Ethical Issues in Studying the Safety of Approved Drugs: A Letter Report

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Ethical Issues in Studying the Safety of Approved Drugs: A Letter Report Committee on Ethical and Scientific Issues in Studying the Safety of Approved Drugs Board on Population Health and Public Health Practice

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract HHSF223200810020I between the National Academy of Sciences and the Food and Drug Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. Additional copies of this report are available from the National Academies Press, 500 Fifth Street NW, Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2010 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2010. Ethical Issues in Studying the Safety of Approved Drugs: A Letter Report. Washington, DC: The National Academies Press.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON ETHICAL AND SCIENTIFIC ISSUES IN STUDYING THE SAFETY OF APPROVED DRUGS RUTH R. FADEN, PhD, MPH (Cochair), Philip Franklin Wagley Professor of Biomedical Ethics and Director, Johns Hopkins Berman Institute of Bioethics STEVEN N. GOODMAN, MD, MHS, PhD (Cochair), Professor of Oncology, Pediatrics, and Epidemiology and Biostatistics, Johns Hopkins University Schools of Medicine and Public Health ALASDAIR BRECKENRIDGE, MD, FRCP, Chairman, Medicines and Healthcare products Regulatory Agency, London, UK LISA EGBUONU-DAVIS, MD, MPH, MBA, Managing Director, LED Enterprise, LLC MIGUEL A. HERNÁN, DrPH, MD, Associate Professor of Epidemiology, Harvard School of Public Health GRACE M. LEE, MD, MPH, Assistant Professor of Population Medicine and Pediatrics, Harvard Pilgrim Health Care Institute, Harvard Medical School, and Children’s Hospital Boston MICHELLE MELLO, JD, PhD, Professor of Law and Public Health, Harvard School of Public Health ERIC M. MESLIN, PhD, Director, Indiana University Center for Bioethics; Associate Dean for Bioethics, Indiana University School of Medicine LARRY I. PALMER, LLB, Professor of Health Administration, Virginia Commonwealth University; Professor of Law, College of William and Mary BRUCE M. PSATY, MD, PhD, MPH, Professor of Medicine, Epidemiology, and Health Services and Codirector, Cardiovascular Health Research Unit, University of Washington, Seattle, WA; Group Health Research Institute, Group Health Cooperative, Seattle, WA THOMAS R. TEN HAVE, PhD, MPH, Professor of Biostatistics, University of Pennsylvania School of Medicine WILLIAM VAUGHAN, BA, Consultant to Consumers Union v

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STUDY STAFF MICHELLE C. CATLIN, PhD, Study Director JENNIFER A. COHEN, Program Officer ALEJANDRA MARTÍN, Research Assistant KRISTEN METHERD, Intern KATHLEEN McGRAW, Senior Project Assistant ALLISON L. BERGER, Senior Project Assistant NORMAN GROSSBLATT, Senior Editor ROSE MARIE MARTINEZ, ScD, Director, Board on Population Health and Public Health Practice vi

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REVIEWERS This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following for their review of this report: Wylie Burke, MD, PhD, University of Washington Susan S. Ellenberg, PhD, University of Pennsylvania School of Medicine Arthur Levin, BA, MPH, Center for Medical Consumers Roger J. Lewis, MD, PhD, University of California, Los Angeles, David Geffen School of Medicine Bernard Lo, MD, University of California, San Francisco Alastair J.J. Wood, MD, Symphony Capital, LLC Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of the report was overseen by Brian L. Strom, MD, MPH, University of Pennsylvania School of Medicine and Elaine L. Larson, PhD, RN, Columbia University. Appointed by the National Research Council and the Institute of Medicine, they were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests with the author committee and the institution. vii

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CONTENTS Context of the Institute of Medicine Study and Charge to the Committee......................................1 Committee’s Approach to Its Charge ..............................................................................................1 The Public Health Context of Drug Safety ......................................................................................2 Regulatory Science and Public Accountability................................................................................4 Design Considerations .....................................................................................................................6 Additional Ethical Obligations to Research Participants...............................................................11 Recommendations..........................................................................................................................13 References......................................................................................................................................13 Boxes BOX 1 Charge to the Committee.....................................................................................................1 BOX 2 Conceptual Framework for Analyzing the Ethics of Postmarketing Randomized Clinical Trials Required by the Food and Drug Administration: Four Central Classes of Considerations and Recommendations ....................................................................................3 viii

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Margaret Hamburg, MD Commissioner US Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002 Dear Dr. Hamburg, In April 2010, the US Food and Drug Administration (FDA) asked the Institute of Medicine (IOM) to respond to five questions about ethical and scientific issues in studying the safety of approved drugs. FDA requested a final report on the five questions in 2011. In light of the scheduling of a joint meeting of FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee on July 13–14, 2010, FDA further requested a letter report addressing question 1 of the charge—“What are the ethical and informed consent issues that must be considered when designing randomized clinical trials to evaluate potential safety risks?”—by July 2010. The attached letter report, which has been reviewed in accordance with IOM review procedures, addresses that question. Sincerely, Ruth R. Faden Steven N. Goodman Cochairs, Committee on Ethical and Scientific Issues in Studying the Safety of Approved Drugs

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