Acceptable Risk in Biomedical Research: European Perspectives

Acceptable Risk in Biomedical Research

INTERNATIONAL LIBRARY OF ETHICS, LAW, AND THE NEW MEDICINE Founding Editors DAVID C. THOMASMA† DAVID N. WEISSTUB, Université de Montréal, Canada THOMASINE KIMBROUGH KUSHNER, University of California, Berkeley, U.S.A.

Editor DAVID N. WEISSTUB, Université de Montréal, Canada

Editorial Board TERRY CARNEY, University of Sydney, Australia MARCUS DÜWELL, Utrecht University, Utrecht, the Netherlands SØREN HOLM, University of Manchester, United Kingdom GERRIT K. KIMSMA, Vrije Universiteit, Amsterdam, the Netherlands DAVID NOVAK, University of Toronto, Canada EDMUND D. PELLEGRINO, Georgetown University, Washington D.C., U.S.A. DOM RENZO PEGORARO, Fondazione Lanza and University of Padua, Italy DANIEL P. SULMASY, The University of Chicago, U.S.A.

VOLUME 50 For other titles published in this series, go to http://www.springer.com/series/6224

Sigmund Simonsen

Acceptable Risk in Biomedical Research European Perspectives

123

Dr. Sigmund Simonsen Norwegian University of Science and Technology (NTNU), Royal Norwegian Air Force Academy Pb. 4133, 7450 Trondheim Norway [email protected]

ISSN 1567-8008 ISBN 978-94-007-2677-2 e-ISBN 978-94-007-2678-9 DOI 10.1007/978-94-007-2678-9 Springer Dordrecht Heidelberg London New York Library of Congress Control Number: 2011943499 © Springer Science+Business Media B.V. 2012 No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface

The topic of this book is the legal requirement of proportionality between risks, burdens, and potential benefits in interventional biomedical research on human beings. The book is based on my more extensive doctoral thesis, which was delivered June 2009 and defended February 2010. The topic was chosen after an investigation of biomedical research law, which revealed that surprisingly little appeared to be known about this old and obviously central professional, ethical, and legal requirement. Although more information about the requirement was found later on, the requirement of proportionality in European biomedical research law appeared largely unexplored in legal theory, in European Convention (ECHR) law and Community (EU) law. The purpose of this book is to contribute to enhanced knowledge about the requirement’s normative content in the first two jurisdictions, and, consequently, also in national law of European countries. Hopefully, this clarification of the law may improve assessments of proportionality in practice, and consequently improve the respect for and protection of research participants’ individual interests, welfare (including health), and human dignity. I am enormously grateful and indebted to many persons who have generously contributed during the course of this project. Firstly, I am grateful to my enthusiastic mentor and principal supervisor of the doctoral project, Professor Dr. med Magne Nylenna. I am also very grateful to my co-supervisors: Judge Sverre Erik Jebens, Professor Dr. Philos Knut Ruyter, Judge Øyvind Smukkestad, and last, but not least, Professor Dr. Juris Henriette Sinding Aasen. I must also thank the opponents of the doctoral committee for a constructive critique; Professors Mette Hartlev, Asbjørn Kjønstad, and Steinar Westin. This project was jointly funded by the Norwegian University of Science and Technology (NTNU) and Middle Norway Regional Health Authority. Many thanks to former dean, now director, Gunnar Bovim, for recruiting me. My place of work has been and still is the Department of Public Health and General Practice, at the Faculty of Medicine, NTNU. Working in a biomedical research community has been enriching, and I am grateful to my many good and caring colleagues there. I also wish to thank service minded librarians at the Medical Library at NTNU, the Kennedy Institute of Ethics at Georgetown University, and the European Court of

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Human Rights. Many thanks also to Head of Bioethics Division, Laurence Lwoff, of the Council of Europe for meeting and valuable assistance. Special thanks goes to the members and the secretaries of the Research Ethics Committee (REC) in Middle Norway, who open-heartedly let me observe their conscientious work for three years to learn about the assessment of proportionality in practice. Sincere gratitude to three seniors: The Danish Professor Dr. med Povl Riis, who participated in the drafting of both the Declaration of Helsinki and the Additional Protocol, and who kindly invited me to his home for a long initial talk on the topic; Professor Dr. med Hermod Petersen, for discussions on the history of biomedical research; former editor of the British Medical Journal (BMJ), Dr. Stephen Lock, who has patiently read the manuscript twice (!) to improve the English language. Yet, remaining mistakes are all mine. I would also thank anonymous referees, Maja de Keijzer and Nicoline Ris at Springer for all the help. Warm thanks to my beloved and supportive wife, Kirsti, and our adorable and lively boys, Simon, William, and Filip – my shining stars. Finally, I express profound gratitude to my dear parents, to whom I dedicate this work. Trondheim, Norway 25 August 2011

Sigmund Simonsen

Contents

Part I

Initial Issues

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 The Topic: Acceptable Risks in Biomedical Research . 1.2 The Legal Basis of the Requirement of Proportionality 1.3 What Is Known and Not Known? . . . . . . . . . . . 1.4 Objectives . . . . . . . . . . . . . . . . . . . . . . . . 1.5 The Scope of This Book . . . . . . . . . . . . . . . .

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2 Method and Material . . . . . . . . . . . . . . . . . . . 2.1 Legal Method . . . . . . . . . . . . . . . . . . . . 2.2 Material . . . . . . . . . . . . . . . . . . . . . . . 2.3 My Observational Study of Researchers and a REC

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3 Initial Conceptual Clarifications . . . . . . . . . . . . . . . 3.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 The Definition of “Risk” . . . . . . . . . . . . . . . . . 3.3 The Definition of “Burden” and “Inconvenience” . . . . 3.4 What Is the Relationship Between Risks and Burdens? . 3.5 The Definition of “Potential (Anticipated) Benefit” . . . 3.6 The Concept of “Direct Benefit” . . . . . . . . . . . . . 3.7 “Therapeutic Research” and “Nontherapeutic Research” 3.8 “Vulnerable Person” . . . . . . . . . . . . . . . . . . .

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4 Origins of the Requirement of Proportionality . . . . . . . . 4.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Early Development . . . . . . . . . . . . . . . . . . . . 4.3 The Nuremberg Doctors Trial and the Nuremberg Code . 4.4 Plausible Explanations for Disproportionate Research in the Early Twentieth Century . . . . . . . . . . . . . . 4.5 The Further Development of the Requirement of Proportionality . . . . . . . . . . . . . . . . . . . . . 4.5.1 The Influence of Human Rights Law . . . . .

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4.5.2 4.5.3 4.5.4 4.5.5 4.5.6

The Declaration of Helsinki and Other Professional Guidelines . . . . . . . . . . American Bioethics . . . . . . . . . . . . The EU and the Regulation of the Pharmaceutical Industry . . . . . . . . . . The Council of Europe and the Oviedo Convention and Its Additional Protocol . . Reflections on the Development of Current Regulations . . . . . . . . . . . . . . . .

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5 The Purpose of the Requirement of Proportionality . . . . . . . . 5.1 Problems Addressed . . . . . . . . . . . . . . . . . . . . . . 5.2 Balancing Different Interests . . . . . . . . . . . . . . . . . . 5.2.1 General . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2 Relevant Interests . . . . . . . . . . . . . . . . . . 5.2.3 Compatible Interests? . . . . . . . . . . . . . . . . 5.2.4 The Weight and Prioritizing of Relevant Interests . . 5.2.5 The Principle of Human Primacy . . . . . . . . . . 5.3 The Requirement of Proportionality as a Safeguard . . . . . . 5.3.1 Problem Addressed . . . . . . . . . . . . . . . . . 5.3.2 Proportionality and Researchers Duty of Care . . . 5.3.3 Conclusions . . . . . . . . . . . . . . . . . . . . . 5.4 The Relationship Between Proportionality and Autonomy . . 5.4.1 Problem Addressed . . . . . . . . . . . . . . . . . 5.4.2 Autonomy – More on the Problem Addressed . . . 5.4.3 Biased Information, Therapeutic Misconception, and the Unreliability and Insufficiency of Consent . . . . . . . . . . . . . 5.4.4 The Relationship Between Participants Right to Self-Determination and Researchers Duty of Care . . . . . . . . . . . . . . . . . . . . . . . . 5.4.5 Is the Requirement of Consent Necessary? . . . . . 5.4.6 Consent by Proxy . . . . . . . . . . . . . . . . . . 5.4.7 Conclusions Regarding Proportionality and Consent 5.5 Proportionality and the Aim of Facilitating Research . . . . . 5.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . .

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6 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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7 Which Risks, Burdens and Potential Benefits Are Relevant? 7.1 The Starting Point . . . . . . . . . . . . . . . . . . . . 7.2 Cause in Fact . . . . . . . . . . . . . . . . . . . . . . . 7.3 Cause in Law . . . . . . . . . . . . . . . . . . . . . . .

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Part II

Which Risks, Burdens, and Potential Benefits Are Relevant, and How Should They Be Estimated?

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Typical Relevant Risks, Burdens, and Potential Benefits . . . . In What Order Should the Factors Be Clarified? . . . . . . . . . Conclusions on Causality and Relevancy . . . . . . . . . . . .

8 How to Estimate Risks, Burdens, and Potential Benefits . . . . . 8.1 Starting Points . . . . . . . . . . . . . . . . . . . . . . . . . 8.2 Risks and Burdens Must Be Minimised, and Potential Benefits Maximised . . . . . . . . . . . . . . . . . . . . . . 8.2.1 General – Problems to Be Addressed . . . . . . . . 8.2.2 The Requirement of Minimising Risks and Burdens 8.2.3 Maximising Benefits . . . . . . . . . . . . . . . . . 8.3 Who Decides? Objective and Subjective Considerations . . . 8.4 The Burden of Proof Concerning the Description of Risks, Burdens, and Potential Benefits . . . . . . . . . . .

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Nontherapeutic Research . . . . . . . . . . . . . . . . . . . . . . . 11.1 Starting Points and Problems Addressed . . . . . . . . . . . . . 11.2 The Challenge of Estimation and Weighing . . . . . . . . . . .

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Part III

The Assessment of Proportionality

9 The Requirement of Proportionality – Initial Clarifications . . . 9.1 Problems Addressed . . . . . . . . . . . . . . . . . . . . . . 9.2 The Provisions’ Wording and Core Content . . . . . . . . . . 9.3 The Differentiation Therapeutic and Nontherapeutic Research, and Between Participants Able and Not Able to Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3.1 General About the Differentiation . . . . . . . . . . 9.3.2 More on the Differentiation: What is the “Main Rule”? . . . . . . . . . . . . . . . . . 9.4 The Way Ahead . . . . . . . . . . . . . . . . . . . . . . . . . 9.5 The Requirement of Proportionality in Broad and Strict Sense 10

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Therapeutic Research . . . . . . . . . . . . . . . . . . . . . . . . 10.1 Problem Addressed . . . . . . . . . . . . . . . . . . . . . . . 10.2 Starting Points . . . . . . . . . . . . . . . . . . . . . . . . . 10.3 More on the Weighing of Direct Benefits and the Assessment of Proportionality . . . . . . . . . . . . . 10.3.1 Problems Addressed . . . . . . . . . . . . . . . . . 10.3.2 Estimating and Weighing Direct Benefits . . . . . . 10.3.3 Estimating and Weighing Burdens . . . . . . . . . . 10.3.4 Estimating and Weighing Risks of Harm . . . . . . 10.3.5 The Overall Assessment of Proportionality . . . . . 10.3.6 Reasonable Choice and Most Favourable Alternative 10.3.7 More on Individual Therapy v. Systematic Research 10.3.8 What if the Direct Benefit Rule Is Not Fulfilled? . . 10.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Estimating and Weighing Potential Benefits to Others . . More on the Assessment of Proportionality and Legally “Acceptable” Risks and Burdens . . . . . . . . . . . . . 11.4.1 Problem Addressed . . . . . . . . . . . . . . 11.4.2 How Great May a Risk Be and Still Be Legally “Acceptable” . . . . . . . . . . . . . 11.4.3 “Acceptable” Risks in Self-Experimentation . 11.4.4 Quantifying High, but “Acceptable” Risks and Burdens . . . . . . . . . . . . . . . . . . 11.4.5 The Overall Assessment of Proportionality and Acceptable Risks and Burdens . . . . . . Repetitive Participation . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . .

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Nontherapeutic Research on “Vulnerable” Participants . . . . . 12.1 Problems Addressed . . . . . . . . . . . . . . . . . . . . . . 12.2 Introduction: Can It Ever Be Justified to Expose Vulnerable Persons to Risks and Burdens for the Sake of Others? . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3 Which Additional Preconditions Apply to Nontherapeutic Research on Vulnerable Persons? . . . . . 12.3.1 Additional Safeguards Applicable to Nontherapeutic Research on Persons Not Able to Consent in the Additional Protocol . . . . . 12.3.2 Additional Safeguards Applicable to Nontherapeutic Research on Children in the Clinical Trials Directive . . . . . . . . . . . . . . . 12.3.3 Additional Safeguards Applicable to Nontherapeutic Research on Adult Persons Not Able to Consent in the Clinical Trials Directive 12.3.4 Additional Safeguards Applicable to Nontherapeutic Research in Emergency Clinical Situations . . . . . . . . . . . . . . . . . . 12.3.5 Additional Safeguards Applicable to Nontherapeutic Research During Pregnancy and Breastfeeding . . . . . . . . . . . . . . . . . . 12.3.6 Additional Safeguards Applicable to Research on Persons Deprived of Liberty . . . . . . . . . . . 12.3.7 Additional Safeguards Applicable to Nontherapeutic Research on Similarly Vulnerable Persons . . . . . . . . . . . . . . . . . . 12.4 The Precondition of “Significant” Potential Benefits to Others 12.4.1 Problems Addressed . . . . . . . . . . . . . . . . . 12.4.2 The Normative Content of the Precondition of “Significant” Potential Benefits to Others . . . . 12.4.3 Conclusions . . . . . . . . . . . . . . . . . . . . .

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The Precondition of Only Minimal Risks and Burdens to the Participant . . . . . . . . . . . . . . . . . . . . . 12.5.1 General . . . . . . . . . . . . . . . . . . . . . 12.5.2 The Definition of Minimal Risk in the Additional Protocol . . . . . . . . . . . 12.5.3 The Definition of Minimal Burden in the Additional Protocol . . . . . . . . . . . 12.5.4 Single Standard or Multiple Standards of Minimal Risks and Burdens . . . . . . . . 12.5.5 Concretisation of Minimal Risk and Minimal Burden . . . . . . . . . . . . . . . . . . . . . 12.5.6 The Necessity of an Individual and Concrete Assessment of Minimal Risks and Burdens . . 12.5.7 Quantifying the Standard of Minimal Risks and Burdens . . . . . . . . . . . . . . . . . . 12.5.8 Applying the Standard of Minimal Risk and Burden – A Case Example . . . . . . . . 12.5.9 US Federal Law’s Definition of Minimal Risk and the Daily Risk Standard . . . . . . . . . . 12.5.10 The Case of Grimes v. Kennedy Krieger . . . Conclusions on Research on Vulnerable Persons . . . .

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Non-interference with Necessary Clinical Interventions and The No Harm Rule . . . . . . . . . . . . . . . . . . . . . . . . . 13.1 Starting Points and Problems Addressed . . . . . . . . . . . . . 13.2 The Notion of “Not Detrimental” . . . . . . . . . . . . . . . .

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Especially on Randomised Clinical Trials, Including Placebo Controlled Clinical Trials . . . . . . . . . . . . . . . . 14.1 Problems Addressed . . . . . . . . . . . . . . . . . . . . 14.2 Legal Starting Points . . . . . . . . . . . . . . . . . . . . 14.3 Proportionality When the Research Project Includes a Control Group . . . . . . . . . . . . . . . . . . . . . . 14.4 Acceptable Risk in Placebo Controlled Clinical Trials . . 14.4.1 Problems Addressed . . . . . . . . . . . . . . . 14.4.2 Article 23 (3) and the Use of Placebo . . . . . . 14.5 Conclusions: Proportionality in Placebo Controlled Trials 14.6 Whole Protocol Approach or Component-by-Component?

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Acceptable Risks and Burdens to Others than the Participant . . . . . . . . . . . . . . . . . . . . . . . . . .

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Later Developments During the Course of the Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Legal Effects of the Requirement of Proportionality . . . . . . . . 17.1 Problem Addressed . . . . . . . . . . . . . . . . . . . . . . . . 17.2 In Breach of Researchers Duty of Care . . . . . . . . . . . . .

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17.3 17.4 17.5 Part IV

Invalid Consent . . . . . . . . . . . . . . . . . . . . . . . . . . Compensation for Damage . . . . . . . . . . . . . . . . . . . . Criminal Liability and Prosecution . . . . . . . . . . . . . . . .

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Summary and Conclusions

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Summary of Results . . . . . . . . . . . . . . . . . . . . . . . . . .

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Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Appendix A: Legal Instruments . . . . . . . . . . . . . . . . . . . . . .

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Appendix B: Case-Law . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Appendix C: Case Examples . . . . . . . . . . . . . . . . . . . . . . . .

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Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations

Regulatory Instruments Additional Protocol

CoE Additional Protocol on Biomedical Research to the Oviedo Convention of 2006 Clinical Trials Directive Directive 2001/20/EC of the European Community Declaration of Helsinki Professional guidelines first adopted by the World Medical Association in 1964, last revised in 2008 GCP Directive EU Commission Directive 2005/28/EC ICCPR UN International Covenant on Civil and Political Rights of 1966 ICESCR UN International Covenant of Economic, Social, and Cultural Rights of 1966 Oviedo Convention CoE Convention on Human Rights and Biomedicine of 1997 UDHR Universal Declaration of Human Rights of 1948 UN Charter Charter of the United Nations of 1945

Other Abbreviations CIMOS CoE EC ECHR ECJ ECtHR EEA EU Explanatory report GCP ICH

Council for International Organizations of Medical Sciences Council of Europe European Community European Convention on Human Rights of 1950 European Court of Justice European Court of Human Rights European Economic Agreement [EØS] European Union The Explanatory report to the Additional Protocol Good Clinical Practice (standards for professional clinical trials with pharmaceutical products (drugs)) The International Conference on Harmonisation (Adopted guidelines for Good Clinical Practice (GCP) in 1996) xiii

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ICJ IRB REC UN UNESCO WHO WMA

Abbreviations

International Court of Justice International Review Board (found in the US, equals REC) Research Ethics Committee (multidisciplinary agency) United Nations UN Economic, Social, and Cultural Organisation World Health Organisation (UN) World Medical Association (professional organisation for physicians)

List of Figure and Tables

Fig. 9.1

Table 7.1 Table 11.1 Table 12.1 Table 12.2

Table 12.3

The tripartition of proportionate risks and burdens implied in Article 6 of the Additional Protocol . . . . . . . . . Examples of typical potential benefits, burdens and risks . . . . . . . . . . . . . . . . . . . . . . . Swedish insurance company’s catalogued research procedures according to entailed risks . . . . . . . . Concretisation of the minimal risk standard in the EU Paediatric Guidelines of 2008 . . . . . . . . . . . . The Nicholson Working Group’s quantification of the “ethical” minimal risk standard in Europe in 1986 . . . . . . . . . . . . . . . . . . . . . . . . My attempt to quantify the current minimal risk standard in Europe . . . . . . . . . . . . . . . . . .

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Part I

Initial Issues

Chapter 1

Introduction

1.1 The Topic: Acceptable Risks in Biomedical Research Thousands of people, patients as well as healthy, daily participate in biomedical research projects throughout Europe. The research projects aim to provide new and enhanced knowledge, which may in the future lead to new or improved methods of diagnosis, treatment and prevention of sickness etc. The research participants (human subjects) are thus means towards that end. However, participants in human experiments are inevitably exposed to risks of harm from mishaps, adverse effects etc., and burdens in terms of pain, discomfort, and the spending of time and effort. Occasionally the research participants may also have reasonable prospects of benefits to their own health, but often this is not the case. The question is then what level of risks and burdens it is acceptable to expose human subjects to in biomedical research in Europe. This book seeks to answer that question. Because of apparent potentially conflicting interests between the researcher and the participant, the level of acceptable risk cannot be left for the researcher alone to decide. That is why there are rules, such as legal, ethical and professional norms. Hence, the level of acceptable risk is subject to binding legal regulations. A central legal norm in this regard is the principle, or more precisely, the requirement of proportionality, which states that the risks and burdens are acceptable if they are outweighed by (proportionate to) potential benefits to the participant or others (such as future patients). The requirement of proportionality implies that the risks and burdens must be weighed against potential benefits to determine whether there is a proportionate relationship and a fair balance between means and ends. This test corresponds with similar tests of proportionality in other fields of law. The regulatory situation concerning the level of acceptable risk in biomedical research is similar in the United States of America (the US). The primary purpose of the requirement is to ensure that participants in research are not exposed to unnecessary, excessive and unreasonable risks and burdens. The history of biomedical research testifies starkly to the hazards of human experiments, and that the experiments were not always carried out in ways palatable S. Simonsen, Acceptable Risk in Biomedical Research, International Library of Ethics, Law, and the New Medicine 50, DOI 10.1007/978-94-007-2678-9_1,  C Springer Science+Business Media B.V. 2012

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Introduction

to the public.1 Furthermore, the exploited were often the most vulnerable: children, sick, disabled, and underprivileged. Thus, the requirement of proportionality implicitly also addresses the potential conflict of interests between science and the individual research participants.2 The requirement of proportionality may also be seen as aiming to mend biased information, therapeutic misconceptions, and the unreliability and insufficiency of participants’ “informed” consent.

1.2 The Legal Basis of the Requirement of Proportionality “European biomedical research law”, or simply “the legal framework”, refers to applicable law in the field of biomedical research on human beings in Europe, and encompasses both “Convention law” and “Community law”. “Convention law” refers to the legal framework under the auspices of the Council of Europe (CoE) established in 1949.3 The CoE has 47 member states. The main legal instruments concerning biomedical research are the Convention on Biomedicine and Human Rights of 1997 (the Oviedo Convention),4 and its Additional Protocol on Biomedical Research of 2005 (the Additional Protocol).5 Both instruments can be said to be based in and elaborating on the European Convention on Human Rights (ECHR) of 1952.6 The Oviedo Convention was the first international legally binding instrument concerning biomedical research. The Additional Protocol specifies the Convention’s provisions concerning biomedical research, and is therefore the instrument of prime interest here. The Additional Protocol is accompanied by an Explanatory Report drawn up under the responsibility of the Secretary General of the Council of Europe.7 “Community law” refers to the legal framework under the auspices of the European Union (EU), as developed from the 1950s into an economic and political union of 27 member states.8 Community law also applies to the European Economic Area (EEA), which includes Norway, Island, and Liechtenstein. The main legal instruments concerning biomedical research are the Clinical Trials Directive

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See for example Beecher (1966); Pappworth (1967); Annas and Grodin (1995); Porter (1997); Moreno (2001); Ruyter (1997). 2 See Explanatory Report to the Additional Protocol, Paragraphs 1–2. 3 McLeod (2005, p. 89); See Statute of the Council of Europe of 1949. 4 Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. 5 Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research. 6 Convention for the Protection of Human Rights and Fundamental Freedoms. 7 The Committee of Ministers authorised its publication on 30 June 2004. There is also an Explanatory Report to the Oviedo Convention. 8 McLeod (2005, pp. 68–69).

1.2

The Legal Basis of the Requirement of Proportionality

5

of 2001,9 and the Commission’s supplementing directive on good clinical practice (the GCP Directive) of 2005.10 Moreover, a requirement of proportionality can probably also be founded in international and national customary law. This is substantiated by the existence of a similar professional norm that has existed at least since the Declaration of Helsinki was first adopted by the World Medical Association in 1964. It is therefore safe to say that the requirement of proportionality is a legally binding norm in Europe, both at the European level and at the national level in most countries. With regard to Convention law, Article 6 (1) of the Additional Protocol contains the following formulation of the requirement of proportionality11 : Research shall not involve risks and burdens to the human being disproportionate to its potential benefits.

Article 3 (2) (a) of the Clinical Trials Directive contains the corresponding provision in Community law, which states: A clinical trial may be undertaken only if, in particular: (a) the foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients. A clinical trial may be initiated only if the Ethics Committee and/or the competent authority comes to the conclusion that the anticipated therapeutic and public health benefits justify the risks and may be continued only if compliance with this requirement is permanently monitored.

Importantly, both provisions are supplemented and specified in subsequent provisions. Since most European countries are members of the Council of Europe and the European Union, they are directly or indirectly legally bound by at least one of these instruments.12 The Oviedo Convention and its Additional Protocol, as well as the Clinical Trials Directive, obligate member states to implement the requirement of proportionality at the national level.13 Member states do however have a certain margin of appreciation.14 The member states of both the CoE and the EU are thus

9

Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. 10 Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products. 11 The provision is a restatement of Article 16 (ii) of the Oviedo Convention (with the addition of the word “burden”). 12 However, not all members of the CoE have ratified the Oviedo Convention, and even fewer, the Additional Protocol. 13 See Article 1 of the Oviedo Convention and Article 3 (1) of the Clinical Trials Directive. 14 Jebens (2004, pp. 41 et seq.). See also Judgement by the ECtHR in Handyside v. UK, A 24 1976.

6

1

Introduction

relatively free as to how they implement the requirement of proportionality (wording, form, and method), as long as reasonable and acceptable results are achieved. The normative content should thus be largely the same.15 The requirement of proportionality in both Convention law and Community law is, for example, incorporated into Norwegian law.16 The wording is not the same (not even in Norwegian law as it is expressed in two different legal instruments), but the normative content is; a different view would be impracticable and legally questionable.17 Especially where the issue at stake concerns interventions into the private sphere of a human being for the sake of others, the margin of appreciation will be very limited; the stronger the interference, and the more infringing, the lesser the latitude.18

1.3 What Is Known and Not Known? Biomedical research has traditionally been governed by guidelines developed by biomedical researchers themselves. During the last decade there has been a move from ethical and professional norms towards the adoption of legally binding norms in this field, both internationally and nationally in Europe.19 The requirement of proportionality stands out as a core norm in current European biomedical research law. But yet it is only one out of several legal norms in this field.20 Another core norm is the requirement of consent to research from the participant.21

15

See Article 249 of the EC Treaty and Article 1 of the Oviedo Convention. See respectively the Health Research Act of 2008 § 22 (2), and Secondary legislation concerning clinical trials of 2003 § 1–5 (b). 17 See Simonsen (2011) on the feasibility and necessity of legal harmony and consistency in European Law. 18 See, for example, the Judgement by the ECtHR in Shtukaturov v. Russia, Judgment of 27 March 2008. See also Aall (2004) and Section 9.3. 19 See Simonsen and Nylenna (2006). 20 Simonsen and Nylenna (2006) where ten basic ethical, professional, and legal principles of biomedical research are identified. 21 See the Additional Protocol Article 13 and 14. Often the requirement of consent is called a requirement of “informed” consent. See Article 14 of the Additional Protocol. Article 2 (j) of the Clinical Trials Directive defines an “informed consent” (and valid) as: “‘informed consent’: decision, which must be written, dated and signed, to take part in a clinical trial, taken freely after being duly informed of its nature, significance, implications and risks and appropriately documented, by any person capable of giving consent or, where the person is not capable of giving consent, by his or her legal representative; if the person concerned is unable to write, oral consent in the presence of at least one witness may be given in exceptional cases, as provided for in national legislation.” The better formulation is, however, to speak about a requirement of “legally valid” consent, in which adequate information is but one central component, see Syse (2000). For simplistic reasons I speak about “the requirement of consent”. 16

1.3

What Is Known and Not Known?

7

Scholars have argued that the requirements of proportionality and consent are the two core norms in biomedical research, both in an ethical and a legal perspective.22 I agree with that notion. The US National Advisory Bioethics Commission, appointed by President Clinton in 1996, offered in its final report in 2001 an observation that is to the point, also in a European legal perspective: An IRB23 may approve a research proposal only if it judges that the risks are reasonable in relation to potential benefits. This judgment may be an IRB’s single most important and difficult determination, because it ensures that when research participants voluntarily consent to participate in a research study, they are offered a “reasonable choice.”24

The requirement of proportionality is among the oldest norms in this field.25 Numerous publications signify the centrality of the requirement of proportionality in the regulation of biomedical research.26 Moreover, the notion of proportionality appears self-evident and has, as put by Evelyn Ellis, “an attractively common-sense ring to it.”27 It is almost like magic formula, which easily resolves whether the risks and burdens are proportionate and acceptable. However, the requirement of proportionality is a complicated and controversial norm. Commentators grabble with and disagree about the content of the norm. In legal literature, the requirement of proportionality has, to my knowledge, only been subject to brief (overview) investigations, which give little guidance as to the more detailed content of this requirement.28 The differences in wording between the two main instruments have only briefly been addressed.29 The acceptability of risks of harm in biomedical research is on the other hand, frequently addressed in bioethical literature. But bioethical publications are seldom related to the existing legal framework to any great extent.30 Rather, they entail subjective opinions about how risks should be assessed in the author(s) opinion. Bioethical literature is therefore not very clarifying or helpful if one seeks knowledge about the legal framework. Moreover, the bulk of legal and bioethical literature is written in an US context. The requirement of proportionality is in addition intrinsically difficult to apply in practice. Several studies suggest that it is difficult to assess risks, burdens, potential benefits, and, not least, proportionality. My own observational study of 22

See, for example, Bergkamp (2004) and Rosenau (2000). IRB stands for Institutional Review Board, comparable with Research Ethics Committees (REC) found in most European countries. 24 The US National Bioethics Advisory Commission, Final Report (2001, p. 74). 25 See Chapter 4 that traces the origin of the requirement. 26 See Section 2.2 on the review of relevant literature. 27 Ellis (1999). 28 See, for example, Bergkamp (1989, 2004); Rosenau (2000); Lötjönen (2002). 29 See Westra et al. (2009) who identify inconsistency, but does not provide solutions, only some broad suggestions; see also de Bijl (2004). 30 See, for example, Weijer and Miller (2007); Miller and Brody (2007). 23

8

1

Introduction

a Research Ethics Committee (REC) substantiates those suggestions.31 The US National Bioethics Advisory Commission stated in this regard: An IRB’s assessment of risks and potential benefits is central to determining that a research study is ethically acceptable and would protect participants, which is not an easy task, because there are no clear criteria for IRBs to use in judging whether the risks of research are reasonable in relation to what might be gained by the research participant or society. . . . Consequently, IRBs often tend to focus more on matters where clearer regulatory direction is available – for example, reviewing the language used for consent forms – rather than on areas that require more judgment. Furthermore, investigators have a tendency to mimic their IRBs in this respect and focus on the more straightforward ethical issues (e.g., avoiding easily recognizable physical harms) and easily defined bureaucratic requirements (e.g., a signed consent form).32

Other commentators in Europe have expressed similar views.33 The statement about the skewed focus is also largely confirmed in my observational study of a REC. Thus, even though the requirement of proportionality appears as a self-evident core legal norm, it remains utterly vague and largely unexplored in a European legal perspective: It is by no means clarified what the requirement means. The vagueness of and lack of knowledge about the requirement of proportionality may lead to non-application, misinterpretations, and misapplications by biomedical researchers, research ethics committees, lawyers etc. As a result, participants may be exposed to unnecessary, excessive, and unacceptable risks and burdens; sound research may also be unduly hindered if an acceptable risk is wrongly determined to be unacceptable. Thus a clarification of the requirement of proportionality in European legal perspective is needed.

1.4 Objectives The overarching objective of this book is to clarify the requirement of proportionality as it currently stands in European biomedical research law (Convention law and Community law). Central research questions are: • What is the requirement’s relationship to the requirement of consent from the participant, and the participant’s right to self-determination? • To what extent are the two cited provisions in the Additional Protocol Article 6 (1) and the Clinical Trials Directive Article 3 (2) (a) reconcilable? • What risks, burdens, and benefits are relevant in the assessment of proportionality? • Are other factors (criteria), circumstances or interests relevant, and, if so, how and to what degree?

31

See Section 2.3. The US National Bioethics Advisory Commission (2001, p. 71). 33 Lenk et al. (2004). 32

1.5

The Scope of This Book

9

• What is the threshold(s) prescribed by the requirement of proportionality that interventional biomedical research projects on human beings must pass in order to be lawful? In other words, what degree of risks and burdens are legally acceptable in human experimentation in Europe today? The questions are addressed through a systematic legal analysis and interpretation of the requirement of proportionality as expressed in the Additional Protocol and the Clinical Trials Directive. I found reason to include both instruments in the analysis. It would, especially from biomedical researchers and research ethics committees’ point of view, be unsatisfactory to pursue and clarify only one of the instruments, and neglect the other. Since member states are obliged to implement European law at the national level, this book should therefore, to a certain degree, also clarify national law in most European countries. Since my knowledge of national law is largely confined to Norwegian law, the references to domestic law have a special emphasis on Norwegian biomedical research law. Both the Additional Protocol and the Clinical Trials Directive have recently been implemented into Norwegian law through the Health Research Act of 2008 and Norwegian secondary legislation concerning clinical trials of 2009.34 Convention law, Community law, and, to a limited degree also, Norwegian law are analysed and compared consecutively. This book may therefore to a certain degree also be seen as a comparative legal analysis. A secondary aim in this book is to clarify central concepts, such as “risk”, “burden”, “inconvenience”, “potential benefit”, “anticipated benefit”, “direct benefit”, “acceptable risk and burden”, “minimal risk and burden”, “therapeutic research”, “nontherapeutic research”, “healthy volunteer”, “vulnerable person” and so on. These are central concepts in the legal framework and the literature, and will be dealt with first in Chapter 2.

1.5 The Scope of This Book The scope of this book is the requirement of proportionality in European biomedical research law as expressed in both the Additional Protocol Article 6 and the Clinical Trials Directive Article 3 (2) (a), and as modified and specified in subsequent provisions in both instruments. “European biomedical research law” was defined above. The more precise scope of this book depends on the scope of the two core instruments. Their scope can in short be expressed as interventional biomedical research involving human subjects carried out in Europe. A keyword is “interventional” which means that something is being done to the participant. And it is this interaction between the researcher and the participant that may cause harm, burdens or benefits. 34

Respectively [Helseforskningsloven] § 22 (2) and (4); [Legemiddelutprøvingsforskriften] § 2–1.

Chapter 2

Method and Material

2.1 Legal Method In order to clarify the legal normative content of the requirement of proportionality one must apply legal method. One cannot apply other methods and expect to get legally valid answers. A public poll about the acceptable level of research risks, for example, will not answer the question about what level of risks human subjects may be lawfully be exposed to. The results from the poll may, on the other hand, be legally relevant in the interpretation of the law, and thus indirectly influence the answer. Legal method can thus be defined as the widely recognised method within legal society used to produce legally valid answers to legal questions. My approach is based on what must be said to be the applicable legal method in Europe law today, primarily based on the method applied and thus acknowledged by the European Court of Human Rights and the European Court of Justice who have the final judicial power concerning the interpretation of the normative content of Additional Protocol and the Clinical Trials Directive, respectively. It must be underscored that I aim to clarify the law as it currently stands, rather than outlining my subjective opinion on how the law ought to be. The natural starting point for a legal analysis is the ordinary meaning of the wording of a written legal instrument. Legal instruments adopted through democratic processes are the ordinary way of establishing a basis for new legal norms. But a mere literal interpretation of the wording may not be sufficient to reveal the provisions’ correct normative content. This illustrate that the wording of a written provision is only a source of law, and that the normative content of the provision may be more or less concurrent with ordinary meaning of the wording. Exceptionally, a written provision may even be interpreted contrary to the ordinary meaning of the provision, for example, because the wording is poorly crafted and contrary to other provisions as well as the provision’s purpose (raison d’être). The relativity of legal norms signifies how two rather differently formulated provisions, like Article 6 (1)

This chapter is a brief account of a more extensive account in my doctoral thesis part II.

S. Simonsen, Acceptable Risk in Biomedical Research, International Library of Ethics, Law, and the New Medicine 50, DOI 10.1007/978-94-007-2678-9_2,  C Springer Science+Business Media B.V. 2012

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2 Method and Material

of the Additional Protocol, and Article 3 (2) (a) of the Clinical Trials Directive, may be interpreted to have a congruent normative content.1 Importantly, one legal norm may also serve as a source of the other, just as general principles of law may serve as a source (means of interpretation) for specific legal norms.2 The obvious basis for the latter is the consideration for the totality and coherence of the legal framework. It may thus be essential to have a broad perspective in the interpretation of a specific provision and legal norm. Nevertheless, even though it may be difficult to ascertain the correct legal content of a norm, law is foreseeable and ascertainable, as there are recognized “sources” available from which the rules may be extracted.3 Thus, law is inescapably largely positivistic and based on empirical data (valid sources).

2.2 Material The main sources of law in this book are as already mentioned the Oviedo Convention and its Additional Protocol as well as the Clinical Trial Directive. The former are supplemented by guiding (but not binding) Explanatory Reports that are prepared by the secretariat (CDBI) of the CoE. Committees appointed by the EU have also prepared recommendations and guidelines. I found no case law directly relevant to the requirement of proportionality in these instruments. Other relevant sources are non-legal instruments like the guidelines issued by non-governmental organisations like the Council for International Organizations of Medical Science (CIOMS), and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use – the ICH GCP Guidelines of 1996. The latter has been especially influential in clinical trials with pharmaceutical products. The most important and influential professional guidelines are found in the Declaration of Helsinki adopted by the World Medical Association in 1964. The Declaration itself is not legally binding. But the principles of the Declaration are by and large restated in legal instruments internationally and nationally, and by that codified into international and national law. Since the material is not as rich as one would wish, it is relevant to draw upon what the European Court of Human Rights calls comparative material. Of particular interest in this case is US Federal law, which is rather detailed and accompanied by several authoritative publications, like the comprehensive Final Report by the

1

See Section 9.2. The dichotomy between legal principles and legal norms are not addressed here. Basically, legal norms are more concrete behavioural norms, while principles are more overarching norms, which may serve as a basis for other legal norms. The requirement of proportionality in biomedical research law is clearly first and foremost a legal norm, although it could be argued that it is also a general principle. 3 Shaw (1997, p. 55). 2

2.3

My Observational Study of Researchers and a REC

13

National Bioethics Advisory Commission from 2001. The influential US Belmont Report of 1974 should also be mentioned. As already mentioned the legal literature in Europe on the subject is sparse. The bioethical literature is on the other hand extensive. I have tried to digest most of those hundreds of publications. However, most of the literature on the subject is written in a US context by researchers and bioethicists. Their significance in a European legal perspective is limited because their analysis often does not relate to current European law. Often, the publications appear as subjective opinions on how things ought to be. As such they may occur misleading when it comes to ascertaining what the level of acceptable risk is today in Europe. On the other hand, biomedical researchers and ethicists do have first hand knowledge about practice. Moreover, the regulation in the US is similar to the European approach in most aspects, which may enhance their relevance. The scholarly work closest to my own is an unpublished doctoral thesis in philosophy by Eric Mark Meslin from 1989, titled: “Protecting human subjects from harm in medical research: A proposal for improving risk judgments by institutional review boards.” Meslin’s monograph is thoughtful and comprehensive, deserving a wider audience than it obviously has had; even now over 20 years after it was written. However, Meslin’s thesis focused on only “one half of the ‘risk-benefit’ analysis . . . [the] ‘risk judgement’”4 ; that is the estimation of risks, while this book rather focuses on the full risk-benefit analysis.

2.3 My Observational Study of Researchers and a REC Studies on research ethics committees’ (REC) indicate that the committees find the requirement vague and struggle with its application.5 However, no publication, does, to my knowledge, include a study of researchers and RECs’ discussions and assessments of risks, burdens and potential benefits of actual cases. During the project I therefore undertook a three-year semi-participating, semistructured, observational study of a REC in Norway. The observed REC handled 650 cases during the observation period. All interventional research projects during a six months period were systematically analysed (n = 47). The systematic analysis included the researchers application to the REC along with the written participant

4

Meslin (1989, p. 311). See Lenk et al. (2004); Shah et al. (2004); Klitzman (2008); In a review article, Edwards et al. (2007) found that “There were twenty-six articles reporting [. . .] discrepancies across Europe, within the United Kingdom, Spain, and United States. Of these studies, there were only five reports of some RECs approving while others rejecting the same protocol. All studies, however, reported differences in the clarifications and revisions asked of researchers regarding consent, recruitment, risks and benefits, compensation arrangements, and scientific issues”; See also Angell et al. (2008); Dal-Re et al. (2004); Liberati (2004); Van Luijn et al. (2002, 2006, 2007); The US National Bioethics Advisory Commission (2001).

5

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2 Method and Material

information, as well as structured observation of the REC’s discussion in meeting, as well as their written decision. The study clearly indicate that many researchers pay too little attention to the risk-benefit assessment, which in turn result in deficient information given to the REC as well as research participants about, especially, risks and burdens. The REC had also a lax relationship to the risk-benefit assessment. Since the risk-benefit assessment is of prime concern for the participants and their wellbeing, the study led to the conclusion that more should be done to improve the researchers and REC’s observance of the requirement of proportionality between risks, burdens and potential benefits in biomedical research.6

6

The study (co-authored with Magne Nylenna) is under publication.

Chapter 3

Initial Conceptual Clarifications

3.1 General In this chapter some central and frequently used concepts in this book are analysed. These concepts are widely used in instruments and literature, but their implied meaning seem to vary, and they therefore appear unclear. I have therefore analysed and clarified those concepts. Some of the discussed issues are further pursued later on.

3.2 The Definition of “Risk” Risk is a term used casually in many settings with varying content.1 However, there seems to be a common understanding on the essence of the term risk, and thus its ordinary meaning. The Oxford Advanced Dictionary entails information about the ordinary meaning of the word. It defines risk as the “possibility of meeting danger or suffering harm, loss, etc.”2 Risk is thus “an expression of the probability – the likelihood – that something unpleasant will happen.”3 Some guidance as to what is meant in Convention law may also be derived from Article 17 (1) of the Additional Protocol, which defines minimal risk as: For the purposes of this Protocol it is deemed that the research bears a minimal risk if, having regard to the nature and scale of the intervention, it is to be expected that it will result, at the most, in a very slight and temporary negative impact on the health of the person concerned.

Risk is here about probability (“at the most”) of “negative impact on the health of the person concerned”, and thus corresponds to the ordinary meaning. Similarly, in the EU Paediatric Guidelines of 2008, where risk is defined as:

1

See Meslin (1989, pp. 14–75), who has a more detailed (philosophical) discussion of this subject. Oxford Advanced Dictionary (1990, p. 1093). 3 BMJ Living with (Risk 1987, p. 13). 2

S. Simonsen, Acceptable Risk in Biomedical Research, International Library of Ethics, Law, and the New Medicine 50, DOI 10.1007/978-94-007-2678-9_3,  C Springer Science+Business Media B.V. 2012

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3 Initial Conceptual Clarifications potential harm (real or theoretical) or potential consequences of an action. It may be physical, psychological, or social, and may be immediate or delayed. It may vary according to age groups. Risk should be assessed in terms of probability, magnitude and duration.4

The World Medical Association’s (WMA) Medical Ethics Manual, which elaborates on the principles of the Declaration of Helsinki, defines risk as: the potential for an adverse outcome (harm) to occur. It has two components: (1) the likelihood of the occurrence of harm (from highly unlikely to very likely), and (2) the severity of the harm (from trivial to permanent severe disability or death).5

The renowned US Belmont Report of 1979 simply defines risk as the “possibility that harm occur”.6 In the US Federal law “minimal risk” is referred to as “the probability and magnitude of harm or discomfort anticipated in the research”.7 Thus, the common understanding of the term risk in this particular field is congruent with the ordinary meaning of the term, and “risk” may be defined as the probability of harm caused by research.

3.3 The Definition of “Burden” and “Inconvenience” In contrast to the Oviedo Convention Article 16 (ii) that only refers to the term “risks”, the Additional Protocol Article 6 (1) refers to “risks and burdens”. The term burden must, however, be interpreted into the Article 16 (ii) of the Oviedo Convention. Hence, the addition “and burden” in the Additional Protocol is not something entirely new, but rather a specification. The Clinical Trials Directive uses the term “inconvenience”. Nevertheless, “burdens” and “inconvenience” must be defined, and the relationship between the terms “risks” and “burdens” and “inconveniences” should be ascertained. The Oxford Advanced Dictionary explains, “burden” as “thing or person that is carried; heavy load . . . (fig) duty, obligation, responsibility, etc. that is hard to bear”. Similarly inconvenience is explained through the synonyms “trouble, difficulty or discomfort; awkward”.8 It is quite possible to construe a different meaning between “burden” and “inconvenience”; for example, that “burden” is taken to mean pain and discomfort related to the obtainment of a blood-sample, while “inconvenience” relates to showing up at the research site, absence from work, waiting, spending time etc. The difference is, however, slight. Moreover, it is dubious whether such a difference is intended. A harmonising interpretation suggests that burdens and inconveniences mean the

4

p. 17. The WMA Medical Ethics Manual (2009, p. 104). 6 The US Belmont Report 1979 Part C.2. 7 The US Federal law 45CFR46 §46.102 (i). 8 Oxford Advanced Dictionary (1990, p. 1093). 5

3.4

What Is the Relationship Between Risks and Burdens?

17

same thing. “Discomforts” should be included in the same category. The term “discomfort” is used in the Clinical Trials Directive Articles 4 (g) and 5 (f), but does not appear to have any original contribution other than a reminder that not only the traditional risk of physical harm is relevant, which is obviously also the intention behind the inclusions of “burden” and “inconvenience”. The Declaration of Helsinki also uses the term “burden” in connection with the term “risk”. Article 17 (2) of the Additional Protocol defines “minimal burdens”: It is deemed that it bears a minimal burden if it is to be expected that the discomfort will be, at the most, temporary and very slight for the person concerned.

At any rate, the ordinary meaning of burdens, inconveniences and discomfort suggests that they are, same as risks, about negative consequences, which result from a research project. Moreover, although these consequences appear to be expected, burdens are also about probabilities. Burden (and inconvenience) may thus be defined as the probability of discomfort caused by research. Burden, inconvenience and discomfort are hereinafter used interchangeably, but with a preference for the word burden.

3.4 What Is the Relationship Between Risks and Burdens? The common denominator of the two terms is that they both refer to possible negative consequence of research. Moreover, since nothing is certain in life, both terms may be said to express probabilities. But the ordinary meaning of the terms suggests that the likelihood of burdens is generally higher than that of risks. Indeed, in practice and daily life “burdens” are commonly used to describe negative consequences that participants in research must expect; for example, pain, fear, and spending time. Burdens thus represent negative consequences that researchers expect prospective participants to voluntarily “bear” and “shoulder”. Such negative effects thus represent the unavoidable burden – the inherent evil of biomedical research and research participation. Risks are, on the other hand, to a larger extent associated with unexpected negative effects; for example, the risk of severe complications in relation to giving a blood-sample. An example that may illustrate the dichotomy is the discomfort or even moderate distress arising with gastro-endoscopy, where the physician basically passes a tube down the patient’s throat and into the stomach. Such discomforts must be labelled as a burden. The likelihood of an unintended infection or serious trauma from gastro-endoscopy is on the other hand more properly labelled as a risk. Another example is the Meningococcal B Vaccine Trial.9 The trial concerned the testing of a new vaccine against meningococcal B in adolescents. The entailed discomforts of a stab wound, the likelihood of inflammation, and even fever, was apparently regarded as burdens that the participants were expected to shoulder. The 9

The Meningococcal B Vaccine Trial is accounted for in Sections 11.3. and 11.4.

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3 Initial Conceptual Clarifications

reasoning appeared to be that such negative effects are common and expected in vaccination; the probability was high, and the magnitude was low. They were in other words, common “side effects” and “adverse events”, as opposed to “serious adverse events” or “complications”. The researchers thus distinguished between common and minor side effects on the one hand, and infrequent but serious vaccine complication on the other. Risk was then taken to mean the possibility of life threatening complications (possible deadly) or complications that can cause enduring or permanent disability.10 Nevertheless, this categorisation does not correspond to the system of adverse event in the Clinical Trials Directive, where an adverse event is defined as “any untoward medical occurrence . . .”,11 and as such relates to both risks and burdens. This is unproblematic as the meanings of the words in their contexts are clear. Thus, what differentiate risks and burdens appears to be that some negative effects of research participation (characterised as burdens) are more or less expected and must be shouldered by the participants. Other negative effects (characterised as risks) are more or less unexpected. This has an interesting implication. The participant is entitled to compensation for damage caused by research.12 This is usually not the case for burdens which the participant is expected to shoulder him- or herself. A participant in a research project cannot seek compensation for the loss of some blood and the pain from a stab wound if a venepuncture and the obtainment of a blood sample was planned. Some payment up front to compensate for the expected burdens is, on the other hand, allowed in most jurisdictions. The obligation should thus be modified to compensation for unexpected but foreseeable damage caused by research13 ; risks, but not burdens. Another feature which follows from the ordinary meanings of the terms risks and burdens, is that burdens appear to be less “dangerous”, durable, and severe than risks, which refer to bodily harm, damage and injury. For example, the possibility of an unexpected loss of a leg is usually characterised as a “risk”, while wasting time, transient and momentary nausea, or other discomforts are more naturally linked to the terms burdens and inconveniences. However, even severe negative consequences may occasionally be characterised as a burden or an inconvenience. Participation in, for example, research involving transplantation or other surgical interventions, the (planned) loss of an organ or a large scar from surgery should be characterised as a burden rather than a risk, because the negative effect is expected and must be

10

The researchers risk report in the Meningococcal B Vaccine Trial, see Report on the Norwegian Meningococcal B Vaccine Trial (2007, pp. 53–62). 11 Clinical Trials Directive Article 2 (m): “‘adverse event’: any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment”. 12 See the Additional Protocol Article 31 and Chapter 17 of this book. The legal liability for damages may vary among jurisdictions. 13 On the issue of foreseeability and causation see Chapter 7.

3.5

The Definition of “Potential (Anticipated) Benefit”

19

shouldered by the participant. See also the Obesity Study14 where the participants were exposed to rather high risks, but also great burdens. The participants in a therapeutic research project had a device implanted into their stomach. Nevertheless, since burdens and inconvenience are used side by side with risks in the Additional Protocol and the Clinical Trials Directive, it is not necessarily all that important to draw a clear and definite line between the two terms. In the Research Ethics Committee I observed, the terms were used casually more or less within their ordinary meaning, but also somewhat randomly. The usage appeared unproblematic, even in a more strict legal perspective, and suggests that there is no need to draw a distinct line between the two terms. US Federal law, for example, uses the wording “harm or discomfort anticipated” when defining “minimal risk”.15 Hence, risk and burden cannot be seen as completely distinctive and separate terms. Apparently the terms represent a continuum with a gradual scale of expectedness and usually also a degree of severity as decisive features. Moreover, this distinguishes between negative effects research participants are expected to shoulder and not. This continuum between risks and burdens also implies that the concrete evaluation of the negative effect is certainly far more important than its label (semantics). However, in a more theoretical analytical perspective the terms are distinctive, and will be treated as such in the following, although some inconsistency may occur. It is primarily risks and burdens to the participant that are of interest. They are the primary risk-carriers and burdened. Occasionally, biomedical research project may also entail risks and burdens to others, such as the participant’s relatives, other patients, and the environment.16

3.5 The Definition of “Potential (Anticipated) Benefit” The Additional Protocol Article 6 speaks of “potential benefits” in the first paragraph, and “the potential to produce results of direct benefit to the health of the research participant” in the second paragraph. The Clinical Trials Directive Article 3 (2) (a) speaks of “the anticipated benefit for the individual trial subject and other present and future patients” in the first sentence, and “the anticipated therapeutic and public health benefits” in the second sentence. Leaving the normative content (consequences) aside, both provisions basically speak about the same thing: the possible positive consequences (effects) of the research project – potential (anticipated) benefits. This corresponds with the ordinary meaning of the word “benefit”, which refers to “profit; gain; future good . . . thing from which one gains or profits; advantage”.17 The term thus contrasts risk and burden, indicating the need for a weighing. 14

The Obesity Study is accounted for in Section 10.3. US Federal law 45CFR46 § 46.102 (i). 16 See Part III and Chapter 10. 17 The Oxford Advanced Dictionary (1990, p. 100). 15

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3 Initial Conceptual Clarifications

Potential benefits from research principally relate to new generalisable knowledge about sickness and health. The principal beneficiaries are thus science and future patients, society, and the researcher.18 Sometimes, some persons or group of persons may benefit indirectly or directly as indicated in the provisions, for example, if a new drug proves effective and cures their disease. The most legally important is research that also entails prospects of direct therapeutic benefits to the participant, which will be explored below. As for risks and burdens, potential benefits are about consequences that are more or less likely to occur. The Additional Protocol stresses the latter point by referring to the “potential” benefits of the research. The Clinical Trials Directive use the word “anticipated”. The ordinary meaning of the words “potential” and “anticipated” may be construed slightly differently, where the word “potential” is looser than the word “anticipated”. However, a different meaning in this context is neither feasible nor sustainable; rather they should be regarded as analogue, since the implied meaning in the instruments obviously is the same. Potential (anticipated) benefits may thus be defined as the probability of positive consequences (effects) from research. Hereinafter the wording “potential benefit” is commonly used, rather than anticipated benefits.

3.6 The Concept of “Direct Benefit” The concept of “direct benefit” is a subcategory of the broader concept “potential benefit” defined above. The concept is pivotal in the assessment of proportionality.19 Furthermore, it is linked to the concept “therapeutic research”, in so far as therapeutic research is defined as research where the research entails prospects of direct benefits to the participant. The concept “direct benefit” is used with slightly varying wording in the Oviedo Convention Article 17 (1) (“the potential to produce real and direct benefit to his or her [the participant’s] health”) and its Additional Protocol Articles 6 (2) (“the potential to produce results of direct benefit to the health of the research participant”), as well as in articles 15 and 18–20. The Clinical Trials Directive Article 3 (2) speaks of “anticipated benefit for the individual trial subject” which appears slightly broader. However, the concept of “direct benefit” is used in Paragraph 4 of the Preamble of the Directive, and is thus also recognised in Community law. It is, nevertheless apparent that the implied meaning is essentially similar in these three legal instruments. The concept is also used in US Federal law.20 Finally, the concept is widely used in legal and bioethical literature. Albeit a bit cryptic, the wording “direct benefit” is thus an established legal concept, which should have a clear content, and is hereinafter applied as such. 18

See Section 5.2 where possible interests and stakeholders are explored. See Part III. 20 See US Federal law 45 CFR 46. 19

3.6

The Concept of “Direct Benefit”

21

Thus, hereinafter the concept potential (“prospects of” or “anticipated”) “direct benefit” is taken to refer to real and expected/anticipated therapeutic benefits to the individual research participant. Its content is further investigated in the following. “Therapeutic” Benefit To be a “therapeutic” benefit, the consequence should have a positive effect on the health and well-being of the individual participant; physically or psychologically. A therapeutic benefit is thus here taken to mean the same as a health benefit. Social, financial, or other “nontherapeutic” positive effects to the participant, may therefore not be regarded as “direct benefits” in this context. At any rate, nontherapeutic benefits to the participant usually carry little weight, if any at all, in the assessment of proportionality.21 “Direct benefits” therefore usually occur in situations where the participant almost per definition is a patient, and is more or less under or in need of some sort of health care, such as diagnostic, prophylactics, medical treatment or other therapy, palliative treatment etc. However, whether the prospective participant is de facto or legally a “patient” is not necessarily decisive for whether the effect can be seen as a direct benefit or not. An example of persons that may just as well be seen as “healthy” participants, are extremely obese people. Obesity is not in itself a disease rather is it a risk factor, which means that the obesity seriously threatens the health of obese people. Even extremely obese people do not necessarily regard themselves as in need of health care or as “patients”. Nevertheless, extremely obese people seeking medical treatment may be enrolled in a research project, and such research participation may yield prospects of “direct benefits”; see the Obesity Study.22 Another illustrative example is the Meningococcal B Vaccine Trial,23 where the aim was to develop a vaccine against meningococcal B bacteria. Participants were given active vaccine to test dosage and safety, and apparently no one even suggested that the potential benefits to the participants should be classified as “direct benefits” for those who got the active vaccine. The reason was apparently that the effectiveness of the vaccine was uncertain, and the participating adolescents were not seen as “patients in need of health care” but rather as “healthy volunteers”, albeit at risk of getting the disease. The correctness of that position is not obvious, especially after phase II of the trial. After phase II the researchers seem to have had reasons to believe that the vaccine was relatively safe and efficient. Moreover, the prospective participants (the adolescents) were at high risk of acquiring meningococcal B because of the ongoing deadly epidemic; they were in other words in the target group and in need of a vaccine. Indeed, it was the public, the adolescents and their parents, who had requested a vaccine against the frightening epidemic. Thus, based on the results from phase I and II, those who received active vaccine could have reasonable prospects of protection (immunisation), and thus “direct benefits”. Such recognition

21

See Part III. Accounted for in Section 10.3. 23 Accounted for in Sections 11.3 and 11.4. 22

22

3 Initial Conceptual Clarifications

would probably have influenced the accuracy of the assessment of proportionality in that case. Thus, even “healthy volunteers” may occasionally have prospects of “direct benefits.” “Real and Direct” Therapeutic Benefit To be “real”, both the likelihood and magnitude of the health benefit must be of some significance. Insignificant or unlikely therapeutic benefits to the participant can therefore not be seen as “direct benefits” in this context. Likewise, Salla Lötjönen, who applies the antonym “unreal” benefits, which she describes as “minimal, theoretical, or imaginary, such as the patient’s own assumption of superior treatment (for example, the placebo effect) or the benefit of a better monitoring of the patient’s condition.”24 To be “real”, the positive effects to the participant should therefore be foreseeable and anticipated. Moreover, they should be planned for and reasonably expectable. Unanticipated benefits are not planned for, although they may occur.25 Such potential benefits are incidental and not “direct”. Typical insignificant therapeutic benefits to the participant are the positive feeling of gratitude as a result of contributing in research, as well as the enhanced positive attention from health personnel and others. For some participants such positive feelings can be important, but in the assessment of proportionality they carry little weight, if any at all. They are certainly not “real and direct benefits”. The US National Bioethics Advisory Commission also took this view in its final report, and the Commission refers to them as indirect benefits.26 Typical unlikely therapeutic benefits are the chance of significant findings from a health check. Occasionally, some researchers advertise that the participants should participate in interventional research projects because they will get a free health check, and that such a check may reveal curable conditions at an early stage, for example, high blood pressure (hypertension) or even cancer. It could be of great importance for the individual if a dangerous tumour was detected at an early stage. Nevertheless, the chance of that happening is usually so remote, that such potential therapeutic benefits generally carry little weight, if any at all. The benefit cannot be expected, and can therefore not be classified as “real and direct”. The same can be said about participants randomised to a control or placebo group. They can usually not expect any direct benefits, even though some participant may respond positively (get better health) because of the placebo effect. Those in the placebo group are, on the other hand, usually not exposed to the same level of risks. In explaining “direct” Salla Lötjönen applies the antonym “indirect”. Lötjönen assert that “indirect benefit” refers to “group benefit rather than benefit directed towards the individual him or herself”, such as enhanced general knowledge about

24

Lötjönen (2002, p. 186). The US National Bioethics Advisory Commission (2001, p. 73). 26 The US National Bioethics Advisory Commission (2001, pp. 73–74). 25

3.7

“Therapeutic Research” and “Nontherapeutic Research”

23

the disease, condition, and so on.27 The explanation is reasonable. It is, however, problematic as the Clinical Trials Directives uses “direct benefit” about group benefits in Article 4 (e), in which it probably refers to “directly usable” knowledge. At any rate, “direct benefit” is in the following only used as defined above in relation to individual research participants to avoid confusion. The term “indirect” benefits will not be used.

3.7 “Therapeutic Research” and “Nontherapeutic Research” The two concepts are not used directly in Convention law or Community law, but they are referred to in the Explanatory report to the Additional Protocol. The meaning of the concepts and their implications are however unclear and highly controversial, albeit most commentators seem to agree about the core content. “Therapeutic research” refers hereinafter to interventional biomedical research on human subjects, where the participant may have reasonable prospects of real and direct therapeutic benefits; see the definition of “direct benefit” above. If the research is not “therapeutic”, it is “nontherapeutic”. The two concepts are thus mutually exclusive. A research project may be characterised as “therapeutic” even though the risks and burdens to the participant are not fully outweighed by the prospects of direct benefit to the participant.28 On the other hand, if research is combined with medical care, one may have to distinguish between the ordinary health care intervention and the research intervention. If the prospects of direct therapeutic benefits to the participant are only related to the ordinary health care intervention, the research is not “therapeutic”.29 Fundamentally, even though the research project entails prospects of direct therapeutic benefits to the participant, the primary and principal objective of the activity is research and the production of new knowledge. Thus, therapeutic research does by no means equal ordinary health care, although it might be similar and even difficult to tell the difference, especially for the participants and the patients.30 “Nontherapeutic research” refers hereinafter to interventional biomedical research on human subjects, where the participants may not have reasonable prospects of real and direct therapeutic benefits. Even though the participant may have prospects of indirect benefits and insignificant or unlikely health benefits, the research is still “nontherapeutic”.31 A research project often consists of several independent components and research interventions (procedures). Arguably one component (research intervention) could 27

Lötjönen (2002, p. 186). These issues are further pursued in other parts of this book. 29 These issues are further pursued in Part II of this book on causality and relevancy. 30 See Chapter 5 of this book. 31 See Section 3.6 on the concept of “direct benefit”. 28

24

3 Initial Conceptual Clarifications

be labelled therapeutic, while another may be labelled nontherapeutic.32 However, it is very difficult and not feasible to maintain entirely such a fine masked systematic argument under the current legal framework, even though it may be helpful, and even necessary, for some research projects.33

3.8 “Vulnerable Person” “Vulnerable person” is a traditional and frequently used concept in the legal and bioethical literature. The concept is used in the Preamble of the Additional Protocol: “Affirming that particular protection shall be given to human beings who may be vulnerable in the context of research.”34 Similarly in the Preamble of the Clinical Trials Directive (Paragraph 3): “Children represent a vulnerable population with developmental, physiological and psychological differences from adults. . .” The history of biomedical research shows that vulnerable persons have been especially prone to exploitation and exposed to disproportionate risks and burdens, even where the vulnerable person’s interests have been safeguarded by the person’s proxy.35 Vulnerable persons are in both the Additional Protocol and the Clinical Trials Directive subject to additional safeguards. Such safeguards significantly limit the level of risks and burdens that they may be exposed to, especially for the sake of others. It is, however, not really clear who should be regarded as a vulnerable person. Since vulnerability is so important in the assessment of proportionality, the question about who is “vulnerable” must be clarified rather detailed.36 It can be argued that most, if not all, participants in biomedical research are vulnerable. It may be only the principal researcher him- or herself who really has the insight to make a truly informed and voluntary choice. Nevertheless, the concept of “vulnerable” is only used about some research participants, who are subject to the additional safeguards. The Explanatory Report to the Additional Protocol states: It can be said that all human beings enrolled in research are vulnerable to harm, since research, by definition, involves uncertainty and the utilisation of human beings in order to further the goal of gathering knowledge. However, some human beings may be more vulnerable than others to the risk of being treated unethically in the context of biomedical research. This can be true even in the case of participants who have given their informed consent to taking part in the research project.37

32

See The US National Bioethics Advisory Commission (2001, pp. 76–80) who, in my opinion, unsuccessfully pursues this approach. 33 See Section 14.5. 34 See also Article 12 of the Additional Protocol, which also uses the concept. 35 See Chapter 4. 36 The implications of vulnerability in the assessment of proportionality are investigated in Chapter 12. 37 Paragraph 68; See the US National Bioethics Advisory Commission (2001, p. 85) which appear to be the origin of the statement in the Explanatory Report.

3.8

“Vulnerable Person”

25

Hereinafter the term “vulnerable person”, “vulnerable participant”, or, simply, “vulnerable” is taken to refer to a person who has reduced ability to protect his or her interests. Therefore he or she is particularly at risk of being exploited. He or she is therefore generally in need of, and entitled to, special protection. In the following I will further outline who may be regarded as vulnerable in accordance with the Additional Protocol and the Clinical Trials Directive. Both the Additional Protocol and the Clinical Trials Directive recognise unequivocally that persons not able to consent should be regarded as vulnerable persons.38 That includes both children and adult persons not able to consent. The Additional Protocol also recognises in articles 18 and 20 that pregnant and breastfeeding women and persons deprived of liberty are generally vulnerable. Pregnant and breastfeeding women are regarded as vulnerable even though they can give a legally valid consent. The probable main reason for classifying pregnant women and breastfeeding women as “vulnerable” is the aim of safeguarding the embryo and the foetus, and the breastfeeding child. Unborn children as well as infants are, in a medical perspective, especially vulnerable to, for example, adverse effects of pharmaceutical drugs. In this respect, the notorious Thalidomide tragedy, which resulted in approximately 10 000 children being born with severe malformations in the 1960s, is the likely triggering episode for this provision.39 Pregnant and breastfeeding may also be vulnerable for others reasons, like postnatal depression, dependency, and other situational vulnerabilities etc. Persons deprived of liberty include prisoners, involuntarily committed patients etc. The apparent reason why they are regarded as vulnerable is that such persons “are in a position of constant dependence on those who provide them with food, health care and the other amenities of life.”40 They may therefore “consent” to research that entail risks and burdens, which they would not have otherwise consented to. The wording “deprived of liberty” in the Additional Protocol Article 20 equals the same expression in Article 5 of the European Convention on Human Rights, which set up the criteria for lawful deprivation of liberty.41 Article 20 of the Protocol is, however, applicable regardless of the lawfulness of their detention.42 According to the Explanatory Report the wording “deprived of liberty” was thus meant to be interpreted in accordance with the European Court of Human Rights’ interpretation of the Article 5 of the European Convention on Human Rights.43

38 See Article 15 of the Additional Protocol and Articles 4 and 5 of the Clinical Trials Directive, see Part VII; this was also the conclusion reached by Anne Gammelgaard and colleagues in their investigations of the consent process involving acute patients with a serious disease (Gammelgaard 2003). 39 See Section 8.4. 40 Explanatory Report Paragraph 110. 41 Explanatory Report Paragraph 110. 42 Explanatory Report Paragraph 111. 43 Explanatory Report Paragraph 111.

26

3 Initial Conceptual Clarifications

In addition, other groups are commonly recognised as vulnerable. The ICH GCP section 1.61 include a definition of “vulnerable subjects” as well as several examples: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.44

Since not all these groups are explicitly mentioned, neither in the Additional Protocol nor in the Clinical Trials Directive, one may ask whether it implies that they are not vulnerable and subject to additional safeguards and stricter standards. The answer is obviously negative. As apparent in the Explanatory Report, vulnerability is a matter of degree and not group belonging.45 An individual approach is therefore required. In relation to Article 12 of the Additional Protocol, concerning “undue influence”, the Explanatory Report maintains that vulnerability may be due to a number of factors or indicators such as “cognitive, situational, institutional, deferential, medical, economic, and social factors.”46 These indicators originate from the final report from the US National Bioethics Advisory Commission in 2001, which again builds on a paper to the Commission by Kenneth Kipnis.47 This suggests a broad international consensus on this issue. Based on the Explanatory Report and the US report, indicators of vulnerability may be: • Cognitive and/or communicative vulnerability: Persons with cognitive vulnerability may, according to the Explanatory Report, “not have the capacity to come to an informed decision on whether to give consent or not. Such persons might be minors or persons suffering from dementia.” Reduced cognitive ability is the classic indicator of vulnerability, and especially reduced communicative skills and competence, such as the lack of legal capacity to give valid consent. Hence, persons not able to consent are, as already mentioned, always regarded as vulnerable, even though they might have a legal representative attending their interests. • Situational vulnerabilities: Another form of communicative vulnerability is situational or contextual vulnerability. Persons with situational vulnerability may, according to the Explanatory Report “have the capacity to make a decision, but are deprived of their ability to exercise their capacity by the situation at

44

ICH GCP section 1.61. Paragraphs 65–69. 46 Paragraph 69. 47 The US National Bioethics Advisory Commission (2001, pp. 85 et seq.); Kipnis (2001). 45

3.8

“Vulnerable Person”

27

hand.”48 A clinical emergency and lack of fluency in the language being used are mentioned as examples. Sickness may also imply such a situational vulnerability. • Institutional vulnerability: Situational vulnerability can be increased by institutional vulnerability. Institutional vulnerability refers to persons who “find themselves subject to the authority of persons or bodies who could have their own, and possibly conflicting, interests in relation to a research project.”49 Prisoners, hospitalised patients, students, soldiers, nurses, or other uniformed services, are typical examples. Such persons can also be seen as “dependent” (see below). Institutional vulnerability, thus, increases the inequality of power between the participant and the researcher, in so far that it threatens the voluntariness of the consent. Dependent persons may “voluntarily” take upon higher risks and burdens than he or she would have if he or she was not dependent. Paradoxically, “dependent” populations have often been included in biomedical research. The likely reason is that such persons were readily available, usually at one site, easy to control, and likely to consent. Some of the worst examples of disproportionate and unethical biomedical research have involved dependent populations.50 • Deferential vulnerability: In contrast to institutional vulnerability, deferential vulnerability is characterised by “informal, rather than formal, hierarchies.”51 The deference and dependence are thus more subjective, and relate to social frameworks, like family opinions or that a patient feels obliged to fulfil the wishes (perceived or real) of his or her physician. The relationship between patients and health personnel is highly challenging in a research context, as it may render the patient “vulnerable”. Since deferential vulnerability is linked to informal hierarchies, it is more subtle and difficult to ascertain. It is, however, well acknowledged, and many physicians would concur with Henry Beecher’s statement that he could talk his patients into almost anything.52 Importantly, this indicator implies that hospitalised patients often should be regarded as vulnerable. • Medical Vulnerability: Medical vulnerability is also mentioned as a factor in its own right. Medical Vulnerability “affects those suffering from ailments for which there is no satisfactory standard treatment.”53 Such patients can be especially vulnerable to flawed expectations (therapeutic misconception), such as promises of miracle cures. They might overrate direct therapeutic benefits, and underrate risks and burdens.

