生物类似药分析相似性评价的相关统计学方法考量  

Some Statistical Considerations in Analytical Similarity Assessment of Biosimilar Studies

作　　者：吴克坚[1,2] 赵清波[2] 李婵娟[1] 王陵[1] 李晨[1] 潘海涛 夏结来[1] Wu Kejian;Zhao Qingbo;Li Chanjuan(Department of Health Statistics, Fourth Military Medical University （ 710032 ）, Xi＇ an)

机构地区：[1]第四军医大学卫生统计学教研室,710032 [2]第四军医大学数理教研室 [3]Department of Biostatistics,St.Jude Children's Research Hospital,Unit-ed States of America

出　　处：《中国卫生统计》2018年第3期343-348,共6页Chinese Journal of Health Statistics

基　　金：国家科技重大专项子课题(2015ZX09501008-004);国家自然科学基金(81773553)

摘　　要：目的在生物类似药的质量比对研究中,为评价候选药与参照药的分析相似性,FDA建议对3个不同层级的关键质量属性采用不同的评价方法。本文建立第1层级的关键质量属性分析相似性评价的步骤及方法,重点讨论如何确定候选药与参照药的样本量n_T,n_R。方法利用判断方差齐性的F检验介绍方差相似性检验假设及统计量的建立;利用高个体差异药物的生物等效性评价方法及双单侧检验的性质等建立分析相似性检验假设及统计量,并由推导得到的检验效能的精确公式确定样本量。结果在分析相似性评价过程中将n_R控制在[n_T,1.5n_T]内,根据数值模拟得到不同参数组合的样本量,提出了确定n_T,n_R的策略,在此基础上给出了评价生物类似药分析相似性的具体步骤和方法。结论本文提出的样本量确定策略及评价分析相似性的步骤与方法可应用到实际的分析相似性研究中;同时由推导得到的检验效能精确公式还可获得其他参数组合的样本量。Objective For assessment of biosimilarity of biosimilar products, the U. S. Food and Drag Administration proposed three evaluation approaches based on the levels of stringency in analytical studies. The evaluation approaches are ap- plied to the three tiers of critical quality attributes （CQAs） based on the criticality ranking and other factors. In this article, we fo- cus on discussing the statistical methods applicable and sample size nT, nR in tier 1. Methods We introduce an adapted F-test for homogeneity of variances and the expression of the hypothesis and test statistics to assess biosimilarity in variability. We pro- pose a power equation based on the two one-sided tests （TOST）procedure and bioequivalence （BE）for highly variable drugs. Ex- act calculation of sample size can be obtained through numerical iteration of the equation. Results We proposed the idea for the selection of nR ： nR ∈ [ nT, 1.5nT ] in analytical similarity assessment. Based on the results of simulation for various parameter combinations, we also propose the method for the selection of nT, nR and the process of analytical similarity assessment. Conclu- sion The trategy for the selection of nT,nR and the process in this article are practically applied in analytical similarity assess- ment. We can get the other sample size easily for various parameter combinations through the exact formulas for the power and sample size.

关 键 词：生物类似药 分析相似性 关键质量属性 样本量 

分 类 号：R95[医药卫生—药学]