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Executive Summary

Hoffmann-La Roche's Hivid is equivalent to Bristol-Myers Squibb's Videx as a treatment for HIV and therefore should be approved as second-line monotherapy, FDA's Antiviral Drugs Advisory Committee concluded at its Sept. 20 meeting. Specifically, the committee voted eleven to one to approve Hivid (zalcitabine, ddC) for "adult patients with advanced HIV who have demonstrated intolerance to AZT or significant clinical deterioration during AZT therapy." The committee's approval recommendation for Hivid as second- line monotherapy was based on a review of data from the Community Program Clinical Research on AIDS (CPCRA) 002 study, comparing the nucleoside analogs ddC and ddI (Videx) in 467 patients who failed or were intolerant to Burroughs Wellcome's Retrovir (AZT, zidovudine). CPCRA 002 trial results were released by the National Institute of Allergy and Infectious Diseases on Jan. 22. Summarizing the trial results, FDA Division of Antiviral Drugs Products Director David Feigal, MD, said that in monotherapy, "the drug [ddC] is safe and effective." Anne Goldman, PhD, University of Minnesota, who presented the 002 trial results to the committee, concluded that the data show that "ddC was at least as efficacious as ddI in delaying disease" and "patients in the ddC group may have had improved survival." Entry criteria for the prospective, open-label comparative trial were a CD4 cell count of less than 300 or AIDS. The committee's decision on Hivid comes 16 months after it initially rejected the monotherapy indication ("The Pink Sheet" April 27, 1992, p. 14). At its spring meeting in 1992, the committee said Hivid should be cleared under FDA's accelerated approval policy as a combo therapy with AZT. In light of the monotherapy recommendation, the committee voted seven to two to recommend withdrawal of the combo approval granted by FDA in June 1992. Deborah Cotton, MD, Harvard Medical School, summarized the committee's sentiments about Hivid as monotherapy, stating: "Let's do what we think is the right thing in terms of the data and approve this for monotherapy...with more detailed labeling." Commenting on Hivid's efficacy levels, Cotton remarked: "Has efficacy been shown? I think equivalence has been shown [to ddI]." Fred Gordin, MD, Veterans Affairs Medical Center, Washington, D.C., agreed with Cotton, saying: "I would approve [ddC] for traditional monotherapy based on equivalence [ddC to ddl] and I would point out [on labeling] that CPCRA 002 was the pivotal study." The committee agreed that labeling issues should be left to FDA as long as it is clear that approval was based on equivalence of ddC to ddI. After the committee voted for the monotherapy indication, committee guest David Barr, Gay Men's Health Crisis, presented a plea for reconsideration on the basis that CPCRA 002 "only shows equivalence." Saying that the "standard" for approval was "lowered with ddI because of the concern about access to drugs for patients," Barr argued: "Those concerns aren't here now" with ddC. "Do you want to codify the standard you set with ddI or do you want to correct it?" Barr continued. He argued there should be "at least another trial, if not more," of ddC "to really get to the answers about how to use this drug and whether or not it is useful as a monotherapy." Barr concluded by asserting that the committee, FDA and the AIDS community "should raise the standards and we must hold the companies' feet to the fire." The committee decided to withdraw the accelerated approval indication for combination therapy of ddC with AZT after viewing the final results of the 1,001-patient AIDS Clinical Trial Group (ACTG) 155 trial comparing AZT, ddC and the combination in patients with prior AZT experience. Margaret Fischl, MD, University of Miami, presented the ACTG 155 data. She presented, the preliminary trial results at the International AIDS Conference in Berlin in June. The results of the ACTG 155 study showed no significant difference between the combination of ddC and AZT and AZT alone for the primary endpoint of "time until an AIDS-defining event or death." However, the study did disclose positive changes in CD4 cell counts, a secondary endpoint in the study, in a subgroup of patients with CD4 cell counts above 150 cells/mm. DAVDP Supervisory Medical Reviewer Steven Gitterman, MD/PhD, said the agency "agrees with the statistical analysis" for ACTG 155. However, he added, "the absolute number of events is small for the indication that is sought." DAVDP Statistical Reviewer Kazem Kazempour, PhD, told the committee that "the ACTG 155 subgroup analyses were not significant due to the heterogeneity of the groups. In conclusion, there was no statistical difference between the combination and [AZT] arms of the study." Cotton commented that FDA should "take it away [accelerated approval for combination therapy because] if you look at [ACTG] 155 as a whole, without subgroup analysis -- that's people [with CD4 cell counts of] less than 300 -- it does not show a benefit." Commenting on the implications from removing ddC's accelerated approval, Cotton said: "I think it would send a much more powerful message...It would send a real statement that we've got to get back to basics in clinical trials." Committee member John Modlin, MD, Dartmouth/Hitchcock Medical Center, dissented, stating: "I am concerned about sending mixed messages to the practicing physician...because a narrow sub- group [CD4 counts above 150] of the 155 study did seem to show some clinical benefit in combination therapy." Noting that ACTG 155 trial results eventually will be published "in some prominent place," Modlin said, "I would argue for maintaining accelerated approval with the proviso that this is an issue that we can revisit." Roche said Sept. 24 that the company is "pleased with the recommendation of Hivid for monotherapy but disappointed with the decision to withdraw Hivid's accelerated approval for combination therapy. This recommendation was unexpected. We believe that combination therapy is important [because] one out of five patients receiving retroviral treatment are receiving combination therapy."

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