48

Explanatory Report, Paragraph 69. Explanatory Report, Paragraph 69. 50 See Chapter 4 and, for example, the US Advisory Committee on Human Radiation Experiments (1995); Ruyter (1997). 51 Explanatory Report, Paragraph 69. 52 Beecher (1966). 53 Explanatory Report, Paragraph 69. 49

28

3 Initial Conceptual Clarifications

• Economic vulnerability: Economic vulnerability is linked to the controversial and (ethically and legally) unsettled issue of payment of participants.54 Economic vulnerability refers to “those with the cognitive ability to consent to participation but who might easily be induced to take part in research in order to obtain a financial gain or in order not to lose access to some benefits, even if they would not otherwise participate in the research.”55 Economic vulnerability may also lead to participants agreeing to risks and burdens they would otherwise not have accepted.56 • Social vulnerability: In a human rights perspective, social vulnerability is especially delicate, because it is linked to the fundamental principle of nondiscrimination and the exploitation of disadvantaged individuals. Social vulnerability may be a result of background, ethnicity, societal class (poverty), lack of education, geographical or linguistic belonging etc. Such persons have often been historically discriminated against and exploited, among others, in biomedical research. It is underscored in the Explanatory Report that “membership of these groups can be overlapping.”57 This also implies the obvious, that some persons can be more vulnerable than others, for example, because there are multiple indications of vulnerability, or a particularly strong indicator of vulnerability. Although the legal framework is rather coarse, the individual degree of vulnerability is surely relevant in the final and overall assessment of proportionality, rendering the assessment more accurate; the more vulnerable, the stricter the researcher’s duty of care.58 The notion of multiple indicators of vulnerability is supported by several empirical studies, investigations, and commentaries. These observations are not new. The US Advisory Committee on Human Radiation Experiment, for example, refers to an interview with a physician who gave a frank explanation why poor patients seem to have been perceived as particularly appropriate subjects for biomedical research by some physicians in the 1950s and 1960s: “We were taking care of them, and felt we had a right to get some return from them, since it wouldn’t be in professional 54 The issue is not pursued here, because it refers more to the requirement of a “free” consent. In Norway, research ethics committees have a strict practice, while the practice appears to be more liberal in the UK. Nevertheless, payment cannot be considered a relevant benefit in the assessment of proportionality. 55 Explanatory Report, Paragraph 69. 56 In Paragraph 70 of the Explanatory Report examples of undue influence are offered, such as “veiled threats to deny access to services to which the person would otherwise be entitled, the insinuation of looking favourably on academic work to be submitted in the future, veiled threats of punishment that the person would otherwise receive or that refusal will diminish the likelihood of career advancement, or the offer of amounts of money large enough to influence the giving or denial of consent.” 57 Paragraph 70. 58 See Section 5.3 concerning researchers’ duty of care and Part III concerning the assessment of proportionality, and the implications of vulnerability in Chapter 12.

3.8

“Vulnerable Person”

29

fees and since our taxes were paying their hospital bills.”59 Another researcher, Dr. Thomas Chalmers, offered in the same report the following explanation why sick patients should be regarded as the most vulnerable research participants, even more vulnerable than prisoners: One of the real ludicrous aspects of talking about a prisoner being a captive, and therefore needing more protection than others, is, there’s nobody more captive than a sick patient. You’ve got pain. You feel awful. You’ve got this one person who’s going to help you. You do anything he says. You’re a captive. You can’t, especially if you’re sick and dying, discharge the doctor and get another one without a great deal of trauma and possible loss of lifesaving measures.60

This led the US Advisory Committee on Human Radiation Experiment to conclude: Thus, as compared with prisoners, who are now generally viewed to be vulnerable to coercion, those who are sick may be even more compromised in their ability to withstand subtle pressure to be research subjects. Appropriate protection for the sick who might be candidates for medical research has proved to be an especially troublesome issue in the era following Nuremberg.61

Hence, it seems right to assume that many sick patients, especially if combined with other factors, like low education, social vulnerability, hospitalisation, dependency etc. can be just as vulnerable (and needy of additional protection) as persons not able to consent to research (who have their interests guarded by their legal representatives (proxy)), and pregnant women and prisoners, who also are explicitly recognised as “vulnerable” in the instruments.62 It is at least safe to say that a person may be vulnerable for several reasons. It would be unreasonable, and therefore unsustainable, to offer additional legal safeguards to one vulnerable group with certain characteristics (for example to pregnant women and those not able to consent), while offering weaker protection persons just as, or even more, vulnerable. The important implication of this is that the identification of a few vulnerable groups in the Additional Protocol and the Clinical Trials Directive cannot be regarded as exhaustive, but only as examples. The interpretation is also compatible with the instruments read in context. The better view is that the examples serve as benchmarks as to which additional protection persons with similar vulnerabilities should be offered. Others with similar vulnerabilities should therefore be offered similar additional safeguards. Thus, vulnerability is then a matter of degree, rather than a matter of group belonging for those persons who are not included in explicitly mentioned groups. Hereinafter I therefore often speak of “persons not able to consent and similarly vulnerable persons” or simply “vulnerable persons”, when I refer to vulnerable research participants who are entitled to similar additional safeguards as those who are not able to consent.

59

The US Advisory Committee on Human Radiation Experiment, Final Report, Chapter 2. The US Advisory Committee on Human Radiation Experiment, Final Report, Chapter 2. 61 The US Advisory Committee on Human Radiation Experiment, Final Report, Chapter 2. 62 But not all patients are “vulnerable persons”. Neither are all patients necessarily less able to protect their own interests and carry risks for the sake of others than “healthy volunteers”, see above. 60

Chapter 4

Origins of the Requirement of Proportionality

4.1 General The requirement of proportionality addresses a weighing of interests and the dilemma between doing good, whilst doing no harm; between promoting the greater good to the detriment of the unfortunate few. This is certainly not a new dilemma or a dilemma confined to biomedical research. The requirement of proportionality can easily be traced back hundreds of years. The objective of this part of the thesis is to outline the origin and the development of the requirement of proportionality between risks, burdens, and potential benefits in biomedical research law. Where did it come from? How did it develop, and why?

4.2 Early Development The first occurrence of a requirement of proportionality in jurisprudence, that I am aware of, stem from Francisco Vitoria (1480–1546), Francisco Suarez (1548–1617), and Hugo Grotius (1583–1645). In their attempts to clarify the second condition of “a just cause” for waging war, they held that only sufficiently weighty and legitimate causes that were in proportion with potential damages of war, could amount to a just cause.1 It is likely that this line of reasoning influenced and was present in other fields facing similar dilemmas between doing good, whilst doing no harm. The requirement of proportionality in the field of laws of war is today well established and thoroughly investigated in legal scholarly.2 The first traces of a need for a weighing of potential benefits against risks and burdens in biomedical research can be found in discussion round the very first scientific

This chapter is an account of a more extensive account in my doctoral thesis. Wicker (2006); Arend and Beck (1993). 2 See for example Gardam (2004); Wicker (2006); Dinstein (2001). 1

S. Simonsen, Acceptable Risk in Biomedical Research, International Library of Ethics, Law, and the New Medicine 50, DOI 10.1007/978-94-007-2678-9_4,  C Springer Science+Business Media B.V. 2012

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4

Origins of the Requirement of Proportionality

clinical trials that took place in the Age of Enlightenment (c. 1690–1800). The trials concerned the testing and use of immunising agents (inoculation and vaccines).3 Sidney A. Halpern gives in her book, Lesser harm, a thorough account of these trials and the ethical question they gave rise to.4 The question was whether to expose people to the risk of harm of inoculation (and later vaccination), or to expose people to the risk of harm of epidemic and deadly diseases, such as small pox. Codes of conduct written by Thomas Percival (1740–1804), William Beaumont (1785–1853) and Claude Bernard (1813–1878) did not include a requirement of proportionality, although their warning against doing harm to the patient might seem to resemble a notion of prohibition against disproportionate (harmful and extensively risky) human experiments. The legal cases concerning the famous biomedical researchers Gerhard Henrik Armauer Hansen (1841–1912) of Norway, and Albert Ludwig Sigesmund Neisser (1855–1916) of Germany, illustrates that the lack of specific written legislation did not necessarily mean that no regulations were applicable to human experimentation in the eighteenth and nineteenth century.5 Surely, researchers could not lawfully expose individuals to excessive risks and harms.6 Applicable regulations were derivable from general criminal law, and probably also tort law concerning researcher physicians’ duty of care. In 1900 the US Congress debated legislation aimed at controlling human experimentation in the District of Colombia. Such legislation was adopted in Pennsylvania in 1913 because of media disclosure of experiments on hospitalised patients and institutionalised children.7 Thus although rules existed they were not always observed, and several accounts of concrete examples of unethical and illegal medical experimentation in the US and Europe exists.8 The Neisser Case led in Germany to the adoption of the so-called Prussian Directive in 1900.9 The Directive prohibited nontherapeutic research if “the human subject was a minor or not competent for other reasons” or if the subject had not given his or her “unambiguous consent” after a “proper explanation of the possible negative consequences” of the intervention. Although the Directive addressed the level of acceptable risks, it apparently did not contain an express version of a requirement of proportionality.

3 Although the testing and usage of vaccines was not necessarily properly designed as research studies by today’s scientific standards, the testing was certainly experimental, and, moreover, the discussions were similar to discussions on the justification of clinical trials today. 4 Halpern (2004). The account given in the following builds on Halperns more detailed account. 5 Armauer Hansen was the discoverer of the leprosy basillus, and Neisser was the discoverer of the gonococcus bacillus. See respectively Vogelsang (1968) and Blom (1973); Vollman and Winau (1996). 6 Halpern (2004). 7 Halpern (2004, p. 33). 8 Abrams in Spitz (2005, pp. xvi–xvii); See also Moreno (2001, pp. 308–309); Vollman and Winau (1996). 9 Vollman and Winau (1996).

4.3

The Nuremberg Doctors Trial and the Nuremberg Code

33

Ironically, the Reich Government in Germany issued in 1931 the first legal instrument in Europe specifically addressing biomedical research. The background was unveiling unethical human experimentation in the press, and unrest in the parliament. The instrument was called “Guidelines for new therapy and human experimentation” and set out what appear to have been legally binding rules. The Guidelines included a requirement of informed consent or proxy consent. Preanimal testing was also obligatory. According to Vollman and Winau the Guidelines also required a careful risk-benefit assessment. Hence the Guidelines recognised what appear to have been a requirement of proportionality between potential benefits and risks.

4.3 The Nuremberg Doctors Trial and the Nuremberg Code In the aftermath of World War II the victorious states sought to bring justice by setting up an ad hoc military tribunal in Nuremberg in Germany. One such case concerned 20 physicians and three other leading Nazi officials in the medical services of the Third Reich – “the Nuremberg Doctors Trial”.10 The 23 persons merely represented the tip of the iceberg of health personnel and researchers who had planned and commenced the experiments. Thus the purpose of the trial was to set an example. The trial took place between 9 December 1946 and 20 August 1947. The defendants were charged with war crimes and crimes against humanity.11 The permissibility and legality of medical experiments had preoccupied the whole trial and was argued in length.12 The Court could not hold the defendants accountable for transgressions of the law as it ought to have been. That would have been contradictory to general principles of criminal law prohibiting retroactive effects of new penal provisions. The Court would then act beyond powers, which could have undermined the legitimacy of the Court and the very purpose of the Nuremberg trials. Thus, the Prosecution had to establish that legal penal norms had existed during the war, and prove that the defendants had violated them. In the task of clarifying the law, the Court heard several medical expert witnesses testify to accepted scientific practices and professional norms for the commencement of biomedical research. Two central experts were Leo Alexander (1905–1985) and Andrew Ivy (1893–1978). They listed ethical principles, which they claimed that US physician researchers endorsed, and even more so, observed. Their testimony do, however, appear to have been exaggerated, in so far that the existence of such professional norms and the ethical practice was questionable.13 Nevertheless,

10

The Nuremberg Military Tribunal’s decision in the case of the United States v. Karl Brandt et al. of 19th of August 1947. The Control Council Law No. 10 was adopted by the allied forces. 11 Count two and three of the Charge. Count One was related to the Common Design or Conspiracy, Count Four to Membership in a Criminal Organization (the SS). 12 See Grodin (1995). 13 Bernard (1996).

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Origins of the Requirement of Proportionality

the Court also consulted the Reich Guidelines from 1931. The Court also applied more general sources of law, especially general criminal law, which the judges assumingly were experts of. The Court listed its primary sources of law, and thus the basis of the Nuremberg Code, in the judgment. Apparently, the Court relied most heavily on basic and general penal provisions recognised by most countries, which were tantamount to an “international” consensus.14 Thus, based on a wide range of available, relevant, and valid sources of law, the Court obviously meant that there existed a legal framework during World War II applicable on human experimentation, which the defendants could be held accountable for violating in a court of law without compromising fundamental legal principles of due process. In this regard the Court stated: The great weight of the evidence before us is to the effect that certain types of medical experiments on human beings, when kept within reasonably well-defined bounds, conform to the ethics of the medical profession generally. The protagonists of the practice of human experimentation justify their views on the basis that such experiments yield results for the good of society that are unprocurable by other methods or means of study. All agree, however, that certain basic principles must be observed in order to satisfy moral, ethical and legal concepts.

Those ten “basic principles” were later called the “the Nuremberg Code”. The Court set out the requirement of consent as the first and foremost principle. It further recognised that human experimentation is an hazardous activity which should not be undertaken unless there are compelling reasons to do so, and comparable results is not obtainable by other less burdensome or risky means (principle 2 and 3). The fourth principle contained a variant of the requirement of minimising risks and burdens to the research subjects. The fifth principle encompassed a distinguishable boundary for the level of acceptable risks and burdens regardless of any consent. It is thus clear that the Court recognised that although valid consent was a necessary precondition, it was not a sufficient precondition.15 The sixth principle contained a version of a requirement of proportionality: “The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.” The sixth principle presupposes a weighing of risks to the participants against the potential benefits to others. This supports the argument that an unwritten legal requirement of proportionality in biomedical research existed at this time. The 7th and 8th principle can be seen as supplementing the requirement of proportionality. Principles number 9 and 10 addresses the issue of new developments and risk management. The principles partly overlap and supplement each other. But it is noteworthy that although the first principle concerned consent, most principles concerned various sides and elements of a requirement of proportionality and researchers duty of care; understood as the level of acceptable risks and burdens to the participant. This point has been underemphasised in other historical accounts on the Nuremberg Code, which have primarily focused on the requirement 14 See the Statues of the International Court of Justice, Article 38 litra c where “the general principles of law recognized by civilized nations” is listed as a primary source of international law today. 15 See Section 5.3 on the fragility of the consent.

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Plausible Explanations for Disproportionate Research in the Early . . .

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of consent. Nevertheless, neither the requirement of consent nor the requirement of proportionality can be said to represent something new or being an invention of the Court. Both requirements existed at that time. The Court merely clarified that. The Court then found that the experiments themselves were manifest and flagrant breaches of the moral, ethical and legal framework. The experiments were so heinous and disproportionate that there were no reasons to undertake a more careful weighing of risks against potential benefits. The Court simply demonstrated that the potential benefits were often low or non-existent, while the risks and burdens were excessive, unacceptable and unlawful by any standard. The Court subsequently found 18 out of 23 were guilty. Seven were sentenced to death by hanging. The others faced imprisonment from ten years to life. The Nuremberg Doctors trial in 1946–1947 was an indisputable milestone event with regard to the regulation of biomedical research involving human subjects in an international perspective.16 The judgment includes the first explicit and written set of international principles in this field of legal character, and may also be seen as an authoritative statement on applicable and universal international law and ethics in this field at that time. It is however important to underscore that the enlisted ten principles are not as such a code or a legal instrument in itself; it is merely part of the premises of a judgement by an ad hoc American Military Tribunal. Nevertheless, it may be more accurate to regard the Nuremberg Code as an event of consolidation, rather than a paradigm shift, since the judgment does not represent a dramatic change of course in regulation of biomedical research. At any rate, the Code has had tremendous influential effects on subsequent regulations of biomedical research. The basic principles of the Code, like the requirement of consent and proportionality, have not changed significantly and are pursued in all other instruments in force today. Apparently the Nuremberg Code did not significantly influence the conduct of scientists. The common conception in scientific circles appears to have been that the Nazi-experiments where performed by crazy barbarians, and that the Nuremberg Code “was a good code for barbarians but an unnecessary code for ordinary physicians.”17

4.4 Plausible Explanations for Disproportionate Research in the Early Twentieth Century As shown in Section 4.2, the problem was not lack of rules, but some researchers lack of respect for the rules, including common morality. One plausible reason for the neglect might have been enthusiasm and high believes in the potential benefits of the new science, and a likewise neglect for the risks and burdens to the research subjects. 16

See, for example, Shuster (1998) and Annas and Grodin (1995). Katz J, cited in the US Advisory Committee on Human Radiation Experiments, Final Report (1995, chapter 2); Rothman (2003, pp. 62–63). 17

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Another striking and disturbing pattern is that it was usually, if not always, vulnerable persons that were abused, such as ethnic minorities, indigenous people, orphans, hospitalised poor patients, institutionalised persons, prisoners and soldiers. This may explain today’s strict regulations concerning biomedical research on vulnerable persons.18 Vulnerable persons were probably readily available, usually at one site, easy to control and likely to “consent”. Presumably they also lacked resources to pursue wrongful acts. Moreover, due to their dependency, they were not only vulnerable, but they also were indebted to the society at large. A common justification by researchers was that these people actually could contribute to, and not only sponges on, the society by participating in research. Those persons were deliberately or not regarded as of lower value than the ordinary citizen and a suitable mean in science. Hence, the ends could more easily justify the risks and burdens to these people. This may also explain why so few reacted to the practice, especially among the peers. The concept that some individuals could be used as mere means in the pursuit of the greater good is what has in other contexts been called the banality of evil.19 That is: in the eyes of the perpetrator the act was not evil: The end justified the means, as the means – the value of the research subjects – were so low. In such a perspective some “low-lives” could be used as guinea pigs for the greater good. In the Nazi-camps, the value of some subjects was obviously close to nothing.

4.5 The Further Development of the Requirement of Proportionality 4.5.1 The Influence of Human Rights Law The flourishing of research ethics, research law and human rights in the aftermath of World War II, especially the Nuremberg Code, must, in my opinion, be understood as an unequivocal reaction to the gross disregard of human dignity which was totally out of proportion by any standards. There is thus a clear and fundamental link between the atrocities revealed during World War II, the Nuremberg Trials and the founding of the United Nations (UN) in 1945 with the promotion of human rights as one of its purposes.20 There is also a fundamental link between the development of international human rights law in the second half of the twenty first century, and the development of international biomedical research law.21 18

See Chapter 12 and the Additional Protocol Article 15 and the Clinical Trials Directive Articles 4 and 5. 19 Annas and Grodin (1995). 20 Steiner and Alston (2000). 21 See also Simonsen (2011) and Section 5.2 where the current relationship is explored.

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That the adoption of human rights law fundamentally influenced the development of the regulation of biomedical research is evident in later instruments in that field. Indeed, the Additional Protocol is intended to: build on the principles embodied in the [European Convention on Human Rights], with a view to protecting human rights and dignity in the specific field of biomedical research. Its purpose is to define and safeguard fundamental rights in biomedical research, in particular of those participating in research.22

It is also noted in the Preamble of the European Union’s Clinical Trials Directive of 2001 that: The accepted basis for the conduct of clinical trials in humans is founded in the protection of human rights and the dignity of the human being with regard to the application of biology and medicine, as for instance reflected in the 1996 version of the Helsinki Declaration. The clinical trial subject’s protection is safeguarded through risk assessment. . .23

This shows that the human rights law and reasoning has not only influenced current biomedical research law. Current biomedical research law must be regarded a special branch of international human rights law, which specifies and make operational research participants fundamental freedoms and human rights in that particular field.

4.5.2 The Declaration of Helsinki and Other Professional Guidelines In 1947 the World Medical Association (WMA) was founded. The foundation was a response to the revealed abuses of members of the profession, and with that a pressing need for international professional standards.24 In September 1948 a “dedication by the physician to his profession of medicine” was adopted by the WMA in Geneva. This dedication is renowned as the Declaration of Geneva, a modern restatement of the Hippocratic oath. In 1954 the WMA General Assembly adopted the International Code of Medical Ethics, still functioning as the most prominent professional standards in the field of ordinary medical clinical practice. It was not until 1953 that the WMA began to consider the need for professional guidelines with regard to research. One reason for the regulatory initiatives was the need for a set of professional guidelines that could reach and influence the researchers to a greater extent than the Nuremberg obviously did. In the apparent opinion of the WMA there was a need for guidelines designed by physicians for physicians, as opposed to the Nuremberg Code, which was drafted by lawyers. The medical professions’ scepticism towards “external” governmental regulations is viable even today. Another reason for initiating self-regulations was that the 22

Paragraph 1 of the Explanatory Report. Clinical Trials Directive, Preamble, Paragraph 2. 24 See first issue of the WMA Bulletin at www.wma.net. 23

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Nuremberg Code was regarded as an imperfect instrument written under special circumstances with a special and concrete research environment in mind. In 1961 a code of conduct for research was drafted, and it was adopted at the 18th General Assembly in Helsinki, Finland, in 1964 – “The Declaration of Helsinki”. The Declaration of Helsinki was revised and amended in 1975, 1983, 1989, 1996, 2000, and, most recently, in 2008. The principle of proportionality has had prominent positions in the Declaration since the beginning, although the wording has been altered several times. The third basic principle of the original version of 1964, state: Clinical research cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject.

The principle is repeated relatively unchanged in the versions of 1975, 1983, 1989 and 1996 (basic principle no. 4). In 2000 the wording was altered. Today’s version (2008) reads in Paragraph 20: Medical research involving human subjects may only be conducted if the importance of the objective outweighs the inherent risks and burdens to the research subjects.

The word “proportion” has been replaced, and the word “burden” has been added. The core content and intention of the original principle are, however, clearly retained. That it is a requirement of proportionality is beyond doubt. The WMA Medical Ethics Manual states: Once the scientific merit and social worth of the project have been established, it is necessary for the researcher to demonstrate that the risks to the research subjects are not unreasonable or disproportionate to the expected benefits of the research, which may not even go to the research subjects.25

Clarence Blomquist was a psychiatrist and professor of medical ethics. After participating in the drafting of the Declaration of Helsinki, he also drafted the first international code of ethics for psychiatry, the Declaration of Hawaii. The World Psychiatrist Association (WPA) adopted the Declaration of Hawaii in 1977. Paragraph 9 concerned clinical research and entailed a version of the requirement of proportionality: In clinical research, as in therapy, every subject must be offered the best available treatment. . . . there must always be a reasonable relationship between calculated risks or inconveniences and the benefit of the study.

In the WPA’s current guidelines, the Madrid Declaration on Ethical Standards for Psychiatric Practice adopted in 1996, revised in 1999, 2002 and 2005 the requirement of proportionality has fallen out. This does, however, not mean that it is no longer recognized. Research is not specifically addressed in either the international codes of conduct for Nurses or Psychologists. The Ethical Principles for conducting Research with Human Participants of the British Psychological Society, first adopted in 1978, which does, however, specifically addresses psychological research on 25

World Medical Association, Medical Ethics Manual 2nd ed. (2009, p. 104).

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human beings, including the level of acceptable risks and burdens. Principle 8 (1) reads: Investigators have a primary responsibility to protect participants from physical and mental harm during the investigation. Normally, the risk of harm must be no greater than in ordinary life, i.e. participants should not be exposed to risks greater than or additional to those encountered in their normal lifestyles. Where the risk of harm is greater than in ordinary life the provisions of 3.8 [concerning “real” (qualified?) consent] should apply. Participants must be asked about any factors in the procedure that might create a risk, such as preexisting medical conditions, and must be advised of any special action they should take to avoid risk.

4.5.3 American Bioethics In the US the “National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research” (The US National Commission) was appointed in 1974 with a basis in the National Research Act.26 The move was part of a compromise of not adopting detailed legislated rules for research on humans and a permanent national regulatory body. The US National Commission’s work resulted in the widely acknowledged Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, published in 1979. The Commission also issued supplementary reports.27 The Belmont Report emphasizes three basic ethical principles which have had a profound impact on especially the bioethical community (and thus subsequently in a legal context as well): The principles of (1) respect for persons, (2) beneficence and (3) justice.28 The second principle, the principle of beneficence, involves reasoning reflecting a requirement of proportionality between risks, burdens and potential benefits. The Commission states that the principle contains two general rules “as complementary expressions of beneficent actions in this sense: (1) do not harm and (2) maximize possible benefits and minimize possible harms.” However, the requirements appear clearer when the Commission reformulate the principles into three applicable requirements concerning “informed consent, risk/benefit assessment, and the selection of subjects of research.”

26

Capron (2005, p. 30). The additional reports concerned: Research on the Fetus (1975); Research Involving Prisoners (1976); Research Involving Children (1977); Psychosurgery: Report and Recommendations (1977); Disclosure of Research Information Under the Freedom of Information Act (1977); Research Involving Those Institutionalized as Mentally Infirm (1978); Ethical Guidelines for the Delivery of Health Services by DHEW (1978); Institutional Review Boards (1978); Implications of Advances in Biomedical and Behavioral Research (1978). 28 See, for example, Beauchamp and Childress (2001); Brody (1998); Veatch (2003). 27

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The Belmont Report led the US Department of Health and Human Services (HHS) to revise and expand its regulations for the protection of human subjects in the late 1970s and early 1980s. The Act was endorsed by 14 other Federal departments and agencies in 1991, and the regulations have thereafter often been called the “Common Rule.”29 The Common Rule, which contains an equivalent requirement of proportionality, is still in force and its latest revision took place in 2005.30

4.5.4 The EU and the Regulation of the Pharmaceutical Industry Medicinal product’s (drugs) was well suited for standardisation and production on an industrial scale. Graham Dukes highlights the major biomedical advances regarding inter alia the development of smallpox vaccines (Jennings 1796), chloroform (1831), paraldehyde (1884), sedatives, antibiotics, and penicillin (Fleming 1929).31 Despite a few occasional set-backs the pharmaceutical industry have at large been successful and “one of the most profitable sectors of commerce.”32 Accordingly, commercial interests have become influential interests in biomedical research. Commercial interests are, not always consistent with the interests of science, society, or research subjects. Hence, with the industrialisation and commercialisation of medicine, yet another potential conflict of interest was added, and again was it the vulnerable individual research subjects that suffered the most. Dukes offers the following explanation of the potential conflict of interests: There is therefore a constant temptation to extract additional income from a drug by astute presentation (which stresses its merits and lays little weight in its shortcomings) an by opportunistic pricing. . . . The need in this field for clear rules, whether purely ethical or imposed by law, is . . . a direct consequence of the fact . . . that medicines have such an extraordinary potential to do great good on the one hand, yet also to inflict serious harm on the other.33

The commercialising of biomedical research has probably also “augmented the selfish interests of researchers”34 increasing the potential conflict of interests between the researcher and the research subject. There were sporadic regulatory attempts in Europe and the US in the early twentieth century. Curiously, Norway established the first national medicinal agency to approve new drugs in 1928.35 But it was not until later that more major regulatory initiatives were taken at the national as well as the international level. 29

The US Department of Health and Human Services (2008). US Code of Federal Regulations (CFR), Title 45, Public Welfare, Department of Health and Human Services (DHHS) Part 46 Protection of Human Subjects. 31 Dukes (2006, pp. 6–7). 32 Dukes (2006, pp. 6–7). 33 Dukes (2006, p. 9). 34 Tzamaloukas et al. (2008, p. 159). 35 Dukes (2006, p. 106). 30

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One incident that contributed to increased regulations was the Thalidomide tragedy. Thalidomide was a drug developed by a German pharmaceutical company and sold in almost 50 countries (except the US) from 1957 to 1961. It was distributed widely, mainly to pregnant women, to relieve morning sickness and aid sleep. The drug’s side effects led to approximately 10,000 children being born with severe malformations. Many children died during pregnancy or shortly after. As transatlantic research increased a harmonising project was initiated, involving the European Union, the US and Japan “to provide a unified standard” applicable on clinical trials, in order to “facilitate the mutual acceptance of clinical data by regulatory authorities in these jurisdictions.” At the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, the ICH guidelines for Good Clinical Practice (ICH GCP) were adopted in 1996. The GCP Guidelines are rather detailed, and includes a variant of the requirement of proportionality: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.

The guidelines are not as such legally binding. They are merely an expression of broadly accepted guidelines for good clinical practice. The nonlegally binding character of the ICH GCP Guidelines led to the adoption of a legal instrument by the European Union in 2001, The Clinical Trials Directive, and the GCP Directive in 2005.

4.5.5 The Council of Europe and the Oviedo Convention and Its Additional Protocol The Council of Europe (CoE) has 46 member states and has played a leading role in the protection of fundamental freedoms and human rights in Europe. In 1985 an Ad hoc Committee of experts on Bioethics (CAHBI) was set up. Their work led in 1990 to the adoption of Recommendation (No. R (90) 3) an explanatory memorandum to member states concerning medical research on human beings. In 1992 the CAHBI was replaced by a permanent committee, the Steering Committee on Bioethics (CDBI). The CDBI prepared a legally binding Convention in the field of biomedicine (including biomedical research). The Convention was adopted in Oviedo, Spain, in 1997. The thereinafter-called Oviedo Convention entered into force in 1999. It was the first legally binding international convention in this field. A version of the requirement of proportionality is entailed in Article 16 ii: Research on a person may only be undertaken if [. . .] the risks which may be incurred by that person are not disproportionate to the potential benefits of the research.

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Already in 1991, a Working Party of independent experts began preparing an Additional Protocol concerning biomedical research (the Additional Protocol). After numerous meetings and consultations, the Committee of Ministers adopted the Additional Protocol on 30 June 2004, and opened it for signature on 25 January 2005. The Additional Protocol is stricter and clearer on a number of points concerning acceptable risks, than the Recommendation from 1990. The Additional Protocol entered into force in 1 September 2007. The Additional Protocol builds “on the principles embodied in the Convention, with a view to protecting human rights and dignity in the specific field of biomedical research.”36 Article 6 (1) of the Additional Protocol contain a slightly amended version the requirement of proportionality: Research shall not involve risks and burdens to the human being disproportionate to its potential benefits.

As the Clinical Trials Directive, the Additional Protocol concerning Biomedical Research was not adopted as a reaction to revealed human abuses. Rather it was an attempt to seize control over an important, controversial and constantly emerging field that was largely regulated by non-legally binding “guidelines” either adopted by or, at least, heavily influenced by the biomedical profession, including the pharmaceutical industry.37 Thus, the Oviedo Convention and its Additional Protocol, together with the Clinical Trials Directive, are currently the most prominent legal instruments at the European concerning interventional biomedical research on human beings. With their adoption the public, through their elected representatives and international agreements, were in control over the rules governing experiments on themselves. The adoption of those legally binding instruments can thus be seen as a significant, and somewhat final, step towards a legal framework in Europe, although additional and elaborative instruments are likely to be adopted in the future.

4.5.6 Reflections on the Development of Current Regulations In the second half of the twentieth century, the requirement of proportionality gained foothold as a central professional and legal requirement. This period is, however, as the foregoing period, marked by some biomedical scientists’ neglect of existing rules, including the requirement of proportionality. There are many documented examples of (at that time) ethically and legally dubious research. A telling example from Europe is the Vipeholm Caries Study initiated by the Swedish government. The aim was to study the food intake’s influence on people’s dental health, in order to provide evidence for public advice. The study population was mentally retarded children at Vipeholm Mental Hospital. During 1945 and 36

Paragraph 1 of the Explanatory Report. Personal communication with Povl Riis, member of the drafting expert group, 20 November 2006. 37

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1955 the children were divided into several groups and given different food. Some were given caramels, others chocolate and coke.38 One group received 24 caramels between each meal every day, and had to provide saliva tests every 15 minutes during the test period. The study showed that enhanced sugar intake led to more caries. No one questioned the use of the mentally retarded children, the lack of parental consent, and the burden and harm imposed on the vulnerable children.39 The disturbing fact is that, although some dissenters criticised this behaviour, the majority apparently accepted this behaviour and even defended scientists accused of unethical and unlawful behaviour. This may in part be a result of utilitarian thinking and strong beliefs in the advance of natural sciences within the scientific community. Increasing careerism and commercialism in biomedical research are additional contributing factors. Revelations of abuses contributed to a degree of public ambiguity towards medical science. They also paved way for more regulations. The Thalidomide Scandal and the Tuskegee Scandal are important examples. Parallel, the UN and the Council of Europe started, in the aftermath of World War II, focusing on the individual and the individual human rights. This work gained momentum, especially in the 1990s, until it was at the forefront in all regulations, including the regulation of biomedical research. It was, however, professional self-regulations, such as the Declaration of Helsinki and the ICH GCP Guidelines, and not legal regulations adopted by society at large that had the greatest impact on the attitudes and behaviour within the scientific community. The drafters of these professional guidelines were, however, sensitive to public trends and regulations, including the emergence of international human rights law. That is particularly evident in the revision of the Declaration of Helsinki in 1975. It is today beyond doubt that biomedical research law must be regarded as a special branch of international human rights law, and that the overarching purpose of biomedical research law, including the requirement of proportionality, is the protection of human dignity and individuals human rights. This culminated at the European level in the adoption of the legally binding Oviedo Convention in 1996. The subsequent adoption of the Clinical Trials Directive in 2001, and the Additional Protocol to the Oviedo Convention in 2005 has only reaffirmed that view. At the turn of the century there has thus been a shift from professional selfregulations towards legally binding instruments, and a move from physicians’ paternalism towards patients’ (subjects) autonomy.40 The move towards increased legalisation reflects a broader societal trend of so-called “juridification”.41

38

Bommenel (2006). Ruyter (2003b, pp. 327–328). 40 Rothman (2003). 41 “Juridification” is a rather new shorthand term with an ambiguous content. It is sometimes used as more or less synonymous with the terms “judicialisation” and “legalisation” or the “proliferation of law”, see Blichner and Molander (2005). Here it simply refers to the societal tendency in increasing (and more detailed) legal regulation of human behaviour. 39

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The regulatory initiatives have primarily come from international and supranational agencies, such as the United Nations, the Council of Europe, and the European Union. One may therefore talk about “international juridification”. One reason behind the latter trend is that the both the UN and the CoE traditionally has had the responsibility of promoting human rights, now also in this field. Another reason, particular evident in Community law, is the goal of regulatory harmony between member states, and the facilitation of international research cooperation. The requirement of proportionality has been included in both professional and legal instruments. The wording has varied, but it may be asserted that the core content has been relatively stable. The requirement of proportionality has thus developed from being a natural and inherent way of reasoning and justifying conduct otherwise unacceptable, to become a more principled based legal norm. It can be argued that the requirement should be seen as part of international customary law.

Chapter 5

The Purpose of the Requirement of Proportionality

5.1 Problems Addressed The purposes of legal norms and instruments functions as an overarching guide to the provisions reasonable, intended, and therefore correct normative content. As maintained in the case-law of the European Court of Human Rights: the aim of legal interpretation of legal norms is to realise the purpose of the norm.1 The purpose of the norm is especially important in human rights law and in the interpretation of law-making treaties, such as the Oviedo Convention and its Additional Protocol. The norm’s purpose may typically lead to a more restrictive or extensive interpretation than a mere literal interpretation. A clarification of the purpose (the raison d’être) and role of the requirement of proportionality is therefore essential to fully understand and, not least, ascertain the correct content of the requirement of proportionality. Information about the purpose is usually found in the Preamble of the instrument, in preparatory works, explanatory reports, and from a reading of the provisions in context with other provisions. The importance, but also the complexity, of the purpose justifies a thorough analysis. The analysis may appear theoretic, but knowledge about the principle’s underlying rationale is indeed important in practice.

5.2 Balancing Different Interests 5.2.1 General Like other legal norms, the requirement of proportionality aims at the promotion and protection of certain interests. Both the European Court of Human Rights and the European Court of Justice use the general principle of proportionality as a balancing tool for striking a “fair balance” between competing interests – especially between the individual human being and society at large. 1

Jebens (2004).

S. Simonsen, Acceptable Risk in Biomedical Research, International Library of Ethics, Law, and the New Medicine 50, DOI 10.1007/978-94-007-2678-9_5,  C Springer Science+Business Media B.V. 2012

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There is a multitude of more or less legitimate interests present in this field. These interests are not necessarily fully compatible. Particularly actual interests will be briefly investigated, before the balancing is further addressed.2

5.2.2 Relevant Interests The Interests of Science The interests of science itself are, of course, prominent in biomedical research. Science can be seen as an ideal and altruistic activity conducted for the best of mankind, where knowledge is in itself a value. Science’s main interest may then be seen as to further the general body of knowledge. Freedom of research is undoubtedly a cherished ideal in our society. In that respect research has an interest in being free, independent and unrestricted. Such interests weigh against regulations. On the other hand, research should also be valid, verifiable, and unbiased, to attain the overarching goal of gaining obtaining generalisable knowledge. Furthermore, biomedical research should be carried out on terms palatable to society at large to ensure voluntary participants, practical and formal facilitation, and funding by the public. Science has therefore an interest in observing existing regulations. Thus it is, to some extent, in the interest of science to have the public’s expectations clarified by way of regulations and guidelines. Since some scientists may be tempted to bend or disregard “non-binding” guidelines, clear legally binding rules may be necessary. Biomedical research entailing disproportionate risks and burdens to the research participants would be publicly condemnable, and therefore contrary to the long-term interests of science. This is the case even though results of great scientific value were obtained. Science has no interest in unreasonably exploiting human subjects for the sake of science. The Interests of the Individual Researcher The interests of the individual researcher do not necessarily equal the interests of science. Most researchers are, however, probably involved in research for more or less altruistic reasons. Researchers’ therefore also have an interest in furthering the general body of knowledge. This necessitates freedom; freedom of thought, freedom of research, freedom of expression and as few restrictions as possible. Restrictions on those basic freedoms are characteristic of totalitarian regimes. Those freedoms are recognised and protected in human rights law.3 Researchers may also have more selfish and short-sighted interests, such as prestige, career advancement, and personal financial gain. Such interests are, however, not necessarily particularly worthy of protection. 2

This section is partly based on Simonsen and Nylenna (2004). See, for example, Freedom of thought and expression (ICCPR Articles 18 and 19 and ECHR Articles 9 and 10), and more specifically ICESCR Article 15 (1) (b) and the Oviedo-Convention Article 15. 3

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Their presence should, nevertheless, be recognised, because they may influence both the conduct of research and the researchers’ assessment of proportionality. A selfish careerist may, for example, be willing to expose his or her participants to greater risks than a researcher who is more sensitive to the public and participants’ expectations and interest. The aim of personal gain may intensify the aim of gaining scientific results, and those aims may conflict the public and the research subject’s interests, as well as the long term interests of science, as illustrated by history.4 The tension between the interest of the researcher and the research subject is clearer and greater in research, than in health care. In research the principal goal is to obtain new knowledge. In ordinary patient health care the principal aim of both the physician and the patient is to improve the patient’s health and welfare. Ideally, there should be no contradiction between ambitiousness on the one hand, and a sense of responsibility and care for the individual on the other. Researchers should also be interested in conducting research at terms with public and participants expectations to preserve trust, and avoid negative reactions and sanctions. In so far, researchers should also have an interest in clear rules setting out society’s expectations. They should also have an (personal) interest in observing the rules. Commercial Interests A great portion of today’s biomedical research are initiated and funded by private companies driven by commercial interests, rather than purely altruistic interests. Commercial interests may intensify other interests, such as a bias towards positive results of science. Positive results are results that verify the hypothesis, for example, that a specific drug is effective and safe. Commercial interests may thus increase the tension between the interests of science and researchers on the one hand, and the interests of the individual research subjects and the public on the other. For example, in relation to a lawsuit, a large pharmaceutical company allegedly made plans to “neutralise” and “discredit” physicians and researchers sceptical of their drug, as well as threatening that academic institutions would not receive more funding.5 Another commercial interest is the interest in having “a level playing field”, and predictable rules. “Level playing field” is an economic term used to describe the market’s demand for equal conditions to promote fair competition. This implies an interest in clear and harmonised regulations. This interest is recognised in both Convention law and Community law, which expressly aim to harmonise national regulations in this field, and as such create a “level playing field” and facilitate multinational research.6 Nevertheless, commercial interests should ideally be largely in parallel with most other ideal interests. That includes a common interest in playing by the rules, as 4

See Nicholson (1986, p. 64). Rout (2009). 6 “Level playing field” is an economic term used to describe the market’s demand for equal conditions to promote fair competition. 5

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transgressions may backfire and lead to loss of reputation, market loss, lower share value, lawsuits etc. That was the case in the aforementioned lawsuit.7 The Interests of Present and Future Patients Present and future patients take, for obvious reasons, a special interest in the advances of biomedical research, as it may lead to better health and health care. It is also recognised as a human right that everyone has a human right to health – that is a right “to the enjoyment of the highest attainable standard of physical and mental health.”8 A good health service, prevention of sickness and promotion of health, and effective treatment of disease, are dependent on reliable knowledge. The demand for knowledge is increasing; people expect more and more of health services and health personnel in respect of service, influence, quality, and effectiveness. The gold standard for the obtainment of reliable knowledge is research. Biomedical research is therefore regarded as a fundamentally positive and useful activity on which both today’s and tomorrow’s patients rely.9 In such a perspective, biomedical research can be seen as an ethical imperative, and as a means for fulfilling people’s human rights and their interests in good health care. Restrictions on biomedical research may thus be contrary to future patient’s interests. Future patients are, on the other hand, also potential research subjects, as well as fellow human beings. Future patients should therefore also be interested in ensuring the research participant’s interests. Public Interests and the Interests of Society In line with ordinary usage, I use the term public and society (at large) interchangeably about the broad community of individuals and institutions, represented by our democratically elected representatives (the government). Thus, society consists of a multitude of interest. Nevertheless, it may be said that the societal interests are idealistic and altruistic in nature, and lies largely in promotion of the common good. The history of biomedical research illustrates that the interests of society are not always at terms with the interests of science and, even less so, some scientists. This conflict of interests led to a certain degree of public ambiguity towards research.10 This may appear strange, as the scientists often defended their transgressions by arguing that they exposed human subjects to excessive risks without a valid consent for the common good.

7

See Rout (2009); Brown (2008). ICESCR Article 8 (1). 9 NOU (2005:1, chapter 21). 10 See Chapter 4. 8

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This signifies that the society’s interests are not purely utilitarian or consequential11 : On the one hand, society is interested in the best possible health for everyone. Biomedical research may lead to improved and more effective (including costeffective) health care, and subsequently preserve or enhance citizens’ health. The promotion of biomedical research is therefore an expressed and rated societal goal and interest. On the other hand, society has an interest in (and duty of) protecting the individual citizen against harm, exploitation, and infringements.12 In fact, the society at large (in Europe) has taken a relatively clear stand in favour of the latter.13 Society’s (nation state’s) principal responsibility to protect their citizens is firmly based in international law, including the UN Charter and international human rights law.14 Consequently, society’s interests lies principally with the protection of the individual (research subject), and only subsidiary with the progress of science and new knowledge.15 The Interests of the Individual Research Participant Individual persons have individually varying interests. That also applies to research participants. Interventional biomedical research on human subjects is an invasive and hazardous activity, which occasionally causes harm and infringements.16 It is therefore reasonable to presume that most research participants have an interest in the protection against unreasonable burdens and risks of harms, as well as respect for their autonomy and self-determination. Participants in biomedical research assumingly also share a greater or lesser interest in the advancement of science, if not they would not volunteer. Such an interest may result from (realistic or not) prospects of direct therapeutic benefits. But even without prospects of direct benefits, such interests might be a result of more or less altruistic interests.17

11

Consequentialism (and utilitarianism) basically refers to the position that the consequences (or utility) of an act are decisive for the judgement of the act’s rightness as the ends may justify the means. Hence, the consequences are more important than other normative criteria, such as the moral rightness of the act as such. This implies that if a research project may lead to positive consequences (better health and more happiness) to a great number of people, exposing a few persons to risks and burdens can be justifiable. Deontology, on the other hand, basically refers to the position that the rightness of the act is more important than the rightness of the consequences of that act, as the ends do not necessarily justify the means. In this context it implies that the research subjects’ interests must be observed and cannot be overridden, no matter what the end. 12 See Simonsen (2004); Boyle and Simonsen (2004), on the nation’s states primary responsibility to protect their citizens flowing from international law, including UN law and human rights law. 13 See the principle of human primacy discussed in Section 5.2.5. 14 See Simonsen (2004); Boyle and Simonsen (2004) with further references. 15 This issue is further addressed in Section 5.2.4 immediately below. 16 See the Declaration of Helsinki, Paragraph 7. 17 See Mangset et al. (2008) who found that one reason for critically ill patients giving consent to participation in a randomised clinical trial was altruism; see below.

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Altruistic interests then expand the scope of the individual’s interests beyond a narrow self-interest in avoiding any harm or burden, and gaining direct benefits for him- or herself. Indeed, it is largely such a broader notion of participants’ interests that renders nontherapeutic biomedical research legitimate. But is also applies to therapeutic research projects where the risks and burdens are not fully outweighed by reasonable prospects’ of real and direct therapeutic benefits to the participant. In bioethical literature it is sometimes pointed out that it may even be more “dignified” to be altruistic than egocentric, understood as self-protectionistic.18 And several bioethicists have discussed whether individuals have a moral duty to participate in biomedical research, even though it may entail risks and burdens.19 An egocentric and risk avert person would probably not consent to participate in research where the principal aim was to benefit others. The requirement of consent is therefore important in the clarification of the individual person’s interests. In other words, the requirement of consent let the individual decide for him- or herself what is in his or her interest. Maintaining respect for autonomy can therefore also be seen as an important interest in this context.

5.2.3 Compatible Interests? The description of relevant interests in biomedical research above is by no means complete or necessarily very precise. Other interests, aspects, or relations, not mentioned here, may also be relevant, such as the interests of research institutions, communities hosting research institutions, relatives and dependants of the research subject, and so on.20 The description of various interests does, however, signify that designating and weighing interests is utterly complex: One cannot simply assume that all researchers want to (ab)use humans as mere means, and that no rational individual would carry risks and burdens for the sake of others. Moreover, the description illustrates the tension between the ideal and the reality. In a more ideal perspective there is apparently a significant degree of overlap and compatibility between the different interests. In such a perspective, for example, the interests of science, researcher, and commerce, will share a mutual interest with society and the individual participant, in respecting and protecting human dignity, and by that preserve mutual trust and even a union towards a common goal: doing good, whilst doing no harm. It is therefore principally more to the point to speak of a “potential” conflict of, or tension between, interests, than a factual conflict of interests.

18 See for example Human Dignity and Bioethics. Essays Commissioned by the US President’s Council on Bioethics, Washington (2008). Beyleveld and Brownsword (2001); Da Silva (2006). 19 Harris John (2005); opposite Shapshay and Pimple (2007). 20 Evans and Evans (1996, pp. 15–17).

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51

On the other hand, the interests, and even more so, their character and strength, may obviously vary individually and contextually in both theory and practice. Such variations may lead to or increase tension(s) between different interests as well as conflicts.

5.2.4 The Weight and Prioritizing of Relevant Interests Where conflicts and tensions occur, some interests and values must be given preference over other(s). Hence, there is a need for weighing and prioritising (balancing) of those interests. Considering the potential conflict of interests, the Preamble of the Additional Protocol states, with regard to the purpose of the Additional Protocol as a whole: Conscious of the fact that the advancement of biomedical science and practice is dependent on knowledge and discovery which necessitates research on human beings; . . . Convinced that biomedical research that is contrary to human dignity and human rights should never be carried out; Stressing the paramount concern to be the protection of the human being participating in research; Affirming that particular protection shall be given to human beings who may be vulnerable in the context of research [italics added]

Thus, the Additional Protocol takes an unequivocal stand in favour of the interest in protecting human dignity and human rights. Moreover, it is stated in Article 1 of the Additional Protocol that the primary purpose of the Additional Protocol as a whole is to protect the research participant. Similar statements are found in the second paragraph of the Preamble of the Clinical Trials Directive: The accepted basis for the conduct of clinical trials in humans is founded in the protection of human rights and the dignity of the human being with regard to the application of biology and medicine as for instance reflected in the 1996 version of the Helsinki Declaration. The clinical trial subject’s protection is safeguarded through risk assessment based on the results of toxicological experiments prior to any clinical trial, screening by ethics committees and Member States’ competent authorities, and rules on the protection of personal data.

The purpose and content of the requirement of proportionality must obviously be understood against this background. The Concepts of Human Dignity, Integrity, and Identity The concepts of human dignity, integrity, and identity are central and obviously related. But they are also rather vague, complex, and even controversial.21 A full account of the concepts and the controversies would go beyond the scope of this book. It is however clear that human dignity, which is the core concept, builds 21 See for example Human Dignity and Bioethics. Essays Commissioned by the US President’s Council on Bioethics, Washington (2008). Beyleveld and Brownsword (2001); Wheathley (2001); Da Silva (2006).

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on Kant’s moral philosophy, and must be understood in light of general international human rights law. The concept of human dignity is elaborated on in the UN Universal Declaration of Human Rights. The Preamble of the UDHR speaks about “the inherent dignity . . . of all members of the human family”, and states accordingly in Article 1: All human beings are born free and equal in dignity and rights. They are endowed with reason and conscience and should act towards one another in a spirit of brotherhood.

“Human dignity” can be understood as valuable human qualities every human being possesses and which are worthy of respect and protection.22 Human dignity is regarded as an inherent (unconditional) quality all human beings have simply because they are human, just like human rights. Moreover, individuals’ human rights are meant to protect and ensure respect for their human dignity. This notion is in line with classical humanism. António Barbosa da Silva notes that human dignity in this context is constant, insofar that it neither increases nor decreases with the individual human being’s “ontogenetic development”, such as age, race, sex, social or civil status, abilities etc. Human dignity is also ungraded insofar that it is equal for rich and poor, healthy and sick etc. Moreover, people’s dignity is inviolable insofar that everyone should respect it. Additionally, human dignity is inalienable, as it cannot be lost or deprived.23 These benchmarks are rather vague, but nonetheless operational. “Human identity”, understood as a person’s distinctive individuality, is one human quality worthy of respect and protection. “Human integrity”, which refers to the private sphere that every human being has, is another. Human integrity includes a person’s physical integrity, but also his or her psychological integrity as well as the protection of personal data about that person. Law against harmful infringements usually protects human integrity, and interventions of human integrity (including research interventions) must thus be based on the person’s consent or other legal authority.24 Thus, these concepts are linked to “human autonomy”, which refers to a person’s right to self-determination concerning personal matters.25 Society is, according to international human rights law, not only obliged to passively respect people’s dignity but also to more actively protect it. To some extent society is also obliged to fulfil person’s basic human rights.26 This implies firstly that no individual should be included or offered participation in a research project that violates human dignity.27 Using human subjects as mere means, without due respect for the person or human value, is regarded as contrary to human dignity. It also implies that even though a valid consent is obtained, the usage of human subjects may be contrary to human dignity, for example, if a person volunteers to

22

Hartlev (1999). Da Silva (2006, p. 63). 24 See Hartlev (1999). 25 More on human autonomy in Section 5.4.2. 26 See, for example, Rehman (2003); Møse (2002); Høstmælingen (2003). 27 See the Preamble of the Additional Protocol, cited above. 23

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participate in an excessively risky or detrimental and disrespectful research project. Thus, human dignity encompasses more than respect for human autonomy. The implications of nation state’s international obligations to respect, protect, and fulfil individual’s human dignity and human rights are difficult to define. International human rights instruments, including the Oviedo Convention and the Additional Protocol, and more specifically the requirement of proportionality are, however, crucial in establishing standards for the protection and promotion of human dignity. The requirement of proportionality must be understood and applied on this basis.

5.2.5 The Principle of Human Primacy The aim of protecting human dignity and the balancing of different interests are further and more explicitly addressed in Article 3 of the Additional Protocol: The interests and welfare of the human being participating in research shall prevail over the sole interest of society or science.

This, so-called, “principle of human primacy” is a restatement of Article 2 of the Oviedo Convention.28 It is also found in the GCP Directive Article 2 (1) and the Clinical Trials Directive Articles 4 (i) and 5 (h).29 The principle echoes Kant’s second imperative. The principle of human primacy was first formulated in the Declaration of Helsinki as amended in 1974.30 The principle of human primacy has been criticised for being vague and illfounded or redundant in bioethical literature.31 A critical analysis of the principle as such falls outside the scope of this book. But, despite occasional criticism, the principle is obviously fundamental.32 It has also since its explicit adoption into international professional ethics in 1974 and European law in 1997 been widely acknowledged. The principle of human primacy has two roles: 1. It is a legal norm in its own right. 2. It is important in the interpretation of other provisions, such as the requirement of proportionality.

28

Article 2 of the Oviedo Convention state: “The interests and welfare of the human being shall prevail over the sole interest of society or science.” 29 Article 2 (1) of the GCP Directive state: “The rights, safety and well being of the trial subjects shallprevail over the interests of science and society.” 30 Paragraph 5 in the current (2008) version of the Declaration of Helsinki states: “In medical research involving human subjects, the well-being of the individual research subject must take precedence over all other interests.” 31 Helgesson and Eriksson (2008). 32 See also Article 4 of the Additional Protocol which state unambiguously: “Research shall be carried out freely, subject to the provisions of this Protocol and the other legal provisions ensuring the protection of the human being.”; see Chapter 11.

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Both roles are of paramount importance in European biomedical research law in general, and for the requirement of proportionality in particular. The latter necessitates a closer investigation of the principle’s role, content, and relationship to the requirement of proportionality. (1) The principle of human primacy’s role as a legal norm In line with the cited statement in the Preamble to the Additional Protocol, the principle rather categorically gives preference to the interest of the research subject: No person shall be exploited and sacrificed for the sake of others – period. Thus, the principle of human primacy seems to suggest that the involvement of humans in more or less hazardous experiments is morally unjustifiable and should be avoided or prohibited altogether, regardless of legitimate ends. In this respect there is no need for a weighing and balancing of different interests, and even less, a weighing of risks, burdens and potential benefits. The wording “the interests and welfare of the human being” is, however, not unambiguous. As shown above, participation in a biomedical research project can be in the best interest, or at least, not contrary to the interests, of the participant. Prospects of direct therapeutic benefits to the participant, may, for example, outweigh risks and burdens to the participant. It may also be argued that research participation is in the interests of the participant if the individual participant decides that it is in his or her interest to do so by giving a legally valid consent.33 Thus “interests . . . of the human being” may also include altruistic interests that go beyond understanding the persons “best interest” as a narrow self-interest of avoiding any risks and burdens. The additional term “welfare” must be taken to concern the person’s dignity and well-being (health), including protection of human integrity against harm. “Welfare” will in most cases be covered by “the interests . . . of the human being”, but may be given independent meaning if the “interests” of the human being for some peculiar reason are contrary to his or her welfare and dignity. A suicidal person may, for example, want to take part in a scientifically interesting but reckless research project. If so, researcher’s obligation to respect and protect the person’s “welfare” may prevent the researcher from offering such participation. Thus the principle of human primacy and the legal framework is sophisticated and pragmatic, rather than categorical and rigid. The Additional Protocol, the Clinical Trials Directive and the Declaration of Helsinki all recognise that biomedical research is necessary for progress in this field, and subsequently people’s health.34 The instruments also recognise the necessity of involving human subjects in research, even if the risks and burdens entailed are not completely, or at all,

33 Solomon E. Salako states that the principles mean that “no human being should be exploited by society. The only method of securing this goal is the doctrine of informed consent – a doctrine which bristles with profound ethical problems”, see Salako (2008, pp. 346–347). 34 See the preambles of the Additional Protocol and the Clinical Trials Directive, as well as Paragraph 8 of the Declaration of Helsinki.

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outweighed by prospects of direct benefits to the participant, and the research participation thus entail additional risks and burdens; that is risks and burdens carried by the research participant primarily for the sake of others.35 The legal framework also allows nontherapeutic research on persons, even if they are not able to consent.36 In, for example, the preparatory work to the provision containing the principle of human primacy in the Norwegian Biomedical research Act § 2, it is emphasised that the wording “welfare of the research subject” indicates that the possible negative effects must be of a certain degree of likelihood and magnitude to be relevant.37 The implied meaning is that not any additional risks and burdens are contrary to the research subject’s welfare and interests, and as such unacceptable. The Ministry of Health held that the opposite view would render interventional biomedical research almost impermissible, which was not an alternative for the government. The Ministry then asserted that the principle of human primacy must be understood as: an outer limit for what may be undertaken in the name of scientific or societal interests, even though those interests clearly exceeds the interests of the individual.38

The Ministry’s interpretation of the principle of primacy is correct. The reasonable, and probably, intended meaning of the principle of human primacy is that the principle sets up outer limits. The interpretation’s plausibility becomes clearer when seen in context with other provisions, such as the requirement of proportionality. The principle of human primacy is then rigid and inflexible in so far that there are certain limits as to what level of risks and burdens participants in biomedical research can legitimately be exposed to, regardless of the potential benefits to science and society. Indeed, the principle may also be seen as an expression of the “trump” of individual human rights over utilitarian calculations.39 That is in line with current international human rights law. This means that a discretionary room is present within these limits. Clearly these limits are relevant and important in the assessment of proportionality between risks, burdens and potential benefits. The fundamental implication is that the assessment of proportionality can be relativistic only to a certain degree. The principle of human primacy thus functions as a constraint against a slippery slope in the assessment of

35 The term is used in Norwegian Tort Law to characterise risks and burdens not otherwise encountered – if it were not for participation in for example a research project, see Rt. 1960.841 (Smallpox Vaccination Case) and Rt. 1992.64 (Birth Pill Case II). See also Chapter 14. 36 See Chapter 12. 37 Ot.prp. nr. 74 (2006–2007). The Norwegian Parliament added the word “and integrity” to underscore that not only threats to people’s welfare (understood as health) were relevant but also threats to people’s privacy. 38 Ot.prp.nr. 74 (2006–2007) point 10.3 [author’s translation]. 39 See Nicholson (ed.) (1986, p. 68); see also immediately below on the interpretation of the Norwegian Health Research Act § 2.

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proportionality. This is probably the most important role of the principle of human primacy as a legal norm in its own right. Within the discretionary room, relevant and legitimate interests and factors must be weighed and balanced. The principle of human primacy is too coarse to be of much help; it does not even facilitate a balancing of interests and concrete considerations. The requirement of proportionality is a more useful device for that purpose. This signifies the relationship between the principle of human primacy as a legal norm in its own right and the requirement of proportionality. The former set up a minimum standard, while the latter specifies and governs the limited discretionary room. As such, the requirement of proportionality supplements the principle of human primacy as a balancing tool for balancing legitimate interests. (2) The principle of human primacy’s role as an interpretational mean Secondly, the principle of human primacy is also paramount in the interpretation of other provisions. The Explanatory Report to Article 3 of the Additional Protocol maintains: The whole Additional Protocol, the aim of which is to protect human rights and dignity, is inspired by the principle of the primacy of the human being, and all its Articles must be interpreted in this light.40

It follows from the investigation above that this certainly also applies to the interpretation of the requirement of proportionality. Obviously, the principle of human primacy plays a role in the weighing and balancing of interests, as it says something about the interests’ weight and which interests should be given preference. The principle of human primacy is utilised as a powerful interpretational mean in the more concrete analysis of the requirement of proportionality in this book.41

5.3 The Requirement of Proportionality as a Safeguard 5.3.1 Problem Addressed As shown above, the paramount purpose of current legal regulations as a whole, as well as the requirement of proportionality in particular, is to ensure “protection of the human being participating in research”; that is to be a safeguard for the interests and welfare of the research participant.42 In this section the requirement of proportionality’s role as a safeguard is further investigated.

40

Paragraph 21. See in particular Part VI. 42 Additional Protocol, Preamble. 41

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5.3.2 Proportionality and Researchers Duty of Care The requirement of proportionality as a safeguard calls into question the requirement’s relationship to health personnel and researchers’ general and legal duty of care. That relationship will therefore be explored. First the legal basis and the content of researchers’ duty of care is briefly outlined. The duty of care stems from tort law, and is familiar in health law.43 The duty of care basically implies that health personnel (as any other person) are legally (and morally) obliged to exercise due patient care. Health personnel owe, in other words “a duty of care to anyone [they] may reasonably foreseeable injure.”44 Irresponsible, negligent, or reckless behaviour, actions or omissions may thus be in breach of that duty. To establish a legal duty of care for researchers conducting biomedical research is straight forward.45 A variant of the duty of care is set out in Article 4 in Chapter I “General provisions” of the Oviedo Convention, titled “professional standard”: Any intervention in the health field, including research, must be carried out in accordance with relevant professional obligations and standards.

A more elaborative, but less stringent, variant is found in the Article 8 of the Additional Protocol, titled “Scientific Quality”: Any research must be scientifically justified, meet generally accepted criteria of scientific quality and be carried out in accordance with relevant professional obligations and standards under the supervision of an appropriately qualified researcher.

The wording of this provision is problematic as it can be seen as only addressing “scientific quality”. That is, however, obviously a too narrow scope, as both provisions essentially addresses the same issue: researchers’ duty of professional care. This is evident in the respective explanatory reports, but the obligations flowing from the provisions remain utterly broad and vague. Paragraph 33 of the Explanatory Report to Article 8 of the Additional Protocol state: All research must be carried out in accordance with the law in general, as supplemented and developed by professional standards.

Thus, the provisions embrace the whole lot of written and unwritten legal and professional norms in this field. As such the provisions may to a certain degree serve as legal basis for duties and rights not explicitly covered in the instruments’ written provisions. The most prominent professional standards in this field are laid out in the Declaration of Helsinki. The Declaration of Helsinki embraces itself a general duty of care in paragraphs 3 and 4: 43

See, for example, Kjønstad (2007, pp. 217–271). Herring (2006, p. 42). 45 There is a magnitude of literature on this subject, both in general health law and in general tort law. I have explored some of this in relation to Norwegian law and UK law; Lødrup (2005); Kjønstad (2005a, b); Nygaard (1992); Hagstrøm (1985); Harpwood (2005); Herring (2006, pp. 40 et seq.); Pattinson (2006, pp. 65 et seq.); Mason and Laurie (2006, pp. 307 et seq.). 44

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5 The Purpose of the Requirement of Proportionality It is the duty of the physician to promote and safeguard the health of patients, including those who are involved in medical research. The physician’s knowledge and conscience are dedicated to the fulfilment of this duty. The Declaration of Geneva of the WMA binds the physician with the words, ‘The health of my patient will be my first consideration,’ and the International Code of Medical Ethics declares that, ‘A physician shall act in the patient’s best interest when providing medical care.’

Article 8 of the Additional Protocol also refers to other unwritten and more specific professional standards, for example, established standards within the paediatric scientific community. Article 1 (2) of the Clinical Trials Directive refers to standards for Good Clinical Practice46 : Good clinical practice is a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects. Compliance with this good practice provides assurance that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trials are credible.

In Norway, the duty of care for both health personnel and biomedical researchers was based in unwritten law until it was explicitly enacted in the Health Personnel Act of 1999 § 4 and the Health Research Act of 2008 § 5, respectively.47 In the UK a general duty of care appears to be based in case-law. It should be safe to assume that comparable duties of care explicitly, or at least implicitly, are applicable in most European countries, and that human experimentation in breach of researchers’ duty of care is professional unacceptable and unlawful. The next question is then: What is the normative content of researchers’ duty of care? As clearly indicated in the two provisions in Convention law, and what is clear in Norwegian law, is that professionals’ duty of care is a “legal standard”. Nestor in Norwegian Health law, Asbjørn Kjønstad, states that being a “legal standard” implies that the law itself (convention, statutory act etc), does not necessarily contain all the norms which must be observed.48 A legal standard’s wording rather refers to a benchmark; that is a commonly recognised standard, as well as other norms within or outside the legal instrument itself. One must therefore go beyond the wording and the instrument to find the content of the standard. That explains the reference to professional standards in the Oviedo Convention and the Additional Protocol. Because these standards constantly evolve in line with the evolution of biomedical knowledge, this gives legal standards a dynamic character.49 Moreover, the written and unwritten professional standards are established and defined by the profession itself, explicitly or implicitly. The professionals are the experts with the technical 46 These were originally set out in the nonlegal instrument the ICH standards of Good Clinical Practice of 1996, but is now also addressed in the GCP Directive of 2005. 47 Simonsen and Nylenna (2005, pp. 186–192); Ot.prp. nr. 74 (2006–2007). 48 Aasen (2000, pp. 265 et seq.); Kjønstad (2007, p. 227); both with further reference to the foundational work on legal standards by Ragnar Knoph in 1948. 49 Kjønstad (2007, p. 227).

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skill. Professionals should therefore know what behaviour is largely accepted, for example, when removing an appendix with surgery or performing an endoscopy.50 Paragraph 34 of the Explanatory Report to the Additional Protocol Article 8 states in this regard: The current state of the art of scientific knowledge and clinical experience determines the professional standards and skill to be expected of professionals in the performance of research. In following the progress of biology and medicine, it changes with new developments and eliminates methods that do not reflect the state of the art. Nevertheless, it is accepted that professional standards do not necessarily prescribe one line of action as being the only one possible or foreclose research seeking to improve or replace an intervention. [Italics added]

Consequently, the practical and popular legal test simply asks how a reasonable and responsible person (researcher) would have acted in the context at bar. A decision on whether a duty of care existed and was breached is thus based on what is commonly referred to as the “reasonable person test”.51 The duty of care is, as underscored by Kjønstad, a minimum threshold, and set out what is at least expected.52 It is a reasonable, realistic and human requirement. It is not a requirement of (in hindsight) perfect action, not even “good practice”. It is rather about “tolerable practice”. If several alternative actions exist, including nonaction (omissions), the researcher would not be in breach of his or her duty of care if he or she acted within a reasonable sphere of discretion, i.e. if he or she acted as a responsible researcher would have done, acknowledging that several acceptable alternative actions existed. In some circumstances the margin of discretion or latitude is wide; in others it is narrow, depending on numerous relevant factors, such as the context, nature, risks etc. Consequently, it is tolerated that a “reasonable person” may, without legal liability, act and perform slightly below what is generally accepted as good practice among peers. Essentially, researchers’ duty of care limits their freedom of behaviour, including their freedom of research. It is however clear that a court of law is not necessarily bound by any alleged standard of practice.53 In a judicial precedence from the United Kingdom, the Bolitho Case,54 Lord Browne-Wilkinson stated: 50

Harpwood (2005, p. 139), which refer to the Bolam Case (Bolam v. Friern HMC [1957] 2 All ER 118) where the Court held that “A doctor is not guilty of negligence if he has acted in accordance with a practise accepted as proper by a responsible body of medical men skilled in that particular art.” 51 Harpwood (2005, p. 127) asserts that the reasonable person test is a traditional formula employed by lawyers and courts to determine “whether the defendant has observed the requisite standard of care in all circumstances. . . . Failure by the defendant to act as a reasonable man would have acted is an indication of negligence.” See also the definition in Black’s Law Dictionary (2004, p. 1294). 52 Kjønstad (2007). 53 Harpwood (2005); Blom (1973). 54 Bolitho v City and Hackney HA [1992] PIQR P334; (1997) 39 BMLR 1, HL, cited in Harpwood (2005).

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5 The Purpose of the Requirement of Proportionality The use of these adjectives – responsible, reasonable and respectable – all show that the court has to be satisfied that the exponents of the body of medical opinion relied upon can demonstrate that such opinion has a logical basis. In particular, in cases involving, as they often do, the weighing of risks against benefits, the judge, before accepting a body of opinion as being responsible, reasonable or respectable, will need to be satisfied that, in forming their view, the experts have directed their minds to the question of comparative risks and benefits and have reached a defensible conclusion on the matter. [Italics added]

Some bioethicists have argued that health personnel’s duty of care is something different than, and must be separated from, researchers’ duty of care, and, moreover, that only the latter applies to research.55 The view is, however, ill-founded in a legal perspective. Health personnel always have a legal duty of care whether or not they are conducting research. Moreover, the principle of human primacy implies that the duty of care prevails over duties owed to, for example, science or commercial interests.56 Health personnel cannot waive his or her duty of care when doing research. Neither may research participants waive their right to due care.57 Hence, interventional biomedical research must be reconcilable with health personnel’s duty of care and accepted clinical practice. This is also the premise and implication of the requirement of “supervision of an appropriately qualified researcher” in Article 8 of the Additional Protocol, and the more elaborative requirement in Article 21 (2): “Research may only be carried out under the supervision of a clinical professional who possesses the necessary qualifications and experience.” A similar statement is found in the Clinical Trials Directive Article 3 (3). The purpose of this requirement, as well as the more general duty of care, is to be a safeguard and hinder persons being exposed to unnecessary, unreasonable, irresponsible, unjust, unfair, excessive etc. risks of harm and burdens.58 Clearly, this is also the primary purpose of the requirement of proportionality.59 As such the requirement of proportionality is inherent in, and easily derivable from, researchers’ professional and legal duty of care.60 This follows from the Explanatory Report to Article 8 of the Additional Protocol, concerning researchers’ professional obligations, including researchers’ duty of care, where it is stated: In particular, an intervention must meet criteria of relevance and proportionality between the aim pursued and the means employed. This is particularly relevant in the case of research that does not have the potential of producing a real and direct benefit for the health of a research participant. The issue of proportionality is addressed specifically in Article 6 of this Protocol.61 [Italics added]

55

Miller and Brody (2007). See Section 5.2.5. This issue is further pursued below in Chapters 13 and 14 on the Additional Protocol Article 23 and on the Clinical Trials Directive Article 3 (3). 57 See Section 5.4.3. 58 Kjønstad (2005); Lødrup (2005); Harpwood (2005). 59 See also Bergkamp (2004, p. 68). 60 Simonsen and Nylenna (2005, pp. 192–194). 61 Paragraph 36; This is also noted in the Explanatory Report to Article 4 of the Oviedo Convention. 56

5.4

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This is also the situation in the Norwegian Health Research Act, where the duty of care is included in a general provision in § 5, while the requirement of proportionality found in § 22 (2) stands out as a supplement to, and a precision of the former, together with, for example, the requirement of lesser means in § 22 (1), and the requirement of consent in § 13.62

5.3.3 Conclusions It may thus be concluded that there is an intimate relationship between researchers’ general duty of care and the requirement of proportionality, as the latter, in part, specifies and render the former operational: If the risks and burdens are disproportionate it would be irresponsible and unreasonable to involve people in research; it would be in breach of the researcher’s duty of care. Researchers’ duty of care and the requirement of proportionality thus share a common purpose of protecting the individual research participant against unreasonable and unjustified interventions, harm, infringements, risks of harm, and burdens. Consequently, and essentially, the requirement of proportionality (and the duty of care) significantly limits researchers’ freedom of behaviour, including their freedom of research. Being a safeguard, which aims to ensure that research participants are not exposed to unnecessary, excessive and unreasonable risks and burdens, is clearly the primary purpose of the requirement of proportionality.

