DeGeorge J J, Meyers L L, Takahashi M, Contrera J F
FDA Center for Drug Evaluation and Research, Office of Review Management, Rockville, MD 28057, USA.
Toxicol Sci. 1999 Jun;49(2):143-55. doi: 10.1093/toxsci/49.2.143.
At the present time, there are no uniform standards for the duration of non-rodent chronic toxicity studies. The European Union (EU) requires a 6-month non-rodent study. In Japan, a 6-month study is sufficient for most, but not all, compounds. The U.S. Food and Drug Administration (FDA) maintains its standard duration of 12 months for non-rodents, with 6-month studies accepted for some clinical indications on a case-by-case basis. To achieve harmonization on the duration of non-rodent toxicity studies, each member regulatory region (EU, U.S., and Japan) of the International Conference on Harmonization (ICH) collected non-rodent studies with significant new toxicological findings that had occurred after 6 months. An ICH expert working group was organized that included representatives from the regulatory authorities of each ICH region, to jointly review all available case studies for the purpose of arriving at a consensus on the best duration time for non-rodent toxicity studies. Eighteen case studies were identified and evaluated (16 original cases plus 2 additional FDA cases); most of the toxicities identified fell into the following categories: (1) toxicities identified at 6 months; (2) toxicities observed at 12 months, which were absent or considered isolated and not noteworthy findings at 6 months; (3) drug-related deaths or morbidity that occurred between 6 and 12 months, with a pattern of toxicity that permitted the interpolation of findings to an intermediate interval between 6 and 12 months; and (4) a shift in the dose response for toxicity with increasing duration of drug exposure. Of the 18 cases evaluated, 11 supported a study-duration of 9-12 months, 4 supported a duration of 12 months, and the 3 remaining cases indicated that a 6-month study would be adequate. The working group concluded that there was sufficient evidence to support a harmonized 9-month duration for non-rodent toxicity studies, which would be applicable for most categories of pharmaceuticals.
目前，非啮齿类动物慢性毒性研究的持续时间没有统一标准。欧盟（EU）要求进行为期6个月的非啮齿类动物研究。在日本，对于大多数但并非所有化合物而言，6个月的研究就足够了。美国食品药品监督管理局（FDA）维持其非啮齿类动物12个月的标准持续时间，对于某些临床适应症，在逐案基础上可接受6个月的研究。为了在非啮齿类动物毒性研究的持续时间上实现协调统一，国际人用药品注册技术协调会（ICH）的每个成员监管地区（欧盟、美国和日本）收集了在6个月后出现重大新毒理学发现的非啮齿类动物研究。组织了一个ICH专家工作组，其中包括每个ICH地区监管当局的代表，共同审查所有可用的案例研究，目的是就非啮齿类动物毒性研究的最佳持续时间达成共识。确定并评估了18个案例研究（16个原始案例加上2个额外的FDA案例）；确定的大多数毒性可分为以下几类：（1）在6个月时发现的毒性；（2）在12个月时观察到的毒性，这些毒性在6个月时不存在或被认为是孤立的且不值得注意的发现；（3）在6至12个月之间发生的与药物相关的死亡或发病，其毒性模式允许将发现推断到6至12个月之间的中间间隔；以及（4）随着药物暴露持续时间的增加，毒性剂量反应发生变化。在评估的18个案例中，11个支持9至12个月的研究持续时间，4个支持12个月的持续时间，其余3个案例表明6个月的研究就足够了。工作组得出结论，有足够的证据支持将非啮齿类动物毒性研究的统一持续时间定为9个月，这将适用于大多数类别的药品。
