Toxicologic Pathology Forum: Opinion on Not Euthanizing Control Animals in the Recovery Phase of Non-Rodent Toxicology Studies

Abstract

Nonclinical toxicology studies that are required to support human clinical trials of new drug candidates are generally conducted in a rodent and a non-rodent species. These studies typically contain a vehicle control group and low, intermediate, and high dose test article groups. In addition, a dosing-free recovery phase is sometimes included to determine reversibility of potential toxicities observed during the dosing phase and may include additional animals in the vehicle control and one or more dose groups. Typically, reversibility is determined by comparing the test article–related changes in the dosing phase animals to concurrent recovery phase animals at the same dose level. Therefore, for interpretation of reversibility, it is not always essential to euthanize the recovery vehicle control animals. In the absence of recovery vehicle control tissues, the pathologist’s experience, historical control database, digital or glass slide repositories, or literature can be used to interpret the findings in the context of background pathology of the species/strain/age. Therefore, in most studies, the default approach could be not to euthanize recovery vehicle control animals. This article provides opinions on scenarios that may or may not necessitate euthanasia of recovery phase vehicle control animals in nonclinical toxicology studies involving dogs and nonhuman primates.

Toxicologic Pathology Forum Opinion Piece: Use of Virtual Control Groups in Nonclinical Toxicity Studies: The Anatomic Pathology Perspective

“…VCG implementation will result in a reduction of animal use complementing other proposed initiatives such not to euthanize recovery control animals and return them to the stock colony at the completion of the recovery phase. 5 Another consideration for use of VCG is a tiered or retrospective approach. In this scenario study findings, such as histopathology, might be interpreted without CCs.…”

Recovery Animals in Toxicology Studies: An Innovation and Quality Consortium Perspective on Best Practices With Case Study Examples

“…A recent survey across 4 major organizations found that in non-rodent nonclinical toxicology studies where a recovery vehicle control group was included and euthanized at the end of the study, euthanasia of vehicle control recovery animals was not necessary for the interpretation of findings in ∼95% (116/122 studies) dog and ∼91% (109/120 studies) NHP studies. 14 In ∼5% dog and ∼9% of NHP studies where euthanasia of vehicle control recovery animals was considered necessary for study interpretation, it was considered to have no impact on the study/program outcome except where historical control data (HCD) were not robust. The survey results further indicate that not euthanizing the vehicle control animals could have saved around 460 dogs and 428 NHPs over 14 years without compromising the overall conclusions.…”