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Executive Summary

LILLY FIAU PHASE I TESTS IN HEALTHY SUBJECTS SHOULD HAVE PRECEDED clinical trials in patients with hepatitis B, Public Citizen's Health Research Group maintained in a Dec. 9 submission to FDA. "It is difficult to understand why a trial intended to evaluate the safety of FIAU in healthy subjects...was not the first human trial initiated," HRG said. HRG characterized the submission as a "response" to FDA's Nov. 15 task force report on Lilly/Oclassen's FIAU (fialuridine) ("The Pink Sheet" Nov. 22, p. 15). Clinical trials of the drug were halted following five deaths associated with FIAU in a National Institutes of Health study ("The Pink Sheet" July 5, T&G-12). HRG maintains that a trial in healthy volunteers "should have been done before the drug was ever studied in patients with chronic compensated HBV infection." A trial in healthy volunteers was not conducted until after the completion of earlier clinical trials in patients with HIV, cytomegalovirus and hepatitis B. The healthy volunteer study was ongoing when the final NIH trial began. Lilly pointed out that the healthy volunteer trial was not conducted as a classic Phase I study but instead to compare Oclassen's syrup formulation to Lilly's newer tablet formulation for FIAU. Safety trials in normal volunteers were never performed because FIAU was on an acelerated track, Lilly noted. A focus of initiatives to shorten the drug development/approval process has been to bring now medicines Into target patient populations as quickly as possible. The HRG report suggests that the FIAU experience can be used as an argument against that approach. HRG argues specifically against the decision to move quickly into hepatitis B patients. Calling hepatitis B "a disease with a variable clinical course," HRG maintains that a different cost- benefit analysis must be made than was relevant to earlier trials in HIV. The report mentions a "study of 379 patients with chronic HBV infection [that] revealed a five-year survival rate of 86%." Data from earlier trials suggested "possible hepatic or pancreatic toxicity," HRG (and the FDA task force) said. HRG charges that "this early data should have halted approval of trial H3X-MC- PPPC," the final NIH trial. The HRG report focuses largely on allegations that Lilly did not properly report safety data that could have prevented the deaths. The report also maintains that preclinical data should have been sufficient to predict the toxicity later seen in humans with FIAU. HRG accuses the FDA task force of "glaring omissions" in its report regarding these subjects. HRG declares that, in the healthy volunteer trial, one subject "was hospitalized...after only two doses of the drug" because of elevated liver enzyme levels. The group charges Lilly with failing "to report this hospitalization to the FDA until July 27, 1993, one month after the NIH trial was stopped and after three of the five deaths in the NIH study had occurred." Lilly maintains that the man was not hospitalized due to side effects but was offered the option of staying in the Lilly clinic until his enzyme levels went down. One of the purposes of keeping him in the non-acute hospital setting was to prevent the man from drinking alcohol, as was his daily habit, the company said. Lilly added that the volunteer never showed any clinical symptoms and that the magnitude of the enzyme elevation was mild. FDA pointed out that its task force was not expected to evaluate the appropriateness of Lilly's conduct. FDA's Division of Scientific Investigations will assess whether the trial sponsors and investigators complied with existing FDA reporting requirements in a review expected to be completed before the end of the year. The HRG report faults FDA for "concluding that there was no evidence of animal hepatotoxicity" after liver enzyme increases were observed in tested monkeys. In addition, the task force is taken to task for omitting "animal data on closely related nucleoside analogs, such as FIAC and FMAU" from its report. According to Lilly, nothing in the animal data warranted the halting of studies. The company maintains that no tissue abnormalities were seen in the monkey livers, suggesting that toxicities were not serious. FDA said that it believes that there needs to be more research on the association of the animal data with human toxicity. Lilly pointed out that the task force report retrospectively accumulated all data that could possibly have predicted the outcome of the NIH trial, and maintained that HRG failed to take into account many "confounding factors" that affected the data. Several other entities have yet to weigh in on the FIAU- related deaths. Rep. Towns' (D-N.Y.) House Government Operations/Intergovernmental Relations Subcommittee may hold hearings on FIAU in early 1994. The Institute of Medicine and NIH are also preparing reports on the FIAU trials.

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