Strategy for reproductive and developmental toxicity (DART) studies for marketing applications in pharmaceutical...

Studies on reproductive toxicity are conducted to assess the effects of chemicals and pharmaceuticals on the reproductive function and fetal development. However, depending on the indication or modality, Fertility and Early Embryonic Development (FEED), Embryo-Fetal Development (EFD), and Pre/Postnatal Development (PPND) studies which evaluate all reproductive stages or EFD studies in a second species may not be necessary. Therefore, based on the Common Technical Document (CTD), PMDA review reports, and other documents of drugs with new active ingredients approved in Japan, we aimed to investigate the implementation status of DART studies by classifying the studies into FEED, EFD, and PPND types, and summarizing the reasons for not conducting the studies. This survey was conducted by the Reproductive and Developmental Toxicity Team of the Japan Pharmaceutical Manufacturers Association (JPMA) to address issues related to DART studies conducted as non-clinical studies for drug development. Of the three DART studies, 35% of drugs received marketing application without conducting EFD studies in at least one species. Among the three study types, PPND studies were the second most frequently waivered, with 36% not conducted. FEED studies had the lowest implementation rate among the three types of studies, with 40% not conducted. The primary reason for waiving at least one study was compliance with ICH S5, S6, S9, and M3 guidelines. In conclusion, the necessity of DART studies varied depending on the applicable ICH guideline and the characteristics of the drug, including therapeutic indication, target, endogenous substances, low exposure, and ADA formation. This suggests that the need for DART studies may be waived because of various reasons, each of which should be justified based on scientific rationale and risk analysis.