Regulatory Forum Opinion Piece*: Transgenic/Alternative Carcinogenicity Assays: A Retrospective Review of Studies Submitted to CDER/FDA 1997-2014.

The International Conference on Harmonization (ICH; S1B of 1997) allows a second species carcinogenicity study to be an alternative to one of the traditional 2-year studies. In the past 17 years, the FDA's Center for Drug Evaluation and Research's (CDER) Executive Carcinogenicity Assessment Committee received 269 alternative carcinogenicity assay protocols for review. This committee's recommendations regarding choice of animal model and dose selection are generally followed by sponsors conducting these studies to increase the acceptability of such studies. The P53(+/-) assay is generally considered appropriate for genotoxic products, and the TgRasH2 assay is appropriate for non-genotoxic or genotoxic drugs. In the United States, the TgAC assay is not used any more and the animals are no longer available. The TgAC assay can detect both tumor promoters and complete carcinogens, and consequently more than half of the dermal TgAC assays resulted in a positive assessment. Currently, more than 75% of mouse carcinogenicity studies are conducted in TgRasH2 mice. Behavior of genotoxic and non-genotoxic drugs in the various assays is reviewed.