5.4 The Relationship Between Proportionality and Autonomy 5.4.1 Problem Addressed To conclude that the requirement of proportionality is a safeguard aimed at protecting research participants against unreasonable and unjustified risks and burdens is uncontroversial. Indeed, Povl Riis who participated in the drafting of the Additional Protocol (and the Declaration of Helsinki) said that the requirement of proportionality was an axiom – a self-evident truth, which needed no further evidence or reason.63 However, the principle of autonomy challenges the requirement of proportionality, as participants’ right to self-determination suggests that prospective participants should be allowed to safeguard their own interests. Consequently, there is little need for a requirement of proportionality, at least in cases involving persons able to consent, or who have a legal representative (proxy) to safeguard their interests.

62 63

Further discussed immediately below; See also Simonsen (2010a). Personal communication to the author 21.11.2006.

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The principle of autonomy and the requirement of consent in biomedical research are not as such a topic in this book. However, the relationship between the requirement of proportionality and the requirement of consent obviously needs further investigation in relation to the discussion of the requirement of proportionality’s purpose as well as normative content. This means that it is the relationship at a more overarching level which is the topic here; while the more precise relationship is discussed in detail later on.

5.4.2 Autonomy – More on the Problem Addressed Our rule-based society is founded on a notion of human freedom and a principle of autonomy, which refers to a legally protected behavioural freedom and a right to self-determination. Actions and interests of the individual should in general, and ideally, be determined by the individual him- or herself. One such action, or choice, is whether to participate in a biomedical research project or not.64 Respect for an individual’s autonomy is a substantial element in the respect for an individual’s dignity.65 Likewise, the requirement of consent is a central element in ensuring the research subject’s autonomy (and thus dignity). Article 14 (1) of the Additional Protocol states: No research on a person may be carried out, subject to the provisions of both Chapter V and Article 19, without the informed, free, express, specific and documented consent of the person. Such consent may be freely withdrawn by the person at any phase of the research.

The Clinical Trials Directive is based on the same notion, and includes a comparable provision in Article 3 (2) (b), cf. Article 2 (j). The researcher is obliged to disclose “the possible risks and benefits of the research project” to prospective participants when obtaining consent.66 Without such disclosure the consent is not informed, and may therefore be void. On this basis, the legal scholar Lucas Bergkamp holds that “in the case of healthy volunteer research, the third party judgement inherent in the proportionality principle is not needed.”67 In his opinion, volunteers with intact cognitive abilities are able to determine whether participation in research is acceptable, and in particular whether the entailed risks and burdens are acceptable. Apparently, Bergkamp’s only premise is that the research participant is provided adequate information, including an adequate description of the risks, burdens and potential benefits. Healthy volunteers should be allowed to protect their own interests themselves. Thus, in the apparent opinion of Bergkamp, the need for a separate and independent requirement

64

This is recognised in the Preamble of the Additional Protocol, see citation above. See Section 5.2.4. 66 Additional Protocol Article 13 (2). 67 Bergkamp (2004, p. 66). 65

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of proportionality between risks, burdens and potential benefits ought to be superfluous. Indeed, an independent requirement of proportionality might be regarded as an unreasonable interference in prospective participants’ right to self-determination.68 Bergkamp’s assertion also calls into question the principle of proportionality’s rationale and role as a fundamental safeguard. Given a valid consent, is the requirement of proportionality really necessary, and if so, to what extent? Does informed consent relieve the researcher of his or her duty of care?

5.4.3 Biased Information, Therapeutic Misconception, and the Unreliability and Insufficiency of Consent The problem identified in the foregoing section raises the question about whether consent is a reliable and sufficient safeguard, rendering the requirement of proportionality superfluous. In other words, does the requirement of consent imply that the requirement of proportionality is more or less unnecessary? In 1966 the US Professor and physician Henry Beecher offered 20 examples of unethical research involving human subjects.69 In his mile-stone publication, Beecher concluded that Ordinary patients will not knowingly risk their health or their life for the sake of ‘science’. . . . When such risks [as in the 20 examples] are taken and a considerable number of patients are involved, it may be assumed that informed consent has not been obtained in all cases.70

Beecher thus suggested that although consent had been obtained in some of the criticised research projects, the consent was probably not adequately informed or understood. Substantiated also by his own clinical experience, Beecher asserted that consent was an insufficient safeguard against unethical research. Numerous studies from the US and Europe have more or less confirmed Beecher’s assertion.71 Current regulations are apparently based on such an assumption of participants’ preferences. Inadequate and Biased Information One possible cause of unreliability of consent is inadequate and biased information provided by the researchers. The cause is related to circumstances with the researcher.72 My review of researchers’ applications to a REC indicated that many researchers tended to overestimate benefits and underestimate risks and burdens in their applications to the Research Ethics Committee; and to an even larger extent, in the written 68 According to the more general principle of proportionality applicable in both European Convention and Community law. 69 Beecher (1966) (Beecher is a legend in international bioethics). 70 Beecher (1966). 71 Sugarman et al. (1999) offer a review of 377 studies on the subject. 72 Bergkamp (2004).

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information to prospective participants. An example is the Meningococcal B Vaccine Trial.73 In another case, the Hip-fracture Study, the researchers claimed that the risk of harm caused by a 10–40% prolongation of the hip-fracture surgery on elderly patients was negligible.74 In the subsequent investigation of that research project, the Norwegian Board of Health Supervision found that such a risk was considerable. Moreover, the Board held that the risks were certainly not justified by the potential benefits, as the potential benefits were regarded dubious, which suggested that the potential benefits had been overrated by the researchers. Researchers’ tendency of overestimating benefits and underestimating risks and burdens is substantiated by the more widely recognised phenomena that researchers are more inclined to publish and emphasise positive results of their research, than negative results.75 Inadequate and biased information is, assumingly and hopefully, seldom a result of ill will and fraudulent behaviour. Rather it may be a result of enthusiasm and optimism; a legitimate interest in furthering science and treatment of future patients. Another probable cause is fear of non-approval from the Research Ethics Committee, and even more so, non-consent from prospective participants. This assertion is supported by the circumstance that researchers were more inclined to withhold information about risks and burdens to prospective participants, than the Research Ethics Committee.76 The potential conflict of interests between researchers and research participants increases the risk of inadequate and biased information.77 Researchers are the stronger part in the researcher-participant relationship. The researcher is the expert and largely controls the information. Prospective participants (and their legal representative) are usually laymen or – women, highly dependent on the researcher and the provided information. This indicates a situation of inequality of power, rendering research participants more or less vulnerable.78 The US National Bioethical Advisory Commission stated in its final report: It is essential that participants and investigators not be led to believe that participating in research is tantamount to being in a traditional therapeutic relationship. Regardless of whether there is the possibility or even the likelihood of direct benefit from participation in research, such participation still alters the relationship between a professional and the participant by introducing another loyalty beyond that to the participant, to wit, loyalty to doing good science. It is too often forgotten that even though the researchers may consider participants’ interests to be important, they also have a serious, and perhaps conflicting, obligation to science. . . .79

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Report on the Norwegian Meningococcal B Vaccine Trial (2007). The Norwegian Board of Health Supervision (2006). 75 Melander et al. (2003); Pich et al. (2003); Hall et al. (2007). 76 See Section 2.3. 77 See Section 5.2. 78 The concept and causes of vulnerability is analysed in Section 3.8. 79 The US National Bioethics Advisory Commission, Final Report (2007, p. iii). 74

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Based on his experience as a clinician, Henry Beecher noted that he could talk his patients into consenting to almost anything, including high-risk nontherapeutic research.80 Several clinicians I have talked to confirm Beecher’s assertion. In fact, the potential conflict of interests and the risk of biased researchers was the primary rationale behind the inclusion of a requirement of independent ethics review in the Declaration of Helsinki in 1975.81 This is worrying as empirical data show that “[p]erceptions of risks and benefits, by both lay people and doctors, are strongly influenced by the way data are presented.”82 This worry should not be regarded as an attempt to throw suspicion on a whole profession pursuing legitimate aims. In reality it is probably more about a gradual scale from the overly-cautious researcher who would overestimate risks and burdens and underestimate potential benefits, and by that hinder sound and ethical research; to the (ideal) reasonable and responsible researcher; to the slightly too optimistic researcher; to the unwise and seductive enthusiast; to the fraudulent researchers, who intentionally conceal risks and burdens and invent benefits.83 Nevertheless, this danger of abuse of power reduces the reliability of consent, and suggests that consent is not necessarily a sufficient safeguard, even for “healthy volunteers”. Additional safeguards, such as the requirement of proportionality, are thus needed. Therapeutic Misconception and Other Misconceptions Etc Another documented cause of unreliability is circumstances related to the research subject. Many studies show that prospective participants confuse research with ordinary health care, and thus misunderstand the premises of research. A term used in literature to describe this circumstance is “therapeutic misconception”. In contrast to the more delicate and, seemingly, tabooed circumstances discussed above, the phenomena of therapeutic misconception is well documented and frequently discussed in bioethical literature.84 The precise definition of “therapeutic misconception” has been debated in bioethical literature.85 But the exact definition is of little importance here. The concept was introduced by Paul S. Appelbaum and colleges in 1982. Appelbaum et al. used the concept to describe that interviews with patients with psychiatric disorders revealed the phenomena that “research subjects fails to appreciate the distinction between 80

Beecher (1966). See Section 4.5.2 for further details. 82 Skolbekken (1998). 83 On scientific fraud see, for example, Simonsen (2007); Nylenna and Simonsen (2006); Nylenna et al. (1999); Lock and Wade (1996). 84 A search on “therapeutic misconception” in PubMed gave 81 hits (78 of them from year 2000 and onwards). Search date: 04.03.09. 85 Henderson et al. (2007, p. 1737): “Therapeutic misconception exists when individuals do not understand that the defining purpose of clinical research is to produce generalizable knowledge, regardless of whether the subjects enrolled in the trial may potentially benefit from the intervention under study or from other aspects of the clinical trial.” 81

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the imperatives of clinical research and of ordinary treatment, and therefore inaccurately attributes therapeutic intent to research procedures.”86 [Italics added] The US National Bioethics Advisory Commission adopted a similar definition, and stressed that: It is not a misconception to believe that participants probably will receive good clinical care during research. But it is a misconception to believe that the purpose of clinical trials is to administer treatment rather than to conduct research.87

Henderson et al. made an observation, which reflects a common view in bioethical literature: That “regardless of the potential for benefit to participants, research is always conducted in order to achieve scientific goals and contribute to generalizable knowledge.”88

A recent French study involving 303 patient research subjects or parent proxies found that “therapeutic misconception was present in 70% of respondents, who expected to receive better care and ignored the consequence of randomisation and treatment comparisons.”89 Durand-Zaleski and colleagues suggested “that the risk of therapeutic misconception [should] be specifically addressed in consent forms as an educational tool for both patients and investigators.” The likelihood of misconceptions most certainly increases if the research intervention takes place in a clinical setting and, even more so, if the participants are patients seeking, in need of, or under treatment. The reason is that the setting in clinical research is seemingly similar to ordinary clinical practice, although the premises and interests involved are fundamentally different. The same applies if the researcher is the participant’s physician; wears a white coat and stethoscope etc. Hadskis and colleagues found that: vulnerabilities associated with neurological and developmental conditions, the parental need for hope, and the expectation of parents that new medical advances can benefit their child . . . [lead to] . . . therapeutic misconception on the part of parents and other key research stakeholders. . . . this misconception can compromise consent given by parents.90

The apparent high prevalence of therapeutic misconception in biomedical research suggests that even though a person is provided adequate information by an unbiased researcher, and the person gives his or her consent voluntarily, the consent is unreliable, as the provided information is often not sufficiently understood. Participants may, for example, find the relationship betweens risks, burdens and potential benefits to be proportionate, although they would not, had they properly understood and appreciated the information. Furthermore, the high prevalence of therapeutic misconception indicates that its occurrence cannot be completely eliminated; only decreased. Moreover, in practice 86

Appelbaum et al. (1982). The US National Bioethics Advisory Commission, Final Report (2001). 88 Henderson et al. (2007) with further references. 89 Durand-Zaleski et al. (2008, p. 1). 90 Hadskis et al. (2008). 87

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it is difficult to identify all those who may be at risk of therapeutic misconception. Consent is thus an insufficient safeguard against exploitation. This strongly suggests that additional safeguards, like the requirement of proportionality, are needed. Other Causes of Unreliability The insufficiency and unreliability of consent are not only restricted to therapeutic misconception. Empirical data also show that many participants misjudge the possible consequences of research participation, both positive (benefits) and negative (risks and burdens).91 Lidz and colleagues, for example, undertook a study in the US, and found that subjects often consented to participation in clinical trials “with only the most modest appreciation of the risks and disadvantages of participation”92 In a US study involving participants in cancer trials, Stryker and colleagues found reason to recommend that more “effort is needed to ensure that clinical trial participants fully understand the risks and benefits of participation and are satisfied with their decision to enrol in a trial prior to signing consent forms.”93 A Norwegian study by Mangset and colleagues is interesting as it largely confirm common views in a particular illustrative way. The study included interviews with 11 acute stroke patients who had been thoroughly informed and asked to participate in a randomised thrombolytic trial, found that none of the patients had any clear understanding of the purpose of the trial, and the consequences of participation. Seven patients thought that the offer was recommended and, for them, the best treatment that they thought the physician was obliged to offer. Some patients compared randomisation with Russian roulette, human experiments during war or animal trials. Five patients argued that they regarded randomisation as a sign of immorality. The study also reported that “[n]one of the patients said that they had been exposed to any improper pressure to give their consent. Still, several statements revealed that they did not seem to be fully aware that their participation was voluntary.” One of the patients stated in this regard: I didn’t think that much about it, I probably thought it was common, that that’s the way things are. And because of that I don’t think it’s normal to react negatively, in other words not a good time to object, either.

Reportedly, “[t]ime pressure and anxiety during the first few hours after stroke onset also restricted the possibility of a free choice.” Trust in the researchers was an important reason for giving consent. As in other studies, misconceptions occurred. With regard to rejections the “two patients who rejected participation did so because they were conscious of the risk of death as a consequence of intracranial bleeding.” One of those patients stated in this regard: Because, as I said when I heard there was a chance of dying, then I’d had it with that test. I know I’m going to die, but I don’t want to die in an experiment like that, cause what happens, happens. I don’t want to risk my life for an experiment.

91

Sugarman et al. (1999) with references to 377 research projects on consent to research. Lidz et al. (2004). 93 Stryker et al. (2006). 92

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Seven patients had, on the other hand, “a fundamental belief in the importance of research and felt that they had a duty to participate.” Four patients meant that it was immoral to involve patients in the consent procedure and argued “such judgements are the doctors’ responsibility.” Six patients appreciated being asked to consent.94 A review of studies concerning randomised clinical trials and research participants’ understanding of randomisation, showed that: recent literature continues to report trial participants’ failure to understand or remember information about randomisation and equipoise, despite the provision of clear and readable trial information leaflets . . . a majority of participants judged it unacceptable for a doctor to suggest letting chance decide when uncertain of the best treatment.95

Such empirical data have led bioethicists to discuss whether it is a condition for the consent to be valid, that the participants understand the implications of randomisation.96 Indeed, it can be asked if consent ever is adequately understood and valid. The issue is not pursued here. As in many other situations in daily life, it is commonly accepted that people may consent to a lot of things, even though they do not fully understand the implications. The mere point to be made here is that consent is clearly an unreliable and insufficient safeguard. The Role of Participants’ Trust in the Researcher Consequently, participants apparently end up basing their consent on trust in the researcher, and thereby the participants seem to disregard the potential conflict of interest. At any rate, the central role of trust is frequently acknowledged in the bioethical literature. Using focus-group interviews of participants in a large scale Norwegian population study, Skolbekken and colleagues reported that: the consenters base their participation on trust in the researchers and the regulation of research in Norwegian society, rather than on specific information on the research in question.97

The conclusion in an often cited article, “Trust, the Fragile Foundation of Contemporary Research” written by bioethicists Kass and colleagues, may serve as a summary and timely reminder: Patient-subjects often trust their physician to guide them through their decisions on research participation. Clinicians, investigators, and IRBs must assure that such trust is not misplaced.98

In order to ensure that the trust is not misplaced, additional safeguards, like the requirement of proportionality, are surely needed.

94

Cf. the Stroke Studies accounted for in Section 10.3.6. Robinson et al. (2005); see also Robinson et al. (2004); Mills et al. (2003). See also Featherstone and Donovan (2002). 96 Wendler (2009a). 97 Skolbekken et al. (2005). 98 Kass et al. (1996). 95

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Conclusion Even though prospective participants are able to consent, consent is not necessarily a sufficient and reliable safeguard. The consent does not render the requirement of proportionality superfluous. In general, the requirement of proportionality may thus be seen as a necessary and therefore legitimate additional safeguard to the requirement of consent, aimed at hindering undue exploitation.

5.4.4 The Relationship Between Participants Right to Self-Determination and Researchers Duty of Care It can be argued that at least some prospective participants (and legal representatives) are able to sufficiently foresee and appreciate the possible consequences of participating in biomedical research. Besides, possible positive and negative consequences of participation may be easily comprehensible. The prospective participants can, in addition, be especially able and informed (typically health personnel). Furthermore, the participants may be especially altruistic and keen on research, and thus perceive risks and burdens differently than most others. If so, it may yet be asked if such circumstances render the requirement of proportionality superfluous. In other words, the consent should be, at least for these persons, regarded as a sufficient safeguard, in accordance with Bergkamp’s position, which resembles the principle in Roman law that he who consents, suffer no wrong – volenti non fit injuria.99 Restricting individuals’ possibilities of participating in research, and thereby to contribute to the advancement of science, can be seen as an unreasonable limitation of autonomous individuals’ right to self-determination. It can also be seen as contrary to individuals’ altruistic interests and the ethical principle of benevolence.100 It may be asked whether it is an unnecessary and disproportionate interference with prospective research participants’ right to private life and self-determination in Article 8 (1) of the European Convention on Human Rights.101 Should not an informed, voluntary, understanding and motivated person be able to consent to being infected by a potentially lethal virus, for example, HIV or swineflu, if participation in an otherwise meticulous research project might lead to an effective treatment (vaccine etc.) and potentially stop a global epidemic?102 In Scandinavian legal theory this question has been mainly related to the boundary of self-determination and consent as a defence for criminal impunity and legal

99

Bergkamp (2004); see Section 5.4.2; see Andenæs (1997, p. 177). See Section 4.5.3 (the Belmont Report). 101 Disproportionate does here refer to the general principle of proportionality in Convention law. 102 The question was actually raised in the 1980s at the onset of the HIV-epidemic, see Ruyter (2000). 100

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liability: what may a person legally consent to?103 The debate also concerns whether a contractual or a paternalistic approach should be applied. A contractual approach sees the prospective research participant as an equal party to the researcher. The offer to participate in a research project should then be seen as a contractual offer. The consent should be regarded as an acceptance, making up a regular agreement. As a starting point, the prospective participant is, according to this approach, free to enter into any contract with the researcher. In such a perspective a person should be allowed to volunteer for high risks biomedical experiments, because people are allowed to conduct base-jumping, mountaineering, military service and so on. It has been held in Norwegian and Danish legal theory that a consent which is contrary to “decency” or which is manifestly unreasonable is invalid.104 According to the Norwegian Penal Act § 235, consent to “serious bodily harm” cannot be used as a defence for criminal impunity. It has been suggested that the limit goes with the unnecessary amputation of a finger or the like.105 In biomedical legal theory this stand has been criticised for being too liberal.106 Kjell Andorsen have stated that it is “tempting to interpret the Penal Act § 235 (1) restrictively by requiring that the intervention must be reasonable, based on a broad ethical assessment.”107 With such a strict censorship the contractual approach does not end up far from the more paternalistic approach. The paternalistic approach holds, as a starting point, that the human body and dignity is an inalienable good. Thus, an individual’s right to self-determination, with regard to his or her own body, is limited. People who are able to safeguard their own interests should be allowed to do so, but only as long as the behaviour is not contrary to human dignity. People are not entirely free to do what they want. As shown above, the interest of protecting human dignity is also a public interest.108 Examples of this are prohibition of active euthanasia, restrictions on transplantations, prohibitions on sale of organs, sale of sex, outright slavery and so on.109 The rationale behind such restrictions is not just to protect the person against him- or herself, but also to preserve human dignity and public morality. Allowing excessively risky research may devalue humans to mere means and, thereby be contrary to human dignity and public morality. As such it is easily associated with state induced paternalism. An additional rationale should, as the empirical data on therapeutic misconception and other misunderstandings suggest, be that the risk of exploitation is

103

See Syse (2000). See Aasen (2000) and Hybel (1998). 105 Aasen (2000, p. 234) with further references to Matningsdal who put forward the suggestion. 106 Aasen (2000, p. 234) with further references. 107 Andorsen (1992). 108 See Section 5.2.2. 109 See Aasen (2001); Andorsen (1992); Halvorsen (1998, pp. 56–62). 104

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nonneglectable, but this argument carries little weight here, as I, for the sake of argument, assume that the prospective participant fully understands the consequences of his or her own actions. The discussion is highly relevant in an analysis of the requirement of consent to research, but it is not necessary to explore the full debate, with all its nuances, here. It is difficult to argue convincingly and consistently that the constraints on individuals’ autonomy should be so strict that they would include substantial restraints on biomedical research, other than in rather obscure and outright harmful research projects. Why should I possess the freedom to scale Mount Everest, but not participate in a HIV-study of possibly great public utility? This discussion also touches delicate matters in relation to the issue of accept of risk in tort law, which is of little guidance here.110 The reason why the material limitations of individuals’ right to selfdeterminations is of limited interest is that researchers are not relieved from their duty of care by participants’ consent (or “accept of risk”). Consent is not a carte blanche for the researcher. The researcher’s duty of care exists regardless of consent. The requirement of proportionality is inherent in the researchers’ duty of care. And the duty of care limits researchers’ freedom to manoeuvre. The discretion only goes so far. This stance has a firm legal basis in Norwegian Health law (and surely also in Health Research law).111 Consequently, since the requirement of proportionality is first and foremost a safeguard and a central element in researchers’ duty of care, the risks and burdens must be in proportion to potential benefits before the participant is asked to consent. Research participation should be a reasonable choice – before consent. As underscored in the US case Grimes v. Kennedy Krieger,112 consent does not make an inappropriate research project appropriate. Excessive and unreasonable risks and burdens do not become proportionate and acceptable upon the participant’s consent. This recognition is essential, as it implies that researchers’ behavioural freedom is more limited than prospective participants’ freedoms, including their right to self-determination. Put more bluntly, individuals may, generally speaking, act in a “foolhardy” manner, and even “careless”, as long as it only concerns themselves, for example, by consenting to take part in a reckless or unnecessary experiment. Researchers’ are on the other hand restricted by their duty of care, professional guidelines (“first to do no harm”), ethics and legal norms, such as the requirement of proportionality; we – the society at large, including prospective participants, but also other researchers – expect more from a responsible researcher.113 Thus, research projects that involve unreasonable or excessive risks and burdens might be contrary

110

With regard to Norwegian tort law, see Kjønstad (2005a, b); see also Anfinsen (2008). See Aasen (2000, p. 236); Kjønstad (2005, pp. 211–263); Halvorsen (1998, pp. 57–62). 112 Accounted for in Section 12.5.10. 113 Likewise Brody (1998, p. 49). 111

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to society’s expectations and trust in researchers. It may also be the first step down a very slippery slope. Thus, participant may act foolhardy, but researchers may not. Consequently, the competent, informed, and motivated participant is, in principle, free to take upon almost any risks and burdens for the sake of science and future patients. Researchers are, however, not allowed to include persons in biomedical research projects that involve unacceptable and disproportionate risks and burdens. It therefore becomes less important to determine the outer limits of prospective participants’ right to self-determination, as the crux will be the assessment of proportionality and the researcher’s duty of care. This illustrates the independence of the requirement of proportionality from the requirement of consent. Some of the confusion in literature about the requirement of proportionality, such as Bergkamp’s hasty and ill-founded position,114 seems in part to relate to a misconception about relationship between the requirement of proportionality and the requirement of consent and individuals right to self-determination. Furthermore, my impression from a review of much of the literature is that the autonomy of prospective participants is both underrated and overrated, sometimes simultaneously: Meaning that some participants are assigned unnecessarily restraining safeguards (paternalism), while others are insufficiently protected. The former tendency relate to well-informed and altruistic persons, while the latter primarily relate to vulnerable persons.115 The implication is that the former are not allowed to take legitimate risks for sake of others, while the vulnerable are exposed to unjustified risks and burdens for the sake of others. This recognition does not, however, mean that prospective participants’ understanding, willingness, and ability to consent are irrelevant, not even in the assessment of proportionality. On the contrary, whether risks and burdens are proportionate varies individually and contextually. Whether the requirement of proportionality is fulfilled depends on individual conditions such as whether the participant voluntariness.116

5.4.5 Is the Requirement of Consent Necessary? The insufficiencies and unreliability of the requirement of consent may rush some to argue that the obtainment of consent is illusory and hence in vain. Moreover, the consent process is time-consuming, and information, which the participants anyhow do not understand, can even cause anxiety and distress among some of the participants. Information can thus be a risk factor in itself.

114

Bergkamp (2004), accounted for in the introduction of this section. See the definition of vulnerable person in Section 3.8 which implies that the many research participants in interventional biomedical research probably should be regarded as vulnerable. 116 See Chapters 8 and 9. 115

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It may also be argued that many patients make “irrational” choices and decline because they do not understand, leaving the study population not representative, and the results biased. Thus important research may be impaired. This line of argument may lead to the conclusion that the requirement of consent should be abandoned completely or at least substantially loosened up. Research (and common knowledge) does, however, clearly indicate that people want to be informed, even if they do not fully understand everything.117 Many do probably also want information, even if it may be unpleasant. In this perspective, the requirement of consent is less about ensuring due care and protecting the participants welfare. Rather it is about ensuring respect for the patients’ autonomy and right to self-determination. As such, the obtainment of consent is about common courtesy. Thus, the arguments put forward above about the centrality of the requirement of proportionality by no means undermine the firm foundation of the requirement of consent in biomedical research law. The discussion merely signifies that consent is an unreliable and insufficient safeguard. Others are obviously needed. And arguably, the most important is the requirement of proportionality. The requirement of proportionality does not make the requirement of consent superfluous, or vice versa.

5.4.6 Consent by Proxy Prospective research participants may be unable to give a legally valid consent because of circumstances such as minority, dementia, permanent or momentary mental or physical illness, unconsciousness etc. Individuals unable to consent are vulnerable to exploitations as they generally have insufficient abilities to protect their own interests. The cognitive abilities and requirements vary individually and contextually, and the decision whether a person is able or not, is often difficult in practice.118 A widely recognised and adopted safeguard for individuals not able to consent is that they should have their interests attended to by a legal representative or an authority, who should give a legally valid consent (so-called consent by proxy). A legal representative is then a natural or legal person who by national legislation is designated to attend the interests of the individual not able to consent, and to take certain decisions on behalf of that person.119 117

See, for example, Sugarman et al. (1999); Skolbekken et al. (2005); Mangset et al. (2008). See, for example, Drane (1985); Appelbaum (2007); Aasen (2000, pp. 356–361). 119 Oviedo Convention Articles 17 and 6; Additional Protocol Article 15; Clinical Trials Directive Articles 4 and 5, Preamble (5). The legal representative for children will normally be their parents or legal guardian, and for adults not able to consent, normally their next of kin, who presumably have concrete knowledge about the person’s interests and preferences. A legal representative may, if the law permits, also be a more distant legal person or an authority, such as a Research Ethics Committee or a governmental agency. The latter arrangement may be the only available 118

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The safeguard of proxy consent raises the question whether the legal representative is equally capable of judging the acceptability of risks and burdens as the individual him- or herself. The law is unambiguously negative: The legal representatives’ freedom of choice on behalf of the prime subject does by no means equal that of the subject him or herself. European Convention law and Community law prescribe unambiguously that the degree of acceptable additional risks and burdens to persons not able to consent is as a starting point lower than for persons able to consent, see Articles 15 and 19 of the Additional Protocol, and Articles 3, 4 and 5 of the Clinical Trials Directive.120 The apparent reasoning behind those rules is that each individual is generally more capable of safeguarding, and not least knowing, his or her own interests. Moreover, it is ethically and legally problematic that it is not the one who will have to carry the risks and burdens who decide whether the risks and burdens are acceptable or not.121 Thus, consent by proxy does not coincide with a valid consent from the individual concerned. It is sort of a next best arrangement – the best available option. This also applies to parents, who have limited legal capabilities of consenting to research involving their children.122 Parents may, for example, not consent to children taking part in high risk activities contrary to the best interest of the child, such as hazardous research entailing disproportionate risks and burdens.123 Thus, the rationale and legitimacy of the requirement of proportionality as outlined above, apply even more so to research on persons not able to consent than does on persons able to consent.

5.4.7 Conclusions Regarding Proportionality and Consent Based on empirical studies on consent, neither consent nor consent by proxy provides a sufficient safeguard for human subjects in biomedical research. This assertion is supported by the obvious potential conflict of interest between the participant and the researcher. This is further supported by the recognition of inequality of power between the often inadequately informed and thus vulnerable participant and the expert researcher. option where the next of kin is unavailable etc., for example in emergency clinical research where there may be no time for consultation. Some, in practice very few, prospective participants (adults) may also be placed under legal guardianship with an appointed guardian to attend their interests. Who may represent an incapacitated person, will not be elaborated here. Both Convention law and Community law refer to national legislation and member states’ margin of appreciation. National variations may thus occur. 120 See Chapter 12. 121 See Maar (2007). 122 See Maar (2007) (Norway); Similarly: Ross (2006) (US). 123 Maar (2007); See also Grimes v. Kennedy Krieger, accounted for in Section 12.5.10.

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Thus a legitimate aim of the requirement proportionality is to mend the insufficiency and unreliability of consent, and offer additional protection of the participants’ interests, welfare, and human dignity. The two requirements then stand out as twin core principles, independent and sufficiently justified in their own right.

5.5 Proportionality and the Aim of Facilitating Research As shown, the predominant purpose of the requirement of proportionality is to protect research participants. It may therefore be asked whether the beneficial aspects of biomedical research are neglected in the eagerness to protect the individual. Occasionally scholars state that “participation in medical research very rarely is in the very best medical interests of the participant in the strict sense”.124 The wording “strict sense”, or similar “narrow sense”, suggests that a person’s best interests are not necessarily that narrow. The term “strict sense” suggests an opening for other considerations than pure protectionism and isolationism. One such consideration may be the long term effects of research, the potential scientific and societal benefits, such as benefiting our common knowledge base, future patients, relatives and even oneself as a future patient. As shown above, altruistic considerations are recognised as legitimate in the instruments. People may take upon risks and burdens for the sake of others. Moreover, the instruments assume that most people are altruistic and to a certain degree inclined to take upon risks and burdens for the sake of others, as long as the end justifies the mean. This controversial assumption is, for example, evident in the provisions on the requirement of proportionality providing an opening for research on persons not able to consent even though there are no prospects of direct therapeutic benefits to the participants. This view is most notable in Article 19 of the Additional Protocol concerning research in clinical emergency situations where it is not possible to obtain consent from neither the participant nor his or hers next of kin. Yet, Convention law allows that such persons are exposed to risks and burdens for the sake of others in an emergency situation, although only minimal risks and burdens. Hence, the potential scientific and societal benefits of research are recognised as a relevant factor in the assessment of proportionality. It is sufficient to point to the wording of both the Additional Protocol and the Clinical Trials Directive. In the Preamble of the Additional Protocol it is recognised: that progress in medical and biological sciences, in particular advances obtained through biomedical research, contributes to saving lives and improving quality of life [and that] the advancement of biomedical science and practice is dependent on knowledge and discovery which necessitates research on human beings.

The requirement of proportionality is thus not solely aimed at protecting the narrow self-interests of the participants (best interest in a strict sense), that is the protection 124

Lötjönen (2006) [Italics added].

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from human experimentation as such, or from any additional risks and burdens. Rather it is about protecting individuals from disproportionate and unacceptable risks and burdens. The requirement then also aim at facilitating research; that is to determine when research and the exposure of human subjects to additional risks and burdens may be justifiable and lawful. Thus, the requirement of proportionality aims to dissolve the overriding dilemma of biomedical research; gaining new and useful knowledge, whilst doing no harm; and by that entertaining common good whilst respecting and protecting the dignity and rights of the individual participant. It is about setting a fair balance between the interest of the individual research subject and the interest of science and society. Hence, the principle of proportionality modifies the principle of human primacy, as it assumes that the interests of science and society can override the narrow selfinterest of individual protection in some cases; but then on certain strict conditions, and only to a very limited degree. The apparent reasoning is that a modest modification assumingly has general public support, and that nontherapeutic research is not contradictory to human dignity and basic human rights. Presumably, if the public opinion did not accept putting people at any risk for the sake of science and future patients, the legislators would have to withdraw from international obligations and revise national legislation. In such a perspective the requirement of proportionality functions as a reasonability test. Indeed, the US National Bioethical Advisory Commission asserted in its final report in 2001 that the end goal of assessing risks and potential benefits is to ensure that prospective participants who are asked to consent are provided with a “reasonable choice”.125 The reasoning is that if research participation is not a reasonable choice, it may be assumed that participation contradicts prospective participants’ interests. Similarly, Donald Evans and Martyn Evans call their book on the ethical review of clinical research “a decent proposal”, which could very well be seen as the aim of the requirement of proportionality; that is to ensure that an invitation to participate in biomedical research is a decent proposal.126

5.6 Conclusions The requirement of proportionality is a safeguard primarily aimed at protecting the interests of the individual, while at the same time facilitating necessary research, giving precedence to the former as prescribed by the principle of human primacy. As such it is a balancing tool for dissolving the ever present tension between various interests in biomedical research within certain strict limits; both at an overarching

125 126

The US National Bioethics Advisory Commission, Final Report (2001, p. 74). Evans and Evans (1996).

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level and at more concrete level in the weighing of risks, burdens and potential benefits. In such a perspective the purpose of the requirement of proportionality resembles, builds on and operationalises the core purpose of the legal instruments themselves. This demonstrates the centrality of the requirement of proportionality in the regulation of biomedical research involving human subjects. The purposes (raison d’être) of the requirement of proportionality can be summarised to be: 1. To ensure due care, hinder that participants and others are exposed to unnecessary, unreasonable, and excessive risks and burdens, and ensure that participation represents a reasonable choice. 2. To protect vulnerable persons and hinder exploitation; and thereby mend the unreliability and insufficiency of participants’ consent. 3. To facilitate justifiable research and scientific progress in biomedicine by providing a test for determining when risks and burdens are acceptable and justified by the potential benefits, and thereby, when human experimentation legitimately can be undertaken.

Part II

Which Risks, Burdens, and Potential Benefits Are Relevant, and How Should They Be Estimated?

Chapter 6

Introduction

Before it can be determined whether a research project “involves risks and burdens to the human being disproportionate to its potential benefits” as required in Article 6 (1) of the Additional Protocol, relevant risks, burdens, and potential benefits must have been identified and estimated. They must be described before they are weighed. The appendix to the Additional Protocol requires, amongst other things, that the information to research ethics committees must entail: (ii) the aim and justification for the research based on the latest state of scientific knowledge; (ix) a description of the nature and degree of foreseeable risks that may be incurred through participating in research; (x) the nature, extent and duration of the interventions to be carried out on the research participants, and details of any burden imposed by the research project

Article 8 of the GCP Directive, concerning the content of the Investigator’s Broschure, clearly foresees a description of relevant risks, burdens, and potential benefits1 : 1. The information in the investigator’s brochure, referred to in Article 2(g) of Directive 2001/20/EC, shall be presented in a concise, simple, objective, balanced and nonpromotional form that enables a clinician or potential investigator to understand it and make an unbiased risk-benefit assessment of the appropriateness of the proposed clinical trial.

The Norwegian Health Research Act includes an explicit requirement in § 22 (2) (1): Before research on human beings is commenced, a thorough evaluation of risks and burdens to the participants must be undertaken [My translation].

1 Article 2 (g) of the Clinical Trials Directive defines “investigator’s brochure” as “a compilation of the clinical and non-clinical data on the investigational medicinal product or products which are relevant to the study of the product or products in human subjects”.

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Introduction

Thus, both Convention law and Community law requires an adequate description of risks, burdens, and potential benefits. This requirement raises the following questions: 1. Which risks, burdens, and potential benefits are relevant in the assessment of proportionality? 2. How should risks, burdens, and potential benefits be estimated?

Chapter 7

Which Risks, Burdens and Potential Benefits Are Relevant?

7.1 The Starting Point “Risk”, “burden”, and “potential benefit” were defined in Section 2.3. The question addressed in this chapter is which risks, burdens and potential benefits are relevant in the assessment of proportionality. That a risk, burden, or potential benefit is relevant, means that it is generally legally permissible, and maybe also obligatory to take it into account in the assessment of proportionality.1 The legal starting point is relatively straightforward: Only harm, burdens, and benefits that may result from the research are relevant. Harm, burdens, and benefits stemming from other activity, such as ordinary health care, are then by and large irrelevant in the assessment of proportionality.2 In accordance with general principles on causality, two essential conditions must be fulfilled: • Cause in fact, and • Cause in law In legal practice, the question of causality is difficult, because of practical difficulties in proving a causal relationship. The question in a negligence suit is usually not whether the risk or the harm is relevant, but rather whether a satisfactory causal relationship between the activity and the harm can be established. The practical challenges and rules on onus of proof fall, however, outside the scope of this book.

1 Similar Eckhoff (revised by Helgesen) (2001, p. 25), and Nygaard (2004, p. 111), in relation to general legal method. 2 This starting point is natural and follows from general legal principles on causality, see Nygaard (2002) with further references to Norwegian case-law. In US Federal law this is stated explicitly in the “Common Rule” “46.111: In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research).”

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7.2 Cause in Fact Cause in fact refers to the notion that there has to be a possible factual connection between the activity (the research) and the outcome (harm, burden, or benefit). An activity “is cause of the victim’s damage if, in the absence of the activity, the damage would not have occurred”; in Latin: conditio sine qua non.3 If research is the sole activity it is clear that all harm, burdens and potential benefits the research project may result in (all possible positive and negative consequences), are relevant, and must be considered. The theoretical and practical challenges often relate to the circumstance that biomedical research is intertwined or combined with ordinary health care. Research projects may consist of several procedures with different characteristics and effects. An example is therapeutic research, such as a clinical trial aimed at testing a new surgical method for hip-fracture operations. The main reason for testing the new method is to obtain new knowledge about the method (research). Simultaneously, the patient’s hip-fracture will also be treated (health care). If the main purpose of the intervention is research, the procedures are all research procedures even if they have multiple effects (including direct therapeutic effects). The reason is that the participant would not have undergone this procedure, at this exact time, in this setting, if it were not for the research project – conditio sine qua non. This implies that risks and burdens resulting from participation in a research project are “extraordinary”, because the individual had not been exposed to them if it where not for the research project; a research risk is thus not a risk of daily life.4 If it is the other way round, the solution is different. An example is a patient who, as part of ordinary health care, is set up to undergo a liver biopsy because of abdominal pain. The risks, burdens, and potential benefits entailed in the procedure would then be related to ordinary health care and not research. The interventional procedure would be purely therapeutic. The fact that some researchers designed a research project that subsequently would further analyse all liver biopsies from that health ward after the diagnostic procedure was finished would not alter this. The research project would then be an observational study rather than an interventional study. The research is undertaken subsequent to health care, and the two activities, as well as the possible

3 The European Group on Tort Law, which has drafted Principles of European Tort Law intended to express common legal principles. Article 3:101. 4 I mention this as it is a condition for liability on a no-fault basis in Norwegian Tort law, cf. Rt.1960.841 “Vaccine judgment” where the Norwegian Supreme Court found that risks of vaccination was extraordinary (although remote) and something individuals was not exposed to in daily life. Moreover, vaccination was undertaken in the interest of society: In Rt. 1960.429 “Tuberculoses Judgment No. I”, the result was opposite as the risk of being infected with tuberculosis was just as high in the civil society as it was in the army (a recruit had sued the Army because he had been infected with tuberculosis). The risk was therefore not extraordinary in the latter case; see further Kjønstad (2005a, pp. 110 et seq); Simonsen and Nylenna (2005, pp. 287–302).

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consequences thereof, should be clearly distinguishable. The research project would not interfere with the health care.

7.3 Cause in Law Cause in law refers to rules concerning remoteness of damage, and the general principle that the consequence (harm, burden or benefit) must be reasonably foreseeable.5 There has to be a reasonable closeness and connection between the research procedure and the potential harm, burden or benefit. A “proximate cause” must be established.6 It is thus mainly risks, burdens, and potential benefits that are naturally associated with biomedical research that is of interest. As formulated in Norwegian tort law, the effect (harm/burden/benefit) should be typical for this activity.7 For example, the risk that a research participant may get a heart attack when taking the steps instead of the lift to the research site is usually an irrelevant risk in the assessment of proportionality. The risk of the research building collapsing is similarly remote and not typical in biomedical research. Such accidents are commonly referred to as “freak accidents”. They are neither common, nor typical. The risk from falling off a treadmill, or getting a heart attack when measuring maximum oxygen uptake as part of a research project is, on the other hand, clearly relevant, even if the probability is very low. Such incidents are fortunately infrequent, but yet typical for this kind of activity. The observed Research Ethics Committee frequently underscored that the risk of running on a treadmill to exhaustion was relevant, and did not tolerate that the researchers stated that there were “no risks involved”, even when the research projects involved young athletes accustomed to such a risk in their daily lives.8 Another risk discussed by the observed Research Ethics Committee, was whether research interviews with suicidal patients increased the risks of suicide, and whether the participants should be insured against harm that could have a causal relationship to the interview. Traditionally the Committee held that such a risk usually existed. However, empirical data challenged this view. Indeed, the data suggested that participation in research interview studies reduced the chance of suicide. The Committee acknowledged the empirical data, but argued that although the chance of suicide was reduced for the research population as a whole, that was not necessarily the case at an individual level. If a participant committed suicide, it would be quite possible to establish both causality and proximity of cause between the interview and the suicide, if the interview and subsequent suicide took place close in time, even though most other participants experienced no negative effects or even positive 5

European Group on Tort Law. Article 3:103 (1). Harpwood (2005). 7 Cf. Rt. 1960.841 Norwegian Supreme Court, the Vaccine Judgement. 8 See Section 2.3. 6

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effects. The Committee thus concluded that the participants had to be insured on a no-fault basis.9 The Committee’s decision was appealed to the National Committee, who apparently did not share that view.10 The Research Ethics Committee was, however, correct because it is the individual risk that is important: The assessment of proportionality must in principle be assessed individually. This means that the researcher has to take the participant as he or she is. The latter is a central legal maxim in Norwegian Tort law,11 but is applicable also in this context. The maxim implies that the researcher must also take into consideration that some individuals might, because of physical or psychological predispositions for injury, particular vulnerability, or otherwise (re)act differently than the average participant; the latter also include odd and “irrational” behaviour. That may imply that some individuals, who are at increased risks, should, if practically possible be identified and excluded from participation in research. Thus, the deduction that a risk is low if the risk is low for most participants is not necessarily accurate. If the risk is high for some (unidentified) participants, it may imply that the general risk also is high. For example, if there is a chance that out of 100 participants, five (preunidentifiable participants) might suffer from severe and enduring psychological reactions. The overall risk of serious harm is 5%, which is generally a rather high risk in nontherapeutic research,12 even though the risk of harm for the remaining 95 participants is zero. The MIDIA Study might serve as an example of the latter calculations.13 Particularly About So-called “Known Unknown Risks” The latter concern raises the issue of “known unknown risks”. The Clinical Trials Directive states that only “foreseeable risks and inconveniences” are relevant in the assessment of proportionality.14 One may then argue that “unknown risks” are not relevant, simply because they are not known. The argument is partly right. However, some unknown risks are known, that implies that we know that something negative might happen, but we do not know exactly how, when, and to whom, thus the formulation “known unknown risks”. In clinical trials, for example, it is foreseeable (known) that unexpected negative things may happen, especially if many participants are included, typically in a vaccine trial. Experience testifies to that. Unexpected complications may be a result of unknown and unexpected qualities with the medicinal product or the individual

9

REC meeting 21 February 2008. The National Committee overruled the REC decision; but this may have been for other reasons (an overall judgement) which also were discussed in that case. 11 See, for example, Rt. 1992 p. 64 The Norwegian Supreme Court in the second contraceptive pill judgment, and Rt. 1997 p. 1 the Rossnes judgment; see Kjelland (2008) for an in-dept account of the “vulnerability-principle” in Norwegian Tort Law. 12 See Part III where the acceptable risk is sought clarified and calculated. 13 Accounted for in Section 12.5.8. 14 Article 3 (2) (a). 10

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participants. Some individuals may, for example, be predisposed or especially vulnerable for certain diseases, which the new drug may trigger. It may be impossible to single out these especially vulnerable subjects beforehand. Yet such unknown risks might be considered relevant, as they are known to exist. In that respect the risks, although unknown, are foreseeable and expected. The reason is that such risks are typical and common in biomedical research.15 In Norwegian tort law, such risks are commonly referred to as “concrete unforeseeable, but generally inevitable” hazards, which implies that for the researcher it is virtually impossible to foresee and hinder the harm, but we know by experience that such complications sometimes occur in biomedical research.16 In the Meningococcal B Vaccine Trial17 the researchers were criticised for not informing prospective participants of the remote chance of unknown serious complications. Of the first 117 657 participants in the phase III of the trial, maybe as many as five participants suffered various rare, but severe, neurological complications (Gillain Barré syndrome, myelopathy/myelitis, multiple sclerosis, myalgic encephalomyelitis (ME), transverse myelitis etc). Injured participants felt betrayed, since they had not been informed about the unknown risk of severe complications. On the contrary, the vaccine was said to be “safe”. Some of the victims were compensated, as it was more likely than not, that the vaccine had caused or contributed to (triggered) the damage. These complications were unexpected, but they still had a reasonable closeness to the trial and the intervention. The researchers were also beforehand acquainted with the existence of an “unknown risk”, which any vaccine trial carries. Thus the risk was unknown, but foreseeable and “known”. This implies that worst case scenarios may be relevant, and should be considered in the assessment of proportionality. Nevertheless, in my observational study of a REC I found that information on worst-case scenarios (the unlikely risk of serious complications) was seldom provided to participants. However, the observed Research Ethics Committee consequently corrected researchers who claimed that their intervention was “risk-free”. The Meningococcal B Vaccine Trial showed that the latter practice was imperative. To state that an intervention is safe or risk-free, when it in fact carries risks of severe (but largely unexpected) complications, is clearly inadequate and misleading information. It is, however, difficult to say something general about to what extent – how detailed – the information should be about remote but possible catastrophic consequences. Sometimes a general sentence might do in order to not “drown” or “obscure” more important information, for example, about expected burdens, and more probable, but lesser harms.

15 In Norwegian Tort law the risks would be typical [“særegen”] and common [“stadig”], see Rt. 1905.715 the Norwegian Supreme Court in the Water drain judgment, and Rt. 1960.841 the Vaccine judgment. 16 Hagstrøm (1985) on explaining harms covered by a no-fault responsibility. 17 Accounted for in Sections 11.3 and 11.4.

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7.4 Typical Relevant Risks, Burdens, and Potential Benefits In lay language the identification of relevant risks, burdens, and potential benefits is about clarifying possible consequences (effects) of biomedical research. Risks, burdens and benefits may vary in nature. The Explanatory Report to the Additional Protocol does for example differentiate between physical, psychological, and social risk of harm, and the same categories may be applied to burdens and potential benefits. Recommendations elaborating on the Clinical Trials Directive regarding research on children use similar terminology.18 Table 7.1 Examples of typical potential benefits, burdens and risks Typical potential benefits

Typical burdens

Typical risks

Benefits to society at large, to science, and medical practice in general.

Inconveniences, spending time on travel, testing etc.

New, enhanced, or verifying knowledge about the human body, causes of sickness, diagnostics, treatment, etc. Basic science as well as applied science. Knowledge that verify knowledge, or lead to better research methods, or new hypothesis etc. (method) Development of new medicinal products (drugs), equipment or surgical methods. Direct health benefits to other identifiable patients currently in treatment. Direct health benefits to the participant him- or herself.

Efforts related to undergoing a test, exercising, taking a drug etc.

Risk of physical harm, such as unexpected momentary or enduring illness and pain. Reduced life expectancy. Death. Etc. Risks of psychological harm. Inflicted insight and emotional distress and suffering. Loss of self esteem, depression, sleep deprivation etc.

Benefits to the researcher (scientific credit, recognition, money etc.), research institutions, and others.

18

Discomforts related to for example gynaecological or gastrological examinations.

Risk of infringements of private life, such as unauthorised access to sensitive personal data.

Pain related to expected side effects, pain from a venepuncture etc.

Risk of dignitary harm caused by disrespectful treatment.

Travel expenses, sick leave because of expected side effects etc. Fear, anxiety, distress or discomfort (rational or not) related to for example knowing and not knowing, uncertainty etc. Burdens to others, such as relatives, employer etc.

Risk of social, legal and economic harm.

Guidelines on Paediatric Research 2008.

Risk of mishaps and negligence, which in turn may lead to the aforementioned harms. Risks of harm to others like relatives, employer, society, environment etc.

7.5

In What Order Should the Factors Be Clarified?

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It may be asked whether this differentiation is legally relevant, meaning that it has any legal effects. The answer is surely no. The intention behind the differentiation is to underscore that not only traditional physical interventions and consequences are relevant. But that point would have been clear without the categories. Thus the categories are mere examples and conceptual tools. In Table 7.1, typical risks, burdens, and potential benefits in biomedical research noted. It is underscored that the examples are by no means exhaustive. Some examples could easily have been put in another category, and some examples are similar and even overlapping. The intent is to illustrate the variety and complexity, but also to further clarify and illustrate the most important and common elements in the assessment of proportionality.

7.5 In What Order Should the Factors Be Clarified? One may ask in which order risks, burdens and potential benefits should be clarified. It is common in bioethical literature to start with a description of risks and ends with a description of benefits. This approach makes sense, as this is the order in which the central elements are listed in regulatory instruments. However, in practice the order was reverse: 1. The observed Research Ethics Committee usually, probably intuitively, started with a clarification of potential benefits, i.e. aims and method of the project; what are the researcher going to do and why? What may be gained from this particular research project for society, science, the participants etc? Such a start is natural and logical, as the potential benefits constitute the fundamental justification for human experimentation, and determines whether the research project is necessary. Hence, if there are no potential benefits, the research project is unnecessary, and should not be commenced.19 If so, there is no need to investigate risks and burdens. 2. After the clarification of possible positive consequences (the justification), it is natural to describe the expected negative consequences – burdens: What are the costs and burdens, and to whom? Then more severe, largely unexpected, but inevitable, negative consequences are addressed – risks: What can go wrong if everything that can go wrong does go wrong? Which conditions make this particular research project or procedure dangerous, and to whom? 3. Finally, the possible positive consequences are weighed against the possible negative ones in order to assess whether there is a proportionate relationship: Do the potential benefits justify the burdens and risks involved? What can be called “the practical approach” appears to be far more natural than the traditional “theoretical approach” and is therefore to a certain degree applied in this 19

See Section 9.5 on the requirement of necessity.

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book. However, the popular wording “risks, burdens, and potential benefits”, which is also used in the Additional Protocol Article 6 (1), will still be frequently used in the following. This should be unproblematic and merely signifies that the order does not have any legal implications as such; it is the concrete result that is of interest.

7.6 Conclusions on Causality and Relevancy Only risks, burdens, and potential benefits that may wholly or partly be a result of research are relevant in the assessment of proportionality. The risks, burdens and potential benefits must be “foreseeable”, and a “proximate cause” must be established. There has to be a reasonable closeness and connectivity between the research procedure and the potential harm, burden, or benefit. This does not preclude the relevance of known unknown risks and possible mishaps. Risks, burdens, and potential benefits that are solely a result of ordinary health care or other activities, and which would have taken place regardless of the research project, are generally irrelevant (even though they may be taken into account in an overall contextual assessment of proportionality). Relevant elements should be identified to the extent possible and reasonable. That a risk, burden, or potential benefit is relevant imply that it is generally legally permissible, and maybe also obligatory to take it into account in the assessment of proportionality.20 Whether, and to what degree the relevant factor will influence the assessment of proportionality largely depends on its weight. Risks, burdens and potential benefits must therefore be estimated to assess their weight.

20

Similarly Eckhoff (2001, p. 25), and Nygaard (2004, p. 111) in relation to general Norwegian legal method.

Chapter 8

How to Estimate Risks, Burdens, and Potential Benefits

8.1 Starting Points To carry out a meaningful, rigorous, and satisfactory assessment of proportionality, relevant risks, burdens, and potential benefits must not only be identified, they must also be estimated and adequately described.1 In my observational study of a REC I found that only few researchers included a satisfactory description of risks, burdens, and potential benefits in their applications to the Committee.2 The elements were hardly ever estimated, except in some clinical trials sponsored by the pharmaceutical industry. Unsatisfactory descriptions cast doubts on whether the researcher had estimated the relevant factors diligently, and thus, assessed proportionality correctly. Moreover, it posed the question whether research ethics committees would be capable of assessing proportionality in a great variety of research projects based on inadequate descriptions. While identifying relevant factors is difficult, the estimation is by no means easier. It is intrinsically difficult to predict and estimate possible effects of a research project. The estimates must often rely on uncertainties, predictions, and, more or less, “subjective” perceptions with regard to the factor’s magnitude and likelihood of occurrence. It must, nevertheless, be undertaken to the extent reasonable, as the research project’s justification relies on it. A recent case illustrates the seriousness of neglecting the task of identification and estimation of risks and burdens: The US Food and Drug Administration (FDA) submitted in 2008–2009 fictitious research protocols to test three selected Institutional Review Boards (IRB; equivalent to REC). In one of the IRBs the FDA found serious violations of the legal framework which represented “risks to the rights and welfare” of participants in research. The IRB’s activities were suspended in April 2009 by the FDA. One of the violations concerned the identification and estimation of risks:

1 2

See Chapter 7 for the explicit legal foundation. See Section 2.3.

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8 How to Estimate Risks, Burdens, and Potential Benefits The IRB failed to determine that risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result. [21 CFR § 56.111(a)(2)]. As noted above, Coast IRB did not have sufficient information to identify risks to subjects; nor was sufficient information available to assess anticipated benefits.3

The objective in this chapter is to discuss some general aspects with regard to the estimation of potential benefits, burdens, and risks, before the weighing and assessment of proportionality is fully addressed in Part IV.

8.2 Risks and Burdens Must Be Minimised, and Potential Benefits Maximised 8.2.1 General – Problems to Be Addressed It is partly an explicit, and partly an implicit, requirement that risks and burdens are minimised, and that potential benefits are maximised before prospective participants are asked to consent. Ideally, the minimisation and maximising should take place before the factors are estimated. There is no need to estimate and weigh a risk that later on is minimised and thus reduced or eliminated. Moreover, only “minimised” risks and burdens can be acceptable. Minimisation may thus be seen as a precondition for proportionality. However, in practice as well as in theory (including here), the identification, estimation, assessment and minimisation of risks and burdens or maximising of potential benefits interact and interchange. The minimisation of risks and burdens may therefore occur early or late in the process of identifying and estimating risks, burdens, and potential benefits, and the assessment of proportionality, as it relatively often did in the practice of the Research Ethics Committee I observed. The objective in this section is to briefly clarify the requirements’ legal basis, content, and role in relation to the assessment of proportionality. The requirement of minimising risks and burdens has a clearer legal basis, and is therefore addressed first.

8.2.2 The Requirement of Minimising Risks and Burdens The requirement of minimising risks and burdens is based in Article 21 (1) of the Additional Protocol: All reasonable measures shall be taken to ensure safety and to minimise risk and burden for the research participants.

3

FDA (2009); See Tanne (2009).

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The underlying reasoning is that it would be inappropriate and unreasonable to ask people to carry risks and burdens that with reasonable efforts could have been decreased or eliminated. Such a requirement may therefore also be interpreted into the Clinical Trials Directive, as it can be derived from the requirement of proportionality itself, see also Article 4 (g) of the Clinical Trials Directive, which prescribes that clinical trials on minors must be: designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and developmental stage; both the risk threshold and the degree of distress have to be specially defined and constantly monitored.

A similar provision is found in Article 5 (f) of the Directive concerning clinical trials on adult persons not able to consent.4 The Directive must thus be seen as largely in harmony with the Additional Protocol on this point. In the following, the main focus will be on the wording of the Additional Protocol, as the Protocol contains the most detailed provisions. The requirements of “ensuring safety” and “minimising risks and burdens” are largely overlapping. By ensuring safety, the risks are minimised. Minimised means that the risks and burdens are decreased, either through a reduction of the harm or burden’s magnitude or its likelihood, or both. It surely also covers the elimination of risks and burdens, which is, of course, usually the better alternative. The central formulation in the provision is “all reasonable measures”. The formulation is familiar in law, and prescribes a contextual reasonability test.5 The test asks what a competent and reasonable researcher would have done in a comparable situation, given comparable recourses etc. More is required if the risks and burdens are considerable, than if they are very low. Likewise, more is required if the research project involves children or other vulnerable persons; and the more vulnerable, the stricter the standard of care. Some of the efforts that reasonably ought to be taken are mentioned explicitly in the Additional Protocol Article 21 (2), and Articles 22–24. Other necessary steps can be derived from the general provision in Article 21 (1) and professional standards, see Article 8. Necessary steps may thus be general and apply to all research projects, while others may be more situational. As such the requirement of minimising risks and burdens can also be derived from researchers’ general duty of care.6 First, the researchers must be certain that they can manage the risks and burdens involved. Article 21 (2) of the Additional Protocol requires in this regard:

4 Article 5 (f) of the Clinical Trials Directive: “clinical trials have been designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and developmental stage; both the risk threshold and the degree of distress shall be specially defined and constantly monitored”. 5 See Section 5.3.2 where the reasonable person test is explained. 6 See Section 5.3 where researchers’ duty of care and the role of professional standards are explored.

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8 How to Estimate Risks, Burdens, and Potential Benefits Research may only be carried out under the supervision of a clinical professional who possesses the necessary qualifications and experience.

The researchers must thus have necessary clinical qualifications and experience, as well as scientific qualifications and experience. Which qualifications and experience that are necessary depends on the context. Obviously, research in a clinical emergency situation requires high scientific and clinical competence among the researchers, in comparison to a low-risk study on healthy athletes. The Explanatory Report acknowledges that “students and non-health care professionals may be members of a biomedical research team”. If so, research interventions on persons must be under the supervision of a professional clinician.7 Clinical competence is often a prerequisite for managing risks entailed in interventional research. It is also a prerequisite for the requirement in the Additional Protocol Article 22 (1): The researcher shall take all necessary steps to assess the state of health of human beings prior to their inclusion in research, to ensure that those at increased risk in relation to participation in a specific project be excluded.

In, for example, an exercise study involving persons with spinal cord injury, the observed Research Ethics Committee required that the participants’ health status was assessed by measuring the blood pressure and by excluding persons with pacemaker, cancer, or severe autonomic dysreflexia, as well as pregnant women.8 The Committee also required a general assessment of the participants’ health, and that a doctor was present during the testing of the participants maximum oxygen uptake, see also below on supervision. These requirements are recognised in the literature. Weijer and Fuks, for example, have added that “the clinical investigator has a duty to screen for, and exclude, potential research subjects who may be unduly vulnerable to the risks of a particular clinical trial.”9 Weijer and Fuks left the impression that this was a controversial and dubious requirement. Not so in a legal perspective, as the requirement’s legal base is clear and easily derivable from researchers’ duty of care.10 Other “reasonable efforts” not explicitly mentioned in the provisions in the Additional Protocol can be various safety arrangements. In the Pain Relief Study11 the participants were under palliative care (pain reduction). Some participants were, however, given placebo or lower doses than usual. The Research Ethics Committee found that this would have been unacceptable if those participants had not been provided with so called “rescue-medicine”, which they could use if the pain became intolerable. Another example is the use of independent experts who may assess the risks and burdens, presumably, more accurately and objectively, and also suggest steps 7

Explanatory Report to Article 21 (2), Paragraph 116. REC Middle Norway Case 4.2006.2737. 9 Weijer and Fuks (1994). 10 See Section 5.3. 11 Accounted for in Section 14.4.2. 8

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Risks and Burdens Must Be Minimised, and Potential Benefits Maximised

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to minimise them. Accuracy and rigorousness is thus an important safety measure. Phase I of the Meningococcal B Vaccine Trial12 apparently included all thinkable safety measures. Another aspect is that confidential and sensitive data and biological material must be treated and stored carefully to minimise the risk of unlawful insight, misuse and other burdensome infringements of privacy, see Article 12 of the Additional Protocol. Clearly, Article 21 (1) of the Additional Protocol not only addresses necessary initiatives prior to the commencement of the research project. It also applies to the whole research process from planning to end. The risks and burdens must continuously be supervised and monitored. The Explanatory Report to Article 21 (1) underscores: These must include appropriate arrangements for monitoring the health of participants and promptly recording and assessing adverse events. Best practice recommends, especially in research involving particular risk, the establishment of a safety monitoring board to follow the conduct of a trial. In the course of formulating an opinion on the proposed research project, the ethics committee shall consider the arrangements for monitoring adverse events, including the intention to establish (or not) a safety monitoring board.

This statement must be seen in connection to Article 24 of the Additional Protocol concerning new developments and the researcher’s duty to re-examine the research project “if this is justified in the light of scientific developments or events arising in the course of the research”. A requirement of risk supervision is explicitly included in Article 3 (2) (a) of the Clinical Trials Directive when it states that the risk-benefit relationship must be “permanently monitored”. These issues are further discussed later in the chapter on later developments. The requirement of minimising risks and burdens to the participants can also be seen in connection with the principle that “persons who have suffered damage resulting from their participation in research shall be fairly compensated according to the conditions and procedures prescribed by law” set forth in Article 31 of the Additional Protocol.13 The Clinical Trials Directive Article 3 (2) (f) requires that “provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor.” It may be asked whether the existence of an adequate insurance policy can be regarded as minimising risks and burdens. An adequate insurance obviously reduces the participant’s chances of financial losses and may also mitigate damage. In so far insurance can be seen as a necessary step to minimise risks and burdens. Insurance is, however, not a relevant potential benefit in the assessment of proportionality. In the Meningococcal B Vaccine Trial, the promised compensation was extremely difficult to obtain. The government and their legal counsels were heavily criticised

12

Report on the Norwegian Meningococcal B Vaccine Trial (2007): Accounted for in Section 11.4.2. 13 The issue concerning liability for damages is discussed in Chapter 17 concerning legal effects of disproportionality.

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for their apparent intentional delay and unfair reluctance. Surely the Government’s inappropriate behaviour worsened the victims’ sufferings.14 Importantly, research participants may be exposed to unnecessary and excessive, and, thus, disproportionate risks and burdens, if the duty to minimise risks and burdens is not observed. This illustrates the intimate relationship with the requirement of proportionality.

8.2.3 Maximising Benefits A requirement of maximising potential benefits is not expressly set up in the Additional Protocol or the Clinical Trials Directive. Such a requirement may, however, be derived from researchers duty of care and the requirement of proportionality itself15 : It can be unfair and unreasonable to let individuals participate in a risky and burdensome research project, if the potential benefits could be increased by reasonable efforts. An example of such reasonable efforts is to ensure adequate study design and statistical strength (that enough participants are included). Another is to ensure that the researchers are scientifically competent. Thus, much that was said about the minimising of risks and burdens can be applied analogical in relation to maximising potential benefits.

8.3 Who Decides? Objective and Subjective Considerations The estimation and weighing of a risk, burden or potential benefits of biomedical research largely depends on predictions about what might happen, and perceptions about whether the possible consequences are good or bad, small or large, terrifying or neglectable, weighty or not, acceptable or unacceptable and so on. The perceptions of risks’, burdens’, and potential benefits’ magnitude, probability, and weight will naturally vary contextually and individually among experts, other researchers, laypersons, and research participants. The classic example is the risk of infertility associated with a research intervention. An elderly father of four and a young man without children probably views the magnitude of the potential harm quite differently. Even if the likelihood of infertility is low, the possibility of great harm may render the risk to be relatively high, at least higher than minimal risk, from the younger man’s perspective, while the elderly father may regard it as a minimal risk. An important question is thus whose perception of risks, burdens and potential benefits counts in the estimation and weighing of different factors (including the assessment of proportionality). Is it a lay perspective or an expert perspective?

14 15

Report on the Norwegian Meningococcal B Vaccine Trial (2007, pp. 163–168). See, for example, The US National Bioethics Advisory Commission, Final report (2001, p. 71).

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Should the more “subjective” perceptions of the individual prospective participant be decisive; or should it be the more “objective” perceptions of the “experts”, such as the researcher and his or her peers; or should it be a more “neutral” and “mixed” perceptions as presumably promoted by multidisciplinary a research ethics committee with both expert and lay representation? Predictions, estimates, and judgements about the magnitude and likelihood of harm, burden or benefit should be as objective (unbiased) as possible. This implies that judgments should to the extent possible be based on reliable and unbiased knowledge. Empirical data exists on various interventions undertaken in research, but far from all, as many research studies aim to provide such data. But objectivity can only be an ideal, simply because rationality is subjective.16 As with the truism that no intervention is risk free; no prediction or estimation of risks can be completely certain and objective. Indeed, exact data on the risks, burdens, and potential benefits of a research project rarely exists. That is one reason why objectivity can only be a starting point. Another reason is that such “empirical data” must be interpreted, valued, and weighed, which inherently involves subjective judgments.17 Moreover, experts (biomedical researchers) does not control whether a risk is small and acceptable, as they are also biased and subjective as anyone else. Eric M. Meslin states in his doctoral thesis on the subject: Regardless of different perceptions of risk people have, judgments must be made regarding whether or not to permit an activity presenting a risk. But it is wrong to assume, for instance, that expertise in the perception and assessment of risk automatically confers expertise in deciding about a risk’s acceptability.18

In effect, a Court of law is, for example, not bound by opinions among “experts” about whether a risk was acceptable or not.19 It is in addition widely recognised in physiological literature that the question about whether a risk is high or low, acceptable or unacceptable, does not only rely on qualified predictions and quantifications, but also on individual perceptions about risks (and burdens and potential benefits, for that matter). This goes for the expert as for the layperson. Personal preferences, perceptions and bias are inevitable, which means that objectivity is at best only partly achievable.20 Risk assessment and risk perception in general is also an issue addressed by scholars in psychology.21 Paul Slovic and his colleagues appear to be among the leading scholars in this field. They have undertaken psychometric studies that confirmed the truism that risk means different things to different people as illustrated 16

See, for example, Slovic (2000); Adams (2001); Nicholson (1986). Meslin (1989). 18 Meslin (1989, p. 130). 19 See Section 5.3.2 and the statements in the Bolam Case (UK), the Bolitho Case (UK). 20 See Meslin (1989, pp 94–143) who gives a thoughtful and comprehensive account of the issue. 21 See for example Slovic (2000); Adams (2001). 17

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by the infertility example. They found a clear discrepancy between the perception of risks between experts and laypeople: When experts judged risk, their responses correlated highly with technical estimates of annual fatalities. Laypeople could assess annual fatalities if they were asked to (and they produced estimates somewhat like the technical estimates). However, their judgments of “risk” were sensitive to other factors as well (eg. catastrophic potential, controllability, threat to future generations) and, as a result, differed considerably from their own (and experts’) estimates of annual fatalities.22

Slovic and colleagues also observed that other studies found that: people tend to view current risk levels as unacceptably high for most activities. The gap between perceived and desired risk levels suggested that . . . our respondents were not satisfied with the way that market and other regulatory mechanisms had balanced risks and benefits. However, studies of expressed preferences did seem to support Starr’s conclusion that people are willing to tolerate higher risks from activities seen as highly beneficial. Nevertheless, while Starr concluded that voluntariness of exposure was the key mediator of risk acceptance, studies of expressed preference have shown that other characteristics, such as dread, familiarity, control, catastrophic potential, equity and level of knowledge, also seem to influence the relationship between perceived risk, perceived benefit and risk acceptance.23

These findings suggest that a researcher and research participant would perceive risks, burdens, and potential benefits differently, and that the assessment of whether the risks and burdens are acceptable and in proportion or not, may also differ. This finding must be seen in relation to biomedical researchers’ tendency to overestimate potential benefits and underrate risks and burdens of their research.24 In relation to the question whether risk assessments should be based on “objective” calculations and analysis, or more “subjective” evaluations and experiences, Slovic and colleagues assert The rational and the experiential systems operate in parallel and each seems to depend on the other for guidance. Studies have demonstrated that analytic reasoning cannot be effective unless it is guided by emotion and affect. Rational decision making requires proper integration of both modes of thought. Both systems have their advantages, biases, and limitations.25 [Italics added]

In another work entitled “the Risk Game” Paul Slovic argues that, in the context of health decision about acceptable risk, the choice among alternatives, “involves value judgments that reflect much more than just the probability [likelihood] and consequences [magnitude] of the occurrence of an event.”26 Slovic argues that such a contextual approach may bridge the gap between scientific experts and the public perceptions of risk, as it embraces “the need for allowing the interested and affected 22

Slovic (2000, p. Xxiii). Slovic (2000). 24 See Section 5.4.2; see also Meslin (1989). 25 Slovic et al. (2004). 26 Slovic (2001, p. 17). 23

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parties to define and play the game.”27 Slovic thus argued that although experts’ perceptions are of interest, the perceptions of the risk-carriers are also of interest. There is little explicit guidance in the legal instruments concerning biomedical research on whose perceptions should count. The instruments seem to presume that objective data are available, which is rarely the case in practice.28 Nevertheless, since the predominant purpose of the requirement of proportionality is to protect the interests of the individual participant, it should be safe to assert that prospective participants’ perceptions of risks and burdens, is not only “of interest”, it may be of prime importance. Thus the assessment must to a certain degree be subjective, simply because subjective considerations also must be taken into account. The reason is that research participation must be a reasonable choice, seen from the prospective participants’ (the risk-carriers) perspective, not only from the non participating researcher’s or expert’s perspective. This position is also substantiated by the obvious potential conflict of interest between the participant on the one side, and the researcher on the other.29 It is further substantiated by the fact that researchers and scientists in general are more inclined to let participants take upon risks for the sake of science, than laypersons and the participants themselves are.30 Moreover, studies undertaken in the 1950s by J.A.F. Stoner showed that a group of people, such as a Research Ethics Committee, “will be more likely to permit a ‘risky’ choice than an individual.”31 These findings led a Nestor in US bioethics, Robert M Veatch, to propose that IRBs (US equivalent to REC) may tend to support research that has a greater risk of harm to participants than would have been accepted by an individual committee member.32 Based on my own experiences, Veatch assertion may be correct. Eric Mark Meslin presents similar findings in his doctoral thesis on the subject.33 The risk-carriers (the participants) may thus be largely dependent on risk evaluations made by persons (e.g. researchers and groups (e.g. research ethics committees)) which are generally less risk-avert than themselves. That laypeople and participants may perceive risks and burdens differently, and that their perceptions therefore are of interests in the assessment of proportionality, is acknowledged in a US handbook for ethics committees (IRBs): IRBs should be sensitive to the different feelings individuals may have about risks and benefits. Some subjects may view surgery (and thus avoiding chronic illness or prolonged medication) as a benefit while others would consider it a significant risk (and instead view chronic medication as a benefit because they can avoid the need for surgery). An elderly person might consider hair loss or a small scar an insignificant risk, whereas a teenager 27

Slovic (2001, p. 17). See also Meslin (1989, p. 101). 29 See Section 5.2 on the involved interests, and the legal instruments’ preferences. 30 See also Meslin (1989, pp. 94 et seq.). 31 In Meslin (1989, p. 110). 32 In Meslin (1989, p. 110). 33 Meslin (1989). 28

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could well be concerned about it. IRB members should remember that their appraisals of risks and benefits are also subjective.34

The foregoing discussion, including the purpose of the requirement of proportionality, clearly suggests that being “sensitive” is a too weak directive.35 Thus after the initial and “professional” identification and estimation, it must be asked how prospective participants would perceive the risks, burdens, and potential benefits. And in line with what has been said above, the individual participants’ (at least, assumed) perceptions should normally be decisive for whether a risk, burden or potential benefit is estimated to be high or low, acceptable or not, and, finally, whether potential benefits outweigh the risks and burdens. “Individual” means that although most prospective participants would perceive a risk as low and acceptable, there may be some who would not. To the extent possible and reasonable, such individual conditions should be duly regarded. These complex questions are further addressed in relation to the more concrete assessment of proportionality in Part IV. In practice, the participants will usually not have their say in the estimation and assessment of risks, burdens, potential benefits, and proportionality. The researcher must therefore try to put him- or herself in the position of the prospective participant and ask how he or she would perceive the risks, burdens, and potential benefits. Because of the obvious potential conflict of interests, this judgement is supposed to be reviewed by a multidisciplinary research ethics committee with necessary medical and scientific expertise as well as lay representation to ensure sensitivity with regard to the prospective participant’s perceptions and interest. Whether research ethics committees are designed to properly meet those expectations may be questioned. At least it must be recognised that the Committees resources are limited, and that there is a potential for bias.

