CARCINOGENICITY TESTING AND THE EVALUATION OF REGULATORY REQUIREMENTSFOR PHARMACEUTICALS

The results of rat and mouse carcinogenicity studies for 282 human pha rmaceuticals in the FDA database were analyzed and compared as part of an International Conference on Harmonization (ICH) evaluation of rode nt carcinogenicity studies and their utility for carcinogenicity testi ng. A majority of the carcinogenicity studies in the FDA database were carried out in Sprague-Dawley-derived rats and Swiss-Webster-derived CD-1 mice in contrast to Fisher 344 rats and B6C3F1 mice employed in N ational Toxicology Program (NTP) studies. Despite the differences in r odent strains, the relative proportion of compounds with positive find ings (44.3%) and the degree of overall concordance between rats and mi ce (74.1%) in the FDA database were similar to the NTP rodent carcinog enicity database. Carcinogenicity studies in two rodent species are ne cessary primarily to identify trans-species tumorigens, which are cons idered to pose a relatively greater potential risk to humans than sing le species positive compounds. Two-year carcinogenicity studies in bot h rats and mice may not be the only means of identifying transspecies tumorigens. Sufficient experience is now available for some alternativ e in vivo carcinogenicity models to support their application as compl ementary studies in combination with a single 2-year carcinogenicity s tudy to identify trans-species tumorigens. Our analysis of the rodent carcinogenicity studies supports such an approach for assessing carcin ogenic potential without compromising the public health. (C) 1997 Acad emic Press.