EMBATTLED: Merck CEO Raymond Gilmartin, whose company made the painkiller Vioxx, looks on as David J. Graham, associate director for science at the FDA's Office of Drug Safety, spells out the oversight errors culminating in the drug's withdrawal in a Senate hearing last November. Image: KEVIN LAMARQUE/REUTERS/CORBIS
"Too cozy" is how Senator Charles Grassley of Iowa referred to the relationship between the U.S. Food and Drug Administration and pharmaceutical companies in the aftermath of the Vioxx debacle. Although the FDA admits no substantive lapse in vigilance, congressional pressure and consumer outrage are forcing officials to rethink the agency's role and perhaps even the drug approval process itself.
The furor began last September, when Merck, Vioxx's manufacturer, withdrew the popular anti-inflammatory drug after a study revealed that long-term use doubled the risk of heart attack and stroke. In a congressional hearing last November, David J. Graham, a drug safety reviewer at the agency, estimated that as many as 55,000 Americans may have died as a result of taking the painkiller, a member of the COX-2 inhibitor class of drugs.
Worse, early studies had shown elevated cardiovascular risks for patients taking Vioxx, but the FDA took no action against the drug other than adding a "precaution" to its label in 2002. Such a response led Graham to testify that "the FDA, as currently configured, is incapable of protecting America against another Vioxx."
FDA officials have defended themselves by claiming that they lacked enough information to order a recall of Vioxx. Sandra Kweder, deputy director of the FDA's office of new drugs, says the agency and its advisory committee were "stumped" by the conflicting results of studies done before and after Vioxx was approved in 1999.
Medical experts point out, however, that this confusion arises from the systemic problems surrounding unreliable preapproval trials and an inadequate system for monitoring new drugs after they come on the market. Because many adverse drug effects are rare or hard to detect, researchers often cannot grasp the full extent of the dangers until hundreds of thousands of patients are taking the medication. (The clinical trials required for FDA approval typically involve no more than a few thousand subjects and can, as in the case of Vioxx, be too short-lived to indicate long-term trends.) The FDA orders drug companies to conduct postmarketing research as a condition of approval, but fewer than half of such studies are actually completed. And the FDA's MedWatch program, which gathers reports of adverse effects voluntarily submitted by doctors, has garnered criticism from prominent medical journals and epidemiologists for its underreporting and unreliability.
The current problems appear to stem in part from the 1992 Prescription Drug User Fee Act, which sought to speed the introduction of new drugs by allowing the FDA to accept user fees from pharmaceutical companies, which were then siphoned into hiring additional drug reviewers. By focusing the agency's resources on the approval process, the law left less money for postapproval monitoring. Drummond Rennie, a deputy editor of the Journal of the American Medical Association, says the financial contributions of the drug companies have also made the FDA less likely to confront them. "The FDA has lost its will and courage," he asserts.
To remedy the situation, Senator Grassley has proposed an independent body for oversight. "It doesn't make sense from an accountability standpoint to have the office that reviews the safety of drugs already on the market to be under the thumb of the office that puts drugs on the market in the first place," he contends. Other policymakers have urged the FDA to be more aggressive about adding warnings to drug labels or to establish a public database containing the results of all major drug studies so that consumers can make more informed decisions. Under scrutiny, the FDA has hired the National Academy of Sciences's Institute of Medicine to study possible changes to the drug safety system.
The Vioxx withdrawal may also mark a turning point for the industry. Instead of seeking blockbuster drugs aimed at large numbers of consumers, companies may focus on niche medications designed for particular groups of ailing people. Garret A. FitzGerald of the University of Pennsylvania School of Medicine, an expert on COX-2 inhibitors, notes that Vioxx might have been able to stay on the market if its use had been restricted to people who have a low risk of cardiovascular disease but a history of gastrointestinal problems. (Vioxx is less likely to irritate the digestive tract than nonprescription painkillers.) "Here are drugs that are very useful in a segmented market," he says, "and their usefulness is being put at risk by the pursuit of a blockbuster strategy. I think, inevitably, the trend is going to be toward more segmented indications."