8.4 The Burden of Proof Concerning the Description of Risks, Burdens, and Potential Benefits A complete description, including identification and accurate estimation of all relevant risks, burdens, and potential benefits, should be the ideal, although this is virtually impossible in practice. The requirement is more humane. The description of risks, burdens, and potential benefits must be satisfactory and adequate, and reasonably accurate. As with the requirement of minimising risks and burdens, the researcher is expected to spend reasonable efforts, in relation to the nature and context of the research project. For example, normally researchers are not expected to carry out a prior research project to assess the risks. However, in large and hazardous research projects,

34 35

IRB Handbook (2009, chapter III.A). See Chapter 5 for a detailed account of the purpose.

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small pilot studies CAN be required. In large-scale clinical trials they are usually obligatory. Such trials are therefore commonly undertaken in several phases (steps) as, for example, the Meningococcal B Vaccine Trial, which was divided into three phases and several progressive sub-studies. Moreover, even though data that proves that a new medicinal product (drug) may cause such and such complications do not exist, one cannot assume that the drug is risk free. On the contrary, as asserted by Rosenau: “in dubio contra experimentum”36 ; which means that any benefits of the doubt must be given to the participant or society at risk, not science. This view corresponds to the promotion of a precautionary principle in biomedical research by the legal scholar Lucas Bergkamp, which implies that we should “err on the side of caution (and thus prohibit such research) and assign the burden of proof to those proposing the research.”37 The rule’s underlying reasoning is obvious, and it can easily be founded in the overarching principle of human primacy.38 The implication is that it is the researcher who initiates the research that must provide satisfactory data on risks, burdens, and potential benefits. It is the researcher who must “prove” that the potential benefits justify the risks and burdens involved. Additionally, the Research Ethics Committee must review whether the data and the assessments are satisfactory, sufficiently reliable, and reasonable, and that the offer of participation is a reasonable choice, from the perspective of that particular research participant him- or herself.

36

Rosenau (2000). Bergkamp (2004). 38 See Section 5.2.5 where this principle is investigated. 37

Part III

The Assessment of Proportionality

Chapter 9

The Requirement of Proportionality – Initial Clarifications

9.1 Problems Addressed The objective in this part of the book is to analyse and clarify the assessment of proportionality, and the threshold that must be passed. The general question being addressed is: When are risks and burdens outweighed by and in proportion to potential benefits? In this chapter, some initial clarifications are sought. The objective is to get an overview of the requirement of proportionality, further clarify central concepts, and identify a useful chronology for further investigations.

9.2 The Provisions’ Wording and Core Content As already made clear, the requirement of proportionality in European biomedical research law is stated in two main provisions: the first in relation to Convention law, the second in relation to Community law. Article 6 (1) of the Additional Protocol, concerning Convention law, states1 : Research shall not involve risks and burdens to the human being disproportionate to its potential benefits. [Italics added]

Article 3 (2) (a) of the Clinical Trials Directive, concerning Community law, states: A clinical trial may be undertaken only if, in particular: (a) the foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients. A clinical trial may be initiated only if the Ethics Committee and/or the competent authority comes to the conclusion that the anticipated therapeutic and public health benefits justify the risks and may be continued only if compliance with this requirement is permanently monitored [Italics added]

1 The provision is a restatement of Article 16 (ii) of the Oviedo Convention. The corresponding provisions in Norwegian law are § 22 (2) of the Health Research Act of 2008 § 22 (2), and § 2-1 of the Secondary legislation concerning clinical trials of 2009.

S. Simonsen, Acceptable Risk in Biomedical Research, International Library of Ethics, Law, and the New Medicine 50, DOI 10.1007/978-94-007-2678-9_9,  C Springer Science+Business Media B.V. 2012

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The first question addressed here is whether the normative content of the two provisions differs or is essentially the same. The two central terms in the provisions that must be interpreted are respectively “disproportionate” and “justify”. The “ordinary meaning” of the words, is the starting point.2 Information about the ordinary meaning can be found in, for example, the Oxford Advanced Learner’s Dictionary, which explains “disproportionate” as “being out of proportion”,3 which in turn may be understood as “being unreasonable”.4 “Justify” is explained as to “show that somebody or something is right, reasonable or just” and corresponds to “justification” explained as an “acceptable reason for doing something”.5 “Proportionate” is explained as “corresponding in size, amount or degree (to something)”.6 Thus, the ordinary meaning of the words seems to suggest that they are more or less overlapping and commensurable. “[N]ot . . . disproportionate” in Article 6 (1) of the Additional Protocol then apparently means that the risks and burdens are proportionate, acceptable, and justifiable, because the risks and burdens are outweighed (justified) by potential benefits. The fact that the provision in the Additional Protocol can be explained by using the wording of the corresponding provision in the Clinical Trials Directive suggests that the normative content of the two provisions is essentially the same. An earlier draft of the Clinical Trials Directive contained a provision using the word “disproportionate”, but this was later changed. Nevertheless, the draft suggests that the original intended meaning was, regardless of the final wording, to include a requirement of proportionality.7 The suggestion is substantiated by the fact that both provisions originate from formulations of a requirement of proportionality in the Nuremberg Code and in the Declaration of Helsinki.8 Furthermore, requirements of proportionality are common in other fields of law, nationally, but also in general Convention law and Community law.9 In general Convention law and Community law, proportionality implies that a proportionate relationship between the means and ends can be established. Consequently, means and ends must be weighed (balanced) against each other, to see whether there

2 See Vienna Convention Article 31; see also Judgement by the ECtHR in Johnston v. Ireland, A 112 1986. 3 Fourth edition, 1989, p. 348. 4 The treaty and directive texts in other languages, for example, French, could have been checked for significant linguistic nuances, but has not been undertaken as it is unlikely that it would have revealed significant nuances. 5 Fourth edition, 1989, p. 680. 6 Fourth edition, 1989, p. 1001. 7 Draft Article 3 (2). 8 See Chapter 4 for wording and an account of the development. 9 General Convention law and Community law are used in contrast to Convention law and Community law in this particular legal field; the field of biomedical research. See Chapter 10 where it is showed that the Norwegian Health Research Act § 22 (2) (2) uses this language; see also Rasmussen (1995) and Graver (2002).

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is a proportionate relationship or “a fair balance”.10 This is in harmony with the understanding in this particular field. Nothing in the preparatory works to the similar wording in the Oviedo Convention suggests that “not disproportionate” implies something different than “proportionate”, or “justify” for that matter, and that there was a significant underlying reasoning behind the choice of words.11 Moreover, a normative discrepancy between Convention law and Community law is undesirable considering both instruments aim of contributing to regulatory harmony in European. To argue that the two provisions entail a significantly different basic normative content is neither feasible nor legally sustainable, especially when seen in relation to the provisions origin and the overarching aim of regulatory harmony in Europe. A possible difference refers to the fact that the Clinical Trials Directive uses a more positively wording (“justify”), indicating that it is the potential benefits that should outweigh the risks and burdens. The wording in the Additional Protocol (“not . . . disproportionate”), on the other hand, is a more negative wording. It can thus be asked, as done in legal theory on the principle of proportionality in international law concerning use of armed force and state responsibility, whether the requirement of proportionality should preferably be formulated negatively (“not disproportionate”) or positively (“proportionate”/“justify”).12 A negative wording is taken to favour the intervener (here: the researcher), because it may give him or her greater latitude.13 A positive wording, on the other hand, favours the intervened (here: the research participant), as it is the intervener who has to make the case that the ends justify the means. The discrepancy becomes more distinct if the word “manifest” or “obviously” is put before either “disproportionate” or “proportionate” or “justify”. “Manifestly disproportionate” is something entirely different than “manifestly proportionate” or “manifestly justifies” as a qualified (overwhelming) preponderance would be required either way. Since a negative wording may give the researchers the benefits of the doubt, the interpretation is unsustainable and probably unintended. Clearly, it is the researcher who carries the burden of proof and is the one who must justify the project.14 The benefit of the doubt must thus, as a matter of principle, be given to the participant at risk.15 A positive wording of the requirement of proportionality is therefore in better harmony with the underlying reasoning of the instruments as well as the provisions.16 It is 10 The wording “fair balance” is also occasionally used by the European Court of Human Rights when there is a reasonable relationship between legitimate but conflicting interests, typically between the individual and the society at large. See, for example, the Case of Saadi v. The United Kingdom (Judgement by the ECtHR of 29. January 2008). 11 Preparatory works to the other provisions have not been available. 12 See Wicker (2006, pp. 81et seq.). 13 See Wicker (2006, pp. 81et seq.). 14 See Section 8.4. 15 Bergkamp (2004). 16 See Section 8.4 where this issue is addressed.

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thus more accurate to talk about a requirement of proportionality, than a requirement of not disproportionate. Article 3 (2) (a) of the Clinical Trials Directive also cover issues (additional conditions) that do not seem to be covered by Article 6 (1) of the Additional Protocol, when the Directive speaks about “if the Ethics Committee and/or the competent authority comes to the conclusion” and “if compliance with this requirement is permanently monitored”. This is, however, only on the face of it, as these “additional issues” are easily derivable from the Additional Protocol. These additional issues are addressed elsewhere in the book. It may, nevertheless, be noted, that although a research ethics committee must review the assessment of proportionality, it is first and foremost the researcher’s responsibility to ensure that the risks and burdens entailed in his or her research project are proportionate to potential benefits throughout the research project. In the following it is, however, the provisions core normative content that is of primary interest; namely the requirement of proportionality. In conclusion, even though the wording of Article 6 (1) of the Additional Protocol and Article 3 (2) (a) is slightly different, the core normative content is the same. The normative content is, for all practical purposes, a traditional requirement of proportionality between means and ends in the field of biomedical research. The requirement implies that the risks and burdens entailed in a biomedical research project are reasonable, acceptable, and justifiable if there is a proportionate relationship between the risks, burdens, and potential benefits. Thus the wordings “justifiable”, “not . . . disproportionate”, and “proportionate” are in the following taken to mean the same, and they are used interchangeably in the further investigation of the requirement of proportionality.

9.3 The Differentiation Therapeutic and Nontherapeutic Research, and Between Participants Able and Not Able to Consent 9.3.1 General About the Differentiation The purpose in this section is to further outline the legal framework, and by that identify a suitable chronology for the subsequent investigations. In this regard the differentiation between research with or without potential direct benefits to the participant, and between participants able and not able to consent, is of particular interests. Clearly, the requirement of proportionality, as expressed in Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive, applies both to research which entails prospects of direct therapeutic benefits to the participant (“therapeutic research”), and to research without prospects of direct benefits

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to the participant (“nontherapeutic research”).17 The “general” requirement of proportionality in Article 6 (1) of the Additional Protocol is, however, supplemented with two additional provisions in the second paragraph: In addition, where the research does not have the potential to produce results of direct benefit to the health of the research participant, such research may only be undertaken if the research entails no more than acceptable risk and acceptable burden for the research participant. This shall be without prejudice to the provision contained in Article 15 paragraph 2, sub-paragraph ii for the protection of persons not able to consent to research. [Italics added]

Article 15 (2) (ii) maintain that in nontherapeutic research on participants not able to consent: the research [may entail] only minimal risk and minimal burden for the individual concerned; and any consideration of additional potential benefits of the research shall not be used to justify an increased level of risk or burden. [Italics added]

The more detailed normative content of these provisions will be discussed later on. Here, the more overarching consequences of the provisions are addressed: What do the two provisions in Article 6 (2) of the Additional Protocol imply? The wording “In addition” in Article 6 (2), first sentence, of the Additional Protocol indicates that the provisions supplement the requirement of proportionality in Article 6 (1). In the Explanatory Report the provisions are called “additional preconditions” for nontherapeutic research. The Explanatory Report then states: Whether or not the risk and burden are acceptable will be considered carefully by the ethics committee and competent body that approves the research project. The final decision on whether or not the risk and burden are acceptable will be made by the persons concerned when they decide to give or withhold consent. Because these participants are able to consent to research, the level of risk and burden permitted (acceptable) is higher than that allowed for persons not able to consent (minimal risk and minimal burden).18

The statement is not particularly enlightening, because it does not offer guidance as to when the risks and burdens are acceptable, except from saying that this will be decided by a research ethics committee and finally the prospective participant (if he or she is able to consent). The latter is, however, also the case when it comes to therapeutic research on persons able to consent, which renders the statement confusing. Moreover, as already noted, it is surely first and foremost the researcher who must ensure that the risks and burdens are proportionate and acceptable. It may be asked if the statement imply that the researcher is relieved of his duty to assess proportionality, and, furthermore, that the research ethics committee may conclude that even the highest risks and burdens in nontherapeutic research may be acceptable, regardless of the potential benefits. May a person consent to any risks? The answers are obviously negative to all three questions. The implied meaning of calling the provisions in Article 6 (2) “additional preconditions” is the opposite, namely that less risks and burdens are generally acceptable 17

Explanatory Report to Article 6 of the Protocol, Paragraphs 25–27. See Section 3.4 for the definition. 18 Paragraph 27.

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if the research does not entail prospects of “direct benefits.” (And even less risks and burdens if the participants are not able to consent). This is clearly the meaning of the wording “no more than acceptable”, and even more so the wording “only minimal risks and minimal burdens”. The wording of the provisions thus merely indicates that some risks and burdens can be imposed, but without giving the same guidance that “proportionate” gives. Thus the wording “no more than acceptable”, as well as the statement in the Explanatory Report, gives in itself little guidance as to what level of risks and burdens that is permissible, other than that the upper level of acceptable risks and burdens are somewhere in-between minimal risks and burdens and the upper level of risks and burdens that may be acceptable in therapeutic research. Hence, the intended meaning of Article 6 (2) is to make it clear that while Article 6 (1) indicates a more or less linear relationship between proportionate risks and burdens to the participant and potential direct benefits to the participant (therapeutic research), this is not the case if the research only entails potential benefits to others: no matter how beneficial the research project may prove to be to others, and no matter how willing the participant is, it is not acceptable to expose an individual to risks and burdens above “acceptable risks and burdens”. The apparent reasoning is that (in an assessment of proportionality) prospects of direct benefits to the participant generally carry more weight than potential benefits to others. If the research entail no prospects of direct benefits, and involve persons not able to consent, the risks and burdens can only be minimal. This reflects, as illustrated by Fig. 9.1, a tripartition concerning the legal notion of proportionate levels of risks and burdens to the participant that is fundamental in the Additional Protocol:

A: Therapeutic research Risks and burdens to the participant “not ... disproportionate” risks and burdens

B: Nontherapeutic research Risks and burdens to the participant

“No more than acceptable” risks and burdens

“Minimal” risks and burdens

Prospects of direct benefits to the same participant

Potential benefits to others

Fig. 9.1 The tripartition of proportionate risks and burdens implied in Article 6 of the Additional Protocol

9.3

The Differentiation Therapeutic and Nontherapeutic Research, and Between . . .

Category 1:

Category 2:

Category 3:

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The most risks and burdens may be proportionate if they are outweighed by direct benefits to the same participant (whether or not the participant is able to consent).19 Some risks and burdens may be proportionate if they are outweighed by potential benefits to others and if the participant is relatively invulnerable and able to consent.20 If the participant is not able to consent or similarly vulnerable, the least (only “minimal”) risks and burdens may be proportionate and outweighed by potential benefits to others.21

Figure 9.1 illustrates the tripartition of proportionate risks and burdens implied in Article 6 of the Additional Protocol, (which perhaps may also be interpreted into the Clinical Trials Directive): (1) The most risks and burden may be acceptable if they are outweighed by prospects of direct benefits to the participant. (2) “No more than acceptable” risks and burdens may be outweighed by potential benefits to others, if the participant is able to consent. (3) Only “minimal” risks and burdens may be outweighed by potential benefits to others if the participant is unable to consent or similarly vulnerable. Importantly, the tripartition does not imply that therapeutic research and nontherapeutic research are subject to different standards. Both therapeutic research and nontherapeutic research are subject to the same “general” standard: the requirement of proportionality, but if the risks and burdens are not outweighed by prospects direct benefits to the participant, then additional preconditions apply. In the following, the term “acceptable” is used in line with its ordinary meaning. As such “acceptable” may be seen as meaning the same as “not . . . disproportionate”, “justified”, as well as “proportionate”. That the risks and burdens, at any rate, must be proportionate implies that even without the specification of these “additional preconditions”, essentially the same results would be derivable from the “general” requirement of proportionality itself. It is clear that, even without the additional preconditions, whether the research entails prospects of direct benefits to the participants or not is of pivotal importance for the assessment (judgement) of proportionality, simply because such benefits generally carries considerable weight in the assessment (this is what Article 6 (2) essentially intends to clarify). Moreover, it is also of pivotal importance for the assessment of proportionality whether the prospective participants are able to consent or not able to consent. This 19

Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive; Article 15 (1) which regulate therapeutic research on persons able to consent is “silent” on the level of acceptable risks and burdens, which implies that the “general” requirement of proportionality apply. Thus the category could have been split up in two categories, but since the “rule” is the same they are treated simultaneously, see, however, Section 10.3.5 where the “differences” are addressed, see also Section 9.3.2. 20 Article 6 (2) (1) of the Additional Protocol, cf. Article 3 (2) (a) of the Clinical Trials Directive. 21 Article 6 (2) (2), cf. Articles 15–20 of the Additional Protocol and Articles 4 and 5 of the Clinical Trials Directive.

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follows from the purpose of the requirement of proportionality.22 In this perspective, the “additional preconditions” may be seen as largely superfluous and as a mere specification of the “general” requirement of proportionality (although I think the specifications (additional preconditions) are very important to hinder a slippery slope). Nevertheless, this observation is important because the Oviedo Convention, the Clinical Trials Directive, and the Norwegian Health Research Act do not explicitly include “all” the “additional preconditions” that are found in the Additional Protocol. All these instruments do, however, to a certain degree recognise the preconditions, implicitly or explicitly. At any rate, the “additional preconditions” may clearly be interpreted into Article 16 (ii) of the Oviedo Convention, simply because the Additional Protocol elaborates on the Oviedo Convention. They may also be interpreted into the Norwegian law, since the Norwegian Health Research Act expressly aims to incorporate the Additional Protocol into Norwegian law, and because Norway has ratified the Oviedo Convention. The “additional preconditions” may probably also, at least to a certain degree, be interpreted into Article 3 (2) (a) of the Clinical Trials Directive.23 I am thus arguing that the legal instruments are largely in harmony when it comes to the identified “differentiation” and the broad legal framework, simply because the opposite view is legally unsustainable (at least if the deviation is significant). The main reason is that such “additional preconditions” can be derived from the “general” requirement of proportionality itself, which all instruments include. It also follows from the fact that these additional preconditions are internationally recognised “common” minimum standards for the protection of the individual participant, and other instruments should offer nothing less. This interpretation also better realises the purposes of the instruments as a whole and the provisions in particular (human protection and regulatory harmony). Importantly, a combination of the first category and the second or the third category is thinkable and practical, although it is not explicitly recognised in the Additional Protocol.24 A combination implies that the risks and burdens to the participant may be outweighed partly by prospects of direct benefits to the participant, and partly by potential benefits to others. A combination is especially practicable if the risks and burdens to the participant are partly, but not fully, outweighed by prospects of direct benefits to the participant.25 The question is then whether the additional (surplus/excess) risks and burdens may be outweighed by potential benefits to others.26 Risks and burdens carried by the participant partly or fully for the sake of others are here called additional risks and burdens.27 22

See Chapter 5. See Chapters 11 and 12 respectively; The same will then also apply to Norwegian secondary legislation concerning clinical trials § 2-1. But this provisions must also be interpreted in light of and in harmony with § 22 (2) of the Health Research Act. 24 See Section 10.3.8 where the reason for this position is further elaborated. 25 See further Chapter 11. 26 Addressed in Section 10.3.6. 27 See Section 5.2. 23

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The Differentiation Therapeutic and Nontherapeutic Research, and Between . . .

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Risks and burdens to others than the participant is then an independent (fourth) category. It is dealt with separately in Chapter 15. In the following the focus will be on risks and burden to the individual participant, unless otherwise stated.

9.3.2 More on the Differentiation: What is the “Main Rule”? Question Addressed The differentiation, and the outline of the legal framework above, shows that there are essentially two alternative conditions for proportionality: 1. Either the risks and burdens to the participant are outweighed by prospects of direct benefits to the same participant (called the “direct benefit rule” in the Explanatory Report), or 2. The (additional) risks and burdens to the participant are outweighed by potential benefits to others (science, society, future patients etc). This applies both to research on persons that are able to consent, and to research on persons that are not able to consent. The Explanatory Report uses the term “rule” instead of condition. The other condition is, however, not called a rule in the Explanatory Report. It could have been called “the nondirect benefit rule”, but I can find no reason to introduce such a new term here. The identification of two alternative conditions (distinguishable “rules”) gives thus rise to the question about ranking. The issues addressed in this section is then whether a main rule can be identified, or whether the two alternative conditions (“rules”) are of equal rank but applicable in two different situations. In other words: Are the Additional Protocol and the Clinical Trials Directive indifferent to whether the risks and burdens to the participant are outweighed by prospects of direct benefit to the participant, as compared with potential benefits to others? Research on Persons Not Able to Consent to Research Participation The answer is clear when it comes to research on participants not able to consent and similarly vulnerable persons. Vulnerable participants are subject to additional safeguards in Articles 15, and 18–20 in the Additional Protocol.28 Article 15 (1) (i) maintains that “[R]esearch on a person without the capacity to consent to research may be undertaken only if . . . the results of the research have the potential to produce real and direct benefit to his or her health.” [Italics added] Article 15 (2) maintain: Exceptionally and under the protective conditions prescribed by law, where the research has not the potential to produce results of direct benefit to the health of the person concerned, such research may be authorised subject to the conditions laid down in paragraph 1, sub-paragraphs ii, iii, iv, and v above, and to the following additional conditions . . . [Italics added] 28

These provisions are further investigated below in Chapter 12.

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Moreover, The Explanatory Report underscores that “Paragraph 2 [of Article 15] provides exceptionally, under the protective conditions prescribed by domestic law, for the possibility of waiving the direct benefit rule given very strict conditions.”29 [Italics added] Thus it is clear that the direct benefit rule is the main rule when it comes to research on persons not able to consent. Additional risks and burdens to such persons may only exceptionally be outweighed by potential benefits to others, and then on very strict “additional” conditions. The regulatory situation in the Clinical Trials Directive is similar. Paragraph 3 of the Preamble to the Directive states: Normally these persons [not able to consent] should be included in clinical trials only when there are grounds for expecting that the administering of the medicinal product would be of direct benefit to the patient, thereby outweighing the risks. [Italics added]

The statement refers to research on both children and adults not able to consent. The direct benefit rule is thus identified as the main rule when it comes to research on persons not able to consent in the Clinical Trials Directive. The word “normally” also points to an exception clause. The exception clause is found in Article 4 (e) of the Directive that exceptionally allows nontherapeutic research on children on certain conditions. Interestingly, no such exception exists with regard to nontherapeutic research on adult persons not able to consent. Article 5 (i) requires that “there are grounds for expecting that administering the medicinal product to be tested will produce a benefit to the patient outweighing the risks or produce no risk at all.” Hence, the rule of direct benefit is not just the main rule; it is the only rule when it comes to research on adult persons not able to consent.30 The Additional Protocol and the Clinical Trials Directive are on this point in harmony with the UNESCO’s Universal Declaration on Bioethics and Human Rights. Article 7 (b) of the UN Declaration, concerning research on persons not able to consent, states: (b) research should only be carried out for his or her direct health benefit, subject to the authorization and the protective conditions prescribed by law, and if there is no research alternative of comparable effectiveness with research participants able to consent. Research which does not have potential direct health benefit should only be undertaken by way of exception, with the utmost restraint, exposing the person only to a minimal risk and minimal burden and, if the research is expected to contribute to the health benefit of other persons in the same category, subject to the conditions prescribed by law and compatible with the protection of the individual’s human rights. [italics added]

Thus, the provisions, read in context, as well as in the light of the Explanatory Report and the UN Declaration, make it clear that the direct benefit rule is the main rule when it comes to research on persons not able to consent, in both Convention

29

Paragraph 87 [italics added]. Nontherapeutic research on children and adult persons not able to consent is analysed in Chapter 19. 30

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The Differentiation Therapeutic and Nontherapeutic Research, and Between . . .

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law and Community law.31 This means that risks and burdens to such participants as a main rule should be outweighed by prospects of direct benefits to the participants themselves. Only exceptionally may (additional) risks and burdens be outweighed by potential benefits to others. Research on Persons Able to Consent to Research Participation The next question is then whether the direct benefit rule is the main rule also when it comes to research on persons able to consent. The wording of both Article 6 of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive is ambiguous. The answer must thus be found in the provisions and the underlying reasoning of the provisions and the instruments. Several principally different rationales are thinkable: A “utilitarian” and an altruistic approach would be inclined to favour taking risks and burdens for the sake of others (altruism), and put less emphasis on an individual’s narrow self-interests. In such a perspective one might argue that the two rules should, at least, have equal rank, which would imply that it does not matter whether the risks and burdens to the participant were outweighed by prospects of direct benefits to the participant or potential benefits to others, as long at the risks and burdens were outweighed. This approach is, however, largely dismissed by the principle of human primacy.32 An approach primarily based on the individual participant’s autonomy and right to self-determination, could also be put forward. In such a perspective the explicit preferences of the individual participant and his or her consent would be decisive, and the rules should accordingly have equal rank. Such an approach suggests regulatory indifference to whether the research entails prospects of direct benefits to the participants or not, and whether the risks are high or low, as the individual can decide for him- or herself by consenting or not.33 However, the requirement of proportionality is first and foremost justified as an additional and independent safeguard to the requirement of consent; a safeguard not primarily aimed at protecting the participant’s autonomy, but rather his or hers interests, welfare (including health) and human dignity. Although individual autonomy is an essential value, it is not the only value that is protected. An individual may not consent to (or rather: be offered participation in) research that are detrimental to his or her health, or contrary to human dignity.34 A third approach is to argue that research which entail prospects of direct benefits, are comparable to health care interventions carried out in ordinary clinical practice (hereinafter called the therapeutic analogy). Any “ordinary” clinical intervention is associated with risks and burdens, as any research intervention is. The risks and burdens associated with the clinical interventions are outweighed by the 31

The same is clear in Norwegian law, see Norwegian Health Research Act § 18, and Norwegian secondary legislation concerning clinical trials § 2-8 and § 2-9; see Chapter 12. 32 Investigated in Section 5.2.5. 33 See Bergkamp (2004) who seem to promote this perspective. 34 Cf. Section 5.3; See Preamble of the Additional Protocol, cited in Section 5.2.4 and Article 23 (1) in the Additional Protocol, discussed in Chapter 13.

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prospects of direct therapeutic benefits to the patient. Thus, apparently there is no significant difference between ordinary clinical practice and research participation, as long as the risks and burdens are outweighed by the prospects of direct therapeutic benefits to the participant (patient).35 This line of reasoning, which is prominent in the Explanatory Report, presumes that research participants are not exposed to risks and burdens for the sake of others, but rather for their own sake. Indeed, it might be in their interest to participate in research. The therapeutic analogy is supported by what might be called a paternalistic36 or protective (risk-averse) approach, which suggests that a researcher physician or other health personnel should not offer a patient participation in an interventional research project, unless it is in the patient’s best interests to do so from a medical point of view. In that perspective it is unacceptable to let people participate in interventional research unless the risks and burdens are outweighed by prospects of direct therapeutic benefits to the participant. The paternalistic approach appears to preclude taking risks and burdens on behalf of others (science or society). To tolerate or encourage a patient taking upon risks of harm for the sake of others, could even be seen as contrary to the ethical obligation of physicians to do no harm as well as their legal duty of care. Taking additional risks and burdens for the sake of others could in fact be detrimental to the participant’s health. The reasoning is then, at least in its more paternalistic version, rather indifferent to the individual person’s consent, perceptions, and altruistic interests. The reasoning suggests that the direct benefit rule should be the main rule, if not the only rule, because research is comparable to ordinary clinical practice. Thus, despite fundamental differences between ordinary clinical practice and therapeutic research,37 the therapeutic analogy strongly suggests that the direct benefit rule should be the main rule if the participants are not able to consent, but also when the participants are able to consent.38 The reason is that if the direct benefit rule is fulfilled, then the participant is not exposed to risks and burdens for the sake of others, and, by that, being exploited and used as a mere means towards a greater end against his or her (“best”) narrow self-interests.39 This underlying reasoning is for obvious reasons particularly evident and strong when it comes to research on persons not able to consent. Moreover, the fact that the direct benefit rule is clearly the main rule in both Convention law and Community law when it comes to research on persons not able to consent, suggests that the same should apply to research on 35

There are, however, differences. These are investigated in Section 10.3, see in particular Section 10.3.7. 36 Paternalism refers to situations where the physician or a governmental agency (fatherly) takes choices for the individual, and thus limits the individual’s self-determination. Physician paternalism has been prevalent in clinical practice (also research), see Chapter 4. Paternalism is nowadays largely replaced by patients and research subjects’ right to self-determination and a fundamental requirement of informed consent; see the Oviedo Convention Article 5. 37 These are investigated in Section 10.3, see in particular Section 10.3.7. 38 Explanatory Report to Article 6 of the Protocol, Paragraphs 25–27. 39 See Section 5.2.

9.4

The Way Ahead

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persons who are able to consent. The fact that nontherapeutic research is addressed in the second paragraph of Article 6 of the Additional Protocol, also support this notion. It may therefore be concluded that the direct benefit rule may be seen as the main rule, also when participants are able to consent. The fact that probably most interventional biomedical research projects commenced today do not fulfil the direct benefit rule cannot alter this.

9.4 The Way Ahead The (tripartite) differentiation identified above results in the following chronology for the clarification of the requirement of proportionality in European biomedical research law: Category 1:

Category 2:

Category 3:

The most risks and burdens may be proportionate if they are outweighed by direct benefits to the same participant (whether or not the participant is able to consent).40 (Chapter 10) Some risks and burdens may be proportionate if they are outweighed by potential benefits to others and if the participant is relatively invulnerable and able to consent.41 (Chapter 11) If the participant is not able to consent or similarly vulnerable, the least (only “minimal”) risks and burdens may be proportionate and outweighed by potential benefits to others.42 (Chapter 12)

That the first category is addressed first is also supported by the fact that the direct benefit rule may be regarded as the main rule. Yet another additional precondition for proportionality is addressed in Chapter 13; the so-called no harm rule, which addresses noninterference with necessary clinical interventions. The assessment of proportionality in clinical trials, (including) the use of placebo, is especially complicated because of the occurrence of multiple alternatives, and is therefore addressed specifically in Chapter 14. In the end some complementary issues are briefly addressed: Chapter 15 addresses the question about what degree of risks and burdens to other than the participants may be acceptable and proportionate. Chapter 16 addressed the requirement 40 Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive; Article 15 (1) which regulate therapeutic research on persons able to consent is “silent” on the level of acceptable risks and burdens, which implies that the “general” requirement of proportionality apply. Thus the category could have been split up in two categories, but since the “rule” is the same they are treated simultaneously, see, however, Section 10.3.5 where the “differences” are addressed, see also Section 9.3.2. 41 Article 6 (2) (1) of the Additional Protocol, cf. Article 3 (2) (a) of the Clinical Trials Directive. 42 Article 6 (2) (2), cf. Articles 15–20 of the Additional Protocol and Articles 4 and 5 of the Clinical Trials Directive.

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of proportionality during the course of the research project (later developments). Finally, Chapter 17 addresses the legal effects of the requirement of proportionality, and the consequences of disproportionality. The chronology reflects the structure of the Additional Protocol, as well as the Clinical Trials Directive.

9.5 The Requirement of Proportionality in Broad and Strict Sense It should be noted that the requirements of proportionality in other fields of law, such as general EU-law and ECHR-law, are associated with three related but independent requirements: 1. A requirement of necessity in strict sense; which basically requires that the aim of the intervention is legitimate and not unnecessary (“legitimate aim”). 2. A requirement of lesser mean; which basically requires that the aim cannot be obtained through lesser (less risky and burdensome) means (“last resort”). 3. A requirement of proportionality in strict sense; which basically requires that there is a proportionate relationship between the aim and the means. Although the first two requirements can easily be derived from the current legal framework concerning biomedical research, the requirement of proportionality between risks, burdens and potential benefits in biomedical research, obviously refers to the requirement of proportionality in strict sense, which implies a weighing of ends against means. However, not only are the two former requirements often included in a principle of proportionality in broad sense, they are also often included in the assessment of proportionality in practice. These three requirements can, and should, be seen as independent legal norms in their own right, especially, in a theoretical analysis. However, it must be underscored that they also are so closely related, that it can be difficult to hold them apart in practice, as exemplified in the case-law of the European Court of Human Rights and the European Court of Justice. In the following, the latter requirement is of primary interest. But for that requirement to apply, it is a precondition that the two former requirements are fulfilled.

Chapter 10

Therapeutic Research

10.1 Problem Addressed The rule of direct benefit maintains that the risks and burdens to the participant are proportionate if they are outweighed by the prospects of direct therapeutic benefits to the participant him or herself (therapeutic research1 ). The question addressed in this chapter is then: when do prospects of direct benefits outweigh the risks and burdens entailed in a research project?

10.2 Starting Points As shown above, the implied meaning of Article 6 of the Additional Protocol was that the participants’ may volunteer to take upon higher risks and burdens for their own sake, than for the sake of others.2 The reason is that prospects of direct benefits to the participant generally carry more weight than potential benefits to others in the assessment of proportionality. This position also follows from the Clinical Trials Directive read in context, and it is widely recognised internationally. The Explanatory Report to Article 6 of the Additional Protocol state accordingly: When medical research may be of direct benefit to the health of the person undergoing research, a higher degree of risk and burden may be acceptable provided that it is in proportion to the possible benefit.3 [Italics added]

Similarly in the ethical guidebook of the World Medical Association, which holds that a “likely risk of a serious harm would be unacceptable unless the project provided the only hope of treatment for terminally ill research subjects”.4 1

Therapeutic research is defined in Section 3.7. Cf. Section 9.3. 3 Paragraph 25. 4 WMA Medical Ethics Manual 2nd ed. (2009, p. 104). 2

S. Simonsen, Acceptable Risk in Biomedical Research, International Library of Ethics, Law, and the New Medicine 50, DOI 10.1007/978-94-007-2678-9_10,  C Springer Science+Business Media B.V. 2012

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Consequently, there is a more or less linear relationship between acceptable risks and burdens and potential direct benefits to the same participant as indicated in Fig. 9.1. Clinical trials in oncology are, for example, often associated with high risks and burdens. To kill the cancer cells, the drug can be so toxic that it would not be acceptable to give it to healthy volunteers. However, for the participant, the new drug may provide the only hope of cure, and the risks and burdens may thus be outweighed by the prospects of direct benefits. A less dramatic example is the Interval Training Case: Interval Training Case5 Background: Interval training is known to produce more rapid and greater health effects than other forms of training. It is also known to be more strenuous. Study aim: To determine whether interval training may decrease the chance of lifethreatening cardiac disorder among post-cardiac arrest patients. Method: Randomised clinical trial. The intervention group should undergo a physical training program involving interval training (short but very intensive periods of work out), three times a week for three months. The control group would not be subject to any intervention. REC evaluation: REC recognised that the participants were vulnerable as they were at high risk of a new cardiac arrest, especially when exercising. REC therefore decided to discuss the matter with the principal investigators in plenum. In the meeting, the investigators acknowledged that the risks were considerable, even though the training was adapted to the patients’ ability and was not for athletes. On the other hand, it was asserted that there were prospects of real and direct therapeutic benefits for the participants in the interventiongroup, as they would improve their health and thus reduce the risk of a new cardiac arrest. The researchers maintained that the potential direct benefits therefore clearly outweighed the risks, as it was highly probable that the risk of cardiac arrest would decrease (although the aim of the project was to verify this hypothesis). The Committee endorsed the researchers’ evaluation and approved the project.

The Interval Training Case illustrates, among other things, that rather high levels of risks and burdens, even a risk of death, can be acceptable as long as they are outweighed by prospects of direct benefits to the participant.

10.3 More on the Weighing of Direct Benefits and the Assessment of Proportionality 10.3.1 Problems Addressed The question whether the potential direct benefits outweigh the entailed risks and burdens can be organised into several sub-questions. The first question is how great the prospects of direct benefits are; how significant are they; and how likely is it that they will occur? The same questions must be addressed in relation to risks and burdens. Seemingly, the estimation, and thus also the weighing of risks, burdens, 5

REC Middle Norway Case 4.2007.1168.

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More on the Weighing of Direct Benefits and the Assessment of Proportionality

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and potential benefits, primarily relies on quantifiable data and a mathematical calculation. This raises the question about what role more qualitative and subjective elements play. These questions are investigated successively in the following.

10.3.2 Estimating and Weighing Direct Benefits If a research project also entails prospects of direct benefit to the participants, it is paramount to determine what the participants may expect in terms of benefits. In other words: “what’s in it” for the participants; what is it that justifies the risks and burdens? The weight of prospective direct benefits depends on how significant the direct benefits are in terms of magnitude and duration and on how likely it is that the direct benefits will occur.6 The nature of the effect is important when estimating the magnitude and significance of the expected therapeutic effect. The nature of the effect will often depend on the context and to what degree the individual participant (assumingly) values the positive effect. It can be generally assumed that prospects of cure of an otherwise incurable disease are of great magnitude. The magnitude would be even greater if the disease is severe (deadly), than if it is less restraining. The treatment or impediment of Alzheimer’s disease or cancer is generally of greater magnitude than treatment or impediment of migraine, and even more so than treatment or impediment of hair loss. However, some individuals, for example, young women, may value the impediment of hair loss rather high, and assumingly far higher than a forty-year-old man. This signifies that the individual’s perceptions of the direct benefit’s magnitude and significance are of utmost importance and even decisive in the weighing.7 An example: The Obesity Study8 Background: More effective treatment methods are needed for obese people who have not responded to lesser invasive alternatives, such as diets, exercise programs, and medicinal products. Study aim: To study the safety, efficiency, and treatment algorithms of a new device that would reduce (down regulate) or block the intra-abdominal vagus nerve in order to reduce food intake etc. If successful the device could supplement or substitute available standard treatment, such as gastric bypass operations and gastric banding procedures. Method: At a University Hospital in Norway the device was going to be operated into extremely obese patients (BMI > 50). REC-evaluation: REC recognised that the human subjects had prospects of direct benefits if the device worked as planned. REC also recognised that available alternatives were far from optimal, and thus that improved treatment methods were needed. On the other hand, REC reasoned that any surgical procedures involving extremely obese people, even just the use

6

“Direct benefit” is defined in Section 3.6. See Section 8.3 on who decides. 8 REC Middle Norway Case 4.2005.1813. 7

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of anaesthesia, are bound with a considerable risk of severe complications, ultimately death. The device had only been tested on pigs before. The intervention was therefore classified as high risk, especially on this particular group. REC found that the experimental intervention was clearly unacceptable if there were no prospects of direct therapeutic benefits to the participants. (Hence, a nontherapeutic study design would have been unacceptable). The Research Ethics Committee also recognised the potential societal and direct benefits of the project, as well as the researchers’ competence. The Committee was, however, seriously uneasy with the project because of the risks involved. The Committee held several meetings with the principal investigators. Two independent expert opinions were obtained, reviewing physiological as well as surgical aspects. The physiological review was positive and reassured the Committee. The surgical review was worrying. It was asserted that the surgery posed risk of serious complications such as bleeding, damages to the vagus nerve, liver, spleen etc, and that the risks (including risk of death) were downplayed in the proposed information sheet to prospective participants. It was then stated that the sum of risks was considerable, and that it had to be balanced against potential direct benefits (enduring and substantial weight loss). It was also asserted that established and alternative surgical methods for this patient group (gastric bypass or reducing the stomach) were associated with even greater risks. The potential direct benefits of those “standard” procedures were, on the other hand, well documented. On this basis the Committee asked the researchers to re-evaluate the project and propose adjustments. The Committee emphasised three possible changes (1) adjustment of inclusion and exclusion criteria’s to exclude those persons at increased risks, that is the most obese patients by lowering the BMI-criteria, (2) ensure prospective participants alternatives (to avoid research participation being the only option for presumably desperate patients who may be inclined to undertake greater risks than they otherwise would have), and (3) better and more comprehensive information to prospective participants, both written and oral, especially with regard to information on risks.9 The Committee was also concerned with the insurance coverage. The principal investigators made adjustments to the protocol, such as the exclusion of the most extremely obese, improved surveillance, better information to patients especially on risks, benefits and alternatives etc. The Committee then approved the project.

The Obesity Study is an example of a research project which entailed considerable risks and burdens to the participants, and where the Research Ethics Committee thoroughly investigated the risks, burdens, and potential benefits. The Committee approved the project after the protocol had been adjusted. The case example may thus be seen as a boarder issue, and as an example of how far a research ethics committee was willing to go in terms of accepting risks and burdens to the participants. From my perspective the Committee’s judgment appears fair. It may be noted that the risks and burdens in the Obesity Study could clearly not be outweighed by potential benefits to society and science (even though they were great). There had to be prospects of weighty direct benefits to the participants. Moreover, although the Research Ethics Committee emphasised that the prospective participants were rather vulnerable as they were suffering from serious health threats, the prospective participants were able to consent and thus to a certain degree able to safeguard their own interests. In fact, the prospective participants appeared (based on information from the clinicians) well informed and motivated. It is improbable that the Committee would have found the risks and burdens acceptable (proportionate) if the 9

4.2005.1813c Letter to principal investigator.

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prospective participants had not been able to consent. Other factors were also found to be relevant in the Committee’s assessments (than just the prospects of direct benefits). The principal investigators were, for example, regarded as responsible, professional, and highly competent (trustworthy). The nature of the experiment (its great potential benefits to other obese people) also weighed in. It could be argued that the Committee in reality left it to the participants to make the final decision as to whether the direct benefits were so great that they outweighed the risks and burdens, but I do not think that the Committee did that, nor would it be appropriate.10 Rather, the Committee went far to ensure that research participation was a reasonable choice for the participants, and that other alternatives were available. Moreover, from the discussions in the Committee, it may be asserted that the risks and burdens were not completely outweighed by the prospects of direct benefits, but the additional risks and burdens were outweighed by the potential benefits to others than the participant.11 Since the participants were able to consent and was particularly well informed and ensured other alternatives, the Committee was probably correct when they found the additional risks and burdens to be acceptable (and proportionate). Whether the most obese (and most at risk) should be excluded represented a dilemma for the Committee, since these participants also “needed” the intervention (the treatment) the most. The Committee concluded, nevertheless, that the most obese should be excluded from the study because they were at increased risks, and because the trial was in such an early face that the prospects of direct benefits were rather uncertain. Participation was in other words not a reasonable choice for them, as the risks were disproportionate. Consent could not alter that. The Committee’s decision on this issue also appear correct and within the legal framework. Nevertheless, the Obesity Study illustrates the necessity of an overall assessment of proportionality, and that in such an overall assessment circumstances of the prospective participants (such as their vulnerability, presumed interests, and ability to consent) are highly relevant. Usually the research interventions are less dramatic and risky than in the Obesity Study. But then the direct benefits may also be less weighty, and, in effect, the risks and burdens must be lower to be proportionate. Often the direct benefits are also less conspicuous or comprehensible than in the Obesity Case, at least for the prospective participants. For example, the new surgical method may be slightly more effective than standard method, which may imply shorter operation time and a reduced chance of infections and complications. The “weight” of such direct benefits is difficult to ascertain. A more effective (speedy) surgical method may, on the one hand, be rather important for patients, and thus carry considerable weight. But on the other hand, the surgeons may not be familiar with the new method that increases the risks of mishaps and harm.

10 11

Cf. Section 5.4.4. See below, Chapter 11.

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As already shown, the magnitude or likelihood may be so low that the potential benefit to the participant cannot be called a “direct benefit”.12 If the magnitude is so low that no significant therapeutic benefit is expectable, the direct benefit rule does not apply; typically enhanced positive attention (and gratitude) from health care personnel. The same applies if the likelihood of therapeutic benefits is very low, typically an ordinary “health check” or a lottery-ticket. This must be the solution even though some participants may perceive “enhanced attention” or a “health check” as important and as a “direct benefit”. This issue was addressed in the MIDIA Study13 where the Norwegian National Committee on Research Ethics concluded that the benefit of knowing that ones child carried a gene which implied that the child had an increased life-long risk of getting incurable diabetes type I, did not amount to a direct benefit, even though it is possible, and likely, that some parents perceived the information as valuable. The magnitude was in the Committee’s opinion not significant enough, as the parents could make little use of the information. At any rate, the Committee found that the possible benefit of knowing did not outweigh the entailed risks and burdens, which were considerable (above minimal). The judgment about whether the direct benefit rule is fulfilled resembles judgements made daily in ordinary clinical practice, in so far that the risks and burdens to the participants have to be outweighed by prospects of direct benefits to the participant. In that assessment, potential benefits to others are largely irrelevant.14 The estimations, predictions, and weighing of direct benefits should then, as in ordinary clinical practice, have each individual’s best interest in mind. Although the weighing is comparable to those undertaken in ordinary clinical practice, there are several differences. Firstly, the magnitudes of the direct benefits, which may result from the research intervention, are often greater than the magnitude of direct benefits resulting from the standard clinical intervention. This may increase the weight of the prospective direct benefit in comparison to standard intervention or nonintervention. The reason is that often the researchers aim to improve standard clinical practice and develop better treatment methods, diagnostic tools etc. A new surgical method may be faster and thus safer, than the standard long-winded method. The research intervention may also be more favourable and weighty if no other or comparable alternative interventions exist. Participants in a cancer (oncology) trial may, for example, provide hope of cure, while nonparticipants are put off with palliative care. Secondly, a main difference between the weighing of direct benefits in research and in ordinary clinical practice is that less is usually known about the possible effects of the research intervention than of the standard health care intervention, since the study aim often is to obtain such knowledge. Consequently, the uncertainty

12

Cf. Section 3.6. Accounted for in Section 12.5.8. 14 Potential benefits to others are primarily relevant when the direct benefit rule is not fulfilled, see Chapters 11 and 12. 13

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with regard to both the magnitude and the likelihood of the direct benefits from the research intervention is often greater. Uncertainty decreases the weight of the prospective direct benefits, because the more likely the positive effect is, the more it weighs. In fact, to be called a “direct benefit”, the benefit must be more or less expected. And the more expected the benefit is, the more it generally weighs. One may suggest that for a direct benefit to be real and expected, it should at least be more likely than not that the benefit occurs. That is a strict requirement – probably too strict. Lower likelihood appears to be accepted in the practice of research ethics committees and researchers. For example, in the early stages of a clinical trial the prospects of cure from thyroid cancer are at best uncertain, yet there is a slight chance that the newly developed chemotherapy will work (the prospective participants do not respond to other (available) treatment methods). Pre-trial tests in the laboratory and on animals are promising (otherwise further testing (research) should not be carried out). Let us say that the chance of cure (a direct benefit) from the new chemotherapy is realistically predicted to be 10% (although the researchers hope that the initial tests will show a higher efficiency). That means that one in ten participants may expect to be cured. If so, is cure “expected”? Are the prospects of cure a “direct benefits”? Or is it pure gambling – a potential, but yet relatively unlikely, benefit to the participant? Is the likelihood so low that the possible positive effect should not be called a direct benefit? Should the trial be characterised as a nontherapeutic research project, rather than a therapeutic research project? Current practice seems to suggest that although the likelihood is low, the project may still be seen as entailing prospects of direct benefits, and it should therefore be characterised as a therapeutic research project, which suggests that even if the likelihood is low, the research may be seen as entailing prospects of direct benefits to the participant. In bioethical theory the US paediatrician Lainie Friedman Ross, who has written extensively on the subject, has raised the question. She refers to phase I clinical trials in oncology on children. In such trials the treatment is often toxic, and thus painful and dangerous (risk of death), while the potential benefits (cure) are at best very slight. She maintains that phase I oncology trials “are designed to determine toxicity [safety], although a small number of subjects (less than 5%) receive an unintended direct benefit defined as some degree of tumor response.”15 Ross is sceptical to characterise and promote such “unintended” and “unlikely” positive consequence as prospective “direct benefits” that may outweigh the considerable risks and burdens, especially in paediatric research on children. Her solution appears convincing, also in a European legal perspective. However, the crucial point must be that whether or not the potential (but relatively unlikely) benefit is characterised as a “direct benefit” or not, is of less importance than its weight. Thus even though the likelihood is low, for example, only 5% it does not really matter if such a potential benefit is characterised as a

15

Ross (2006, p. 67).

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“direct benefit”, because it is the weight of that potential benefits which matters in an assessment of proportionality. Thus, if the risks and burdens are low, one may come to the conclusion that the prospects of direct benefits (despite the low likelihood) outweigh the entailed risks and burdens; hence that the direct benefit rule is fulfilled as a proportionate relationship is established. But since low likelihood significantly reduces the weight of the prospective direct benefit, it may not outweigh considerable risks and burdens, as illustrated by the Obesity Case where the most obese persons were excluded from participation because the risks were too high in relation to the prospects of direct benefits. This means that Ross’s solution (essentially an ascertainment of disproportionality) probably is correct, but her argumentation is not accurate because too much emphasis is apparently put on the potential effect’s label (i.e. whether the potential benefit is a direct benefit to the participant or not). The difficulty of labelling and estimating potential benefits to the participants underscores the importance of a concrete and overall judgement of the benefit’s weight. At some point, the likelihood of a significant benefit to the participant’s health is so low, that it cannot be seen as “direct”, but rather as outright “gambling” or “wishful thinking” or non-weighty “indirect” or unintended benefits to the participant, such as an ordinary health check. Similarly, the magnitude of the possible benefit to the participants’ health may be so low that the benefit must be seen as insignificant. Nevertheless, whether the benefits are “direct” is legally relevant, because it determines whether the direct benefit rule applies. However, and crucially, whether a benefit is “direct” or not, does not in itself determine whether the requirement of proportionality is fulfilled. It is the concrete weight of the potential benefit that is decisive for whether a proportionate relationship can be established. Thus, whether the direct benefit rule is fulfilled also depends on the weight of the risks and burdens; and subsequent a weighing of the risks and burdens against the potential benefits.

10.3.3 Estimating and Weighing Burdens Burden is defined above as the probability of discomfort caused by research.16 Burdens are, and should be, highly relevant in the assessment of proportionality, because burdens are something most people would rather not face and shoulder, if it where not for the potential benefits to themselves or others. If researchers ask a lot, they are expected to give a lot. One can, for example, not expect research participants to waste time and efforts on unnecessary research, such as research without reasonable prospects of any new valuable knowledge. If so, even filling out a questionnaire or giving a blood sample, may be disproportionate. 16

Section 3.3.

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Burdens vary according to magnitude, duration and likelihood. Characteristic for burdens is that they are usually not causing enduring harm; their magnitude is therefore often low compared to risks. Burdens are, on the other hand, usually expected. Hence, their likelihood is usually high compared to risks. Since burdens are likely to occur, their weight might be considerable, even though the magnitude is low, especially if added together. For example, in the MIDIA Study17 concerning genetic testing of infants with the aim of identifying risk-factors for diabetes type I, the child would have to undergo regularly blood testing (18 blood samples per child over a period of 15 years). The risk associated with blood testing is normally very low, but the burden of repeated testing may be considerable. It takes time to meet up for testing. Many children probably also find the testing painful and frightening, although the pain is transient. In the MIDIA Study the parents of those in the follow up-group were asked to provide diaper (stool) tests monthly. Providing diaper tests regularly is also timeconsuming. Thus, the participants’ (both the children and the parents) sacrifices were not negligible, at least for presumably busy parents and pain-averse children. Parents or their child would probably not want to participate unless this burden was reasonable in relation to expected benefits for themselves or, at least, other children.18 Another case example where the burdens were considerable (although apparently largely neglected in the pre-trial assessment of proportionality) is the Meningococcal B Vaccine Trial, where the burdens were pain in the stab wound and temporary nausea, which could last a day or two and require sick leave.19 The context, and individual conditions and perceptions, should also be considered in the estimation and weighing of burdens. Some individuals may, for example, be less sceptical to spend time, experience discomfort and so on, than others. One apparent reason why burdens are usually found acceptable by research ethics committees is that shouldering burdens is something most individuals should be able to consent to. The burdens are, nevertheless, generally not negligible and should therefore weigh in together with other possible negative effects, such as the risk of harm. Thus, albeit one burden is trivial and seemingly “acceptable”, the sum of possible negative effects may be unacceptable. Participants may also misconceive burdens, as they frequently misconceive risks and potential benefits.20 But usually burdens are more easily comprehensible and thus probably also more easily acceptable. In practice, it is first and foremost where the potential benefits are low, that burdens “alone” may render the direct benefit rule nonfulfilled.

17

Accounted for in Section 12.5.8. See Section 12.5.8 for a full discussion of the case and the assessment of proportionality. 19 Accounted for in Section 11.4. 20 See Section 5.4.2 concerning the prevalence of misconceptions in research. 18

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10.3.4 Estimating and Weighing Risks of Harm The definition of risk as the likelihood of harm resulting from research identifies two distinct components: the possible harm (magnitude and duration), and the probability that the harm will occur.21 The harm may be transient or permanent, mild or severe. The ultimate harm is often referred to as death. Although the consequences are usually not that dramatic, harm may imply reduced life expectancy or enhanced likelihood of a more serious harm, for example, as a result of too many radiation from x-rays. As with benefits and burdens, the estimation and weighing of risks depends on numerous factors, and not only a quantification of the likelihood of harm. The nature and duration of the possible harm, the context, as well as individual conditions and perceptions of risk, must be considered. An apparently trivial harm, may, for example, be severe for some. As found above, the individual participant’s (assumed) perceptions are important in establishing the weight of the risk.22 In general psychological literature on perceptions of risk, some key factors have been identified and recognised as valid in the assessment of risks.23 Those “general” findings are also relevant in this particular context (biomedical research). Most important is the degree of voluntariness. Generally, people tend to accept risks that they knowingly and voluntarily take, rather than involuntary or suppressed (under-communicated) risks. The degree of voluntariness thus influences not just the acceptance of risks, but also its weight. In the Obesity Study,24 the Research Ethics Committee assumed that the participants’ level of knowledge and motivation (voluntariness) was high. Risk familiarity and risk control are also widely recognised as important in the estimation and assessment of risks. This means that chronically sick persons may be less risk- or pain-averse than healthy persons, but this may not justify exposing sick (and vulnerable) persons to relatively greater risks and burdens than healthy and invulnerable persons.25 Whether a risk is associated with dread and catastrophic potential is important in the estimation of risks. Generally ordinary people tend to regard the risk of dreaded and catastrophic effects as higher and weightier, than “experts” do. Laypersons may perceive such risks as high and weighty, even though the likelihood is very remote. An example is that some participants may regard a remote chance of severe complication from taking a new vaccine, as a high risk. This was evident in the subsequent reactions from people who had participated in the Meningococcal B Vaccine Trial.26 Such perceptions must be duly considered in the estimation and weighing.

21

Risk is defined in Section 3.2. See Section 8.3. 23 See section Slovic (2000). 24 Accounted for in Section 10.3.2. 25 This issue is further addressed in Section 12.5.9. 26 Accounted for in Section 10.3. 22

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A sense of fair distribution and equity of risk may also influence the weight of a risk. The observed Research Ethics Committee did, for example, in a case question the research group’s frequent testing of dying cancer patients in palliative care. The principal investigator did explain that palliative patients were usually motivated to participate in research. The Committee accepted the explanation. The nature and situation are of utmost importance when estimating risks and assessing proportionality. Typically, in an emergency clinical situation there is little room and tolerance for mishaps and additional new risks. Even a, under other circumstances, very modest intervention, for example, the obtainment of some additional tissue samples for research purposes, may be considered to entail high, and therefore unacceptable, risks. In an emergency situation the randomisation process may occasionally be seen as an undue delay of effective treatment of persons with, for example, cardiac arrest outside the hospital, were assumingly seconds were of importance. Participants’ vulnerability and possible predisposal’s for certain diseases or negative effects should be considered as these may render otherwise trivial risks as high and unacceptable. Fundamentally, an estimation of solely the risks is insufficient to judge whether the risks are acceptable or not, as it is a concrete weighing of risks against potential benefits in an overall assessment of proportionality that is decisive.

10.3.5 The Overall Assessment of Proportionality The difficulty of estimating and weighing risks, burdens, and potential benefits signifies a need for an “overall” assessment of proportionality, which raises the question: what does such an overall assessment imply? Clearly, a simple mathematical weighing and calculus of the risks’, burdens’, and prospective direct benefits’ magnitude and likelihood is usually not sufficient in the assessment of proportionality, and thus in determining whether the direct benefit rule is fulfilled. The simple reason is that such precise data rarely exists. For that reason it is rarely possible. Another reason is that individual considerations, and the nature and context of the research project, must be taken into account in what can only be an overall assessment of proportionality. The necessity of undertaking an overall assessment of proportionality is also recognised in legal theory regarding the principle of proportionality in the laws of war, where the distinction between “quantitative” and “qualitative” proportionality has been discussed.27 The prevailing view seem to be that the assessment of proportionality should not only include quantitative elements (for example, a costbenefit assessment of deaths caused and lives saved), but also qualitative elements

27

Wicker (2006, p. 87).

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such as the importance of the interests promoted or protected, and the nature of the interference seen in its particular context.28 The legal scholar Christian Wicker has asserted that proportionality “applies to quantities, though it does not find its limits in the field of quantifiable things, but it also applies to qualities.”29 This can also be said about the assessment of proportionality between risks, burdens, and potential benefits in European biomedical research law. The interpretative style of both the European Court of Human Rights and the European Court of Justice is unmistakably dynamic and contextual. This suggests a dynamic, flexible and concrete (pragmatic) approach towards the assessment of proportionality. The observed Research Ethics Committee always undertook an overall assessment, which suggests that a dynamic and contextual approach is natural. The fact that the composition of the committee must be multidisciplinary composed substantiates such an approach. The implication of this is that although available quantitative data on risks, burdens and potential benefits are relevant and important, the weighing cannot solely depend on a mathematical calculus. The quantitative assessment is only a means in the overall assessment of proportionality. Qualitative factor are also legally relevant in an overall assessment of proportionality. This resembles the findings in Chapter 8 that although objectivity is the natural starting point in the assessment of proportionality, subjective circumstances inevitably play an important role, such as values and perceptions among both experts and laypersons (participants). The Implication of Participant’s Consent An interesting question is the role (relevancy) of participants’ ability to consent in the application of the direct benefit rule (i.e. the assessment of proportionality in therapeutic research). In the assessment of proportionality in nontherapeutic research, the Additional Protocol Articles 6 (2), 15, 18, 19, and 20 and the Clinical Trials Directive Articles 4 and 5 make it clear that participants who are able to consent may consent to carry greater risks and burdens for the sake of others, than participants unable to consent.30 However, neither the Additional Protocol nor the Clinical Trials Directive explicitly distinguishes between participants’ ability to consent when it comes to the assessment of proportionality in therapeutic research. An antithetical interpretation of the instrument’s wording, suggests that the same threshold applies; hence that the assessment of proportionality is indifferent to the participants ability to consent if the research entail prospects of direct benefits to the participants. The question addressed is then: is that really so; what is the implication of participant’s consent in the assessment of whether the direct benefit rule is fulfilled? 28 See for example the Case concerning the Gabcikovo-Nagymaros Project, ICJ Reports, 1997, paragraph 85. 29 Wicker (2006, p. 88). 30 This issue is addressed in the next chapter, Chapters 11 and 12.

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The likely underlying reasoning of the direct benefit rule suggests an affirmative answer: If the direct benefit rule is fulfilled, then participation in research is not contrary to the person’s best interests, because the risks and burdens to the participants are outweighed by prospects of direct benefits to the same participant. Either they are outweighed, or they are not. The participant’s consent will not alter the relationship between risks, burdens, and prospective direct benefits. In principle, and as a starting point, this interpretation must be correct. This means that the direct benefit rule itself does not afford individuals unable to consent additional protection, by, for example, demanding a clear, obvious, or qualified preponderant of direct benefits if the research involve individuals unable to consent. The likely reason is that the additional protection afforded persons unable to consent and similarly vulnerable participants is primarily found elsewhere in the legal framework. Article 15 (1) (ii) of the Additional Protocol, for example, requires that “research of comparable effectiveness cannot be carried out on individuals capable of giving consent” (a variant of the requirement of lesser mean).31 The requirement of necessity is also stricter when it comes to research on vulnerable persons.32 The Clinical Trials Directive entails similar additional safeguards in Article 4 (children) and Article 5 (adult persons not able to consent).33 It exceeds the scope of this book to investigate these additional safeguards, but it is important to note that research on persons not able to consent and other similarly vulnerable participants are subject to stricter regulations than research on relatively invulnerable persons. This also applies when the risks and burdens are outweighed by the prospects of direct benefits (therapeutic research). A likely reason for the enhanced legal protection of persons not able to consent and other similarly vulnerable participants is that even though the risks and burdens are outweighed by prospects of direct benefits, the prospective participants’ alternatives (participation or nonparticipation) may not be comparable. The nature of the risks and burdens may, for example, not be comparable although the risksbenefits ratios of the alternatives are. Moreover, research interventions will almost by nature often appear as more uncertain than the alternative (nonparticipation and standard treatment). But even a requirement of overwhelming preponderance would not ensure that research participation is the alternative everyone would choose. That challenge is primarily supposed to be met by the requirement of consent, and the additional safeguards set out for participants not able to consent and other similarly vulnerable participants (by way of consent by proxy, accommodated information, respect for objections and previously expressed wishes etc), as well as the requirement of necessity and lesser mean.34

31

See Section 9.5 on the general requirement of lesser mean. See Section 9.5 on the general requirement of necessity; See Section 3.8 on the definition of “vulnerable person”. 33 See Articles 4 (e) and 5 (e). See Chapter 19. 34 See Additional Protocol Article 15 (1) and the Clinical Trials Directive Articles 4 and 5. 32

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Thus, as a starting point the direct benefit rule is indifferent to participants’ ability to consent as illustrated by the Stroke Studies35 which concerned high risk research on individuals in a clinical emergency situation in which they were unable to consent. However, this can only be a starting point, because other factors, including individual perceptions, are, as shown, highly relevant in the identification and estimation of risks, burdens, and potential benefits. The example used above may illustrate this point: The only alternative for cancer patients not responsive to standard available therapy is palliative care; offering no chance of cure, only improved comfort awaiting an impending death. The risk-benefit ratio for research subjects will therefore often appear favourable compared to the risk-benefit ratio for patients without any alternative, despite a major increase in short-term absolute risks (a considerable risk of death caused by the research intervention).36 This implies that while a risk of death from the research intervention around 5% for a research intervention would be unacceptable and disproportionate for a healthy volunteer, it could be acceptable for persons with no other prospects of cure because of the entailed prospects of direct benefit (cure). Interestingly, this would in principle also apply to children and adult persons not able to consent to research.37 But qualitative and subjective factors may influence that judgement and imply that a research intervention is regarded as proportionate when it comes to adult persons who are able to consent, but not when it comes to children. As noted above, individuals are generally more inclined to accept risks that they knowingly and voluntarily take, than involuntary or suppressed (under-communicated) risks. This implies that the ability to consent is, at least, indirectly relevant in the assessment of proportionality in therapeutic research.38 Thus although the threshold of acceptable risks and burdens in principle are the same for participants able and unable to consent in therapeutic research, the direct benefit rule is, in practice, not completely indifferent to whether the participant is able to consent. Similarly the direct benefit rule (and the requirement of proportionality) is not indifferent to other factors that are relevant in the weighing of and for the relationship between risks, burdens, and potential benefits. But the likely reason why the legal framework do not operate with a different threshold for participants who are, and who are not, able to consent when it comes to the direct benefit rule, is that if the direct benefit rule is fulfilled, research participation is not contrary to the prospective participants narrow self-interests. As such it does not challenge researchers’ and health personnel’s duty of care. The Relevancy of Community Consultations in the Assessment of Proportionality To make the assessment more accurate, it has been suggested that representatives from the prospective research population should be involved in the development of 35

See Section 10.3.6. Ross (2006). 37 Ross (2006). 38 See Sections 8.3 and 10.3.4. 36

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the research protocol, including the assessment of proportionality and the framing of the consent procedure. Martin and colleges, for example, assert that since “RECs cannot assess the balance of incommensurable risks and benefits”, prospective participants should be “. . . invited to provide input in protocol development” as “only the individuals involved know how different incommensurable consequences will affect them personally. . . . [O]nly those who might be harmed by research can judge whether the potential benefits to others within the community justify the risks.”39

The suggestion is sensible. However, since community consultations can be resource-demanding (perhaps a research study in its own way), such consultations may in practice be timely for particularly large or ethically challenging research projects, such as, for example, in the Meningococcal B Vaccine Trial. An absolute legal obligation for the researcher to perform such a pre-trial survey cannot be derived from the current legal framework. The performance of such a survey would, on the other hand, surely enhance the accuracy of the assessment of qualitative proportionality. It would therefore be legally relevant in both a prospective and retrospective review of whether the researchers had fulfilled their duty of care or not. Such surveys should therefore be promoted and recommended. Conclusions In conclusion, Article 6 (1) of the Additional Protocol as well as Article 3 (2) (a) of the Clinical Trials Directive clearly prescribes an overall assessment of proportionality were many factors may be relevant. The judgment of proportionality (including whether the direct benefit rule is fulfilled) cannot be solely based on a mathematical calculation (although such a calculation may be helpful in the assessment). To some extent it is correct to characterise the overall assessment as rough and approximate. The use of wordings like a “proportionate” or “fair” or “reasonable” relationship between risks, burdens, and potential benefits substantiate that view. The observed Research Ethics Committee did, for example, rarely carry out a systematic assessment of proportionality, which included fine tuned calculations and estimates. Rather the Committee undertook a qualified gut-feeling assessment of proportionality. Although, both the Committee and the assessments occasionally possibly could have benefited from a more systematic approach, I do not argue that a qualified gut-feeling assessment necessarily is inaccurate and incorrect. On the contrary, subtle, qualitative, and subjective factors may, just as much, be seen as contributing to the accuracy of the assessment of proportionality for this particular research project and the particular research participant, since particular nuances can be legitimately considered. This may make it more difficult to control the assessment, but accuracy is probably more important for science, society, and prospective research participants. And it is such sensible, and thus more correct, judgments the requirement of proportionality prescribes. This does, however, not mean that the assessment of proportionality is entirely “free”, hence that the researcher or the research ethics committee may come to any 39

Martin et al. (1995, p. 9).

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conclusion they may see fit. On the contrary, the overall assessments (judgments) must be within the minimum standards that follow from the legal framework to be legally acceptable (lawful).40 Additional Observations I have not encountered discussions of qualitative and quantitative proportionality in bioethical or legal literature on the subject, but Eric Mark Meslin adopt a similar approach which includes both objective and subjective circumstances in his account of risk judgments.41 In my opinion, the discussion signifies the necessity and inevitability of an overall and contextual judgement towards the assessment of proportionality and whether the direct benefit rule is fulfilled. The absence of this discussion may also explain the inclination in some of the literature towards quantification and the establishment of rather coarse and categorical thresholds for the acceptable risks and burdens; that is thresholds rather indifferent to context and individual circumstances.42 Arguments for a categorical and formalistic approach are the difficulty of assessing proportionality and the risk of a slippery slope. As I see it, the inclination towards “categorical formalism” is neither sound nor legally sustainable, because it would render the review of research projects too categorical and inflexible; it could also be contrary to the societal interests in biomedical research, as well as participants’ altruistic interests and their right to self-determination. Nevertheless, such formalism has no basis in European biomedical research law, as the requirement of proportionality clearly demands an overall judgement in which qualitative and subjective elements are highly relevant. This does not mean that there are no absolute limits and thresholds, and that the assessment is completely “free”. On the contrary, that there must be a proportionate (reasonable) relationship between risks, burdens, and potential benefits, is certainly an absolute requirement. Moreover, for the direct benefit rule to be fulfilled, it is an absolute requirement that the prospects of direct benefits to the participant’s health, are, after an overall and contextual assessment, found to outweigh the entailed risks and burdens to the participant. This implies that not “any” risk will be acceptable and proportionate as long as the “potential direct benefits” are great enough. At some point the risk will be so great, that research participation may be seen as reckless and, even, outright detrimental and harmful. If, so, almost no matter how great the potential direct benefits are, they may probably not outweigh the risks.

