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BRISTOL-MYERS DDI (VIDEX) TREATMENT IND APPROVED FOR AIDS, SEVERE ARC PATIENTS INTOLERANT TO AZT; PROTOCOL ENCOURAGES SIGN-UP IN PHASE II TRIALS

Executive Summary

Bristol-Myers DDI Treatment IND and open safety distribution protocols are set up to protect the viability of efficacy studies by requiring all candidates to first seek eligibility in the clinical trials. In order to ensure enrollment in the efficacy trials, Bristol-Myers noted: "All patients will be reviewed for eligibility to participate in Phase II trials before they will be considered for participation in either the Treatment IND or compassionate distribution protocols." Bristol-Myers' DDI Treatment IND was approved by FDA on Sept. 28 for use in patients with AIDS and advanced ARC who cannot tolerate therapy with Retrovir (AZT or zidovudine). "Under the Treatment IND, AIDS patients who have experienced severe anemia or other dose-limiting adverse reactions to zidovudine will be eligible to receive DDI through a program administered and funded by Bristol-Myers," HHS announced in a Sept. 28 press release. FDA and the National Institutes of Health "have developed a comprehensive plan for clinical evaluation and expanded availability of DDI," the release states. That plan includes protocols for three large-scale Phase II trials, the Treatment IND protocol, and an "open safety protocol" for AIDS patients whose disease has progressed despite treatment with AZT and who have no other therapy options. The DDI Treatment IND approval and open safety protocol represents FDA's first attempt to allow wide distribution of an unapproved AIDS drug during early testing. Bristol-Myers completed Phase I safety trials in August. Further, the open safety protocol marks the first use of a "parallel track"-type mechanism. DDI is the second drug, after AZT, for specifically treating AIDS that FDA has made available. DDI's Treatment IND is the fifth AIDS-related distribution protocol to be approved by FDA. Bristol-Myers said it is currently ready to start processing applications for the Treatment IND and the open safety protocol. According to HHS, the company expects that physicians with patients eligible for enrollment in the two protocols "should begin to receive the drug in about two weeks." The company said that DDI is available now and that it "expects no problems" with supply of the drug. Bristol-Myers has established an "800" number phone line to provide enrollment information to physicians. Doctors calling the number will receive a package that includes "the appropriate protocol and patient entry and physician registration forms," Bristol-Myers said. "The physician will be requested to refer patients to the Phase II clinical program in their geographic area and will be given instructions on how do to this." Ineligible patients will then be considered for enrollment in the Treatment IND and compassionate use protocols. Once a patient is accepted into a program, the physician will receive a 30-day supply of DDI, the company noted. Patient follow-up and adverse experience forms must be sent by the physician on a monthly basis, and only after receipt of these, will additional DDI be provided. Physicians, patients and others can also obtain information on the three programs through HHS's toll-free service, 1-800-TRIALS-A. AIDS patients will be eligible for the compassionate distribution protocol if they fail the eligibility criteria for the clinical trials and the Treatment IND and if they have been diagnosed "as clinically deteriorating after receiving a minimum of six months of AZT therapy," Briston-Myers said. According to HHS, the "entrance criteria for the ]open safety[ protocol will continue to be evaluated, and appropriate adjustments made, as data are accumulated and more information on safety and efficacy becomes available." The distribution program will be established in both the U.S. and Canada. Bristol-Myers "is not charging for the cost of the drug in any of these programs," HHS reported. However, the HHS release notes, "there are likely to be physician and laboratory charges associated with receiving DDI through either the Treatment IND or open safety protocols." The Phase II trials of DDI in AIDS and ARC patients will be conducted by the National Institute of Allergy and Infectious Diseases' AIDS Clinical Trials Group (ACTG) in collaboration with Bristol-Myers. The trials will enroll approximately 2,600 patients. NIAID has 32 adult ACTG units in the U.S. One protocol calls for a randomized, double-blind comparison of DDI and AZT in 1,500 patients, "900 of whom have had little or no previous treatment with zidovudine and 600 of whom have taken zidovudine from two months to a year," HHS explained. The patients in each of the two groups will first be randomized to receive either DDI or 200 mg of AZT every four hours or as previously tolerated, NIAID said. Patients taking DDI will be randomized to receive 500 mg or 750 mg of DDI a day, adjusted down for body weight. Another study will evaluate DDI and AZT in 750 patients who have been on AZT for at least one year. Patients will receive either 500 mg or 750 mg of DDI daily, adjusted down for body weight or 200 mg of AZT every four hours or as previously tolerated, NIAID noted. In the third study, three different doses of DDI, 200 mg, 500 mg, or 750 mg per day, adjusted down for body weight, will be compared in 360 persons intolerant to AZT. HHS stressed that "despite the promising early results with DDI, it is important to emphasize that zidovudine is the only drug with proven efficacy for the treatment of patients with AIDS and advanced ARC." The results of a DDI Phase I trial, sponsored by NIAID, were reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy in Houston Sept. 17-20. In the trial of 37 patients, significant changes in surrogate markers, 50% increases in CD4 levels and 50% decreases in p24, were "noted in patients at all dose levels from oral doses as low as 1.6 to 4 mg/kg per day and on up," investigator J. S. Lambert, MD, University of Rochester, reported. Adverse reactions occurring in the DDI study that were considered dose-limiting included neuropathy in eight patients and pancreatitis in six patients. Seven out of the eight patients with neuropathy developed the condition while in the dose range of 20 mg/kg per day. "Of note in the toxicity profile of DDI," Lambert remarked, "is the absence of myelosuppression, except for the thrombocytopenia, whose relationship to DDI administration is unclear." HHS said that the "protocols announced today take these most recent data into account by selecting doses that appear to be well tolerated and have evidence of activity against the AIDS virus." The DDI Treatment IND and open safety protocol, the Department release states, "is consistent with the parallel track concept and is an interim measure to make a promising investigational therapy available for people with AIDS who do not have satisfactory treatment options." HHS is currently "developing procedures to expand availability of investigational therapeutic agents through a parallel track mechanism," the release points out. An HHS working group representing both government and non-government groups was formed recently to help resolve disagreement over details of the parallel track mechanism ("The Pink Sheet" Aug. 21, p. 10). At its first meeting, the group concluded that the parallel track system should be administered by the AIDS Advisory Committee created by the Omnibus Healthcare Act of 1988. The idea of a parallel track mechanism was first proposed by NIAID Director Anthony Fauci. Subsequently, FDA Commissioner Young publicly stated that a parallel track system and a Treatment IND could be used simultaneously when they are implemented for different indications of a drug ("The Pink Sheet" July 31, T&G-3). "The epidemic of AIDS is extraordinary, and must be met with extraordinary measures," Young is quoted as saying in the HHS press release. "It is important to offer the drug now to people with AIDS for whom the standard treatment of zidovudine is not an option even though there are some potentially serious side effects," Young added. HHS pointed out that "continuation of the Treatment IND and open safety protocol depends on satisfactory results with respect to the drug's safety and efficacy as well as adequate enrollment in the clinical trials."

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