Bioassays of shortened duration for drugs: Statistical implications

Declining survival rates in rodent carcinogenesis bioassays have raised a c oncern that continuing the practice of terminating such studies at 24 month s could result in too few live animals at termination for adequate patholog ical evaluation. One option for ensuring sufficient numbers of animals at t he terminal sacrifice is to shorten the duration of the bioassay, but this approach is accompanied by a reduction in statistical power for detecting c arcinogenic 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 carcinog enesis using the 2-stage clonal expansion model as a context. These dose-re sponse models, which were chosen to represent 6 variations of the initiatio n-promotion-completion cancer model, were employed to generate a large numb er of representative bioassay data sets using Monte Carlo simulation techni ques. For a variety of tumor dose-response trends, tumor lethality, and com peting risk-survival rates, the power of age-adjusted statistical tests to assess the significance of carcinogenic potential was evaluated at 18 and 2 1 months, and compared to the power at the normal 24-month stopping time. T he results showed that stopping at 18 months would reduce power to an unacc eptable level for all 6 submodels of the 2-stage clonal expansion model, wi th the pure-promoter and pure-completer models being most adversely affecte d. For the 21-month stopping time, the results showed that, unless pure pro motion can be ruled out a priori as a potential carcinogenic mode of action , the loss of power is too great to warrant early stopping.