ABSTRACT
The incidence of cancer was so frightening that in 1971 President Richard Nixon declared a war against cancer. An enormous amount of resources has been directed toward the fight against cancer. However, the battle against this leading killer disease has not been very successful. Continued human suffering due to this disease has prompted the demand for strategies to effectively identify human carcinogens. In the development of new drugs, the assessment of the carcinogenic potential of chemical compounds in humans is a fundamental step. The risk assessment of the carcinogenic potential of a new drug usually begins with experiments in animals. The law requires the sponsor of a new drug to conduct short-and long-term carcinogenicity studies in animals to assess the carcinogenic effect of the drug compounds. There are different applications of these short-and long-term animal carcinogenicity studies in the determination of the carcinogenic potential of chemical compounds. The first is to use the results merely for screening the unsafe chemical compounds. The second is to conduct risk assessments of chemicals in humans. This process involves the extrapolation of results from animals to humans and from high to low doses. The third is to verify specific scientific hypotheses about the mechanisms of carcinogenesis. Various federal government agencies in the United States play important roles in
the national effort to reduce the threat of cancer. Two of the most important agencies in this effort are the U.S. Environmental Protection Agency (EPA) and the U.S. Food and Drug Administration (FDA). The EPA is responsible for protecting Americans from environmental cancer-causing agents. The FDA is responsible for ensuring the safety of human drugs, animal drugs, medical devices, and food additives. The evaluation of the carcinogenic effect of medical products is one of FDA’s most important responsibilities. These two agencies regularly review and evaluate carcinogenicity studies conducted by various sponsors mostly in different rodent species. Other U.S. government agencies involved in the review and evaluation of animal oncology experiments include the National Toxicological Program (NTP), the National Cancer Institute (NCI), and the National Center for Toxicological Research (NCTR). The International Agency for Research on Cancer, a branch of the World Health Organization (WHO), also monitors animal carcinogenicity data from different sources. The Pharmacology and Toxicology (Pharm=Tox) Team at the Office of Biosta-
tistics (OB) of the Center for Drug Evaluation and Research (CDER) in the FDA is responsible for the statistical review and evaluation of carcinogenicity studies of pharmaceuticals included in investigational new drug (IND) and new drug application (NDA) submissions. The statistical review and evaluation of pharmacology and toxicology studies is an important and integral part of the FDA approval process for new drugs. In a regular carcinogenicity study review the FDA statisticians review and evaluate the appropriateness of designs of experiments, methods of statistical analysis of data, and methods of interpreting the study results. In addition to reviewing the reports submitted by the drug sponsor, statisticians in the CDER=FDA also perform analyses of their own using the tumor data submitted
by the sponsors to verify the sponsor’s results and to answer questions that are not addressed by the sponsor. The designs, methods of statistical analysis of data, and interpretation of results recommended in the 2001 FDA draft document titled Guidance for Industry; Statistical Aspects of the Design, Analysis, and Interpretation of Chronic Rodent Carcinogenicity Studies of Pharmaceuticals are generally followed by CDER=FDA statisticians in their reviews of regular 2 year studies for IND and NDA submissions. This FDA draft guidance for industry document includes methods of analyzing data from carcinogenicity studies using regular rodents but does not cover the designs and methods of data analysis and interpretation of study results for short-term studies using special mice, known as transgenic mice. The CDER=FDA statisticians have been using methods developed both within the FDA and outside the FDA in their statistical reviews of this type of carcinogenicity study for new drugs. The purpose of this chapter is to provide an update, with detailed discussions on
the topics presented in the FDA guidance for industry document and in chapters on the same subject in various editions of other books by the second author, and to present some new designs and methods of data analysis and interpretation of results currently used by FDA=CDER statisticians in the review of carcinogenicity studies using transgenic mice that were not included in publications mentioned here.
