medical service provided by the ASF. Amendment The submission of information to a pending license application or supplement to revise or modify the application as originally submitted. Animal drug product The active ingredient of a new animal drug (as that term is used in the Act) that is not primarily manufactured using recombinant deoxyribonucleic acid (DNA), recombinant ribonucleic acid (RNA), hybridoma technology, or other processes involving sitespeciﬁc genetic manipulation techniques, including any salt or ester of the active ingredient, as a single entity or in combination with another active ingredient. Applicant (1) Any person who submits an application or an amendment or supplement to an application under 35 USC 156 seeking patent term restoration. (2) Any person who submits or plans to submit an application to the FDA for premarket review.

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Application An application for patent term restoration submitted under 35 USC 156. Application for research or marketing permit Includes: (1) A color additive petition, described in 21 CFR 71. (2) A food additive petition, described in 21 CFR 171 and 571. (3) Data and information regarding a substance submitted as part of the procedures for establishing that a substance is generally recognized as safe for use, which use results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food, described in 21 CFR 170.35 and 570.35. (4) Data and information regarding a food additive submitted as part of the procedures regarding food additives permitted to be used on an interim basis pending additional study, described in 21 CFR 180.1. (5) An investigational new drug application, described in part 312 of Chapter I (Food and Drug Administration, Department of Health and Human Services). (6) A new drug application, described in 21 CFR 314. (7) Data and information regarding an overthe-counter drug for human use, submitted as part of the procedures for classifying such drugs as generally recognized as safe and effective and not misbranded, described in 21 CFR 330. (8) Data and information about a substance submitted as part of the procedures for establishing a tolerance for unavoidable contaminants in food and food-packaging materials, described in 21 CFR 109 and 509. (9) Data and information regarding an antibiotic drug submitted as part of the procedures for issuing, amending, or repealing regulations for such drugs, described in Section 314.300 of Chapter I. (10) A Notice of Claimed Investigational Exemption for a New Animal Drug, described in 21 CFR 511. (11) A new animal drug application, described in part 514. (12) and (13) An application for a biological product license, described in 21 CFR 601. (14) An application for an investigational device exemption, described in 21 CFR 812. (15) An Application for Premarket Approval of a Medical Device, described in 21 CFR 515. (16) A Product Development Protocol for a Medical Device, described in 21 CFR 515 of the act. (17) Data and information regarding a medical device submitted as part of the procedures for classifying such devices, described in 21 CFR 860. (18) Data and information regarding a medical device submitted as part of the procedures for establishing, amending, or repealing a performance standard for such devices, described in 21 CFR 861. (19) Data and information regarding an electronic product submitted as part of the procedures for obtaining an exemption from notiﬁcation of a radiation safety defect or failure of compliance with a radiation safety performance standard, described in subpart D of 21 CFR 1003. (20) Data and information regarding an electronic product submitted as part of the procedures for establishing, amending, or repealing a standard for such product, described in section 358 of the Public Health Service Act. (21) Data and information regarding an electronic product submitted as part of the procedures for obtaining a variance from any electronic product performance standard as described in 21 CFR 1010.4. (22) Data and information regarding an electronic product submitted as part of the procedures for granting, amending, or extending an exemption from any electronic product performance standard, as described in 21 CFR 1010.5. Batch A speciﬁc quantity of a drug or other material that is intended to have uniform character and quality, within speciﬁed limits, and is produced according to a single manufacturing order during the same cycle of manufacture. Become aware An employee of the entity required to report has acquired information reasonably suggesting that a reportable adverse event has occurred. Device user facilities are considered to have “become aware” when medical personnel employed by or otherwise formally afﬁliated with the facility acquire such information about a reportable event. Manufacturers are considered to have “become aware” of an event when: (1) Any employee becomes aware of a reportable event that is required to be reported within 30 days or that is required to be reported within 5 days pursuant to a written request from FDA under 803.53(b); and (2) any employee who is a person with management or supervisory responsibilities over persons with regulatory, scientiﬁc, or technical responsibilities, or a person whose duties relate to

