Assessment of chronic toxicity study designs and development of a weight-of-evidence-based decision-making model for biopharmaceuticals: A survey of Japanese pharmaceutical companies.

We surveyed 17 pharmaceutical companies in Japan, covering 121 biopharmaceutical projects-including mAbs, bispecific antibodies, Fc-fusion proteins, and other protein therapeutics, to characterize chronic toxicity study designs and rationale, assess the predictive value of animal toxicity studies for clinical adverse events (AEs), and identify opportunities for methodological refinement. Toxicities relevant to human risk predominantly emerged within 13 weeks of dosing, with minimal added value from extending studies to 26 weeks. We also examined Target Safety Assessment (TSA) alongside cynomolgus monkey studies, showing substantial concordance and supporting Weight of Evidence (WoE)-based study optimization, while exploring features linked to AEs not predicted by animals. Based on these findings, we developed a flowchart-style decision-making model incorporating WoE approach for determining the necessity and duration of chronic toxicity studies, integrating TSA upstream with in vitro methods and targeted animal studies downstream. This model supports predictive, ethical, and efficient safety evaluation strategies in line with recent FDA guidance and global 3Rs commitments.