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Executive Summary

AIDS MASTER PROTOCOL FOR EXPERIMENTAL DRUGS PROPOSED by FDA Antiviral Drug Products Division Director Ellen Cooper, MD, at a Sept. 18 meeting of FDA's Antiviral Drugs Advisory Committee. The meeting was scheduled to consider trial designs for new antiretroviral agents and immunomodulators. Cooper noted that one approach "undergoing active discussion by various groups around the country is the concept of an ongoing master protocol for studying different [AIDS] drugs." Patients "would be randomized to a single control arm or to one of several drugs or drug regimens under investigation," Cooper explained. In the control arm, patients would receive the current standard AIDS therapy, which is now AZT (Burroughs Wellcome's zidovudine, Retrovir). New arms to the study would be created as experimental drugs are added into the protocol. In such a way, new treatments could be compared in well-controlled trials to the standard therapy as well as other new agents. "Clearly this approach would require active government and industry-wide support," Cooper observed, since drugs would be entering into head-to-head comparisons. Problems with the protocol may arise from an interest by companies to gain quick approval for their particular drugs, committee member and statistician Paul Meier, PhD, University of Chicago, suggested. A manufacturer participating in an AIDS trial may not support "that entire venture," Meier observed. "He has got just one drug [and] he would like to tailor everything to what he is doing." Cooper also suggested the possibility of using historical controls to complement the master protocol. "Given the enormous difficulty the [National Institutes of Health] are experiencing in completing randomized controlled trials, perhaps the most constructive approach to take in this disease at this time is to plan careful historically controlled trials in more advanced patients who have no other therapeutic options," she said. Such trials would use "a large prospective observational database at selected centers with the capability and commitment to collect data systematically," Cooper suggested. Historically controlled data from a nationwide observational database would avoid attempts by companies "to reinvent the wheel with every new drug," Cooper remarked. Patients from the observational database who meet eligibility criteria could be enrolled into "the investigational drug study, whose design could be improved by including two or three dose levels." Drugs in historically controlled trials, however, must show relatively "dramatic, common and sustained" improvements to demonstrate efficacy for approval, Cooper noted. During the committee meeting several other observations were made how the quality of clinical data on AIDS drugs can be improved. National Institute of Allergy and Infectious Diseases-AIDS Division Director Daniel Hoth, MD, remarked that the Bristol-Myers Squibb (dideoxyinosine) ddI trials demonstrates "that when we are trying to do things as quickly as possible, as we have, the Phase I trials have got to be as pristine as possible." In particular, dose escalation should not be conducted within patients, he said, since it "contaminates" data for long-term follow-up of the patients at multiple doses. FDA consultant Loretta Itri, MD, Hoffmann-La Roche, concurred with Hoth that Phase I experience is of paramount importance for subsequent studies. Commenting on Roche's experience with ddC (dideoxycytodine), she noted that because the firm was "in a hurry to get the drug out there, we have chosen wrong doses [and] have not done careful evaluation of lower doses, which ultimately are so important for combination use." Roche has had "to back track and ended up losing more time than gaining time," she said. Itri observed that the company "probably lost a whole year and hurt some patients inadvertantly because [the] dose finding was imperfect." However, the current Phase II studies, Itri said, "hopefully will provide approvability." Roche has completed enrollment of 600 patients into the studies as of August and is currently performing an interim analysis of the data collected. A combination arm with ddC and AZT is scheduled to be added to the ongoing trials, Itri said.

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