Hauck W W, Anderson S
Department of Epidemiology & Biostatistics, University of California, San Francisco 94143-0560.
Stat Med. 1991 Jun;10(6):959; discussion 959-60. doi: 10.1002/sim.4780100616.
Current procedures for assessing the bioequivalence of two formulations are based on the concept of average bioequivalence. That is, they assess whether the average responses between individuals on the two formulations are similar. We show first that average bioequivalence is not sufficient to assure that an individual patient could be expected to respond similarly to the two formulations. To have such reasonable assurance requires a different notion of bioequivalence; individual (or within-subject) bioequivalence. Second, we propose a simple statistical procedure for assessing individual bioequivalence. This decision rule, TIER (test of individual equivalence ratios) requires the specification of the minimum proportion of subjects in the applicable population for which the two formulations being tested must be bioequivalent (a regulatory decision). The TIER rule is summarized in terms of the minimum number of subjects with bioavailability ratios falling within the specified equivalence interval necessary to be able to claim bioequivalence for given sample size and type I error. We recommend that the corresponding lower bounds (one-sided confidence intervals) for the proportion of bioequivalent subjects be calculated.
目前评估两种制剂生物等效性的程序是基于平均生物等效性的概念。也就是说，它们评估的是两种制剂在个体之间的平均反应是否相似。我们首先表明，平均生物等效性不足以确保个体患者对两种制剂的反应相似。要有这种合理的保证需要一个不同的生物等效性概念；个体（或受试者内）生物等效性。其次，我们提出了一种评估个体生物等效性的简单统计程序。这个决策规则，即个体等效比检验（TIER），要求指定适用人群中两种受试制剂必须生物等效的受试者的最小比例（一项监管决策）。TIER规则是根据在给定样本量和I型错误情况下，为了能够宣称生物等效性，生物利用度比落在指定等效区间内的受试者的最小数量来总结的。我们建议计算生物等效受试者比例的相应下限（单侧置信区间）。
