Invited Commentary: Predicting Human Pharmaceutical Cancer Risk

Abstract

Prediction of the human carcinogenic risk of xenobiotic exposure is one of the most difficult challenges faced by toxicologists. The rodent lifetime bioassays (long-term carcinogenicity studies in rat and mice) have been used for the assessment of potential carcinogenic risk to humans for more than 40 years. There has been considerable debate and controversy over the years on the limitations and relevance of the bioassays. The International Conference on Harmonization’s (ICH’s) acknowledgment of the limited utility of conventional the 2-year mouse bioassay for pharmaceuticals in 1996 provided further encouragement to explore new approaches for assessing carcinogenic potential. The current ICH recommendation is to conduct one long-term rodent carcinogenicity study, typically in rats, plus another in vivo test, either another bioassay in a second rodent species (typically, mice) or a shortor medium-term rodent test (ICH, 1998, ‘‘Carcinogenicity: Testing for Carcinogenicity or Pharmaceuticals,’’ topic No. S1B). The rat carcinogenicity study is the longest and largest animal study in the battery of toxicology studies required for the registration of pharmaceuticals. Several attempts have been made to predict the outcome of carcinogenicity studies based on data generated in shorter term studies. The implication is an elimination of the requirement to conduct the rat bioassay, leading to a substantial reduction in animal use and better use of resources for drug development. Reddy et al (this issue) present a retrospective analysis of the pharmaceutical industry’s experience with rat carcinogenicity studies and chronic toxicity studies. They conclude by offering a new pragmatic approach based on the idea that the absence of evidence for preneoplasia in any tissue in a rat chronic toxicity study can accurately predict the negative outcome of a 2-year carcinogenicity study in the species. Although the idea is not controversial as a concept, the difficulties arise with the definition of what constitutes ‘‘evidence for preneoplasia’’ and what study duration is necessary for accuracy. The data set, supportive of the authors’ conclusion, came from the internal archives of Merck & Co, Inc, and from freedom-of-information data publicly available on rat-based 6-month and 12-month chronic toxicology and 2-year carcinogenicity studies for pharmaceuticals. The derived database has several features that affect its representativeness to some degree—specifically, relatively small numbers of drugs and some data from old studies. The authors made every effort to maximize the robustness of the analysis. Inconsistencies may have occurred because information on individual drugs varied from a full data set (Merck compounds) to a secondary source of summarized data (Leadscope Database). That the majority of compounds are approved drugs does not appear to be a bias for the analysis. The authors briefly present the method and criteria used to identify which histopathologic changes were indicative of preneoplasia in each case. Many pathologists would probably find a follow-up publication useful, discussing the details of the methodology and the few cases where difficult decisions were made. Indeed, it may be unclear to some pathologists how diagnoses such as multinucleated cells or tumors would fit within one of the three diagnostic categories (hyperplasia, cellular hypertrophy, and atypical cellular foci) indicative of preneoplasia, as defined by the authors. However, one could argue that this is an unnecessary complication for the purpose of the exercise, which is to decide whether a study is positive on the basis of the information in hand. The rationale for the decision for compounds in the Leadscope Database—that all incidences higher than the control values were considered positive—needs to be discussed given that it may create false-positive or falsenegative results, as in those cases where the control values in the study are high or low, respectively. The proposed method for application of the 6-month chronic toxicology data identified most noncarcinogens but misidentified 5 compounds (Tumors were observed in the rat carcinogenicity study but no preneoplastic changes were found in the 6 month study). As expected, the negative predictivity improved when based on the 12-month study, with the authors considering the improvement marginal. Given the facts that the five false negatives are marketed drugs approved for non-lifethreatening conditions and are associated with rat-specific mechanisms, the authors conclude that absence of preneoplasia in the whole animal in 6-month rat studies is a reliable predictor of negative tumor outcome in 2-year studies. They suggest that the pragmatic regulatory acceptance of such drugs as noncarcinogens in rats—specifically, drugs with no preneoplastic histopathology signal in any tissue in the 6-month chronic study—would make the rat carcinogenicity study unnecessary