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

发育毒性 指南 医学 怀孕 临床试验 毒性 危险系数 不利影响 胎儿 儿科 内科学 置信区间 生物 病理 遗传学
作者
Paul Barrow
出处
期刊:Teratology [Wiley]
卷期号:115 (2): 218-223 被引量:2
标识
DOI:10.1002/bdr2.2108
摘要

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.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.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.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.
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