Current Status and Emerging Opportunities in Replacement of the Lifetime Mouse Cancer Bioassay *

Abstract

The approach to evaluating the carcinogenic potential of pharmaceuticals is a matter of debate and has undergone important changes related to increasing knowledge of the mechanisms of carcinogenesis, accumulated data from carcinogenicity studies, and technological progress. The discussions held during the International Conference of Harmonization (ICH) led to the proposal of a basic principle for carcinogenicity testing: one rodent lifespan study plus an additional short-term study carrying mechanistic insight to the carcinogenicity endpoints. Alternatively, a second lifespan study is acceptable. This approach is in line with the development of alternative models, primarily genetically-modified mice that are conceived on the basis of known mechanisms of carcinogenesis. Such models have been evaluated through studies sponsored by the International Life Sciences Institute. These studies are in their final stage. Important data have already been presented.

This paper includes a critical analysis of the results available from the models and thinking in Europe about their contribution to risk assessment. It provides “a ” European view, rather than “the ” European view, of the problem, since the latter is dependent upon ongoing analysis of the available data being performed by the Committee for Proprietary Medicinal Products' Safety Working Party.