Formal requirements for genotoxicity testing of drug candidates to support clinical entry have been in place since the issue of initial regulatory guidance over 25 years ago and subsequent update a decade ago. An evaluation of such testing, supporting first clinical entry of 108 small molecule drug candidates over the last decade, showed that the most common approach (75 % of tested compounds) was for a Good Laboratory Practice test battery in the form of 2 in vitro (a bacterial reverse mutation and a mammalian cell) assays and one in vivo assay. The majority of other tested compounds involved in vitro testing only in bacterial reverse mutation and mammalian cell assays. Testing using a bacterial reverse mutation assay and an in vivo assessment of genotoxicity with 2 different tissues was limited to 2 occasions. For in vitro mammalian cell testing, the chromosome aberration test was most commonly used (70 % occasions), followed by a micronucleus test (16 % occasions) or a mouse lymphoma assay (14 % occasions). For in vivo evaluation, the most common test was a rodent bone marrow micronucleus test (87 % occasions). A positive in vitro mammalian cell assay result was seen on 13 % occasions but was not confirmed with further in vivo testing and the drug candidates were taken into the clinic. In conclusion, the present evaluation showed that the current test battery paradigm for genotoxicity testing has an integral part in supporting clinical entry to confirm candidate drugs taken into the clinic are unlikely to have genotoxic activity.

自 25 年前发布初始监管指南和十年前后续更新以来，支持临床进入的候选药物基因毒性测试的正式要求已经到位。对此类测试的评估，支持 108 种小分子候选药物在过去十年中首次进入临床，表明最常见的方法（75% 的测试化合物）是采用 2体外形式的良好实验室实践测试组合（一种细菌回复突变和一种哺乳动物细胞）测定和一种体内测定。大多数其他测试化合物仅涉及细菌回复突变和哺乳动物细胞分析的体外测试。使用细菌回复突变试验和体内试验进行测试对 2 种不同组织的遗传毒性评估仅限于 2 次。对于体外哺乳动物细胞检测，最常用的是染色体畸变试验（70%），其次是微核试验（16%）或小鼠淋巴瘤试验（14%）。对于体内评估，最常见的测试是啮齿动物骨髓微核测试（87% 的情况）。在 13 % 的情况下观察到阳性的体外哺乳动物细胞测定结果，但未进一步在体内证实测试和候选药物被带到诊所。总之，目前的评估表明，目前用于遗传毒性测试的测试组合范式在支持临床进入以确认进入临床的候选药物不太可能具有基因毒性活性方面具有不可或缺的作用。