Once touted as the world’s most rigorous drug regulator, the FDA is now being scrutinized by congressional committees and the Government Accountability Office for possible regulatory lapses.   

The agency’s transformation started in the 1980s, when AIDS and cancer activists pushed for quicker access to potentially life-prolonging drugs for severely ill patients. But that acceleration was subsequently applied to all medicines, including those for problems that aren’t life-threatening as well as for “me too” drugs, which offer little or no advantage over existing medicines whose risks are well known.

In 1992 Congress passed the Prescription Drug User Fee Act (PDUFA), which forced a sea change at the FDA. The law imposed tight deadlines for drug evaluation and required companies to pay fees earmarked for hiring more reviewers. In fiscal year 2004 the FDA collected some $250 million from drug companies, almost half of its drug-review budget. That year, the agency boasted in a report to the president and Congress that “drug-approval time has been cut almost in half” since the advent of PDUFA.

Current deadlines require that reviews be completed within 10 months for standard drugs, compared with an average of more than 20 months before PDUFA; priority drugs, including at least two high-risk medicines on our list, Celebrex and Zelnorm, are assessed in 6 months. The FDA maintains that it hasn’t lowered its standards. But even with the extra reviewers, meeting the deadlines can be difficult.  “With the clock ticking, you did the best you could,” says Elizabeth Barbehenn, Ph.D., a drug reviewer at the FDA’s Office of New Drugs for 13 years before leaving in 1998 for the nonprofit Public Citizen Health Research Group. “It was extraordinarily frustrating.”  Close to 20 percent of FDA reviewers say they “have felt pressured to approve or recommend approval” of a drug despite “reservations about its safety, efficacy, or quality,” according to a 2003 survey of some 400 agency reviewers by the Department of Health and Human Services’ inspector general. Fewer than one-fourth of the 400 indicated that the “work environment” allowed “expression of differing scientific opinions.” The accompanying report concluded: “Workload pressures increasingly challenge” the effectiveness of the review process.

Cruzan, the FDA spokeswoman, said the agency has recently taken several steps to improve communication on scientific disagreements within the agency. For example, investigators as well as drug sponsors can now contact an “ombudsman for dispute resolution on procedural issues regarding reviews,” she said.  But the data with which FDA reviewers work aren’t always the best. Federal law allows drug makers to submit as few as one clinical trial plus confirmatory evidence. Typically companies need show only that their product works better than a placebo, rather than an established drug, to achieve an effect that may have little relevance for patient outcomes, according to an opinion piece in the September 8, 2005, issue of The New England Journal of Medicine. Such a “minimal standard” would be “unacceptable anywhere else in research,” the piece said.

Some of the studies, involving drugs that will be taken for decades, last as little as a few months, said Marcia Angell, M.D., former editor-in-chief of The New England Journal of Medicine, by e-mail. She added that drug companies typically recruit patients who are younger and healthier than those who would ultimately use the drug. Such patients “are less likely to experience side effects,” Angell said.

POWERLESS AFTER APPROVAL

While longer, more realistic studies and tighter scrutiny should theoretically detect more risks before approval, some hazards will unavoidably emerge only after drugs are used by a larger group of consumers. Monitoring such “postmarketing” drug reactions is therefore critical.

But the FDA lacks the legal authority to force companies to do the necessary research. In a report in the Federal Register in February 2005, the agency noted that companies had committed to conducting 1,191 postmarketing studies of approved drugs. But 68 percent were still “pending” as of late September 2004, meaning they hadn’t been started.

Many of those studies were pending for good reasons, Goldhammer says, notably difficulty lining up research sites and recruiting patients. But Randy Juhl, Ph.D., a former dean of the School of Pharmacy at the University of Pittsburgh and a former FDA advisory panel member, says the drug companies’ failure to meet post-marketing study commitments shows that they “do not take these responsibilities seriously.” The FDA should ask Congress “for additional enforcement power,” possibly an “umpteen-million-dollar fine per day” to get the studies done, he says.

An injection of resources may be equally important: The FDA’s Office of Drug Safety, which monitors adverse reactions to a medication after approval, is one-tenth the size of the agency’s Office of New Drugs, which handles the original approval process. And the new-drug office, not the safety office, has the final say about post-approval safety concerns.

That’s a bad setup, says Eric J. Topol, M.D., chairman of the department of cardiovascular medicine at the Cleveland Clinic and a former FDA advisory panel member. New-drug officials who approve the medication in the first place are, in effect, “champions of the drug,” he said. “They cannot be objective” if safety issues arise after it’s marketed, he added.

Cruzan, the FDA spokeswoman, said by e-mail that the agency has asked the National Academy of Science’s Institute of Medicine to study “the effectiveness of the nation’s drug-safety system,” emphasizing the post-market phase. The report may suggest structural changes at the FDA’s Center for Drug Evaluation and Research, the agency said in a statement released in November 2004. But the results are not expected until the summer of 2006. As we went to press, the FDA proposed modestly reorganizing its drug-safety office, but few details were available.

David Graham, M.D., associate director for science and medicine at the FDA’s Office of Drug Safety, testified before a Senate committee in November 2004 that officials in the new-drug office had made clear that his department should not offer recommendations that contradict their department. He said, too, that senior management in his own office pressured him to change his conclusion that high doses of the pain reliever Vioxx increased the risk of heart attack.

The FDA immediately issued a denial, stating that Graham’s testimony “does not reflect the views of the agency.” Drug-safety scientists have “independent authority,” and “when drug safety issues are identified, they must be factored into the risk-benefit equation,” the statement said.

weakness about warnings

The FDA cannot force companies to add newly emergent risks to drug labels. “I think it’s unconscionable,” says Arthur Levin, M.P.H., director of the Center for Medical Consumers in New York City, a nonprofit advocacy organization. “We want the FDA to get stricter about this stuff, but we don’t give them the means to enforce their decisions.”

Six of the 12 high-risk drug types we identified had no black-box warning, the strongest kind, when we went to press, though in most of those cases the FDA should request that warning, says Marvin Lipman, M.D., chief medical advisor for Consumers Union, the publisher of Consumer Reports. In February 2005 an FDA advisory committee recommended severe warnings about the two eczema drugs we cited, Elidel and Protopic, because of a possible increased risk of cancer. The agency issued a public-health advisory a few weeks later and requested black-box warnings, but as of October 2005, neither drug manufacturer had made the change. Representatives of both companies say their research shows no need for the severe warning, though they were still discussing it with the FDA as we went to press.