Comparisons of false negative rates from a trend test alone and from a trend test jointly with a control-high groups pairwise test in the determination of the carcinogenicity of new drugs

ABSTRACT

Interest has been expressed in using a joint test procedure that requires that the results of both a trend test and a pairwise comparison test between the control and the high groups be statistically significant simultaneously at the levels of significance recommended in the FDA 2001 draft guidance for industry document for the separate tests in order for the drug effect on the development of an individual tumor type to be considered as statistically significant. Results of our simulation studies show that there is a serious consequence of large inflations of the false negative rate through large decreases of false positive rate in the use of the above joint test procedure in the final interpretation of the carcinogenicity potential of a new drug if the levels of significance recommended for separate tests are used. The inflation can be as high as 204.5% of the false negative rate when the trend test alone is required to test if the effect is statistically significant. To correct the problem, new sets of levels of significance have also been developed for those who want to use the joint test in reviews of carcinogenicity studies.

KEY WORDS:

• Carcinogenicity studies of pharmaceuticals
• control-high groups pairwise comparison of a drug-induced increase
• false positive and false negative rates
• Gamma simulation models
• joint test
• positive dose response test
• tumor incidence rate
• Weibull simulation models

Acknowledgments

The authors thank Dr. Yi Tsong, Director of Division of Biometrics 6, Office of Biostatistics, CDER/FDA, for encouraging them to publish the results of their simulation studies; to their former FDA colleague Dr. Matthew T. Jackson for pointing out the drug effects on mortality and on tumor prevalence of the additional treated group in the our simulation studies; and to Dr. S. Edward Nevius, their current colleague and former Deputy Director of the Office of Biostatistics, for his time and great efforts in going over the manuscript and in making all the valuable suggested editing changes and comments to further meet the FDA manuscript clearance guidelines. The authors sincerely appreciate the time and the efforts of the referees and of the editor in their thorough reviews the drafts of the manuscript. The manuscript has been greatly improved by their valuable comments and suggestions.