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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 No. 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 author(s) and do not necessarily reflect the view of the organizations or agencies that provided sup - port for this project. International Standard Book Number-13: 978-0-309-21813-9 International Standard Book Number-10: 0-309-21813-6 Library of Congress Control Number: 2012944110 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www. iom.edu. Copyright 2012 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 Museum in Berlin. Suggested Citation: IOM (Institute of Medicine). 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press.
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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.
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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 examina - tion 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 iv
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COMMITTEE ON ETHICAL AND SCIENTIFIC ISSUES IN STUDYING THE SAFETY OF APPROVED DRUGS RUTH R. FADEN (Co-Chair), Philip Franklin Wagley Professor of Biomedical Ethics and Executive Director, Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD STEVEN N. GOODMAN (Co-Chair), Professor of Medicine and Health Research and Policy, Associate Dean for Clinical and Translational Research, Stanford University School of Medicine, CA ALASDAIR BRECKENRIDGE, Chairman, Medicines and Healthcare Product Regulatory Agency, London, UK LISA EGBUONU-DAVIS, Executive Advisor, Booz Allen Hamilton, Washington, DC MIGUEL A. HERNÁN, Professor of Epidemiology, Harvard School of Public Health, Boston, MA GRACE M. LEE, Associate Professor of Population Medicine & Pediatrics, Harvard Pilgrim Health Care Institute, Harvard Medical School & Children’s Hospital Boston, MA MICHELLE MELLO, Professor of Law and Public Health, Harvard University, Cambridge, MA ERIC M. MESLIN, Director, Indiana University Center for Bioethics, Associate Dean for Bioethics, Indiana University School of Medicine, Indianapolis LARRY I. PALMER, (Retired), Professor, Department of Health Administration, Virginia Commonwealth University and Professor of Law, College of William & Mary Law School, Richmond, VA BRUCE M. PSATY, Professor, Medicine, Epidemiology, and Health Services; Co-Director, Cardiovascular Health Research Unit, University of Washington; Investigator, Group Health Research Institute, Seattle THOMAS R. TEN HAVE, Professor of Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia WILLIAM K. VAUGHAN, (Retired), Health Policy Analyst, Consumers Union, Washington, DC Consultants THOMAS J. BOLLYKY, Senior Fellow, Council of Foreign Relations, Washington, DC RICHARD A. MERRILL, Professor of Law Emeritus, University of Virginia, Charlottsville EMILY L. EVANS, Ph.D. Candidate, Georgetown University, Washington, DC v
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IOM Staff MICHELLE C. CATLIN, Study Director ALEJANDRA MARTÍN, Research Assistant ALLISON L. BERGER, Senior Project Assistant (June 2010–August 2011) THOR YOUNG, Senior Project Assistant (August 2011–November 2011) NORMAN GROSSBLATT, Senior Editor ROSE MARIE MARTINEZ, Director, Board on Population Health and Public Health Practice CAROL MASON SPICER, Associate Program Officer 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 for objectivity, evi - dence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Jesse Berlin, Janssen Research & Development Dan Carpenter, Harvard University Perry D. Cohen, Project Director for the Parkinson Pipeline Project Susan Ellenberg, University of Pennsylvania School of Medicine Barbara Evans, University of Houston Thomas R. Fleming, University of Washington Sean Hennessy, University of Pennsylvania Peter Honig, AstraZeneca Karen Jenni, Insight Decisions, LLC Cato T. Laurencin, University of Connecticut Bernard Lo, University of California, San Francisco Jon Merz, University of Pennsylvania Richard Platt, Harvard Medical School Joseph Rodricks, ENVIRON Paul D. Stolley, University of Maryland School of Medicine vii
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viii REVIEWERS Although the reviewers listed above have provided many constructive com- ments and suggestions, they were not asked to endorse the conclusions or recom - mendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Ron Brookmeyer, University of California, Los Angeles, and Brian L. Strom, University of Pennsylvania School of Medi- cine. Appointed by the National Research Council and the Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
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Preface This report comes, not coincidentally, at an extraordinary time for both the US Food and Drug Administration (FDA) and this country. With half of all Americans taking at least one prescription drug daily and many older Americans using five or more, and with an increasing array of drugs available to treat more illnesses and more people, the public health consequences of drug exposure— both negative and positive—could not be higher. At the same time, the costs of health care consume a steadily increasing proportion of our nation’s budget, with drug expenditures representing a sizable fraction of total health care dollars. Finally, there is the role of US academic and industry pharmaceutical research as an engine of innovation, bringing enormous economic, scientific, and medical benefits to our populace. In the middle of this stands FDA, whose goal is to balance those pressures appropriately and to ensure that the drugs it approves do not have risks that outweigh their benefits, while not acting in ways that stifle biomedical innova- tion. The passage of the FDA Amendments Act of 2007 has afforded FDA broad new powers to monitor the safety of drugs after they reach the marketplace and to take corrective action if drugs’ risks are judged to be unacceptable in light of their benefits. Over the last few decades, there has been a series of high-profile episodes in which drugs in wide use after approval were found to cause harms that justified their withdrawal or restricted use. The highest-profile of these involved Vioxx ® (rofecoxib), selective serotonin reuptake inhibitors (SSRIs) in children, Fen-Phen (fenfluramine and phentermine), and most recently, Avandia® (rosiglitazone). It is no secret that the present report was born amid the challenges that FDA was fac- ing in its consideration of the cardiovascular risks associated with the antidiabetic ix
