FDA Overhaul Needed to Ensure Drug Safety, IOM Says

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 (IOM).

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“ misbranded.”

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 use.”

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 confirmation.

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>.▪