Dutch Medicines Evaluation Board, Utrecht, the Netherlands.
Centre for Health Protection, Dutch Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
Crit Rev Toxicol. 2024 Oct;54(9):619-633. doi: 10.1080/10408444.2024.2374281. Epub 2024 Aug 2.
Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies.
胚胎胎儿发育 (EFD) 研究旨在确定孕妇和胚胎胎儿发育过程中药物的风险。根据 ICH S5(R3) 指南，这些研究通常在一种啮齿动物和一种非啮齿动物物种中进行，通常是大鼠和兔子。然而，在两种物种中进行 EFD 研究对风险评估的附加价值是有争议的。在这项研究中，评估了大鼠和兔子的 EFD 研究，以分析第二种物种的附加价值。从荷兰药品评估委员会的数据库中收集了 2004 年至 2022 年期间提交给欧洲药品管理局上市许可的人类药物的大鼠和兔子 EFD 研究信息，以及用于已知人类致畸物的 EFD 研究。总共在数据库中包含了 369 种化合物。对于 55.6%的化合物，在大鼠和兔子 EFD 研究中观察到相似的效果。对于 44.6%的化合物，观察到不一致。不一致通常可以根据母体毒性的发生或化合物的作用机制来解释。对于其他化合物，由于高暴露限度或较少的 EFD 毒性，不一致被认为具有有限的临床相关性。对于 6.2%的化合物，不一致无法解释，被认为具有临床相关性。此外，对于特定的治疗类别，大鼠和兔子之间的一致性可能会有所不同。总之，在许多情况下，在两种物种中进行 EFD 研究的附加价值是有限的。这些数据可以帮助确定可以豁免（额外的）EFD 研究或创建证据权重模型以确定是否需要（额外的）EFD 研究的情况。