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the collection and reporting of adverse events and becomes aware that a reportable MDR event or events, from any information, including any trend analysis, necessitate remedial action to prevent an unreasonable risk of substantial harm to the public health. Bioavailability The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reﬂect the rate and extent to which the active ingredient or active moiety becomes available at the site of action. Bioequivalence The absence of a signiﬁcant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain controlled-release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no signiﬁcant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action. This applies only if the difference in the rate at which the active ingredient or moiety becomes available at the site of drug action is intentional and is reﬂected in the proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insigniﬁcant for the drug. Bioequivalence requirement A requirement imposed by the FDA for in vitro and/or in vivo testing of speciﬁed drug products that must be satisﬁed as a condition of marketing. Biological product Any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of humans. (1) A virus is interpreted to be a product containing the minute living cause of an infectious disease and includes but is not limited to ﬁlterable viruses, bacteria, rickettsia, fungi, and protozoa. (2) A therapeutic serum is a product obtained from blood by removing the clot or clot components and the blood cells. (3) A toxin is a product containing a soluble substance poisonous to laboratory animals or to humans in doses of 1 milliliter or less (or equivalent in weight) of the product, and having the property, following the injection of nonfatal doses into an animal, of causing to be produced therein another soluble substance which speciﬁcally neutralizes the poisonous substance and which is demonstrable in the serum of the animal thus immunized. (4) An antitoxin is a product containing the soluble substance in serum or other body ﬂuid of an immunized animal which speciﬁcally neutralizes the toxin against which the animal is immune. (5) A product is analogous: (a) to a virus if prepared from or with a virus or agent actually or potentially infectious, without regard to the degree of virulence or toxicogenicity of the speciﬁc strain used; (b) to a therapeutic serum, if composed of whole blood or plasma or containing some organic constituent or product other than a hormone or an amino acid, derived from whole blood, plasma, or serum; (c) to a toxin or antitoxin, if intended, irrespective of its source of origin, to be applicable to the prevention, treatment, or cure of disease or injuries of humans through a speciﬁc immune process. Blood Whole blood collected from a single donor and processed either for transfusion or further manufacturing. Blood and blood product A drug that consists of human whole blood, plasma, or serum or any product derived from human whole blood, plasma, or serum (referred to as “blood product”). Bulk product substance Any substance that is represented for use in a blood product and when used in the manufacturing of a blood product becomes an active ingredient or a ﬁnished dosage form of such product. Caused or contributed A death or serious injury was or may have been attributed to a medical device, or that a medical device was or may have been a factor in a death or serious injury, including events occurring as a result of: (1) failure, (2) malfunction, (3) improper or inadequate design, (4) manufacture, (5) labeling, or (6) user error.

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Center for Biologics Evaluation and Research (CBER) Center for Biologics Evaluation and Research of the FDA. Chemical description A concise deﬁnition of the chemical composition using standard chemical nomenclature so that the chemical structure or structures of the components of the ingredient would be clear to a practicing chemist. When the composition cannot be described chemically, the substance shall be described in terms of its source and processing. Citation or cite A document and any attachments thereto that provide notice to a person against whom criminal prosecution is contemplated of the opportunity to present views to the agency regarding an alleged violation. Clinical investigation Any experiment that involves a test article and one or more human subjects and that either is subject to requirements for prior submission to the FDA under section 505(i), 507(d), or 520(g) of the Act or is not subject to requirements for prior submission to the FDA under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the FDA as part of an application for a research or marketing permit. The term does not include experiments that are subject to the provisions of 21 CFR Part 58, regarding nonclinical laboratory studies. Clinical investigation or study Any experiment that involves a test article and one or more subjects and that either is subject to requirements for prior submission to the FDA under Section 505(i), 507(d), 512(j), or 520(g) of the Federal Food, Drug, and Cosmetic Act, or is not subject to the requirements for prior submission to FDA under those sections of the Federal Food, Drug, and Cosmetic Act, but the results of which are intended to be submitted later to, or held for inspection by, the FDA as part of an application for a research or marketing permit. The term does not include experiments that are subject to the provisions of Part 58 regarding nonclinical laboratory studies. Clinically superior A drug has been shown to provide a signiﬁcant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug) in one or more of the following ways: (1) greater effectiveness than an approved orphan drug, as assessed by effect on a clinically meaningful endpoint in adequate and well controlled clinical trials (generally, this would represent the same kind of evidence needed to support a comparative effectiveness claim for two different drugs) — in most cases, direct comparative clinical trials would be necessary; (2) greater safety in a substantial portion of the target populations (for example, by the elimination of an ingredient or contaminant that is associated with relatively frequent adverse effects) — in some cases, direct comparative clinical trials will be necessary; or (3) in unusual cases, where neither greater safety nor greater effectiveness has been shown, a demonstration that the drug otherwise makes a major contribution to patient care. Color additive Any substance that meets the deﬁnition in 21 CFR 201(t) and which is subject to premarketing approval under Section 721 of the Act. Combination product (1) A product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity. (2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products. (3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually speciﬁed drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed (e.g., to reﬂect a change in intended use, dosage form, strength, route of administration, or signiﬁcant change in dose). Commercial distribution of a blood product Any distribution of a blood product except pursuant to the investigational use provisions of 21 CFR 312 but which does not include internal

