Review of embryo-fetal developmental toxicity studies performed for recent FDA-approved pharmaceuticals

• Details of developmental toxicity studies compiled for 43 NDAs and 37 BLAs.
• Rat and rabbit used in 93% of NDAs; both contributed equally to risk assessment.
• DART studies were not required for some mAbs due to existing scientific knowledge.
• Cynomolgus used for 75% of mAbs; homologous murine antibodies in rodents also contributed.
• Dose levels >50-X human exposure (>10-X for mAbs) frequently used, but rarely warranted.

Details of embryo-fetal development (EFD) studies were compiled from published FDA approval documents for 43 small molecule drugs (2014–2015) and 37 monoclonal antibodies (mAbs, 2002–2015). Anti-cancer agents were analyzed separately. Rats and rabbits were the species used for EFD studies on 93% of small molecule drugs. Overall, the rat and rabbit were equally sensitive to maternal and fetal toxicity (including teratogenicity). Dosages equivalent to more than 50-times the human exposure (or 10-times for mAbs) were frequently used, but were unnecessary for 90% of drugs. EFD studies were not required for several recently approved mAbs owing to pre-existing scientific knowledge. The cynomolgus monkey was used for developmental toxicity testing of 75% of mAbs, frequently using an ePPND study design. Studies in pregnant rodents using homologous murine antibodies supplemented or replaced monkey studies under some circumstances. Most anti-cancer small molecules and mAbs were tested for developmental toxicity in at least one species.