10.3.6 Reasonable Choice and Most Favourable Alternative This section addresses the relevancy and necessity of comparing participants’ alternatives in an assessment of proportionality, and its implications. 40

Possible legal consequences of disproportionality are investigated in Chapter 17. Meslin (1989). 42 See, for example, Wendler and Miller (2007). 41

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The issue is not explicitly addressed in the Additional Protocol or the Clinical Trials Directive. The legal solutions must then be sought in an interpretation of the requirement of proportionality as expressed in Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive, and other relevant sources. First, the problem addressed, is going to be further outlined. In general, theoretical works on risk management, the assessment and management of risks are seen as a decision problem. One has to choose among alternatives, and the attractiveness of the available alternatives depends on many factors. Scholars in the general field of risks assessment, Fischhoff and colleges, found: [Deciding] which of a set of options is most attractive is inherently situation specific. That is, there are no universally acceptable options (or risks, costs, or benefits). The choice of an option (and its associated risks, costs, and benefits) depends on the set of options, consequences, values, context and facts examined in the decision-making process. . . . In short, search for absolute acceptability is misguided.43

The statement is largely in line with the findings in the previous section. It also signifies another aspect which till now has only been briefly touched upon: that the requirement of proportionality and the acceptability of risks and burdens essentially concern the clarification of alternatives and the assurance that research participation is a reasonable choice for the prospective participant.44 Both the Interval Training Study and the Obesity Study illustrated the importance and relevance of a broad approach and a comparison of available alternatives.45 The Research Ethics Committee compared research participation (and intervention) to nonparticipation (standard intervention and nonintervention). In the Interval Training Study, the Committee found that not only did the direct benefits outweigh the risks; research participation also appeared to be a more favourable alternative than nonparticipation. In the Obesity Study this was more dubious, but yet the Committee concluded research participation was a reasonable choice that wellinformed persons could consent to because it was within an acceptable sphere of discretion (the participants’ “margin of appreciation”). This was, however, in the opinion of the Committee not the case with the most extremely obese patients, which were excluded from the study. Since the prospective participants were assumed to be in “desperate” need of treatment, the Committee made sure that other treatment was available to them, so that the research participation was not the only “choice”. Another case example may further illustrate the addressed issue: The Stroke Studies46 Background: Less than 5% of those who suffer from cerebral infarction (acute stroke) receive approved (by the health authorities) thrombolytic treatment, which dissolves the blood cloth in the brain. Such treatment is not approved for patients above 80 years. The

43

Fischhoff et al. (1983). See Chapter 5. 45 Accounted for in Sections 10.2 and 10.3 respectively. 46 REC Western Norway [not observed], case 264.06 and case 265.06. 44

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inclusion criteria for thrombolytic treatment are strict because there are considerable risks attached to such treatment. Study aim: To extend the inclusion criteria so the physicians may try to dissolve the blood cloth on patients who would not receive such treatment in ordinary clinical practice. Method: An extension of the ordinary treatment regime. The study consisted of several sub-studies. [The exact scientific method is not described in the available information]. REC evaluation: The Committee recognised that the study involved considerable risks for the patients, even a “real” risk of death. The studies were therefore characterised as ethically very challenging, and thus subject to thorough investigations. The studies were discussed in three consecutive meetings. The Committee also met with the principal investigator. In particular, the Committee challenged the researcher to make a more detailed account for the risks and benefits involved for the patients. The Committee asked the researcher to set up the risks and potential benefits for each alternative, so that the committee could compare the risk-benefit ratio of one alternative (nontreatment) with the other (research intervention (thrombolytic treatment)). The Committee had to be assured that inclusion in the research project was not a poorer alternative for the patient than ordinary treatment. This was especially important, as it would not be practically possible to obtain valid consent because of the patients’ condition and the clinical emergency situation (short time frame). The Committee concluded that it was not possible to say that one alternative stood out as more favourable than the other. Research participation was thus a reasonable choice, and the studies were approved after some adjustments. One “adjustment” was the establishment of a monitoring body that should survey the safety (the risks-benefit ratio) after every ten patient included. Hence, if one alternative appeared to be poorer than the other, the treatment could be adjusted.

The Stroke Studies illustrate the intuitiveness and importance (and difficulties) of comparing alternatives when determining whether the risks and burdens are proportionate to prospective direct benefits to the patients. In that study the very aim was to determine which alternative was the better for the patient. The researchers hoped (predicted) that research intervention should be the better alternative, but they could not be sure. Hence, research intervention could also prove to be a poorer, and a more lethal, alternative. The need to compare alternatives is addressed in CIOMS Guideline 8, which concerns the assessment of risks and benefits: For all biomedical research involving human subjects, the investigator must ensure that potential benefits and risks are reasonably balanced [a general requirement of proportionality] and risks are minimized. • Interventions or procedures that hold out the prospect of direct diagnostic, therapeutic or preventive benefit for the individual subject must be justified by the expectation that they will be at least as advantageous to the individual subject, in the light of foreseeable risks and benefits, as any available alternative. Risks of such “beneficial” interventions or procedures must be justified in relation to expected benefits to the individual subject. [italics added]

The Guidelines thus clearly supports a notion or a requirement of research participation being an alternative at least as favourable as the alternatives, although the CIOMS Guidelines weight is limited in a European legal perspective.47 47

See Section 5.3.

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A similar requirement is included in the Guidelines on the practice of ethics committees in medical research with human participants by the Royal College of Physicians of London. The Guidelines maintain: If an investigator knows that the interventions being tested are not equivalent for the individual participant, the superior treatment should be recommended. Equipoise implies that there is a balance of knowledge as to the outcome between the interventions being tested.48

The UK Guidelines thus also substantiate a requirement that research participation should be an alternative at least as favourable as other alternatives, although the UK Guidelines carries little weight in a European legal perspective. Such a notion is apparently more or less established in bioethical literature. As indicated in the UK Guidelines, the notion is linked to the bioethical concept of “equipoise”. “Equipoise” basically means that the risk-benefit ratio of research participation roughly equals the risk-benefit ratio of available alternatives.49 Hence, it refers to “genuine uncertainty” about which (therapeutic) alternative is the most favourable for the participant. The concept of equipoise originates from a publication in 1974 by Charles Fried.50 Some commentators refer to the betterknown publication in 1987 by Benjamin Freedman.51 The requirement of equipoise has since been developed, discussed, elaborated and widely embraced in bioethical literature, most enthusiastically by the bioethicists Christian Weijer and Paul Miller.52 Weijer and Miller, writing primarily in a US bioethical context, have asserted that the doctrine is an independent norm in itself, and that the norm is applicable on research with direct benefits, (while a different norm is applicable to research without direct benefits).53 The US National Bioethics Advisory Commission largely embraced the concept and held that research participation could be a reasonable choice only if equipoise existed.54 The UK legal scholar Shaun D Pattinson refers to equipoise as a moral concept and not a legal concept, but does not take a clear stance with regard to its legal merits and role in a legal framework.55 Others have refuted the concept of equipoise on different grounds, although not legal ones.56 Thus, the concept of equipoise is controversial in bioethical literature, but the majority of

48 Royal College of Physicians of London. Guidelines on the practice of ethics committees in medical research with human participants (4th ed.) (2007, p. 36). 49 Being a controversial bioethical concept and doctrine, there are many opinions about its content, status etc. 50 Miller and Weijer (2003). 51 Freedman (1987). 52 Weijer and Miller (2007). 53 Weijer and Miller (2007, p. 118). 54 The US National Bioethics Advisory Commission, Final report (2001, p. 70). 55 Pattinson (2006, pp. 351–354). 56 See for example Miller and Brody (2007).

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commentators seem to favour it.57 The relatively broad support for this concept substantiate that a requirement that research participation should be an alternative at least as favourable as other alternatives can and should be interpreted into the legal framework. Nevertheless, clearly, in an assessment of proportionality, it is not only relevant, but also necessary, to take into account available alternatives, especially in a clinical context. The necessity of a comparison of alternatives is substantiated by empirical studies. The latter suggest that many patients expect to be offered the better alternative (be that research intervention or standard intervention), as this is in his or her narrow self-interests.58 At least they do not expect to be offered a poorer alternative. Protection of the best interests of the patients as well as physicians’ duty of care thus substantiates a requirement of research participation being an option at least as favourable as other alternatives. The principle of human primacy also suggests that such expectations should, as a main rule, be met. In conclusion, if research participation is a poorer alternative (even a slightly poorer) than the alternatives, then the direct benefit rule is not fulfilled, because research participation is associated with additional risks and burdens that are not fully outweighed by the prospects of direct benefits to the participant. Consequently, for the direct benefit rule to be fulfilled, research participation should be an alternative at least as favourable as any other available alternatives (including nonparticipation).59 It can even be seen as a precondition for the fulfilment of the direct benefit rule. This legal solution can be derived from the requirement of proportionality (and the direct benefit rule) itself: The assessment of proportionality of one alternative cannot be assessed completely independent from and indifferent to other available alternatives. It would be unreasonable to argue that the prospects of direct benefits of a particular research intervention outweigh the risks and burdens, and therefore represent a reasonable choice, if better alternatives exist. A comparison of alternatives may thus be legally mandatory to realise the purpose of the requirement of proportionality, which may be said to be to ensure that research participation is a reasonable choice.

10.3.7 More on Individual Therapy v. Systematic Research Above two common differences between therapeutic research and ordinary clinical practice were investigated (the magnitude of potential benefits are often greater

57 Although the concept is most useful (and frequently applied) in relation to clinical trials with several arms (intervention alternatives), there is no reason for such a limitation. 58 Coleman (2004, pp. 8–10); Mangset et al. (2008 and 2009). 59 Occasionally research interventions vary so that some participants are offered one kind of intervention (typically active drugs) and other participants are offered another (typically placebo). There are thus several alternatives. This situation is addressed in Chapter 14.

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in research than in clinical practice, but the likelihood that the benefits will come into being is often lower). In this section a third distinction and its implications are investigated. Research is undertaken primarily for the sake of others, although the participants occasionally may have prospects of direct therapeutic benefits. This fundamental difference in the primary objective between therapeutic research and ordinary clinical practice is important. The difference implies, among other things, that participants in a research project are usually treated systematically in accordance with a predetermined research protocol, and not as individual as in ordinary clinical practice. This is done to isolate and more accurately determine the differences between the various interventions. Consequently, although the research participants as a whole might get better “treatment”, a few individuals may get poorer treatment if individual needs are ignored or suppressed for the sake of scientifically valid results. The systematic approach required by science may thus conflict with the individualistic best interest approach applied in ordinary practice. This may imply that, although the risk-benefit ratio (proportionality) is acceptable at a “group” level, the risk-benefit ratio may not be acceptable at the individual level. Hence, although the risk-benefit ratio of research intervention is expected to be more favourable than the risk-benefit ratio of nonintervention and nonparticipation at a group level (for the participants as a whole), there may be a few individuals with particular conditions which may be exposed to excessive (disproportionate) risks and burdens. Such (unfortunate) individuals would surely benefit from an individual approach, and research participation would, for them, be a poor and unacceptable alternative because the risks and burdens would be disproportionate to the potential benefits. To justify research on persons not able to consent, a presumed consent from the participant must be established.60 Consequently, if it is probable that one of the participants, because of special individual circumstances, runs additional risks and burdens, the direct benefit rule is not fulfilled, even though it is fulfilled for the other participants. That person should then either be excluded or included only if the exception clauses are fulfilled. It is in practice obviously difficult to identify this “unfortunate” individual because no one may know that he or she is predisposed or particularly vulnerable, but that is exactly the nature or risks and what the description of risks aim to communicate. In other words: if there is one in, for example, a 1 000 chance that a participant may react abnormally to a new drug, then the overall risk of harm is 1 in 1 000 for the group as a whole. It is unreasonable to say that because the new drug is harmless to most of the participants (999), the drug is harmless.61 That argument is only valid if the “unfortunate one” could be pre-identified and excluded.

60 61

See Chapter 12. See phase III of the Meningococcal B Vaccine Trial discussed in Section 11.4.

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10.3.8 What if the Direct Benefit Rule Is Not Fulfilled? If the direct benefit rule is fulfilled, the participant does not carry any additional risks and burdens for the sake of others. Consequently, research participation is obviously a reasonable choice. However, many biomedical research projects entail risks and burdens to the participants that are not completely outweighed by the prospects of direct benefits to the participant. For example, the experimental medicine is hoped to be an alternative at least as good as the standard (control) medicine, but since little is actually known about the experimental medicine, including its effectiveness and safety, it can not yet be said to be an alternative as favourable as the other alternatives. Even though the alternatives are comparable, research participants may have to undergo additional testing (blood draws, questionnaire etc.), and the risks and burdens thereof are not outweighed by the prospects of direct benefits from taking the medicine (experimental or control). Furthermore, the researcher would like a randomly assigned group of participants to take placebo medicine, and the risks and burdens thereof are certainly not outweighed by prospects of direct benefits, as there are no such prospects. The direct benefit rule is then obviously not fulfilled. The alternatives are not equal. The question is then; can the risks and burdens still be seen as acceptable and proportionate? In other words, are there any exceptions to the direct benefit rule? As already shown in Chapter 9, the answer is obviously yes. The reason why I still raise the question is because of controversies in bioethical literature that mainly relate to the view held by some commentators that equipoise is the only norm in therapeutic research, while another norm is applicable in nontherapeutic research.62 According to the supporters of an independent “norm of equipoise” (as well as the CIOMS Guideline 8), there are no exceptions. In fact the inclusion of individuals in projects where participation is not as good as other alternatives is regarded in breach of researchers’ duty of care. This implies that additional risks and burdens cannot be outweighed by potential benefits to others, even if the participants are well informed, and able and willing to consent. In effect, the CIOMS Guideline 8 and supporters of the norm of equipoise promote double standards, one standard for research with prospects of direct benefits and another standard for research without such prospects. Such a double-standard approach has not much support in the Additional Protocol or the Clinical Trials Directive which prescribe the same standard for therapeutic research and nontherapeutic research: the requirement of proportionality, although some additional preconditions apply.63 The Explanatory Report to Article 6 in the Additional Protocol does for example state: However, it must be noted that benefits referred to in this article include not only direct benefits but also the benefits of the research to science or society. This is particularly relevant

62 63

Weijer and Miller (2004). Cf. Chapter 10.

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in the case of research that has not the potential to produce results of direct benefit for the health of the person concerned.

The wording “particularly relevant” clearly suggests that potential benefits to science or society may also be relevant in the assessment of research with prospects of direct benefits to the participants, although such benefits are most important where there are no prospects of direct benefits. Similarly the Clinical Trials Directive talks about justifying risks and burdens by “anticipated benefit for the individual trial subject and other present and future patients” [italics added]. Hence, the Directive also favours an approach where all relevant factors weigh in when the assessment of proportionality is undertaken, not only direct benefits where prospects of such benefits are present. Certainly, both Convention law and Community law recognise the inherent difference between therapeutic research and nontherapeutic research, as reflected in the direct benefit rule being the main rule. But to say that the mere presence of prospects of direct benefits render prospects of benefits to society and science totally irrelevant is something else. To argue that only participants, who cannot expect any direct benefits are allowed to carry risks and burdens for the sake of science and society, is not only logically problematic, it would certainly also be contrary to these persons’ autonomy and right to self-determination, not least their possible altruistic interests. It is not the type or labelling of research that is decisive for the level of acceptable risks and burdens. Whether additional (excess/surplus) risks and burdens that are not outweighed by prospects of direct benefits are proportionate must in principal be determined in the same way as the acceptability of risks and burdens entailed in nontherapeutic research, as illustrated by the Research Ethics Committee’s overall evaluation in the Obesity Study.

10.4 Conclusions The requirement of proportionality in Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive is fulfilled if the risks and burdens to the participant are completely outweighed by the prospects direct therapeutic benefits to the same participant, i.e. that the so-called “main rule of direct benefit” is fulfilled. For the direct benefit rule to be fulfilled, the risk-benefit ratio of research participation should also be at least as favourable as other alternatives. If the direct benefit rule is fulfilled the participants does not take on any additional risks or burdens for the sake of others, just other kinds of risks and burdens (a different (treatment) option). If so, research participation may therefore be a reasonable choice, even for participants that are not able to consent. If the prospects of direct benefits to the participants do not fully outweigh the risks and burdens to the participants, the direct benefit rule is not fulfilled because the research project entail additional risks and burdens. Such additional

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risks and burdens are then carried for the sake of others, and can only exceptionally be acceptable according to the requirement of proportionality, and the additional preconditions contained in the instruments.64 Whether additional risks and burdens are acceptable must in principal be determined in the same way as the acceptability of risks and burdens entailed in nontherapeutic research, because in nontherapeutic research all risks and burdens are “additional” and carried for the sake of others. This issue is addressed in Chapters 11 and 12.

64

Cf. Section 9.3; cf. Articles 6 (2), 15 (2), 18 (1), 19 (2), and 20 of the Additional Protocol; Articles 3 (2) (a), 4, and 5 of the Clinical Trials Directive. See Chapters 11 and 12.

Chapter 11

Nontherapeutic Research

11.1 Starting Points and Problems Addressed Biomedical research often entails risks and burdens to the participant that are not outweighed by prospects of direct benefits to the health of the same participant. Since the main rule in European biomedical research law is found to be the direct benefit rule, individuals may only exceptionally be exposed to additional risks and burdens for the sake of others.1 In this chapter the second category identified in Section 9.3 is addressed: that is research on relatively invulnerable persons who are able to consent to research participation, but where the research does not entail prospects of direct benefits to the participants – so-called “nontherapeutic research”.2 This includes research on so-called “healthy volunteers”, but it also includes nontherapeutic research on hospitalised “patients” and others.3 In accordance with what is said in Section 10.3.8, this chapter may also be seen as addressing “therapeutic research” which entails risks and burdens that are not completely outweighed by prospects of direct benefits, so-called additional (excess/surplus) risks and burdens to the participant. The legal framework is, as already mentioned, in Convention law Article 6 of the Additional Protocol: 1. Research shall not involve risks and burdens to the human being disproportionate to its potential benefits. 2. In addition, where the research does not have the potential to produce results of direct benefit to the health of the research participant, such research may only be undertaken if the research entails no more than acceptable risk and acceptable burden for the research participant. [Italics added]

The corresponding provision in Community law is Article 3 (2) (a) of the Clinical Trials Directive: 1

See Chapter 9; nontherapeutic research and therapeutic research are defined in Section 3.7. Nontherapeutic research is defined in Section 3.7. 3 These concepts are defined in Chapter 3. 2

S. Simonsen, Acceptable Risk in Biomedical Research, International Library of Ethics, Law, and the New Medicine 50, DOI 10.1007/978-94-007-2678-9_11,  C Springer Science+Business Media B.V. 2012

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A clinical trial may be undertaken only if, in particular: (a) the foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients. A clinical trial may be initiated only if the Ethics Committee and/or the competent authority comes to the conclusion that the anticipated therapeutic and public health benefits justify the risks and may be continued only if compliance with this requirement is permanently monitored [Italics added]

As found in Chapter 9, the core normative content of Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive is the same: a traditional requirement of proportionality between risks, burdens, and potential benefits. However, the “additional precondition” expressed in Article 6 (2), first sentence, of the Additional Protocol, (“no more than acceptable”), is not explicitly expressed in Article 3 (2) (a) of the Clinical Trials Directive (Neither in the Oviedo Convention nor the Norwegian Health Research Act). As found in Chapter 9, the intended meaning of Article 6 (2) is to make it clear that while Article 6 (1) indicates a more or less linear relationship between proportionate risks and burdens to the participant and potential direct benefits to the participant (therapeutic research), this is not the case if the research only entails potential benefits to others. Consequently, no matter how beneficial the research project may prove to be to others, and no matter how willing the participant is, it is not acceptable to expose an individual to risks and burdens above “acceptable risks and burdens”, see Fig. 9.1. To act otherwise would be in breach of the researcher’s duty of care. There are therefore limits as to what levels of risks and burdens to the participants that can be outweighed by potential benefits to others. Thus, the main legal question in Convention law in this chapter is then: when are risks and burdens “acceptable” as required in Article 6 (2), first sentence, of the Additional Protocol? In Community law the question is: when do the potential benefits to others “justify” the risks and burdens to the participant, as required in Article 3 (2) (a) of the Clinical Trials Directive? As shown above, the answer to these two questions should be essentially the same. The questions may therefore be merged into one core question: when are risks and burdens to the participant proportionate to potential benefits to others. In other words: what level of risks and burdens may a relatively invulnerable person consent to carry for the sake of others (potential benefits to science, society, future patients etc.)? More on the Problems to be Addressed and the Legal Starting Points: The Purpose (raison d’être) of the “Additional Precondition” The additional precondition in Article 6 (2), first sentence, (“no more than acceptable risks and acceptable burden”) stands in contrast to the not uncommon proposal by the Dutch legal scholar Lucas Bergkamp that relatively invulnerable individuals should be allowed to take upon as much risks and burdens as they want (consent to). Bergkamp’s proposal thus indicates that there is no need for an assessment of proportionality and restrictions when it comes to nontherapeutic research on healthy

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volunteers.4 This view is, however, as shown, obviously ill-founded in European law.5 This issue is fully discussed in Chapter 5 but is, however, briefly recaptured here, to clarify the purpose of the “additional precondition” in Article 6 (2), first sentence. The reasons why Bergkamp’s view is ill-founded in European law is that the requirement of proportionality can be seen as a specification of researchers duty of care: If the risks and burdens of a research intervention are not proportionate, then the researcher is in breach of his duty of care. As found by the US Court in the case Grimes v. Kennedy Krieger: participants’ consent does not make an inappropriate and disproportionate research project appropriate and proportionate (the requirement of proportionality is independent of the requirement of consent).6 Thus, the requirement of proportionality limits what prospective research participant legitimately can be offered to take part in. Although, highly competent and motivated individuals may consent to take part in research projects entailing higher risks and burdens, than “vulnerable individuals” may be included in, the level of acceptable risks and burdens is not unlimited. The reason is that researchers’ duty of care is, as shown in Section 5.4.4, more restricted, than prospective participants’ autonomy and self-determination: individuals may act foolhardy, but researchers may not. Surely, research ethics committees and the researchers task is not just to facilitate an “informed” consent, and leave the judgment regarding whether the risks and burdens are acceptable with the participant, although this view may (wrongfully) be drawn from paragraph 27 of the Explanatory Report.7 The researcher and the Research Ethics Committee must make independent and responsible judgments to ensure that the risks and burdens are acceptable and proportionate, and that research participation is a reasonable choice that prospective participants may consent to if they want. The additional rationale for this limitation is also the unreliability of individual’s consent: ordinary participants often misconceive the information given.8 In addition, researchers tend to overestimate potential benefits, and under-communicate the risks and burdens involved.9 Researchers are also the stronger party in the researcher-participant relationship, and there is an obvious potential conflict of interest between the researcher and the research participant.10 This is the main reason why a multidisciplinary research ethics committee must undertake an

4

Bergkamp (2004, p. 66). See Section 5.4. 6 Accounted for in Section 12.5.10 – although this is a US judgment, the result would most probably be the same in a European court. 7 Cited and discussed in Section 9.3.1. 8 See Section 5.4.3. 9 See Section 5.4.3. 10 Cf. Section 5.2. 5

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overall assessment of proportionality and the acceptability of the entailed risks and burdens must review a research project.11

11.2 The Challenge of Estimation and Weighing As shown in the forgoing chapter, judging whether the direct benefit rule is fulfilled is difficult. But at least the weighing is between rather commensurable entities: the risks and burdens to the participant, and the prospects of direct benefits to the same participant. Striking the balance between risks and burdens to the participants and the potential benefits to others is obviously even more complicated. The variables are more heterogeneous, and may appear incommensurable. The physical risks and burdens assumed by the participant are not very commensurable with the potential benefits of gaining new knowledge assumed by science. How should, for example, the value of new dubious knowledge about yet another possible risk factor for cancer for a billion men, be weighed against the disvalue of the likelihood of harming 3 out of 300 research participants? The Canadian philosopher Alex Rajczi challenges the view that it is meaningful to attempt a weighing of potential benefits against risks and burdens, because it suggests a mathematical calculation of quantifiable data, which is impossible, except where there is a gross imbalance between risks and potential benefits.12 He asserts that it is difficult to identify risks, not least to estimate the magnitude (including duration) and likelihood of possible harms occurring. Potential benefits are even harder to estimate. Even if there is a slight possibility of estimating risks and benefits, he argues that in most cases it is virtually impossible to assess whether the ends justify the means. A case handled by the observed Research Ethics Committee illustrates the challenge: The Anorectics’ Metabolism Study13 Background: Anorexia nervosa is an eating disorder and a serious health threat. Medicinal metabolism (the body’s ability to take up and make us of pharmaceutical drugs) in underweight persons had according to the researchers never before been systematically studied, although medicinal therapy is common in this patient group. Increased knowledge about medicinal metabolism might help clinicians prescribe more appropriate dosing. Study aim: To investigate the capacity of medicinal metabolism in underweight patients with anorexia nervosa compared with healthy controls. Method: An interventional longitudinal study divided into two separate studies: Sub-study I: an intervention study where 40 consenting participants would be given test medicinal products (drugs) on two separate occasions. This included repeated observations

11

See also Section 5.4.3 where this argumentation is addressed in full. See also Section 4.5.3 on the historical background of the requirement of REC review. 12 Rajczi (2004, p. 339). 13 REC Middle Norway 4.2007.1954

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during weight restoration. The test drugs were selected to measure the activity of the five most common Cytochrome P-450 enzymes involved in drug metabolism. The 40 patients in the interventional group would then receive a so called “cocktail” of five different drugs. The data would be compared to data from a control population of 100 healthy persons. Sub-study II: A therapeutic drug monitoring study where 500 consenting patients on psychotropic drugs would get their drug serum level measured on two separate occasions. There were no prospects of direct benefits for the participants. With regard to the risks, the researchers asserted that the “test drugs have been well tolerated with few and mild side effects and the risk for serious events is negligible.” The patient safety was to be taken care of according to inpatient procedures. Trained medical personnel would at all times attend the patients. The study would not interfere with the necessary inpatient treatment. Invasive procedures were limited to two additional blood samplings and two urine samplings (which were going to be repeated 1 to 6 months later). REC evaluation: The Research Ethics Committee recognised that the research population was vulnerable, and questioned the justification for giving medicines to anorectics without prospects of direct benefits. The Committee also questioned the risks of using “cocktails”. The Committee was, however, reassured by the principal investigator’s complementary statement on risks along with the researcher’s references to a pilot study and similar testing of metabolism in other patients group. The Committee also emphasised the societal benefits, especially the potential benefits for this patient group with a great need for enhanced knowledge. The researcher’s qualifications and the system for risk management were additional arguments for approval. The project was approved. The Committee did, however, not carry out a systematic assessment of risks and potential benefits. The Committee’s reasoning was that the risks involved were small (minimal), while the potential societal benefits were judged as relatively high.

The Anorectics’ Metabolism Study illustrate the intrinsic difficulty of assessing proportionality between various risks, burdens, and potential benefits. This challenge is by no means new. Already in 1979, the US National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research recognised in the Belmont Report that [o]nly on rare occasions will quantitative techniques be available for the scrutiny of research protocols. However, the idea of systematic, non-arbitrary analysis of risks and benefits should be emulated insofar as possible.14

The Commission’s suggestion is still applicable. Regardless of practical, conceptual, and theoretical difficulties, proportionality must be assessed. The alternative – to say that a fair assessment is impossible – is fatalistic. To neglect the assessment of proportionality because it is difficult is also unacceptable, because researchers and research ethics committees are legally obliged to make such an assessment to the best of their ability and by reasonable efforts in relation to the nature of the research project and the entailed risks and burdens. Moreover, prospective participants reasonably expect that researchers and research ethics committees have spent reasonable effort in making an assessment to the best of their ability. To neglect the assessment of proportionality would

14

Belmont Report (1979, section C.2).

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be in breach of researchers’ duty of care, and also the core duty of the research ethics committee.15 Finally, the judiciary might be called upon to re-examine researchers’ and research ethics committees’ assessments of proportionality, typically if a claim for compensation occurs, as done in the US case Grimes v. Kennedy Krieger where the Court found that the researchers had breached their duty of care.16 It may also be added, that assessing proportionality between incommensurable effects is not exclusive to this field. Assessments of proportionality are also be made in other fields, and questions about whether the aims justified the means employed, are regularly tried before the European Court of Human Rights and the European Court of Justice. In, for example, a case concerning freedom of speech (Article 10 of the ECHR) the question may be whether public interest of free speech justifies offensive public expressions about an individual. Thus, the question is not whether to assess, but how to assess proportionality.

11.3 Estimating and Weighing Potential Benefits to Others The estimation and weighing of risks and burdens to the participant were investigated in Sections 10.3.3 and 10.3.4 above. Potential benefits to others are the primary justification for exposing research participants to such risks and burdens if they are not outweighed by prospects of direct benefits. The term “potential benefit” was defined in Chapter 3. In this section the estimation and weighing of potential benefits to others are further investigated, before the more concrete assessment of proportionality is addressed in Section 11.4. Occasionally, but usually not, the potential benefits to society can be more or less quantifiable and tangible. Quantification may then increase the accuracy of the estimation of potential benefits. In, for example, the Meningococcal B Vaccine Trial,17 the number of lives expected to be saved if the vaccine proved effective and was introduced into the official vaccine program as originally planned, could have been predicted and estimated rather precisely by the researchers. They had data on the prevalence of the disease (without the vaccine), and they had reasonable prospects about the vaccine’s efficiency and safety. The researchers did, however, apparently not attempt to estimate the potential benefits to society in their “risk-report”. This failure must have rendered the assessment of proportionality difficult, and possibly even flawed. It must also have rendered the external review of the project very difficult. The

15 This is explicitly required in Article 3 (2) (a) of the Clinical Trials Directive, see also the Norwegian Health Research Act § 22 (2), first sentence. This is implied in Article 6 of the Additional Protocol; see the appendix to the Protocol; This issue was also partly addressed in Chapter 7. 16 See also Chapter 17 where the legal effects of disproportionality are outlined. 17 Accounted for in Section 11.3.

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Directorate of Health, who reviewed the project, (rightly) required a more thorough estimation of the risks, but should also have required a more accurate estimation of the potential benefits. The then newly established Research Ethics Committee that reviewed phase III of the trial, neither, required such information. It is thus legitimate to ask: If the researchers, the Directorate of Health and the Research Ethics Committee did not have more accurate data about the potential benefits, how could they judge whether the risks and burdens to 100 000 adolescents were proportionate and acceptable? The Meningococcal B Vaccine Trial – Introduction18 Background: In the late 1970s and early 1980s Norway experienced an epidemic situation of meningococcal B infection (meningitis). The disease primarily attacked children, adolescents and military recruits. The epidemic created considerable fear among the public, and a public demand for “something to be done.” No vaccine against this particular disease was available at the international market. The Norwegian National Institute of Public Health (hereinafter “The Institute of Public Health”) proposed that they could develop a vaccine. The trial was discussed in and supported by the Norwegian Parliament. The Institute of Public Health then created a project group who planned and led the trial. The trial was marketed as a national community task [dugnad], and received much publicity. Study aim: Develop a safe and effective vaccine against meningococcal B infection. Method: The trial was designed as a clinical trial in accordance with international standards (Good Clinical Practice), and was divided into several substudies in three phases.

There was little in the written material on the magnitude and likelihood of the potential benefits of the Vaccine trial. The potential benefits had apparently not been estimated. Clearly the researchers and the health authorities envisaged that the development and use of the vaccine would significantly forestall a serious and deadly epidemic. The potential benefits of the trial were therefore assumed to be great; maybe the greatest. However, the information and assumptions on potential benefits in the risk report seem, at best, to have been inaccurate. The incidence rate of the disease was reported in the information to prospective participants and controlling agencies to be between “300–400 cases a year”. Although these numbers says little about the potential benefits, the implied meaning behind these numbers was apparently that the development of a vaccine could possibly prevent 300–400 cases of Meningococcal B disease a year. On the face of it, this sounds like great potential benefits to society and people as risk of infection. However, available data, which the researchers had, shows that the highest incidence during the epidemic was approximately 360. Moreover, the yearly incident rate in the early 1980s varied between slightly above and slightly below 300 per year. Additionally, these numbers referred to all types of meningococcal disease (types A, B and C), while the vaccine was aimed at preventing only type B, which represented approximately 80% of the incidents. Thus the more correct number appears to have been (at most) among 250 cases a year. The year before the start of the trial the incidence rate of meningococcal B was declining to 211 cases (in 1986), i.e. almost half

18

Report on the Norwegian Meningococcal B Vaccine Trial (2007) (which I co-authored).

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of the reported incidence rate. This also should have indicated that the epidemic may was declining naturally (and that no vaccine was really necessary). At any rate, with 211 cases a year and a mortality rate of 10% this amounts to 21 deaths per year in the entire population (21 in 4 200 000), with an additional 20–60 serious complications (10–30%). The fatalities were probably, but not necessarily, within the target group (adolescents), as the disease also attacked adults and young children. Moreover, it was clear that it would not be possible to develop a 100% effective vaccine; hence a significant reduction of infections in the target group was the best one could hope for; perhaps a prevention of 10–20 deaths and 10–60 serious complications a year was realistic. The “real” potential benefits was thus to prevent these. These potential benefits are rather tangible, and could thus have been weighed against the risks and burdens of vaccination. Nevertheless, the potential benefits appear to have been overrated in the written information given to prospective participants and governmental agencies. Although there were real potential benefits, it can be questioned whether the potential benefits were so great that they outweighed the risks and burdens involved.19 A negative answer implies that 275 000 individuals (mostly adolescents) may have been exposed to largely unnecessary and disproportionate risks and burdens. The Meningococcal B Vaccine Trial signifies that it can be possible to estimate the potential benefits to others rather accurately. The case example also underscores the importance of a thorough estimation of the potential benefits, not just the risks. More on the Estimation and Weighing of Potential Benefits A potential benefit’s value is the product of its magnitude and likelihood. Magnitude refers to the amount, type, and utility of the knowledge produced. Likelihood refers to the probability that such knowledge will be produced and prove useful. Only a few research projects have great potential benefits to others, such as future patients, society, or science.20 In my observational study of a REC, I observed that the bulk of biomedical research projects had modest ambitions and entailed modest potential benefits to others. Quite a few research projects are repetitive (aimed at confirming what we largely know), poorly planned or designed. Occasionally, the only beneficiary is the researcher him- or herself who get credited. At any rate, many small, even seemingly insignificant, contributions may make a great difference. Modest projects may therefore be seen as having the potential of benefiting not only science, but also society, and should, of course, be promoted; reflecting Isaac Newton’s (1643–1727) truism: we stand on the shoulders of giants. Nevertheless, a research project must entail at least some potential benefits. If not it is useless and largely unnecessary, and there is no need to undertake an estimation or weighing of risks and burden, and even less so an assessment of proportionality. This follows from the requirement of necessity as well as the requirement of proportionality. Without any potential benefits, the risk-benefit ratio will always be 19

See below in Sections 11.4.2 and 11.4.4 where the development of the trial, including the risks and burdens of the trial are investigated. 20 See Getz et al. (2008).

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negative and unfavourable. This is also underscored in the Explanatory Report to Article 8 of the Additional Protocol concerning scientific quality: It is considered that research that does not meet these criteria is, by definition, unethical and should not be approved by the ethics committee or competent body reviewing the research. The participation of persons in research of sub-standard scientific quality is not considered permissible. Scientific quality must be present in the project before its approval and throughout the implementation of the research.21

The statement in the Explanatory Report may also serve as a brief compilation of the criteria for potential benefits. These criteria are going to be further outlined. The Demand For and Necessity of Biomedical Knowledge If a clear lacuna in our common base of biomedical knowledge can be identified, the potential benefit of obtaining that knowledge may be great, especially if an adequate method exists and the outcome (that reliable knowledge will be produced) is rather certain. Ambitious research projects stand in contrast to research projects that simply try to verify what we by and large know already. An ambitious project may, on the other hand, be over-ambitious and likely to fail, because of “unwise enthusiasts”. The results may also be so-called “negative” which means that the answer to a hypothesis, for example, that the new medicine A is better than the existing medicine B, is negative. Negative results may, however, also be of use for science and society, as they may hinder needless repetitions. The necessity and utility (societal value) of the potential new knowledge are important. Are the results likely to provide incurable patients with a cure? Or is it “just” aimed at slightly improving the well-being of already well off people? Effective vaccines are, for example, commonly regarded as “the greatest mansaver”, since they often aim to prevent lethal and harmful epidemics or even pandemics. The knowledge of yet another possible risk factor for pimples, may, on the other hand, be of limited value. The Reliability and Degree of Generalisation of the Research Results The reliability and degree of generalisation of the research results are always important, because the overall aim of almost any research project should be to obtain reliable and generalisable (“true”) knowledge. As underscored in the Explanatory Report, the statistical power of the study is important in this regard.22 If the statistical power is not calculated and not enough participants are enrolled in the study, the knowledge may not be generalisable and therefore largely unreliable and useless. In my observational study of a REC I found that few researchers had attempted to calculate the statistical power of their research project, although the application form specifically asked for it. This omission was, however, seldom criticised by the Research Ethics Committee.

21 22

Paragraph 37. Paragraph 37 of the Explanatory Report.

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To develop new medicinal products, and to obtain reliable knowledge on its efficiency and safety, large randomised clinical trials, lasting many years, and involving hundreds of thousands participants, may be needed. This requires resources, such as highly qualified researchers, adequate research facilities, and sufficient funding. In the preparatory work to the Norwegian Health Research Act it is underscored that the responsible sponsor of a research project must be sure that the project has sufficient funding before it is commenced.23 The reasoning is that it would be unethical to include individuals in a risky and burdensome study that would not be brought to an end, and thus would be useless. The potential benefits of smaller research projects carried out by a single and inexperienced researcher, involving only a few participants, are therefore usually very low. In some cases they are close to nothing, although a few exceptional examples of the opposite exist in the history of medicine. The classic example is Ignaz Philipp Semmelweis (1818–1865), who discovered that the incidence of puerperal fever and deaths among infants and women in labour could be drastically cut, simply by the improvement of hand washing standards among the physicians who moved between the autopsy table and the labour ward without washing their hands.24 The Communication of Research Results The magnitude and likelihood of potential benefits to science and society also depend on the communication of results. Results produced by a professional group of researchers generally stand a far better chance of getting known in large circles of the scientific community, for example, through the publication in top rated international journals, such as the Lancet and the British Medical Journal (BMJ),25 than results produced by inexperienced loners. In the latter case the results may not only be unreliable, they may also end up in a drawer. “Low-beneficial” research projects were debated repeatedly in the Research Ethics Committee observed. Often the problem, from the Committee’s point of view, was that the de facto principal investigator was a student (on bachelor or master level) or otherwise inexperienced “researcher”, and that the senior supervisor appeared absent. Moreover, the “research” projects often had ambitious hypothesis and involved vulnerable, although only a few participants. The latter reduced the risk of the project as a whole, but, of course, not for the individual participant. Besides, that only a few subjects were included reduced the potential benefits. The Committee did, on the other hand, recognise that the student researcher him- or herself might benefit from the project. The “dilemma” haunting the Committee was that while training was needed to recruit researchers, it was dubious if it legitimised exposing human beings to risks and burdens (trivial or not), not least vulnerable populations. At the end of the observation period the Committee’s practice was tightened-up, and several projects of this kind were rejected. It may be asked if the “students”, prospective participants, and 23

NOU (2005:1, chapter 25); Ot.prp. nr. 74 ((2006–2007), section 10.4). Lund (2006). 25 Those two are the top European journals; the two top American journals, the New England Journal of Medicine and the Journal of the American Medical Association (JAMA), may also be mentioned. 24

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society had not been better of the students had undertaken a review of literature or other noninterventional research project instead. The Closeness of the Beneficiary Potential benefits to a, more or less, identifiable group of people, is an important category. This is implicitly and explicitly recognised in Articles 15, 17, 18, and 19 in the Additional Protocol, and Articles 4 and 5 of the Clinical Trials Directive. For nontherapeutic research on vulnerable persons, it is a requirement that the research entails potential benefits to a more or less identifiable group of people. The rationale behind group benefit’s relatively high rank appears to be that such benefits are more direct and usable (more “beneficial”). Additionally, the potential beneficiaries are more closely related to the burdened and the risk-carriers (the participants). Thus the closer the beneficiaries are to the risks-carriers (the participants), the more the potential benefits generally weighs.

11.4 More on the Assessment of Proportionality and Legally “Acceptable” Risks and Burdens 11.4.1 Problem Addressed Whether potential benefits to others outweigh the entailed risks and burdens to the participants, depends on an overall assessment where both quantitative and qualitative factors, objective and subjective circumstances, and experts and lay-views count. Thus the nature and context of the research project, as well as individual circumstances and interests plays a deceive role in an overall judgment. These factors are investigated above in Section 10.3.5, and shall not be repeated here. The question about who decides is answered in Chapter 8. In this section the objective is to further clarify when are risks and burdens to the participant proportionate to potential benefits to others. Since the assessment of proportionality is largely contextual, the following approach focuses on the analysis of concrete cases and risks to further ascertain the threshold. Since the assessment of proportionality here concerns research on rather invulnerable participants who are able to consent, the task in this section is in reality to identify the highest level of legally acceptable risks and burdens. It may therefore be assumed in the following that the potential benefits to others are “great”, (unless otherwise said so). Obviously, if the potential benefits are lower, for example “modest”, “low” or “minimal”, then less risks and burdens can be proportionate.

11.4.2 How Great May a Risk Be and Still Be Legally “Acceptable” The greatest risks and burdens in nontherapeutic research are often related to procedures and interventions that have previously not been tested on human beings.

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Thus little is frankly known about potential benefits as well as risks and burdens. As such, the research may appear to entail great potential benefits precisely because of the lack of knowledge. Coincidentally, the research may also be associated with great risks and burdens precisely because of the lack of knowledge about the safety of the intervention. Pilot studies and phase I clinical trials are typical examples of high risk research. The aim of a pilot study is often to test the adequacy of a hypothesis, and whether it is sustainable and safe to pursue the hypothesis in a full-scale research project. Pilot studies, typically, consist of only a few research participants – maybe only the researchers themselves (so-called “self-experimentation” or “auto-experiments”). The principle aim of phase I clinical trials, with, for example, pharmaceutical products, is to test human tolerance and the safety of the new product, typically whether it is toxic (outright harmful) or not. This is usually done after it has been tested in the laboratory and on animals in accordance with the requirement of lesser mean.26 However, it has been reported that “[t]he advent of increasingly potent and selective compounds for human-receptor systems led to situations in which predictability from animal data was diminishing”.27 Phase I clinical trials are carried out on a regular basis in Europe. In 2006 such a trial took an unexpected and tragic turn, when all six participants suffered lifethreatening complications.28 The case attracted massive public attention (which indicates that this does not happen very often), as did a phase I research project in the US, where two participants in a gene-therapy research project died.29 The great uncertainty and risks involved in Phase I studies is the main reason why such studies involves only a few participants. The efficacy of the new product or procedure is then tested in subsequent phases. Hence, the participants in early phase research may hope for therapeutic benefits, but they are usually not to be expected, and thus not “direct”.30 In fact, the participants in early phase research are often not in need of any treatment, they are usually in good health. The primary reason for this is twofold: Such participants have better immunity and might put up with more strain. They are generally also more able to understand the trial’s nature and risks. It is therefore generally assumed that such so-called “healthy volunteers” are among the most invulnerable and competent, and they may therefore be exposed to the highest degree of (additional) risks and burdens for the sake of others. This assumption is clearly reflected in the current legal framework.31 Phase I of the Meningococcal B Vaccine Trial is illustrative of the commencement of a phase I trial:

26

See Section 9.5 on the requirement of lesser mean. Kenter and Choen (2006). 28 Kenter and Choen (2006). 29 See Steinbrook (2002). 30 See the definition of “direct benefit” in Section 3.6. 31 See, amongst others, Article 6 (2) of the Additional Protocol and the Preamble of the Clinical Trials Directive. 27

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Phase I of the Meningococcal B Vaccine Trial32 Background: A new vaccine was needed to combat an ongoing epidemic. Study aim: Phase I aimed at testing the vaccine’s safety when introduced in various doses. Method: Phase I of the trial was associated with considerable degree of unknown risk of harm, as the substance had not been tried out on humans before. In accordance with common professional standards, the first phase of the trial therefore included only 18 persons between 20 and 50 years of age of good physical and mental health. The participants were given oral and written information, and asked to give written consent. All were employees at the Institute of Public Health. As such, the participants were assumingly acquainted with the purpose and nature of the trial, as well as the risks involved. The participants were given gradually increasing doses from 14 to 100 micrograms. Injections were given to two participants at a time. A 24 hours observation period was then applied before the next two participants were injected. All participants were observed intensely during the first hour. Their blood pressure, pulse, temperature, and EKG were monitored. Repeated tests, for example, skin-tests, were conducted during the first 24 hour observational period. The participants also filled out self-reporting forms during the first two days. All this was done to minimize and supervise risks (prepare for unexpected, but yet foreseeable, complications). No signs of serious side effects or complications were reported. Only expected mild discomforts similar to those associated with other vaccines were reported. The vaccine was therefore determined to be safe enough for a Phase II trial. The risks and burdens were thus regarded as acceptable and proportionate by the researchers. REC Evaluation: REC was not operative at that time in Norway (in 1986).

All reasonable efforts appear to have been taken by the researchers in Phase I of the Meningococcal B vaccine Trial to minimise and supervise the risks. The caseexample also illustrates that, although the researchers expected the vaccine to be safe, they did not know, thus the risks was nonneglectable, possibly considerable. The efforts taken to minimize and supervise risks, signifies the degree of risks of severe complications. Although the researchers hoped for the best, they prepared for the worst. Apparently, no quantifiable data existed on the risks of harm. Nevertheless, the risks do in hindsight not appear to have been excessive. No considerable harm was expected or likely, only some minor and temporary discomforts. Such discomforts, the intervention itself, the anxiety and the surveillance can be classified as burdens, but yet clearly acceptable for a competent and well-informed person to consent to. The participants could not expect any direct therapeutic benefits, and the potential societal benefits to future “patients” were distant. The primary justification was then potential benefits to science, i.e. to determine whether the new vaccine was safe or not. The potential benefits were not the development of an effective vaccine – only a small, but necessary, step of the way. As shown above, even though the potential scientific and societal benefits had not been accurately estimated, they were seemingly assumed to be “great”. The potential benefits were thus apparently judged to outweigh the risks and burdens. The Investigative Commission of the Vaccine Trial did not find reason to question or investigate the acceptability of the risks and burdens in Phase I. 32

Report on the Norwegian Meningococcal B Vaccine Trial (2007).

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Thus, phase I of the Meningococcal B vaccine Trial signifies that it may be acceptable that well informed and relatively invulnerable individuals may take upon themselves considerable “high” risks and burdens for the sake of others by participation in nontherapeutic research of public utility. The criteria for proportionality must, however, be further explored.

11.4.3 “Acceptable” Risks in Self-Experimentation The greatest risk in nontherapeutic research that may be legally “acceptable” as required in Article (2) first sentence of the Additional Protocol, are possibly related to self-experimentation were the research impose the risks and burdens on himself. This issue is therefore addressed first, before nontherapeutic research on “ordinary” individuals. In the Meningococcal B Vaccine Trial a factor in the assessment of proportionality seems to have been that the participants were well-informed health personnel (researchers). This resembles the long tradition of so-called self-experimentation (“auto-experiments”) within the biomedical scientific community. To test a new procedure or intervention on oneself has traditionally been regarded as not just a noble act, but also as an ethical imperative among researchers.33 The expert-witness in the Nuremberg Doctors Trial, Leo Alexander, is quoted as saying that “it is ethically permissible for an experimenter to perform experiments involving significant risks only . . . if he considers the solution of the problem important enough to risk his own life along with those of his non-scientific colleagues.”34 In line with this tradition, it was made public in the Meningococcal B Vaccine Trial that the Director at the Institute of Public Health received the first dosage of the new vaccine. The purpose of the pr-stunt was to ensure prospective participants that the vaccine was safe. The ethics and law of self-experimentations are not being pursued in full here. Apparently, self-experimentation is no longer widely practiced and it does no longer seem to be regarded as an ethical imperative. Some physicians and bioethicists have argued against self-experiments on both ethical and scientific grounds, pointing to that the research population is very small and not controlled, and that the researcher/participant may be less risk avert and not medically typical, research assistants (juniors) may experience undue pressure.35 Nevertheless, it is hard to argue against the notion that those who should be able to carry the highest risks in biomedical research are the researchers themselves. In nontherapeutic research the principal researcher is usually the one who is most interested in seeing the research done, since he or she has initiated the research. As such, self-experimentation is to a certain degree comparable to research entailing direct benefits to the participants. 33

Ruyter (2003a). Cited in Jonsen (1989); See Section 4.3 on the Nuremberg Doctors Trial. 35 Davis (2003). 34

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Moreover, bearing in mind individual’s autonomy and right to selfdetermination,36 it is difficult to argue, at least legally, for a strict limitation of acceptable risks and burdens in biomedical research, as long as the research intervention is not outright excessively harmful and futile. Researchers’ duty of care primarily restricts what researchers may legitimately do to others. Thus, researchers must, as anyone else, be relative free to participate in rather hazardous activities (including socially beneficial research). Self-experimentation is also difficult to regulate and control, as most selfexperiments probably are preliminary pilot studies carried out quietly. However, today’s working instructions, set out by the employer with a base in working environment legislation, will probably also restrict the risks and burdens that may be taken by the employed researchers. Importantly, self-experimentation may involve only the principal researcher(s) him- or herself. Research gets gradually more problematic when it includes co-researchers, junior researchers, laboratory assistants and, even more so, administrative personnel (secretaries, cleaners and so on). The “volunteer” may then quickly be regarded as a dependent and therefore as a vulnerable participant, instead of a particularly eligible participant. And vulnerable individuals are subject to substantially stricter limits of acceptable risks.37 The inclusion of staff members, especially subordinates, in high-risk research can therefore be legally questionable. Such research can certainly not be classified as self-experimentation.

11.4.4 Quantifying High, but “Acceptable” Risks and Burdens The wording “no more than acceptable risks and acceptable burdens” in Article 6 (2), first sentence of the Additional Protocol, may leave the impression that it is possible to quantify a fixed limit of “acceptable” risks and burdens. Hence, that any consenting individual may carry risks and burdens below this fixed limit, and none may carry risks and burdens below that limit. Although, a notion of a fixed limit would make researchers and research ethics committees work much easier, the notion is obviously ill-founded. The assessment of acceptable risks and burdens must, as the assessment of proportionality, be based on a contextual overall assessment where many elements play a role, see Section 11.4.5. Nevertheless, it may be of interest (for the overall assessment) to try to be concrete and quantify high, but still “acceptable” risks and burdens in nontherapeutic research to get an idea about what level of legally acceptable risks and burdens are we really talking about. Few scholars have approached the acceptability of high risks in nontherapeutic research. It is thus difficult to ascertain the threshold, and even more so to quantify it. This “silence” apparently reflects reluctance among commentators towards 36 37

See the discussion on individual autonomy in Section 5.4.3. See Chapter 12.

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high risk in nontherapeutic research. A thoughtful article from 1989 by a senior in US bioethics, professor emeritus Albert R. Jonsen (b. 1931), concerning the acceptability of high risks in nontherapeutic research, is therefore particularly interesting.38 First, Jonsen underscored the fundamental difference between high-risk selfexperimentation and high-risk nontherapeutic research on healthy volunteers: The volunteer is in quite a different situation [than the researcher]. They are being asked to lend their bodies or parts of their bodies to the researcher. They are being asked to trust that the researcher has a worthwhile idea and that the researcher will carefully use what is being willingly donated. The volunteer will appear momentarily in the research and then disappear; he or she will have no place in the subsequent developments or in the history books. Almost always, the volunteer will be a transitory and partial participant in the research endeavour. It might be reasonable, then, that while the auto-experiments should be allowed to take any risks whatsoever, the volunteer should be invited to undertake only risks proportionate to the transitory and partial nature of his participation. . . . Major risks should be reserved for major participants, namely, the research team itself.39

Jonsen’s statement coincides with the findings concerning self-experimentation above. Jonson further suggested that the level of acceptable risks and burdens should be significantly lower for healthy volunteers than for the self-experimenter. Although, recognising that this reasoning may lead to a rather strict level of acceptable risks and burdens, Jonsen pointed out that a more liberal level might lead to a slippery slope. Jonsen asserted in this regard: the relatively invulnerable volunteer must meet very high standards of comprehension and freedom. Such a volunteer must almost be as informed and uncoerced as the investigator, but given the rarity of such persons and the dynamism of research, the temptation to compromise these standards would be great. It might not be long before an IRB [REC] that was willing to approve offerings of high risk to relatively invulnerable volunteers would find itself wrestling with the perplexing “but how relative?”40

Jonsen’s article was related to a concrete case concerning the acceptability of doing liver biopsies in two healthy volunteers for nontherapeutic research purposes. Jonsen was uncertain whether a liver biopsy ought to be characterised as a “high risk” research intervention. Nevertheless, emphasising the slippery slope-argument, Jonson was highly sceptical of allowing even competent persons to take upon such risks for the sake of others. This suggests that doing a liver biopsy can be regarded as a border issue, meaning that it exemplifies the threshold of acceptable risks in nontherapeutic research on healthy volunteers. My own personal consultations with physicians, sustain that notion, which implies that they would be sceptical to accept performing nontherapeutic liver biopsy on healthy volunteers.

38

Jonsen (1989). Jonsen is a Catholic priest with a doctorate in religious studies. Jonsen took part in the preparation of the Belmont report and was one of the first bioethicsts appointed to a medical faculty in the US. 39 Jonsen (1989, p. 207). 40 Jonsen (1989, p. 207) [My emphasis].

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Jonson’s example and attempt to ascertain a threshold of acceptable high risks, is interesting as it involves the evaluation of concrete research interventions. Moreover, liver biopsies are common in ordinary clinical practice (especially in gastroenterology), and involve the removal of a small sample of tissue from the liver. The risks of doing liver biopsy are therefore largely known. In a patient information sheet (not research) published by US National Digestive Diseases Information Clearinghouse, a governmental agency, the following is stated about the risks of doing liver biopsy: “Like any surgery, liver biopsy does have some risks, such as puncture of the lung or gallbladder, infection, bleeding, and pain, but these complications are rare.”41 A similar patient information service in the UK provides the following information on the risks involved: Complications are uncommon. In a small number of cases there is some bleeding from the biopsy site. This is usually minor, and soon stops. Occasionally, the bleeding is more severe, and rarely it requires a blood transfusion and/or an operation to deal with it. The main reason you are monitored for several hours after the biopsy is to check for bleeding. A rare complication is for bile to leak from the liver internally. There is a small risk that the small wound will become infected after the biopsy.

From a reading of this information the risks of doing a liver biopsy do not stand out as particularly high, even though it appears to be above minimal (and hence unacceptable if the participant is “vulnerable”). Indeed, to a person not trained in medicine, the intervention sounds rather trivial and safe. In a scientific publication, the physicians Atif Zaman, Kenneth Ingram and Kenneth D. Flora provide numbers on the risk of doing liver biopsy.42 The burdens relate to the possibility that 1 in 3 (30%) suffers from pain. The risk relates to that 1 in 50 (2%) may require hospitalization for the management of an adverse event. The risk of serious complications is somewhere around 3 in 1 000 (or 1 in 333), and some of these may be fatal (mortality rate: 0.0088–0.3%). These numbers indicates that doing a liver biopsy is today associated with considerable burdens and risks. This must be considered a fairly “high risk” of serious complications in nontherapeutic research. If a nontherapeutic study included 333 voluntary participants, and where one of them would suffer from serious complications, it is questionable whether the risks are legally acceptable and proportionate, almost no matter what the potential benefits are to others, and no matter the “willingness” of the participants. Such a risk would, at least, be legally unacceptable for “ordinary participants”, which often misconceives the consequences of participation.43 For comparison, between 1922 and 1996, 10 094 climbers attempted to scale Mount Everest. 2 972 succeeded, while 207 died in the attempt, which gives a mortality rate of 1 in 50 climbers (2.08%).44 However, few would probably suggest that ordinary competent volunteers should be exposed to risks close to those taken by 41

US National Digestive Diseases Information Clearinghouse a NIH (2009). Zaman et al. (2008). 43 See Section 5.4.3. 44 AdventureStats.com (2009). 42

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daredevil and adventurous mountaineers climbing Everest. This is so even though a climb up Everest is usually an ego-trip, while biomedical research is done for the greater good. Thus the numbers sustain Jonson’s sceptics, confirming the notion that doing a liver biopsy on healthy volunteers is normally unacceptable and disproportionate regardless of the potential benefits to others. The interesting consequence of this submission is that similar risky interventions would then also be legally questionable; and in effect normally unlawful. The liver biopsy example may thus be compared to other intervention. Of interest here is a cardinal scale developed in the late 1970s by a Swedish insurance company to set the rate of insurance overage for research injury in Sweden, see Table 11.1.45 Although the rating maybe incorrect or outdated (because a risky intervention then is rather safe today) it provides ideas regarding the threshold of acceptable risks and burdens in nontherapeutic research: Table 11.1 Swedish insurance company’s catalogued research procedures according to entailed risks Risk group

Research procedures (examples)

Code 1

Sampling of venous blood. Administration of approved drugs in recommended doses. Intravenous and intramuscular injections. Skin biopsies. Etc. Sternal and spinal structures. Intravenous and intraarterial infusions. Muscle biopsies. Endoscopy and biopsies of the gastro-intestinal tract. Etc. Biopsies of liver, lung, kidney. Catheterization of peripheral arteries. Angiography of abdominal organs. Testing of allergens. Etc. Right heart catherization. Angiograph of coronary and pulmonary vessels. Exercise testing of patients with known coronary diseases. Etc. Transhepatic portal vein catherisation. Left heart catherization by puncture of atrial septum. Exercise testing of patients with recent myocardial infarction Combination of several procedures according to Codes 5–8.

Code 2 Code 3 Code 5 Code 8 Code 9

Interestingly, doing a liver biopsy is rated code 3 along with similar risky procedures. This suggests that risks up until code 3 in the Swedish table may be acceptable in nontherapeutic research. Risks within and above code 3 will normally be unacceptable regardless of the potential benefits to others. If the categorisation in the Swedish table is applied on, for example, the Interval Training Study,46 that study appeared to have entailed high risks, maybe as high as code 8 (“exercise testing of patients with recent myocardial infarction”). This signifies that the study would not have been legally acceptable because of disproportionate risks, had it not been for the expected direct therapeutic benefits to the participants (regardless of the participants consent). This was exactly the Research Ethics Committee’s reasoning. 45

Skandia insurance company, cited in Meslin (1989, p. 326). Note that code 4, 6, 7, and 9, for unknown reasons, is nonexisting. 46 Accounted for in Section 10.2.

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The liver biopsy example also signifies that a relative high degree of risks and burdens can be proportionate (“acceptable”), even in nontherapeutic research.47 The acceptable risk level is clearly above “minimal risks and minimal burdens”. It is, on the other hand, limited. Very high risks (risks above those associated with doing a liver biopsy) are generally not acceptable in nontherapeutic research, although such risks may be acceptable in therapeutic research (if the risks are fully or, at least, partly outweighed by prospects of direct benefits to the participants). Clearly, no considerable enduring harm should be preponderant likely (more than 50%). If that was the case, the risks and burdens would be excessive and disproportionate, regardless of the potential benefits.48 In fact, the limit for legally acceptable risks and burdens, even for competent volunteers, is probably significantly lower. The likelihood of severe complications and considerable harm should normally be rather remote, even if the potential scientific and societal benefits are great. That further implies that if the potential benefits to others are not great, but only modest or, at best, low or minimal, then the level of proportionate risks and burdens are, as mentioned, significantly lower. It may, based on the liver biopsy example, be cautiously suggested that the highest risk of harm that may be legally acceptable in normal nontherapeutic research on ordinary healthy volunteers is probably somewhere between 1 in 10 000 and 1 in 1 000 for fatal harm, provided the potential benefits to others are great.49 A mortality rate above 1 in 1 000 is probably normally unacceptable, unless there are reasonable prospects of real and direct therapeutic benefits to the participant.50 Some might argue that these suggestions are too liberal, others that they are too strict rendering the progress of innovative and groundbreaking, and potentially lifesaving, biomedical research almost impossible. Nevertheless, it is worth recapturing the overarching principle of human primacy: “The interests and welfare of the human being participating in research shall prevail over the sole interest of society or science.”51 The example of doing liver biopsy also illustrates another practical and important point. In my observational study of a REC I observed that many researchers, in their description of the risks, referred to “ordinary risks”. The reference obviously meant that the risk of the research intervention was comparable with that of a similar, but ordinary, clinical intervention carried out regularly in health care, and therefore minimal and neglectable. Hence, there was no need for further specifications or assessments. Such references were not uncommon even though there were no prospects of direct benefits to the research participants. Apparently, in the view of the researcher, the risks entailed in ordinary clinical practice were regarded to represent the risks of daily life, and, if it were so, the risks were largely neglectable. 47

The legal basis discussed is (still) Article 6 of the Additional Protocol, and Article 3 (2) (a) of the Clinical Trials Directive, cf. Section 11.1. 48 See below on “the no harm rule”. 49 Patient.UK (2009). 50 See Chapter 9 on the direct benefit rule. 51 See the Article 5 of the Additional Protocol and Article 2 (1) of the GCP Directive.

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However, such comparisons between clinical risks and research risks can often be seductive and inappropriate, as illustrated by the liver biopsy example: In clinical practice the risk of doing a liver biopsy is regarded trivial and acceptable, because of the direct benefits to the participant. In nontherapeutic research where no such benefits can be expected, the risk of doing a liver biopsy is on the contrary high and usually unacceptable. In this regard it may be of interest to note that the risks of ordinary clinical practice are generally substantial, and by no means trivial, if it were not for the expected health benefits to the patient. For example, in 2008 it was asserted that as many as 20% of patients in Norwegian hospitals suffered harm that was not a natural result of their disease and condition, but rather mishaps and other adverse effect or untoward medical occurrence as a result of hospitalisation and treatment. Almost half of the adverse effects (5–10%)52 were a result of hospital infections (i.e. infections which were not a natural result of the patient’s disease). The Norwegian Institute of Public Health found a prevalence of hospital infections between 5.2 and 6.3%,53 but it is commonly assumed that the actual number is higher. Infection can lead to severe temporary and enduring complications. Infections may even be fatal. In a widely acclaimed popular scientific report called Living with risk, and published by the renown British Medical Journal, it is asked whether “doctors as well as patients – truly understand what are the risks of medicine and surgery?”54 The report states that a physician handles too few cases to fully appreciate the actual risks. Moreover, “[s]urprisingly few surgical procedures, for example, have been validated for their effectiveness, either in absolute terms or by comparing alternatives for the treatment of a given disease.”55 Although written over 20 years ago, the question and the answer are probably still accurate. Thus, to say that a risk entailed in nontherapeutic research is acceptable because the risk of the same intervention is regularly accepted in ordinary clinical practice can be seductive and highly inappropriate. The two cited examples of patient information concerning liver biopsy in regular health care would thus not be acceptable if used in a nontherapeutic research project. The report, Living with risk, uses another example: Most surgical operations involve the use of anaesthetic, and indeed for many procedures the risk of the anaesthetic is more significant than that of the procedure itself [as pointed out by the independent expert in the Obesity Case]. However, the risk of receiving an anaesthetic has fallen dramatically over recent years from over 600 deaths per million operations (just under 1 in 1 500) in 1950 down to around 40 per million in 1970 (about one death in 25 000 operations).56

52

TV2 news 03.12.08. The Norwegian Institute of Public Health (2008a). 54 BMJ Living with risk (1987, p.123). 55 BMJ Living with risk (1987, p.124). 56 BMJ Living with risk (1987, p. 124). 53

11.4

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This illustrate that the risk of ordinary clinical practice may be considerable, and thus not necessarily transmissible to nontherapeutic research (although it may be tempting). Even though the threshold of acceptable risks and burdens can not be established as an absolute quantified limit applicable on all research projects, (i.e. 1 in 10 000 is always acceptable, while 1 in 1 000 is always unacceptable), more empirical (quantitative) data could obviously contribute to shed light on the ascertainment and the threshold. Nevertheless, numbers (as those suggested above) can only be guiding and a starting point in the assessment of proportionality. That is why reservations, such as “normally”, “suggests” etc. must be included.

11.4.5 The Overall Assessment of Proportionality and Acceptable Risks and Burdens The assessment of proportionality as prescribed by Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive must be based on an overall judgement.57 This must also apply to an assessment of “acceptable” risks and burdens in accordance with Article 6 (2), first sentence of the Additional Protocol. As shown in Section 10.3.5, in such an overall judgment qualitative and subjective factors do play a central role in the assessment of proportionality between risks, burdens, and potential benefits (surely not just quantifiable empirical data, if such data exists). Relevant and important factors are the nature of the risks and the research project, the context, characteristics and perceptions of the participants and others. The nature, magnitude, and likelihood of the potential benefits are, of course, also relevant and important. If the potential benefits are not high, the level of acceptable risks and burdens is lower. Likewise, if the participants are rather vulnerable, or if it is likely that a participant would perceive the risks as excessive, then the risks and burdens would normally not be proportionate. Occasionally this will imply that scientifically sound and important research projects cannot be lawfully carried out (or approved by a research ethics committee). At other times, it may imply that ethically challenging, but still acceptable, research projects should be allowed to proceed. To further illustrate the points made, phase II and III of the Meningococcal B Vaccine Trial are explored: Phase II of the Meningococcal B Vaccine Trial58 Study aim: Phase II of the trial aimed to further evaluate the safety of the vaccine and its efficacy and dosage in line with Good Clinical Practice.

57 58

Cf. Section 11.1. Report on the Norwegian Meningococcal B Vaccine Trial (2007).

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Method: Phase II was divided into four steps, and designed as a randomised single blinded placebo controlled clinical trial, (the participants did not know whether they received placebo or not, but the researchers did). Step one included 113 health personnel who received various dosages. In step two to four additionally 604 participants were included, most of them army recruits. Although the army recruits were in the target group (those who were at risk of getting the disease) the trial were justified primarily by the potential benefits to science and society. The potential benefits were apparently still regarded great. Phase I had increased the knowledge about risks and burdens. The risks and burdens were therefore significantly lower in phase II than in phase I. Yet the number of participants in Phase I was only 18, so there was still considerable uncertainty about the safety of the vaccine. Furthermore, the safety measures were by no means as extensive as in Phase I (which increases the risks). Nevertheless, the researchers apparently regarded the risks and burdens acceptable. [The trial was not submitted to REC approval as no formal system of approval was fully operative at this time in Norway]. The subsequent investigation: The acceptability of the risks and burdens involved in phase II of the trial was not questioned or investigated by the Ad hoc Investigative Commission. The Commission did, however, question the involvement of army recruits in phase II, as little was known about the risk of unforeseen complications. Moreover, the Commission pointed out that soldiers should generally be regarded as vulnerable because of subordination and dependency. Nevertheless, the Commission found that the information about risks given to the participants was clearly inadequate, as the actual risks were downplayed and undisclosed.

Although the risks of harm were lower in phase II than in phase I, the risks were far from negligible. The risks were probably above “minimal risk”, perhaps “modest” (understood as somewhere between “minimal” but yet acceptable for well informed volunteers). The inclusion of army recruits was thus questionable, because of their dependency, regardless of the information given.59 Moreover, for such modest risks to be acceptable, the potential benefits to others should still have been relative great, (which it is dubious that they were because of the declining epidemic). However, assuming the potential benefits to others were great, it is clear that a relatively invulnerable person may, according to Article 6 (2) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive, voluntarily consent to participation in such a modestly risky research project. Phase III of the Meningococcal B Vaccine Trial60 Study aim: Phase III aimed to provide data on the efficiency and safety of the vaccine. Method: Double blinded randomised clinical trial, where half of the participants received active vaccine, while the other half received sham-vaccine (placebo). Neither, the researchers nor the participants knew who got what, as that information was encrypted. The researchers “risk report”: In the run up to Phase III, the trial was discussed in public and among several governmental agencies. The existing estimates were rather sparse. The Norwegian Board of Health had asserted that a fatality rate of 1 per 10 000 would be clearly unacceptable. Apart from that assertion few numbers or other more concrete guidelines were put forward. The discussion of risks led the Board of Health to request a more thorough risks assessment. In response, the principal investigator speedily drafted a risk

59 60

See the next chapter. Report on the Norwegian Meningococcal B Vaccine Trial (2007).

