The U.S. Food and Drug Administration's (FDA's) ability to monitor the
safety of marketed medications has been severely impeded by numerous problems,
according to a report released last month by the Institute of Medicine
These problems include a clear lack of regulatory authority, long-standing
underfunding, organizational problems, and an alarming paucity of data on the
efficacy and safety of medications after their approval.
The report pointed out that because of the funding mechanism Congress set
up in 1992 in the Prescription Drug User Fee Act (PDUFA), the FDA's resources
are significantly skewed toward the drug-approval process, hampering the
agency's ability to monitor the safety of marketed medications. The result is
a history of recent medication recalls due to serious safety concerns, as well
as ongoing controversies surrounding the safety of many medications still on
the market, including antidepressants, antipsychotics, and medications to
treat attention-deficit/hyperactivity disorder.
At the request of the FDA, the IOM assembled a broad group of experts to
study the FDA's efforts on product safety. In their report, those experts
offered 25 broad recommendations "to ensure that the FDA's consideration
of safety extends from before product approval through the entire time the
product is marketed and used."
"The 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, M.P.A., R.N., chair of the IOM 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
preapproval functions are substantially greater. Regulatory authority that is
well defined and robust before approval diminishes after a drug is introduced
to the market," Burke said.
Prior to initial approval of a drug, if a drug's manufacturer disagrees
with an FDA request for additional efficacy or safety data (which could
include requests for the company to conduct additional clinical trials),
specific labeling language, or an FDA request to impose certain conditions
upon a product's marketing, the FDA cannot grant final approval to the
product. However, once the drug is approved, the only regulatory action the
agency has available to it is the FDA's option to determine that a product is"
While not clearly defined, "misbranding" essentially means that
a drug does not comply with the FDA regulations and thus the agency considers
that the product no longer is approved for marketing. However, short of this
withdrawal of product approval, the FDA has little regulatory authority to
force postmarket label changes or marketing restrictions and is left to
negotiate with product manufacturers. Historically, the FDA has rarely used
the option to declare a product misbranded.
"Few high-quality studies are conducted after approval," Burke
continued, "and the data are generally quite limited. Many of the [IOM]
report's recommendations are intended to bring the strengths of the
preapproval process to the postapproval process to ensure ongoing attention to
medications' risks and benefits for as long as the products are in
The IOM report called for several new initiatives, among them new labeling
carrying a symbol for a two-year period alerting patients and health care
professionals that the products are new and that there may be uncertainties
about their risks and benefits. 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 reality, the report noted, eliminating all
uncertainties prior to approval could cause considerable delay in new products
reaching patients in need. The report also called for a formal review of the
information that accumulates about a drug's benefits and risks in the
five-year period after a drug enters the market.
The IOM report called for a moratorium on direct-to-consumer advertising
during a product's first two years on the market, but acknowledged legal
uncertainties surrounding such an imposition. Thus, advertising should
explicitly note that "evidence for the product's risks and benefits is
less-developed than for older drugs," and labels should urge consumers
to discuss the products with their physicians.
The IOM report strongly criticized the FDA's organizational and cultural
makeup, recommending that the agency integrate its approval and postmarketing
safety staffs. The agency should give its Office of Surveillance and
Epidemiology (OSE; formerly the Office of Drug Safety) joint authority with
the office of New Drugs for conducting postapproval regulatory activities.
Likewise, the report continued, OSE staff members should be part of the teams
that review each application for a new drug approval.
Furthermore, in an attempt to shield the FDA commissioner from presidential
influence, the commissioner should be appointed to a six-year term, providing
greater stability in leadership regarding drug safety. Currently, the
commissioner serves at the discretion of the president, subject to U.S. senate
The IOM report included a critical section noting that the FDA needs clear
authority and appropriate enforcement tools—such as fines and
injunctions—to ensure that the pharmaceutical industry complies with
label changes, requests for additional safety or efficacy data, and marketing
conditions imposed on new products upon or after approval.
In addition, the report observed, there is currently no single organization
charged with responsibility for gathering and analyzing data on medications'
risks and benefits after approval, when safety problems are more likely to
appear. The FDA should assume this role, the report recommended.
The IOM report stressed the importance of increasing the public's access to
information on medication safety and effectiveness and strongly endorsed a law
to require registration of all clinical trials (including all phase II through
phase IV clinical trials) on<www.clinicaltrials.gov>.
Moreover, the report stressed, the FDA advisory committees must be free of
conflicts of interest. The IOM report called on the FDA to require that"
a substantial majority" (60 percent) of advisory committee
members be "free of significant financial involvement with companies
whose interests may be affected by the committee's deliberations."
Lastly, it is widely acknowledged that the FDA is severely underfunded, and
implementing the report's recommendations, the IOM report noted, will require
additional financial and staff resources. The report urged Congress to
appropriate a substantial increase in funding, which the FDA could use in part
to boost staffing. However, if appropriations are not sufficient, Congress
should at least lift most of the PDUFA restrictions on how the agency can
apply fees paid by drug company sponsors. Currently the bulk of these fees can
be used only for preapproval activities.
In addition to the FDA, the IOM report was sponsored by the National
Institutes of Health, Agency for Healthcare Research and Quality, Centers for
Medicare and Medicaid Services, and Department of Veterans Affairs.
"The Future of Drug Safety: Promoting and Protecting the
Health of the Public" can be purchased online at<http://newton.nap.edu/catalog/11750.html>.▪