Review of the Fialuridine (FIAU) Clinical Trials (1995) / Chapter Skim
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Review of the FDA Task Force Report 'Fialuridine: Hepatic and Pancreatic Toxicity'
Review of the FDA Task Force Report 'Fialuridine: Hepatic and Pancreatic Toxicity'
Pages 104-120
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From page 104... ...
infection, raised the question of whether differences in process could have averted the disaster. A special Task Force of FDA undertook a retrospective assessment of FlAU and FlAC with the stated objective "to determine what data and what analyses of data were available to sponsors and the FDA at the start of the H3X-MC-PPPC study, and whether improvement in the rules governing design, analysis and reporting of data from clinical trials is warranted." From the outset the FDA Task Force recognized and prefaced their presentation with the recognition that this was a retrospective review initiated in response to the deaths and restricted to the three clinical studies undertaken before the PPPC study.
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From page 105... ...
The definition was constructed following discussions with Willis Maddrey, a hepatologist with expertise in drug-induced hepatotoxicity, with the statement: "Although arbitrary, the ratio appears reasonable based on the natural history of chronic hepatitis associated with HBV infection." Clinical Events These were defined as any events "suggestive or indicative of hepatic or pancreatic damage within 6 months of the final dose of FIAC or FIAU that required inpatient or outpatient evaluation by a health professional." The Task Force clearly states that this definition did not require a causal attribution to the drug and could be related to the underlying disease. This analysis thus involved a worst-case assessment that presupposes that all untoward events are attributable to drug effects.
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From page 106... ...
On examination of the hepatic enzyme data in those subjects who died of this toxicity, a unique feature was that despite the presence of extensive metabolic acidosis, encephalopathy, and coagulopathy, changes in AST and ALT were unremarkable and there was a lack of temporal association between rises in these enzyme markers of hepatic necrosis and other evidence of acutely progressive liver dysfunction. In the opinion of the lOM committee, a rise in ALT or AST did not provide a useful marker of the FIAU hepatotoxicity responsible for the deaths in the PPPC trial.
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From page 107... ...
to induce pancreatitis, and the natural history of HBV infection progressing to chronic liver failure does permit attribution of causation to the observed toxic events. In the committee's view, attribution of all adverse hepatic and pancreatic clinical events to FlAC or FTAU as proposed by the FDA Task Force would inappropriately ignore potentially important information.
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From page 108... ...
Identification of the mechanism of toxicity and the role of FlAU incorporation into nuclear and mitochondrial DNA may in the future lead to a better understanding of the role of total dose, dose duration, and reexposure to dose to the risk of toxicity. Attribution of Toxicity to Adverse Clinical Events The FDA Task Force observed that none of .the ~ O adverse clinical events they identified in patients from the trials conducted prior to the PPPC trial were attributed to FIAU toxicity by the investigators or sponsors.
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From page 109... ...
We now turn to another section of the FDA Task Force Report, in which the authors review adverse clinical events associated with the studies immediately preceding the disastrous PPPC trial. In the following sections, we summarize the Task Force review and comment where it differs from our own.
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From page 110... ...
The FDA Task Force designated this a drug-associated clinical event and considered it relevant because FIAC is predominantly metabolized to FIAU. It is possible that this attribution is correct, but two cardinal features of FIAU toxicity, namely, lactic acidosis and microvesicular steatosis, were not described.
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From page 111... ...
It is possible that FlAU contributed to the pancreatic toxicity, but the undoubted association of dd] therapy and fulminant pancreatitis, together with the absence of lactic acidosis, microvesicular steatosis, and fulminant liver failure make this a less likely attribution.
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From page 112... ...
In the opinion of the IOM committee, a more plausible relationship is to ddI, a well-known pancreatic toxicant. It is feasible that FIAU produces pancreatic toxicity, but this patient did not have any other evidence of the FIAU toxicity syndrome.
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From page 113... ...
Subject lC This 56-year-old patient with HBV infection received FTAU at 0.05 mg/kg/day for 28 days in June 1992. in October 1992 the patient developed right upper quadrant pain and had a biliary stone removed from the cystic duct.
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From page 114... ...
These deserve review and discussion before being implemented as a unilateral decision. Clinical Trial Design and Execution The FDA Task Force recommends greater attention in the design of clinical trials to the possibility that drug toxicity could mimic the underlying disease process or effect of other drugs.
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From page 115... ...
A major focus could be to develop techniques enabling the use of historical data from previous trials to match patients and events with study participants, thus allowing for more accurate and objective attribution of adverse events to an investigational drug or other causes. Matching of subjects should not be confined to consideration of entry criteria, but should also include personal demographics, disease extent, disease complications, concomitant therapy, or any other relevant dimension.
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From page 116... ...
These should be individualized to the study context and not be rigidly defined to embrace all study designs. Assess Expected Incidence of Death or Serious Events in the Study Population in the Absence of the Investigational Drug The TOM committee agrees with the principle that observed events should be compared with the expected events in the study population, but we wish to emphasize our prior comments that selection of comparison groups is difficult.
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From page 117... ...
However, it must be realized that the longer the follow-up the greater the chance that non-drugrelated events are confounding variables in drawing causal inferences. The IOM committee recommends flexibility in study design in terms of requirements of end point measures, the use of independent review committees, and the development of new methodologic approaches as described above to integrate and anticipate adverse events to be expected in the absence of the investigational drug.
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From page 118... ...
A major concern identified by the TOM committee is that adoption of reporting requirements would decrease the signal-to-noise ratio in interpretation of clinical studies. A further consideration that is relevant not only to what data should be included in the investigators' brochure but to what information should be made available to institutional review boards and prospective patients via consent form is that relevant adverse event information will be at risk of being trivialized if judgment is not exercised in data evaluation.
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From page 119... ...
One possible avenue that should be explored is a joint funding venture with other organizations, both public and private, to explore new approaches to patient safety management in Phase ~ and Phase TI drug trials. The organization of and access to available information from previous studies could be a major resource for such an approach, but the only way to have this information readily available would be through a computerized relational data base.
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From page 120... ...
120 REVIEW OF THE FIALU~DINECLINICALTMALS cancer chemotherapeutic strategies, as well as the introduction of gene therapy, have the potential to induce changes in nuclear and nonnuclear DNA. There is therefore an urgent need to develop model systems that predict clinical outcomes if we are to see development of drugs free of this toxicity in the future.
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