Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2018 and 2019.

ABSTRACT

Details of embryo-fetal development (EFD) studies were compiled for all FDA drug approvals in 2018-19. EFD studies were performed for 82 % of approvals (84 % of small molecules and 70 % of biopharmaceuticals). Rats and rabbits were used for 84 % of small molecule (SM) drugs for which EFD studies were submitted. There was at least a 2-fold difference in sensitivity between the rat and the rabbit relative to the human exposure for the majority of drugs (62 %, small molecules and biopharmaceuticals combined) tested in both species. On average, however, the rat and rabbit were equally sensitive to developmental toxicity. Over the last 2 years, the use of non-human primates (NHP) for the developmental toxicity testing of biopharmaceuticals has fallen (26 % of biologics license applications), with many more biopharmaceuticals now tested in rodents (44 % of BLAs). EFD studies were not required for oncology drugs when the mode of action was associated with known developmental risk. One-third of SM non-oncology drugs and two-thirds of SM oncology drugs induced dysmorphogenesis in at least one species. The newly revised ICH S5(R3) guideline will bring about changes to the design of future EFD studies, particularly with respect to high dose selection. The revised guideline will also influence the interpretation of the findings in EFD studies (e.g. fetal morphological variations) and risk assessment.