SILVER SPRING, Md. _ The FDA's Antiviral Drugs AdvisoryCommittee (ADAC) recommended on Tuesday that the FDA tighten itsguidelines for manufacturers to develop post-marketing clinical trialplans for drugs that receive accelerated approval.Although confirmatory studies are already mandated under FDA rules,ADAC panel members said that companies should develop detailedplans for post-marketing efficacy studies in advance of seekingaccelerated approval so that the plans may be thoroughly reviewed bythe FDA and ADAC. In addition, they said that companies shouldexecute the studies in a specified time frame and that the FDA shouldenforce its written policies more vigorously.Accelerated approval allows companies to obtain FDA approval fordrugs that treat serious or life-threatening diseases on the basis of early-stage studies measuring activity against "surrogate markers" of disease.Those studies are supposed to be followed by post-approval studies toconfirm clinical benefit against "harder" clinical endpoints, such asdisease progression or death.However, AIDS activists complained during the two-day ADACmeeting that promised post-marketing studies of antiretroviral agentswhich received accelerated approval have not been completed aspromised. They said the FDA has not enforced its policies to requiresuch studies. As a result, it's not clear that some approved AIDS drugsare efficacious."Neither this committee nor the FDA can force a company to conduct aspecific study," Spencer Cox of the New York-based AIDS advocacyorganization, Treatment Action Group, told ADAC panel members onTuesday. "However, if you fail to ensure that at some point in thedevelopment process companies produce data that are adequate toreliably determine whether or not their products are better than nothing,you will have done people living with this disease a terribledisservice."Some panel members expressed concern that accelerated approval ruleshave dangerously lowered the FDA's safety and efficacy hurdles fornew drugs. Panel member and Columbia University statistician PaulMeier worried that the FDA will not have the political will to removedrugs from the market if so-called confirmatory studies don't confirmanything."The political pressure will be intense to keep a drug on the market ifpatients believe it is helping them, even if there's no proof," arguedMeier."We're not talking about lowering the standard for drug approval,"responded FDA Commissioner David Kessler. "The confirmatorydecision will be based on the same evidence used for standard drugapproval. We have the resolve to put the genie back into the bottle. Ifwe don't do that, the whole [accelerated approval] process falls apart."Kessler said that the FDA wants to retain "judgment and flexibility" inallowing "reasonable amounts of time to lapse" between acceleratedapproval and completion of confirmatory studies. But Meier and otherADAC panel members called for pre-specified time frames, from oneto three years, in which companies would be required to complete thestudies or have their drug's license revoked by FDA.Daniel Hoth, senior vice president of Cell Genesys Inc., member of theNational Task Force on AIDS Drug Development and former directorof the division of AIDS at the National Institute of Allergy andInfectious Diseases, told BioWorld that what AIDS activists reallywant and need is disease management trials. Such trials could yieldcrucial information about the efficacy gains or losses of administeringdifferent treatment strategies at different stages in the disease process."The real issue here is getting trials that answer disease managementquestions, the kinds of question that drug approval trials done bycompanies don't answer," he said. "Most of our learning about howbest to use a drug goes on, post-approval, in these types ofmanagement trials."But Hoth said that industry is unlikely to fund disease managementtrials since they compare treatment regimens of multiple drugs andaren't needed for obtaining FDA approval. In addition, they can beexpensive. He said that the National Institutes of Health might be thebest agency to fund disease management trials that could begin toprovide the answers AIDS patient are seeking. n

-- Lisa Piercey Washington Editor

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