Table Of ContentEthical and Scientific Issues in Studying the
Safety of Approved Drugs
Board on Population Health and Public Health Practice
THE NATIONAL ACADEMIES PRESS
Ethical and Scientific Issues in Studying the Safety of Approved Drugs
Ethical and Scientific Issues in Studying the
Safety of Approved Drugs
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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Ethical and Scientific Issues in Studying the Safety of Approved Drugs
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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.
Ethical and Scientific Issues in Studying the Safety of Approved Drugs
Ethical and Scientific Issues in Studying the Safety of Approved Drugs
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Ethical and Scientific Issues in Studying the Safety of Approved Drugs
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, B.A., J.D., Consultant
RICHARD A. MERRILL, L.L.B., Consultant
EMILY L. EVANS, M.P.H., Consultant
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
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Copyright © National Academy of Sciences. All rights reserved.
Ethical and Scientific Issues in Studying the Safety of Approved Drugs
ROSE MARIE MARTINEZ, Director, Board on Population Health and
Public Health Practice
CAROL MASON SPICER, Associate Program Officer
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Copyright © National Academy of Sciences. All rights reserved.
Ethical and Scientific Issues in Studying the Safety of Approved Drugs
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, 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 individual’s 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.
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Ethical and Scientific Issues in Studying the Safety of Approved Drugs
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Ethical and Scientific Issues in Studying the Safety of Approved Drugs
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 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
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