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or interplant transfer of a bulk product substance between registered domestic establishments within the same parent, subsidiary, and/or afﬁliate company. Any material change includes but is not limited to any change in the name of the blood product, in the quantity or identity of the active ingredient(s) or in the quantity or identity of the inactive ingredient(s) where quantitative listing of all ingredients is required pursuant to 21 CFR 607.31(a)(2) and any signiﬁcant change in the labeling of a blood product. Changes that are not signiﬁcant include changes in arrangement or printing or changes of an editorial nature. Commercial distribution of a cosmetic product Annual gross sales in excess of $1000 for that product. Commissioner The Commissioner of the FDA. Compatibility testing The in vitro serological tests performed on donor and recipient blood samples to establish the serological matching of a donor’s blood or blood components with that of a potential recipient. Component (1) Any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product. (2) That part of a single-donor unit of blood separated by physical or mechanical means. Consignee Anyone who has received, purchased, or used a product being recalled. Container (“ﬁnal container”) The immediate unit, bottle, vial, ampoule, tube, or other receptacle containing the product as distributed for sale, barter, or exchange. Control article Any food additive, color additive, drug, biological product, electronic product, medical device for human use, or any article other than a test article, feed, or water that is administered to the test system in the course of a nonclinical laboratory study for the purpose of establishing a basis for comparison with the test article. Correction Repair, modiﬁcation, adjustment, relabeling, destruction, or inspection (including patient monitoring) of a product without its physical removal to some other location. Cosmetic product A ﬁnished cosmetic for which the manufacture has been completed. Any cosmetic product which is also a drug or device or component thereof is also subject to the requirements of Chapter V of the Act. Cosmetic raw material Any ingredient, including an ingredient that is a mixture, which is used in the manufacture of a cosmetic product for commercial distribution and is supplied to a cosmetic product manufacturer, packer, or distributor by a cosmetic raw material manufacturer or supplier. Dating period The period beyond which the product cannot be expected beyond reasonable doubt to yield its speciﬁc results. Device family (1) A group of one or more devices manufactured by or for the same manufacturer and having the same: (a) basic design and performance characteristics related to device safety and effectiveness, (b) intended use and function, and (c) device classiﬁcation and product code. (2) Devices that differ only in minor ways not related to safety or effectiveness can be considered to be in the same device family; factors such as brand name and common name of the device and whether the devices were introduced into commercial distribution under the same 510(k) or premarket approval application (PMA) may be considered in grouping products into device families. Device user facility Hospital, ambulatory surgical facility, nursing home, outpatient diagnostic facility, or outpatient treatment facility as deﬁned in paragraphs (l), (b), (s), (t), and (u), respectively, of this section, which is not a “physician’s ofﬁce,” as deﬁned in paragraph (w) of this section. School nurse ofﬁces and employee health units are not device user facilities. Director Director of FDA’s Ofﬁce of Orphan Products Development. Distributor Any person, including any person who imports a device into the United States, who furthers the marketing of a device from the original place of manufacture to the person who makes ﬁnal delivery or sale to the ultimate user but who does not repackage or otherwise change the container, wrapper, or labeling of the device or device package. One who

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repackages or otherwise changes the container, wrapper, or labeling, is a manufacturer under Section 804.3(k). Distributor Report Number Number that uniquely identiﬁes each report submitted by a distributor. Distributors who receive or submit reports shall use their seven-digit FDA registration number, calendar year that the report is received, and a sequence number. For example, the complete number will appear as follows: 1234567-1991-0001. Distributor report numbers shall also be required on FDA form 3500A. Drug product A ﬁnished dosage form (for example, tablet, capsule, or solution) that contains an active drug ingredient generally, but not necessarily, in association with inactive ingredients. The term also includes a ﬁnished dosage form that does not contain an active ingredient but is intended to be used as a placebo. Due diligence petition Petition submitted under Section 60.30(a). Emergency use the use of a test article on a human subject in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufﬁcient time to obtain IRB approval. Establishment (1) a place of business under one management at one general physical location; the term includes, among others, human blood and plasma donor centers, blood banks, transfusion services, other blood product manufacturers, and independent laboratories that engage in quality control and testing for registered blood product establishments. (2) A place of business where cosmetic products are manufactured or packaged. Expected life of a device (required on the manufacturer’s baseline report) The time that a device is expected to remain functional after it is placed into use. Certain implanted devices have speciﬁed “end of life” (EOL) dates. Other devices are not labeled as to their respective EOL dates but are expected to remain operational through maintenance, repair, upgrades, etc., for an estimated period of time. Expiration date Calendar month and year and, where applicable, the day and hour that the dating period ends. Facilities Any area used for the collection, processing, compatibility testing, storage, or distribution of blood and blood components. Family member Any one of the following legally competent persons: spouse; parents; children (including adopted children); brothers, sisters, and spouses of brothers and sisters; and any individual related by blood or afﬁnity whose close association with the subject is the equivalent of a family relationship. FDA Food and Drug Administration. Fiber Any particulate contaminant with a length at least three times greater than its width. Filed screening procedure Procedure that is: (1) on ﬁle with the FDA and subject to public inspection; (2) designed to determine that there is a reasonable basis for concluding that an alleged injury did not occur in conjunction with the use of the cosmetic product; and (3) which is subject, upon request by the FDA, to an audit conducted by the FDA at reasonable times and, where an audit is conducted, such audit shows that the procedure is consistently being applied and that the procedure is not disregarding reportable information. Five-day report A medical device report that must be submitted by a manufacturer to FDA pursuant to 21 CFR 803.53, on FDA Form 3500A or electronic equivalent as approved under 21 CFR 803.14, within 5 work days. Flavor Any natural or synthetic substance or substances used solely to impart a taste to a cosmetic product. Food additive Any substance that meets the deﬁnition in Section 201(s) of the Act and which is subject to premarketing approval under Section 409 of the Act. Fragrance Any natural or synthetic substance or substances used solely to impart an odor to a cosmetic product.

