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Executive Summary

Roche's ddC (Hivid) will be made available through an open-label safety study to AIDS and advanced ARC patients who are intolerant to or have failed on AZT (Burroughs Wellcome's Retrovir) and also are intolerant to ddI (Bristol-Myers' Videx). On May 31, the company and FDA announced details of the program, which begins June 25 and is modeled on the "parallel track" concept in that it provides an experimental drug to AIDS patients that have no alternative treatment. FDA approved the expanded access protocol on May 2. Roche said the expanded access program is not expected to affect patient enrollment in ongoing efficacy trials of the antiviral drug (dideoxycitidine) because they involve different patient populations. Patients enrolling in the formal ddC (dideoxycytidine) trials either have not taken AZT or ddI, or they can tolerate the drugs. Patients eligible for the expanded access study have taken both drugs and can no longer tolerate them, the company explained. Only patients with no other treatment option can enter the expanded access program. The expanded access protocol for ddC, Roche noted, was developed independently of the parallel track proposal, but "is in keeping with the spirit of parallel track -- the idea of making the drug available to people who need it outside of the clinical trials." The protocol was developed jointly by the company, FDA and investigators from the ddC trials. The Public Health Service recently published a proposed parallel track policy in a Federal Register notice, which sets out approval criteria for parallel track applications ("The Pink Sheet" May 21, p. 8). The expanded access program for ddC marks the second time a mechanism similar to parallel track has been devised for distribution of an experimental AIDS drug. The first such open-label safety study was established last September for Bristol-Myers Squibb's ddI (dideoxyinosine) for treating patients who fail on therapy with AZT. In order to qualify, enrollees must be ineligible to enter the contemporaneous trials and Treatment IND program ("The Pink Sheet" Oct. 2, p. 5). Roche's "ddC Coordinating Center" has a telephone hotline (800-ddC-21-HIV) currently providing a recorded message with limited details on the protocol. Beginning June 25, the hotline will provide further information to physicians on how they can enroll patients into the program. Physicians who call the ddC hotline about enrollment information receive an information package. The materials ask for information to verify that the patient meets enrollment criteria. They also include patient consent forms, patient entry forms and physician registration forms. Physicians will begin receiving ddC within a few weeks after enrollment, Roche said. The company will provide ddC free of charge. In its press release, Roche pointed out that because ddC has not been evaluated in patients intolerant to AZT and ddI, "during the first phase of this study, only investigators having experience with ddC will be permitted to administer the drug." However, the firm continued, "after data have been reviewed on the first 25 patients receiving four weeks of ddC treatment, and if no serious toxicities have occurred, any licensed physician who has experience in treating AIDS will be eligible to participate in the study." Physicians will be required to send case report forms to the company so that any unexpected drug-related toxicities will be detected. After receiving initial shipments of ddC, physicians will be required to submit the case report forms before they can receive the next supply of drug. In its press statement, FDA pointed out that "early clinical trials indicated that ddC at higher doses caused painful peripheral neuropathy in most patients after several months." Therefore, the agency added, "patients who have peripheral neuropathy, including those who may have developed it as an adverse reaction to ddI, will be excluded from entering this new study." Roche noted that doses involved in the expanded access program will be lower than the doses that have caused peripheral neuropathy. Patients in the open-label study will be randomized to receive either one or two 0.375 mg tablet of ddC every eight hours. The total dose of the two-tablet regimen is equivalent to the dose being used in two pivotal ddC trials. Roche said it expects to gather some efficacy information as well as safety data. The formal Hivid clinical trials include three studies being conducted by the National Institute of Allergy and Infectious Diseases (NIAID). One is a Phase II/III double-blind, randomized, comparative study of ddC versus AZT in AIDS or ARC patients at 26 study sites. Roche said the researchers have enrolled about 500 patients and hope to enroll 100 more. The firm expects to present preliminary data from this trial at the upcoming Sixth International Conference on AIDS in San Francisco. Six months of trial data will be evaluated this fall, the firm added. The other pivotal trial is a Phase II/III open-label, randomized, comparative study of ddC versus AZT in AIDS or ARC patients who have completed one year of AZT therapy. The study has a target enrollment of 320 patients, but it currently has less than 20 patients, Roche said. Nine more clinical sites are being added to increase accrual. Another NIAID study -- a Phase I open-label, randomized, dose-finding study of concomitant ddC and AZT in AIDS or ARC patients -- is near completion. A fourth clinical, sponsored by the National Cancer Institute, is a Phase I trial testing the feasibility of a sequential regimen of one week of AZT with acyclovir (Burroughs Wellcome's antiviral Zovirax), one week of ddI, and one week of ddC. The cycle is repeated over a one-year period.

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