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Executive Summary

Bristol-Myers Squibb's Videx (ddI) should be approved for the treatment of HIV infection in both adults and children who are intolerant or resistant to Burroughs Wellcome's Retrovir (AZT), FDA's Antiviral Drugs Advisory Committee recommended at its July 18-19 meeting. Six of the eight voting members on the committee voted in favor of recommending Videx for approval in treating adults with AIDS who are intolerant or resistant to AZT, and five of the committee members voted for approval of the drug as a second-line therapy in children. Earlier, the committee had voted in favor of an unqualified approval recommendation for use in adults and children with AIDS by a five-to-two vote with one abstention. The committee determined that ddI was effective against HIV based primarily on data that depended heavily on surrogate markers, especially CD4 levels. Committee member Donald Abrams, MD, San Francisco General Hospital, stated: "I think from the data that we're seeing here both in adults and children, there is definitely biologic activity to ddI. Because the data presented by Bristol-Myers Squibb during the first day of the meeting were derived mostly from nonrandomized dose-ranging Phase I studies, the committee was not convinced of ddI's immunologic activity until the second day of the meeting when FDA presented CD4 level data from ongoing Phase II/III efficacy trials being conducted by the National Institute of Allergy and Infectious Diseases' AIDS Clinical Trial Groups. Commenting on the preliminary CD4 results with ddI from the ACTG trials, Abrams said: "I believe that we see superiority in patients who have been on zidovudine for a long period of time. So I think that gives me confidence that I'll be able to sleep tonight after recommending, in fact, the drug be approved." Early on in the committee discussion, several members of the panel expressed support for a conditional approval of ddI, pending the outcome of the ACTG trials. The committee's misgivings about the data in Bristol-Myers Squibb's NDA led one member David Feigal, MD, University of California-San Diego Medical Center, to introduce the idea of conditional approval into the committee discussion during the first round of questions on July 18. Subsequently, the committee asked FDA Commissioner Kessler how FDA would view a recommendation for conditional approval. Kessler responded that FDA has "over the last several months looked at alternative mechanisms to allow re-review of data and would allow a streamlined withdrawal, but it's not out yet." Kessler described the "accelerated approval . . . mechanism" as an approval process that "would be based on a surrogate endpoint pending completion of clinical trials" after which FDA would "allow re-review of the data." Kessler advised the committee that if it had "a strong opinion" regarding a conditional approval for ddI, "so be it." However, he added: "we're not urging that." After Kessler's comments, the committee backed off the conditional approval idea and decided, instead, to support a traditional approval recommendation. Committee member Theodore Eickhoff, MD, Presbyterian-St. Luke's Medicial Center, Denver, said: "I would vote at least weakly 'Yes,' if there were no such thing as conditional approval. The review process and the process we've been through in the last two days was distinctly nontraditional, and I would wonder whether this doesn't demand some equal flexibility on the part of the agency, in terms of how it licenses or approves drugs." Despite FDA's unreadiness to proceed with a conditional approval approach, the agency demonstrated a wide range of innovations in the ddI review that may indicate a growing flexibility on the part of FDA. One example was FDA's decision to extract interim data from the ongoing ACTG trials. As an introduction to ACTG data presentations, Center for Drug Evaluation and Research Director Carl Peck, MD, pointed out "the exceptional nature" of FDA's request for the preliminary data. He noted that the agency was interested in finding a data source that could support Bristol-Myers Squibb's NDA database. However, Peck also stressed the importance of the ACTG trials being completed in order to understand the clinical effects of ddI. The ongoing studies are three Phase II/III trials -- ACTG 116, 117 and 118 -- which include a total of 2,384 patients. ACTG 116 is a comparison of ddI and AZT in AIDS patients. One section of this study (116-A) involves patients who received AZT for less than 16 weeks before beginning ddI treatment. The other section (116-B) involves patients who received AZT for more than 16 weeks. ACTG 117 is a comparison of ddI and AZT in patients who had long- term treatment. Trial 118 is a randomized double-blind study of ddI in AIDS patients intolerant to AZT. FDA decided to look at data from 116-B and 117 since the patients in those trials have characteristics that are comparable to those of the patients in the Phase I trials included in the Bristol-Myers Squibb NDA. Because 116-B and 117 have similar patient populations, they were combined for the interim data analysis. Of the 893 patients entered into 116-B and 117, CD4 counts were obtained for 412 patients from the first 24 weeks of therapy. The patients in the studies had been randomized to three arms: 500 mg/day of ddI, 750 mg/day of ddI or 600 mg/day of AZT. The arms were coded A & C for the ddI arms and B for the AZT arm. FDA Antiviral Drugs Division Assistant Director for Medical Affairs Dianne Murphy reported that the average CD4 count in arm A at baseline was "120 and by week 12 was 151." In arm C, Murphy continued, "you have the same trend, baseline of 106, and by week 24 still going up -- the number is now 128." However, she noted that "arm B is different. The baseline CD4 is 107, and by week 24 it is 89." NIH expects the primary efficacy analyses of the data from ACTG 116A and 117 to be completed by the first quarter of 1992. The first efficacy data from ACTG 118, however, is not due until the first half of 1992. Bristol-Myers Squibb presented a pooled analysis from eight clinical trials to support its claims of efficacy in adults. Data demonstrating ddI's clinical, virological and immumological effects were extracted from four Phase I safety trials conducted in 1989 and 1990 and were compared to placebo data from four controlled AZT trials with similar populations. Of the 170 patients in the Bristol-Myers Squibb Phase I trial database, 22% achieved an immunologic response, the company reported. Bristol-Myers Squibb defined an "immunologic response" as a 50% increase in a patient's CD4 cell count sustained over a four-week period. Bristol maintained that the response rates are "comparable to those of AZT." FDA, however, did not appear to share the firm's confidence in the early clinical data that was the basis for the company's NDA. Several FDAers, including Office of Drug Evaluation II Director James Bilstad, MD, emphasized early in the committee deliberations on July 18 that especially impressive and irrefutable data would be necessary to merit approval of an NDA that made such heavy use of surrogate markers and historical controls. "Surrogate markers and historical controls make this trial especially difficult," Bilstad commented.

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