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x PREFACE drug Avandia. FDA first requested a letter report from this committee to aid in its deliberation about the scientific and ethical issues surrounding the continuation of the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial, which had been required of the Avandia manufacturer by FDA. The letter report was presented during the Avandia hearings and is included as an appendix. But both the letter report and this longer, final report are about much more than the Avandia case. The final report was prepared in response to a series of questions about the kinds of studies and protections for research participants that could or should be mounted by FDA in response to drug safety concerns in the postmarketing period. The committee quickly recognized that the questions posed were not readily answerable when framed from the vantage of a postmarketing crisis where there are few, if any, good options. To provide useful guidance, the committee found itself inexorably drawn to how FDA could have avoided these moments of crisis when the costs in human suffering and dollars to get the evi- dence it needed were seen by many as unacceptable. The committee hopes that its recommendations, if adopted, will go much further toward resolution of the questions that were posed to it than would have been the case if it had taken a more narrow approach. This journey took longer than we expected it to, but it produced a report that should stand the test of time. The committee’s most important recommenda - tion is that FDA, in its role as a public health agency, be active in shaping its postmarketing drug safety monitoring role, taking it as seriously as it does its responsibility to approve safe and efficacious drugs. The committee calls this, as did an Institute of Medicine (IOM) committee that preceded it, “the lifecycle approach”. Obtaining new information about a drug’s benefits and risks in the postmarketing context is expected in the lifecycle approach. If acquired and responded to in a timely way, new information need not and should not result in controversies of the Avandia or Vioxx type. The committee hopes that if FDA adopts its findings and recommendations, these kinds of controversies will be minimized in the future and the public will have renewed faith in the agency as protecting of its health while allowing access to the marketplace for drugs that have great potential to cure disease and relieve suffering. The committee thanks colleagues, organizations, and agencies that were willing to share their expertise, time, and information during the committee’s information-gathering meetings (see Appendix C for the names of speakers). Their contributions informed the committee deliberations and enhanced the quality of this report. The committee learned a great deal about drug safety in the context of regulatory science, pharmacovigilance, science and ethics, and the perspectives of both public and patient interest groups. The study sponsor, FDA, gladly provided information and responded to questions. The committee is particularly grateful to Joshua Sharfstein and Janet Woodcock, who provided valuable information and feedback during the committee’s deliberation process; to Joshua Sharfstein and Margaret Hamburg for commissioning this study; and to
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xi PREFACE Carolyn Clancy and Francis Collins for their interest and their agencies’ financial support of the study. We are honored to have worked with wise, creative, and indefatigable com- mittee members, whose names are listed in this volume. The IOM staff, including board director Rose Marie Martinez, study director Michelle Catlin, and research assistant Alejandra Martin, as well as Allison Berger, Thor Young, Carol Mason Spicer, Joel Wu, Erin Rusch, and Hope Hare, were critical in shepherding the report through all its stages and incarnations. The committee was also assisted in its work by study consultants Emily Evans, Thomas Bollyky and Richard Merrill, and by senior editor Norman Grossblatt. Finally, with deepest gratitude and great sorrow, we dedicate this report to a member of our committee, Thomas Ten Have, who succumbed to a chronic illness during the creation of the report and did not survive to see his contribu - tion take flight. We hope that the report serves as an appropriate capstone to his brilliant and productive career in biostatistics and public health. Ruth R. Faden and Steven N. Goodman, Co-Chairs Committee on Ethical and Scientific Issues in Studying the Safety of Approved Drugs
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In Memoriam This report is dedicated to Dr. Thomas Ten Have, a leader in biostatistical analysis of health outcomes, a humanitarian, a valued member of the committee, and an irreplaceable colleague and friend. xiii
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Contents ABSTRACT 1 SUMMARY 3 Charge to the Committee, 4 Committee’s Approach to Its Charge, 4 Benefit–Risk Assessment and Management Throughout a Drug’s Lifecycle, 4 Evidence and Decision-Making, 7 Selection and Oversight of Required Postmarketing Studies, 8 Responses to the Charge Questions, 11 Findings and Recommendations, 14 1 INTRODUCTION 29 The Evolution of the Food and Drug Administration’s Responsibilities in the Postmarketing Setting, 30 The Context of This Report, 46 Charge to the Committee, 47 The Committee’s Approach to Its Charge, 50 Overview of the Report, 56 References, 57 2 INCORPORATING BENEFIT AND RISK ASSESSMENT AND BENEFIT–RISK MANAGEMENT INTO FOOD AND DRUG ADMINISTRATION DECISION-MAKING 61 Evaluating Benefit and Risk Over a Drug’s Lifecycle, 61 xv
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xvi CONTENTS Three-Stage Framework for Regulatory Decision-Making, 63 Benefit and Risk Assessment and Management Plan Document, 94 Special Considerations in the Decision of Whether to Require a Postmarketing Study, 98 Summary, 109 Findings and Recommendations, 109 References, 113 3 EVIDENCE AND DECISION-MAKING 121 Statistical Inference and Decision-Making, 122 Why Scientists Disagree, 128 Implications for Regulatory Decisions: The Importance of Understanding the Sources of Disagreements, 156 Reproducible Research, Data Sharing, and Transparency, 157 Findings and Recommendations, 158 References, 162 4 SELECTION AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES 169 The Postmarketing Context, 170 Requiring Observational Studies and Randomized Controlled Trials, 173 Design, Analytic, and Ethical Considerations in Selecting Specific Observational and RCT Designs to Require, 181 The Food and Drug Administration’s Ethical Obligations Regarding the Conduct and Oversight of Required Postmarketing Studies, 187 Summary, 201 Findings and Recommendations, 202 References, 207 5 SYNTHESIS 213 Responses to the Charge Questions, 214 References, 226 APPENDIXES A Other Elements of the Food and Drug Administration Amendments Act 227 B Committee’s Letter Report 231 C Open Session Agendas 251 D Decision Conferencing and Multicriteria Decision Analysis 255 E Benefit and Risk Assessment and Management Plan Document Template 261 F Committee Biosketches 269