Common Challenges in Evaluating the Reproductive System in Nonclinical

According to the ICH Harmonised Tripartite Guideline: Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals M3(R2), both men and women of child bearing potential (WoCBP) can be included in Phase I and II trials before the conduct of the male and female nonclinical fertility studies, since an evaluation of the male and female reproductive organs is performed in the repeat-dose toxicity studies. As such, much of the early assessment of potential test article-related effects on the reproductive system falls on the nonclinical toxicologic pathologist. This requires the pathologist to have a have a sound understanding of spermatogenesis, stage-aware evaluation of the testis, estrous and menstrual cyclicity, and normal physiology and endocrinology in order to carefully and thoroughly evaluate potential xenobiotic-related effects on the reproductive system. However, even with the most thorough pathology assessment, the design and conduct of nonclinical general toxicity studies can greatly impact the pathologist’s evaluation of the reproductive system. Commonly encountered challenges include age (onset of puberty and reproductive senescence), body weight changes and systemic toxicity, husbandry practices, strain differences, small sample size (non-rodents), and even histologic sectioning patterns.