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Executive Summary

Simultaneous early trials and the use of dose-response designs can avoid problems associated with studies of therapies for life-threatening illnesses, FDA Drug Evaluation Office I Director Robert Temple, MD, maintained at an Oct. 26-27 conference jointly sponsored by FDA and the American Medical Association. In the drug approval process, "evidence of effectiveness ordinarily requires replication of the critical results," Temple noted. However, requiring additional studies for therapies to prevent death or irreversible morbidity is problematic, even if an initial trial produces only "marginal effects." Therefore, Temple advised, "it's usually wise, although expensive, to start more than one study of the drugs [for] life-threatening illness" to run concurrently. "The studies can be identical, they can look at separate patient populations, [either] of which can support effectiveness and not be mere redundancies." Dose-response studies "can resolve many" of the difficulties associated with drugs for the seriously ill, particularly highly toxic ones, the FDAer continued. "Although one tends to use doses at or near the maximum tolerated dose to treat serious illness, it may be possible to discover a smaller dose that is effective and better tolerated," he said. "This actually seems to have been the result in AZT studies recently, when both full and lower doses of AZT were superior to placebo." Other problems with testing such therapies involve the choice of controls. Using a control is facilitated, Temple suggested, by randomizing patients "very early" in testing rather than looking for a response in uncontrolled early stages and expecting to randomize patients after a potential benefit is seen. When study protocols "randomize the first patient" to a control group, before there is any indication of the experimental drug's utility, they avoid "inappropriate ethical constraints," Temple said. "One of the most important aspects" of the expedited approval rules, he suggested, "is that in a sense they are an attempt to implement" this approach by encouraging randomization "very early." The use of an active control creates a problem because, for example, "there is no reason" to expect DDI to prove superior to an AZT control, though it may be effective, Temple noted. "One way to avoid these difficulties is to alter the study design: rather than comparing two treatments to show them equivalent, one could compare the combination of the treatments with a single entity," he said. "Not only would such a trial be easier to interpret, assuming the combination is better, but it would also provide a real advance in therapy, not just an alternative." FDA Center for Drug Evaluation & Research Director Carl Peck, MD, urged physicians, patients, academe, and industry to share the responsibility with FDA for the inevitable failures of therapies given expedited approval. The Treatment IND and the parallel track procedures "embody a collective decision to buy into increased risk with a decrease" in knowledge of efficacy and time of development, Peck noted. "There are likely to be some failures; we are likely to see a Treatment IND that will result in some harm or a parallel track drug that will unfortunately result in injury," he said. "I ask for a sharing of the responsibility both in the decisions to make these drugs available and in the post-event analysis of how we can do it better in the future." * Covington and Burling's Peter Hutt called for FDA to standardize the various provisions making investigational drugs available on a pre-approval basis. FDA's early-release options are an "ad hoc groping for a new policy," Hutt asserted. "The policy isn't here yet. I think that it would be very useful if, instead of all this complexity and confusion. . . , if we can standardize terminology so that we all know what we are talking about." Hutt recommended that FDA relax its Treatment IND requirements in order to provide broader access to drugs for desperately ill patients while curbing black market activities. He said: "I think we have to open up Treatment INDs, we have to make a system work that will make these drugs available so that they'll be manufactured right, they'll be sold not at a gouging profit, and that people can get them when they want to; in short, prevent commercialization. Don't return to laissez-faire." Hutt maintained that "the whole concept of the Treatment IND has virtually become unimportant in terms of making investigational drugs available for treatment use," noting that more drugs are being provided through compassionate use and open label protocols than through the Treatment IND process. In a comparison of the AIDS crisis to the 1970's Laetrile controversy in which thousands of cancer patients went to illegal clinics to receive the FDA-banned drug, Hutt said current regulatory attention should be directed at preventing fraud and profiteering rather than restricting access to unapproved drugs. Temple also discussed the Laetrile situation in his commentary on FDA's liberalized policy toward providing access to drugs for life-threatening diseases. Of Laetrile, Temple noted: "Many people were charged a lot of money, and many people were turned away from therapy and died because of it. So, the removal of data as a basis for making things available has some potential consequences . . . I recognize the counter argument is [if] people are willing, let them do it. But I find that unpleasant and fairly ugly." However, Temple pointed to the AZT clinical experience as a demonstration that access to unapproved critical drugs will not deter patients from entering clinical trials. "AZT placebo-controlled trials in earlier stages of AIDS were completed in the context of AZT already being marketed. So, obviously people were willing to enter placebo controlled trials of a question that hadn't been answered yet," Temple said.

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