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Executive Summary

Miles is focusing its AIDS development on suramin analogs and multiple agent therapy, VP-R&D Paul Spiekermann, MD, told a July 1 hearing on AIDS drug development before the House Intergovernmental Relations Subcmte. It is a "recent decision of ours that we would enter very actively into AIDS research and development . . . and we would study suramin analogs," Spiekermann said. He suggested that the disease will require "a variety of therapeutic approaches." Seven years ago, suramin was found to be an inhibitor of reverse transcriptase, an enzyme required for the replication of retrovirus, Spiekermann noted. In 1984, it was discovered to inhibit the in vitro replication of human immunodeficiency virus, which causes AIDS. However, he commented that the compound has been found to be of little use clinically as a single therapeutic agent. "In light of the clinical results presented at the Paris Conference last week on Tuesday, June 24, by B. D. Cheson on behalf of the U.S. Suramin Working Group and by [Paris hospital investigators], it appears that suramin as a single agent cannot be recommended for the treatment of AIDS," Spiekermann said. Natl. Institute on Allergy & Infectious Diseases (NIAID) Director Anthony Fauci, MD, said that drugs that show safety and efficacy should be tested in combination with other drugs or therapies. "The prospect of combinations in AIDS is one we're all looking towards and are very enthusiastic about," Fauci said. One of the issues addressed by the hearing, chaired by Rep. Weiss (D-N.Y.), was the use of placebo controls in testing a drug for a fatal disease. Burroughs Wellcome VP-Research David Barry, MD, maintained that the unpredictability of clinical results requires blinded, placebo controlled testing. Ultimately, placebo controlled trials determine the usefulness of a drug sooner than other means, Barry told Weiss. "This type of study has the greatest potential for quickly establishing whether or not a drug is effective," the B-W exec declared. Making the drug generally available for use under treatment INDs would be "repeating errors of the past," Barry maintained, because fewer patients would participate in studies where they might receive placebo, and further knowledge about the drug would be delayed. He noted that his company plans to administer azidothymidine (AZT) to 1,500 patients over the next six months in such trials. NIAID's Fauci contended that AIDS drugs cannot be effectively compared to historical controls, even though the disease inevitably leads to death. "Virtually all investigators today realize that, given the complexity o the disease and the variety of the defects and the manifestation of the disease, we're not going to see a penicillin-like effect," Fauci said. Pointing out that with bacterial infections, signs of recovery are manifest "within a few months" after penicillin administration, Fauci said, "perhaps under those circumstances historical controls might be appropriate." However, in AIDS research there are only "subtle effects on size of the lesions, on frequency of opportunistic infections, and perhaps on immunologic parameters," he explained. These effects, as well toxic effects, might be missed "if the controls are not done as they should be." For example, Fauci continued, French data on HPA-23, which was generated outside of adequately controlled trials, "is totally worthless." Placebo-controlled trials are not necessary "if you have an absolute certainty of the natural course of a disease in every case," he acknowledged. With AIDS, "although one can project that within a five-year period most of the patients will succumb to the disease . . . in fact, the natural [course of the disease] is quite variable," Fauci said. The hearing followed a June 30 announcement by NIAID that it has awarded five-year contracts totaling $100 mil. to 14 medical centers to conduct clinical trials of experimental AIDS drugs. Fauci said that agents likely to be tested in the first year of the program are antivirals and immune modulators, including AZT, Foscarnet, HPA-23, ribavirin, alpha interferon, and dideoxycytidine. The medical centers will include Harvard, Johns Hopkins, and Stanford Universities, UCLA, and Memorial Sloan-Kettering. B-W AZT Trials Will Be Designed To Limit Placebos To Well Less Than Half The Patients Massachusetts General Hospital and Harvard University researcher Martin Hirsch, MD, said that clinical trials can adequately protect patients and still be well controlled. "There are ways of designing trials [so] that you can maintain placebo groups" without leaving half the patients untreated, Hirsch said. For example, AIDS patients might be randomized into five comparable groups, with four different test drug groups and one control group, he suggested. Barry said that B-W's AZT study protocols include techniques that will ensure that "a considerably smaller percentage of patients will receive placebo than those receiving AZT or some other potentially active drug. This percentage will decrease even further as our knowledge of the safety and tolerance profile of AZT increases." Mathilde Krim, MD, American Foundation for AIDS Research, maintained that placebo administration in trials involving fatal diseases like AIDS is unethical if there is any sign that the test drug is effective. "As soon as you know that the treatment is likely to be better than nothing, it is unethical to use placebo," Krim said. Yale researcher Robert Levine, MD, suggested that enough test drug, both for controlled trials and for distribution under compassionate INDs, could be produced if manufacturers were compensated at cost. Noting that broad availability of a potentially beneficial drug can draw resources from formal placebo-controlled trials, Levine asked: "Why is it that the industrial sponsor should be asked to do this thing that we all think is good -- provide drug for more and more people?" He questioned why funding could not be handled as it is in the medical device industry so that a drug company "could find some way to recover at least some of its costs in producing all of this drug that is not being used to develop data to support an NDA."

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