Best Practices for Clinical Pathology Testing in Carcinogenicity Studies

Abstract

The Society of Toxicologic Pathology (STP) and American Society for Veterinary Clinical Pathology (ASCVP) convened a Clinical Pathology in Carcinogenicity Studies Working Group to recommend best practices for inclusion of clinical pathology testing in carcinogenicity studies. Regulatory guidance documents and literature were reviewed, and veterinary pathologists from North America, Japan, and Europe were surveyed regarding current practices, perceived value, and recommendations for clinical pathology testing in carcinogenicity studies. For two-year rodent carcinogenicity studies, the Working Group recommends that clinical pathology testing be limited to collection of blood smears at scheduled and unscheduled sacrifices to be examined only if indicated to aid in the diagnosis of possible hematopoietic neoplasia following histopathologic evaluation. Additional clinical pathology testing is most appropriately used to address specific issues from prior toxicity studies or known test article-related class effects. Inadequate data were available to make a recommendation concerning clinical pathology testing for alternative six-month carcinogenicity assays using genetically modified mice, although the Working Group suggests that it may be appropriate to use the same approach as for two-year carcinogenicity studies since the study goal is the same.

Pathobiology of Aging Mice and GEM

“…The studies are scrutinized by the Food and Drug Administration (FDA) and other agencies, and best practices are reviewed regularly. 117,164,184,251 Methods and data are accessible from the NTP Web site (http://ntp.niehs. nih.gov/) or from PubMed (http://www.ncbi.nlm.nih.gov/pubmed).…”

Nontraditional Applications in Clinical Pathology

“…Transgenic mouse models, such as the rasH2-Tg model have received considerable attention in efforts to identify alternatives to the current long-term (2y) rodent carcinogenicity studies (Young et al 2011). The rasH2-Tg mice have no obvious differences in clinical pathology relative to their parental strain.…”

Repeated‐Dose Toxicity Studies in Nonclinical Drug Development

“…Rodent studies, due to their size and blood volume limitation, typically employ satellite groups of animals used for TK evaluation. It is strongly recommended that a TK satellite group be used in the study since repeated blood sampling of rodents can result in undesirable impact on haematological end-points, for example, haematocrit (Young et al, 2011). The evaluation of toxicokinetics in chronic toxicology studies is typically conducted on Day 1 following dosing and again at the end of the treatment period.…”

“…If additional blood samples are required in rodents, then collections should be carefully planned due to limited blood volume in these animals. Collections should not impact haematological parameters and should be toxicologically relevant (Young, 2011). Inclusion of additional animals in each dose group to ensure that adequate blood can be drawn could resolve this issue.…”