Vuorinen J, Turunen J
Orion Corporation, Farmos Research, Department of Biometrics, Turku, Finland.
Stat Med. 1996 Dec 30;15(24):2635-55. doi: 10.1002/(SICI)1097-0258(19961230)15:24<2635::AID-SIM444>3.0.CO;2-X.
Bioavailability data arising from a standard two-period cross-over study are routinely analysed to establish bioequivalence between test and reference formulations. Current regulatory guidelines only require evidence of equivalence in average bioavailability for the assessment of bioequivalence. Under normality assumptions, this is achieved by demonstrating equivalence between the formulation means (step 1). However, the equivalence of formulation variances should also be assessed to get evidence of population bioequivalence (step 2), since a difference in variability of bioavailability may also pose significant problems in drug safety and efficacy. On the other hand, even population bioequivalence does not ensure that an individual subject could be expected to respond similarly to the two formulations. Therefore, whenever individual bioequivalence is the ultimate goal, the magnitude of intra-subject correlation should always be examined as the final stage (step 3). In this paper, these three successive concepts of bioequivalence are cast into the general mixed model framework and a stepwise testing procedure for the global assessment of bioequivalence is proposed. In addition to this, important issues addressed in the regulatory guidelines, such as verification of the model assumptions and application of the log-transformation, are discussed. Lastly, an example is presented to illustrate the proposed three-step procedure on the original and log-transformed scale of measurement.
来自标准两周期交叉研究的生物利用度数据通常会进行分析，以确定试验制剂和参比制剂之间的生物等效性。当前的监管指南仅要求提供平均生物利用度等效性的证据来评估生物等效性。在正态性假设下，这通过证明制剂均值之间的等效性来实现（步骤1）。然而，还应评估制剂方差的等效性，以获得总体生物等效性的证据（步骤2），因为生物利用度变异性的差异也可能在药物安全性和有效性方面带来重大问题。另一方面，即使总体生物等效性也不能确保个体受试者对两种制剂的反应相似。因此，每当个体生物等效性是最终目标时，受试者内相关性的大小应始终作为最后阶段进行检验（步骤3）。在本文中，这三个连续的生物等效性概念被纳入一般混合模型框架，并提出了一种用于生物等效性全局评估的逐步检验程序。除此之外，还讨论了监管指南中涉及的重要问题，如模型假设的验证和对数转换的应用。最后，给出一个例子来说明在原始测量尺度和对数转换测量尺度上所提出的三步程序。
