Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2016 and 2017

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2018-09, Vol.80, p.117-125
• Main Author: Barrow, Paul
• Format: Article
• Language: English
• Subjects: BLA; Developmental and reproductive toxicity; Embryo-fetal development; ICH S5; NDA; Teratogenicity
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2018.04.008

•Details of developmental toxicity studies compiled for all FDA approvals in 2016 and 2017.•Rat and rabbit used in 63% of NDAs; both species were useful for risk assessment.•DART studies were not required for some mAbs due to existing scientific knowledge.•Cynomolgus monkey used for 47% of mAbs, but rodents and/or rabbits used when possible.•Maternal or fetal toxicity seen below 25-X human exposure for 89% of small molecule drugs. Details of embryo-fetal development (EFD) studies were compiled for all FDA drug approvals in 2016–17. Rats and rabbits were used for 63% of small molecule (SM) drugs. The cynomolgus monkey was used for 47% of biopharmaceuticals. Rodent studies using the clinical mAb or animal homologue replaced monkey studies under some circumstances. EFD studies were not required for anti-cancer drugs when the mode of action was associated with known developmental risk. One quarter of SM non-oncology drugs and all tested SM anti-cancer drugs were teratogenic in at least one species. The rat and rabbit were essentially equally sensitive to developmental toxicity. Eighty-nine percent of SM non-cancer drugs induced maternal or fetal toxicity in at least one species at below 25-times human exposure (proposed maximum exposure in the draft revised ICH S5(R3) guideline). The pregnancy and lactation labeling rule (PLLR) has brought consistency to the presentation of EFD data in drug labels.