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Gang-printed labeling Labeling derived from a sheet of material on which more than one item of labeling is printed. Group of ﬁnal containers Identical in all respects: ﬁlled with the same product from the same bulk lot without any change that will affect the integrity of the ﬁlling assembly. Holder Sponsor in whose name an orphan drug is designated and approved. Hospital A distinct entity that operates for the primary purpose of providing diagnostic, therapeutic (medical, occupational, speech, physical, etc.), surgical, and other patient services for speciﬁc and general medical conditions. Hospitals include general, chronic disease, rehabilitative, psychiatric, and other special-purpose facilities. A hospital may be either independent (not a part of a provider of services or any other facility) or operated by another medical entity (under the common ownership, licensure, or control of another entity). A hospital is covered by this regulation regardless of whether it is licensed by a federal, state, municipal, or local government or whether it is accredited by a recognized accreditation organization. If an adverse event meets the criteria for reporting, the hospital must report that event regardless of the nature or location of the medical service provided by the hospital. Human drug product Active ingredient of a new drug, antibiotic drug, or human biologic product (as those terms are used in the FD&C Act and the Public Health Service Act), including any salt or ester of the active ingredient, as a single entity or in combination with another active ingredient. Human subject Individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy human or a patient. Inactive ingredient Any component other than an active ingredient. Incident ﬁles Files containing documents or other information related to adverse events that may have been caused by a device. Information that reasonably suggests that there is a probability that a device has caused or contributed to a death or serious injury or serious illness means information, including professional, scientiﬁc, or medical facts, observations, or opinions, that would cause a reasonable person to believe that a device caused or contributed to a death, serious injury, or serious illness. IND application Investigational new drug application, synonymous with “Notice of Claimed Investigational Exemption for a New Drug.” Ingredient Any single chemical entity or mixture used as a component in the manufacture of a cosmetic product. In-process material Any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the drug product. Institution Any public or private entity or agency (including federal, state, and other agencies). The term facility as used in Section 520(g) of the Act is deemed to be synonymous with the term institution. Institutional Review Board (IRB) Board, committee, or other group formally designated by an institution to review biomedical research involving humans as subjects and to approve the initiation of and conduct periodic review of such research. The term has the same meaning as the phrase Institutional Review Committee as used in 21 CFR 520(g). Investigational new drug New drug, antibiotic drug, or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes. The terms “investigational drug” and “investigational new drug” are deemed to be synonymous for purposes of this part. Investigator An individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team.

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Label Any written, printed, or graphic matter on the container or package or any such matter clearly visible through the immediate carton, receptacle, or wrapper. Legally authorized representative An individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject’s participation in the procedure(s) involved in the research. Letter of designation Written notice issued by the product jurisdiction ofﬁcer specifying the agency component with primary jurisdiction for a combination product. Letter of request An applicant’s written submission to the product jurisdiction ofﬁcer seeking the designation of the agency component with primary jurisdiction. Leukapheresis The procedure in which blood is removed from the donor, a leukocyte concentrate is separated, and the remaining formed elements and residual plasma are returned to the donor. Location Includes all buildings, appurtenances, equipment, and animals used and personnel engaged by a manufacturer within a particular area designated by an address adequate for identiﬁcation. Lot A batch, or a speciﬁc identiﬁed portion of a batch, having uniform character and quality within speciﬁed limits; or, in the case of a drug product produced by continuous process, a speciﬁc identiﬁed amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within speciﬁed limits. Lot number, control number, or batch number Any distinctive combination of letters, numbers, or symbols, or any combination of them, from which the complete history of the manufacture, processing, packing, holding, and distribution of a batch or lot of drug product or other material can be determined. Malfunction Failure of a device to meet any of its performance speciﬁcations or otherwise to perform as intended. Performance speciﬁcations include all claims made in the labeling for the device. The intended performance of a device refers to the objective intent of the persons legally responsible for the labeling of the device. The intent is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the device. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It also may be shown by the circumstances that the device is, with the knowledge of such persons or their representatives, offered and used to perform a function for which it is neither labeled nor advertised. Manufacture (1) All steps in propagation or manufacture and preparation of products; includes but is not limited to ﬁlling, testing, labeling, packaging, and storage by the manufacturer. (2) The collection, preparation, processing, or compatibility testing by chemical, physical, biological, or other procedures of any blood product that meets the deﬁnition of a drug as deﬁned in 21 CFR 201(g) and including manipulation, sampling, testing, or control procedures applied to the ﬁnal product or to any part of the process. The term includes packaging, labeling, repackaging, or otherwise changing the container, wrapper, or labeling of any blood product package in furtherance of the distribution of the blood product from the original place of manufacture to the person who makes ﬁnal delivery or sale to the ultimate consumer. Manufacture of a cosmetic product The making of any cosmetic product by chemical, physical, biological, or other procedures, including manipulation, sampling, testing, or control procedures applied to the product. Manufacturer (1) Any legal person or entity engaged in the manufacture of a product subject to license under the Act; the term also includes any legal person or entity who is an applicant for a license where the applicant assumes responsibility for compliance with the applicable product and establishment standards. (2) Any person or agency engaged in the manufacture of a drug that is subject to investigation and approval under the act or the biologics provisions

