Jiang Wenlei, Makhlouf Fairouz, Schuirmann Donald J, Zhang Xinyuan, Zheng Nan, Conner Dale, Yu Lawrence X, Lionberger Robert
Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
AAPS J. 2015 Jul;17(4):891-901. doi: 10.1208/s12248-015-9753-5. Epub 2015 Apr 4.
Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00-125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE limits and (2) a scaled average BE approach where BE limits are tightened based on the RLD's within-subject variability. Addition of a variability comparison (using a one-tailed F test) increased the difficulty for generic NTIs more variable than their corresponding RLDs to demonstrate bioequivalence. Based on these results, the authors evaluate the fully replicated, 2-sequence, 2-treatment, 4-period crossover study design for NTI drugs where the test product demonstrates BE based on a scaled average bioequivalence criterion and a within-subject variability comparison criterion.
多个健康领域团体对测试药物与参比药物几何均值比的90%置信区间的平均生物等效性（BE）限度（80.00 - 125.00%）是否足以确保普通窄治疗指数（NTI）药物与其参比上市药品（RLD）之间的治疗等效性表示担忧。开展了模拟研究，以调查NTI药物不同BE方法对研究效能的影响，包括（1）直接收紧平均BE限度，以及（2）一种按比例缩放的平均BE方法，即根据RLD的受试者内变异性收紧BE限度。增加变异性比较（使用单尾F检验）增加了普通NTI药物（比其相应RLD变异性更大）证明生物等效性的难度。基于这些结果，作者评估了NTI药物的完全重复、2序列、2治疗、4周期交叉研究设计，其中测试产品基于按比例缩放的平均生物等效性标准和受试者内变异性比较标准证明BE。
