WASHINGTON - A new letter report from the Institute of Medicine recommends a conceptual framework to help the U.S. Food and Drug Administration evaluate the ethical issues involved in determining whether companies should start or continue clinical trials on approved drugs and in ensuring that these studies are ethically conducted.  FDA has recently gained enhanced authority to require drug companies to undertake studies of their products after they are put on the market, which presents the agency with additional challenges.


The report's proposed framework underscores the importance of FDA's decision-making processes and study design considerations.  FDA should ensure that any randomized, controlled trial to evaluate the efficacy and safety of an approved drug that is suspected of causing serious adverse events is conducted only when the existing evidence and any evidence from new observational studies would be insufficient to enable the agency to make responsible policy decisions.  The agency should determine that questions about a drug's possible risks or risk-benefit balance rise to the level of requiring a policy decision, such as whether to revise the product's label. 


In addition, FDA should make sure that trials are appropriately designed to resolve uncertainties about efficacy and safety and to minimize risks to participants.  Risks should be judged acceptable by appropriate oversight bodies, and participants and studies should be continuously monitored to assure that the risks continue to be acceptable.  The process of informed consent should continue over the course of the trials, and participants should be promptly advised of substantial changes in clinical practice or professional standards and new research findings that could affect their willingness to accept the risks associated with a trial.  FDA should apply principles and practices of regulatory science to ensure that its policy decisions reflect the best available scientific evidence and analytic techniques and that they are made in a transparent way to ensure public accountability.


The report responds to one of several questions FDA asked IOM to explore in a review of ethical and scientific issues related to studying the safety of drugs on the market.  Specifically, this letter report addresses the ethical and informed consent issues that must be considered when designing randomized clinical trials to evaluate potential safety risks.  FDA requested an initial report on the ethical issues in advance of a meeting it will hold July 13 and 14 to discuss the case of the diabetes drug Avandia.  The report addresses issues at play in this case, but does not delve into or respond to the specifics of the Avandia case.  Rather, the authoring committee provided a conceptual framework that would be broadly applicable to many situations. 


Given the short time frame available to prepare the letter report, the study committee did not detail all the ways the issues raised in the report can affect the ethics of a study, or explore issues related to the ethical and scientific justifications of clinical trials in depth.  A more detailed analysis of these issues and their implications and effects will be included in the committee's final report, which will be completed in the spring of 2011.


The report was requested by the U.S. Food and Drug Administration.  Established in 1970 under the charter of the National Academy of Sciences, the Institute of Medicine provides independent, objective, evidence-based advice to policymakers, health professionals, the private sector, and the public.  The National Academy of Sciences, National Academy of Engineering, Institute of Medicine, and National Research Council make up the National Academies.  A committee roster follows.



Copies of Ethical Issues in Studying the Safety of Approved Drugs: A Letter Report are available from the National Academies Press; tel. 202-334-3313 or 1-800-624-6242 or on the Internet at  Reporters may obtain a copy from the Office of News and Public Information (contacts listed above). 


[ This news release and report are available at ]




Board on Population Health and Public Health Practice 


Committee on Ethical and Scientific Issues in Studying the Safety of Approved Drugs



Ruth R. Faden, Ph.D., M.P.H. (co-chair)

Philip Franklin Wagley Professor of Biomedical Ethics, and


Berman Institute of Bioethics

Bloomberg School of Public Health

Johns Hopkins University



Steven N. Goodman, M.D., M.H.S., Ph.D. (co-chair)

Professor of Oncology, Pediatrics, Epidemiology, and Biostatistics

Bloomberg School of Public Health and School of Medicine

Johns Hopkins University



Alasdair Breckenridge, M.D., F.R.C.P.


Medicines and Healthcare products Regulatory Agency



Lisa Egbuonu-Davis, M.D., M.P.H., M.B.A.

Managing Director

LED Enterprise LLC

Montclair, N.J.


Miguel A. Hernán, M.D., Dr.P.H.

Associate Professor

Department of Epidemiology

Harvard School of Public Health



Grace M. Lee, M.D., M.P.H.

Assistant Professor

Department of Population Medicine

Harvard Medical School; and

Assistant Professor of Pediatrics

Division of Infectious Diseases, and

Associate Medical Director of Infection Control

Children's Hospital Boston



Michelle Mello, J.D., Ph.D.

Professor of Law and Public Health

Department of Health Policy and Management

Harvard School of Public Health



Eric M. Meslin, Ph.D.


Center for Bioethics, and

Associate Dean for Bioethics

School of Medicine

Indiana University



Larry I. Palmer, LL.B.

Professor of Health Administration

School of Allied Health Professions

Virginia Commonwealth University

Richmond, and

Professor of Law

Marshall-Wythe School of Law, and

Research Professor

Thomas Jefferson Program in Public Policy's Schroder Center for Healthcare Policy

College of William and Mary

Williamsburg, Va.


Bruce M. Psaty, M.D., Ph.D., M.P.H.

Professor of Medicine, Epidemiology, and Health Services, and


Cardiovascular Health Research Unit

University of Washington; and


Group Health Research Institute

Group Health Cooperative



Thomas R. Ten Have, Ph.D, M.P.H.

Professor of Biostatistics,

Associate Director Biostatistics Unit, and

Faculty Director

Biostatistics Analysis Center

Center for Clinical Epidemiology and Biostatistics

University of Pennsylvania School of Medicine



William Vaughan B.A.


Consumer's Union

Washington, D.C.





Michelle C. Catlin, Ph.D. 

Study Director