Review of embryo-fetal developmental toxicity studies performed for recent FDA-approved pharmaceuticals.
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.
Roche Pharmaceutical Research and Early Development, F. Hoffmann La-Roche, Ltd., Basel, Switzerland.
Kana
K
Ishihara-Hattori
Roche Pharmaceutical Research and Early Development, F. Hoffmann La-Roche, Ltd., Basel, Switzerland. Electronic address: paul.barrow.pb1@roche.com.
Paul
P
Barrow
D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity*; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D054852:Small Molecule Libraries / Q000633:toxicity*; D013045:Species Specificity; D014481:United States; D014486:United States Food and Drug Administration
D000911:Antibodies, Monoclonal; D054852:Small Molecule Libraries
BLA; Developmental and reproductive toxicity; Embryo-fetal development; NDA; Teratogenicity