Minimizing use of nonhuman primates to inform risk to fertility and of adverse pregnancy outcomes with pharmaceuticals

An assessment of potential developmental and reproductive toxicity (DART) is generally required to support clinical trials and marketing of pharmaceuticals. Although typically performed in rodents and rabbits, nonhuman primates (NHPs) are often used when they are the only pharmacologically relevant species. Regulatory guidances allow for weight of evidence (WoE) risk assessment for DART such that mature NHPs may not be needed to confirm expected or low risk of adverse pregnancy outcome. As such, there are numerous examples of WoE strategies to inform risk of adverse pregnancy outcome, but fewer to assess risk to male and/or female fertility, although emerging data indicate mature NHPs have limited impact on fertility risk assessment in product labels. Mature NHP data are most impactful to fill safety gaps when there are no relevant data from other species, limited information to establish WoE, and/or limited human data is available to characterize risk. In this review, we propose a detailed decision tree and examples to inform risk of adverse pregnancy outcome or male/female fertility impact by emphasizing and prioritizing WoE supplemented by experimental data where necessary, including use of NHPs as a last resort. Additional refinements to NHP use are also summarized.