Steinijans V W, Hauschke D
Department of Biometry, Byk Gulden Pharmaceuticals, Konstanz, FRG.
Int J Clin Pharmacol Ther Toxicol. 1990 Mar;28(3):105-10.
Statistical methods to assess bioequivalence of a test and a reference formulation are reviewed with emphasis on the distribution of bioequivalence characteristics and the consumer risk of erroneously accepting bioequivalence. Among the procedures not exceeding a nominal consumer risk of 5%, the one with an acceptably small producer risk of erroneously rejecting bioequivalence is selected. With the exception of tmax, the following strategy is recommended: a decision in favour of bioequivalence is made if the shortest 90%-confidence interval for the ratio of the expected medians is in the bioequivalence range for the chosen characteristics of rate and extent of absorption. If the assumption of a logarithmic normal distribution is not valid, the analogous nonparametric (distribution-free) 90%-confidence interval, which is also based on the two-sample approach for the sequences reference/test and test/reference, is the procedure of choice. The issue of a modification of the bioequivalence range of 80-120% to other values for bioequivalence characteristics other than AUC (e.g. Cmax) is also addressed. Finally, a decision rule for tmax is presented.
回顾了评估试验制剂与参比制剂生物等效性的统计方法，重点关注生物等效性特征的分布以及错误接受生物等效性的消费者风险。在不超过标称消费者风险5%的程序中，选择生产者错误拒绝生物等效性风险可接受地小的程序。除达峰时间（tmax）外，推荐以下策略：如果预期中位数比值的最短90%置信区间在所选择的吸收速率和程度特征的生物等效性范围内，则判定生物等效。如果对数正态分布的假设不成立，类似的非参数（无分布）90%置信区间（同样基于参比/试验和试验/参比序列的两样本方法）是首选程序。还讨论了将生物等效性范围80 - 120%修改为除AUC（例如Cmax）之外的其他生物等效性特征的其他值的问题。最后，给出了达峰时间（tmax）的判定规则。
