It's been a tough season for drug safety: FDA's long-awaited analysis of antidepressant use in children found that there were indeed safety issues; one of the world's best-selling drugs was pulled from the market; and the United States lost half of its flu vaccine supply when a plant was shut down over manufacturing concerns.
Behind these questions looms a larger one that promises to become a central issue for policymakers: Have efforts during the past decade designed to accelerate drug approval and streamline research requirements been a mistake? If that is the case, is it then time to return to a tougher, older-fashioned approach to safety?Warnings for Children The debate over antidepressants has escalated all year, since evidence surfaced that FDA and manufacturers had failed to make public adverse event data on the use of selective serotonin reuptake inhibitors (SSRIs) by children. The issue grabbed public attention in June when New York Attorney General Eliot Spitzer brought a civil suit against GlaxoSmithKline for withholding data on Paxil (paroxetine).
In Congress, the Senate Finance Committee, which was already investigating FDA, focused on the question of whether the agency acted improperly in withholding information about SSRI adverse events. The House Energy and Commerce Committee grilled manufacturers and FDA officials at two hearings in September. A joint meeting of FDA's advisory committees for psychopharmacologic and pediatric drugs recommended that antidepressants carry a black box warning on the possibility of suicidal behavior in young patients. In October, FDA carried out the recommendation, requiring that 32 antidepressants carry a black box warning and provide MedGuides through unit-of-use packaging. The policy rules out DTC broadcast promotion and reminder ads for these products.
The SSRI debate has raised genuine concerns about the conduct of clinical research and FDA oversight of the process. One troubling set of questions emerged over FDA's program to grant additional marketing exclusivity to companies that perform certain pediatric trials. Robert Temple, director of FDA's Office of Medical Policy, explained to the House panel that sponsors generally design studies "with good intent and according to high standards," but he noted that the failure of a supplemental pediatric study to show efficacy is not nearly as devastating as failure in a similar trial pre-approval. As a result, companies may sponsor too few studies to obtain clear results or recruit too few patients who fully meet enrollment criteria.
Temple says FDA will require future pediatric studies of antidepressants to have three arms that compare the test drug to both placebo and fluoxetine. This will show more clearly if poor results arise from an ineffective drug or a poorly designed study. FDA and other regulatory authorities also are reviewing adverse-event databases to see whether the SSRI effects found in children also show up in adults. Until now, researchers have not found data indicating increased risk of suicide in mature patients but don't know why there should be an age-based difference.
Chronic Concerns Congressional analysts expect to use their experience probing antidepressant safety in investigating Merck's decision to pull the COX-2 inhibitor Vioxx (rofecoxib). Legislators have already pounced on FDA for not being quicker to disclose concerns about side effects and "silencing" an agency staffer who was studying the issue.
Analysts estimate that about 20 million US patients have used Vioxx since its approval in 1999, and almost 100,000 individuals had some cardiovascular event after taking the drug for more than 18 months. Liability claims could exceed $10 billion.