高变异药物生物等效性评价确切样本量计算  

Exact sample size calculation for bioequivalence evaluation for highly variable drugs

作　　者：刘甜甜[1] 陆梦洁[1] 周憧憧 钟伟华[1] 杨劲[2] 刘玉秀[1] LIU Tian - tian LU Meng - jie ZHOU Chong - chong ZHONG Wei -hua YANG Jan LIU Yu - xiu(Department of Medical Statistics, Jinling Hospital, Southern Medical University, Jinling Hospital, Nanjing Medical University, Nanjing General Hospital of Nanjing Military Region, Nanjing 210002, China China Pharmaceutical University College of Pharmacy., Nanjing 210009, China)

机构地区：[1]南方医科大学南京临床医学院、南京医科大学金陵临床医学院、南京军区南京总医院医学统计学教研警,南京210002 [2]中国药科大学药学院,南京210009

出　　处：《中国临床药理学杂志》2017年第12期1152-1157,共6页The Chinese Journal of Clinical Pharmacology

基　　金：国家自然科学基金资助项目(81473066)

摘　　要：目的探讨高变异药物生物等效性评价(BE)的确切样本量计算方法。方法基于常规2×2交叉设计生物等效性评价双单侧检验原理和统计分布理论,阐明其确切样本量估计的方法。分析美国食品药品监督管理局(FDA)和欧洲药品管理局(EMA)对高变异药物BE研究指南所涉及的方法学内涵,推导出高变异药物生物等效性评价两种重复交叉设计下确切样本量计算的方法。借助SAS编程计算出两种重复交叉设计下不同参数设定的确切样本量列表,并与已发表文献的公式近似法结果进行比较,分析其差别规律。结果因为EMA指南利用参比制剂个体内变异调整生物等效限值的标准比FDA指南更加严格,故其在同样的参数设定下所需的样本量更大。与文献公式近似法的结果对比,当几何均数的比值(GMR)为1时,确切法的样本量均大于近似法,而对于GMR不为1的情形,确切法普遍小于或等于近似法。本文还给出EMA指南要求下确切样本量计算的SAS程序代码,可容易实现不同参数设定下的确切样本量计算。结论本文给出的FDA和EMA指南高变异药物BE研究生物等效性评价的确切样本量计算方法具有严谨的统计理论基础,提供的SAS程序代码简明实用,希望能为开展高变异药物BE研究的样本量确定提供方法学支持。Objective To explore the exact sample size calculation method of bioequivalence evaluation（BE） for highly variable drugs.Methods Based on the two one-sided tests of bioequivalence evaluation for conventional 2 × 2 cross-over design and the statistical distribution theories to elucidate the exact sample size estimation method. Under the Food and Drug Administration（FDA） guidance and the European Medicines Agency（EMA） guideline on the investigation of bioequivalence for highly variable drugs,by using the reference-scaled average bioequivalence（RSABE） criteria to define the relationship between biological equivalent limits and various within-subject variability of reference product,the sample size required for replicated 3-and 4-period cross-over design is deduced exactly respectively. Using SAS programming to calculate the exact listings of sample size for different parameter settings of two types of replicated cross-over design,and compared with the formula approximation results published. Results Because of stricter RSABE criteria for EMA guideline than for FDA guidance,the required sample size is larger under the same parameter settings for EMAguideline. Compared with the results of formula approximation method,when the geometric mean ratio（GMR） is 1. 0,the exact sample sizes are greater. When the GMR is increased or decreased from 1. 0 the required sample sizes rise,and the exact sample size is generally less than or equal to the approximation result. The SAS program codes are provided to easily calculate the exact sample size under various parameter settings. Conclusion The methods of the sample size calculation proposed under FDA guidance and EMA guideline are exact with rigorous statistical theory. The SAS program codes are concise and practical,hope to provide methodological support for the sample size calculation of bioequivalence evaluation for highly variable drugs.

关 键 词：高变异药物 生物等效性 样本量 

分 类 号：R97[医药卫生—药品]