Toxicological Sciences 55, 415-432 (2000)
Copyright © 2000 by the Society of Toxicology
Bioassays of Shortened Duration for Drugs: Statistical Implications
* Division of Biometry and Risk Assessment, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079;
Division of Biometrics II, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland 20857; and
R.O.W. Sciences, Inc., National Center for Toxicological Research, Jefferson, Arkansas 72079
Declining survival rates in rodent carcinogenesis bioassays have raised a concern that continuing the practice of terminating such studies at 24 months could result in too few live animals at termination for adequate pathological evaluation. One option for ensuring sufficient numbers of animals at the terminal sacrifice is to shorten the duration of the bioassay, but this approach is accompanied by a reduction in statistical power for detecting carcinogenic potential. The present study was conducted to evaluate the loss of power associated with early termination. Data from drug studies in rats were used to formulate biologically based dose-response models of carcinogenesis using the 2-stage clonal expansion model as a context. These dose-response models, which were chosen to represent 6 variations of the initiation-promotion-completion cancer model, were employed to generate a large number of representative bioassay data sets using Monte Carlo simulation techniques. For a variety of tumor dose-response trends, tumor lethality, and competing risk-survival rates, the power of age-adjusted statistical tests to assess the significance of carcinogenic potential was evaluated at 18 and 21 months, and compared to the power at the normal 24-month stopping time. The results showed that stopping at 18 months would reduce power to an unacceptable level for all 6 submodels of the 2-stage clonal expansion model, with the pure-promoter and pure-completer models being most adversely affected. For the 21-month stopping time, the results showed that, unless pure promotion can be ruled out a priori as a potential carcinogenic mode of action, the loss of power is too great to warrant early stopping.
Key Words: chronic; dose-response; Food and Drug Administration (FDA); Monte Carlo; MVK model; power; survival; trend.
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