Clinical trials toxicity testing

Prior to phase I clinical trials, process steps and assays that relate to safety should be validated. For example, sterility assays and sterilization processes must be validated. Cell lines should be qualified prior to any clinical trials, including testing for adventitious agents and identifying and quantifying indigenous virus. Virus clearance steps should be validated, and removal of any potentially toxic or otherwise harmful agents should be validated [41,42],... 

Two phase I clinical trials have tested the regimen of 72-h continuous infusion every two weeks in humans (83, 84). Seventy-six patients were treated in the NCI phase I trial. The dose-limiting toxicity (DLT) was secretory diarrhea with a maximally tolerated dose (MTD) of 50 mg/m2/day for 3 days. Flavopiridol was later found to induce chloride ion secretion in intestinal epithelial cells (85) and to have an enterohepatic circulation that may play a role in potentiating this toxicity (86). With antidiarrheal prophylaxis a higher MTD is reachable at 78 mg/m2/day for 3 days with orthostatic hypotension as the DLT. At the MTD in this study,... 

It is essential to determine the concentration of each isomer and define limits for all isomeric components, impurities, and contaminants of the compound tested preclin-ically that is intended for use in clinical trials. The maximum level of impurities in a stereoisomeric product used in clinical studies should not exceed that in the material evaluated in nonclinical toxicity studies. This point is expanded in the ICH impurities guideline (Section 13.5.3). 

Doses should be selected that are reasonable multiples of the proposed therapeutic dose to be employed, especially since in many cases the amount of material available for testing may be limited and not available in Kg amounts. Preclinical rodent or primate studies should merely provide the flags to monitor during Phase I clinical trials. Reason should prevail, not only in the selection of methods and models for assessing the potential toxicity of the new agents, but also in the use of these data for extrapolation to humans. Whether U.S. industry succeeds or fails in the biotechnology arena will depend on the quick resolution of issues such as... 

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