Abstract
As changes to carcinogenicity assessment of pharmaceuticals are being considered through ICH S1 modification, the weight-of-evidence approach being proposed opens up much broader opportunity for alternative short term mouse models to play a more expansive role in the future of pharmaceutical carcinogenicity testing. Recent experience with alternative transgenic mouse models in pharmaceutical development will be summarized, and the heightened value of using these animals from a scientific and business perspective will be described. The focus will be on the p53+/- and rasH2 mouse models, with which the pharmaceutical industry has the greatest experience and which have the highest level of acceptance by Regulatory Authorities. The p53+/- mouse model may be the preferred model for compounds with direct or equivocal evidence of genotoxicity, while the rasH2 mouse model developed by the Central Institute for Experimental Animals in Japan, is the only model acceptable for compounds with positive, equivocal or negative genotoxicity findings. The rasH2 model is becoming the choice of pharmaceutical companies that have adopted an alternative mouse model into their carcinogenicity risk assessment paradigm. The proposed modification of the ICH S1 guideline addresses the elimination or replacement of a 2-year rat study based on a weight-of-evidence argument to improve human risk assessment while reducing, refining, and replacing animal testing. In case-by-case situations, the alternative mouse models have the potential to contribute to this weight-of-evidence, and may be the only carcinogenicity study needed to adequately assess carcinogenic risk.