11.4

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report in 1988. The risk report did not describe the potential benefits. The absence of a more accurate description of potential benefits must have made an assessment of proportionality and the acceptability of risks and burdens difficult. Nevertheless, the risk report provided a detailed account of the risks (defined in the report as the likelihood of severe complications) and burdens (defined in the report as expected negative side effects). It was acknowledged that the vaccine’s efficacy, as well as the risks involved, was largely unknown, as clarifying this was the very purposes of the trial. The risk report did point to similar trials conducted in other countries, which provided some numbers related to the risk of severe complications. Based on this, the risk was regarded as “acceptable”. The burdens involved, such as momentary nausea, pain etc, was mentioned, but apparently did not play a significant role in the assessment of the acceptability of the project. Two independent experts reviewed the risk assessment. One of them had some qualms about the risk of unforeseen complications and therefore recommended a pre-trial of the vaccine on an adult population of 5 000 participants before providing it to the planned 100 000 adolescents between 13–18 years of age (the trial was later extended, and involved totally 275 000 adolescents and army recruits). Approval: The experts’ review resulted in turmoil within the involved (approving) governmental authorities. A national research ethics committee (later replaced by today’s’ system of RECs) had suggested that potential societal benefits could not justify any risks. The Justice department did not support such a notion, as it basically would render research impossible. The risks were finally regarded as acceptable and phase III was initiated. Phase III of the trial was also approved by the newly established research ethics committee (REC). Subsequent developments: A monitor group consisting of independent senior researchers monitored the trial. The Monitor group received reports on the adverse effects and had the authority to break the protocol (decrypt data), for example, to see whether complications reported were in the vaccine group or the placebo group. They could also stop the trial. In its final report (which was based on the researchers own report on adverse effects) the Monitor group submitted that among 117 657 vaccinated, eleven serious incidences were reported, of which four were severe and enduring neurological complications. The causality was uncertain, which implies that the number could be higher or lower. At any rate, this indicated a complication rate of 4.3 in 100 000. The incidence was lower in the placebo group. (The fatality rate of Meningococcal B infection without vaccination was approximately 20–60 in 4 200 000 (0.002–6%) for the whole population in 1988). In 1991, the opinion about whether the risk – in hindsight – was acceptable differed among the members of the Monitor group. One of the members expressed in a letter of concern that the serious complication rate was (too) high if it really was as high as “1, 2, 3 or 4 per 100 000 – 150 000 of those vaccinated”. The National Committee on Adverse Effects from pharmaceutical products discussed the final report in a meeting. The Committee found that the registration of adverse effects appeared poorly planned, and it was thus dubious whether all adverse effects had been reported. Moreover, the reported incidence of serious adverse effects, where causality cannot be written off, appeared “high, especially with a reference to CNS [the Central Nervous System].” The Committee was also sceptical to the follow-up of patients, and the information provided prospective participants. The researchers rejected the critique and concern. The researchers maintained that the reported incidents were idiopathic diseases (of which the causes where unknown) rather than a result of the vaccine. The National Committee or any other authorities did at any rate, not follow up the critique. The researchers then moved on as initially planned and vaccinated the placebo group of approximately 90 000 adolescents as part of a non-blinded trial. The Ad-hoc Investigating Commission later questioned this decision in its report, because data available to the researchers at that time on the potential benefits (far lower than expected) as well as the risks (higher than expected), clearly suggested a disproportionate relationship between the risks and potential benefits. The Commission was especially critical of the information provided to participants in all parts of trial. The information about risks (possible severe complication) was found to be clearly inadequate, given the available

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information at that time. The written information basically maintained that the vaccine was “safe”, indicating zero-risk.61 The vaccine had a low efficiency rate (57.2%), and was not included in the public vaccination program as initially planned. The epidemic had also declined. Four or five participants (no record exists) sought compensation for damages immediately after the trial. Some of them got compensation several years later. The Ad-hoc Investigating Commission heavily criticised the Norwegian Government for the handling of those claimants and other possible victims (deliberate delays etc.), as the compensation were supposed to be awarded on a no-fault basis. Several years later, more than 300 claims for damages was put forward of persons suffering from [myalgisk encefalopati] (ME); (which was the actual cause of the appointment of the Ad-hoc Investigating Commission). Most of these (some still pending) claims have been rejected by the The Norwegian System of Compensation to Patients (NPE), as no causality could be established.62 Some minor trials on the vaccine were conducted after 1991. In 2000 the intellectual property rights of the vaccine was sold to a private pharmaceutical company. The company later sold the vaccine to New Zealand, where there was an ongoing epidemic of Meningococcal B among infants. The vaccine was then included in New Zealand’s public vaccine program for infants. Allegations of unacceptable risks led to public turmoil in New Zealand and Norway. The Ad hoc Investigating Commission did not find reason to criticise the Norwegian Institute of Public Health’s role in this transaction, as the Institute had provided all relevant information to the pharmaceutical company.

The Meningococcal B Vaccine Trial illustrates several aspects of relevance in this context. Firstly, it illustrates the possibilities of quantifying risks, burdens, and potential benefits which may enhance the chance of making more precise and informed judgements of proportionality. In this case, an accurate and updated description of potential benefits, risks and burdens would probably have led to the termination of the trial before it had begun, and thus the unnecessary exposure of 275 000 individuals (mostly adolescents). At least it should have led to the termination of the “placebo-study” involving approximately 90 000 adolescents, since potential benefits of vaccine probably did not outweigh the risks and burdens of trial participation. Phase III of the Meningococcal B Vaccine Trial illustrates in particular the point made in Article 6 (2) of the Additional Protocol that even though the potential benefits are assumed to be great, the risks and burdens may be “no more than acceptable” (for adolescents they should be no more than “minimal” (see Article 6 (2) second sentence and Article 15) if the research did not entail prospects of direct benefits to the participants. Hence, the risks and burdens must be assessed also in themselves. Researchers did this in that case, and both the researchers and the health authorities found the risks and burdens to be acceptable (but none of them seem to have expected serious complication in 1–4 in 100 000 participants).

61

See also the BMJ Report, Living with risk, which also holds that “safe” usually is understood as zero-risk, and therefore should be avoided as nothing is risk free. The researchers, on the other hand, claimed that “safe” meant “safe enough”, i.e. that the risks were minimal and therefore acceptable and (almost) neglectable. 62 See Jørstad and Kjønniksen (2008).

11.5

Repetitive Participation

167

My primary concern in this case is that the potential benefits (which had not been sufficiently estimated) did probably not outweigh the risks and burdens involved, at least in the vaccination of those who had previously received placebo – “the placebogroup.” Moreover, the judgements made both by the researchers, the Monitor group, the National Committee on Adverse Effects and the Ad Hoc Investigational Commission signify disagreement on the acceptability of risks. The researchers and the majority of the Monitor group clearly judged the level of acceptable risks differently than did the minority of the monitor group as well as the Committee on adverse effects and the Ad hoc Investigational Commission. As to the level of “acceptable” risks and burdens the Meningococcal B Vaccine Trial illustrates that a risk of serious and enduring neurological complication of 1–4 in 100 000 is probably not acceptable given this particular population (adolescents). See also the following chapter where it is shown that non-therapeutic research on adolescents is subject to the threshold of minimal risk. In comparison, less than 1 in million of fatal complications appear to have been commonly regarded as a negligible risk. It could be argued that the participants in Phase III who received active vaccine could expect direct benefits (immunisation), and that these potential direct benefits to the participant outweighed the risk to the participant. The argument is valid and probably correct if the potential direct benefits as well as the potential benefits to other (future) adolescents had been high as initially assumed (but which they were probably not). Again, this crucial point (the existence of direct benefits) signifies the necessity of an accurate description of all risks, burdens, and potential benefits (including direct benefits), and not least an accurate and thorough assessment of proportionality. This also signifies that an independent assessment of the acceptability of risks and burdens, as prescribed by the “additional preconditions” in Article 6 (2) of the Additional Protocol is insufficient in a review of research projects. Researchers and research ethics committees must also ensure that the risks and burdens to the participants are in proportion to the potential benefits to others; hence, that the requirement of proportionality is fulfilled, as prescribed by Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive.

11.5 Repetitive Participation Paragraph 26 in the Explanatory Report to Article 6 (the requirement of proportionality) of the Additional Protocol addresses a special situation that occasionally occurs in practice, when it states: An individual may choose to take part in research a number of times or regularly, provided that continued participation in research does not endanger the participant’s health.

The implied meaning is apparently that repeated participation may be seen as excessively risky or burdensome.

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The statement in the Explanatory Report may, however, merely be taken to mean that in the overall assessment of proportionality in a particular research project, it may be relevant to take into account that this particular research population or participant, have been included in research studies before, and that special care should therefore be taken, especially if the participants are more or less vulnerable. The observed Research Ethics Committee discussed the issue in relation to repetitive studies on hospitalized cancer patients in palliative care. The observed Research Ethics Committee concluded, after confronting the principal investigator, that the study could take place because of the low risks and burdens involved, and because the participants were well-informed and motivated. The case could be seen as a border case, in which the circumstance of repetitive participation almost led the Committee to conclude that the project entailed excessive and disproportionate burdens. Thus, the element of repetitive participation may be relevant in an overall assessment of proportionality and acceptability of risks and burdens.

11.6 Conclusions The investigation above shows that the European legal framework set up broadly defined, but binding limits (minimum standards) for what level of risks and burdens competent, well-informed and willing person’s can be exposed to. The risks and burdens may be “no more than acceptable” in accordance with Article 6 (2), first sentence, which is an additional precondition for proportionality. This means that such participants cannot legally be included in research projects entailing unacceptable, and therefore excessive, risks, regardless of the greatness of the potential benefits. The additional precondition is particularly important as an additional safeguard where the level of risks and burdens is relative high: That is to ensure that research participation is not too hazardous or outright “foolhardy” or harmful. The risks and burdens must also be in proportion to potential benefits to others,63 as required by the requirement of proportionality in Article 6 (1) of the Additional Protocol and Article 3 (2) (a) the Clinical Trials Directive. Thus even tough the risks and burdens are judged to be low and acceptable; they may not necessarily be in proportion to the potential benefits, because the potential benefits may also be low. The numbers offered on legally acceptable risks can only be roughly guiding, as more qualitative and subjective factors also play a significant role in an overall and contextual assessment of proportionality that the researcher and Researcher Ethics Committee must undertake. An overall assessment is meant to ensure that contextual and individual factors are duly considered so that research participation appears to be a reasonable choice that research participant may consent to if they want. 63

Article 6 (2), first sentence, of the Additional Protocol.

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Conclusions

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This resembles an observation made in the “general” academic field of “risk management”. Jardine and colleagues asserted that “risk management will continue to be a balancing act of competing priorities and needs. Flexibility and good judgement is ultimately the key to successfully making appropriate risk decisions.” They then set up what they call the golden rule of risk management: “Impose no more risk than you would tolerate yourself.”64 The rule resembles the popular question: Would you let your daughter participate? The daughter-test is, however, not especially accurate. The discussion above on the highest, but still “acceptable”, risks, showed that some people are competent and willing, and they may therefore be allowed to take upon more risks and burdens for the sake of science, society and future patients, than most people would consent to. Parents are legally competent to consent to only minimal risks and burdens to their daughters and sons.65 And minimal risks and burdens are way below the highest level of risks and burdens that may be legally acceptable for the most competent and motivated participants in a well-designed research project with great potential benefits. In the first section of this chapter the question was raised whether the additional precondition “no more than acceptable risks and acceptable burdens” in Article 6 (2), first sentence, of the Additional Protocol could be interpreted into the requirement of proportionality as expressed in the Oviedo Convention Article 16 (ii), the Clinical Trials Directive Article 3 (2) (a), and the Norwegian Health Research Act § 22 (2) which do not explicitly contain the that additional Protocol. For the Oviedo Convention an affirmative answer could simply be derived from the fact that Additional Protocol elaborates and supplements the Oviedo Convention. For the Norwegian Health Research act an affirmative answer could be derived from the fact that Norway has ratified the Oviedo Convention and also intended to incorporate the Additional Protocol into the new Act. For the Clinical Trials Directive the answer is not that clear. However, since it is possible to interpret the additional precondition into the requirement of proportionality, by arguing that potential benefits to others does generally not carry as much weight as prospects of benefits to the participant, there are limits as to what level of risks and burdens an individual (even a healthy volunteer) may consent to carry for the sake of others. Moreover, in light of the discussion above, it is hard to argue convincingly that the Clinical Trials Directive suggests a different (more liberal) legal solution than the Additional Protocol. Thus the more concrete investigation of proportionality shows that the initial (preliminary) interpretation of the provisions, which indicated that these provisions must be regarded to contain essentially the same normative content (a requirement of proportionality, but with the implied additional precondition of only “acceptable” risks and burdens), probably is correct.

64 65

Jardine et al. (2003). See Chapter 12; see also Maar (2007, pp. 400–405).

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This interpretation is substantiated by the fact that the additional precondition is an internationally recognised “common” minimum standards for the protection of the individual participant, and that other instruments should offer nothing less.66 This interpretation also better realises the purposes of the instruments as a whole and the provisions in particular (human protection and regulatory harmony).67

66 67

Cf. Section 4.3. Cf. Section 4.3 and Chapter 12.

Chapter 12

Nontherapeutic Research on “Vulnerable” Participants

12.1 Problems Addressed Roughly half the research projects submitted to the observed Research Ethics Committee planned to include “vulnerable persons ”. Many participants in biomedical research are thus especially vulnerable. Vulnerability is usually linked to reduced ability and capacity to protect one’s own interests. Vulnerable persons are therefore, as history shows, at increased risk of being exploited and abused in biomedical research. Vulnerability may be a result of sickness and the dependent situation many patients are in, or that the individual is not able to give a legally valid consent (e.g. children). “Vulnerable person” as defined in Section 3.8 is not a legal term. But vulnerability does have legal implications in so far that additional safeguards are set up to protect vulnerable persons participating in biomedical research. Vulnerability is, as already underscored, also a weighty factor in the overall assessment of proportionality. The Additional Protocol states in the Preamble that “particular protection shall be given to human beings who may be vulnerable in the context of research.” Similar in Paragraph 3 of the Preamble to the Clinical Trials Directive: “Persons who are incapable of giving legal consent to clinical trials should be given special protection.” In this chapter, the aim is to clarify the European legal framework concerning the assessment of proportionality and acceptable1 risks and burdens in interventional biomedical on vulnerable persons without prospects of direct benefits (nontherapeutic research or therapeutic research entailing additional risks and burdens).2 The legal question being addressed is: what level of risks and burdens may a vulnerable person be exposed to for the sake of others? Clearly, the “general” requirement of proportionality between risks, burdens, and potential benefits as expressed in Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive, do apply. 1 2

The term “acceptable” is here used in accordance with is ordinary meaning, cf. Section 9.3. Therapeutic and nontherapeutic research is defined in Section 3.7.

S. Simonsen, Acceptable Risk in Biomedical Research, International Library of Ethics, Law, and the New Medicine 50, DOI 10.1007/978-94-007-2678-9_12,  C Springer Science+Business Media B.V. 2012

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However, additional safeguards, or rather additional preconditions for proportionality, do also apply. The question is therefore addressed in two main steps. • Firstly, the applicable additional preconditions for proportionality in the Additional Protocol and the Clinical Trials Directive are identified and compared (Section 12.3). • Secondly, the identified additional preconditions for proportionality are further investigated and concretised (Sections 12.4. and 12.5) The current legal framework is intricate and controversial, which necessitates a relative lengthy analysis. But first the justification behind interventional nontherapeutic research on vulnerable persons is briefly addressed (Section 12.2).

12.2 Introduction: Can It Ever Be Justified to Expose Vulnerable Persons to Risks and Burdens for the Sake of Others? If “the best interests of the child shall be a primary consideration” as maintained in Article 3 of the Child Convention,3 it may be asked initially if it would ever be in the best interest of a child (or another similarly vulnerable person) to participate in interventional research where the risks and burdens to the child is not outweighed by the prospects of direct benefits to the same child. Is the exposure of children and similarly vulnerable persons to risks and burdens for the sake of others ever consistent with the principle of human primacy? The Explanatory Report to Article 15 (2) of the Additional Protocol states in this regard: Were such research to be banned altogether, progress in the battles to maintain and improve health and to combat diseases only afflicting children, mentally disabled persons or persons suffering from senile dementia would become impossible. It is the aim of such research to benefit persons in those groups through a better understanding of the factors which will help to maintain and improve health and well being or through a better understanding of disease processes.4

The justification for research on vulnerable persons is further elaborated in Paragraph 92 of the Explanatory Report. A similar statement is found in Paragraph 3 of the Preamble to the Clinical Trials Directive: . . . there is a need for clinical trials involving children to improve the treatment available to them. Children represent a vulnerable population with developmental, physiological and psychological differences from adults, which make age- and development-related research important for their benefit.

The challenge with research on vulnerable persons is thus that the vulnerable person obviously needs special protection against exploitation and abuses. 3 4

The UN Convention on the rights of the child. Paragraph 87.

12.2

Introduction: Can It Ever Be Justified to Expose Vulnerable Persons to Risks . . .

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It is, on the other hand, equally clear that many vulnerable persons often have self-interest in the promotion of biomedical research. The adopted additional safeguards (minimum standards) have, however, reportedly rendered research on vulnerable persons difficult.5 In effect it has become difficult to obtain knowledge that in the end would be beneficial to vulnerable persons. Hence, vulnerable persons are not only excluded from research participation, but also from enjoying the fruits of scientific progress. The paediatrician and bioethicist Lainie Friedman Ross found that the pendulum had shifted throughout history – back and forth.6 In the early history of biomedical research, children were exposed to excessive risks and burdens. Then additional safeguards were adopted, which effectively made research on children very strict. This implied that children were not included and a knowledge-gap soon became evident. The trend in the US has then been to adopt guidelines that ensure the inclusion of children in biomedical research, including nontherapeutic research. Ross fears that the Guidelines went too far in disfavour of the child.ss7 Nevertheless, EU regulations adopted in December 2006 require that new medicinal products as a main rule should be tested on children.8 The controversial question on how the law and guidelines ought to be; and how the two legitimate, but irreconcilable, interests should be balanced, will not be further discussed here since both the Additional Protocol and the Clinical Trials Directive recognise that nontherapeutic research on vulnerable persons may take place on strict conditions which are meant to ensure that a fair balance between the potentially conflicting interests can be struck; a recognition which appear reasonable. It is only conditions of particular (direct) relevance for the assessment of proportionality between risk, burdens, and potential benefits that is of interest here. It should be noted that the Additional Protocol and the Clinical Trials Directive include several comparable additional safeguards which does not directly influence the level of acceptable risks and burdens in nontherapeutic research, such as provisions that require that participants unable to give (legally valid) consent is given tailored information, and that the opinion of the person shall be taken into consideration as an increasingly determining factor in proportion to his or her age and degree of cognitive abilities (“assent”), and that any objections (even irrational) should be respected, maybe with a possible exception for the youngest children below three or four years of age. Thus a person’s legal capacity to refuse participation in biomedical research is far wider that his or hers capacity to consent.9 Such additional safeguards, as well as cognitive abilities and other relevant

5

See, for example, Westra et al. (2009). Ross (2006). 7 Ross (2006, p. 67). 8 Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medical products for paediatric use; See also: The EU Paediatric Guidelines (2008). 9 Maar (2007). 6

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factors already highlighted, may influence (more indirectly) the overall assessment of proportionality.10 These factors are, nevertheless, not of primary concern in the following.

12.3 Which Additional Preconditions Apply to Nontherapeutic Research on Vulnerable Persons? 12.3.1 Additional Safeguards Applicable to Nontherapeutic Research on Persons Not Able to Consent in the Additional Protocol There are some differences in the regulations concerning research on persons not able to consent between the Additional Protocol and the Clinical Trials Directive. The Additional Protocol is investigated first, and then compared with the provisions in the Clinical Trials Directive to reveal differences in the normative content. In relation to the requirement of proportionality and nontherapeutic research on persons not able to give a legally valid consent to research participation, Article 6 (2) second sentence refers to Article 15 (2) (ii) of the Additional Protocol. Article 15 (2) states11 : 2. Exceptionally and under the protective conditions prescribed by law, where the research has not the potential to produce results of direct benefit to the health of the person concerned, such research may be authorised subject to the conditions laid down in paragraph 1, subparagraphs ii, iii, iv, and v above, and to the following additional conditions: i. the research has the aim of contributing, through significant improvement in the scientific understanding of the individual’s condition, disease or disorder, to the ultimate attainment of results capable of conferring benefit to the person concerned or to other persons in the same age category or afflicted with the same disease or disorder or having the same condition; ii. the research entails only minimal risk and minimal burden for the individual concerned; and any consideration of additional potential benefits of the research shall not be used to justify an increased level of risk or burden. [Italics added]

Thus, Article 15 (2) identifies two additional conditions: 1. The potential benefits should be a “significant improvement” and be related to the participants condition or group-belonging (“significant” potential benefits) 2. The risks and burdens to the participant should be “only minimal” The two safeguards must both be fulfilled before proportionality between risks, burdens, and potential benefits can be established. They may thus, as with the additional precondition in Article 6 (2), first sentence (discussed in the foregoing chapter), be seen as additional preconditions for proportionality: If one of them is not fulfilled, 10

See Sections 10.3.5 and 11.4.5. Article 15 of the Additional Protocol is as mentioned equivalent to Article 17 in the Oviedo Convention. References are therefore primarily given to the former provision. 11

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the risks and burdens are either too high or the potential benefits are too insignificant; and the risks and burdens may thus be seen as disproportionate (or legally unacceptable and unreasonable). Likewise, if both preconditions are fulfilled, the risks and burdens will probably be in proportion to potential benefits. Proportionality must, nevertheless, be assessed according to the “general” requirement of proportionality in Article 6 (1) of the Additional Protocol to establish whether the risks and burdens in this particular research project are in proportion to the potential benefits; the minimal risks and burdens must be weighed against the significant potential benefits. This implies, that in principle, the risks and burdens can be found to be disproportionate even if the two preconditions are fulfilled (although this is hard to imagine). The two preconditions may be seen as reflecting the limited legal capacity that parents and other legal representatives (proxies) have to consent on the behalf of the child or other persons not able to consent12 : Legal representatives cannot give legally valid consent to participation in largely unnecessary (insignificant potential benefits) interventional research. Neither can they consent to interventional nontherapeutic research that entails more than minimal risks and burdens, no matter how significant the potential benefits to others are.13 The precondition of “significant” potential benefits has not gotten as much attention as the precondition of minimal risk and burden. The reason for this is not clear, since Article 15 (2) of the Additional Protocol does not give priority to one over the other. Article 6 (2) second sentence of the Additional Protocol does, on the other hand, refers only to Article 15 (2) (ii), the precondition of minimal risk and burden, and not the precondition of significant potential benefits. The Explanatory Report to Article 15 (2) states: While Article 6 restricts research in general by establishing a criterion of risk/benefit proportionality, this article lays down a more stringent requirement for research without direct benefit to persons incapable of giving consent, namely only minimal risk and minimal burden for the individual concerned.14

An interpretational alternative is that the precondition of significant potential benefits is then somehow nonapplicable. Such a view is obviously ill founded. The two preconditions in Article 15 of the Additional Protocol stand on their own feet, regardless of the wording in Article 6 (2) second sentence. The better interpretational alternative is that Article 6 (2) refers only to the degree of acceptable risks and burdens, which the provision intends to specify beyond the more vague requirement of proportionality in Article 6 (1). Indeed, the purpose of Article 6 (2) is, as shown above, to make clear that in nontherapeutic research there are limits as to the level of risks and burdens that individual research participants may carry for the sake of others, no matter how great the potential benefits to others.

12

See Section 5.4.6. See also Oviedo Convention Article 6. 14 Paragraph 91. 13

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The new Norwegian Act on Biomedical research has not explicitly adopted the precondition of “significant” potential benefits with regard to research on persons not able to consent (§ 18), although such a requirement is adopted for research on persons not able to consent and who are in emergency clinical situations (§ 19). The reason for this is not clear. As head of the law-committee’s secretariat, I participated in the drafting of the first draft of the Act, and no difference was intended. It is thus likely that difference is unintentional and simply an inadvertence. On the contrary, the Act was intended to be fully compatible with the Oviedo Convention and the Additional Protocol, and the Norwegian Act § 18 (c) must be interpreted that way as such an interpretation better realises the main purpose of the provision and the Act.

12.3.2 Additional Safeguards Applicable to Nontherapeutic Research on Children in the Clinical Trials Directive Unlike the Additional Protocol, the Clinical Trials Directive differentiates between clinical trials on “children” (“minors”)15 and adult persons not able to consent. The additional safeguards are largely similar, but some differences concerning the assessment of proportionality apparently exist. Article 4 (e) of the Clinical Trials Directive, concerning clinical trials on minors, contains a similarly strict precondition concerning the potential benefits when it makes clear that “a clinical trial on minors may be undertaken only if: some direct benefit for the group of patients is obtained from the clinical trial and only where such research is essential to validate data obtained in clinical trials on persons able to give informed consent or by other research methods; additionally, such research should either relate directly to a clinical condition from which the minor concerned suffers or be of such a nature that it can only be carried out on minors.” [Italics added]

Although the wording differs between Article 15 (2) (i) of the Additional Protocol and Article 4 (e) of the Clinical Trials Directive, the normative content should be largely the same. For all practicable purposes the two provisions should be seen as coincident; especially in the light of the need for regulatory harmony, and because it is unlikely that subtle linguistic nuances will make a difference in an overall judgments in practice. Hence, a precondition of significant potential benefits to other children may also be derived from the Clinical Trials Directive.16 Article 4 of the Clinical Trials Directive does not include the controversial precondition of only minimal risks and burdens. However, the Directive also indicates that a more rigorous and stricter approach is needed in the judgment of acceptable risks and burdens, when intent Article 4 (g) of the Directive states that clinical trials must 15 “Child” and “minor” are here understood as synonyms referring to born persons below 18 years of age, cf. the Child Convention Article 1. 16 See Section 9.5 on the requirements of necessity and lesser mean. This view is also taken in the Community Paediatric Guidelines of 2008.

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have been designed to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and developmental stage; both the risk threshold and the degree of distress have to be specially defined and constantly monitored.

Although the “additional” requirements mentioned in the provision must be seen as applicable to any clinical trial, also clinical trials on adults able to consent, the likely intention behind the statement in Article 4 concerning clinical trials on children, is that these measures are particularly important when doing research on children. This interpretation is clearly in line with the EU Paediatric Guidelines of 2008.17 Nevertheless, the question remain whether Article 4 of the Clinical Trials Directive is compatible with the precondition of only minimal risks and burdens in the Additional Protocol Article 15 (2) (ii). The EU Paediatric Guidelines apparently adopts the approach in US Federal law (although differentiating nuances occur),18 and propose the following distinct risk levels “as a means to decide on the ethical acceptability of trials: • Minimal risk, which could be defined as probability of harm or discomfort not greater than that ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests • Minor increase over minimal risk • Greater than minor increase over minimal risk”

As will be shown, the EU Paediatric Guidelines definition of “minimal risk” essentially coincides with the definition of “minimal risk” in the Additional Protocol Article 17 (1).19 The EU Paediatric Guidelines provide examples on when these “levels of risks are considered to be in balance with the benefit for a trial with the paediatric population: • Minimal risk with benefit for the individual or benefit for the group • Minor increase over minimal risk, with benefit to individual or benefit to the group, and with the benefit to risk balance being at least as favourable as that of available alternative approaches. • Greater than minor increase over minimal risk with benefit for the individual that is especially favourable in relation to available alternative approaches for the individual’s condition.

The three standards are not easy to understand. If research participation is “especially favourable in relation to available alternative approaches for the individual’s conditions”, then how can research participation entail greater than minor increase over minimal risk? A possible understanding is that the first bullet point refers to pure nontherapeutic research in which only minimal risks can be acceptable (as in Convention law). The next two bullet points refer to research where the risks to the child are, at least 17

Accounted for in Chapter 2. US Federal law “Common rule” 45 CFR 46. 19 Cf. Section 12.5. 18

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partly, outweighed by prospects of direct benefits to the same child. Nevertheless, in line with what was found above in Section 10.3, it may be more accurate to say (in relation to the third bullet point) that research participation is an alternative as favourable as other alternatives, but the uncertainty associated with research participation renders it a riskier alternative, and the additional risk must be said to be greater than a minor increase of minimal risk. There are two interpretational legal solutions to this apparent normative conflict: One is to disregard (or stretch) Convention law and give precedence to the Guidelines (at least in Community law). The other alternative is to interpret the Guidelines in line with Convention law, which would render Convention law and Community law compatible. The EU Paediatric Guidelines are not weighty enough to set aside the rather clear standards set forth in Convention law. A deviation from Convention law on such a crucial and controversial point needs a more substantial and clearer legal basis. Neither has the Guidelines tried to address and solve the apparent normative conflict. Instead the Guidelines adopt US standards without any explicit deliberations. But in US Federal law additional safeguards for such research have been adopted, which are stricter than the safeguards provided in the Clinical Trials Directive, for example, the approval of a national agency (not just a research ethics committee).20 Since similar safeguards, as in the US, are not in place, it is hard to argue convincingly that nontherapeutic research on children may entail more than minimal risks and burdens, even a minor increase, in Community law given the precondition of only minimal risks and burdens in the Oviedo Convention Article 17 (2) and its Additional Protocol Article 15 (2). Moreover, the EU Paediatric Guidelines make a direct reference to the Oviedo Convention Article 17 (2) (which equals Article 15 (2) of the Additional Protocol) in order to show that it is widely recognised that nontherapeutic research on children may exceptionally include risks and burdens not outweighed by direct benefits to the participant. The Guidelines thus apparently presume that the Guidelines are in harmony with Convention law. This also supports a harmonising interpretation. The discussion in Section 4.3 must also be recalled, including the principle developed in the case-law of the European Court of Human Rights that Community law is presumed to be consistent to human rights, and the principle that the better protection should be offered the individual, especially the vulnerable child. It is also dubious whether allowing more than minimal risks and burdens can be compatible with the principle of human primacy recognised in both Convention law and Community law. The CIOMS Guideline 9 titled “Special limitations when research involves individuals who are not capable of giving informed consent” states: When there is ethical and scientific justification to conduct research with individuals incapable of giving informed consent, the risk from research interventions that do not hold

20

See US Federal law CFR 45 §46.406 and §46.407.

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out the prospect of direct benefit for the individual subject should be no more likely and not greater than the risk attached to routine medical or psychological examination of such persons. Slight or minor increases above such risk may be permitted when there is an overriding scientific or medical rationale for such increases and when an ethical review committee has approved them.

Although not a minimal risk standard, the CIOMS embraces a “low-risk standard”.21 “Guidelines on the practice of ethics committees in medical research with human participants” issued by the London Royal College of Physicians promote a minimal risk standard for nontherapeutic research on both adults and children.22 As the EU Paediatric Guidelines, the Royal College uses US Federal law as a reference point (benchmark), instead of the European Oviedo Convention. This appears strange, and indicates lack of knowledge or “forum shopping”.23 In conclusion, to argue that Community law does not recognise the minimal risk standard set out in the Additional Protocol, would imply that children participating in such research are offered weaker protection in Community law than in Convention law. Such a solution would be unsustainable for those countries that have ratified the Oviedo Convention (including Norway). Vulnerable participants are entitled the better protection.24 The mere intention behind the vague wording of Article 4 of the Clinical Trials Directive might therefore have been to have a more flexible framework than offered by Convention law, not weaker protection. Thus, the better and probably most correct interpretation and legal solution is that nontherapeutic clinical trials on children in Europe must fulfil the preconditions of significant potential benefits to other children, and only minimal risks and burdens to the participating child (minor).25 Community law must as a result be interpreted in line with Convention law.26 This legal solution is maintained in the following.

21

Note that CIOMS Guideline 9 apparently recognise a “relative” minimal risk standard that is not acceptable in European law, see Section 12.5.9. 22 The Royal College of Physicians of London (2007, pp. 36–38). 23 “Forum shopping” is a common term used about the dubious practice (in this context) where one chooses the subjectively preferable legal solution (framework, jurisdiction, research ethics committee, and so on). 24 Cf. Section 4.3 and Article 34 of the Additional Protocol: “None of the provisions of this Protocol shall be interpreted as limiting or otherwise affecting the possibility for a Party to grant research participants a wider measure of protection than is stipulated in this Protocol.” 25 It may be noted if one opt for the more liberal interpretational alternative which may seem to tolerate a minor increase over minimal risk, it is clear that a “minor increase”, nevertheless must be understood as just that: a minor increase. In practice where the assessments often are rough and approximate assessments, such a “more liberal” solution should not amount to much difference. It is clear that a risks which is double as risky as a minimal risk is not a minor increase. Hence, the minor increase terminology cannot be used to pave way for a slippery slope in the practice of researchers or research ethics committees. 26 See Simonsen (2011) on the relationship and need for harmonisation between Convention law and Community law.

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12.3.3 Additional Safeguards Applicable to Nontherapeutic Research on Adult Persons Not Able to Consent in the Clinical Trials Directive The additional safeguards provided “adult persons not able to consent” in Article 5 of the Clinical Trials Directive are similar to those provided for children, but with some differences affecting the assessment of proportionality. A statement in Paragraph 4 of the Preamble indicates an even stricter approach than on research on children: In the case of other persons incapable of giving their consent [than children], such as persons with dementia, psychiatric patients, etc., inclusion in clinical trials in such cases should be on an even more restrictive basis. Medicinal products for trial may be administered to all such individuals only when there are grounds for assuming that the direct benefit to the patient outweighs the risks. [Italics added]

Article 5 indent (e) concerns the principle of lesser mean27 and the level of potential benefits: Research on adult persons not able to consent must be “essential to validate data obtained in clinical trials on persons able to give informed consent or by other research methods and relates directly to a life-threatening or debilitating clinical condition from which the persons not able to consent to research adult concerned suffers”. [italics added]

The wording “essential” and “relates directly to a life-threatening or debilitating clinical condition” are strong and strict formulations. The ordinary meaning of the word “essential” is absolutely necessary. The words “life-threatening” or “debilitating” are also strong. The language is clearly stronger, and consequently more restrictive, than the language in Article 4 of the Clinical Trials Directive and the language in the Additional Protocol Article 15 (2). The provision (Article 5 (e)) thus suggests that clinical trials on persons not able to consent should be carried out only where the knowledge to be gained is, at least, significant (“essential”), and were the patient’s condition is serious, or at least not trivial. The reason why such strong and restrictive language was chosen with regard to research on adult persons not able to consent, and not with regard to research on children, is not clear. One reason may be that nontherapeutic research on children is inevitable because of differences in physiology between children and adults (it not just about “halving the dosage” for children). However, there are plentiful examples of important and highly beneficial nontherapeutic studies that can only be carried out on adult persons not able to consent, and which is primarily aimed at benefiting other (future) adult persons not able to consent in a similar situation. Nontherapeutic research on Alzheimer’s disease and dementia are typical examples. It is also seems difficult to argue that children are less vulnerable both physiological and psychological than adult persons not able to consent. The same goes for 27

See Section 9.5 on the requirements of necessity and lesser mean.

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the risks of exploitation. One could argue that parents (should) have wider legal capacity to give proxy consent than the legal representatives of adult persons not able to consent. But if the legal representative is the participant’s wife or husband, the argument is not very convincing. Parents’ legal capacity is, probably in most national jurisdictions, very restricted when it comes to their capacity to consent to their child’s participation in interventional (risky) nontherapeutic research. Thus the rationale behind the difference is hard to grasp. This may be taken to suggest that there are no obvious reasons why the threshold for nontherapeutic research on adult persons who are not able to consent, should be significantly higher than the threshold applicable to clinical trials on children. This view is supported by the fact that in the Additional Protocol the same standards apply to nontherapeutic research on adult persons not able to consent as to nontherapeutic research on children. This seems to be the better interpretational solution, and is thus maintained here. Consequently, Article 5 (e) of the Clinical Trials Directive should in line with what is said above and to promote regulatory harmony, been interpreted to have essentially the same normative content as Article 4 (e) of the Clinical Trials Directive and Article 15 (2) (i) of the Additional Protocol: i.e. that nontherapeutic clinical trials on adult persons not able to consent must entail “significant” potential benefits related to the participants condition or group-belonging. This interpretation should be uncontroversial as the differences between the provisions are nevertheless marginal. This is not the case when it comes to the level of acceptable risks. Article 5 (i) of the Clinical Trials Directive concerns the level of acceptable risks for nontherapeutic research on adult persons not able to consent: there are grounds for expecting that administering the medicinal product to be tested will produce a benefit to the patient outweighing the risks or produce no risk at all.

The normative content is on the face of it unambiguous: any risks to the participant must be fully outweighed by prospects of direct therapeutic benefits to the same participant (the direct benefit rule). Thus, the provision seem to effectively rule out nontherapeutic clinical trials on adult persons not able to consent (that is, research where the direct benefit rule is not completely fulfilled), unless the testing entails “no risk at all”. But, interventional clinical trials always entail risks. The apparent threshold is higher than for children in Community law (Article 4 (g)), and higher than for adult persons not able to consent in Convention law (Article 15 (2) (ii)). The cited statement in Paragraph 4 of the Preamble to the Clinical Trials Directive clearly indicates that this difference is intentional. Consequently, there is a an apparent normative conflict between the Article 5 (i) of the Clinical Trials Directive and Article 15 (ii) in the Additional Protocol which must be solved, since both instruments apply to interventional clinical trials with pharmaceutical products. In § 18 of the Norwegian Health Research Act of 2008 essentially the same standards applies to children and adult persons not able to consent, which implies preconditions of significant potential benefits, and only minimal risks and burdens. Similar provisions are adopted in § 2–8 and § 2–9 of Norwegian secondary law concerning clinical trials of 2009, which incorporate the EU Clinical Trials Directive of 2001. Thus, despite the wording of

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the Clinical Trial Directive, Norwegian secondary law permits that adult persons not able to consent can be exposed to minimal risks in clinical trials in Norway (this is also the understanding in written guidelines published by the Norwegian Medicine Agency28 ). This raises the question whether Norwegian secondary law is contrary to Community law and Norway’s international obligations.

A “no risk at all” standard is a very tall order. For example, if a clinical trial only involve one extra blood draw which is undertaken for purely research purposes (nontherapeutic) the clinical trial cannot be undertaken, because such a blood sampling is a physical intervention that involves risks of harm, although a minimal risk (see Section 5.5). One may argue that such small risks are “neglectable” and thus equals “no risks”, but that interpretation is difficult to sustain as other legal instruments and professional guidelines recognises that even such small risks should be considered.29 It is likely that research entailing minimal risks (not outweighed by prospect of direct benefits) is regularly commenced by researchers and tolerated by research ethics committees in Europe today. The “no risk at all” standard therefore appears unrealistically restrictive. As stated in the Explanatory Report to Article 15 (2) of the Additional Protocol: Were such research to be banned altogether, progress in the battles to maintain and improve health and to combat diseases only afflicting children, mentally disabled persons or persons suffering from senile dementia would become impossible.30

Moreover, a literal interpretation appears to be contrary to the purpose of the provision and the Clinical Trials Directive as a whole. Thus, a liberal interpretation that allows minimal risks, probably better realises the purpose of the provision and the Directive; which is (first) to offer participants adequate protection, but also (although secondary) to render legitimate and beneficial research permissible.31 It may be argued that a liberal interpretation is contrary to the principle that the participant should always be assured the better protection. However, the fact that the Additional Protocol, US Federal law, Norwegian law, the CIOMS Guidelines, UK Royal College Guidelines, most commentators, permit nontherapeutic research on adult persons not able to consent involving only minimal risks, strongly suggests that the Clinical Trials Directive should be interpreted liberally.32 The liberal interpretation is, however, legally dubious, because of the unambiguous wording. The Clinical Trial Directive should thus be amended as soon as possibly to make clear that legitimate research is lawful. The liberal and rather bold interpretation is nevertheless maintained in the following. Consequently, “no risk at all” id interpreted as “only minimal risk”.

28

Norwegian Medicine Agency Guidelines concerning clinical trials (2009). Cf. Section 12.5. 30 Paragraph 87. 31 Cf. Chapter 12. 32 See “Common rule” 45 CFR §46.111 (adults) and §46.404 – §46.406. 29

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However, it should be noted that researchers and research ethics committees ought to be cautious, at least if the interpretational result may, as in this case, be seen as weaken a research participant’s legal protection. Article 5 (i) of the Clinical Trials Directive refers only to risks. It may thus be asked whether the increased threshold also refers to burdens. Since the general provision in Article 3 (2) (a) of the Directive specifically refers to risks and burdens (“discomforts”) it can be asserted that the omission of discomforts in Article 5 (i) is intentional. This implies that a certain limited degree of burdens (minimal burdens) may be acceptable even though there are no prospects of direct therapeutic benefits to the adult person not able to consent. This interpretation is strongly supported by Convention law and other regulations.33 Consequently, a precondition of “only minimal burdens” can be interpreted into Article 5 (i) of the Clinical Trials Directive. This means that Community law may be seen as largely compatible with Convention law, in this regard.34 Both Article 4 (h) and Article 5 (g) require that experts are involved in the risks assessment undertaken by the Research Ethics Committee. The observed Research Ethics Committee applied this requirement, at least in relation to research on children. The Committee also relative frequently (approximately 1 in 10 projects) invited the principal investigator to meetings to inquire about the risks or the potential benefits (the research aim).35 This practice improved accuracy of the assessment of proportionality, as illustrated by the Obesity Study.

12.3.4 Additional Safeguards Applicable to Nontherapeutic Research in Emergency Clinical Situations Nontherapeutic research on persons in emergency clinical situations is an ethical and legal challenge specifically addressed in Article 19 of the Additional Protocol. On the one hand, there is an almost desperate need for research and new knowledge in this field to save people from life-threatening and serious conditions. The Explanatory report to the Additional Protocol Article 19 states: Present medical treatment for some conditions giving rise to a clinical emergency situation, for example severe head injury, is still limited, and the risk of death is high. If the person does survive, they may develop serious disability. It is therefore important that research is undertaken both into new treatments for these conditions, and in some cases into the underlying mechanisms that lead to the damage. However, any treatment or research intervention may need to be started rapidly if there is to be any chance of it being effective. Without

33

See Chapter 14, which more specifically addresses the use of placebo in clinical trials. See Section 2.2 and Simonsen (2011) on the relationship and need for harmonisation between Convention law and Community law. 35 This means that in most projects that involved modest to high risks, this was done. Approximately half of the studies were noninterventional. 34

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research, the outcome for patients in a clinical emergency situation, particularly situations in which the risk of death or serious disability is high, is unlikely to improve.36

On the other hand, people in emergency clinical situations are particularly vulnerable because of an urgent need for health care. Moreover, in emergency clinical situations it is often impracticable to obtain a legally valid consent from either the participant or his or her legal representative (proxy). Yet, the Additional Protocol Article 19 permits research in emergency clinical situations, even nontherapeutic research. Article 19 of the Additional Protocol resembles Article 15, but what distinguishes Article 19 from Article 15 is that Article 19 not only permits derogation from the main requirement of consent from the participant, but also the subsidiary requirement of consent from the participant’s legal representative. Article 19 therefore represents a more extensive exception from the main requirement of the participant’s consent than Article 15, and such research thus represents a more serious and controversial act.37 Moreover, Article 19 addresses what often must be regarded as a more critical (in terms of the seriousness of the participant’s condition), and therefore a more legally challenging situation. These points underscore that research in clinical emergency situations are highly exceptional in several aspects. In fact, since consent from neither the participant nor his or her legal representative is obtained, the situation is close to coercive and involuntary physical interventions. Such interventions are in the case-law of the European Court of Human Rights rated among the strongest interferences and thus subject to the strictest scrutiny.38 Involuntary inclusion in nontherapeutic research is irreconcilable with Articles 3 and 5 of the European Convention of Human Rights, and thus normally illegal. Thus for such research in emergency clinical situations to be justifiable, the participation must be presumed to be voluntary; which means that if the participant and/or his or her legal representative had been informed and asked, it is reasonable to assume that they would have consented. Whether such a presumption of consent can ever reasonably be established in an emergency clinical situation for all participants is questionable. At least the research should then be clearly necessary and justifiable, in so far that the knowledge sought is of vital importance for future patients and reasonably obtainable; and that the knowledge cannot be obtained through any lesser means.39 Moreover, the risks and burdens must, as an absolute minimum, be proportionate and thus assumingly acceptable for the participants. This surely leads to a stricter duty of care, which also indicates a more rigorous and stricter assessment of proportionality than more regular research on persons not able to consent to research.40 36

Paragraph 105. See Lötjönen (2002, p. 183). 38 See, for example, the case of Shtukaturov v. Russia, Judgment by the ECtHR of 27 March 2008. 39 This follows from the general requirements of necessity and lesser means, see Section 9.5, and Article 19 (2) (i). 40 Likewise Lötjönen (2002, p. 183). 37

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The additional safeguards in Article 19 (2) of the Additional Protocol reflect this, although it is not explicitly underscored. This also follows from Article 19 (2) indent (ii), which requires that the research project “has been approved specifically for emergency situations by the competent body”. The latter requirement implies that persons in an emergency clinical situation cannot be included in a more “ordinary” research project; that is research projects that primarily concern research on persons that are not in an emergency clinical situation. The level of acceptable risk and burdens for nontherapeutic research in emergency clinical situation is addressed in Article 19 (2) (iv): where the research has not the potential to produce results of direct benefit to the health of the person concerned, it has the aim of contributing, through significant improvement in the scientific understanding of the individual’s condition, disease or disorder, to the ultimate attainment of results capable of conferring benefit to the person concerned or to other persons in the same category or afflicted with the same disease or disorder or having the same condition, and entails only minimal risk and minimal burden. [Italics added]

Thus the two “common” preconditions of significant potential benefits to future patients and only minimal risks and burdens to the participant, also applies in nontherapeutic research in emergency clinical situations. The preconditions are identical to those set up for nontherapeutic research on other persons not able to consent in Article 15 (2) of the Additional Protocol. It is noteworthy that this implies a tightening compared to an early draft of the Additional Protocol, insofar that the research has to be related to the participant’s condition. The regulation is largely in harmony with US Federal law.41 Clinical trials in emergency situations are not explicitly addressed in the Clinical Trials Directive; hence the more general provisions apply. The crux in Article 4 and Article 5 of the Clinical Trials Directive is that while they permit research on persons not able to consent, they still require a written consent from the participant’s legal representative. Aurora Plomer sees, correctly, the requirement of consent by proxy as a possible “stumbling block”.42 It is, however, unlikely that the Clinical Trials Directive was indented to make research in clinical emergency situations a legal impossibility. Such clinical trials have been carried out regularly in Norway and probably also in other countries (although perhaps without a clear and firm legal basis), see, for example, the Stroke Studies.43 A liberal interpretation suggests that these provisions are not intended to regulate such an extreme and extraordinary situation, thus neither prohibit nor permit such research. But this leaves such research in a “legal limbo”, which is morally and legally unacceptable when it comes to interventional nontherapeutic research in so vulnerable persons. The “crux” may be passed by the interpretation that the legal representative can, exceptionally (where the next of kin is nonavailable), be an independent physician 41

CFR 21 §50.24. Plomer (2001). 43 Accounted for in Sections 10.3.6 and 10.3.7. 42

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or another person authorised, for example, by the research ethics committee etc. According to paragraph 5 of the Preamble, the “notion of legal representative refers back to existing national law and consequently may include natural or legal persons, an authority and/or a body provided for by national law.” A better, but still liberal, legal solution may be to argue that the Clinical Trials Directive does not explicitly prohibit member states to set up legal standards which may exceptionally permit research in emergency clinical situations. In, for example, the written guidelines to Norwegian secondary legislation concerning clinical trials, published by the Norwegian Medicine Agency, such a solution is maintained, although the legal basis can be questioned, at least before the adoption of the Health Research Act which explicitly incorporate Article 18 of the Additional Protocol into Norwegian law (§ 19).44 If so, the protection offered in national law should be at least as good as the protection offered to persons not able to consent. Moreover, Article 19 of the Additional Protocol, should, if not directly applicable, be regarded as evidence for internationally recognised minimum standards. Research on persons in emergency clinical situations is not regulated specifically in the Oviedo Convention. With the adoption of the Additional Protocol, this is unproblematic as the provisions included in the Protocol constitute additional provisions to the Oviedo Convention.45 Hence, the two “common” preconditions also apply in this regard.

12.3.5 Additional Safeguards Applicable to Nontherapeutic Research During Pregnancy and Breastfeeding Pregnant and breastfeeding women participating in nontherapeutic research are in Article 18 of the Additional Protocol offered similar additional safeguards as persons not able to consent, even though the woman may give a legally valid consent. If she is not able to consent, Article 15 or Article 19 applies. Whether consent from the father is necessary, is not mentioned in the Protocol. When the child is unborn, the question is difficult as it touches the issue of women’s right to decide over their “own” body. It could be argued that the father’s assent is as a main rule necessary in nontherapeutic research; if it is known who he is. It is at least reasonable that his objection is respected, if there is a chance that the child may be negatively affected. When it comes to research on breastfeeding women (when the child is born), which directly or indirectly involve the child, the father should probably also, at least as a main rule, consent to child’s “inclusion” in interventional nontherapeutic research, if the parents have joint legal responsibility. The direct or indirect involvement in a risky nontherapeutic interventional research project may be a matter where 44 45

Norwegian Medicine Agency Guidelines concerning clinical trials (2009). Plomer (2001).

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it may be reasonable that both parents have their say.46 The issue concerns the requirement of consent and is not further pursued here. Research on Pregnant Women Article 18 (1) concerns nontherapeutic research on pregnant women. Intent (i) entails a stricter test of necessity and potential benefits, as the research must have the aim of contributing to the ultimate attainment of results capable of conferring benefit to other women in relation to reproduction or to other embryos, foetuses or children.

The Explanatory Report to the provision holds that the wording “in relation to reproduction” should be understood “broadly”.47 Research “relevant to the health of women following pregnancy, or research relevant to women’s choice on whether or not to become pregnant” are offered as examples.48 The provision does, however, not include the wording “significant improvement in the scientific understanding of the individual’s condition, disease or disorder” [italics added], which is included in Article 15 (2) concerning nontherapeutic research on the persons not able to consent, including children. The latter wording suggests a higher threshold than the former. This difference between Article 15 (2) (i) and Article 18 (1) (i) is not addressed in the Explanatory report. A likely underlying reason is that pregnant women have the capacity to give a legally valid consent, and are, as such, not as vulnerable as persons not able to consent.49 However, it may be argued that the embryo and foetus cannot consent, and thus should be entitled protection which is as good as the protection offered born children that are not able to consent. The provision is primarily aimed at protecting the unborn child, which might be affected by the research or which might be more or less the subject of research. The distinction therefore appears arbitrary and not particularly well founded. It can be argued that the woman can consent and thus ensure the unborn or born child’s interests. However, the same applies to born children. The US regulations do include a precondition of significant potential benefits.50 Thus, a precondition of significant potential benefits may be interpreted into Article 18 (1) (i) if the nontherapeutic research involves or possibly may negatively affect the embryo or foetus, because such an interpretation better realises the main purpose of the provision that is to ensure adequate protection of the (unborn) child. 46 According to Article 15 of the Additional Protocol. See, however, US regulations CFR 45 Section 46 subpart B where this is regulated. 47 Paragraph 103. 48 Paragraph 103. 49 If she does not have the capacity to give a legally valid consent the stricter additional safeguards in Article 15 (2) of the Additional Protocol applies. 50 US law 21 CFR Subpart B §46.204 (b): “The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means; (c) Any risk is the least possible for achieving the objectives of the research.” [Italics added]

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Article 18 (1) indent iii addresses the level of acceptable risks and burdens and states that nontherapeutic research may be undertaken only if “the research entails only minimal risk and minimal burden”. Thus this precondition is the same as for research on persons not able to consent.51 That precondition also resembles US Federal law.52 Research on Breastfeeding Women Where research includes breastfeeding women, the Additional Protocol has a different approach than towards pregnant women. Article 18 (2) simply states that “particular care shall be taken to avoid any adverse impact on the health of the child.” It may be asked if this is something different than the twin preconditions of significant potential benefits, and minimal risk and burden. The provision is not commented in the Explanatory Report. One interpretational alternative is that the general requirement of acceptable risks and burdens in Article 6 (2) first sentence applies, but “particular care” should be taken. Another interpretational alternative is to argue that breastfeeding children are generally “vulnerable persons”. Research on breastfeeding women should therefore be subject to the strictest thresholds, namely the twin preconditions of significant potential benefits, and minimal risks and burdens. Both interpretational alternatives are legally acceptable, and in an overall contextual assessment of proportionality the solutions should be largely the same. Nevertheless, the twin precondition of significant potential benefits and only minimal risks and burdens should probably be interpreted into Article 18 (2) if the nontherapeutic research involves or possibly may negatively affect the breastfeeding child, because such an interpretation better realises the main purpose of the provision which is to ensure adequate protection of the child. Clinical trials involving pregnant or breastfeeding women are not specifically addressed in the Clinical Trials Directive; hence the more general provisions apply. The Additional Protocol Article 18 will, however, serve as a weighty source of internationally recognised minimum standards in the overall assessment of proportionality prescribed by Article 3 (2) (a) of the Clinical Trials Directive.53

51

See Article 15 (2) (ii), as well as Articles 19 and 20. See US Federal law 45CFR46 §46.204 (d): “If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means, her consent is obtained in accord with the informed consent provisions of subpart A of this part.” 53 See Chapter 2 on the relationship between Convention law and Community law. 52

12.3

Which Additional Preconditions Apply to Nontherapeutic Research on . . .

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12.3.6 Additional Safeguards Applicable to Research on Persons Deprived of Liberty If the national law of the member states allows research on persons deprived of liberty, Article 20 of the Additional Protocol sets up additional safeguards for nontherapeutic research, which are similar to the safeguards applicable to research on pregnant women in Article 18 (1). Article 20 of the Additional Protocol state: Where the law allows research on persons deprived of liberty, such persons may participate in a research project in which the results do not have the potential to produce direct benefit to their health only if the following additional conditions are met: i. research of comparable effectiveness cannot be carried out without the participation of persons deprived of liberty; ii. the research has the aim of contributing to the ultimate attainment of results capable of conferring benefit to persons deprived of liberty; iii. the research entails only minimal risk and minimal burden.

The preconditions of “significant” potential benefits to others (implied in indent (i) and (ii)), and “only minimal risks and burdens” (indent (iii)) is thus included in the provision. The Explanatory Report stresses that other safeguards also applies, and particularly emphasises Article 12 which deals with undue influence,54 and Article 23 which deals with noninterference with necessary clinical interventions and the use of placebo, which is discussed in Section 14.4. Clinical trials involving persons deprived of liberty are not specifically addressed in the Clinical Trials Directive, hence the more general provisions apply. The Additional Protocol Article 20 will also in that regard serves as an internationally recognised standard. Research on prisoners is subject to strict approval procedures in the US. Moreover, such research must concern “the possible causes, effects, and processes of incarceration, and of criminal behaviour” and the research should entail “no more than minimal risk and no more than inconvenience to the subjects”.55 As such, US Federal law is congruent with European Convention law.

12.3.7 Additional Safeguards Applicable to Nontherapeutic Research on Similarly Vulnerable Persons As shown, the Additional Protocol contains additional preconditions for proportionality applicable to nontherapeutic research on children, adult persons that are not able to consent, pregnant women, breastfeeding women, and persons deprived of liberty. The Clinical Trials Directive (explicitly) contains only additional preconditions applicable to the first two groups of research participants. 54 55

Explanatory Report Paragraph 114. US Federal law 45CFR46 §46.306.

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It may thus be asked whether individuals who do not fall within either category, but who are just as vulnerable, are subject to similar additional preconditions for proportionality. The question is whether the twin additional preconditions for proportionality may be interpreted into the “general” requirement of proportionality as expressed in Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive. The answer must surely be affirmative: the twin additional preconditions of “significant” potential group benefits and only minimal risks and burdens can and must be interpreted into the requirement of proportionality, and hence the two “general” provisions. In Section 3.8 where “vulnerable person” is defined, it was found that individual (contextual) vulnerability is relevant in both Convention law and Community law. Individuals who are just as vulnerable as those who are generally characterised as “vulnerable persons” (such as children and adult persons not able to consent) should therefore be subject to similar minimum standards of protection. Consequently, many research participants in biomedical research, such as impaired hospitalised patients, must often be regarded as “vulnerable persons” entitled to stricter legal protection. This interpretation is strongly supported by the findings in Section 5.4.3 concerning the unreliability and insufficiency of consent, because of participants’ frequent misconceptions, as well as conflicting interests and inequality of power between the researcher and the participant. The “degree” of vulnerability must therefore be reflected in the overall contextual assessment of proportionality; in so far that the more vulnerable the participant is the more rigour and stricter the assessment of proportionality must be.56 The assessment must be stricter if the research involves young children than adolescents able to assent; and the assessment should be just as strict, if not stricter, if it involves dependent, underprivileged, hospitalised ethnic minorities, as research on cognitive and socially strong, but imprisoned, healthy persons. This interpretation is in part based on analogy from Article 15 (2) of the Additional Protocol, and Article 5 of the Clinical Trials Directive. Moreover, the interpretation may in part be based on notions of justice and fair distribution: similar situations should be subject to similar standards. It is in part also based on the need for regulatory harmonisation. This interpretation of the requirement of proportionality as expressed in Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive is most probably correct because it increases the likelihood of realising the main purpose of, not only the provisions (the requirement of proportionality), but also the legal instruments as a whole; which is to protect the most vulnerable amongst us against disproportionate, unreasonable, and excessive risks and burdens, and thus undue exploitation; whether or not the vulnerable person is capable of giving a “legally valid” consent.

56

See Sections 10.3.5 and 11.4.5.

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12.4 The Precondition of “Significant” Potential Benefits to Others 12.4.1 Problems Addressed The discussion above showed that the legal framework read in context entail two additional legal preconditions for proportionality applicable to nontherapeutic research on particularly vulnerable persons. The two additional preconditions that may be derived from provisions that aim to protect vulnerable persons and from the requirement of proportionality itself are (as expressed explicitly in Article 15 (2) of the Additional Protocol: 1. The potential benefits must be a “significant improvement” and be related to the participants condition or group-belonging (“significant” potential benefits) 2. The risks and burdens to the participant must be “only minimal” A main argument is the aim of regulatory harmony and that similar situations should be subject to similar minimum standards of protection, especially when it comes to the protection of the most vulnerable amongst us. This increases the likelihood of realising the main purpose of, not only the provisions (including the requirement of proportionality), but also the legal instruments as a whole. Within this single standard perspective the two identified preconditions or minimum standards will be further investigated in the following, with Article 15 (2) of the Additional Protocol as the central point of reference.57 The question to be addressed in this section is the normative content of the precondition of “significant” potential benefits. The normative content of the precondition of “only minimal” risks and burdens is addressed in Section 12.5.

12.4.2 The Normative Content of the Precondition of “Significant” Potential Benefits to Others The first precondition, as expressed in Article 15 (2) (i), has two elements: The research must have “the aim of contributing, through [1]significant improvement in the scientific understanding [2] of the individual’s condition, disease or disorder” [italics added]. The First Element: “Significant” Potential Benefits to Others The wording “significant improvement in the scientific understanding” appears very strict, and obviously means that the potential benefits to others must be significant. I therefore find it clarifying to speak of this additional precondition as a requirement of “significant potential benefits to others”. 57

The issue of “single standard” or “multiple standards” is addressed in Section 12.5.9 in relation to the definition of “minimal risk”.

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Although Article 15 (2) (i) speak of the “individual’s condition” it is clearly not direct benefits to the participant which are the issue, but rather that increased knowledge about the individual research participant’s condition may benefit others with the same condition (but not the individual him or herself; usually because it takes time (years) from the research is conducted to the knew knowledge find its way into clinical practice. If the research also may benefit the individual research participant’s health, then the research entail prospect’s of direct benefits. If the individual him- or herself may expect prospects of direct benefits, is has, as shown in Chapter 17, important consequences for the assessment of proportionality.

The additional precondition is also intended to be “very strict”. As stated in the Paragraph 87 of the Explanatory Report to Article 15 (2): “Paragraph 2 [of Article 15] provides exceptionally, under the protective conditions prescribed by domestic law, for the possibility of waiving the direct benefit rule on certain very strict conditions.” [Italics added] The language in, for example, Article 5 (e) of the Clinical Trials Directive is similarly strong and restrictive, as the word “essentially” is used. The obvious intention behind this strong and restrictive language is to make it clear that research involving vulnerable persons, such as children and adults not able to consent, when the direct benefit rule is not fulfilled, may only exceptionally be justifiable and legally permissible. The consequence is that insignificant interventional biomedical research projects, such as small projects conducted by inexperienced researchers, must not include vulnerable persons. The estimation of potential benefits to others is difficult.58 Based on the general factors for the estimation of potential benefits discussed above, there are acknowledged indicators of “significant” potential benefits to science and society. These indicators may affect both the likelihood of new knowledge and the magnitude and utility of the knowledge sought: Firstly, the research should be clearly necessary; if it is questionable that the research project is necessary, than the precondition may not be fulfilled. To require that the expected new knowledge is almost an imperative for future patients in a similar situation as the vulnerable participant, is may be a too tall order. But the aim must be clear and original; the knowledge sought should be of interest and clearly worth pursuing. At any rate, the precondition presupposes a more rigorous control of the research project’s background and justification (literature studies, pre-trials on animals, healthy volunteers etc). These assertions are obviously controversial as they presuppose value judgments and prioritisations of research questions and research projects that may conflict with the fundamental freedom of research and researchers’ academic freedom. The observed Research Ethics Committee was reluctant towards such judgments, probably because the judgment could frustrate scientists’ freedom of research and academic freedoms. Nevertheless, the European legal framework is crystal clear that the protection of the participants has priority. Article 4 of the Additional Protocol states unequivocally: Research shall be carried out freely, subject to the provisions of this Protocol and the other legal provisions ensuring the protection of the human being.

And it is especially in relation to nontherapeutic interventional research on vulnerable persons that the freedom of research and unnecessary or unimportant 58

See section above on the estimation of potential benefits and the relevant factors therein.

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research must yield. This is also derivable from the principle of human primacy in Convention law and Community law.59 Another important indicator of significant potential benefits to others is the competence of the researchers. The researcher(s) should be scientifically and clinically competent, especially when doing nontherapeutic interventions on vulnerable persons. The design should unquestionably be adequate. The statistical power should be proven “right”, ensuring a sufficient, but not excessive, number of participants. If such conditions are fulfilled, it is also likely that the results would be published in a reputable scientific journal making it more probable that the results – the knowledge gained – will have wider application and greater impact in clinical practice. Hence, all indicators of potential benefits are relevant, but the indicators should be applied more rigorously and stricter, in order to determine whether the potential benefits are significant or not. On the other hand, the judgments should not be too strict. The research does not need to be groundbreaking or directly lifesaving in order to fulfil the precondition of significant potential benefits. Most research is not. Thus, whether the potential benefits are significant is also dependent on the risks and burdens, as well as other factors relevant in the overall assessment of proportionality.60 The context and nature of the research project as well as individual characteristics and perceptions of the participant are essential. The important implication of being a precondition for proportionality, is that although an overall weighing of potential benefits against risks and burdens is necessary, the precondition of significant potential benefits must be fulfilled regardless of the degree of risks and burdens. Thus, a scientifically insignificant research project involving vulnerable persons can be unacceptable and disproportionate, even though the project itself appears harmless (the risks and burdens are minimal). It is questionable whether some of the projects approved by the observed Research Ethics Committee met this standard. The primary reason why the Committee approved the projects was that they appeared harmless. The risk was low, and involved only a few participants. What appeared to be a secondary reason was that the Committee did not want to be an obstacle for “wannabe” (inexperienced) and “idealistic” (dedicated to do good for the vulnerable) researchers, or the freedom of research. The Committee did, on the other hand, often have serious qualms as the “researcher” (often a student together with a distant supervisor) was not very competent, the design was poor, and the statistical power was weak. Hence, it was likely that the only beneficiary was the researcher him or herself, who acquired training and possibly academic credit. During the three-year observational period the Committee did, however, tighten their practice. It can be argued that the precondition of significant benefits is too strict, and that it will exclude aspiring scientists and thus the long-term progress of science. Is not research an exercise in trial and error? The implicit, but unambiguous answer given 59

Article 3 of the Additional Protocol; and Article 2 (1) of the GCP Directive; see Section 5.2 where the principle, and this issue, is investigated at a more principal level. 60 See Section 10.3.5 where some of these factors are noted.

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by the legal framework is that aspiring scientists or poor scientists should be allowed to carry out insignificant, but harmless, projects, but only as long as the “research” project involves relatively invulnerable volunteers, or, even better, no human beings at all; it should not be necessary to include vulnerable persons in research training, quasi-research, hopeless or otherwise relative insignificant research. The Second Element: A Demand for “Closeness” Between the Burdened and the Beneficiaries Article 15 (2) (ii) state: the research has the aim of contributing, through significant improvement in the scientific understanding of the individual’s condition, disease or disorder, to the ultimate attainment of results capable of conferring benefit to the person concerned or to other persons in the same age category or afflicted with the same disease or disorder or having the same condition [Italics added]

The wording is difficult to grasp. But the two italicized parts of the text, expresses essentially the same: The “significant improvement in the scientific understanding” must refer to “the individual’s condition, disease or disorder.” This is the same as demanding that the “ultimate attainment of results” should be “capable of conferring benefit to the person concerned or to other persons in the same age category or afflicted with the same disease or disorder or having the same condition”.61 This wording constitutes the second element of the additional precondition of significant potential benefits to others: there must be a certain closeness between the burdened risk-carrier (the vulnerable participant) and the beneficiaries. The same can be derived from Articles 4 (e) and 5 (e) of the Clinical Trials Directive. This specification of relevant potential benefits significantly narrows down the possible aims of interventional nontherapeutic research on vulnerable persons. The precondition should be seen in the light of the requirement of lesser mean and the main rule of direct benefit.62 Hence the participants should preferably benefit directly, but at least more or less “indirectly”; and the closer the relationship between the burdened risk-carrier (the participant) and the beneficiaries, the better. The apparent rationale behind this maxim is that it would be unjustifiable and unfair to perform interventional research on a vulnerable person if the research had nothing to do with the participants’ clinical conditions etc. Such research either appears unnecessary or it should be possible to conduct research of comparable effectiveness on relative invulnerable persons or persons closer related to the aim of the research. This may also be derived from the requirement of lesser mean. In the Explanatory Report the following explanation is given: This means, for example, that a minor may participate in research on a condition from which he or she suffers even if the minor would not benefit by the results of the research, provided that the research might be of benefit to other children suffering from the same condition. In the case of healthy minors undergoing research it is obvious that the result of the research might be of benefit only to other children; however such research may well be of ultimate benefit to healthy children taking part in this research. While this article allows research 61 62

All citations from Article 15 (2) (i) of the Additional Protocol. See Section 9.5 for an account of these two norms.

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on minors for the benefit of other minors, it would be ethically inappropriate to undertake research on minors who may also be vulnerable for other reasons, if the research could be conducted on those without such additional vulnerabilities.63

The explanatory report then offers some guiding examples: The research on “the individual’s condition” might include, with regard to research on children, not only diseases or abnormalities peculiar to childhood or certain aspects of common diseases that are specific to childhood, but also the normal development of the child where knowledge is necessary for the understanding of these diseases or abnormalities.64

The Lactic Acid Study where 20 boys and girls between 10 and 12 years of age were going to run to exhaustion on a treadmill to measure their maximum oxygen uptake is illustrative. The Research Ethics Committee was sceptical about the nontherapeutic benefits of the project. Even if the risks were minimal, there had to be good scientific and medical reasons for undertaking the project. Moreover, the new knowledge should not be of only general use, it would have to be of particular interest for children. The Committee also questioned the aim of the study, which was to develop methods for maximal effective training among children. The Committee asked whether there was a need for such knowledge. The project was postponed, and later disapproved because of a negative statement by an independent expert.

12.4.3 Conclusions The precondition of significant potential benefits to others, applicable to interventional nontherapeutic research on vulnerable persons, establishes an absolute lower limit – a minimum standard: no matter how harmless, the potential benefits to others (future patients) have to be “significant” or “essential”, and they must be reasonably related to the burdened risk-carrier (the participant). Moreover, the stronger the link between the burdened and the beneficiaries, the better. In effect, only the most competent and careful researchers should be allowed to conduct or supervise interventional research on the most vulnerable amongst us, because only those may be expected to make a “significant” contribution to our common base of knowledge. This may imply fewer research projects on vulnerable persons, but not necessarily less knowledge about vulnerable people’s health and treatments.

12.5 The Precondition of Only Minimal Risks and Burdens to the Participant 12.5.1 General The second precondition applicable to nontherapeutic research on persons not able to consent to research and similarly vulnerable, is that such research can entail “only 63 64

Paragraph 89. Paragraph 90.

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minimal risk and minimal burden for the individual concerned”.65 The precondition is also recognised in US law.66 In contrast to the first precondition, it has been frequently discussed in literature.67 As shown in Chapter 11, the threshold of minimal risk and minimal burden is obviously higher than the threshold of “acceptable risk and acceptable burden” entailed in the first sentence in Article 6 (2) of the Additional Protocol. The Explanatory Report to Article 15 (2) (ii) of the Additional Protocol (which Article 6 (2) points to) states that while . . . Article 6 restricts research in general by establishing a criterion of risk/benefit proportionality, this article lays down a more stringent requirement for research without direct benefit to persons incapable of giving consent, namely only minimal risk and minimal burden for the individual concerned.68

An assessment of proportionality is still required, but the latitude is significantly restricted, as not only must the potential benefits to others be significant, the risks and burdens to the participants may only be minimal, no matter the greatness of the potential benefits to others. Thus, the precondition of “only minimal risks and burdens” indicates a high threshold and a strict minimum standard.

12.5.2 The Definition of Minimal Risk in the Additional Protocol The meaning of “minimal risk” is sought clarified in Article 17 (1) of the Additional Protocol: For the purposes of this Protocol it is deemed that the research bears a minimal risk if, having regard to the nature and scale of the intervention, it is to be expected that it will result, at the most, in a very slight and temporary negative impact on the health of the person concerned. [Italics added]

The definition clearly reflects the intended strictness towards nontherapeutic interventional research on vulnerable persons.69 However, the definition of minimal risks is problematic. Firstly, the definition coincides poorly with the definition of risk as the product of the magnitude of harm and the probability of the harm to occur, as the definition uses the wording “to be expected”70 : Interventional research is always associated with risks of harm, even severe complications. Usually these risks are

65

Article 15 (2) (ii) of the Additional Protocol. See US Federal law 45CFR46 Subpart B, C, and D. 67 See, for example, Nicholson (1986); Lötjönen (2002); Wendler (2005); Ross (2006); Westra et al. (2009). 68 Paragraph 91. 69 See the Explanatory Report to Article 15 (2) Paragraph 87, cited above. 70 See Section 3.2 on the definition of “risk”. 66

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remote; the harm is certainly not expected in the ordinary meaning of the word.71 On the contrary, it is the unexpected, but yet inevitable, risk (chance) of harm which the requirement of proportionality may render legitimate, not expected harm detrimental to participants’ health, whether it is temporary or not, typically the chance of severe infections or mishaps. If temporary or enduring harm is expected it is more natural to talk about a “burden” that prospective participants are asked to accept and shoulder, typically the pain (even nausea) and the “loss” of blood from doing a blood sample.72 See phase III of the Meningococcal B Vaccine Trial as for an illustrative example.73 The wording “is to be expected that it will result” therefore has more in common with a plausible definition of burdens (an expected negative consequence).74 Another problem with the wording of the definition is that by referring to “only very slight and temporary negative impact” [italics added] the provision appears to suggest that if there is even a very remote or a theoretical chance of severe complications or enduring harm, the risks cannot be seen as minimal. Such an interpretation is difficult to sustain, as any participation in interventional research is associated with, at least, a theoretical possibility of severe complications and enduring harm. For example, a woman successfully sued a university for damages after giving a blood sample in a large population health survey carried out under the auspices of researchers at a Norwegian university. The case was settled out of court.75 The intervention, nevertheless, surely entailed only minimal risks (even in hindsight). The Explanatory Report to Article 15 (2) does, for example, state that “taking a single blood sample from a child would generally only present a minimal risk, and might therefore be regarded as acceptable”.76 Another example: School children’s balancing was tested as part of a biomedical research project. The project required the children to balance on an approximately 20 cm. high and 15 cm. wide wooden bench commonly used for this purpose (improving balance) in ordinary gymnastics at school. The intervention must have appeared harmless and entailing only minimal risks. Unfortunately, a child slipped and his jawbone was crushed when it hit the bench. The risk was thus similar to risks normally encountered in healthy children’s daily life, and it was probably below minimal risks, although the harm was surely not just “a very slight and temporary negative impact”.77 Hence, according to the definition in Article 17 (1) the risk could not have been classified as minimal, and according to Article 15 (2) (ii) the research should not 71

In the Oxford dictionary (1989) “expect” is explained by “If you expect something to happen, you believe that it will happen.” p. 421. 72 See the definition of “burden” in Section 3.3 and the discussion of the relationship to risks in Section 3.4. 73 Accounted for in Section 11.4.5. 74 See Section 3.3 on the definition of “burden”. 75 Personal communication with the plaintiff’s lawyer June 2007. 76 Paragraph 96. 77 Personal communication with REC Middle Norway June 2007.

