Ethical and Scientific Issues
in Studying the Safety of
Committee on Ethical and Scientific Issues in
Studying the Safety of Approved Drugs
Board on Population Health and Public Health Practice
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
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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 support for this project.
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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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OF THE NATIONAL ACADEMIES
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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
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
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
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, evidence, 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
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 this report was overseen by Ron Brookmeyer, University of California, Los Angeles, and Brian L. Strom, University of Pennsylvania School of Medicine. 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.
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 innovation. 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 facing in its consideration of the cardiovascular risks associated with the antidiabetic
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 evidence 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 recommendation 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
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 committee 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 contribution 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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This report is dedicated to
Dr. Thomas Ten Have,
a leader in biostatistical analysis of health outcomes,
a valued member of the committee,
and an irreplaceable colleague and friend.
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