Time Magazine February 20, 2005 CAN THE FDA HEAL ITSELF? A permanent director and a new safety panel may not be enough to bring the agency back to health By Christine Gorman Like any government agency that has been around for almost a century, the U.S. Food and Drug Administration (FDA) has endured its share of rough patches. But "rough patch" hardly begins to describe all the bad news that has battered the agency over the past few months, from the possible suicide risks with antidepressants like Prozac, Paxil and Zoloft to the cardiac risks of pain-killers like Vioxx, Celebrex and Bextra. Americans depend on the FDA to carefully weigh the benefits and risks of all drugs before approving them, but the agency has had trouble lately shaking the growing perception, justified or not, that it has been working harder protecting the pharmaceutical industry than the public it's supposed to serve. The pressure for action grew so intense by last week that the FDA was forced to take action. On the eve of an extraordinary three-day hearing to air grievances resulting from the Vioxx and Celebrex snafu, it announced plans to create a new safety board to monitor drugs for unexpected side effects that show up after the drugs have gone on sale. Meanwhile, the Bush Administration finally moved to fill a one- year power vacuum at the top of the organization by nominating its acting chief, Dr. Lester Crawford, to be the FDA's permanent head. Crawford wasted no time signaling a change in direction. "Our culture is not to alarm the public," he told employees at a department briefing, referring to the agency's practice of keeping mum about apparent side effects until they have been scientifically confirmed. "That era has passed. What the public is demanding is to know as soon as we know." So far, however, the flurry of activity has done little to mollify critics both outside the agency and within. "I think the FDA is beginning to admit, in sort of a halting and hesitating fashion, that it hasn't done a good job with drug safety," says Dr. David Graham, the associate director for science and medicine in the agency's Office of Drug Safety and its chief whistle-blower. Graham calls the latest changes "cosmetic." An FDA official counters, saying they are "significant" and promise to have "a profound impact." Democrats in Congress argue that the latest dustups show that the FDA needs more regulatory power and a bigger budget to stand up to the pharmaceutical industry. But the most aggressive attacks have come from a Republican, Iowa Senator Chuck Grassley, 71, chairman of the Senate Finance Committee. Normally the FDA would be the province of the Senate Health Committee, which usually has to approve any changes at the agency. But Grassley, whose state has many elderly constituents, has focused on the FDA for a year -- ever since he learned that the agency held close to its chest worrisome data suggesting that certain antidepressant drugs might increase a teenager's risk of suicide. Grassley plans to introduce a bill next month that would create a new Office of Drug Safety independent of the FDA department that approves drugs. "We've seen some evidence over the last year that the agency has been too cozy with drugmakers," Grassley says. An independent safety board, he argues, would ensure that the experts who are responsible for finding and publicizing unexpected side effects are not the same ones who originally gave the drug a clean bill of health. It's a humiliating turn of events for an agency whose approval was once considered the world's gold standard of drug safety, especially after 1960, when it refused to approve thalidomide for use in the U.S. until it had more data and thus spared Americans the birth defects that plagued newborns in Europe and South America. In some ways, the FDA's recent troubles can be traced back to a pair of reforms that were made in the 1990s and hailed at the time as great innovations. Responding to complaints from AIDS activists and the pharmaceutical industry that drug approval was taking too long, the agency in 1992 announced a "fast track" for vital medications to treat life- threatening diseases. Although they would not be subjected to lengthy safety trials, fast-tracked drugs were supposed to be carefully monitored by their manufacturers after release to the public for any unexpected side effects. It was a compromise that made sense because problems are more likely to surface when millions of patients are taking a drug as opposed to the few thousand in a clinical trial. Over the years, however, as the drug-approval part of the arrangement grew, manufacturers became increasingly reluctant to undertake expensive postapproval safety studies. Then, in 1997, the FDA -- this time under pressure from drug manufacturers and their friends in Congress -- loosened the rules on direct-to-consumer advertising of prescription medications. Soon the airwaves were saturated with pharmaceutical messages, complete with big-budget videos and catchy jingles. Side effects received scant play, and most viewers assumed that if the drugs were FDA approved, the risks were probably minimal. Patients bombarded their doctors with requests for the new drugs. Harried physicians often acquiesced so they could address what they thought were more pressing needs. Demand for heavily promoted blockbuster drugs quickly soared. By late 1998, when the first of the cox-2 inhibitors won FDA approval, the stage was set for a debacle. The easiest side effects to detect, once a drug is used by large numbers of people, turn out to be the rare ones. Most doctors don't see very many cases of liver failure, for example. So they notice right away if more and more of their patients get hospitalized for it. The problem with cox-2 inhibitors like Vioxx is that they increase the risk of two very common ailments: heart attacks and strokes. It's much harder to tell, without careful statistical analyses, when common events become more common. "The [drug-approval] system was tested in ways it was never tested before," says Dr. Eric Topol, chairman of cardiovascular medicine at the Cleveland Clinic. "In an era of mass marketing, where data may show uncertainty and where the FDA has no real authority to take action, this class of drugs was set up to fail." Beefing up the FDA's safety portfolio or farming it out to another agency are two ways to address that kind of failure. Another would be for manufacturers to design their drug trials so that more attention is paid to the effects on all patients who take them, not just the relatively healthy ones usually used in their studies. A fourth would be to force drug companies to publish all their clinical data, not just the data that show their product in the best light. Editors at several prominent research journals are calling for measures that would do just that. In the meantime, the FDA keeps plugging along. It's a small agency with a fine old tradition dwarfed in both budget and political power by the pharmaceutical giants it is being asked to police. It's going to take more than a three-day hearing to straighten that out. -- Reported by Perry Bacon Jr. and Mark Thompson/Washington and Alice Park/New York Copyright 2005 Time Inc.