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an extended post-treatment period. It is noteworthy, however, that while mild excursions in serum alanine or aspartate aminotransferase activity were observed in some studies, no corresponding morphologic hepatic changes were reported. Furthermore, no mention of pancreatic changes are noted in the reports.

The preclinical toxicity data available prior to the PPPC clinical trial was judged to be adequate by the Food and Drug Administration, and, therefore, the clinical trial could proceed as planned. A retrospective evaluation of the material available in 1993 still supports this position. The acute and multiple dose studies performed in different laboratory animals (mice, rats, dogs, and monkeys), a chronic study in one species (mice), a battery of mutagenicity studies, and studies on reproduction yielded patterns of observations that were more or less consistent with the biologic characteristics of FIAU. Furthermore, dose-dependent relationships were generally clear, and the toxic effects usually occurred at dosages near the maximum tolerated range in each species. There was nothing in the preclinical toxicity studies that was suggestive of the tragic episode that transpired in the PPPC clinical trial. Furthermore, unfortunately, there is nothing to indicate that other laboratory animal studies would have been more appropriate or capable of better prediction of the fatal outcome.



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