WASHINGTON, Sept. 22, 2006 -- Lack of clear regulatory authority, chronic underfunding,
organizational problems, and a scarcity of post-approval data about drugs' risks
have hampered the U.S. Food and Drug Administration's ability to evaluate and
address the safety of prescription drugs after they have reached the market,
says a new report from the Institute of Medicine. Noting that resources and therefore
efforts to monitor medications' risk-benefit profiles taper off after approval,
the committee that wrote the report offered a broad set of recommendations to
ensure that consideration of safety extends from before product approval through
the entire time the product is marketed and used. Recommendations include:
"FDA has an enormous and complex mission -- both to make innovative new drugs
available to patients as quickly as possible and to assess the long-term risks
and benefits of these products once they are on the market," said Sheila Burke,
chair of the committee that wrote the report. "We found an imbalance in the
regulatory attention and resources available before and after approval. Staff
and resources devoted to pre-approval functions are substantially greater. Regulatory
authority that is well-defined and robust before approval diminishes after a
drug is introduced to the market. Few high-quality studies are conducted after
approval, and the data are generally quite limited. Many of the report's recommendations
are intended to bring the strengths of the pre-approval process to the post-approval
process, to ensure ongoing attention to medications' risks and benefits for as
long as the products are in use."
When new medications, formulations, and delivery systems are introduced to the
market, their package labels should carry a symbol for a two-year period alerting
patients and health care providers that the products are new and that there may
be uncertainties about their risks and benefits, the report says. It is a widely
held misperception that FDA approval of a new drug denotes a guarantee of safety
and certainty about its risk-benefit profile. In fact, eliminating all uncertainties
prior to approval could cause considerable delay in new products reaching patients
in need, the committee noted. Five years after a product is introduced to the
market, FDA should conduct a formal review of all accumulated information about
its benefits and risks.
The committee would favor a moratorium on direct-to-consumer advertising during
the period when a product carries the symbol denoting newness, but it acknowledged
the legal uncertainties surrounding such an imposition. Such advertising should
at least explicitly note that evidence for the product's risks and benefits are
less-developed than for older drugs, and urge consumers to talk with their physicians
Citing organizational and cultural problems within FDA that hinder its post-approval
drug safety activities, the committee recommended a number of ways to bolster
the role and expertise of its drug safety staff. The agency should give its Office
of Surveillance and Epidemiology -- formerly known as the Office of Drug Safety
-- joint authority with the Office of New Drugs for conducting post-approval
regulatory activities. OSE staff members also should be part of the teams that
review each application for a new drug approval. And a six-year term should be
established for the FDA commissioner to provide greater stability in leadership
for drug safety, the report says.
FDA also needs clear authority and appropriate enforcement
tools -- such as fines and injunctions -- to ensure that industry complies
with label changes and conditions
imposed on new products upon or after approval. FDA now has only limited ability
to ask for and negotiate with drug sponsors on these regulatory matters, and
its only enforcement option is to withdraw approval. Strengthening the agency’s
ability to react to safety problems that arise after approval would help mitigate
concerns that timely approval of drugs leads to sacrifices in safety.
Currently, no single organization is charged with responsibility for gathering
and analyzing data on medications' risks and benefits after approval, when safety
problems may become evident as products become more widely used. FDA should assume
this role, the report says. The agency needs the expertise and resources to pursue
more sophisticated research that can spot changes in the balance of products'
risks and benefits. FDA should communicate pertinent findings to the public in
a timely manner.
The committee stressed the importance of increasing the public's access to information
on medication safety and effectiveness. Current registration of trial data and
results is largely voluntary and is not adequately systematic or standardized,
the committee concluded. Congress should require companies to register all phase
II through phase IV clinical trials on the federal Web site ClinicalTrials.gov
if data from the studies is to be submitted to the agency. Registration should
include summaries of all studies' results, regardless of the outcomes.
The advisory committees that FDA consults as a source of independent insight
on questions about new products have attracted criticism because the agency allows
individuals with financial ties to the pharmaceutical industry to serve. Noting
that the agency does not impose limits on the number of committee members waived
to serve despite financial ties, but also acknowledging that a zero-tolerance
policy is unrealistic, the report recommends that a substantial majority -- at
least 60 percent -- of advisory committee members be free of significant financial
involvement with companies whose interests may be affected by their deliberations.