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have been carried out. Such a conclusion is clearly too strict. Its implication would render most, if not all, interventional nontherapeutic research on children and similarly vulnerable persons unlawful, and that is obviously not the intention of the Additional Protocol.78 The definition of minimal risk in Article 17 (1) can therefore not be taken literally. Clearly, both a very low magnitude (including durability) and a very low likelihood may render a risk minimal. “Minimal risk” is further, and more successfully, elaborated and concretised in the Explanatory Report to Article 17 (1), which is investigated in Section 12.5.5.

12.5.3 The Definition of Minimal Burden in the Additional Protocol The definition of minimal burden in Article 17 (2) of the Additional Protocol is less problematic as it is more in harmony with the definition of “burden”: It is deemed that it bears a minimal burden if it is to be expected that the discomfort will be, at the most, temporary and very slight for the person concerned. In assessing the burden for an individual, a person enjoying the special confidence of the person concerned shall assess the burden where appropriate.

In contrast to the definition of minimal risk, the definition of minimal burden is in better harmony with the common understanding of the concept of “burden” (and “inconvenience”). The burden of research participation must be “temporary” and “very slight” to be characterised as minimal. While temporary is rather intuitively understandable, very slight is not. A more concrete approach is needed, see Section 12.5.5.

12.5.4 Single Standard or Multiple Standards of Minimal Risks and Burdens A principally important question is whether the standard of minimal risks and burdens should be regarded as a single standard or subject to various standards dependent on the situation and who the research participants are. Is a minimal risk a minimal risk regardless of the circumstances? It could be argued that there should be one standard for every group identified in the Additional Protocol. In this way there would be one minimal risk standard for children, one for pregnant women, one for prisoners, one for adult persons not able to consent, and one for persons in an emergency clinical situation. One could further argue rather convincingly that there should be separate standards for neonates, infants, toddlers, adolescents, pregnant prisoners, male prisoners, old prisoners, prisoners not able to consent to research prisoners and so on. The same would then 78

See Preamble and paragraph 87 and 92 of the Explanatory Report.

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apply to minimal burden. The establishment of an, in theory, endless list of standards is, however, neither feasible nor legally sustainable. Firstly the common definition of minimal risks in Article 17 (1) of the Additional Protocol, strongly suggests that there is one common standard of minimal risk, which all the other specific provisions refer to. Thus, the provisions read in context, suggests a single common standard of minimal risks. A single standard approach does not necessarily mean that individual or contextual factors are irrelevant in the determination of whether the risks and burdens are acceptable or not. On the contrary, as made clear in Article 17 (1) of the Additional Protocol one must consider “the nature and scale of the intervention”. Article 17 (2) uses the formulation “for the person concerned” to express the same in relation to the standard of minimal burden. Qualitative factors are always relevant in the overall assessment of proportionality, for example, the obtainment of a single blood sample may entail risks above minimal if the child is a bleeder (haemophiliac). But in the definition of minimal risk it is not just undesirable to have separate standards; it is also not feasible because differences between the standards would be so marginal that they in practice would be lost.79

12.5.5 Concretisation of Minimal Risk and Minimal Burden In paragraph 99 of the Explanatory Report to Article 17 of the Additional Protocol some concrete examples of “research with minimal risk and minimal burden” are given. Notably the Explanatory Report does not discern between examples of “minimal risk” and “minimal burden”, which is unproblematic and just illustrates the point made earlier; that the terms are closely related and that the “correct” labelling is largely unimportant in practice. The examples given are: – obtaining bodily fluids without invasive intervention, e.g. taking saliva or urine samples or cheek swab, – at the time when tissues samples are being taken, for example during a surgical operation, taking small additional tissue samples, – taking a blood sample from a peripheral vein or taking a sample of capillary blood, – minor extensions to non-invasive diagnostic measures using technical equipment, such as sonographic examinations, taking an electrocardiogram following rest, one X-ray exposure, carrying out one computer tomographic exposure or one exposure using magnetic resonance imaging without a contrast medium. [italics added]

The concrete examples contribute to the ascertainment of the standard of minimal risk and burden by establishing palpable and familiar benchmarks. X-ray exposure is, for example, a familiar procedure for most people. And ordinary people probably 79

Wendler (2005), reaches the same conclusion; In a publication four years later David Wendler (2009b) leaves his original position and argues for a double standard for children, in so far that he argued that there should be one standard for children below 14 years of age, and one for those above. Again, the argumentation is convincing, but the result is not practically or sustainable.

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consider the risk of X-ray to be very remote and, even, negligible. Yet, only two extra X-rays are above minimal risk, according to the Explanatory report. It is also telling that one exposure to magnetic resonance imaging (MR) with a contrast medium is above minimal risk. In 2007 one fatality and two serious complications from the use of a widely used contrast medium were reported to the Medicinal Agency in Norway.80 All three injured had kidney problems, which was a likely mitigating factor. The cases were made public because of a publication in a Danish newspaper that 60 similarly serious complications had been reported in Denmark.81 In a scientific review publication in CMAJ, Ilan Goldenberg and Shlomi Matetzky, reported that: The rate of contrast-medium nephropathy [damage to the kidney caused by the administration of a contrast-medium] reported in studies that included patients with pre-existing renal dysfunction [kidney failure] or diabetes mellitus [ordinary diabetes] in whom a standard hydration protocol was not administered is between 12 and 26%. Lower rates (3.3%) have been reported among patients without these risk factors. Experimental studies suggest that contrast-medium nephropathy results from a combination of renal ischemia and direct toxic effects on renal tubular cells.82

Such a risk is thus as a starting point above minimal risk. This further illustrates the point made above, that standard interventions carried out routinely in ordinary clinical practice, and therefore often seen as attached with a negligible or minimal risk or burden in clinical practice, may represent a risk or burden that is above minimal in the context of non-therapeutic research. Comparing a research risk with a therapeutic risk can therefore be seductive and greatly misleading. The attempted concretisations in the Explanatory Report coincide with, and are therefore substantiated by, a similar attempt in Annex 4 (Table 12.1) to the Community Guidelines on Paediatric Clinical Trials of 2008, which includes the following introduction: The following table provides examples of risk evaluation of measures carried out for the purpose of a trial. This evaluation is not fixed because the circumstances of child influence evaluation of risks. For example, an existing central venous line may reduce the pain and invasiveness of blood sampling, but also increases the risk of infection and of excess blood losses with line handling. The risk evaluation of some of the measures (including, but not limited to those marked∗ ) is very much dependent on such circumstances and on the context of its use in the trial. In addition, the risk level increases with the increase in frequency of the measures and with the susceptibility to harm of involved/exposed organs. The categorisation proposed in the table applies to single or very infrequent use of the measure. The examples presuppose that the measures are carried out to the highest professional standards

The apparent coincidences suggest that the understanding and concretisation of the minimal risk standard is widely acknowledged. The examples do also appear to coincide with the understanding of the minimal risk standard in the US.83 80

VG 22. February 2008. Extra Bladet 21 February 2008. 82 Goldenberg and Matetzky (2005). 83 See Field and Behrman (2004). 81

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Table 12.1 Concretisation of the minimal risk standard in the EU Paediatric Guidelines of 2008 No or minimal risk   

History taking Clinical examination Auxological measurements  Tanner staging  Behavioural testing  Psychological testing∗  Quality of Life assessment  Venipuncture∗  Heel prick∗  Finger prick∗  Subcutaneous injection  Urine collection with bag∗  Breath condensate collection  Collection of saliva or sputum  Collection of hair sample  Collection of tissue removed from body as part of medical treatment∗  Topical analgesia∗  Stool tests  Bio-impedancemetry  Transcutaneous oxygen saturation monitoring (pulse oxymetry)∗  Blood pressure monitoring  Electroencephalography  Electrocardiography  Vision or hearing testing  Ophthalmoscopy  Tympanometry Lung function tests (peak flow, exhaled NO, spirometry)  Oral glucose tolerance test

Minor increase over minimal risk

Greater than minor increase over minimal risk



     

Urine collection via endoluminal or suprapubic catheter  Arterial puncture  Umbilical catheter  pH metry  Nasogastric tube insertion and use  Transcutaneous oxygen or carbondioxide tension monitoring  Electrophysiological measurements (using stimulation)  Exercise testing (ergometry, spiroergometry)  Raised volume pulmonary function testing (infants)  Peripheral venous lines  Polysomnography  Fasting (≥ 1 meal)  Spinal CSF tap  Bone marrow aspiration  MRI scan  X-ray other than digitally amplified chest or limb X-ray  CT scan∗  X-ray DEXA bone density measurement  Use of contrast media  Paracentesis  Skin punch biopsy  Airways or skin hyper-reactivity challenge test

Heart catheterisation Endoscopy Biopsy Surgery or modification of standard surgical procedure carried out as part of medical treatment  Sedation Anaesthesia  Systemic analgesia  Hypoglycaemia test  Unstable isotope usage  PET scanning

Notwithstanding this, the minimal risk standard is difficult to apply in practice. A research study was set up to determine how 118 randomly selected chairpersons in research ethics committees [IRBs] in the US would apply the US Federal minimal risk standard in paediatric research84 :

84

Shah et al. (2004).

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A single blood draw was the only procedure categorized as minimal risk by a majority (152 or 81%) of the 188 respondents. An electromyogram was categorized as minimal or a minor increase over minimal risk by 100 (53%) and as more than a minor increase over minimal risk by 77 (41%). Allergy skin testing was categorized as minimal risk by 43 IRB chairpersons (23%), a minor increase over minimal risk by 81 (43%), and more than a minor increase over minimal risk by 51 (27%). Regarding benefits, 113 chairpersons (60%) considered added psychological counseling to be a direct benefit, while participant payment was considered a direct benefit by 10% (n = 19).

This led the researchers to conclude that the application of the US Federal standards for paediatric research by IRB chairpersons is: variable and sometimes contradicted by the available data on risks and the regulations themselves. To protect children from excessive risks while allowing appropriate research, IRB chairpersons need guidance on applying the Federal risk and benefit categories and also need data on the risks children face in daily life and during routine physical or psychological tests.85

Nevertheless, the results sustain that the risks and burdens associated with a venepuncture are widely recognised as acceptable in the US, as they are in Europe, even in nontherapeutic research on vulnerable persons. The results further suggest that the risk of electromyography (EMG) appears to be associated with risks and burdens slightly above minimal. An EMG involves sticking needle(s) into the muscle for the measurement of electric activity in the muscle. The measurement can “detect abnormal electrical activity of muscle that can occur in many diseases and conditions, including muscular dystrophy, inflammation of muscles, pinched nerves, peripheral nerve damage (damage to nerves in the arms and legs), amyotrophic lateral sclerosis (ALS), myasthenia gravis, disc herniation, and others.”86 EMG is usually associated with some pain and muscle soreness (temporary discomforts). The risks probably relate to the risk of infections and mishaps. For relatively invulnerable persons able to consent, this degree of risks and discomfort should be relatively unproblematic and thus usually acceptable. But for children and adult persons not able to consent, that is not necessarily the case.

12.5.6 The Necessity of an Individual and Concrete Assessment of Minimal Risks and Burdens Both the Explanatory Report and the Guidelines underscores that the examples provided are mere examples. The Explanatory report states in this regard that for certain participants, “even these procedures might entail risk or burden which cannot be considered minimal. Assessment on an individual basis must therefore be carried out”87 [italics added]. 85

Shah et al. (2004). Shiel (2009). 87 Paragraph 100 of the Explanatory Report. 86

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Furthermore, it is stated that “the nature and scale of the intervention” must be born in mind.88 Risks and burdens attended with the exemplified procedures, can, because of the nature and scale of the intervention, or because of individual circumstances, be above or below, the threshold of minimal risks and burdens.89 The risk associated with obtaining a blood sample from a peripheral vein (ordinary venepuncture in the arm) varies. At MedlinePlus, a web-based information service by the US Federal government, it is underscored that: veins and arteries vary in size from one patient to another and from one side of the body to the other. Obtaining a blood sample from some people may be more difficult than from others. Other risks associated with having blood drawn are slight but may include: Excessive bleeding; Fainting or feeling light-headed; Hematoma (blood accumulating under the skin); Infection (a slight risk any time the skin is broken).90

This means that the minimal risk standard cannot be misused to expose infants or other particularly vulnerable (unfortunate) individuals to excessive and disproportionate risks and burdens. For example, the collection of additional tissue during standard surgery may entail only minimal risk for some individuals (e.g. otherwise healthy and strong persons), but not necessarily for others (e.g. critically ill and impaired persons).91 In those circumstances it is not the threshold (or standard) of minimal risks and burdens that changes, it is the concrete degree of risks and burdens. The exemplifying procedures might thus occasionally entail more than minimal risks and burdens. For example, many trivial research procedures can be unacceptable in clinical emergency situations, because even the slightest delay or additional burden can be fatal for the impaired patient. The risks and burdens can, on the other hand, be minimal even though the procedure(s) in a strict perspective are attended with risks and burdens that surpass the examples given. For example, the obtainment of several blood samples and distribution of several questionnaires can be necessary in a long lasting prospective study. Added together, the risks and burdens surpass a very strict understanding of minimal risk. If the interventions are spread out over a reasonable period of time, the risks and burdens may still be regarded minimal, see the MIDIA Study92 where the National Ethics Committee did not question the obtainment of 18 blood samples per child over a period of 15 years. Other agency did, however, question the extensiveness of the testing.93 The demand for an individual approach further implies that a procedure may entail minimal risks for an adolescent, but not for an infant or an impaired adolescent. If, for example, a certain intervention carries the risk of fatal harm of 1 in 88

Paragraph 97 of the Explanatory Report. See Section 12.5.6 below on research in clinical emergency situations where even these procedures occasionally will be above minimal risk because of the nature and context. 90 Lentnek (2007). 91 Explanatory Report to Article 17 of the Additional Protocol, Paragraph 99. 92 Accounted for in Section 12.5.8. 93 This position is also taken by an American committee of scholars, see Field and Behrman (2004, p. 123). 89

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500 000 for healthy adolescents, but more than 1 in 10 000 for impaired adolescents, the intervention may entail minimal risk for the healthy, but surely not for the impaired. The cardinal question is whether this particular intervention, in this context, at this time, represents risks and burdens to this particular individual, which, all things considered, must be said to be above minimal or not. This means that the researcher has to take the participant as he or she is. The latter is a central maxim in Norwegian Tort law,94 but is applicable also in this context. The maxim implies that the researcher must also take into consideration that some individuals might, because of physical or psychological predispositions, be particularly vulnerable. Consequently, the standard of minimal risk and burden is absolute, but whether a research intervention entails risks and burdens above or below that standard is relative. In effect, interventional research with additional risks and burdens (not outweighed by prospects of direct benefits) will hardly ever be justifiable in an emergency clinical situation. The only way to justify such research is then to ensure that the research also entails prospects of direct benefits to the participants, for example by more rigorous and extensive preparations; more and better retrospective or observational studies, laboratory studies, animal testing, and so on, which could significantly increase the predictions on whether standard treatment should be altered.

12.5.7 Quantifying the Standard of Minimal Risks and Burdens The examples given in the Guidelines and the Explanatory Report are not accompanied with empirical data or attempted quantifications. It is thus difficult to assure the quality of the examples’ in relation to accuracy, consistency, justness etc. Moreover, the necessity of an individual and concrete assessment of minimal risks and burdens signifies that one procedure may entail minimal risks for some, but considerable risks for others. It is therefore of interest to try to quantify the standard of minimal risks and burdens, as attempted in relation to the additional precondition of “acceptable” risks and burdens for relatively invulnerable persons in Section 11.4.4 (see Article 6 (2), first sentence of the Additional Protocol). Several have attempted to quantify minimal risks in relation to biomedical research. An interdisciplinary working group on the ethics of paediatric research based in the United Kingdom undertook an ambitious attempt in 1986. Richard H. Nicholson (editor) led the group (hereinafter called the Nicholson working group).95 (Interestingly, this also suggests that the minimal risk standard was well established in Europe long before the adoption of the Oviedo Convention in 1997). The Nicholson working group used vaccination programs as a benchmark, since “the aim of immunization is to protect against a potential illness, rather than to treat 94 95

See Kjelland (2008). Nicholson (1986, chapter 5 , pp. 76–125).

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an actual illness, and is therefore rather closer to medical research in risk/benefit implication than most of medical practice”. They found that smallpox vaccination in UK between 1951 and 1970, which had “risks of 5 per million for death [1 in 200 000], and 37 per million [3.7 in 100 000] for severe complications”, were accepted in the general population, even when smallpox had become an extremely rare disease in the UK. They also found that an overall fatality risk of 1 in a million for the eight most common immunizations was accepted. The risk of permanent brain damage from whooping-cough immunisation was at a time (in the 1970s) assumed to be 4 in 100 000. This led to a halving of the number of parents that wanted the vaccine for their children, which suggests that the incident rate was too high for many. However, in reality the rate was probably closer to 1 per 100 000, and on this basis the Nicholson working group stated that “it is tempting to suggest that a risk of 10 per million [1 in 100 000] of morbidity is therefore ignored by about one-half of parents, but there are many other influences.” The example may on the other hand just as much be seen as indicating that a fatality rate of 1 in 100 000 for children was regarded unacceptable by half the parents, even though the participants had prospects of, at least some, direct benefits, namely immunisation, which again suggests that the risk of nontherapeutic research should be lower to be minimal and acceptable. The Nicholson working group also referred to the so-called “Swine Flu Affair” which occurred in the US in 1976: A virus similar to the virus that had caused the Spanish flu pandemic in 1918–1919 killed an army recruit in 1976. A massive immunization programme was undertaken. After 45 million doses had been given it was recognised that there was an approximate risk of 1 in 100 000 for the GuillainBarré syndrome (a severe disabling condition). This led President Jimmy Carter to suspend the vaccination program. This suggests that a fatality rate of 1 in 100 000 was in the 1980s commonly regarded unacceptable even in an adult population, and even though the participants had prospects of, at least some, direct benefits, namely immunisation. The Nicholson working group then concluded: The evidence of these medical examples suggests that in medical practice a risk of death of one per million is indeed neglected by both doctors and the general public. Risks of the order of 10 per million [1 in 100 000], however, whether death or of severe non-fatal consequences, are not in general ignored by non-medical people although they may be neglected by doctors, it appears that the borderline of negligibility for doctors probably lies at about 50 per million [5 in 100 000] although larger risks are effectively ignored when the patient’s condition already puts him at a high risk of death.

The Nicholson working group’s suggestions are comparable to expressions on acceptable risk in phase III of the Meningococcal B Vaccine Trial,96 where a risk of severe and enduring complications (e.g. Guillain-Barré syndrome) of 1–4 in 100 000 adolescents was regarded unacceptable by at least one expert in the monitor group. The same expert expressed that a fatality rate of 1 in a million was generally regarded as a neglectable and theoretical risk that usually may be disregarded. In

96

Accounted for in Section 11.4.5.

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that case it was furthermore stated by the health authorities that a fatality rate of 1 in 10 000 was surely totally unacceptable in a research setting involving adolescents. It should be noted that the Vaccine trial was regarded as a nontherapeutic trial, even though the intervention group had reasonable prospects of immunisation. In the US David Wendler and colleagues attempted to quantify minimal risk by references to the empirical data on the risks of daily life of children, relating to car rides and various sporting activities.97 I do, however, concur with another leading US scholar, the paediatrician Lainie Friedman Ross, who asserted in a comment to Wendler’s paper that: The minimal risk standard is both a statistical and a normative concept and cannot be reduced to the simplistic claim that because children experience certain risks in daily life, we should be able to expose these children to a similar level of risk within research. The empirical data could permit much greater risk than would be appropriate.98

At any rate, quantification may be a useful tool in the ascertainment of minimal risks. Moreover, it is reasonable to assert that for a risk to be regarded as minimal, a majority of prospective participants should be ready to accept it. Because of the likelihood of therapeutic misconception, conflicting interests, and so on; research participation must appear to be a reasonable choice for prospective participants. The thresholds are set to protect the individual, and prospective participants’ (and their legal representatives’) individual perceptions of risk must prevail over researcher physicians and other experts’ opinions.99 As already noted, generally people tend to regard the risk of dreaded and catastrophic effects as higher and weightier, than “experts” do.100 If so, the examples above which refer to interventions on children, suggests that a risk of fatal harm around 1 in 100 000 is above the minimal risk. Today’s prospective participants (and parents) are probably more risk avert than in the 1970s. Thus, maybe the risk of fatal harm should be around 1 in 500 000 to be regarded minimal, and, at least, less than 1 in a million to be regarded as neglectable (and then largely irrelevant because of the remoteness of damage101 ). 1 in 500 000 is indeed a very remote chance of fatal harm. Nevertheless, such a remote risk appears to be more or less compatible with the definition given in Article 17 (1) if the Additional Protocol as “at the most, . . . a very slight and temporary negative impact on the health of the person concerned”, which refers to the risk of minor harm. Consequently, the minimal risk standard is a very strict standard, which it is indented to be. The Nicholson Working Group provided a table with numbers as a guiding tool in the assessment of minimal risk, Table 12.2. The numbers provided in Table 12.2 appear to be (grossly) inaccurate considering the “very strict” standard the minimal risk standard in current legal framework 97

Wendler (2005). Ross (2006). 99 Cf. Section 8.3. 100 Slovic (2000). 101 See Section 7.3. 98

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Table 12.2 The Nicholson Working Group’s quantification of the “ethical” minimal risk standard in Europe in 1986 British definition

Negligible

Minimal

More than minimal

Risk of death Less than 1 per million 1 to 100 per million Greater than 100 per million Risk of major Less than 10 per 10 to 1 000 per million Greater than 1 000 per complication million million Risk of minor Less than 1 per 1 to 100 per thousand Greater than 100 per complication thousand thousand

in Europe. It is simply highly unlikely that most parents would consider a risk to their child remotely close to 1 in 10 000 for death, 1 in 1 000 for major complication, and 1 in 10 for minor complication, to be a “minimal risk” that they would consent to being carried by their child for the sake of other children. Psychometric studies clearly suggest that ordinary people shy away from even very remote risk of catastrophic harm unless the risk is carried in their own person self-interest, as illustrated by individuals’ aversion against living next to a nuclear power station which may explode.102 Based on the discussion above, the case examples, and the examples provided in the Explanatory Report, the numbers suggested in Table 12.3 are perhaps more accurate. More empirical data are needed. These numbers can, at any rate, only be used as a guiding point in an overall judgment. They may be too rigid or too liberal. Nevertheless, they may serve as a starting point in further discussions. It is far more difficult to quantify the standard of minimal burdens than the standard of minimal risks. The standard of minimal burdens is thus, as illustrated by the Body Sensor Study, even more dependent on the nature and context of the research, and, not least, individual circumstances.

Table 12.3 My attempt to quantify the current minimal risk standard in Europe Negligible Risk of death Risk of major complication Risk of minor complication

102

Minimal

More than minimal

Less than 1 in a million 1 in 500 000 Greater than 1 to 5 in 500 000 Less than 1 in 500 000 1 to 10 per 100 000 Greater than 1 in 10 000 Less than 1 in 10 000

1 to 50 per 10 000

Greater than 1 in 100 per

Slovic (2000); the risk of dying in any one year from the release of radiation from nearby nuclear power station is approximately 1 in 10 000 000 (BMJ Living with risk (1987, p. 23)).

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12.5.8 Applying the Standard of Minimal Risk and Burden – A Case Example The examples provided in the Explanatory Report suggest that “minimal risks and burdens” is a very strict threshold as intended.103 This may be difficult to accept for researchers and future patients who are seeking new knowledge about health. Still the law is unequivocal. The plausible rationale behind the threshold of minimal risk and burden appears to be a fear of liberal interpretation and the development of a slippery slope. It is therefore difficult to argue for a liberal interpretation. Consequently, the threshold appears absolute: No matter how great the potential benefits to others are, the risks and burdens to the vulnerable participant must be minimal. The precondition is also independent of the degree of potential benefits. The latter point is underscored in the provision itself when it states that “any consideration of additional potential benefits of the research shall not be used to justify an increased level of risk or burden.”104 In the Explanatory Report it is underscored that “[t]o act otherwise would be to exploit these persons contrary to their dignity. . . . The risk for such participants [persons not able to consent to research] cannot be increased beyond minimal even if the research promises a higher level of benefit [to others].” These statements are also supported by the overarching principle of human primacy recognised in both Convention law and Community law.105 The implication of this strict threshold is then that even sound and good research as well as the possibility of great societal benefits must give way for the interest of the individual persons not able to consent to research and thus vulnerable participant. An example is the MIDIA Study. A similar research project has taken place in Sweden, Finland, Germany and the USA (the multinational TEDDY-study).106 The MIDIA Study:107 Background: Type 1 diabetes is a serious condition that affects many people. Little is known about the causes of the disease. 2.2% (1 in 50 persons) have the “diabetes gene”. These persons are at high risk of getting diabetes type I during their life (1 in 5 with the diabetesgene gets diabetes I sooner or later). Study aim: To gain knowledge about the environmental causes (triggers) of type 1 diabetes, and in particular why some persons with the diabetes-gene get diabetes, while others don’t. Method: A prospective cohort-study initiated by the Norwegian Institute of Public Health in 2001. Parents were asked to consent to the collection of a buccal cell sample with a small brush from their infant’s mouth. This sample would then show if the child carried the 103

See Paragraph 87 of the Explanatory Report. This specification occurs only in Article 15 (2) (ii) of the Additional Protocol, but it is also implied in Article 17 (2) (ii) of the Oviedo Convention. 105 Article 3 of the Additional Protocol and Article 2 (1) of the GCP Directive. See Section 5.2.5 on the principle of human primacy. 106 The TEDDY-study. 107 My account is primarily based on the statement of The Norwegian National Committee for Medical Research Ethics (2007). 104

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diabetes genes. 100 000 infants were going to be included. 2 000 children with the diabetes gene were then going to be followed from birth until 15 years of age. Consequently, the researchers wanted to collect fecal samples from each child every month in the first year of life to identify viral antigens. The researchers also wanted to collect other environmental variables, in particular nutritional data. The project was associated with (a sub-part) the Norwegian mother and child cohort study, which would give access to other variables from pregnancy, including blood samples.108 REC-evaluation: The project was approved by REC in 2001. The researchers gave information about risks and burdens, but REC did not comment on it in its written decision. The Norwegian Data Inspectorate also approved the project. Subsequent events: Parents were informed about the results. Some parents reacted very negative when they learned that their child carried the diabetes genes. Half way through the study, in 2007, these concerns were brought forward. This led to a re-review of the project’s legality and ethicality by several independent public agencies. The Norwegian National Committee for Medical Research Ethics’s review: Of particular interest is the “ethical” review by the Norwegian National Committee for Medical Research Ethics, because the Committee specifically addressed the assessment of proportionality. It also applied the Additional Protocol – but only as “guidance”. In its written judgement the Committee first discussed whether the research entailed prospects of direct benefits.109 The researchers had claimed that parents who were made aware that their child had an increased risk of diabetes could avoid a dramatic debut of the illness by earlier detection, so that the children could be provided with lower doses of insulin in the initial treatment, than if the illness was detected at a later stage. The Committee did, however, assess this “benefit” as too slight and remote to be regarded as a direct benefit to the participants.110 At any rate, it applied only to children who actually developed diabetes (1 in 5 of those who had the diabetes-gene). The Committee did, on the other hand, recognise that the project entailed great potential benefits to science and society, as the occurrence of diabetes is a serious and increasing health problem, nationally and internationally. The Committee thus implicitly found that the precondition of significant potential benefits to others was fulfilled. The question for the Committee was then whether the potential benefits justified the risks and burdens involved. The Committee did not mention the physical risk of harm associated with the obtainment of repeated blood samples (totalling 18 samples). It appears that this risk, in the implicit opinion of the Committee, could be neglected. The same goes for the physical burden of providing the researchers with repeated diaper (stool) tests (totalling 36). The crucial element for the Committee was the psychological burden (or harm) for the parents in receiving information that their child had an increased risk of developing a serious disease that could not be prevented, and for which there was no treatment. The principal investigator had reported to the Committee that ten parents (1 pair of parents in 5 000) had reported serious negative reactions. 1% (1 in 100) of the parents considered the risk of diabetes daily. This had led the researchers to conclude that the given risk information was unproblematic “for most parents”. The Committee found that the burden of knowing was acceptable, provided that the parents had been given adequate information. The Committee noted, however, that the current information was not adequate. The Committee then moved on to discuss the burden shouldered by the child associated with receiving and living with risk information when it became older. The Committee noted

108

The Norwegian Institute of Public Health (2008b). www.fhi.no (accessed 20.06.11). The Norwegian National Committee for Medical Research Ethics (2007). Statement of 10 October 2007 at www.etikkom.no (accessed 20.06.11). 110 See Section 3.6 on the concept of “direct benefit”. 109

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that this issue appeared to have been largely overlooked by the researchers. In the opinion of the Committee, children in the follow-up group would sooner or later find out that they had the diabetes-gene, and that they had a life long high risk of developing diabetes. The Committee then referred to the Additional Protocol Article 15 (2) (ii) and the precondition of “minimal burden” as well as the definition of minimal burden in Article 17 (2); “at the most, temporary and very slight” discomforts. It noted that little is known about the burden of living with the knowledge of having an increased risk of developing a serious disease. Nevertheless, two studies indicate that the burdens of knowing are greater than the benefits. The Committee was divided in its conclusions. A slim majority concluded that the psychological burdens were far from “minimal” and “temporary” as required by the Additional Protocol. The project could therefore not proceed even if the study design and the information to the parents were improved. The majority stated that society should refrain from obtaining such knowledge when it involved burdens of that magnitude. The minority put more emphasis on the societal benefits and concluded that, with an improved design and information, the societal benefits justified the burdens. The Committee, as a whole, also noted that the best would be to recommend a design that implied not informing the parents or the children, but recognised that such a design would not be lawful because of the participants’ right to know. The Norwegian Biotechnology Advisory Board’s review: The Board identified a number of relevant arguments, and argued that the risk of stigmatisation and sickening of a healthy child was considerable, and probably above ethically acceptable standards. The Board also found that the project had not been approved according to the Biotechnology Act of 2003 § 5–3, cf. § 7–1, and that it probably did not fulfil the conditions for predictive genetic testing of children without reasonable prospects of real and direct health benefits. The majority of the Board advised against further inclusion of children.111 The Norwegian Ethical Committee for Physicians review: The Physicians Committee considered the same arguments as the two foregoing agencies. In addition, the Physicians Committee underscored the frequent taking of blood samples during many years and at an age where many children are afraid of needle sticks. There was thus a considerable risk of anxiety for both needle sticks and outbreak of illness. The Committee questioned whether the research was detrimental to the children’s health, and thus in breach of the fundamental “do no harm” rule.112 The Norwegian Directorate of Health: The Directorate, which is a governmental agency, had been asked to approve the continuation of the research project, since the Directorate had not approved it earlier. The researchers, mistakenly, did not know that the project involved predictive genetic testing which had to be approved under the biotechnology act of 2003. The Directorate relied on the foregoing reviews, but grabbled with the law, as it operated with an ill-founded distinction between research ethics (international guidelines) and the law. Nevertheless, the Directorate also sought advises from four independent paediatrics. Three of the experts agreed on the great potential benefits of the project for science and future patients. They also acknowledged that the participants did not have prospects of real and enduring direct benefits. The children were not sufficiently cared for in the project, in so far that participation was associated with considerable burdens (anxiety, stigma etc). One expert, with particular expertise on diabetes, held that participants had prospects of direct benefits, as outbreak of the disease could be detected under less dramatic circumstances and that the families would also have access to improved information. The Directorat’s own reference group held that the prospects of direct benefits were marginal, and advised against further inclusions. Based on an overall evaluation of the project and arguments produced by various agencies, internal and external experts etc., the Directorate concluded that the 111 112

The Norwegian Biotechnology Advisory Board. Statement of 13 September 2007. The Norwegian Ethical Committee for Physicians (2007). Statement of 30 October 2007.

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project did not fulfil the conditions in the Biotechnology Act of 2003 § 5–7, cf. § 7–1 and § 5–3, and that it therefore could not be approved for further research.113 Subsequent developments: The researchers wanted to continue the research on the already obtained material. The Directorate of Health disapproved the request because the material had been obtained illegally. A complaint was brought before the Ministry of Health, which concluded that research on the obtained material was acceptable, if a new approval from REC and the Data Inspectorate were given. The reasons were that the material was of great scientific and societal value, and that most of those who had participated probably expected that their contribution would not be in vain. That both REC and the Data Inspectorate had approved the project also weighed in. The Ministry held that new and further genetic testing was not acceptable.114 The Norwegian Parliament was orientated about the decision.

The case illustrates the recurring dilemma of biomedical research of doing good whilst doing no harm; promoting the health of the many beneficiaries, while protecting the health of the few burdened participants. It also illustrates the consequences of the legal framework. Of main interest here is the deliberation of the Norwegian National Committee for Medical Research Ethics. It could be argued that since the Committee was divided in two halves, it is an example of a border-issue of minimal risk and burden. However, as will be shown, it was the approach and applied standards that differed, not the view on whether the risks and burdens were minimal or not: The majority regarded minimal risks and burdens as a rather absolute threshold. The crucial judgment for the majority, was thus whether children were asked to shoulder a burden above minimal or not. (Since, it was probable that only some of the children and parents would suffer serious negative psychological reactions, it would in my opinion be more accurate to talk about risk of psychological harm. But that formalistic point is of less importance for result.) If as many children as parents found the information harmful, the probability was high (1 in 5 000).115 The numbers were probably even higher than 1 in 5 000, as it is reasonable to assume that not all parents with negative serious reactions had complained. For the risk or burden to be high, the magnitude of the harm must also be of some significance. Living with a daily anxiety of getting an incurable and serious disease is significant. Thus, when both the likelihood and the magnitude were found to be high, the risk/burden was considerable. The precondition of minimal risk and burden was therefore not fulfilled.116 The result was therefore given, and it really did not matter how great the potential benefits to science and society were. The majority’s conclusion was then within the European legal framework. If the National Research Ethics Committee had, as the

113

The Norwegian Directorate of Health (2007). Decision of 10 December 2007. The Norwegian Ministry of Health (2008). Letter from the Ministry of Health dated 1 July 2008. 115 Cf. the foregoing section. 116 The US paediatrician and bioethicist, Liain Ross, came to the same conclusion in 2006 after investigating similar studies in other countries (Ross 2006). This indicates that US Federal law and the US minimal risk standard is comparable to European law and the European minimal risk standard. 114

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Physicians Committee and the Directorate of Health did, also included the burden of frequent needle sticks, the National Research Ethics Committee’s conclusion might have been even clearer. The minority of the National Research Ethics Committee had a more “free” approach. It seems as though they did not regard themselves as obliged by international or national legal norms, as their approach was “purely ethical”. In their free overall evaluation, they also put more emphasis on the potential benefits to science and future patients. Given the magnitude of the risks and burden involved, the minority’s conclusion was probably in breach with European legal framework. Not only did the minority disregard the precondition of minimal risk and burden set out to protect the most vulnerable. The minority’s conclusion also appeared to be in breach of the principle of human primacy. It is thus dubious if it was in line with Norwegian law as it stood before the Health Research Act was adopted of 2008.117 Apparently the minority overemphasised the potential benefits, and was ready to accept a high risks and burdens since it “only” affected a few (1 in 5 000). The majority, on the other hand, assessed the proportionality more consciously and with more rigour. Amongst other things the Committee consulted publications on the risk of knowing.118 The assessment was thus more accurate, and the majority was ready to take the consequences. This illustrates the value of rigour, including both a qualitative as well as a quantitative approach, in the assessment of proportionality. Interestingly, Norway ratified the Oviedo Convention in 2006. None of the agencies seem to have been aware of that, or ready to take the consequences of its Article 17 (2). None of the agencies thus seemed to be aware of the fact that the requirement of proportionality was a legally binding norm, as it had been for decades.119 It was not simply an ethical “guideline”, which could be disregarded when faced with scientific imperatives. Thus, this case also illustrates the necessity of a clarification of and information about the law. The US paediatrician and bioethicist, Liain Ross, also came to the conclusion that similar studies conducted in other countries, including the US, entailed risks and burdens to the child which were clearly above minimal and thus legally unacceptable according to US Federal law and the US minimal risk standard.120 This indicates that US Federal law and the US minimal risk standard is comparable to European law and the European minimal risk standard.

117 After 2009 the question is beyond doubt as the Act explicitly incorporates the provisions entailed in the Oviedo Convention and the Additional Protocol into Norwegian law. 118 See, for example, Ross (2006, pp. 191–206). 119 See Simonsen and Nylenna (2005, pp. 192–201). 120 See, for example, Ross (2006, pp. 191–206).

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12.5.9 US Federal Law’s Definition of Minimal Risk and the Daily Risk Standard Apparently the European minimal risk standard is comparable to the US minimal risk standard. It may therefore be of interest to compare the European minimal risk standard with the US minimal risk standard. The minimal risk standard is recognised in US Federal law (the so-called Common Rule) concerning biomedical research on pregnant women, human fetuses,121 prisoners,122 and children.123 For neonates no “added” (additional/extraordinary) risks are allowed.124 Risks above “minimal risk” to children can exceptionally be acceptable if several additional conditions are fulfilled. Minimal risk is in the US Federal law 45CFR46 §46.102 (i) defined as: 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.

An almost identical definition is adopted in Australia.125 It is not clear whether the term “minimal risk” in European Convention law is intended to be identical or in harmony with the term in US Federal law. Those who drafted the Additional Protocol and the Explanatory Protocol were assumingly aware of the US regulations. And since the same concept (“minimal risk”) is used in European law, a certain degree of intended harmony may be presumed. Furthermore, the Community Guidelines on Paediatric Clinical Trials understands “minimal risk” as done in Convention law, and uses the same system as in US law. The “daily life standard” is also occasionally used in a European biomedical research context,126 and is, for example, commonly used as a benchmark in tort law.127 The standard of “daily risks” is therefore of interest also in a European perspective, as there are reasons to believe that the meaning of the “minimal risk” is rather similar in both Europe and the US, although the wording of the legal definitions varies.

121 Common Rule 45CFR46 §46.204 (b): “The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means.” 122 Common Rule 45CFR46 §46.306, see §46.303 (d) which defines minimal risk in this context as: “(d) Minimal risk is the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons.” 123 Common Rule 45CFR46 §46.404 et al. 124 Common Rule 45CFR46 §46.205 (b) (ii): “The purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate resulting from the research.” 125 Wendler (2005, p. 38). 126 See, for example, London Royal College of Physicians, p. 36. 127 See, for example, Rt.1960:841 The Vaccine Judgment of the Norwegian Supreme Court.

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The US definition of “minimal risk” and the daily life standard will therefore be briefly explored with the aim of identifying relevant arguments that can be used in the clarification of the European standard of minimal risk and burden. The provision in US Federal law is regularly criticized in American bioethical literature.128 A question of interest is whether “daily life” applies to healthy individuals (called an “objective/absolute standard”) or the target group of the research, for example, hospitalised patients (called a “relative standard”). A relative standard would imply that bone marrow aspiration could be judged to represent a minimal risk in relation to the experience of a child with acute leukaemia, while the risk would not be regarded minimal in relation to the daily life of a healthy child.129 The research participant’s experience is then used as the benchmark. The second alternative of the provision could be interpreted as legitimatising a relative standard. The CIOMS Guideline 9 may also be understood as supporting such an interpretation.130 In Australia the alternative has been omitted; obviously to prevent such an interpretation. The US National Bioethics Advisory Commission found in its final report in 2001: A relative standard for minimal risk would allow ill participants to be exposed to greater risks than healthy participants. Such a standard would impose disproportionate burdens of research on the ill and provide weaker protections for them than for healthy individuals. This would violate the ethical principle of justice. IRBs should use a standard related to the risks of daily life that are familiar to the general population for determining whether the level of risk is minimal or more than minimal. The standard should not refer to the particular risks encountered by particular persons or groups. It should refer, therefore, to common risks – for example, driving to work, crossing the street, getting a blood test, or answering questions over the telephone. Research, then, involves no more than minimal risk when it is judged that the level of risk is no greater than that encountered in the daily lives of those in the general population. The general population standard is less restrictive than the healthy individuals standard; however, the general population standard more accurately captures the risks that are familiar to most persons.131

On this basis the US Commission rejected the relative standard. According to David Wendler, most other commentators and committees have also rejected the relative standard . . . . . . on the grounds that it would allow researchers to expose some people to greater risks simply because they already face greater risks in their daily lives. In order to avoid exploiting individuals’ unfortunate circumstances in this way, most commentators now endorse the

128

See, for example, Wendler (2005). The US National Bioethics Advisory Commission, Final report (2001, p. 84). 130 “When there is ethical and scientific justification to conduct research with individuals incapable of giving informed consent, the risk from research interventions that do not hold out the prospect of direct benefit for the individual subject should be no more likely and not greater than the risk attached to routine medical or psychological examination of such persons. Slight or minor increases above such risk may be permitted when there is an overriding scientific or medical rationale for such increases and when an ethical review committee has approved them.” [Italics added] 131 The US National Bioethics Advisory Commission, Final report (2001, p. 83). 129

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“objective” interpretation [standard], according to which the standard refers to the risks in the daily lives of average healthy individuals.132

In an acknowledged report, a US committee of academics on the Ethical Conduct of Clinical Research Involving Children held that: The relative interpretation of the minimal-risk standard is inconsistent both with an ordinary or commonsense understanding of the concept of minimal risk and with the objective of providing special protections to child participants in research. It misinterprets and undercuts the moral and social purpose behind the minimal-risk standard . . . what is minimal risk for an 8-year-old may be high risk for an infant. Also, in some cases, a procedure that is judged to involve minimal risk to healthy children may present more than minimal risk to children with certain medical conditions. For example, intramuscular injections that are safe for healthy children would be risky for children with hemophilia.133

With regard to the second alternative in the definition of minimal risk – “routine examination”, the Committee stated that: Just as the committee concluded that the assessment of “risks of daily life” standard should be indexed to the experiences of normal, healthy, average children, it likewise concluded that the “routine examination” standard be interpreted with reference to the experiences of normal, healthy, average children. Ill children may routinely undergo much more burdensome and risky examinations.134

Results as suggested by the relative standard are surely also contrary to European biomedical research law as explained above. The participant’s experience and perceptions of risks is certainly relevant, but to accept the exposure of especially vulnerable and disadvantaged persons to greater risks than less vulnerable persons, would be in breach of the legal framework and go against everything the instruments intends to prevent. It would probably also be in breach of the prohibition against discrimination in Article 14 of the European Convention on Human Rights. It may thus be concluded that while comparison with the risks of daily life can be appropriate and relevant in European law, one may not argue that because some “unfortunate” and “vulnerable” individuals are at high risks, they are accustomed to higher levels of risks, and they may therefore be exposed to higher level of risks in biomedical research than individuals that are better off.

12.5.10 The Case of Grimes v. Kennedy Krieger A renowned US judicial decision that addresses the topic is Grimes v. Kennedy Krieger.135 The case is illustrative of several issues discussed in this book; especially the relationship between researchers’ duty of care (the requirement of proportionality) and participants consent (the requirement of consent), and is therefore referred to in some length here. 132

See, for example, Wendler (2005). Field and Behrman (2004, p. 122–123). 134 Field and Behrman (2004, p. 124). 135 Grimes v. Kennedy Krieger 782 A.2d 807 (Md. 2001). 133

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The case concerned two minor research participants (Grimes and Higgins) who sued a well-respected research institution (Kennedy Krieger Institute). The plaintiffs lost in the Circuit Court (first instance), and appealed to the Maryland Court of Appeals. The extensive judgment of 16 August 2001 deals, both principally and concretely, with various topics of interest. The more principal deliberations were, according to the judges, necessary because virtually no case-law existed on nontherapeutic research on children. The lack of European case-law on the subject implies that the case is of interest also in European biomedical research law. The case also illustrates and substantiates several points made in the foregoing sections. The aim of the concerned research study was to determine how effective varying degrees of lead paint abatement (reduction) procedures were. Families living in or moving into certain houses with various degrees of lead bearing paint were asked to consent to participate in the study. Families with small children were especially encouraged to move in to the housing by the landlord. Consequently, the children were exposed to lead dust. They received some money for refurbishment. The two plaintiffs claimed that Kennedy Krieger owed a duty of care to the participants and that they had breached that duty. They claimed concretely that the children were poisoned, or at least exposed to the risk of being poisoned, by lead dust due to negligence of the part of Kennedy Krieger. Allegedly Kennedy Krieger had “discovered lead hazards in their respective homes and, having a duty to notify them, failed to warn in timely manner or otherwise to act to prevent the children’s exposure to the known presence of lead.”136 Kennedy Krieger primarily held that the research were justified by the potential benefits for society and science (greater good) and that the children might have, lawfully, exposed themselves to lead dust from paint etc in their daily life. The Court noted initially that researchers would, amongst other things, measure the extent to which the theretofore healthy children’s blood became contaminated with lead, and comparing that contamination with levels of lead dust in the houses over the same periods of time. . . . Apparently, it was anticipated that children, who were the human subjects of the program, would, or at least might, accumulate lead in their blood from dust, thus helping the researchers to determine the extent to which the various partial abatement methods worked. There was no complete and clear explanation in the consent agreements signed by the parents of the children . . . It can be argued that the researchers intended that the children be the canaries in the mines but never clearly told the parents. . . . The researchers and their Institutional Review Board [IRB] apparently saw nothing wrong with the research protocols that anticipated the possible accumulation of lead in the blood of otherwise healthy children as a result of the experiment, or they believed that the consents of the parents of the children made the research appropriate. . . . One of the most important objectives of [IRB] review is the review of safety and the health hazard impact of a research project on the human subjects of the experiment, especially on vulnerable subjects such as children. Their function is not to help researchers seek funding for research projects.137

The Court was thus highly sceptical towards both the researchers’ and the IRB’s priorities, and their understanding of legal and moral obligations. The Court further 136 137

Grimes v. Kennedy Krieger at p. 818. Grimes v. Kennedy Krieger at p. 813.

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addressed the relationship between participants’ consent and the researchers’ duty of care: If the research methods, the protocols, are inappropriate then, especially if the IRB is willing to help researchers avoid compliance with the applicable safety requirements for using children in non-therapeutic research, the consent of parents, or any consent surrogates, in our view, cannot make the research appropriate or the actions of the researchers and the Institutional Review Board proper.138

The Court further found that the duty of informed consent translated into a duty of care arising out of the unique relationship between researcher-subject, as opposed to doctor-patient. Such “a special relationship” could itself give raise to further obligations. With regard to Maryland law, and with references to Federal law, the Nuremberg Code, and the Declaration of Helsinki , the Court held (p. 850): In our view, otherwise healthy children should not be the subjects of non-therapeutic experimentation or research that has the potential to be harmful to the child. It is, first and foremost, the responsibility of the researches and the research entity to see to the harmlessness of such non-therapeutic research. Consent of parents can never relieve the researcher of this duty.

With regard to the consent the Court found that the signed Consent Form “created a bilateral contract between the parties.”139 The Court further found that “[t]he ‘informed’ consent was not valid because of full material information was not furnished to the subjects or their parents.”140 The Court held that “the risks associated with exposing children to lead based paint were not only foreseeable, but were well known by [Kennedy Krieger], and, in fact, it had been reasonably foreseeable by [Kennedy Krieger] that the children’s blood might be contaminated by lead because the extent of contamination of the blood of the children would, in significant part, be used to measure the effectiveness of the various abatement methods” (p. 849). Although, apparently not directly applicable, the Court also addressed the minimal risk standard in US Federal law,141 and found (p. 848): The research did not comply with the regulations. There clearly was more than minimal risk involved. Under the regulations, children should not have been used for the purpose of measuring how much lead they would accumulate in their blood while living in partially abated housing which they were recruited initially or encouraged to remain, because of the study. [Italics added]

In this relation the Court comes with a statement that has express references to the principle of human primacy (p. 853): It is, simply, and we hope, succinctly put, not in the best interest of any healthy child to be intentionally put in a non-therapeutic situation where his or her health may be impaired, in order to test methods that may ultimately benefit all children. To think otherwise, to turn over human and legal ethical concerns solely to the scientific community, is to risk 138

Grimes v. Kennedy Krieger at pp. 815–817. P. 843. 140 P. 844. 141 Discussed in the foregoing section. 139

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embarking on slippery slopes, that all to often in the past, here and elsewhere, have resulted in practices we, or any community, should be ever unwilling to accept.

The Court further concurred with the case, T.D. v. New York State Office of Mental Health, in which that court held that it was parents could not give consent on behalf of minors for participation in greater than minimal risk nontherapeutic research.142 Finally the Court asserted “no degree of parental consent, and no degree of furnished information to the parents, could make the experiment at issue here, ethically or legally permissible. It was wrong in the first place.” Without explicitly saying so, the cause of the wrong, was obviously that the risk of harm was clearly excessive and disproportionate as the risks was above minimal risks. In conclusion the Court held that (p. 858): . . . in Maryland a parent, appropriate relative, or other applicable surrogate, cannot consent to the participation of a child or other person under legal disability in nontherapeutic research or studies in which there is any risk of injury or damage to the health of the subject.

The ruling of the circuit court for Baltimore city was vacated and case remanded to the City court for proceedings consistent with the Court of Appeals of Maryland’s opinion. The Court’s message to researchers, research institutions, and institutional review boards [RECs] is loud and clear. The legal situation in Europe is comparable, and the judgement would probably be similar in relation European law (and courts). The US Court was unclear as to what degree of risks and burdens, if any, it would be ready to tolerate. This has created some discussion on theory, as to whether the Court endorsed the US Federal minimal risk standard or not.143 It is clear that the wording “any risk” in the conclusion, is too strict in relation to both US Federal law and European law if taken literally. Other statements in the judgment, could, however, be taken to mean that the Court would have accepted risks and burdens that were “minimal”. Thus, the better view seems to be that the Court did not identify or define a specific threshold. The Court did, however, clearly maintain that the margin of acceptable risks to children and persons not able to consent to research should be very restrictive (regardless of proxy consent), and that the research project at bar entailed risks far beyond that notion.

12.6 Conclusions on Research on Vulnerable Persons Both Convention law and Community law clearly recognise that vulnerable persons are subject to additional preconditions for proportionality. Two largely “common” preconditions (minimum standards) for proportionality in Convention law and Community law that may be derived from specific provisions read in context and

142 143

P. 850. See Ross (2006).

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interpreted into to the requirement of proportionality.144 The additional preconditions apply to nontherapeutic research on vulnerable persons, or research where the risks and burdens to the participants are not fully outweighed by the prospects of direct benefits to the participant. The two preconditions are: 1. The potential benefits must be a “significant improvement” and be related to the participants condition or group-belonging (“significant” potential benefits) 2. The risks and burdens to the participant must be “only minimal” The two preconditions are minimum standards. This means that national law may entail stricter, but not more liberal, standards. The preconditions are independent, which implies that they must be fulfilled irrespectively of each other. No matter the greatness of the potential benefits to others, the research may only entail minimal risks and burdens to the vulnerable participant. Even though the research entails only minimal risks and burdens to the vulnerable participant, the potential benefits to others should be significant. Being “preconditions” for proportionality, means that they must be fulfilled before proportionality can be established. Nontherapeutic research on vulnerable persons must thus comply with intentionally very strict standards. That is to prevent a slippery slope. As stated in the Explanatory Report to Article 17 of the Additional Protocol: It is only in respecting this and the other preconditions of Article 15 that such research may be carried out. To act otherwise would be to exploit these persons contrary to their dignity. . . . The risk for such participants cannot be increased beyond minimal even if the research promises a higher level of benefit.145

144 See the Additional Protocol Articles 6, 15 (2), 18 (1), 19 (2), and 20; and the Clinical Trials Directive Articles 3 (2) (a), 4 and 5. 145 Paragraph 96.

Chapter 13

Non-interference with Necessary Clinical Interventions and The No Harm Rule

13.1 Starting Points and Problems Addressed Prospective participants’ voluntariness, cognitive abilities, perceptions of risk, altruism, and motivation may increase the level of acceptable risk and burdens. However, the risk and burdens should not, at any rate, be disproportionate to potential benefits. A circumstance that may render the risks and burdens unacceptable and disproportionate, is that the research interfere with necessary clinical interventions and delay or deprive the participant of medically necessary treatment, which consequently harm the participant because he or she does not receive the necessary treatment. The issue is addressed in Article 23 (1) of the Additional Protocol: Research shall not delay nor deprive participants of medically necessary preventive, diagnostic or therapeutic procedures.

The purpose of the provision is to ensure patient safety and their right to due health care, which should as a matter of principle take precedence of scientific imperatives, as prescribed by the principle of human primacy.1 Necessary biomedical research on human beings can be acceptable, even if it does involve exposing participants to risks of harm and burdens. But it is not acceptable to intentionally harm individuals for the sake of science and biomedical progress, for example, by delay or depriving of treatment. Thus, the core normative content of the provision is simply that it is unacceptable to cause harm to research participants. As such the provision resembles Hippocrates’ classic professional guideline to physicians: “First, do no harm.” I have therefore called it the no harm rule. It is clear that the provision applies to all clinical research (understood as research involving patients), even if the research does not entail prospects of direct benefits (nontherapeutic research). The provision further applies whether or not the individual is formally a “patient” etc. As mentioned before, clinical research (research in

1 This follows from Article 23 (1) as well as the principle of human primacy in Article 3 of the Additional Protocol and Article 2 (1) of the GCP Directive; cf. Section 5.2.5.

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the clinic involving patients) often does not entail prospects of direct benefits to the participant, typically because the participating patient is included in a control group that receives only sham (placebo) treatment. This wide scope of application also follows from the fact that the provision can be seen as an expression of an general principle of biomedical research law which easily derivable from the principle of human primacy and the requirement of proportionality. The no harm rule may also be seen as a minimum standard derivable from researchers’ duty of care. To offer and include patients in harmful research is in breach of researchers’ duty of care.2 Thus, even though this provision – the no harm rule – is not explicitly included in the Clinical Trials Directive, it is certain that the no harm rule also applies in Community law. The omission cannot be interpreted antithetically. On the contrary, the no harm rule must be interpreted into Article 3 (2) (a) of the Directive (the requirement of proportionality). If the research participant is delayed or deprived effective and necessary treatment, the participant is clearly also offered a less favourable (poorer) alternative than nonparticipation in research would be: In other words: research participation does in such circumstances not necessarily represent a reasonable choice.3 Because the no harm rule is intended to ensure that the patient is not harmed, the rule may be seen as a precondition for proportionality: If the participants are delayed or deprived necessary medical treatment, the risks and burdens may be so great that then cannot be outweighed by the potential benefits to others. It cannot be reasonably assumed that prospective participants will volunteer to such a project. An example: The COPD Study4 Background: Chronic obstructive pulmonary disease (COPD) is a serious chronic disease. Its main cause is smoking. COPD makes it hard to breath. Some patients inhale steroids to reduce airway inflammation (swelling). Study Aim: Get efficacy and safety data on a specific dosage (150 ug) of indacaterol (a new type of steroids) inhaled by patients with COPD. Method: A multi-national randomised clinical trial. The intervention with indacaterol was going to be compared with placebo as well as best available treatment. A total of 972 patients with moderate and severe COPD were going to be included. During the six months trial period the participants would undergo extensive testing. REC evaluation: The Committee recognised the potential benefits for future patients and the expertise of the research group. The Committee did, on the other hand, find that taking seriously sick people off long-term effective treatment in order to provide them with placebo drugs was worrying. Independent expert advice was therefore sought. The expert advised against the use of placebo, because the prospective participants’ were seriously ill and the treatment they were undergoing was effective. The Committee did then approve the project on the condition that placebo was not used. The protocol had therefore to be amended. The principle investigator accepted the condition.

2

Cf. Section 5.3.2 on researchers general duty of care. Cf. Section 10.3.6. 4 REC Middle Norway Case 4.2007.1683. 3

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The Research Ethics Committee arguably found that inclusion in the placebo-group would be detrimental to the health of those participants, and therefore unacceptable. The Committee could just as well have said that the risks and, not least, the burdens were disproportionate to potential benefits. As such the no harm rule may arguably be seen as superfluous, as it is clearly embedded in the requirement of proportionality itself, as argued above. Nevertheless, on the face of it, the provision entails an important, simple and selfexplanatory norm: do no harm. However, in biomedical research patients in need of treatment are regularly included in research, such as placebo controlled clinical trials, without prospects of direct benefits. Does that mean that any interference with necessary clinical interventions is unacceptable and unlawful? Obviously, the norm is not that simple and must be interpreted to clarify the normative content and its relationship to the requirement of proportionality.

13.2 The Notion of “Not Detrimental” The Explanatory Report specifies that “delay” should be understood as “any delay that would be detrimental to the medical care of a patient. The treatment of a patient should not be altered in a detrimental manner in order to facilitate research” [italics added]. This implies that delays and deprivations can be acceptable as long as they are not detrimental. “Detrimental” is thus obviously the central normative criterion in the norm. The question addressed is then: what does “detrimental” mean? The ordinary meaning of the word detrimental is harmful. While the term “risks” refers to a likelihood (mere possibility) of harm, the term “detrimental” refers here to something that is outright harmful. If a patient is undergoing effective treatment, the denial of such treatment because of a transition to participation in research can obviously be detrimental (outright harmful). But this is not necessarily always the case. For example, although the probability of direct benefits (effective treatment) is lower than standard treatment, the magnitude of positive health effects may be considerably higher. Research participation may then appear as a reasonable choice after all. This implies that the term “detrimental” is and must be related to the requirement of “proportionality”. Such an interdependent relationship is implied in Explanatory Report to Article 23 (3) in paragraph 121. Detrimental must then be understood as a substantially negative consequence of research participation – usually physical or physiological harm. Examples of burdens which can be detrimental include: amputation, scars from sham surgery, great and not momentary pain, negatively altered self-perceptions, anxiety, enduring fear, reduced health and welfare more generally and so on. Detrimental is thus a powerful, but also strict, concept. Thus, not any risk of harm and burden is detrimental. A very slight and temporary harm will usually not be seen as “detrimental”. This interpretation is also in line with the definition of minimal risks and burdens in Article 17 of the Additional Protocol. In practice, it is often accepted that participants carry burdens such as momentary

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and passing pain, nausea, anxiety etc. In The Meningococcal B Vaccine Trial,5 for example, momentary pain and nausea that could result in the need for one or two sick-days were expected to be common, but something participants should bear. Thus, even rather significant harms (burdens) do not necessarily amount to being detrimental. A stab wound related to the obtainment of human biological material is surely harmful, but it is usually not “detrimental” in the meaning of the Article 23 (1) of the Additional Protocol. Another example: Prior to inclusion in a medicinal clinical trial, a so called “wash-out-period” may be needed because the drug currently used must have left the body entirely which may take days and even several weeks. This may imply that the patient is left with gradually reduced treatment, and then no treatment at all for a short period of time, before a new drug is offered. This time of reduced treatment must surely be labelled a burden (even a harm) that prospective participants must be made aware of and consent to. This burden can be substantial and therefore detrimental, but not necessarily. If it is not “detrimental”, the burden can be acceptable if it is outweighed by potential benefits to the participant him or herself (direct benefits) or others. In the Pain Relief Study6 the participants were under palliative care (pain reduction). Some patients were, however, given placebo or lower doses than usual. The observed Research Ethics Committee found that this would be unacceptable if the participants had not been provided with so-called rescue medicine, which they could use if the pain became intolerable. The decision appeared reasonable and is illustrative of the flexibility of the legal norms, as well as the necessity and value of an overall judgement. It is difficult to specify how negative the consequence (harm) must be to be regarded detrimental. Thus, again, a concrete overall judgment of all relevant factors is necessary. But clearly, whether a consequence is detrimental depends on both the magnitude and the likelihood of the harm. It is natural to put emphasis on the likelihood: For a negative consequence to be regarded outright harmful (detrimental), it must be rather likely and expected. In the COPD study the negative consequences of taking placebo was highly expectable. That is probably why the observed Research Ethics Committee rejected the use of placebo so readily. Actions detrimental to a person’s health may therefore be regarded as excessive and unreasonable burdens. If the likelihood is low or remote, it is more natural to talk about risk of harm. For example, doing a liver biopsy is not in itself harmful or detrimental, if so it would not be undertaken so frequently in ordinary clinical practice. However, the risk of serious harm is so high that it can only exceptionally be acceptable in nontherapeutic research.7 In conclusion the concept of “detrimental”, which is the central normative criterion in Article 23 (1) of the Additional Protocol (“the no harm rule”), may thus be understood as outright harmful acts involving excessive and unreasonable burdens

5

Accounted for in Section 11.3. Accounted for in Section 14.4.2. 7 See Section 11.4.4 where the liver biopsy example is discussed more extensively. 6

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for the research project, rendering research participation an unreasonable choice for prospective participants. A detrimental research project would entail excessive and unreasonable burdens to the participant, and thus be disproportionate. To judge whether the research intervention is detrimental one need to assess whether there is proportionate relationship between risks, burdens, and potential benefits. A certain degree of burdens and risks can, however, be acceptable in accordance with the requirement of proportionality. Whether a research intervention is detrimental must also been related to researchers duty of care as clinicians. The degree of discretion is dependent upon the nature of the experiment, the context, and individual conditions, such as participants presumed perceptions of risks, burdens and potential benefits. Detrimental will always imply disproportionality. However, risks and burdens can be found disproportionate to potential benefits, even if research participation is not “detrimental”, typically because the potential benefits are insignificant or low.

Chapter 14

Especially on Randomised Clinical Trials, Including Placebo Controlled Clinical Trials

14.1 Problems Addressed Until now the analyses in this book have primarily addressed the issue of proportionality when prospective participants are faced with two alternatives: participation in research or nonparticipation. The assessment of proportionality becomes more complicated when participation in research consist of multiple alternatives, typically because the included participants will be divided into two or more groups; and each group of research participants will be subject to different interventions, and thus different risks, burdens, and potential benefits. The assessment of proportionality in such situations is among the most topical issues in bioethical literature, and concerns so called randomized clinical trials, including placebo-controlled trials with pharmaceutical drugs. A randomised clinical trial is a research project where research participants by chance are randomly selected to two or more groups of participants: Typically: One interventional group, which receives the new experimental intervention (e.g. a new drug); one or (active) control group, which receives standard (active) treatment (or no treatment at all if none exists); and one control group which receives sham (placebo) treatment. Occasionally groups are called arms; the foregoing description thus describes a three armed randomised placebo controlled clinical trial. Randomised clinical trials are usually double blinded, which means that neither those health personnel that carry out the treatment, nor the patient who receives the treatment know whether they get the experimental treatment, standard treatment, or placebo treatment (this information is encrypted and can be decrypted in case of an emergency). The idea behind the randomisation and the blinding is to reduce bias and confounders, and thus make the results as accurate and reliable as possible. Randomised clinical trials are the preferred scientific method – “the gold standard” – for obtaining generalisable knowledge about the positive and negative effects of an intervention, especially in the testing of new drugs. The reason for this is that it is possible to rather accurately compare positive and negative effects from the experimental group with positive and negative effects in the control groups.

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Randomised clinical trials are ethically and legally challenging. Firstly, it is problematic that participants by random are assigned to two or more groups which are subject to different medical procedures, instead of being offered treatment based on individual professional judgements and the subjects’ preferences. Moreover, participants within each group are systematically offered the same treatment. The patients are in other words subject to a group approach to treatment instead of the more individual approach applied in ordinary clinical practice. Another challenge is the blinding, which means that the participant does not consent to participate in either the experimental group or the control group, but to being randomised into a group. It surely enhances the legal problems that empirical studies clearly show that ordinary patients often does not understand and, if they do, appreciate the concept of randomisation.1 Many participants are sceptical about the idea that they may not be offered the better treatment based on an individual judgement.2 A randomised clinical trial thus raises many ethical and legal questions. Here, the focus will be on the legal assessment of proportionality and whether participation in a randomised clinical trial (including a placebo controlled trial) may be a reasonable choice. The question is addressed in four parts. First, the starting points will be outlined. Then a randomised clinical trial with a control group receiving standard treatment will be investigated. Third, the acceptability of placebo-controlled trials is investigated. Finally, the legal findings will be summarised. In the end, a fifth and peculiar issue is addressed concerning the overall assessment.

14.2 Legal Starting Points The issue is not explicitly addressed in the Clinical Trials Directive, thus the more general requirement of proportionality in Article 3 (2) (a) applies. The issue is, however, elaborated on in Article 23 (2) and (3) of the Additional Protocol concerning the use of control groups and the use of placebo respectively. The two provisions in the Additional Protocol elaborate on the general requirement of noninterference with necessary clinical interventions in Article 23 (1) (“the no harm rule”), investigated in Chapter 20. The provisions in Article 23 (2) and (3) are vague. However, as will be shown, the law is “straightforward”, because it is essentially the same standards that have been investigated above which do apply also on randomised clinical trials (as should be expected). Article 23 is thus superfluous, as it is really not needed. The omission in the Clinical Trials Directive is therefore unproblematic. Article 23 does, on the other hand, serve as a timely reminder of some important legal issues that will be briefly investigated. The precisions in Article 23 may have been deemed necessary because of the controversy of this issue.

1 2

See, for example, Wendler (2009a); Mangset et al. (2008, 2009); see Section 5.4.3. See, for example, Mangset et al. (2008, 2009).

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14.3 Proportionality When the Research Project Includes a Control Group A “control group” consists of research participants who are not subject to the research intervention. The participants are used only as a basis of comparison. Participants in the control group are research participants, but they are usually subject to the same treatment (or nontreatment) as they would have received if they had not participated in the research study. The participants in the control group are, however, usually subject to some extra monitoring to measure the effect of standard treatment or nontreatment. At any rate, the risks and burdens being included in a control group are usually minimal. On the other hand, the prospects of direct benefits are also very low, usually nonexistent. The risks and burdens to the participant must then be outweighed by the potential benefits to others. The potential benefits to others will normally be significant in an adequately designed study, and therefore outweigh minimal risks and burdens. Both relatively invulnerable persons and vulnerable persons may thus normally be included in a control group because the risks and burdens are in proportion to potential benefits.3 This is the normal, and largely unproblematic, situation. Participation in a control group first and foremost becomes ethically and legally questionable if the participants in the control group clearly receive poorer treatment than the participants in the experimental intervention group. Poorer treatment can be justified by the fact that the participants were not undergoing such (superior) treatment upon inclusion in the research project. This may be a result of many factors, such as lack of resources (for example that the better alternative is only available abroad; or that the patient cannot afford the alternative, and it is not provided for by the public health services). The question this arises is whether participation in the control group is reasonable and legally acceptable when better alternatives exist. Article 23 (2) of the Additional Protocol addresses this situation: In research associated with prevention, diagnosis or treatment, participants assigned to control groups shall be assured of proven methods of prevention, diagnosis or treatment. [Italics added]

Article 23 (2) aims to “assure” that research participants assigned to control groups will not be subject to a poorer alternative than those in the experimental intervention group; and by that “assure” participants assigned to control groups their right to due health care. The provision also aims to hinder unreasonable exploitation of, in practice usually underprivileged and vulnerable, research participants. Thus, the fact that a patient has not yet been offered effective treatment (for example because he or she has not sought treatment yet or cannot afford treatment), does not mean the researcher can take advantage of this circumstance, and that such treatment can be delayed or deprived for the sake of science (and comparison). That would be unreasonable and legally unacceptable according not only to Article 23 (2), but also

3

Cf. Chapters 11 and 12.

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according to Article 23 (1) of the Additional Protocol. This legal solution may in addition be derived from the requirement of proportionality itself (Article 6 of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive): If participation in a control group is a significantly poorer alternative than participation in the intervention group, the participation in the control group may be seen as entailing additional (and maybe excessive) risks and burdens to the research participant, which may not necessarily be outweighed by the potential benefits to others. The purpose of the requirement of proportionality is to ensure that research participation is a reasonable choice and that there is a reasonable relationship between risks, burdens, and potential benefits. And it is difficult to argue that the relationship is reasonable and in proportion if a more favourable treatment option exists. The inclusion of participants who have not yet been offered necessary clinical interventions may thus easily be seen as undue exploitation, which the requirement of proportionality aims to hinder (main purpose). There may be many reasons why an individual has not yet been offered necessary clinical interventions, but often it is a result of circumstances that render the subject vulnerable, such as poverty (lack of money or health insurance), lack of knowledge, ethnic minority, and so on.4 Hence, the provision can be seen as particularly aimed at protecting vulnerable research participants who lack knowledge or money to ensure their own health and interests. The existence of a “reasonably” available and more favourable alternative, but which is not offered the participant, may thus lead to disproportionality. The classic example of undue exploitation as a result of the delay and denial of proven methods of treatment to a control group, is the notorious Tuskegee experiment where poor Afro-Americans with syphilis were denied effective treatment with penicillin, because the researchers wanted to study the development of the disease, as well as use the control group for comparison between active treatment with penicillin.5 The research participant obviously did not know that effective treatment existed, because the physician researchers did not tell them, which is a flagrant breach of physician researchers’ duty of care. Thus, an “ordinary”6 assessment of proportionality of each alternative, including a comparison is necessary to judge whether participants in a control group are assured “proven methods of prevention, diagnosis or treatment”. A difficult subsequent question is whether the “proven methods of prevention, diagnosis or treatment” are really available. This question is often linked to the question about whether a local, national, regional or global standard of availability applies. Some guidance can be found in the Explanatory Report to Article 23 (2): It is expected that a proven method of treatment that is available in the country or region concerned be utilised. ‘Region’ may signify several neighbouring countries or an even wider area, to take into account multicentre studies that may cross national boundaries and to recognise the fact that Europeans may often utilise healthcare available in a neighbouring country. [Italics added]7 4

Cf. Section 3.8 where “vulnerable person” is defined. See Jones (1993); accounted for in Section 4.5.3. 6 As described in Chapters 10, 11, and 12. 7 Paragraph 120. 5

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This suggests that an alternative is available even if it is not readily available at the particular hospital or research facility. However, if it is not readily available within a pragmatically defined area, it may be regarded as nonexistent. This means that theoretically or global availability does not necessarily mean that the alternative is available in a particular context. In the literature the issue has especially been addressed with regard to commercial clinical trials in developing countries. The question addressed there is whether a local or global standard should apply. The biomedical researcher, Kenneth Rothman, states in this regard that the application of a local standard implies that no one who enters a trial should receive a treatment that is worse than what he or she would have received in the absence of a trial. . . . The alternative, a global standard, starts from the local standard but adds that no one who enters a trial should receive a treatment that is worse than what he or she would have received if the same trial were conducted anywhere else in the world at the same time.8

To prevent unreasonable exploitation of vulnerable persons, most commentators favour a global standard.9 The question regarding clinical trials in developing countries will not be addressed here as it would exceed the scope of this book.10 However, the discussion on the issue in literature is relevant also in a narrower European perspective, especially the arguments related to fairness and reasonability. The “standard” set forth in Paragraph 120 of the Explanatory Report appears to be somewhere in between a local and global standard, as a “regional” standard. “Availability” then apparently refers to a general and readily availability within a region. In light of the transnational character of the health service in Europe (especially under the auspices of the European Union), a fair understanding of a region is Europe. It may be discussed if it matter whether the intervention is only available in private health care which is based on payment, and not public health care which is “free” (publically funded). Without pursuing this discussion in full because national variances in the public health programs within Europe complicates the issue, on may use as a starting point that one should not be delayed or deprived “necessary” medical interventions, regardless of whether the medical intervention is free of charge or not, because it is morally dubious to do so. It may in this respect be pointed to the legally binding UN International Covenant on Economic, Social, and Cultural Rights of 1966 Article 12 concerning the human right to health. Other international and European instruments, which supplement or specify the human right to health, are also of interests but is not pursued here.