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of the Public Health Service Act (42 USC 262–263). (3) Any person who manufactures, prepares, propagates, compounds, assembles, or processes a device by chemical, physical, biological, or other procedure; the term includes any person who: (a) repackages or otherwise changes the container, wrapper, or labeling of a device in furtherance of the distribution of the device from the original place of manufacture; (b) initiates speciﬁcations for devices that are manufactured by a second party for subsequent distribution by the person initiating the speciﬁcations; (c) manufactures components or accessories that are devices that are ready to be used and are intended to be commercially distributed and intended to be used as is or are processed by a licensed practitioner or other qualiﬁed person to meet the needs of a particular patient; or (d) is the U.S. agent of a foreign manufacturer. Manufacturer report number The number that uniquely identiﬁes each individual adverse event report submitted by a manufacturer. This number consists of three parts as follows: (1) FDA registration number for the manufacturing site of the reported device (if the manufacturing site does not have a registration number, FDA will assign a temporary number until the site is ofﬁcially registered, and the manufacturer will be informed of the temporary number); (2) four-digit calendar year in which the report was submitted; and (3) ﬁve-digit sequence number of the reports submitted during the year, starting with 00001. The complete number would appear, for example, as 1234567-2003-00001). Market withdrawal A ﬁrm’s removal or correction of a distributed product which involves a minor violation that would not be subject to legal action by the FDA or which involves no violation (e.g., normal stock rotation practices, routine equipment adjustments and repairs). Marketing applicant Any person who submits an application for premarketing approval by the FDA under: (1) Section 505(b) or 507 of the Act or Section 351 of the Public Health Service Act (human drug products); (2) Section 515 of the Act (medical devices); (3) Section 409 or 721 of the Act (food and color additives); or (4) Section 512 of the Act (animal drug products). Marketing application An application for a new drug submitted under 21 CFR 505(b), a request to provide for certiﬁcation of an antibiotic submitted under 21 CFR 507, or a product license application for a biological product submitted under the Public Health Service Act. MDR Medical device report. Medical device Any article that meets the deﬁnition in Section 201(h) of the Act and which is subject to premarketing approval under Section 515 of the Act. Medical device reportable event (or reportable event) (1) An event about which user facilities become aware of information that reasonably suggests that a device has or may have caused or contributed to a death or serious injury. (2) An event about which manufacturers have received or become aware of information that reasonably suggests that one of their marketed devices: (a) may have caused or contributed to a death or serious injury, or (b) has malfunctioned and that the device or a similar device marketed by the manufacturer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur. Medical personnel An individual who: (1) is licensed, registered, or certiﬁed by a state, territory, or other governing body to administer health care; (2) has received a diploma or a degree in a professional or scientiﬁc discipline; (3) is an employee responsible for receiving medical complaints or adverse event reports; or (4) is a supervisor of such persons. Minimal risk The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. New drug substance Any substance that, when used in the manufacture, processing, or packing of a drug, causes that drug to be a new drug, but does not include intermediates used in the synthesis of such substance. The newness of a drug may arise by reason (among other reasons) of: (1) the newness for drug use of any substance that composes such drug, in whole or in part, whether it be an active substance or a menstruum, excipient, carrier,

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coating, or other component; (2) the newness for a drug use of a combination of two or more substances, none of which is a new drug; (3) the newness for a drug use of the proportion of a substance in a combination, even though such combination containing such substance in other proportion is not a new drug; (4) the newness of use of such drug in diagnosing, curing, mitigating, treating, or preventing a disease or to affect a structure or function of the body, even though such drug is not a new drug when used in another disease or to affect another structure or function of the body; (5) the newness of a dosage, or method or duration of administration or application, or other condition of use prescribed, recommended, or suggested in the labeling of such drug, even though such drug when used in other dosage or other method or duration of administration or application or different condition is not a new drug. Nonclinical laboratory study In vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety. The term does not include studies utilizing human subjects or clinical studies or ﬁeld trials in animals. The term also does not include basic exploratory studies carried out to determine whether a test article has any potential utility or to determine physical or chemical characteristics of a test article. Non-ﬁber-releasing ﬁlter Any ﬁlter which, after any appropriate pretreatment such as washing or ﬂushing, will not release ﬁbers into the component or drug product that is being ﬁltered. All ﬁlters composed of asbestos are deemed to be ﬁber-releasing ﬁlters. Nursing home An independent entity (not a part of a provider of services or any other facility) or one operated by another medical entity (under the common ownership, licensure, or control of an entity) that operates for the primary purpose of providing: (1) Skilled nursing care and related services for persons who require medical or nursing care; (2) hospice care to the terminally ill; or (3) services for the rehabilitation of the injured, disabled, or sick. Orphan drug A drug intended for use in a rare disease or condition, as deﬁned in Section 526 of the Act. Orphan-drug designation The FDA’s act of granting a request for designation under Section 526 of the Act. Orphan-drug exclusive approval or exclusive approval Effective on the date of FDA approval as stated in the approval letter of a marketing application for a sponsor of a designated orphan drug, no approval will be given to a subsequent sponsor of the same drug product for the same indication for seven years, except as otherwise provided by law. Outpatient diagnostic facility A distinct entity that: (1) operates for the primary purpose of conducting medical diagnostic tests on patients; (2) does not assume ongoing responsibility for patient care; and (3) provides its services for use by other medical personnel. (Examples include diagnostic radiography, mammography, ultrasonography, electrocardiography, magnetic resonance imaging, computerized axial tomography, and in vitro testing). An outpatient diagnostic facility may be either independent (not a part of a provider of services or any other facility) or operated by another medical entity (under the common ownership, licensure, or control of an entity). Outpatient treatment facility A distinct entity that operates for the primary purpose of providing nonsurgical therapeutic (medical, occupational, or physical) care on an outpatient basis or home health care setting. Outpatient treatment facilities include ambulance providers, rescue services, and home health care groups. Examples of services provided by outpatient treatment facilities include: Cardiac deﬁbrillation, chemotherapy, radiotherapy, pain control, dialysis, speech or physical therapy, and treatment for substance abuse. An outpatient treatment facility may be either independent (not a part of a provider of services or any other facility) or operated by another medical entity (under the common ownership, licensure, or control of an entity).

