Discussion on statistical analysis of carcinogenicity studies with an early terminated treated group

Abstract

High rates of mortality on long term carcinogenicity studies can often result in challenges when it comes to the statistical analysis of tumor incidence. The current regulatory advice often results in treated groups being terminated earlier than the control group. However, this advice rarely considers the impact of this action on the statistical analyses. The nature of these analyses means that groups terminated at different times may not be directly comparable due to age differences of the animals. Here we discuss the issues related to this and investigate several approaches of how to incorporate these groups within the statistical analyses. Although no single method appears to resolve these issues consistently, inclusion of the early terminated group is still informative.Depending on the timing of the early termination, either pooling of the groups into a single terminal kill (TK) interval or reassignment of intervals based purely on time of death (ie, no separate TK interval) appear preferable. However, to draw meaningful conclusions the time of onset of a given tumor must also be considered alongside incident rates and any statistical findings.The objectives of a carcinogenicity study are to identify a tumorigenic potential in animals and to assess the relevant risk in humans. In accordance with ICH guideline S1A 1 carcinogenicity studies should be performed for any pharmaceutical with an expected clinical use of at least 6 months. Since carcinogenicity studies are time consuming and resource intensive, we need to ensure that they are designed appropriately and that maximum information can be inferred from them. Current regulatory guidance 2 indicates that a typical study should include at least 50 animals per dose per sex, with three doses of test article (low, mid, and high) dosed daily over the expected lifetime of the species (generally 24 months). For statistical analysis, animals are stratified into predefined intervals based on time of death. Common intervals used are 0-52 weeks, 53-78 weeks, 79-92 weeks, 93-104 weeks, interim sacrifice (if any), and terminal sacrifice. Dose selection is particularly important, and the general goal should be to maximize rodent exposure by testing at maximum tolerated doses (MTD). 2 Design, analysis, and interpretation of carcinogenicity studies are all important topics as the findings in these studies that are not considered to be species related, will appear on the drug label. Correct drug labeling is essential for ensuring proper drug dispensing and thus for patient safety. Labeling errors may result in adverse health outcomes. 3