8

Rothman (2000, p. 444). Rothman (2000, p. 444). 10 This issue is addressed in the Commentary on Guideline 11 of the CIOMS Guidelines; see also The Nuffield Council on Bioethics [UK], The Ethics of Research Related to Healthcare in Developing Countries, 2002. A starting point it is clear that the law as clarified here also applies when doing biomedical research in developing countries, see Article 29 of the Additional Protocol and CIOMS Guidelines. 9

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The question that arises is, however: what is “necessary” medical intervention? The term “necessary health care” is a legal term in Norwegian Health law, as every citizen is entitled to necessary health care (basically free of charge).11 In Norwegian Health law “necessary” implies that the patient is in need of the treatment, and that the patient may expect direct health benefits of the treatments (that outweighs the risks and burdens), and that there is a proportionate relationship between the prospects of direct benefits and the costs of the medical intervention. Whether an intervention is medially “necessary” thus depends on an overall judgment.12 Thus the medical intervention that the participants “shall be assured of” must be “necessary”. Moreover, the medical interventions must be “proven methods of prevention, diagnosis or treatment” (Article 23 (2) of the Additional Protocol). That the method must be proven implies that an experimental research intervention can usually not be regarded as an available alternative. The obvious reason is that too little may be known about the positive and negative effects of the intervention, although preliminary results are promising. Extensive testing (research), and often also permissions, may be needed to clarify whether the research intervention really is as good as hoped. Such a process may take several years. Criticism and disappointments of those in the control group, who do not receive the new experimental intervention, may in such situations be a result of an unfounded faith in the benefits of the experimental intervention, and the lack of treatment alternatives. Lucas Bergkamp asks if it is inappropriate to offer just research participants experimental therapy, as such an offer may amount to a form of sanction rendering the consent not entirely free, i.e. “if you participate we will treat you, if you don’t, we will not treat you.” However, he concludes that “withholding an experimental therapy if the patient does not consent is not a sanction that would render consent ‘not freely given’.”13 Bergkamp’s conclusion is probably correct if the withholding would not be clearly unreasonable. The issue also concerns patients right to health care and the validity of consent, which exceeds the scope of this book. The aim here is merely to highlight the issue and the necessity of a fair overall judgement, and that the requirement proportionality may serve as a legal basis for a reasonability test in that regard. It may thus be concluded that “participants assigned to control groups shall be assured of proven methods of prevention, diagnosis or treatment” (Article 23 (2) of the Additional Protocol). This means that participants assigned to a control group must not be delayed or deprived necessary and effective medical interventional that are (or should be) available to the participants (Article 23 (1) of the Additional Protocol). In other words: the risks and burdens to participants assigned to a control group must be in proportion to potential benefits according to the requirement of

11 § 2-1 of the Norwegian Patients’ Rights Act of 1999 state: “The patient is entitled to emergency care . . .” [public, but unofficial, translation]; See Kjønstad (2005a, pp. 137–211). 12 Kjønstad (2005a, pp. 171–174). 13 Bergkamp (2004, p. 63).

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proportionality in Article 6 of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive (including additional preconditions). If the scientific imperative of having a control groups conflicts the interests of an individual assigned to the control group, the interests of the individual must prevail in accordance with the principal of human primacy in Article 3 of the Additional Protocol and Article 2 (1) of the GCP Directive.

14.4 Acceptable Risk in Placebo Controlled Clinical Trials 14.4.1 Problems Addressed The same requirement of proportionality applies when it comes to research project that includes a placebo group in Convention law and Community law. Nevertheless, the Council of Europe found reasons to specifically address the issue in Article 23 (3) of the Additional Protocol. This provision, and thus this kind of research (placebo controlled clinical trials), is addressed in this section. First, this kind of research is explored and problems addressed are identified. Participants in one of the control groups may in randomised clinical trials receive placebo (sham) treatment. The reason is that it is relevant to compare the experimental drug with a placebo drug to demonstrate whether the experimental drug is more favourable (more effective and safer) than the placebo drug. The comparison is deemed relevant and scientifically necessary because a nonneglectable number of participants do respond positively or negatively when taking placebo drugs, probably because the participant believes he or she is given an active agent (a psychophysiological effect). The same may thus be case with the experimental drug: the drug is not really working, as it may just be the placebo effect that improves the patient’s health. For example, 100 patients receive a new experimental drug against migraine, and 100 patients receive a placebo drug against migraine. Neither the physicians nor the patients know who gets what (they are randomly assigned to the two groups). The trial show that 30 of the patients in the experimental group experience positive health effects, while 20 experience negative health effects, the rest (50) experienced neither positive nor negative health effects. If the participants in the placebo group report the same experiences, it may be just the placebo effect that is working (the participant strongly believes that he or she is going to be better because of the drug, an in effect also feels better). The rationale behind giving placebo drug (instead of no drug at all) is to make the patient believe that he or she is getting a real drug with active agents. Thus the patient is intentionally “deceived”, and to make sure the deception is effective neither the participant nor the health personnel distributing the drug will know which is which. If the effects of the experimental drug are comparable with the effects of the placebo drug, there is no point of providing future patients with the experimental,

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because the patients may just as well be treated with the usually cheaper and safer placebo drug. This illustrates the necessity of placebo controlled clinical trials. The use of placebo is ethically and legally challenging: Firstly, the participants are intentionally “deceived” or kept in blind about whether they receive an active agent or placebo drug. The participants must be informed of this possibility of sham treatment before they consent to participation and random treatment. However, empirical studies show that many participants fail to understand such information, and thus wrongfully believe they are getting an active agent. Moreover, empirical studies show that many ordinary patients do not appreciate (value) the use of placebo controlled trials, because they expect to get the best treatment.14 This is a question that primarily concerns the validity of consent, and is not pursued here.15 Nevertheless, the challenge underscores the necessity of a rigorous assessment of proportionality to ensure that participation in a placebo controlled clinical trial is a reasonable choice. Secondly, taking placebo entails risks and burdens to the participant.16 The risks are usually very low, but it is wrong to insist that taking placebo is “risk free”. By taking a placebo substance, the participant gets a foreign agent into the body, which would not have been taken if it were not for the potential benefits to science. Sometimes the placebo drug is just a sugar pill, other times it consists of other substances. In, for example, phase III of the Meningococcal B Vaccine Trial, the placebo serum had the same content as the active vaccine, except for the active agent.17 Exceptionally, some individuals, who may be predisposed or otherwise anatomically abnormal or sensitive, may get a severe negative reaction to the placebo substance, for example, an allergic reaction. Indeed, 4 in 100 000 of the participants in the placebo group in the Vaccine trial reported serious complications (three neurological reactions). The Monitor group noted that these negative reactions could be a result of the basis liquidation (aluminium hydroxide) or it could be a result of accidental circumstances that had nothing to do with the placebo vaccine. Additionally, things may go wrong when distributing placebo, for example, the needle may crack or the substance may be injected into wrong place. Nevertheless, usually the risks are below minimal because of the very low likelihood of complications. The burdens of taking a placebo drug can be related to the simple fact that it takes time and otherwise is discomforting. These burdens are usually considered to be minimal. Since the possibility of positive placebo effect is very remote, taking a placebo drug cannot be seen as entailing any prospects of direct benefits to the participant.

14

Mangset et al. (2009). See, for example, Wendler (2009a) (Must research participants understand randomization?). 16 See, for example, Cyna et al. (2011). 17 The placebo vaccine consisted of: Aluminium hydroxide (0.33%); Thimersalnatrium (0.01%); Sukrole 3% injection fluid ad (0.5 ml). The active vaccine also consisted of Outer membrane protein (25 µg). 15

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Thus the risks and burdens must be outweighed by potential benefits to others. The potential benefits to others will normally be significant in an adequately designed clinical trial and outweigh minimal risks and burdens. Both relatively invulnerable persons and vulnerable persons may therefore be included in a placebo control group because the risks and burdens are in proportion to potential benefits and thus acceptable.18 This scenario is largely unproblematic. The use of placebo is first and foremost legally problematic if the participants in the placebo group are given delayed or denied (not “assured”) proven methods of prevention, diagnosis or treatment (cf. Article 23 (1) and (2) of the Additional Protocol). If so, participation in a placebo group represents a poorer alternative than the other alternatives (nonparticipation and standard treatment or research participation and experimental treatment or control treatment). A placebo group is even more controversial if it is required that patients are taken off known effective treatment in order to provide the participants with placebo drugs, just for comparison.19

14.4.2 Article 23 (3) and the Use of Placebo Article 23 (3) of the Additional Protocol specifically addresses the use of placebo: The use of placebo is permissible where there are no methods of proven effectiveness, or where withdrawal or withholding of such methods does not present an unacceptable risk or burden.

The provision is elaborated in the Explanatory Report: The third paragraph [Article 23 (3)] permits the use of placebo only where there is no method of proven effectiveness or where withdrawal or withholding of such methods does not present unacceptable risk or burden to the participant. Whether risk or burden is acceptable or not is to be assessed by the ethics committee and competent body, who should pay particular attention to such projects and assess each specific project individually. If placebo is used in research on persons not able to consent to research, Article 15 also applies.20

The provision thus includes two alternative exception clauses that may render the use of placebo control legally acceptable. 1. “there are no methods of proven effectiveness” or 2. “where withdrawal or withholding of such methods does not present an unacceptable risk or burden” This discussion touches and must be read in light of the foregoing discussions. Nevertheless, as to the first alternative, the requirement is that there are in reality no available treatment alternatives other than the experimental intervention being 18

Cf. Chapters 11 and 12. Rothman (2000). 20 Paragraph 121. 19

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tested. Thus, the participants who are assigned to the placebo group are in reality left with an alternative that is largely comparable to the alternative of nonparticipation. The only additional risks and burdens result from taking the placebo drug etc., which usually involves only minimal risks and burdens. That no method is effective on the particular participants is equal to no method available. For example: An effective remedy for migraine exists. However, not all individuals respond to this treatment. Hence, available and proven methods of treatment exist for most individuals, but not for all. If a placebo controlled clinical trial was is designed to test a new drug against migraine, it would be largely unproblematic to assign individuals who do not respond to standard treatment to a placebo control group. The CIOMS Guideline 11, first bullet point, and the Declaration of Helsinki, Paragraph 32 first bullet point, contain equivalent provisions to the first alternative, which indicates a broad international consensus.21 To assign individuals who respond positively to standard treatment to a placebo control group is legally more problematic, because they are then offered a poorer alternative that entails additional risks and burdens to standard treatment. That scenario is addressed in the provisions to the second exception clause in Article 23 (3) of the Additionally Protocol. The exception clause obviously points back to the assessment of proportionality enshrined in Article 6 (including additional preconditions for proportionality). Consequently, placebo may be used if the risks and burdens are outweighed by the potential benefits. This implies that patients and others by consenting to participating in a randomised clinical trial may take upon themselves a certain degree of risks and burdens for the sake of others, but the risks and burdens must not be disproportionate and excessive. The more detailed provisions in Article 23 (2) and (3) in the Additional Protocol is thus fully compatible with the Clinical Trials Directive Article (3) (2) (a) (including additional preconditions for proportionality). The Clinical Trials Directive can surely not be interpreted to allow that participants in a placebo group may be subject to lesser standards than the minimum standards assured everyone else. A scenario that may render the risks and burdens disproportionate is that the participants in the placebo group are given delayed or denied effective treatment as illustrated by the COPD Study.22 Participation in the placebo group was then a poorer alternative, as that alternative entailed additional risks (risks of harm related to not being treated) and burdens (extensive pain and other burdens related to not being treated). Such risks and burdens may easily be judged considerable and above minimal. For vulnerable persons such a level of additional risks and burdens is legally unacceptable in both Convention law and Community law as shown above in Chapter 12. For others it may be not.23 Clearly not any delay or deprival of standard treatment is unacceptable. An illustrative boarder case is the Pain Relief Study: 21

CIOMS Guidelines: “Placebo may be used: when there is no established effective intervention”; The Declaration of Helsinki: ”The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists”. 22 Accounted for in Section 13.1. 23 See Chapter 11.

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The Pain Relief Study:24 Background: Conventional treatment of cancer pain provides analgesia for both persistent pain and breakthrough pain (BTP). According to the research protocol, controlled-release oral morphine had been standard therapy for moderate to severe persistent pain, whereas immediate-release tablet or mixture of oral morphine was commonly used for breakthrough pain. Study aim: To test the efficiency and safety of Inranasal fentanyl for the treatment of breakthrough pain in cancer patients. Method: A phase III randomised, double blinded, placebo controlled, cross-over confirmatory study. Doses of 50, 100 and 200 µg fentanyl and placebo was going to be tested on 175 cancer patients in eight break-through pain periods. The rationale for the trial design was that “according to the guideline for treatment of nociceptive pain (CPMP/EWP/612/00), placebo-controlled designs with appropriate use of rescue medication are recommended for trials not aiming to show superiority to any active cooperator. In the present trial, two of the eight trial episodes of BTP will be treated with placebo. Placebo or the lower fentanyl may not be sufficient to treat BTP for some persons. To ensure adequate pain treatment, patients are therefore allowed to take rescue analgesics as needed after 20 min. Any reservation to the use of placebo may be countered by the facts that the effect of placebo is known to be particularly high in pains, that in this trial only two of eight trial treatments are placebo, and that rescue analgesics are allowed as needed.”25 REC evaluation: The project was approved without expressed consideration of the risks, burdens and potential benefits involved in the meeting or in the written decision.

Since the Research Ethics Committee did not explicitly address the assessment of proportionality and risks entailed in this project, neither in meeting nor in its decision, an ascertainment of which factors where relevant and how they were weighed can only be speculative (it is likely that this was done implicitly). However, the principal investigator was renowned, the design appeared scientifically sound, and the aims appeared legitimate. The same appeared to be the case in the COPD case, which was not approved. What distinguishes the two cases was the level of risks and burdens, and that in the Pain Relief Case the participants in the placebo group were provided with and allowed to use rescue medicine. If rescue medicine had not been allowed to be used by the placebo group in the Pain Relief case, the Committee’s assessment may very well have led to nonapproval. Thus in the Pain Relief Study the Research Ethics Committee apparently found the relationship between risks, burdens, and potential benefits to be proportionate, but not in the COPD case. Both decisions appear reasonable and in line with the legal framework from my perspective. Randomised clinical trials to test the safety and efficiency of a new surgical method are regularly carried out. If the control group receives standard surgery that they would have received regardless of the research project, this is largely legally unproblematic. It has, however, been reported that participants in such a trial also have been assigned to a placebo control group. The patients have then been subject to anaesthesia and surgery for no other reason than deception and placebo control (to make the patients really believe that they have undergone active surgery). 24 25

Case 4.2006.2893 REC Middle Norway. Researchers application to REC.

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Sham surgery may very well be of great scientific value. It is, however, difficult to see how sham (placebo) surgery could ever be legally acceptable, because of excessive and disproportionate risks and burdens to the patient. Indeed, it is difficult to see how sham surgery cannot be detrimental to the patients’ health. Thus regardless of scientific imperatives or the participant’s willingness, there are limits to what level of risks and burdens individuals may be exposed to for the sake of others in biomedical research. These limits have been clarified above.26 The Declaration of Helsinki has been subject to heated debate and repeated revisions on this issue. The current version of the Declaration of Helsinki Paragraph 32, second bullet point, states: Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.[Italics added]

Although the principle does not expressly prescribe a weighing, it is clear that the there should be significant potential benefits and only low, possibly minimal risks and burdens, are acceptable (“any risk of serious or irreversible harm”). The principle in the Declaration of Helsinki is thus more or less compatible with the Additional Protocol. The CIOMS Guidelines, guideline 9, bullet points two and three, entails comparable principles: As a general rule, research subjects in the control group of a trial of a diagnostic, therapeutic, or preventive intervention should receive an established effective intervention. In some circumstances it may be ethically acceptable to use an alternative comparator, such as placebo or “no treatment”. Placebo may be used: • when there is no established effective intervention; • when withholding an established effective intervention would expose subjects to, at most, temporary discomfort or delay in relief of symptoms; • when use of an established effective intervention as comparator would not yield scientifically reliable results and use of placebo would not add any risk of serious or irreversible harm to the subjects.

The CIOMS Guidelines contain elaborative commentaries to guideline 9, including examples of ethically acceptable clinical trials. There is, however, no reason to recapture that here. The main point is that there is a large international consensus which maintains that placebo controlled clinical trials may be justifiable on strict conditions. In a legal perspective, these conditions are easily derivable from the Additional Protocol and the Clinical Trials Directive. In other words: the CIOMS Guidelines and the Declaration of Helsinki are more or less compatible with the European legal framework. If a normative conflict can be established, the legal framework prevails. National law may also contain more protective standards than the minimum standards set out in the Additional Protocol and the Clinical Trials Directive. At any rate, the better protection should be assured participants. 26

These limits have been clarified above in Chapters 9, 10, 11, 12, and 13.

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In the bioethical literature it has been argued that different standards should apply in placebo controlled clinical trials than in ordinary biomedical research. Some commentators have taken a more restrictive view than the European legal framework prescribes; others have taken a more liberal view. The restrictive view is that participants in randomised clinical trials may only be offered alternatives that are at least as favourable as the best standard alternative. Such a standard would imply that a relatively invulnerable patient would not be allowed to volunteer to carry any additional risks and burdens for the sake of others. That view has clearly no basis in the European legal framework that allows that both vulnerable and invulnerable persons may on certain conditions carry risks and burdens for the sake of others in biomedical research.27 The more liberal view is based on scientific imperatives, but also harmonises poorly with the relative strict European legal framework and the principle of human primacy. In the Norwegian Health Research Act, this issue is addressed in § 22 (4). The provision is based on an outdated version of the Declaration of Helsinki. Since the Act – as a whole – is meant to incorporate the Oviedo Convention and the Additional Protocol into Norwegian law, the provision should, nevertheless, be interpreted in line with Article 23 of the Additional Protocol.

14.5 Conclusions: Proportionality in Placebo Controlled Trials The assessment of proportionality in randomised clinical trials is in practice difficult because the research intervention is not just one alternative, but several. A summary may therefore be clarifying. A systematic, step-by-step approach, in line with the more general norms in the Additional Protocol and the Clinical Trials Directive (the requirement of proportionality), as well as the more specific provisions in Article 23 of the Additional Protocol, is needed in the assessment of proportionality: 1. The research (experimental) intervention: Are the risks and burdens to the participants in the intervention (experimental) group outweighed by the potential benefits (including direct benefits)?28 2. The active control: Are the risks and burdens to the participants in the active control group outweighed by the potential benefits to science and society?29 3. The placebo control: Are the risks and burdens to the participants in the placebo control group outweighed by the potential benefits to science and society?30 4. . . . other alternatives must be assessed similarly. 5. Finally, the risk-benefit ratio of each alternative must be compared with each other. It must then be asked whether the additional risks and burdens associated 27

Cf. the discussion in Section 10.3.8. Cf. Chapter 10. 29 Cf. Chapters 11, 12, and 13. 30 Cf. Chapters 11, 12, and 13. 28

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with the poorer alternative(s) are outweighed by the potential benefits to science and society?31 In line with the clarifications in the foregoing chapters it is clear that vulnerable persons may exceptionally be exposed to only minimal risks and burdens for the sake of others (science and society). If one or more alternative entail disproportionate risks and burdens, that alternative must not be offered, despite scientific imperatives, and regardless whether the participant consent or not.32 If that implies terminating the whole research project, then the whole research project must be terminated.33

14.6 Whole Protocol Approach or Component-by-Component? The summary above may be linked to a particular question debated in US bioethical literature concerning whether it is the risks, burdens and potential benefits (added together) of the research project as a whole which should be weighed against each other (“whole protocol approach”), or if it is the risks, burdens and potential benefit from each research component or even each research procedure (componentby-component, or procedure-by-procedure approach).34 The discussion builds on flawed premises related to the doctrine of equipoise, and the debate will therefore not be pursued here.35 At any rate, as shown, a procedure-by-procedure, or component-by-component, approach can be necessary when identifying and maximising/minimising potential benefits, burdens, and risks.36 It may offer a more rigorous approach, especially when assessing long-lasting and complex research projects composed of numerous and various components and procedures. This should, however, not imply that one should loose sight of the research project as a whole. Only rarely will one research procedure result in scientific or societal benefits. On the contrary, it is usually by putting these more or less independent sequences together that an answer to the research question (and benefits to science) may be obtained. The procedures are therefore usually interdependent when referring to potential benefits. The burdens for participants of one research procedure may, for example, be separated more easily, and they may then be evaluated as minimal. But if added together, the burdens to the participant may be significant and not necessarily outweighed by the potential benefits to others. Similarly with the risks of harm: although the risks might in themselves appear trivial, they might be significant if added together. It then seems clear that the requirement of proportionality applies to the research project as such, 31

Cf. Section 10.3.6. Cf. Section 5.4.4. 33 See Section 5.2.5. 34 The US National Bioethics Advisory Commission, Final report (2007, pp. 79 et seq.). 35 Discussed in Section 10.3.8 above. 36 See Chapters 7 and 8. 32

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and that it is the end result which is important; i.e. whether the risks and burdens to the research participant of this research project are disproportionate to potential benefits (to science, society (future patients) as well as direct therapeutic benefits to the participant). The same follows from the Clinical Trials Directive. Also in the practice of the European Court of Human Rights, a holistic approach is favoured. In, for example, the case of Olsson v. Sweeden, it was the overall effect of all the interferences – as a whole – that were decisive in the Court’s finding of disproportionality.37 In such a holistic approach it may be necessary to review the components and even the procedures independently. It may, for example, be necessary to eliminate or modify one procedure which is really not necessary, or because it entail excessive risks and burdens. The observed Research Ethics Committee required modifications of the protocol relatively often. Such an approach may, of course, not imply that prospects of direct benefits from standard therapy (for example, the benefits of a hip surgery) can be used to justify the risks and burdens of a research intervention (for example, the prolongation of the surgery in order to obtain tissue to be used in nontherapeutic research).38 The nontherapeutic research intervention has to be justified by the potential benefits to science or society. It may then be asserted that all research components and all research procedures should be designed to answer the research question, and that the research project as a whole must entail a proportionate relationship between risks, burdens, and potential benefits, also when compared with other available alternatives (including nonparticipation). Thus, although a component-by-component analysis can be helpful, and even necessary, it is the overall and contextual judgment of proportionality that is decisive in the end. This underscores that the assessment of proportionality is first and foremost a reasonability test, which cannot be validly interpreted and applied so that it leads to unreasonable results.39

37

ECtHR Olsson v. Sweden A 130 (1988). See Chapter 7 above that investigates which risks, burdens and potential benefits that are relevant in the assessment of proportionality. 39 Cf. Chapter 5. 38

Chapter 15

Acceptable Risks and Burdens to Others than the Participant

The primary concern of the Additional Protocol and the Clinical Trials Directive, and thus this book, is risks and burdens to the individual research participants. However, it was noted in Chapter 7 that risks and burdens to other persons and entities than the research participants may also be relevant in the assessment of proportionality.1 Typical “other persons and entities”, as well as risks and burdens to such “other persons and entities” were identified there, such as risks to relatives, other patients, society, and the environment. The question, to be briefly addressed in the following, is: what level of risks and burdens to others may be acceptable? The question is not explicitly addressed in the Additional Protocol or the Clinical Trials Directive. However, the answers may be derived from the more general principles identified in this book, since consistency in the legal framework is an aim. In accordance to the requirement of proportionality the risks and burdens to nonparticipants must be outweighed by the potential benefits.2 The nonparticipating risks-carriers will usually be identifiable or unidentifiable persons who do not consent to participate in research. Thus nonparticipants are without their explicit knowledge and consent exposed to risks and burdens in biomedical research for the sake of others. This scenario is comparable to the scenario where research participants are exposed to risks and burdens for the sake of others without either the participant’s consent or consent from the participant’s legal representative; i.e. research in clinical emergency situations.3 This suggests that the rules investigated in Chapter 12, should apply analogously. As shown, such research could only be justifiable on the strictest conditions, requiring utmost care. Moreover, the research should entail significant potential benefits and only minimal risks and burdens.

1 Note that the relevancy of risks and burdens to others presupposes that both causes in fact and causes in law (proximity of cause) can be established, cf. Chapter 7. 2 Cf. Chapter 10. 3 See Section 5.2.4.

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Since the potential benefits will, at best, usually be of remote interests for burdened risk-carrier, risks and burdens above minimal risks and burdens appears unacceptable, regardless of the greatness of the potential benefits to others. The limit should possibly be far lower if the research project put a large number of people at risk (for example, a community, region, ethnic group, country (pandemic) and so on). The risks and burdens associated with living next to a nuclear power station or high-voltage cables are, for example, dreaded by most people, even if the likelihood of harm is very remote and the potential benefits to others are great.4 The US legal scholar David B. Resnik and colleague Richard R. Sharp seemingly argue for a more liberal approach, when they are ready to tolerate even more than minimal risks as long as a strategy for the management of risks is developed.5 Lucas Bergkamp is probably more to the point when he draws upon human rights law and the precautionary principle in environmental law, and maintain that “we should err on the side of caution (and thus prohibit such research) and assign the burden of proof to those proposing the research.”6 Biomedical research that entails risks and burdens to others than voluntary participants should clearly be subject to very strict standards and utmost care. Hence, it appears sensible and correct to recognise a precautionary principle in biomedical research law. A precautionary principle may, as argued by Bergkamp, be based on an analogy to environmental law and biosciences where it is (an emerging) principle of customary international law.7 In an EU communication on the precautionary principle it is stated: The precautionary principle applies where scientific evidence is insufficient, inconclusive or uncertain and preliminary scientific evaluation indicates that there are reasonable grounds for concern that the potentially dangerous effects on the environment, human, animal or plant health may be inconsistent with the high level of protection chosen by the EU.8

Indeed, the requirement of proportionality may be seen as a precautionary rule. At any rate, a precautionary principle is especially imperative when an intervention is associated with uncertainty (unknown risks9 ) and the research entails catastrophic potential, even though the likelihood is extremely low (theoretical/unknown). A precautionary principle would then be of particular interest in novel research interventions in largely unexplored fields of biomedicine, such as gene therapy. It

4

Slovic (2000); the risk of dying in any one year from the release of radiation from nearby nuclear power station is approximately 1 in 10 000 000 (BMJ Living with Risk 1987, p. 23). 5 Resnik and Sharp (2006). 6 Bergkamp (2004, p. 65). 7 See World Commission on the Ethics of Scientific Knowledge and Technology (COMEST) (2005, p. 22). 8 EU communications (2000). 9 Cf. Section 7.3 which discusses the concept of “(known) unknown risks”.

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may also apply to more traditional fields, for example, clinical trials with pharmaceutical drugs where there might be a chance of mutations in (or uncontrolled release of) viruses that may result in new lethal or resistant viruses. Phase III of the Meningococcal B Vaccine Trial Case may illustrate a less dramatic scenario10 : In the subsequent investigation the researchers in that trial were criticised for not have taken due account of the burdens to the general health care system. Many public health nurses at schools spent considerable time on informing participants, vaccinating participants, treating side effects and so on. This implied that (at least some) other tasks, including other nonparticipating children health needs, were downgraded or neglected. The nurses complained about this to the researchers during the trial, but the critique was apparently not duly regarded. In hindsight, it seems clear that the burdens to the health care system, and subsequently other patients, should have been considered in the overall assessment of proportionality prior to the approval of the trial. It may thus be concluded that when biomedical research entail risks and burdens to others than the participants, the utmost care must be exercised. The strictest standards apply, including a precautionary principle that implies that the researchers have, as always, the burden of proof in the justification of the research project.11 In Europe, this implies that the risks and burdens to others (nonparticipants) should, as a starting point, be below the minimal.

10 11

Accounted for in Section 11.4.5. Cf. Section 8.4.

Chapter 16

Later Developments During the Course of the Research

Clearly, the requirement of proportionality applies continually during the course of the research project: from the beginning until the end. Article 3 (2) (a) in fine of the Clinical Trials Directive make this clear when it states that a research project “may be continued only if compliance with this requirement [of proportionality] is permanently monitored.” The provision is natural and easily derivable from the requirement of proportionality itself. The norm is briefly addressed in the following. A related provision is found in Article 24 of the Additional Protocol concerns new developments in the course of the research: 1. Parties to this Protocol shall take measures to ensure that the research project is reexamined if this is justified in the light of scientific developments or events arising in the course of the research. 2. The purpose of the re-examination is to establish whether: i. the research needs to be discontinued or if changes to the research project are necessary for the research to continue; ii. research participants, or if applicable their representatives, need to be informed of the developments or events; iii. additional consent or authorisation for participation is required. 3. Any new information relevant to their participation shall be conveyed to the research participants, or, if applicable, to their representatives, in a timely manner. 4. The competent body shall be informed of the reasons for any premature termination of a research project.

Possible negative developments during a research project are the primary concern of the provisions in Article 24 of the Additional Protocol. The Explanatory Report holds that “an acceptable reason for termination of a research project is when it becomes statistically clear that the research treatment is significantly worse than standard treatment, and hence it would be ethically unacceptable to continue the research project.”1 This would imply that the proportionate relationship between 1

Paragraph 127.

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risks, burdens and potential benefits has been altered so that the relationship is no longer proportionate. The Explanatory Report further notes that “the publication of results by other researchers from studies that may either negate the original justification for the study (although it must be remembered that verification is an essential element of the process of validation in science) or that raises questions about the safety of the research in question” may imply that a previous proportionate relationship later become disproportionate.2 If the risks and burdens become disproportionate during the course of the research project, the research project must be amended or stopped. This follows from Article 3 (2) (a) in fine of the Clinical Trials Directive, as well as Article 24 (and surely also Article 6) of the Additional Protocol. It may also easily be derived from researchers’ duty of care. In the Meningococcal B Vaccine Trial the researchers were criticised for not reconsidering the risks and benefits before initiating an additional study that concerned giving active vaccine to those participants that had been assigned to the placebo group. The vaccination was partly given as a token of gratitude to those who “unfortunately” had been assigned to the placebo group in the main trial. The vaccination of the placebo group was, however, designed as a nonblinded clinical trial. The vaccination of the placebo group had been planned and accepted prior to the main trial, because the researchers expected the vaccine to be safe, effective, and needed, which did not turn out to be quite right. The failure of re-examination in light of new knowledge about risks and benefits was criticised by the investigating commission.3 Possibly, the failure led to the exposure of 58 000 adolescents to unnecessary and excessive risks and burdens.4 However, it is clear that a certain degree of uncertainty and latitude may be acceptable as long as the risks and burdens are within the limits of the requirement of proportionality. Thus, not any changes in the level of the risks, burdens, and potential benefits results in disproportionality. It would be a rather tall order to require equality between all alternatives at all times. Stopping a research project because of a reconsideration of the risk-benefit relationship (proportionality) is, however, a double-edged sword. Trotta and colleagues conclude after an investigation of clinical trials stopped early, that: early termination raises new concerns. The relation between sparing patients and saving time and trial costs indicates that there is a market-driven intent. We believe that only untruncated trials can provide a full level of evidence which can be translated into clinical practice without further confirmative trials.5

2

Paragraph 127. Report on the Norwegian Meningococcal B Vaccine Trial (2007, pp. 148–150). 4 The trial, including the risks, burdens, and potential benefits, are accounted for in Sections 11.3 and 11.4. 5 Trotta et al. (2008, p. 1347). 3

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The necessity, including the costs and benefits, of stopping a project must thus be evaluated thoroughly to reveal any substitutive and dubious motives. It may thus be concluded that as long as the risks and burdens are acceptable and not disproportionate, it may be legitimate to continue the research project. But a research project should be amended or stopped as soon as it becomes fairly clear that the risks and burdens are no longer in proportion to the potential benefits. Moreover, the research project must be stopped immediately if there are reasons to believe that the research is detrimental to anyone’s health, regardless of scientific imperatives of seeing the research project through. In such circumstances it may be prudent (if not obligatory) to adequately inform the participants, sponsors, and the health authorities. See also the Clinical Trials Directive Articles 16 and 17 concerning notification of adverse events.6

6

In Norway this follows from § 23 and § 24 in the Norwegian Health Research Act.

Chapter 17

Legal Effects of the Requirement of Proportionality

17.1 Problem Addressed In this chapter the legal effects of the requirement of proportionality is going to be briefly outlined. The outline is brief as the exact legal effects depend on domestic legislation. Nevertheless, the question is: What is the legal relevance and effect of a disproportionate relationship between risks, burdens, and potential benefits in biomedical research?

17.2 In Breach of Researchers Duty of Care As shown in Section 5.3, the requirement of proportionality specifies researchers’ duty of care towards participants (and possibly others) in the biomedical research project they are involved in and responsible for. This implies that it is in breach of researchers’ duty of care to undertake research that entails disproportionate risks and burdens. A research project may therefore not be undertaken if the risks and burdens are disproportionate. The participants’ perceptions and ability to consent do play a prominent role in the assessment of proportionality. Nevertheless, the consent does not make a disproportionate research project appropriate, because the requirement of proportionality is independent of the requirement of consent.1 The requirement of proportionality must be fulfilled before prospective participants are asked to consent. Consequently, the participants may not waive the requirement of proportionality. To ensure proportionality is a professional obligation applicable to all researchers. That it is a professional obligation further implies that no researcher may be instructed or ordered to carry out an act that entail disproportionate risks and burdens.2 1

Cf. Section 5.4; see Grimes v. Kennedy, accounted for in Section 12.5.10. This principle has, at least, a firm basis in Norwegian Health Law, see the Norwegian Health Personnel Act § 4 and § 16; Kjønstad (2005a, p. 314). 2

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17.3 Invalid Consent If the risks and burdens are disproportionate, as illustrated by the US case Grimes v. Kennedy Krieger, a valid consent cannot make the risks and burdens proportionate.3 However, the validity of consent depends on the information given; disproportionality may thus be of relevance for the validity of the given consent. Disproportionality may then be seen as a failed premise for the consent rendering the consent void (initially failed contractual assumptions).4 The participant may rightly assume (trust) that the research project entails only risks and burdens that are proportionate to the potential benefits. Thus, if it turns out that the risks and burdens were disproportionate (or they became disproportionate during the course of the research and the research was not amended or stopped), the consent may no longer be valid as it may be based on failed premises.

17.4 Compensation for Damage Research participants suffering damage are as a general rule entitled to compensation, usually on a no-fault basis (liability without fault), even if the relationship between the risks, burdens, and potential benefits was proportionate.5 Article 31 of the Additional Protocol state: The person who has suffered damage as a result of participation in research shall be entitled to fair compensation according to the conditions and procedures prescribed by law.

The Clinical Trials Directive Article 3 (2) (f) requires that: . . . provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor.

However, disproportionality may have some important legal effects in this regard, as disproportionate research exposes the participant to unnecessary and unreasonable (unjustified) risks and burdens. Fault-based liability may (probably in most national jurisdictions in Europe) be established if the damage is caused by carelessness or negligent behaviour in breach of the researcher’s duty of care. Thus, if the research entailed disproportionate risks and burdens that have manifested themselves in damage, a more extensive liability for damages applies than liability on a no-fault basis. This is especially important if compensation of damages is not awarded on a no-fault basis.

3

Accounted for in Section 12.5.10. This view was taken by the Court in Grimes v. Kennedy (see Section 12.5.10), and the same legal solution is highly probable in European law, at least, in Norwegian law. 5 Compare the CIOMS Guideline 19; Legal liability on a no-fault basis must be regarded as the general rule in Norwegian law, see Simonsen (2010a, b) in relation to the Norwegian Health Research Act § 51. 4

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Criminal Liability and Prosecution

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Disproportionality may then imply that the researcher may be found to have acted negligently and is to blame (individual liability). Disproportionality and recklessness may also imply that compensation for injury of non-pecuniary character (“aggravated damages”/“punitive damages”) may be awarded. Liability as a result of reckless behaviour may also be relevant when the researcher has failed to undertake a diligent assessment of proportionality.

17.5 Criminal Liability and Prosecution The commencement of research entailing disproportionate risks and burdens may in graver circumstances result in criminal liability and prosecution. Exposing individuals to unjustified, illegal, and unreasonable risks of harm and burdens may be seen as an “assault”.6 Both reckless (negligent) as well as intentional (deliberate) criminal liability may be pertinent in cases of manifest disproportionality.

6

On “assult” in Norwegian Health law see Aasen (2000, pp. 290 et seq.).

Part IV

Summary and Conclusions

Chapter 18

Summary of Results

The Legal Basis and Status of the Requirement of Proportionality The requirement of proportionality between relevant risks, burdens, and potential benefits in interventional biomedical research is a core legal norm in the CoE Oviedo Convention and its Additional Protocol, as well as in the EU Clinical Trials Directive, thus in both Convention law and in Community law.1 The requirement is, despite various wordings, essentially the same in Convention law and Community law. Regulatory harmony is both feasible and legally sustainable. It is also to be expected as the provisions have a mutual origin in the Nuremberg Code, international human rights law, the Declaration of Helsinki etc.2 Most European states are legally obliged by at least one of the mentioned instruments to make this norm effective in national law. The requirement of proportionality is therefore assumingly a legal norm in most, if not all, European jurisdictions, as it is in Norway.3 The legal regulation is mainly similar in the United States of America.4 The Role and Purpose of the Requirement of Proportionality The pivotal importance of the requirement of proportionality is underscored by scientific studies that show that many research participants misconceive and do not fully comprehend the consequences of their own participation, even when “adequately” informed. For example, many participants believe the intervention is undertaken to benefit their own health, when the intervention is in fact undertaken solely for the sake of science. In effect, many research participants apparently base their consent on trust towards the researcher. The requirement of proportionality aims to ensure that this trust is not misplaced.

1

Oviedo Convention Article 16 (ii); Additional Protocol Article 6; Clinical Trials Directive Article 3 (2) (a). 2 See Simonsen (2011). 3 See Health Research Act 2008 § 22 (2) and (4); and Secondary law concerning the Clinical Trials Directive 2003 § 1-5 (b), and § 3-1, § 4-2, and § 4-3. 4 Cf. US Federal law 45 CFR 46 “Common rule”.

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My 3-year observational study of a REC indicates that many researchers have a lax attitude towards the assessment of proportionality. Furthermore, researchers tend to overestimate potential benefits, while simultaneously downplay and undercommunicate risks and burdens in their written information to prospective participants. This may be a result of laxity, enthusiasm, or the fear of refusal from prospective participants. At any rate, biased or misleading information about risks, burdens, and potential benefits may render the consent invalid. Moreover, there is an obvious potential conflict of interests between the interests of the research participant’s and those of the researcher; and in that potential conflict it is the researcher who controls the information and thus is the stronger (professional) party. A potential conflict of interests is evident in the history of biomedical research, and it has not been reduced with increasing public and commercial interests in biomedical research.5 Primarily for these reasons, all interventional biomedical research projects must be submitted to a multidisciplinary research ethics committee before it is commenced.6 However, the observed Research Ethics Committee did not have a clarified and systematic approach towards the assessment of proportionality, as the Committee did have to the review of the consent procedure. The Committee tended to focus on more easily assessable, but less important, issues than the assessment of proportionality. It could thus be asked whether the risks, burdens, and potential benefits were sufficiently assessed. The assessment could, at any rate, be improved.7 This finding is in line with sporadic, but consistent, reports in bioethical literature in both Europe and the US on the practice of research ethics committees. To assess whether the requirement of proportionality is fulfilled is the single most important judgment researchers and researcher ethics committees must make to ensure that the research participants are sufficiently protected. The purpose of the requirement of proportionality is to ensure due care, and by that hinder the possibility that participants and others are exposed to unnecessary, unreasonable, and excessive risks and burdens: research participation should be a reasonable choice. By that the requirement of proportionality is especially aimed at protecting vulnerable persons and hinders exploitation; that is to mend the unreliability and insufficiency of participants consent. A secondary aim of the requirement of proportionality and the European legal instruments is to promote regulatory harmony by establishing common (minimum) standards, and by that also facilitate scientific cooperation and progress in the field of biomedicine in Europe. However, if conflicts of interest occur, both Convention law and Community law have taken an unequivocal stand in favour of protecting the interests, welfare, and

5

See Chapters 4 and 5. See World Medical Association, Medical Ethics Manual 2nd ed. (2009, p. 102). 7 See the recommendations made below. 6

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human dignity of the individual research participant, when embracing the principle of human primacy: The interests and welfare of the human being participating in research shall prevail over the sole interest of society or science.8

The requirement of proportionality supplements and specifies the overarching principle of human primacy, as a tool for balancing various legitimate interests. The requirement of proportionality must, on the other hand, always be interpreted in light of the principle of human dignity. The possible and serious legal effects of disproportionality underscore the vital role of the requirement of proportionality in biomedical research law. Possible legal effects are breaches of researchers’ professional and legal duty of care, individual criminal liability, liability for damages, and invalidity of consent. The Relationship Between the Requirements of Proportionality and Consent The relationship between the requirement of proportionality and the requirement of consent is the key to understand the requirement of proportionality. The requirement of proportionality is independent of the requirement of consent, and as a result both requirements must be fulfilled. This implies that a valid consent does not render a disproportionate research project appropriate or proportionate, and vice versa. The legal effect of disproportionality is that it would be in breach of the researcher’s duty of care to offer individuals participation, regardless of the participants’ consent. Thus, one may say that researchers’ duty of care is stricter and trumps the participant’s consent. To put it bluntly: Individuals may act in a foolhardy manner, but responsible researchers may not. The rationale is to prevent reckless research and undue exploitation of individual persons. The restrictions are also meant to ensure and foster trust in research and respect for human dignity. However, prospective participant’s individual perceptions of risks, burdens, and potential benefits, as well as his or her ability to consent and otherwise protect his or her own interests are important in the assessment of proportionality. When Are Risks and Burdens Proportionate to Potential Benefits, and thus Legally Acceptable? This is the main question addressed in this book. The normative content of Article 6 (1) of the Additional Protocol and the Clinical Trials Directive Article 3 (2) (a) is essentially, and for all practical purposes, a traditional requirement of proportionality between means and ends in the field of biomedical research. The requirement implies that risks and burdens entailed in a biomedical research project are acceptable when there is a reasonable, justifiable, and proportionate relationship between risks, burdens, and potential benefits. This means that all 8 Article 3 of the Additional Protocol. The principle is also expressed in similar language in the Oviedo Convention Article 2; The GCP Directive Article 2 (1); and the Declaration of Helsinki (from which it originates) Paragraph 5.

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relevant risks, burdens, and potential benefits must be identified, estimated, and weighed. The requirement of proportionality is supplemented and specified by several additional preconditions that must be fulfilled before proportionality can be established. In summary the legal conditions for proportionality in European law may be said to be: • Risks and burdens to the participant should as a main rule be outweighed by prospects of direct benefits to the same participant (the so-called “direct benefit rule”). • If not, risks and burdens to the participant may exceptionally be outweighed by potential benefits to others (science, society, future patients etc.). In the second category, both the Additional Protocol and the Clinical Trials Directive differentiate between research on persons able to consent on the one hand, and persons not able to consent and similarly vulnerable persons on the other hand.9 The latter then becomes a third category. This tripartition concerning the legal notion of acceptable levels of risks and burdens is: Category 1:

Category 2:

Category 3:

The most risks and burdens may be proportionate if they are outweighed by direct benefits to the same participant (whether or not the participant is able to consent).10 Some risks and burdens may be proportionate if they are outweighed by potential benefits to others and if the participant is relatively invulnerable and able to consent.11 If the participant is not able to consent or similarly vulnerable, the least (only “minimal”) risks and burdens may be proportionate and outweighed by potential benefits to others.12 • The potential benefits must be a “significant improvement” and be related to the participants condition or group-belonging (“significant” potential benefits) • The risks and burdens to the participant must be “only minimal”

9

See Section 3.8 for the definition of vulnerable. See Chapter 10. Article 6 (1) of the Additional Protocol and Article 3 (2) (a) of the Clinical Trials Directive; Article 15 (1) which regulate therapeutic research on persons able to consent is “silent” on the level of acceptable risks and burdens, which implies that the “general” requirement of proportionality apply. Thus the category could have been split up in two categories, but since the “rule” is the same they are treated simultaneously, see, however, Section 10.3.5 where the “differences” are addressed, see also Section 9.3.2. 11 See Chapter 11. Article 6 (2) (1) of the Additional Protocol, cf. Article 3 (2) (a) of the Clinical Trials Directive. 12 See Chapter 12. Article 6 (2) (2), cf. Articles 15–20 of the Additional Protocol and Articles 4 and 5 of the Clinical Trials Directive. 10

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This is the interpretation of the provisions which best realises the purposes of the requirement of proportionality as well as the purposes of the legal instruments read as a whole.13 In the first category even a considerable risk of death may be acceptable if outweighed by prospects of direct therapeutic benefits to the participant, even if he or she is vulnerable. In the second category considerable risks and burdens may be acceptable, but the level of acceptable risks and burdens is dependent on qualitative and subjective factors, such as the prospective participant’s (assumed) individual perceptions of risks, burdens, and potential benefits, as well as his or her ability to consent and otherwise protect his or her own interests. Importantly, no matter the greatness of the potential benefits to others, no more than “acceptable” risks and burdens can be proportionate. Thus there are limits to what level of risks and burdens a person may consent to carry for the sake of others. For example, a high risk of death (around 1 in 1 000) is as a rough guiding point probably not acceptable even for the most informed and altruistic volunteer, and regardless of the potential benefits to others. A “minimal” risk, applicable in the third category is significantly lower (probably around 1 in 500 000 for death). The practical implication is then that the legal framework does not accept that largely unnecessary or insignificant interventional biomedical research includes vulnerable persons.14 The assessment of proportionality thus requires an evaluation and valuation (weighing) of the research project potential benefits that may conflict with the researchers’ freedom of research and academic freedoms. However, these freedoms must, if conflicts occur, yield way for the protection of the participants’ interests, welfare and human dignity, as illustrated by Fig. 9.1. Randomised clinical trials, including placebo-controlled trials, are subject to the same standards as those outlined above. But such trials often consist of several alternatives (active intervention, active control, placebo control etc.), which may complicate the assessment. It is therefore especially important to compare the risk-benefit ratio of each alternative with other available alternatives (including nonparticipation) to ensure that risks and burdens are not excessive or unacceptable, for example, because a participant is denied or given delayed effective treatment. Research should never be outright detrimental to anyone’s health. In this perspective, the requirement of proportionality may be seen as a precautionary principle that implies that we should err on the side of caution.15 It is therefore the researchers who carry the burden of proof that risks and burdens are proportionate to potential benefits. The requirement of proportionality thus depends on a dynamic and contextual overall judgment. This means that the level of legally acceptable risks and burdens within each of the three main categories varies dependent on numerous factors. The

13

Cf. above and Chapter 5 where the purpose(s) are analysed. See World Medical Association, Medical Ethics Manual 2nd ed. (2009, pp. 102–103). 15 Bergkamp (2004, p. 65). 14

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judgment cannot solely be based on a mathematical calculus (quantification). That is in most, if not all, cases virtually impossible because of the lack of sufficient empirical data. It is besides legally unsustainable as more qualitative and subjective factors are also highly relevant in the assessment of proportionality, such as the nature of the research project and individual considerations and perceptions.16 Although, prospective participants’ experience and perceptions of risks and burdens are relevant, an “objective” standard of minimal risks and burdens applies in at least one respect: vulnerable and disadvantaged persons (e.g. a sick child) cannot be exposed to greater risks than less vulnerable persons (a healthy child) simply because they are accustomed to or at greater risks and burdens. That would be in breach of the legal framework and go against everything the instruments intend to prevent; namely the abuse of the most vulnerable. The legal conditions are minimum standards. This means that national law, ethics or professional guidelines may entail stricter standards (wider protection).17 Interventional biomedical research on human beings must thus comply with intentionally very strict standards. As stated in the Explanatory Report to Article 17 of the Additional Protocol concerning minimal risk and research on vulnerable persons: It is only in respecting this and the other preconditions of Article 15 that such research may be carried out. To act otherwise would be to exploit these persons contrary to their dignity. . . . The risk for such participants cannot be increased beyond minimal even if the research promises a higher level of benefit.18

16

See Chapter 8 and Meslin (1989, p. 130). See Article 34 of the Additional Protocol. 18 Paragraph 96. 17

Chapter 19

Recommendations

There are reasons to believe that many researchers’ and research ethics committees’ assessments of proportionality can be improved. This assessment is difficult because of the lack of empirical data on risks, burdens, and potential benefits, and because numerous contextual and incommensurable elements may be relevant. There are no easy and fixed categorical limits. Nevertheless, an overall judgment must be made, and the most important judgment for the safety and welfare of the participants must be given priority. Faced with limited resources one may make a differentiation between harmless, moderately risky, and high-risk research (but harmless does not always imply proportionality). High-risk research should always be assessed rigorously, and the assessment may benefit considerably if independent experts are consulted (which is explicitly required in Articles 4 (h) and 5 (g) of the Clinical Trials Directive concerning research on children and persons not able to consent).1 A way of improvement is to address the assessment of proportionality between risks, burdens, and potential benefits systematically. A systematic approach may involve asking control questions, such as: • Is the study aim clear and the method adequate? • Is the research project necessary or could a comparable effect (e.g. researcher training or essentially the same knowledge) be obtained by lesser means? • Are risks and burdens minimised, and potential benefits maximised? • What are the potential benefits to science, future patients (society), and the research participants? • What is the participant asked to shoulder (and perhaps sacrifice) in terms of burdens? • What are the risks to the individual participant? • What are the risks and burdens to others than the participants? • Do the prospects of direct therapeutic benefits to the participant outweigh the risks and burdens to the same participant? And is research participation an option 1

The observed Research Ethics Committee regularly did this; see, for example, the Obesity Study.

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• •

• • •

19 Recommendations

just as favourable as other available alternatives, including nonparticipation and standard treatment? If not, are the additional risks and burdens carried for the sake of others, outweighed by the potential benefits to others? If the research project includes vulnerable persons: Are the additional risks and minimal? Are the potential benefits to others significant and related to the participant’s condition or group-belonging? Are the minimal risks and burdens outweighed by the significant potential benefits? Is participation in the research project detrimental to anyone’s health? Is the participant adequately informed about possible consequences (risks, burdens, and potential benefits) and available alternatives? Are adequate mechanisms in place to monitor and ensure that risks and burdens are proportionate to potential benefits throughout the research project?

A systematic and rigorous approach may raise awareness, and should improve both the assessment of proportionality and the information given to prospective participants.

Chapter 20

Perspectives

The European legal framework could have been clearer and easier to harmonise. However, it is both feasible and legally permissible (and often necessary) to harmonise the Oviedo Convention and its Additional Protocol and the Clinical Trials Directive, because of the instruments mutual aim of protecting the research participant and contributing to regulatory harmony in Europe. Indeed, it must be presumed that Community law is in harmony with Convention law in this field.1 Besides, the legal framework appears to reflect a broad and vested international consensus on this subject: Hazardous and burdensome human experiments may take place, but the research subjects must be adequately protected. Putting people at risk for the sake of potentially new useful knowledge is morally challenging. But nothing is risk free. Stopping research and embracing the status quo, also entails risks and burdens. But if adequate protection cannot be ensured, the research project and the progress of science must yield. As stated by the German-born philosopher Hans Jonas (1903–1993) in 1982: Let us not forget that progress is an optional goal, not an unconditional commitment, and that its tempo in particular, compulsive as it may become, has nothing sacred about it. Let us also remember that a slower progress in the conquest of disease would not threaten society, grievous as it is to those who have to deplore that their particular disease be not yet conquered, but that society would indeed be threatened by the erosion of those moral values whose loss, possibly caused by a too ruthless pursuit of scientific progress, would make its most dazzling triumphs not worth having.2

If interpreted and applied correctly the current European legal framework offers adequate protection for human participants in biomedical research. I have identified only a few particular issues where there is an urgent need for amendments because the legal norm is obviously flawed.3 Most challenges can, however, as shown, be

1

Cf. Section 2.2 and Simonsen (2011); See Judgment by the ECtHR in Bosphorus Hava Yallari Turizm ve Ticaret Anonim Sirketi v. Ireland of 30 June 2009 (Grand Chamber, with dissenting opinion), Paragraph 159. 2 Jonas (1982, cited in Meslin 1989, p. 247). 3 See Chapter 12 concerning clinical trials on persons not able to consent.

S. Simonsen, Acceptable Risk in Biomedical Research, International Library of Ethics, Law, and the New Medicine 50, DOI 10.1007/978-94-007-2678-9_20,  C Springer Science+Business Media B.V. 2012

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266

20

Perspectives

overcome by way of interpretation consistent with legal method and the instruments as a whole, including their purpose and underlying reasoning (raison d’être). The difficulty of weighing risks and burdens against potential benefits may be used as an argument against a requirement of proportionality. Indeed, this has some led bioethicists to suggest different and more inflexible standards. Those suggestions are in my opinion ill-founded and contrary to the legal framework. The fate of vagueness and demand for a concrete overall judgement is shared by many legal norms and standards in this and other fields. What characterises the requirement of proportionality is not its irrelevancy, inadequacy or inapplicability, but its strong call for a sound discretionary and concrete assessment; judiciousness. For lawyers, ethicists, or medical professionals such an order should be familiar and not a deterrent. It is also the better way of ensuring sensible solutions. Vagueness and a gradual scale may pave the way for a slippery slope. This is perhaps the other major argument against a requirement of proportionality. The requirement of proportionality is, however, a strict test, which does not legitimate a slippery slope. The principle is not a utilitarian principle, but rather a paternalistic principle aimed at protecting the individual (the few) against undue exploitation by society and science (the many), while at the same time facilitating autonomy, altruism, and sound research. In this perspective it is clear that the requirement of proportionality also has a central role to play in the future. Indeed, there are clear indications that researchers and research ethics committees should devote more attention to the assessment of proportionality. An improved assessment of proportionality may not necessarily mean a stricter assessment, but rather a more accurate assessment. An improved assessment should lead to better biomedical research; understood as beneficial and publically acceptable research. Simultaneously, it should also lead to less bad research, understood as largely unnecessary or excessively hazardous, and thus publically unacceptable research. History has shown that biomedical research must be conducted on terms palatable by the general public. That will be even more important in the future, in order to get public funding, public approval, and not least, voluntary participants. It is thus likely that the requirement of proportionality will play an even greater role in the regulation of interventional biomedical research in the future to strike a fair balance between various interests in a multifarious and rapidly changing field.

Appendix A Legal Instruments

United Nations Year 1945 1945

Title Charter of the United Nations The Statues of the International Court of Justice

1969 1966 1966

The Vienna Convention on the Law of Treaties International Covenant on Civil and Political Rights International Covenant on Economic, Social and Cultural Rights Convention on the Rights of the Child

1989

Reference United Nations Annexed to the Charter of the United Nations United Nations United Nations United Nations United Nations

The Council of Europe (Convention Law) Year 1949 1950 1981

1997

1998

Title Statute of the Council of Europe Convention for the Protection of Human Rights and Fundamental Freedoms Convention for the Protection of Individuals with regard to Automatic Processing of Personal Data Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine Additional Protocol to the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine, on the Prohibition of Cloning Human Beings

Reference Council of Europe. London.V.1949 Council of Europe. Rome, 4.XI.1950 Council of Europe. Strasbourg, 28.I.1981

The Council of Europe. Oviedo, 4.IV.1997

The Council of Europe. Paris, 12.I.1998

S. Simonsen, Acceptable Risk in Biomedical Research, International Library of Ethics, Law, and the New Medicine 50, DOI 10.1007/978-94-007-2678-9,  C Springer Science+Business Media B.V. 2012

267

268 Year 2002

2005

2008

Appendix A: Legal Instruments Title Additional Protocol to the Convention on Human Rights and Biomedicine, on Transplantation of Organs and Tissues of Human Origin Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research Additional Protocol to the Convention on Human Rights and Biomedicine concerning Genetic Testing for Health Purposes

Reference The Council of Europe. Strasbourg, 24.I.2002

Council of Europe. Strasbourg, 25.I.2005 Council of Europe. Strasbourg, 27.XI.2008 [Not yet in force]

The European Union (Community Law) Year 1995 2001

2005

2006

2006

Title The EU Personal Data Directive Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. L 121/34 Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medical products for paediatric use Consolidated Version of the Treaty of the European Union

Reference Directive 95/46/EC Directive 2001/20/EC

Commission Directive 2005/28/EC L 91/13

Regulation (EC) No 1901/2006

29.12.2006 EN Official Journal of the European Union C 321 E/1

Appendix A: Legal Instruments

269

Norway Year 1902 1974 1981

Title The General civil penal code Animal Welfare Act Criminal Procedure Act Section

1999

Patients’ Right Act

1999

Health Personnel Act

2006

Research Ethics Act

2008

Health Research Act

2009

Secondary legislation concerning clinical trials

Reference LOV-1902-05-22-10 [Straffeloven] LOV-1974-12-20-73 [Dyrevernlova] LOV-1981-05-22-25 [Straffeprosessloven] LOV-1999-07-02-63 [Pasientrettighetsloven] LOV-1999-07-02-64 [Helsepersonelloven] LOV-2006-06-30-56 [Forskningsetikkloven] LOV-2008-06-20-44 [Helseforskningsloven] [Expected entry into force 1 July 2009] FOR 2009-10-30 nr 1321 [Forskrift om klinisk utprøving av legemidler til mennesker]

The United States of America Year 2005

Title US Federal law “Common Rule”

Reference US Code of Federal Regulations (CFR), Title 45, Public Welfare, Department of Health and Human Services (DHHS) Part 46 Protection of Human Subjects

Nonlegal Instruments (Soft Law, Guidelines, etc.) Year 1947 1948

Title Universal Declaration of Human Rights The Declaration of Geneva

1953

Code of Ethics for Nurses

1954

The International Code of Medical Ethics Declaration of Helsinki Ethical Principles for conducting Research with Human Participants Recommendation No. R (90) 3 concerning medical research on human beings

1964 1978 1990

Reference United Nations Adopted by the World Medical Association (WMA) International Council of Nurses’ (ICN) (last revised in 2005) Adopted by WMA Adopted by WMA (revised in 2008) British Psychological Society, first adopted in 1978 Council of Europe. Recommendation No. R (90) 3 of the Committee of Ministers to Member States concerning Medical Research on Human Beings

270 Year 1991

1996 1996

1998 2002

2005 2006

2008

Appendix A: Legal Instruments Title The CIOMS International guidelines for ethical review of epidemiological studies ICH GCP: Guidelines for Good Clinical Practice International Code of Ethics for Psychiatry (the Madrid Declaration) Ethical Principles for Nordic Psychologists The CIOMS Guidelines: International Ethical Guidelines for Biomedical Research Involving Human Subjects Declaration on Bioethics and Human Rights Recommendation Rec(2006)4 on Research on Biological Materials of Human Origin Universal Declaration of Ethical Principles for Psychologists

Reference CIMOS: Council for International Organizations of Medical Sciences Adopted at the International Conference on Harmonisation World Psychiatric Association

Adopted by Nordic associations of psychologists CIMOS: Council for International Organizations of Medical Sciences

UNESCO Adopted by the Committee of Ministers at the 958th meeting of the Ministers’ Deputies Adopted by the Assembly of the International Union of Psychological Science and the Board of Directors of the International Association of Applied Psychology in Berlin 2008

Appendix B Case-Law

International Court of Justice (ICJ) Year 1997

Title Case concerning the Gabcikovo-Nagymaros Project

Reference ICJ Reports 1997

European Court of Human Rights (ECtHR) Year 1968

1968 1971 1975 1976 1976 1978 1979 1980 1981 1984 1986 1988 1989 1991 1995 2001 2001 2002 2002

Title Case relating to certain aspects of the laws on the use of languages in education in Belgium Wemhoff v. Germany Ringeisen v. Austria, Golder v. UK Handyside v. UK Engel et al. v. Netherland Tyrer v. UK Marckz v. Belgium, Artico v. Italy Dudgeon v. UK Öztürk v. Germany, Johnston v. Irland Olsson v. Sweden Soering v. UK Asch v. Austria Welch v. UK Boultif v. Switzerland Bankovic et al. v. Belgium and others Pretty v. UK Göktan v. France

Reference A 6 1968

A 7 1968 A 13 1971 A 18 1975 A 24 1976 A 22 1976 A 26 1978 A 31 1979 A 37 1980 A 45 1981 A 73 1984 A 112 1986 A 130 1988 A 161 1989 A 2003 1991 A 307 A 1995 Judgement of 2 August Decision of 12 December 2001 (Grand Chamber) Judgement of 29 April 2002 Judgement of 2 July 2002

271

272

Appendix B: Case-Law

Year 2007

Title Evans v. UK

2008 2008 2008 2008 2009

Saadi v. The United Kingdom Shtukaturov v. Russia Gäfgen v. Germany TV Vest v. Norway Bosphorus Hava Yallari Turizm ve Ticaret Anonim Sirketi v. Ireland

Reference Judgement of 10 April 2007 (Grand Chamber) Judgement of 29 January 2008 Judgement of 27 March 2008 Judgement of 30 June 2008 Judgement of 11 December 2008 Judgement of 30 June 2009 (Grand Chamber)

European Court of Justice (ECJ) Year 1969 1970 1980 1982 1990 1996

Title Stauder v. City of Ulm Internationale Handelsgesellschaft case Fellinger CILFIT v. Ministry of Health Fadesa United Kingdom v. Council

Reference ECR 419. ECR 1125

Shorthand name Water pipeline [Vannledningsdommen] Tuberculosis infection [Tuberkulosesmittedommen I] Vaccination [Vaksinedommen] Lymphatic node [Lymfeknutedommen] Struma [Strumadommen] Birt Pill II [P-pille dom II] Rossnes

Reference Rt. 1905 p.715

ECR 535 ECR 3415 C-331/88 ECR I-5755

Norway Year 1905 1960 1960 1981 1989 1992 1997 2007

Rt. 1960 p. 429 Rt. 1960 p. 841 Rt. 1981.728 Rt. 1989.674 Rt. 1992 p. 64 Rt. 1997 p.1 Rt. 2007 p. 1726

United Kingdom (UK) Year 1957

Shorthand name the Bolam Case

1992

the Bolitho Case

Reference Bolam v. Friern HMC [1957] 2 All ER 118 Bolitho v City and Hackney HA [1992] PIQR P334; (1997) 39 BMLR 1, HL

Appendix B: Case-Law

273

The United States of America (US) Year 2001

Shorthand name Grimes v. Kennedy Krieger

Reference 782 A.2d 807 (Md. 2001)

US Military Tribunal Year 1947

Shorthand name The Nuremberg Doctors Trial

Reference The Nuremberg Military Tribunal’s decision in the case of the United States v. Karl Brandt et al. of 19th of August 1947

Appendix C Case Examples

No 1 2 3

Title The Interval Training Case The Obesity Study The Stroke Studies

4

9

The Anorectics’ Metabolism Study The Meningococcal B Vaccine Trial - introduction Phase I of the Meningococcal B Vaccine Trial Phase II of the Meningococcal B Vaccine Trial Phase III of the Meningococcal B Vaccine Trial The MIDIA Study

10 11

The COPD Study The Pain Relief Study

5 6 7 8

Reference REC MN Case 4.2007.1168 REC MN Case 4.2005.1813 REC Western Norway Case 264.06 and 265.06 REC MN Case 4.2007.1954 Ad hoc Investigating Commission (REC EN) Ad hoc Investigating Commission (REC EN) Ad hoc Investigating Commission (REC EN) Ad hoc Investigating Commission (REC EN) The National Committee for Medical Research Ethics et seq REC MN Case 4.2007.1683 REC MN Case 4.2006.2893

See Section 10.2 10.3 10.3.6

11.3 11.4.2 11.4.5 11.4.5 12.5.8 13.1 14.4.2

275

Glossary

Able to consent and not able to consent: Used about a (prospective) research participant who is competent and able to give a legally valid consent to research participation or not. Burden (and inconvenience): The probability of discomfort caused by research. Direct benefit: real and expected/anticipated therapeutic benefits to the individual research participant. Healthy volunteer: A research participant who is neither under nor in need of health care, and who cannot expect any real and direct therapeutic benefits from research participation. Nontherapeutic research: Interventional biomedical research on human subjects, where the participants may not have reasonable prospects of real and direct therapeutic benefits. Patient: A person who contacts the health service requesting health care, or to whom the health service provides or offers health care as the case may be. A patient may participate in therapeutic as well as non-therapeutic research, and therefore expect or not expect direct therapeutic benefits from research participation. Potential (anticipated) benefits: The probability of positive consequences (effects) from research. Principal investigator: The head researcher who is responsible for the research project. Researcher: The person who conducts the research. Research participant: A person who participates in a research project: Synonymous with the terms “research subject” and “human subject”. A person who is eligible for participation or who is asked to consent to participate (but has yet not consented) is called “prospective participants”. Risk: The probability of harm caused by research. Therapeutic research: Interventional biomedical research on human subjects, where the participant may have reasonable prospects of real and direct therapeutic benefits. Vulnerable person: A person who has reduced ability to protect his or her interests. Therefore he or she is particularly at risk of being exploited. He or she is therefore generally in need of, and entitled to, special protection. 277

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Index

A “Acceptable” risks, 156 Additional Protocol, 4 Additional safeguards, 176 American bioethics, 39 Armauer Hansen, 32 Assessment of proportionality, 163 Autonomy, 61 B Beecher, Henry, 63 Belmont Report, 16, 39 Benefit, 19 Benefits to others, 148 Best interest, 54 Bioethical literature, 7 Breastfeeding women, 186 Burden, 16 Burden of proof, 100 C Causality, 83 Cause in fact, 83 Cause in law, 83 Children, 176 Clinical Trials Directive, 4–5 Commercial interests, 47 Commercialising, 40 Common Rule, 40 Community law, 4 Compensation for damage, 252 Consent, 6, 61 Consent by proxy, 73 Consequential, 49 Control group, 229 Convention law, 4

Council of Europe, 4 Criminal liability, 253 D Declaration of Helsinki, 5, 12, 16–17, 37–38, 43, 53–54, 57, 61, 65, 106, 236, 238–239, 257, 269 Deprived of liberty, 189 Detrimental, 223 Direct benefit, 20 Duty of care, 59 E Emergency clinical situations, 183 Estimate, 91 European Convention on Human Rights, 4 European Economic Area (EEA), 4 European Union, 4 F Fair balance, 107 Foreseeable, 85 G GCP Directive, 5 Germany, 32 H Healthy volunteers, 143 Hippocratic oath, 37 Human dignity, 52 Human identity, 52 Humanism, 52 Human primacy, 53 Human rights law, 36

291

292 I Inconvenience, 16 Indigenous people, 36 Interests, 46, 50 Invalid consent, 252 J Juridification, 43 Just cause, 31 Justify, 106 K Kant, 52 L Laws of war, 129 Legal effects, 251 Legal literature, 7 Legal method, 11 Legal representative, 61 Lesser mean, 118 M Maximising potential benefits, 96 Minimal risk, 177, 195–196 Minimising risks and burdens, 92 Minors, 176 N Nazi-experiments, 35 Necessity, 118 Negligence, 83, 88, 216 Neisser, 32 No harm rule, 221 Non-interference with necessary clinical interventions, 221 Nontherapeutic research, 23, 143 Nontherapeutic research on “vulnerable” participants, 171 Nuremberg Code, 34 Nuremberg Doctors Trial, 33 Nurses, 27 O Omissions, 59 Onus of proof, 83 Origins of the requirement of proportionality, 31 Orphans, 36 Other persons and entities, 243 Oviedo Convention, 4

Index P Paediatric Guidelines, 177 Paternalism, 43 Patients, 27, 48 Perceptions of risks, 96 Placebo controlled clinical trials, 233 Placebo drug, 233 Pregnancy, 186 Principle of human primacy, 53 Prisoner, 27 Proportionality, 105 Proxy, 61 Public interests, 48 Purpose of the requirement of proportionality, 45 Q Quantifying, 157 R Raison d’être, 45 Randomised clinical trial, 227 Reasonable person test, 59 Requirement of consent, 6 Requirement of proportionality, 5, 118 Researcher, 46 Risk, 15 S Safeguard, 56 Science, 46 Scientific quality, 57 Self-determination, 61 Self-experimentation, 156 Sham surgery, 238 Smallpox, 40 Society, 48 Soldiers, 27 Students, 27 T Thalidomide tragedy, 41 Therapeutic misconception, 63 Therapeutic research, 23, 119 Tort law, 57 U United Nations, 36 Universal Declaration of Human Rights, 52 Utilitarian, 49

Index V Vipeholm Caries Study, 42 Vulnerable person, 24, 171

293 W War, 129 Welfare, 55 World Medical Association, 5, 12, 16, 37, 119, 269