FDA should issue waivers for the other committee members very sparingly.
It is widely acknowledged that FDA is severely underfunded, and implementing
the report's recommendations will require additional financial and staff resources.
The report calls on Congress to appropriate a substantial increase in both funding
and personnel for FDA. The committee favors appropriations from general revenues,
noting that all Americans have an interest in a robust drug safety system and
that increasing attention to FDA's post-approval drug safety responsibilities
should not occur at the expense of pre-approval activities. However, if appropriations
are not sufficient, Congress should lift most of the restrictions on how the
agency can apply fees paid by drug sponsors, which for the most part can now
be used only for pre-approval activities.
The study was sponsored by the U.S. Food and Drug Administration, the National
Institutes of Health, Agency for Healthcare Research and Quality, Centers for
Medicare and Medicaid Services, and the Department of Veterans Affairs. 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.
- Labeling requirements and advertising limits for new medications
- Clarified authority and additional enforcement tools for the agency
- Clarification of FDA's role in gathering and communicating additional information
on marketed products' risks and benefits
- Mandatory registration of clinical trial results to facilitate public access to drug safety information
- An increased role for FDA's drug safety staff
- A large boost in funding and staffing for the agency
INSTITUTE OF MEDICINE
Board on Population Health and Public Health Practice
Committee on the Assessment of the U.S. Drug Safety System
Sheila P. Burke, M.P.A., R.N. (chair)
David Blumenthal, M.D., M.P.P.
Institute for Health Policy
Massachusetts General Hospital and Partners HealthCare System, and
Samuel O. Thier Professor of Medicine and Professor of Health Care Policy
Harvard Medical School
Alasdair Breckenridge, C.B.E.
Medicines and Healthcare Products Regulatory Agency of the United Kingdom
R. Alta Charo, J.D.
Associate Dean for Research and Faculty Development and Elizabeth S. Wilson-Bascom
Professor of Law and Bioethics
Law School, and
Department of Medical History and Bioethics
School of Medicine and Public Health
University of Wisconsin
Susan Edgman-Levitan, P.A.
John D. Stoeckle Center for Primary Care Innovation
Massachusetts General Hospital
Susan S. Ellenberg, Ph.D.
Professor of Biostatistics and Associate Dean for Clinical Research
University of Pennsylvania School of Medicine
Robert D. Gibbons, Ph.D.
Professor of Biostatistics and Psychiatry, and
Center for Health Statistics
University of Illinois
George Hripcsak, M.D., M.S.
Professor and Vice Chair
Department of Biomedical Informatics
Columbia University School of Public Health, and
Medical Informatics Services
New York-Presbyterian Hospital
New York City
David Korn, M.D.
Senior Vice President for Biomedical and Health Sciences Research
Association of American Medical Colleges
David O. Meltzer, M.D., Ph.D.
Associate Professor of Medicine and Affiliated Faculty
Department of Economics and Graduate School of Public Policy
University of Chicago
Woodrow A. Myers Jr., M.D., M.B.A.
Former Executive Vice President and Chief Medical Officer
WellPoint Health Networks
Newbury Park, Calif.
Mary K. Olson, Ph.D.
Associate Professor of Economics
Bruce M. Psaty, M.D., Ph.D., M.P.H.
Center for Health Studies
Group Health Cooperative of Puget Sound;
Professor of Medicine, Epidemiology, and Health Services; and
Cardiovascular Health Research Unit
University of Washington
Christopher H. Schroeder, M.Div., J.D.
Charles S. Murphy Professor of Law and Public Policy Studies, and
Program in Public Law
Duke University Law School
Andy Stergachis, Ph.D., R.Ph.
Professor of Epidemiology, Adjunct Professor of Pharmacy, and Interim Chair
Department of Pathobiology
School of Public Health and Community Medicine
University of Washington
Kathleen Stratton, Ph.D.
Alina Baciu, M.P.H.
source: The National
Academies, Institute of Medicine