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Package The immediate carton, receptacle, or wrapper, including all labeling matter therein and thereon, and the contents of the one or more enclosed containers. If no package, as deﬁned in the preceding sentence, is used, the container is deemed to be the package. Packaging of a cosmetic product Filling or labeling the product container, including changing the immediate container or label (but excluding changing other labeling) at any point in the distribution of the cosmetic product from the original place of manufacture to the person who makes ﬁnal delivery or sale to the ultimate consumer. Patient of the facility Any individual who is being diagnosed or treated and/or receiving medical care at or under the control or authority of the facility. The deﬁnition encompasses employees of the facility or individuals afﬁliated with the facility who, in the course of their duties, suffer a device-related death or serious injury that has or may have been caused or contributed to by a device used at the facility. Percentage of theoretical yield The ratio of the actual yield (at any appropriate phase of manufacture, processing, or packing of a particular drug product) to the theoretical yield (at the same phase), stated as a percentage. Permanent Irreversible impairment or damage to a body structure or function, excluding trivial impairment or damage. Person An individual, partnership, corporation, association, scientiﬁc or academic establishment, government agency, or organizational unit thereof, and any other legal entity. Pharmaceutical alternatives Drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates. Pharmaceutical equivalents Drug products that contain identical amounts of the identical active drug ingredient (i.e., the same salt or ester) of the same therapeutic moiety in identical dosage forms but not necessarily containing the same inactive ingredients and that meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates. Phrase related drug(s) Other brands, potencies, dosage forms, salts, and esters of the same drug moiety, including articles prepared or manufactured by other manufacturers; any other drug containing a component so related by chemical structure or known pharmacological properties that, in the opinion of experts qualiﬁed by scientiﬁc training and experience to evaluate the safety and effectiveness of drugs, it is prudent to assume or ascertain the liability of similar side effects and contraindications. Physician’s ofﬁce A facility that operates as the ofﬁce of a physician or other health care professional (e.g., dentist, chiropractor, optometrist, nurse practitioner, school nurse ofﬁces, school clinics, employee health clinics, or free-standing care units) for the primary purpose of examination, evaluation, and treatment or referral of patients. A physician’s ofﬁce may be independent, a group practice, or part of a Health Maintenance Organization. Plasma for further manufacturing The liquid portion of blood separated and used as material to prepare another product. Plasmapheresis The procedure in which blood is removed from the donor, the plasma is separated from the formed elements, and at least the red blood cells are returned to the donor. This process may be immediately repeated, once. Plateletpheresis The procedure in which blood is removed from the donor, a platelet concentrate is separated, and the remaining formed elements and residual plasma are returned to the donor. Possession Term includes, among other possessions, Puerto Rico and the Virgin Islands.

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Potency The speciﬁc ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result. Premarket review The examination of data and information in an application for premarket review described in Sections 505, 507, 510(k), 513(f), 515, or 520(g) or 520(l) of the Act or Section 351 of the Public Health Service Act of data and information contained in any investigational new drug (IND) application, investigational device exemption (IDE), new drug application (NDA), antibiotic application, biological product or establishment license application, device premarket notiﬁcation, device reclassiﬁcation petition, and premarket approval application (PMA). Probability, probable, or probably A person would have reason to believe, based upon an analysis of the event and device, that the device has caused or contributed to an adverse event; this term does not signify statistical probability. Process A manufacturing step performed on the product itself that may affect its safety, purity, or potency, in contrast to manufacturing steps that do not intrinsically affect the safety, purity, or potency of the product. Processing Any procedure employed after collection and before compatibility testing of blood; includes the identiﬁcation of a unit of donor blood, the preparation of components from such units of donor blood, serological testing, labeling, and associated recordkeeping. Product (1) An article subject to the jurisdiction of the FDA, including any food, drug, or device intended for human or animal use, any cosmetic and biologic intended for human use, and any item subject to a quarantine regulation; term does not include an electronic product that emits radiation and is subject to 21 CFR 1003 and 1004; term does include biological products and trivalent organic arsenicals. (2) Any article that contains any drug as deﬁned in 21 CFR 201(g)(1), any device as deﬁned in 21 CFR 201(h), or any biologic as deﬁned in 21 CFR 351(a) of the Public Health Service Act (42 USC 262(a)). Product jurisdiction ofﬁcer The person or persons responsible for designating the component of the FDA with primary jurisdiction for the premarket review and regulation of a combination product or any product requiring a jurisdictional designation under this part. Proper name (as applied to a product) The name designated in the license for use upon each package of the product. Proprietary ingredient Any cosmetic product ingredient whose name, composition, or manufacturing process is protected from competition by secrecy, patent, or copyright. PTO U.S. Patent and Trademark Ofﬁce. Purity Relative freedom from extraneous matter in the ﬁnished product, whether or not harmful to the recipient or deleterious to the product. Purity includes but is not limited to relative freedom from residual moisture or other volatile substances and pyrogenic substances. Quality assurance unit Any person or organizational element, except the study director, designated by testing facility management to perform the duties relating to the quality assurance of nonclinical laboratory studies. Quality control unit Any person or organizational element designated by the ﬁrm to be responsible for the duties relating to quality control. Radioactive biological product A biological product that is labeled with a radionuclide or is intended solely to be labeled with a radionuclide. Radioactive drug Any substance deﬁned as a drug in Section 201(g)(1) of the Act that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons and includes any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of any such substance but does not include drugs such as carbon-containing compounds or potassium-containing salts that contain trace quantities of naturally occurring radionuclides. The term includes “radioactive biological product” as deﬁned in 21 CFR 600.3(ee).

