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DRUG STUDY SPONSORS SHOULD SUBMIT "WORST-CASE" SAFETY DATA ANALYSIS SEMI-ANNUALLY -- FDA FIAU TASK FORCE; TOXICITY MIGHT HAVE BEEN PREDICTED

Executive Summary

Sponsors of clinical trials should be required to submit all adverse event data and analyses of the data, including a "worst- case" analysis, on a semi-annual basis to FDA, the agency's task force assigned to review data from the FIAU hepatitis B trials recommends in a 90-page report released Nov. 15. The task force recommends that sponsors "be required to report all expected and unexpected deaths, serious adverse experiences and discontinuations that occur within six months of the last dose of the study drug or within the prescribed follow-up period." Reports "should be submitted to the IND on a semi-annual basis, with data presented in both a periodic and cumulative manner, and accompanied by a reasonable analysis by the sponsor." Sponsors should be required to include "a 'worst-case' analysis of these data, i.e., assume that the investigational drug is responsible for observed adverse events, and refute as feasible this assumption with appropriate data and evaluations," the task force report recommends. FDA is planning to publish the changes in reporting requirements in a Federal Register proposal. The task force, consisting of CDER Associate Director for Scientific and Medical Affairs Roger Williams, MD, FDA General Counsel Anne Witt, and Division of Scientific Investigations staffer Leland Pierce, MD, reviewed clinical data, from the trials sponsored by Oclassen Pharmaceuticals and licensee Lilly with FIAU (fialuridine) for the treatment of chronic hepatitis B infection. The task force was formed by FDA after five patients died of liver and pancreas failure in a Phase II trial being conducted by the National Heart, Lung & Blood Institute. The task force report is a result of one of several ongoing investigations into the FIAU trials. Rep. Towns' (D-N.Y.) House Government Operations/Intergovernmental Relations Subcommittee is conducting an inquiry into whether patient complaints of adverse reactions were ignored by the trial investigators. HHS Secretary Shalala informed Towns in a Nov. 16 letter that she plans to ask the Institute of Medicine to review "all activities surrounding the clinical trials of FIAU." The National Institutes of Health is assembling a panel of outside experts to assess whether the institute complied with its standing research subject protection procedures during the trials. NIH concluded in a preliminary review that the investigators had complied with all the procedures. In addition, FDA's Division of Scientific Investigations is assessing whether the trial sponsors and investigators complied with existing FDA reporting requirements. Concluding that current reporting requirements may not be adequate, the FDA task force recommends that sponsors be required to submit summaries of all safety data generated during the IND process. Summaries of only the most frequent and serious adverse events are now required in the IND annual report. Events from previous years do not have to be aggregated. The task force states that safety overviews should be designed "to emphasize unusual or extreme changes in study subjects." In addition, FDA would like sponsors to submit a final report or study summary of a clinical study within 90 days of an agency request. In order for the agency to track the information being submitted, the task force recommends that FDA fully computerize its record-keeping and data analysis systems for INDs. The task force report recommends a number of changes in clinical trial design and execution to enable investigators and FDA to recognize more quickly potential drug toxicity during development. With regard to clinical trial design, the task force recommended that the "use of a control group (Placebo, active control, or historical comparison) should be strongly considered in early (Phase I) trials, where the underlying disease process is likely to produce adverse events that might be confused with drug toxicity." Study protocols should also include prospectively identified abnormal lab values or other adverse events, with stopping rules to guide investigators on how to respond to the appearance of such an event. "Observed effects on identified endpoints should...be presumed to be drug toxicity in the absence of a compelling counter-argument accepted by FDA," the report states. Sponsors also should attempt to estimate the expected incidence of death and adverse events in a study population. The task force suggested that investigators pay greater attention during protocol design to determining appropriate follow-up periods after the end of a study. The report adds that FDA should amend its regulations to require sponsors to include the length and type of follow-up in study protocols submitted under INDs to the agency. In order to estimate appropriate follow- up periods, sponsors should "be responsible for developing and evaluating an adequate data base for any investigational drug to help assess whether adverse events are likely to occur at protracted intervals after cessation of drug administration," the report notes. In the process of formulating its recommendations, the task force considered data from three Oclassen-sponsored trials, two (R90-001 and R91-010) with FIAU and a third (R89-001) with its parent compound FIAC (fialcytosine), and the final NIH study (H3X- MC-PPPC), which was sponsored by Lilly. Data from the Lilly- sponsored trial were reviewed at a September meeting of FDA's Antiviral Drugs Advisory Committee, which reaffirmed the need for well-controlled Phase II trials and concluded that it is unclear whether other pyrimidine nucleoside analogs such as AZT, ddI, or ddC have similar toxicities ("The Pink Sheet" Sept. 27, p. 10). The task force concluded that prior data on FIAU's liver and pancreas toxicity might have predicted the adverse events in the final NIH study. "The data about hepatic and pancreatic adverse events associated with the administration of FIAU...though potentially available at the start of [NIH's] study, were not analyzed or reported in a way that might have led to some understanding of FIAU's possible hepatic or pancreatic toxicity by investigators, sponsors and the FDA," the report states. The task force found that "liver enzyme changes and/or clinically significant events, as defined, occurred in 24 of the 79 subjects in the three identified studies (29.1%)." The task force identified 10 clinical events from the three earlier trials of the 79 patients that occurred within the six months of the last dosing with FIAU or FIAC. The report notes that "seven of the 10 events were reported by the sponsors of the studies to the FDA prior to the start of the H3X-MC-PPPC study but were not attributed to the administration of FIAU." The task force identified five previously unreported deaths -- four deaths from the earlier FIAU studies and one from the FIAC study -- that could also have been related to drug toxicity. The report states that "five of the 10 subjects (50%) who exhibited an identified clinical event died in association with the event." The likelihood of experiencing a clinical adverse event, including death, was increased if a patient had received a prior course of FIAU therapy. The report discusses why the researchers might not have attributed the deaths and clinical events to FIAU toxicity. Explanations include: the absence of FIAU toxicity in animals; complicating underlying diseases such as a HIV and hepatitis B infections; concomitant use of other medications; a lag time between the end of the studies and the appearance of liver toxicity; and the association of increases in liver enzymes with an interferon-like "flare." Addressing the attribution of toxicity to underlying HIV disease, the task force states that "while this may have been reasonable on a case-by-case basis, the accumulation of a series of such events calls the attribution into question." While not convinced that FIAU produces an interferon-like flare in liver enzymes, the task force asserted that the rise in aminotransferases should at least have been considered a clinically significant event, which "demanded closer clinical follow-up."
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