Preclinical trials potency

The same process that will be used for commercial-scale production should be adopted to produce the material used in the preclinical and clinical trials. Significant differences in the production process used to obtain this material can invalidate the clinical trial results for the commercial product, unless the comparability is demonstrated by identity, purity, stability, and potency tests (ICH, 1998b). 

A number of naturally derived agents have been entered into clinical trials which have been terminated due to lack of efficacy or unacceptable toxicity. One of these, maytansine (51), was isolated in the early 1970s from the Ethiopian plant, Maytenus serrata (Hochst. ex A.Rich.) R. Wilczek. " Despite very low yields (2 x 10 % based on plant dry weight), its extreme potency in testing against cancer cell lines prompted the production of sufficient quantities to pursue preclinical and clinical development. 

Data on two of these new taxanes, namely BMS-184476 (29) and BMS-188797 (29a), were published by Bristol-Myers-Squibb (BMS), which also developed Paclitaxel [96]. In a comparative preclinical study, both analogues were found to have cytotoxic potency similar to Paclitaxel but overcome two different forms of Paclitaxel resistance. BMS-184476 was found to be clearly superior to Paclitaxel especially on A2780 ovarian carcinoma, HCT/pk, a moderately Paclitaxel-resistant colon carcinoma and L2987 lung carcinoma. BMS 184476 is currently in phase II clinical trials in breast, NSCLC, oesophageal and gastrointestinal cancers [97]. 

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