By Shankar Vedantam
Washington Post Staff Writer
Saturday, September 23, 2006
The federal system for approving and regulating drugs is in serious disrepair, and a host of dramatic changes are needed to fix the problem, a blue-ribbon panel of government advisers concluded yesterday in a long-awaited report.
The analysis by the Institute of Medicine shined an unsparing spotlight on the erosion of public confidence in the Food and Drug Administration, an agency that holds sway over a quarter of the U.S. economy. The report, requested by the FDA itself, found that Congress, agency officials and the pharmaceutical industry share responsibility for the problems -- and bear the burden for implementing solutions.
The report represents a watershed moment after two years of controversy over the safety of such widely used drugs as pain relievers and antidepressants. The Institute of Medicine is part of the National Academies, chartered by Congress to advise the government on scientific and health policy issues. Its recommendations traditionally carry great weight.
The 15 experts drawn from academic and professional organizations were unanimous in endorsing the recommendations, which called for several major policy changes. Several of these have long been urged by drug safety advocates but have been resisted by the industry, Congress and the FDA itself. A number of them would require congressional approval.
The panel called for a moratorium on consumer advertising of newly approved classes of drugs until they have been on the market long enough for unrecognized side effects and risks to emerge. Packaging for new types of medications should also carry a special symbol, such as the black triangle required in Britain, to alert patients that the drug's safety profile would not be fully known until it had been more widely studied, the report said.
The FDA should reevaluate safety and effectiveness data of such new drugs within five years after initial approval, the panel added, and the agency needs new powers to impose fines and requirements on drugmakers. In addition, the report called for the agency to have authority to place a wider range of restrictions on drugs it deems risky.
Manufacturers should also be required to register all clinical trials they sponsor in a government-run database to allow patients and physicians to see the outcome of all studies, not just those published in medical journals, the report said. Studies that show positive results for a drug are more likely to be published by journals than negative ones.
The committee also took aim at FDA management, citing a history of intra-agency squabbling and conflicts of interest on the expert advisory panels appointed by the agency to review the scientific data on proposed new drugs and devices. A substantial majority of advisory panel members should have no ties to industry, it said.
"FDA's credibility is its most crucial asset, and recent concerns about the independence of advisory committee members . . . have cast a shadow on the trustworthiness of the scientific advice received by the agency," the report said.
To reduce turnover and political interference, the institute said, the FDA commissioner should be appointed to a fixed six-year term. Currently, the commissioner serves at the pleasure of the president.
Agency officials said they will take the report seriously but added that changes implemented over the past year meant that the report is somewhat out of date. Acting FDA Commissioner Andrew C. von Eschenbach said the agency is especially focused on improving its scientific, technological and communication methods.
The pharmaceutical industry echoed the agency's response.
"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," the Pharmaceutical Research and Manufacturers of America said in a statement. "After all, fewer than three percent of approved prescription drugs have been withdrawn from the American market for safety reasons over the last 20 years."
But Sen. Charles E. Grassley (R-Iowa), who has led a number of investigations into the workings of the FDA in recent years, said the agency's reaction to a report it had commissioned speaks volumes.
"The FDA appears to be focused on damage control rather than addressing its core problems," Grassley said in a statement. "As a science-based agency, the FDA is remarkable for its lack of introspection, second-guessing, and failure to assess its own performance and capabilities in a systematic way."
Much of the institute's report focused on a central gap in drug regulation: While the FDA demands strict data on efficacy and safety from clinical trials before approving a new drug, less attention is paid after the drug reaches the market.
A safety problem that occurs once in every thousand patients, for example, would be unlikely to show up in clinical studies of a few hundred people, but it could result in thousands of serious side effects once the drug is approved and being taken by millions. The current system for monitoring adverse effects is nowhere near as systematic as the evidence collected before approval, the report said.
Besides, said R. Alta Charo, a panel member and bioethicist at the University of Wisconsin at Madison, patients who participate in drug trials are carefully selected, and hardly typical of patients in the real world who usually suffer from more complex problems.
"A drug tested in a few hundred or thousand people is very different when used by millions, especially over long periods of time and in conjunction with other supplements," she said.
While the agency can negotiate with companies to conduct long-term, post-approval studies, there are glaring gaps in such information, the report said. This is partly why the report also recommended limits on advertising new drugs. The report's authors acknowledged, however, that limits on advertising could run afoul of constitutional free-speech guarantees.
Charo also cited "a lack of collaboration among divisions, tensions [and] inappropriate management" at the FDA, saying officials who focus on safety issues are chronically underfunded compared with those who handle new-drug approvals.
Part of the problem, the report said, is that the money paid by industry to help fund FDA's regulators, under a 1992 law designed to speed up new drug reviews, cannot under the law be diverted to FDA's safety division, which suffers from chronic underfunding.
"What the report does not do very well is explain that the vast majority of interactions at the center are successful," countered Steven Galson, who directs the FDA division that evaluates new drugs. Still, he added, "I accept the recommendation and see it as an opportunity to improve."
Scott Lassman, senior assistant general counsel for the drug industry group, said it would study the report carefully. He said that the industry is open to suggestions for greater transparency but that the FDA already has enough authority to act after drugs are approved.
The trade group also opposes mandatory registration of clinical trials because that would force companies to reveal trade secrets to competitors, Lassman said. Manufacturers also oppose restrictions on advertising, he said, adding that advertisements help educate patients about problems and treatments.