The IOM Report

The US Food and Drug Administration (FDA) is suffering from a "dysfunctional organizational culture" in which the emphasis on reviewing new drugs for market approval significantly outweighs the monitoring and assessing of safety after drugs have been on the market, according to a report from the Institute of Medicine (IOM), a component of the US National Academy of Sciences.

Many of the IOM's 25 recommendations, released in September, focus on bolstering the agency's drug safety monitoring and enforcement mechanisms. These include giving FDA "significant" new funds to support safety oversight activities, requiring drug-makers to register and post summary results of all Phase II through IV clinical trials on the Internet, and mandating drug manufacturers conduct post-marketing surveillance and risk assessments.

The FDA would also have additional enforcement authority to impose fines and injunctions on drug-makers for noncompliance, review all new drugs after they have been on the market for five years, demand label changes, and restrict or ban direct-toconsumer (DTC) advertising, especially during the first two years on the market.

While the FDA has the ability to implement some of the report's recommendations, most will require congressional approval. And it is likely lawmakers next year will act on some of the recommendations, especially those already the subject of pending legislation, such as mandating clinical trials reporting and increasing penalties for noncompliance in conducting post-marketing and other safety studies.

Other IOM recommendations might be incorporated into "user fee" legislation that is up for renewal next year. This must-pass legislation-the Prescription Drug User Fee Act (PDUFA)-allows FDA to collect fees from drug companies to hire additional reviewers in the Center for Drug Evaluation and Research (CDER) to speed the drug review process. The report also recommends Congress introduce specific safety-related performance goals in PDUFA reauthorization. For the fiscal year that started Oct. 1, 2006, FDA has requested user fees of nearly $280 million to review human drugs and biologics in addition to ongoing Federal funding.

"Staff and resources devoted to pre-approval are substantially greater than those available for post-approval functions," said Sheila Burke, IOM committee chair and chief operating officer at the Smithsonian Institution. "Few high-quality studies are conducted after approval, and the data are generally quite limited. Many recommendations are designed to address this imbalance."

The panel recommended FDA receive an unspecified but "significant" infusion of funds to bolster drug safety by hiring additional staff for the Office of Drug Safety (now called Office of Surveillance and Epidemiology) and appointing epidemiologists and safety specialists to interdisciplinary teams to review new drug applications. The panel preferred the extra funds come from Federal appropriations, but acknowledged they could also be drawn from PDUFA fees.

"Speed and safety can be complimentary and synergistic, not antagonistic" said panel member R. Alta Charo, professor of law and bioethics at the University of Wisconsin, Madison. "The more confident we are that we can identify and react to and manage risks in a drug once it's out in general use in the population, the more confident we can be about releasing the drug initially."

FDA requested the IOM report two years ago, following widespread criticism that the agency and the pharmaceutical industry had mishandled safety issues surrounding Vioxx and other COX-2 inhibitors, pediatric antidepressants, and other popular drugs. "The industry's once sterling reputation has been blemished by reported compliance problems, delays in responding to safety concerns, and complying with post-marketing commitments," the report stated.

Drug companies intending to submit applications for new drugs would be required by law to register and post summary results of all Phase II through IV clinical trials on the Internet at www.clinicaltrials.gov, regardless of their outcomes or where the studies were conducted. These postings, which would be vetted for accuracy by the National Library of Medicine, would include structured field summaries of efficacy and safety results. During the first two years on the market, all new drug labels and marketing materials would carry a special warning symbol such as the black triangle used in the UK to inform consumers that safety information may be incomplete. During this time, the FDA could also restrict or ban DTC advertising. "We want the FDA to be in a position to mix and match these tools to achieve appropriate levels of risk management," Charo said.

The panel also recommended the FDA commissioner be appointed for a six-year term to "stabilize" the office and minimize politics in the confirmation process. Acting FDA Commissioner Andrew von Eschenbach, MD, whose confirmation was still pending in the Senate as of press time, praised the report. "While considerable work has been done over the past two years to improve our approach to drug safety, work still remains to be done. All drugs have risks. Our challenge is to uncover these risks as soon as possible," he said.

"This report should be a watershed moment for FDA reform," said Sen. Chuck Grassley (R-Iowa), chairman of the Senate Finance Committee. Grassley plans to reintroduce legislation next year to mandate a clinical trials registry and establish an independent drug safety center. The IOM report, however, stopped short of endorsing the latter idea, recommending instead that Congress give the drug safety office a "substantial" increase in funds and personnel. "It's difficult for us to say how much this would be, but certainly more is better" Burke said, noting the Office of New Drugs has about 1,320 staff members while the Office of Drug Safety has only about 90.

The pharmaceutical and biotech industries responded to the report with caution. "Though there is always room for improvements, it would be a mistake to accept the notion that the FDA drug safety system is seriously flawed," said Caroline Loew, senior vice president at the Pharmaceutical Research and Manufacturers of America, the branded drug company trade group. Jim Greenwood, president of the Biotechnology Industry Organization, said BIO supported increased FDA funding to improve drug safety. But he added: "We must be cognizant that implementing undue hurdles in the drug review process will harm patients by delaying access to life-enhancing and life-saving products."