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Executive Summary

Initial results of Phase I dideoxycytidine trials have found evidence of biological activity against the AIDS virus and instances of peripheral neuropathy which may be reduced or eliminated by lowering dosage of the drug, Roche VP and Director of Exploratory Research Patrick Gage, MD, noted at an Institute of Medicine conference on drug development against AIDS and HIV infection, held in Washington, D.C. Sept. 1. In the Roche study, which is being conducted under a National Institutes of Health (NIH) IND, and in Phase I studies conducted by the National Cancer Institute (NCI), "we have seen . . . some signs of biological activity -- not efficacy, but biological activity -- including some changes in T-4 cells and some reduction in the P-24, one of the viral antigens that's a measure, probably, for AIDS," Gage reported. Roche began a Phase I study of dideoxycytidine three months ago. The company is developing the agent under a licensing agreement with HHS reached in May. According to the agreement, Roche will receive 10 years exclusive marketing rights from the date of first commercial sale ("The Pink Sheet" June 8, In Brief). NCI is also continuing studies with dideoxycytidine. Those studies, which began in late 1986, are currently in Phase I. Discussing adverse events seen with the drug, Gage said that a "serious reaction we've observed is the occurrence of a peripheral neuropathy after patients have been on the drug for a number of weeks." The reaction "occurs at the [dosage of the drug] that was chosen for initiation of these studies, and we are now working hard to study lower doses in order to try and avoid this problem," Gage noted. "We're also trying a different scheduling of the dosage to try and avoid the problem." Gage noted that the trials have also shown two "rather minor" adverse reactions. "The first of these is a rash. Secondly, thrombocytopenia, or platelet reduction, which seems to be transient and not terribly serious." Roche's Phase I studies are being conducted in the National Institute of Allergy & Infectious Diseases' (NIAID) AIDS Treatment Evaluation Units (ATEUs). Gage explained that the Roche-NIAID agreement calls for the company and institute to "work closely together to prepare a clinical development plan designed to study protocols jointly, select investigators, conduct and monitor studies together, as well as collect the resulting data." Gage commented that "although most of the studies to date are being conducted under an NIH IND, we are satisfied that this is appropriate in Phase I." However, he added, "we strongly prefer to carry out the later stages of the drug's development . . . under our own IND, where possible, in order to maintain closer control of this . . . critical data necessary for licensure." The Roche research director explained that while NIH's ATEU clinical trial program plays an important role for the small company inexperienced in conducting studies, R&D firms with extensive clinical trial experience may be able to bring an agent to the market quicker if they have control over the development program. "Taken to its extreme, the pharmaceutical company that contributes a drug for study in the ATEUs is thrust into the position of being merely a drug supplier," Gage said. "For some of the smaller companies, or those companies without a large research base, involvement of the NIH in providing the functions of formulation, toxicology and full-scale clinical trials seems fully appropriate in order to bring drugs provided by those companies to the public," he explained. However, Gage added, "the research-based pharmaceutical companies sponsoring a drug for clinical study have . . . as a singular goal, and reason-for-being, the execution of the most prompt and efficient clinical plan to determine the efficacy and safety of the drug and to achieve its registration by the FDA." Therefore, he said, "we strongly favor a sequential collaboration with the ATEUs, with control of the trials becoming progressively more and more under the control of the sponsoring company as the trial progresses through its various phases." The dideoxycytidine development program is overseen by a steering committee composed of senior Roche and NIH scientists, which "reviews progress towards the goals set in the clinical plan and decides important issues that are not resolved at the working level," Gage said. Noting that "this intensive collaboration is necessary to insure that vital concerns of both the NIH and the pharmaceutical industry are satisfied," Gage suggested that the dideoxycytidine program "might serve as a model for" collaborative drug development programs. "We are pleased with the level of involvement we have now established with the NIH on protocol design and conduct of studies," Gage said. "However," he added, "we feel there is still room for improvement in our collaboration, particularly in the area of study monitoring, simplification of what we consider to be an overly complex case report form, and particularly interaction with and data transfer from an independent data management contractor that has been contracted by the NIH." "Most of these problems," Gage observed, "result from the relative inexperience of the NIH with running clinical trials of this kind. We expect with time and attention to issues by both Roche and NIH that most of the glitches in our collaboration will be put behind us." NIAID AIDS Treatment Branch Chief Maureen Myers, MD, another speaker at the government-sponsored symposium, ackknwledged that NIH/industry collaborative AIDS drug development programs might be strained because of the different perspectives of the collaborators. "We also recognize that since the marketing issue per se is unique to the pharmaceutical sponsor, there will be occasions when the NIAID or its clinical investigators may be more enthusiastic about some studies than the private sponsor," Myers said. Addressing the major role NIH has adopted in evaluating potential therapeutic agents for AIDS, Myers commented that "one could legitimately ask, and it has been at this meeting, why the NIH has assumed responsibility for functions that are available in many cases by the pharmaceutical sponsor." The reasons, she explained, "are laudable and all relate to the concept that the investigators funded by the institute, and the patient populations to which they have access, represent a unique and valuable resource that must be used in the most efficient possible manner." Myers noted that to date NIAID has "looked at" 30 potential AIDS agents. From mid-1986 through early 1987, she reported, 19 ATEU contracts supporting clinical studies were awarded. Myers also pointed out that the ATEU patient enrollment and protocol initiation has dramatically increased over the last few months. Between May and August, average weekly patient accession tripled from 30 to 90, and the number of active protocols jumped from 6 to 23, she said.

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