Animal use and opportunities for reduction in carcinogenicity studies supporting approved new drug applications in the U.S., 2015-2019.

A minimum of 65,341 rats and mice were used in 109 carcinogenicity studies conducted for new drug applications approved by the U.S. Food and Drug Administration from 2015 through 2019. By analyzing how these animals were used, we compared the potential for reducing animal use of implementing existing international guidelines and recommendations. The greatest reduction, 18.7%, would result from evaluating exposure by microsampling blood in main studies to replace toxicokinetics satellites, which used three-fold more mice than rats. A similar reduction, 17.3%, would result from replacing 33 long-term studies in mice with short-term studies in transgenic mice. Based on histopathology findings in chronic studies, 15 long-term studies in rats could have been waived, using 8410 fewer rats. Simply using single, rather than dual, negative control groups would result in a 7.8% reduction, and eliminating positive control groups would use 640 fewer transgenic mice. Combined, an estimated 46% reduction would be achieved, using approximately 29,876 fewer animals. The publication of an addendum to the main carcinogenicity testing guideline promises to decrease the number of long-term studies conducted in rats and mice and presents opportunity to promote full harmonization and implementation of related recommendations that would further dramatically reduce animal use.