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FDA HAS RANGE OF "SCENARIOS" FOR WITHDRAWING DRUGS APPROVED UNDER THE ACCELERATED APPROVAL REG, COMMISSIONER KESSLER TELLS ANTIVIRAL ADVISORY CMTE.

Executive Summary

FDA will have a range of options for withdrawing drugs approved under the accelerated approval procedures, Commissioner Kessler told the Antiviral Drug Products Advisory Committee during its April 20-21 meeting. During its meeting, the committee concluded that clinical data for Bristol-Myers Squibb's Videx (ddI) supported its continued marketing and recommended Hoffmann-La Roche's Hivid (ddC) for accelerated approval (see related stories, p. 14-18). FDA's accelerated approval reg, based on the agency go-ahead for ddI, was published April 15 ("The Pink Sheet" April 20, p. 8). Among its provisions is a streamlined "withdrawal" process for drugs given accelerated approval on the basis of surrogate endpoints that fail to demonstrate post-marketing clinical benefit. Kessler was asked if the agency would have withdrawn ddI if the clinical data reviewed by the committee had not shown benefit, even though patients continued to think the drug valuable. "Just like there's an array of tools to get things onto the market, I think that in each individual instance we would have to tailor the kind of actions we took to the circumstances at hand, and perhaps have different kinds of scenarios," the commissioner said. "Perhaps in certain instances we would yank a drug without providing further access," Kessler said. "Other times, we may want to backpedal to more of an expanded access, investigational mode with informed consent, etc. I think we have to tailor it to the individual case." Kessler sat with the committee during both days of the high- profile meeting. He was an active participant in the committee's deliberations, his main role being to provide clarification and reassurance about the accelerated approval process. The commissioner prefaced the committee's discussion of ddC by describing the proposed reg to them. "Accelerated approval does not represent a change in FDA's traditional standard," he maintained. "Rather, it is an acknowledgement of what we have always stated, that we must be prepared to accept greater risks from a drug when greater benefits are possible." With respect to ddC, Kessler said, "I recognize that the more we look at the data...we all understand that we have a long way to go. Please don't let your frustration...prevent you from at least allowing us to take small steps." The committee did express frustration with the limited amount of data it was asked to review. "There are a lot of unsolved problems," Monto Ho, MD, University of Pittsburgh, said. "We have been under pressure both by the FDA and by the community to approve these drugs as quickly as possible." Kessler was reassuring: "The whole point of [accelerated approval] is to relieve some of the hand-wringing, some of the angst, that once you approve [a drug] it is out and you will never have another shot at it....You can take a risk. You can be wrong." The April 20-21 meeting also highlights the risks that drug sponsor's have to assume when a project is singled out for accelerated approval review. Hoffmann-La Roche was put in the awkward position of defending a drug application with very thin clinical trial results. When a drug gets into the accelerated approval track, the sponsor appears to lose some of its ability to determine the course of the application. Hoffmann-LaRoche appeared to have been pursuing monotherapy as its primary target, but the company was obliged to accept a combination treatment indication with AZT. The company did not have the luxury of the usual development schedule and the ability to look at various treatment regimens and indications. The downside of the accelerated approval process is significant. If there is a delay between the advisory committee review and final approval, the firm may share criticism from patient groups for being too cautious. If, on the other hand, FDA goes ahead with the approval and ddC does not show supporting data in further trials, the firm will probably be the one to take public blame for rushing the product to market. Members of the committee repeatedly returned to the issue of streamlined withdrawal. "Can we put the genie back in the bottle?" asked Mark Smith, MD, VP-Henry J. Kaiser Family Fund. "Dr. Kessler has stood up for his promises in the past," Chairman Henry Masur, MD, National Institutes of Health Clinical Center said. "If he says a drug can and will be withdrawn if that's the appropriate thing to do, we all would assume that that in fact is what will happen." A major concern of the committee about its approval vote for ddC was that word of the approval would jeopardize ongoing trials that are supposed to give more definitive data. Kessler was asked whether the agency could withdraw ddC if that happened. "The burden would remain on the manufacturer," Kessler said. "The absence of showing a clinical benefit in a reasonable period of time I think would be tantamount to almost no clinical benefit. You have to keep the incentive in the direction of getting more data." He added: "We're all learning to walk in this area. This is new ground that we're breaking."

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