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Raw data Any laboratory worksheets, records, memoranda, notes, or exact copies thereof that are the result of original observations and activities of a nonclinical laboratory study and are necessary for the reconstruction and evaluation of the report of that study. In the event that exact transcripts of raw data have been prepared (e.g., tapes that have been transcribed verbatim, dated, and veriﬁed accurate by signature), the exact copy or exact transcript may be substituted for the original source as raw data. Raw data may include photographs, microﬁlm or microﬁche copies, computer printouts, magnetic media (including dictated observations), and recorded data from automated instruments. Recall A ﬁrm’s removal or correction of a marketed product that the FDA considers to be in violation of the laws it administers and against which the agency would initiate legal action (e.g., seizure). Recall does not include a market withdrawal or a stock recovery. Recall classiﬁcation The numerical designation (I, II, or III) assigned by the FDA to a particular product recall to indicate the relative degree of health hazard presented by the product being recalled. Class I is a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death. Class II is a situation in which use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote. Class III is a situation in which use of, or exposure to, a violative product is not likely to cause adverse health consequences. Recall strategy A planned, speciﬁc course of action to be taken in conducting a speciﬁc recall; addresses the depth of recall, need for public warnings, and extent of effectiveness checks for the recall. Recalling ﬁrm The ﬁrm that initiates a recall or, in the case of an FDA-requested recall, the ﬁrm that has primary responsibility for the manufacture and marketing of the product to be recalled. Remedial action Any recall, repair, modiﬁcation, adjustment, relabeling, destruction, inspection, patient monitoring, notiﬁcation, or any other action relating to a device that is initiated by a distributor in response to information that it receives or otherwise becomes aware of that reasonably suggests that one of its marketed devices has caused or contributed to an MDR reportable event. Reportable experience An experience involving any allergic reaction, or other bodily injury and alleged to be the result of the use of a cosmetic product under the conditions of use prescribed in the labeling of the product, under such conditions of use as are customary or reasonably foreseeable for the product or under conditions of misuse, that has been reported to the manufacturer, packer, or distributor of the product by the affected person or any other person having factual knowledge of the incident, other than an alleged experience that has been determined to be unfounded or spurious when evaluated by a ﬁled screening procedure. Representative sample A sample that consists of a number of units that are drawn based on rational criteria such as random sampling and intended to assure that the sample accurately portrays the material being sampled. Respondent A person named in a notice who presents views concerning an alleged violation in person, by designated representative, or in writing. Responsible individual Those in positions of power or authority to detect, prevent, or correct violations of the FD&C Act. Safety The relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time. Same drug (1) If it is a drug composed of small molecules, a drug that contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug, even if the particular ester or salt (including a salt with hydrogen or coordination bonds) or other noncovalent derivative such as a complex, chelate, or clathrate

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has not been previously approved, except that if the subsequent drug can be shown to be clinically superior to the ﬁrst drug, it will not be considered to be the same drug. (2) If it is a drug composed of large molecules (macromolecules), a drug that contains the same principal molecular structural features (but not necessarily all of the same structural features) and is intended for the same use as a previously approved drug, except that, if the subsequent drug can be shown to be clinically superior, it will not be considered to be the same drug. Two protein drugs would be considered the same if the only differences in structure between them were due to posttranslational events or inﬁdelity of translation or transcription or were minor differences in amino acid sequence; other potentially important differences, such as different glycosylation patterns or different tertiary structures, would not cause the drugs to be considered different unless the differences were shown to be clinically superior. Two polysaccharide drugs would be considered the same if they had identical saccharide repeating units, even if the number of units were to vary and even if there were postpolymerization modiﬁcations, unless the subsequent drug could be shown to be clinically superior. Two polynucleotide drugs consisting of two or more distinct nucleotides would be considered the same if they had an identical sequence of purine and pyrimidine bases (or their derivatives) bound to an identical sugar backbone (ribose, deoxyribose, or modiﬁcations of these sugars), unless the subsequent drug were shown to be clinically superior. Closely related, complex partly deﬁnable drugs with similar therapeutic intent, such as two live viral vaccines for the same indication, would be considered the same unless the subsequent drug was shown to be clinically superior. Secretary Secretary of Health and Human Services. Selling agent or distributor Any person engaged in the unrestricted distribution, other than by sale at retail, of products subject to license. Serious illness An event that: (1) is life threatening; (2) results in permanent impairment of a body function or permanent damage to the body structure; or (3) necessitates immediate medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure. Serious injury An injury or illness that: (1) is life-threatening; (2) results in permanent impairment of a body function or permanent damage to body structure; or (3) necessitates medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure. Shelf life The maximum time a device will remain functional from the date of manufacture until it is used in patient care. Some devices have an expiration date on their labeling indicating the maximum time they can be stored before losing their ability to perform their intended function. Special packaging As deﬁned in the Poison Prevention Packaging Act of 1970, packaging that is designed or constructed to be signiﬁcantly difﬁcult for children under ﬁve years of age to open or obtain a toxic or harmful amount of the substance contained therein within a reasonable time and not difﬁcult for normal adults to use properly; does not mean packaging that all such children cannot open or obtain a toxic or harmful amount from within a reasonable time. Specimen Any material derived from a test system for examination or analysis. Sponsor (1) Person who initiates and supports, by provision of ﬁnancial or other resources, a nonclinical laboratory study; a person who submits a nonclinical study to the FDA in support of an application for a research or marketing permit; or a testing facility, if it both initiates and actually conducts the study. (2) A person who initiates a clinical investigation but who does not actually conduct the investigation; that is, the test article is administered or dispensed to or used involving a subject under the immediate direction of another individual. A person other than an individual (e.g., corporation or agency) that uses one or more of its own employees to conduct a clinical investigation it has initiated is considered to be a

