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Executive Summary

Patients with asymptomatic HIV infection and AIDS-related complex taking Bristol-Myers Squibb's Videx (ddI) had fewer new AIDS-defining events and deaths than patients receiving Burroughs Wellcome's Retrovir (AZT, zidovudine or ZDV), AIDS Clinical Trials Group study 116b/117 demonstrates. Based on the presentation of these study results at an April 20 meeting, FDA's Antiviral Drugs Advisory Committee confirmed FDA's October 1991 approval of ddI. The approval was based primarily on the surrogate endpoint of CD4 cell counts with the expectation of confirmatory clinical trials ("The Pink Sheet" Oct. 14, 1991, p. 15). Attending the high-profile advisory committee meeting were members of FDA's top management: Commissioner Kessler, Office of Drug Evaluation II Director James Bilstad, MD, and Center for Drug Evaluation and Research Director Carl Peck, MD. Principal investigator for the trial, James Kahn, MD, San Francisco General Hospital, and copresenter Stephen Lagakos, PhD, Harvard School of Public Health, reported the results of trial 116b/117 to the committee. The investigators had presented the results a week earlier at a meeting of the National Institutes of Health ACTG ("The Pink Sheet" April 20, T&G-4). The randomized, double-blind, placebo-controlled trial compared two doses of ddI (500 mg and 750 mg daily) and AZT (600 mg daily) in 913 patients with AIDS, ARC or asymptomatic HIV infection. The patients had received at least 16 weeks of prior AZT therapy. All patients were required to receive Pneumocystis carinii pneumonia prophylaxis. Looking at the primary efficacy endpoint in the study, progression to a new AIDS-defining event or death, "patients with ARC entered at both 500 and 750 mg ddI...had fewer primary end-points at a p value of .001 and .005 compared to zidovudine," Kahn said. In patients with AIDS, "there was no statistical difference between the three treatment groups." The study also showed that the 500 mg dose of ddI was more effective than the 750 mg dose. "There's a statistically significant decrease in the number of new events or death in the 500 mg ddI arm compared to the AZT arm and no statistically significant difference between" the AZT and 750 mg ddI arms, Kahn noted. Of the new events or deaths, 94 were in the 500 mg arm, 115 in the 750 mg arm and 125 in the AZT arm. There were 160 deaths: 57 in the 750 mg ddI arm, 54 in the AZT arm, and 49 in the 500 mg ddI arm. The main AIDS-defining event was PCP. Kahn concluded that "subjects who were randomized to the 500 mg ddI daily dose were less likely to progress to an AIDS defining event than those who were randomized to remain on [AZT]." The investigator noted that "there was no significant difference in survival between the three treatment groups." There was no difference in time to death between the three arms. "There was a modest but significant CD4 cell change in favor of both doses of ddI compared to zidovudine," Kahn said. Contrary to expectations, "the previous duration of zidovidine therapy does not appear to increase the benefit of ddI." The committee considered whether ddI's indication should be modified to reflect the clinical benefit shown in the ARC and asymptomatic patients, as well as whether ddI should be considered as a first-line drug for AIDS. Committee consultant Mark Harrington, ACT UP, proposed that ddI labeling allow for use in patients with CD4 cell counts of less than 300 who have been on AZT for more than four months. The approved indication is for adults and pediatric patients over six months of age with advanced HIV infection "who are intolerant of zidovudine therapy or who have demonstrated significant clinical or immunologic deterioration during zidovudine therapy." Some committee members were hesitant to change the indication, preferring to wait for results from ACTG trial 116a, a comparison of ddI and AZT in patients with less than 16 weeks of prior AZT therapy. NIH expects the results of this trial to be ready by the end of the summer. Other members said they favored expanding the ddI indication but warned that it would have to be carefully worded. Addressing whether ddI should be indicated as a first-line treatment for AIDS, committee member Monto Ho, MD, University of Pittsburgh, said that "there is some evidence that [ddI] is as good as ZDV and maybe better -- why not use it as a primary drug? Well, I think if you analyze that you'll find that the evidence for that is inadequate because we do not have a situation where ddI is used alone in antiviral therapy." Committee members and consultants agreed that the data were insufficient to recommend a change in ddI's status as a second- line therapy. Zahn noted that trial 116a may provide information on the relative efficacy of ddI and AZT since about two-thirds of the patients had no previous antiretroviral treatment. FDA Division of Antiviral Drugs Director David Feigal, MD, advised the committee not to "worry about fine details today." Feigal said that discussions about expanding the labeling "may be premature as we look more closely at this study." Committee Chairman Henry Masur, MD, NIH, concurred, concluding that it was too soon for the committee to make a recommendation about changing the labeling. In an April 20 press release, Bristol-Myers Squibb noted that it "has not yet formally approached FDA regarding expanded labeling of Videx." Bristol Worldwide Clinical Research and Development Senior VP Stephen Carter, MD, added, "We will negotiate with FDA on how the Videx label could be expanded to encourage the most appropriate use of the drug." Kahn pointed out to the committee that new analyses of ddI data are planned, including "a combined evaluation of the total ddI experience with [the] three large ACTG trials: 116a, 116b/117, and 118." Study 118 is an evaluation of three doses of ddI in AIDS patients who are intolerant to AZT. The results of this study are expected to be available later this year. According to FDA, results from the other ACTG trials are not expected to affect ddI's approval but could support refinements in labeling. Videx is also being studied in ACTG 175, a four-arm trial comparing ddI, AZT, ddI and AZT, and ddC (Roche's Hivid) and AZT (see related story, p. 14). Videx is also being compared to ddC monotherapy in a trial by NIH's Community Programs for Clinical Research on AIDS. The advisory committee met to review its July 19, 1991 approval recommendation for ddI. In prepared questions to the committee, FDA asked: "Do the data presented today demonstrate the 'anticipated clinical benefit' of ddI (that was based on Phase I results and the interim analysis of CD4 data from ACTG 116b/117)?" In response, committee member Fred Valentine, MD, New York University Medical Center, said: "Yes. I think we all agree that clinical benefit was seen in this study." Although abstaining from the vote, committee member Paul Meier, PhD, University of Chicago, noted that for diseases other than AIDS, "the data that we have here would be very hard to use to base an approval [on]." However, he added: "I think there is enough evidence to stay with our primary decision that there were grounds to provide this drug as one that was approved." Affirming that ddI shows clinical benefit, Ho stated that "it's gratifying to see that ddI is not worse than AZT in this type of situation. There is some evidence that it may be better, but I think the evidence is very slight." When ddI was approved, FDA and Bristol agreed to conditions for the continued marketing of the drug. The Videx approval letter states that if "data from the clinical trials do not demonstrate the anticipated clinical effect of ddI, FDA understands that [BMS] expect[s] to withdraw the drug from the market expeditiously."

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