An assessment of the reliability of 52 enhanced preliminary embryofetal development studies to detect developmental toxicity.

BACKGROUND

Preliminary embryofetal development (pEFD) data from two species are currently recommended before inclusion of women of child-bearing potential (WOCBP) in clinical trials in Europe or Japan, but not before trials in the United States. The ICH S5(R3) guideline advises an "enhanced" study design for this purpose.

METHODS

The reliability of pEFD studies was assessed by comparing the outcome of 52 enhanced pEFD studies (25 rat, 23 rabbit, and 4 mouse) with the results of the definitive nonclinical EFD assessment.

RESULTS

Four pEFD studies revealed severe developmental hazard without the need for a main EFD study. Only one pEFD study failed to detect drug-related teratogenicity or pregnancy failure subsequently detected in the main study. There were, however, some false positive and some equivocal pEFD study results. Of the 48 pEFD studies for which a main EFD study was performed, 16 (33%) failed to accurately predict (within two-fold) the no adverse effect level (NOAEL) for developmental toxicity subsequently defined in the main EFD study. Skeletal examination of fetuses in the pEFD study was necessary was to detect drug-induced malformations. One quarter (23%) of EFD investigations revealed malformations and/or pregnancy failure at one dose level or more.

CONCLUSIONS

pEFD studies are effective for the detection of serious or irreversible effects on embryofetal development, provided that full fetal examinations are completed. They are not, however, sufficiently powered to reliably define the NOAEL for developmental toxicity. The regulatory impact of pEFD studies remains obscure since maximum pregnancy prevention precautions are required in clinical trials in all regions until the results of the main EFD studies are available.