SILVER SPRING, Md. _ FDA Commissioner David Kesslerstaunchly defended his agency's accelerated approval and "expandedaccess" programs for AIDS drugs on Monday at a forum to review thepolicies. He told reporters on the first day of a two-day Anti-ViralDrugs Advisory Committee meeting here that the FDA was seekingideas on how to improve the process, not dismantle it."We've worked very hard over the last couple of years to reallyrevamp the drug approval system for life-threatening and seriousdiseases," said Kessler. "On balance, accelerated approval has been asuccess. We are balancing the need to make drugs available to thepatients who need them most with getting good data."But Kessler added that any new program needs periodic review to"make sure we're on the right track." In recent months, some AIDSactivists have questioned the accelerated approval policy, saying itslower standards for clinical efficacy don't provide AIDS physicians orpatients with enough good data on which to base clinical decisions.Finalized in 1992, the FDA's accelerated approval rules were designedto speed the development process of experimental drugs for life-threatening diseases. The rules allow the distribution and use of drugsthat have proven safe in Phase I toxicity testing and have shownactivity against surrogate markers of disease. However, surrogatemarkers in AIDS, such as CD4 cell counts, have not yet been shown tohave a clear affect on disease progression or death in AIDS.The idea behind accelerated approval is that traditional measures ofclinical efficacy would be established in ongoing, controlled studiesconducted by drug companies after their drugs received the conditionalaccelerated approval.However, AIDS activists and others charge that the FDA has been laxin enforcing the requirement for clear proof of efficacy."The pharmaceutical sponsors of the two agents granted acceleratedapproval thus far have not generated the information necessary toresolve the unanswered questions about their use," said a jointconsensus statement prepared by the New York Treatment and DataCommittee of ACT UP and the board of directors of the TreatmentAction Group (TAG). "Worse, there is currently no viable mechanismin place to compel pharmaceutical companies to demonstrate theclinical benefits of these agents."In fact, one group of AIDS activists has proposed that the nextgeneration of drugs, protease inhibitors, be subjected to stricteraccelerated approval standards than its predecessors, the anti-viralnucleoside analogs AZT, ddI, ddC and d4T. Although AZT is widelyconsidered the treatment of choice, some statisticians have pointed outthat the clinical trial data gathered to date do not support theassumption that AZT prolongs the life of AIDS patients.In an information packet titled, "Rescuing Accelerated Approval:Moving Beyond the Status Quo," AIDS activists put forward aproposal to change the way new AIDS drugs are evaluated.Specifically, the proposal calls for Hoffman-La Roche Inc., maker ofthe first protease inhibitor that will reach the FDA for acceleratedapproval, to conduct an 18,000-patient study _ the largest AIDS trialever _ to compare the drug to standard treatment."In regulating the first generation of antiretroviral drugs, many felt thata reduced evidential standard was appropriate, due to the absence ofavailable treatments," they wrote in a letter to Kessler last June. "Now,however, we believe that the development of protease inhibitors offersa new opportunity to rethink this regulatory process in ways that willensure reasonable access to new drugs, while producing clinicallyrelevant information about their use.""We now have a unique window of opportunity to plan prospectively acoherent, rapid and clinically useful development path for HIVprotease inhibitors, and to learn from the lesson gained by five years ofdisappointing and contradictory research on nucleoside analogs. Wemust not let this opportunity slip by," the letter concluded.The proposal has generated a storm of controversy in the AIDScommunity, as was evident by the impassioned statements of activistswho spoke during Monday's public comment period. Many said thatraising the efficacy hurdle for accelerated approval will harm AIDSpatients who need access to drugs faster than the plodding regular drugapproval process can provide them. In addition, many said it would actas a disincentive to companies developing AIDS drugs.Kessler observed on Monday that there is no ideal solution to theproblems posed by accelerated approval. He attributed the frustrationof activists and the agency itself to the mediocre efficacy of mostapproved AIDS drugs. Yet, "no one is calling for the removal of thesedrugs from the market," he noted.Kessler said that the FDA could tighten its control over the conduct offollow-up, confirmatory studies by requiring that drug companies bringdetailed plans for such trials to the table at the time their drugs areconsidered for accelerated approval. In addition, he said that more datacould be collected under expanded access programs (also known astreatment investigational new drug programs), in which individualpatients receive the drug on a "compassionate use" basis but are notpart of a clinical trial.He warned that drugs which do not prove efficacious in follow-upstudies will be yanked from the market. "In the end, the scientific datawill be the arbiter of last resort. If a drug doesn't work, it shouldn't beout there." n

-- Lisa Piercey Washington Editor

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