定量药理学在确定非劣效试验界值中的作用  

Role of pharmacometrics in defining the non-inferiority margin

作　　者：王玉珠[1] 杨进波[1] 

机构地区：[1]国家食品药品监督管理总局药品审评中心,北京100038

出　　处：《中国临床药理学杂志》2017年第23期2515-2520,共6页The Chinese Journal of Clinical Pharmacology

摘　　要：非劣效试验(NI)是药物研发过程中常用的一种统计学设计方法,监管部门可以根据NI试验结果批准新药或新适应证上市。阳性对照相对于安慰剂的效应量(M1)是NI试验的关键设计参数,用以确定非劣界值。M1通常来源于历史研究的荟萃分析,而最终的非劣界值(M2)是M1的一部分,而M2应该占M1多少比例应该结合临床考虑而确定。在新NI试验中,应尽可能使其设计与历史研究的设计一致,才能使其结果更接近于阳性对照效应量的真实值,从而使其结果具有可解释性。但是,有时会发生确实无法得到与新NI试验设计相同的历史研究数据的情况,此时对于非劣界值的确定很棘手,主要是因为无法使用荟萃分析根据历史数据对M1进行计算。本文通过药物研发企业在Everolimus增加新适应证的NI试验以及美国批准其上市的案例,剖析在上述棘手情况下,如何采用定量药理学方法,基于其暴露-效应关系的基础理论,通过构建模型进行数据分析和模拟,并结合统计学的敏感性分析等,确定非劣界值,以进行最终的试验结果分析和评价,以期帮助读者认识和理解定量药理学方法和理念在解决试验设计和结果分析等棘手问题时的重要作用,推动定量药理学在我国药物研发过程中的实践运用。Non-inferiority（ NI） trial is a commonly used design during new drug development and regulatory agencies around the world rely on the results from NI trials to approve new drugs or new indications. One key parameter to design an NI trial is the entire effect size（ M1） of the active control arm relative to placebo. M1 is typically calculated based on a meta-analysis of relevant historical trials. The final NI margin,M2,is a fraction of M1 and the appropriate fraction is determined based on clinical relevance. The condition of the new NI trial should be similar to that of the historical trials so that the effect of the active control arm can be assumed to be the same as that from the historical trials. However,there are cases where no relevant historical trials existed to mimic the new trial condition for the NI trial. Under such a scenario,the calculation of NI margin is rather challenging mainly because it is impossible to apply the meta-analysis to calculate M1 first. This paper demonstrates how to apply a pharmacometric method together with various sensitivity analyses to address such a challenge when a new indication of Everolimus was sought and approved in the US based on an NI trial. The readers are expected to understand the basic concept of pharmacometrics and its rolein solving difficult drug development questions through this case study. The authors hope to achieve the goal of promoting the application of pharmacometrics in the drug development and approval process in China.

关 键 词：定量药理学 暴露量-效应关系 模型-模拟 非劣效试验 非劣界值 敏感性分析 

分 类 号：R97[医药卫生—药品]