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Executive Summary

Four independent biostatisticians who evaluated ICN's lymphadenopathy syndrome (LAS) clinical trial concurred with the company's statistical review of the study, according to a report submitted by ICN to FDA. A copy of the report was also sent to the House Energy & Commerce/Oversight & Investigations Subcommittee. The report, prepared by ICN outside lawyer Harvey Myerson, notes that after FDA denied the firm's request to conduct an expanded ribavirin trial in LAS patients under a Treatment IND, ICN statistician Alan Forsythe, PhD, conducted an analysis of the work to date. Forsythe "refuted each of the FDA's concerns," concluding that "the patients in the placebo group did not have a statistically significantly higher risk for progressing to AIDS than in any expected randomized population of people with LAS and reduced T-4 positive cells," Myerson maintained. Myerson is a partner with New York City law firm Finley, Kumble, Wagner, Heine, Underberg, Manley, Myerson and Casey. Forsythe's statistical work was then reviewed by four independent statisticians, who "have concluded that there is no legitimate basis for the FDA's objections to further LAS trials," Myerson declared. The four independent reviewers were: David Cox, mathematics professor at Imperial College, London; Joseph Fleiss, PhD, head of the biostatistics department at Columbia University School of Public Health; Wilfrid Dixon, senior statistician for The Dixon Group in Los Angeles; and Sang-jew Soong, PhD, director of the biostatistics unit at the University of Alabama in Birmingham School of Medicine. The Myerson report was submitted to FDA in support of the firm's request to begin Treatment IND distribution of ribavirin for LAS. However, FDA denied the second request in a letter to the firm dated Aug. 28. In a Sept. 3 press release, ICN said that it had made the additional data submission, but stated that "FDA has notified [the firm] that it cannot approve the submission at this time." However, the company said it "is in the process of reapplying for a Treatment IND as soon as possible." FDA denied the firm's original request for a Treatment IND last April based on its conclusion that the firm's Phase II LAS study was flawed. The agency's statistical evaluation concluded that more patients with low CD4+ (T4) cell counts, making them at greater risk for progressing to AIDS, were included in the placebo group than in the 600 mg and 800 mg ribavirin treatment groups. FDA concluded that the "imbalances make it difficult to assess the significance" of the favorable results obtained in the study. The evaluation was further complicated, FDA said, because all "symptomatic" patients in the study were enrolled in two institutions in the multi-center trial ("The Pink Sheet" April 20, p. 3). Forsythe's analysis of the FDA review concluded that the agency applied a statistical test which was too rigorous for the type of study conducted. For example, Forsythe said FDA applied a "two-tailed" test, which measures variables that can effect the rate of progression to AIDS. However, Forsythe contended that the test is inappropriate, since the study intended only to discover the number of patients in each group who progressed to AIDS. Forsythe also contended that ICN's original statistical analysis adequately adjusted for the number of placebo group patients with low CD4+ cell counts, but that FDA had "misunderstood" the analysis and interpreted the data incorrectly as evidence of lack of efficacy. Ribavirin could turn out to be the first close call test of FDA's Treatment IND regulations which became effective this summer. Under the regs, FDA can deny a Treatment IND request for drugs intended to treat immediately life threatening diseases if it finds that "available scientific evidence, taken as a whole," provides no basis for concluding that the drug may be effective or that it would not pose an unreasonable risk. In the ribavirin situation, FDA is drawing a rigorous definition of "available scientific evidence."

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