Date:  May 1, 2012




Creation of a Central Management Plan for Every New Drug Needed to Strengthen FDA's Oversight of Approved Drugs' Safety


WASHINGTON — Although the approval of a new drug is based on evidence that its benefits outweigh its risks, the full range of a medication's effects may not become apparent until a product has been used by a larger, more diverse population over an extended period of time.  Problems associated with the anti-diabetes drug Avandia, pain reliever Vioxx, and cholesterol-reducing drug Crestor illustrate the challenges and underscore the need for a more systematic and transparent process to collect, assess, and act on data about a medication's benefit-risk profile throughout its entire "life cycle" from approval until it is no longer marketed, says a new report by the Institute of Medicine. 


According to recent estimates, nearly half of all Americans take at least one prescription drug daily and many older people use five or more, noted the committee that wrote the report.  The report's recommendations build on the new authorities and tools provided to the U.S. Food and Drug Administration through the Food and Drug Administration Amendments Act of 2007, which increased the agency's capacity to monitor drugs after approval and act if signs of safety problems appear. 


One of the committee's key recommendations is that FDA should create a benefit and risk assessment and management plan for each drug.  This would be a single, comprehensive, publicly available document that serves as a central repository of information for each product from its approval throughout its entire time on the market.  The document should include a description of any safety questions that exist when a drug is approved or that emerge over the course of the product's use, as well as benefit and risk assessments specific to these questions.  It should also include details on regulatory actions taken on the medication, such as restrictions on its use or the decision to require further research, as well as the results of these actions.  Much of this information is already being gathered by FDA, but it is currently scattered across multiple records.  Putting the information into an accessible format in a single document would make FDA's commitment to the life-cycle approach concrete and improve its transparency by giving the public easier access to useful data.


There are too many individual factors involved in each case and too great a variety of drugs to provide a single universal set of criteria for determining what should trigger a postmarket study, the committee concluded.  However, it identified some circumstances in which a product's benefits or risks are particularly uncertain, including "first in class" drugs that have been approved based on surrogate endpoints used previously for other drug classes, and drugs for which several endpoints provide conflicting evidence about risk, such as an anti-hypertensive drug that lowers blood pressure but increases weight.  In such cases, the committee recommended that FDA require safety research after approval or provide a public rationale for why it is not necessary.  Early initiation of such studies could limit the harm done by drugs with risks that are later found to be unacceptable and avoid crises in which the agency is faced with few good options, the committee said.


When deciding whether to require manufacturers to conduct postmarket studies, FDA must balance its ethical obligations to protect the public's health and to protect research participants.  The agency should require postmarket research only if a regulatory decision cannot be made based on existing safety evidence; the research can sufficiently reduce uncertainties about the benefit-risk balance to help inform a regulatory decision; the results will be used to make a decision in a timely fashion; and the rights and interests of the research participants can be adequately protected.


FDA should ensure that the postmarket studies it requires are conducted in ways that are ethically and scientifically sound.  Continuing advances in electronic health record systems and analytic techniques likely will mean that observational approaches using large data sets will become more important over time, and these approaches could create new ethical challenges, the committee noted.  The agency should seek additional guidance to assure the public that postmarket research and surveillance are being properly overseen, the committee said.


"It is not possible to know what the full range of a drug's benefits and risks will be until it is used by many different kinds of patients over time, so it is critical that FDA continue to monitor and learn about the effects of drugs after they are marketed," said committee co-chair Ruth Faden, Philip Franklin Wagley Professor of Biomedical Ethics and executive director, Berman Institute of Bioethics, Johns Hopkins University, Baltimore.  "Our report focuses on how the agency can be proactive so that situations in which a drug's benefit-risk profile becomes problematic can be detected earlier, and it details how FDA can get the additional information on a drug's safety in the most ethical and scientifically sound ways when questions arise." 


"We believe that the adoption of a life-cycle approach to drug approval and monitoring will help the agency strengthen its oversight, better tackle these complex decisions, and increase public confidence in the agency's ability to protect public health," said co-chair Steven N. Goodman, professor of medicine, health research, and policy, and associate dean for clinical and translational research, Stanford University School of Medicine, Stanford, Calif.  "This will become increasingly important as FDA looks for ways to safely expedite the drug approval process."


The report was sponsored 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 objective, evidence-based advice to policymakers, health professionals, the private sector, and the public.  The Institute of Medicine, National Academy of Sciences, National Academy of Engineering, and National Research Council together make up the independent, nonprofit National Academies.  For more information, visit or   A committee roster follows.


Additional Resources:

Report in Brief

Full Report

Project Website



Christine Stencel, Senior Media Relations Officer

Luwam Yeibio, Media Relations Assistant

Office of News and Public Information

202-334-2138; e-mail


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

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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

Executive Director

Berman Institute of Bioethics

Johns Hopkins University



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

Associate Dean

Clinical and Translational Research

School of Medicine

Stanford University

Stanford, Calif.


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


Medicines and Healthcare Product Regulatory Agency

London, United Kingdom


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

Executive Adviser

Booz Allen Hamilton

Rockville, Md.


Miguel Hernan, M.D., Dr.P.H., Sc.M., M.P.H.

Professor of Epidemiology

School of Public Health

Harvard University



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

Associate Professor of Population Medicine and Pediatrics

Harvard Pilgrim Health Care Institute

Harvard Medical School and Children's Hospital Boston



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

Professor of Law and Public Health

Department of Health Policy and Management

Harvard University



Eric Meslin, Ph.D.


Center for Bioethics, and

Associate Dean for Bioethics

School of Medicine

Indiana University



Larry I. Palmer, L.L.B.

Professor of Law

College of William and Mary Law School (retired), and


Department of Health Administration

Virginia Commonwealth University



Bruce M. Psaty, M.D., Ph.D.

Professor of Medicine, Epidemiology, and Health Services;


Cardiovascular Health Research Unit

School of Medicine

University of Washington; and 


Group Health Research Institute



Tom Tenhave, Ph.D., M.P.H. (deceased)

Professor of Biostatistics

Perelman School of Medicine

University of Pennsylvania



William Vaughan

Health Policy Analyst

Consumers Union (retired)

Falls Church, Va.




Michelle Catlin, Ph.D.

Study Director