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sponsor (not a sponsor–investigator), and the employees are considered to be investigators. (3) A person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor–investigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor (not a sponsor–investigator), and the employees are considered to be investigators. (4) The entity that assumes responsibility for a clinical or nonclinical investigation of a drug, including the responsibility for compliance with applicable provisions of the act and regulations. A sponsor may be an individual, partnership, corporation, or government agency and may be a manufacturer, scientiﬁc institution, or an investigator regularly and lawfully engaged in the investigation of drugs. For purposes of the Orphan Drug Act, the FDA considers the real party or parties in interest to be a sponsor. Sponsor–investigator An individual who both initiates and conducts an investigation and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor–investigator include those applicable to both an investigator and a sponsor. Standards Speciﬁcations and procedures applicable to an establishment or to the manufacture or release of products that are designed to ensure the continued safety, purity, and potency of such products. State A state or the District of Columbia, Puerto Rico, or the Virgin Islands. Sterility Freedom from viable contaminating microorganisms, as determined by tests prescribed in 21 CFR 610.12. Stock recovery A ﬁrm’s removal or correction of a product that has not been marketed or that has not left the direct control of the ﬁrm; that is, the product is located on premises owned by, or under the control of, the ﬁrm and no portion of the lot has been released for sale or use. Strength The concentration of the drug substance (e.g., weight/weight, weight/volume, or unit dose/volume basis), and/or its potency; that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard). Study completion date The date the ﬁnal report is signed by the study director. Study director The individual responsible for the overall conduct of a nonclinical laboratory study. Study initiation date The date the protocol is signed by the study director. Subinvestigator Any other individual member of that team. Subject A human who participates in an investigation, either as a recipient of the investigational new drug or as a control; a subject may be a healthy human or a patient with a disease. Supplement A request to the Director, Center for Biologics Evaluation and Research, to approve a change in an approved license application. System of commercial distribution of a cosmetic product Any distribution outside the establishment manufacturing the product, whether for sale, to promote future sales (including free samples of the product), or to gauge consumer acceptance through market testing, in excess of $1000 in cost of goods. Test article Any drug (including a biological product for human use), medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the act or under Sections 351 and 354–360F of the Public Health Service Act (42 USC 262 and 263b–263n). Test system Any animal, plant, microorganism, or subparts thereof to which the test or control article is administered or added for study. The term also includes appropriate groups or components of the system not treated with the test or control articles. Testing facility A person who actually conducts a nonclinical laboratory study (i.e., actually uses the test article in a test system). The term includes any establishment required to register

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under Section 510 of the Act that conducts nonclinical laboratory studies and any consulting laboratory described in Section 704 of the Act that conducts such studies. Testing facility encompasses only those operational units that are being or have been used to conduct nonclinical laboratory studies. Theoretical yield The quantity that would be produced at any appropriate phase of manufacture, processing, or packing of a particular drug product, based upon the quantity of components to be used, in the absence of any loss or error in actual production. Trading names used by the establishment Any name used on a cosmetic product label and owned by the cosmetic product manufacturer or packer but is different from the principal name under which the cosmetic product manufacturer or packer is registered. Trivalent organic arsenicals Arsphenamine and its derivatives (or any other trivalent organic arsenic compound) applicable to the prevention, treatment, or cure of diseases or injuries of humans. Unit The volume of blood or one of its components in a suitable volume of anticoagulant obtained from a single collection of blood from one donor. User facility report number The number that uniquely identiﬁes each report submitted by a user facility to manufacturers and the FDA. This number consists of three parts as follows: (1) The user facility’s ten-digit Health Care Financing Administration (HCFA) number (if the HCFA number has fewer than ten digits, ﬁll the remaining spaces with zeros); (2) the fourdigit calendar year in which the report is submitted; and (3) the four-digit sequence number of the reports submitted for the year, starting with 0001. For example, a complete number would appear as follows: 1234560000-1995-0001. Work day Monday through Friday, excluding federal holidays: New Year’s Day, Martin Luther King, Jr.’s Birthday, Presidents’ Day, Memorial Day, Independence Day, Labor Day, Columbus Day, Veterans Day, Thanksgiving Day, and Christmas Day.

© 2005 by CRC Press LLC

FDA Administrative Enforcement Manual

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