ABSTRACT
I. Introduction............................................................................................ 18
II. Validity of the Design ........................................................................... 19
III. Methods of Statistical Analysis............................................................. 21
A. Test of Intercurrent Mortality Data ................................................ 21
B. Contexts of Observation of Tumor Types...................................... 23
C. Statistical Analyses of Incidental Tumors...................................... 23
D. Statistical Analyses of Fatal Tumors.............................................. 28
E. Statistical Analyses of Tumors Observed in Incidental
and Fatal Contexts .......................................................................... 29
F. Exact Analysis ................................................................................ 29
1. The Exact Method..................................................................... 30
2. Comparison of Exact and Approximate Methods.................... 33
G. Statistical Analysis of Data without Information about
Cause of Death................................................................................ 35
H. Combined Analysis of Tumor Types Observed in
Fatal and Incidental Contexts by Exact Permutation Test............. 38
IV. Interpretation of Study Results.............................................................. 39
V. Carcinogenicity Studies Using Transgenic Mice.................................. 46
VI. Data Presentation and Submission ........................................................ 48
VII. Concluding Remarks ............................................................................. 49
Acknowledgments ............................................................................................. 50
References.......................................................................................................... 50
The risk assessment of a new drug exposure in humans usually begins with
an assessment of risk of the drug in animals. It is required by law that the sponsor
of a new drug conducts nonclinical studies in animals to assess the
pharmacological actions, the toxicological effects, and the pharmacokinetic
properties of the drug in relation to its proposed therapeutic indications or clinical
uses. Studies in animals, designed for assessment of toxicological effects of the
drug, include acute, subacute, subchronic, and chronic toxicity studies,
tumorigenicity, reproduction, and pharmacokinetic studies.
