Donor reaction had the most negative impact on the BDRR. There appears to be a synergistic effect between donor reaction, fatigue, and sore arm. Theoretically, amelioration of some AEs has the potential to improve BDRRs.

Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.

The Tg rasH2 transgenic mouse has been developed as an alternative to the lifetime mouse bioassay to predict the carcinogeni c potential of chemicals. Unlike the p53 / mouse, the Tg rasH2 mouse is sensitive to both genotoxic and nongenotoxi c carcinogens . The Tg rasH2 mouse, of cially designated CB6F1-TgN (RasH2), contains multiple copies of the human c-Ha-ras oncogen e and promoter within its genome. These mice develop spontaneou s and chemically induced neoplasms earlier in life and in greater numbers than wild-type mice, re ecting their enhanced sensitivity to neoplasia. The most common spontaneous neoplasms in control Tg rasH2 mice 8 to 9 months of age are lung adenomas and carcinomas (7.4% incidence), splenic hemangioma s and hemangiosarcoma s (5.4%), forestomach squamous cell papillomas and carcinomas (2.4%), and skin neoplasms (1.2%). Simulations have demonstrated that 20 to 25 mice/sex/treatment group are required to provide the assay with adequate statistical power. Four of 6 known or suspected human carcinogens tested in Tg rasH2 mice were positive in this assay. For 19 nonmutageni c agents testing positive in conventiona l rodent bioassays, 7 chemicals were positive, 10 chemicals were negative, and 2 were equivocal. None of the 10 nonmutageni c rodent carcinogen s that were negative in the Tg rasH2 mouse model are considered to be human carcinogens . All nonmutageni c chemicals that were negative in the conventiona l rodent bioassays were also negative in the Tg rasH2 model. Results for 15 of 18 mutageni c chemicals tested in Tg rasH2 mice agreed with the results of conventiona l rodent bioassays, and 3 results were equivocal. The Tg rasH2 mouse model appears to predict known or suspected human carcinogen s as well as the traditional mouse bioassay, but with fewer positive results for nongenotoxi c compounds that are not considered human carcinogens . The Tg rasH2 mouse model is the most thoroughly tested in vivo alternative to the lifetime mouse bioassay for nongenotoxi c compounds administered by oral or parenteral routes. The U.S. FDA Carcinogenicit y Assessment Committee has determined that the Tg rasH2 model has been adequately evaluated for consideration for carcinogenicity testing of pharmaceutica l candidates and its use could contribute to the weight of evidence for carcinogenicity assessment. The FDA will consider proposals to replace lifetime mouse carcinogenicity studies with 6-month Tg rasH2 mouse studies to support pharmaceutical registration on a case-by-cas e basis.