Vuorinen J, Tuominen J
Orion Corporation, Orion-Farmos Pharmaceuticals, Turku, Finland.
Stat Med. 1994;13(23-24):2531-45. doi: 10.1002/sim.4780132315.
The two-period crossover design is the most commonly used study design for bioequivalence of one test formulation to be assessed in comparison to one reference formulation. Consequently, in this paper, all derivation is based on this particular design. It is assumed that for the underlying statistical model the usual assumptions of normality and additivity are satisfied on the original scale of measurement and that it is wanted to base the assessment of average bioavailability on the ratio of the unknown population means for the test and reference formulation. The purpose of this paper is to illustrate that it is reasonable to assume a uniform covariance structure for the two-period crossover design, because the demand of equal variability in bioavailabilities, in addition to equal average bioavailabilities, for the reference and test formulation makes the assumption of uniform covariance structure very realistic, and also because the properties of a decision rule based upon a Fieller's confidence interval under a uniform covariance structure are competitive with those of the corresponding rule based on a general covariance structure.
两阶段交叉设计是评估一种试验制剂与一种参比制剂生物等效性时最常用的研究设计。因此，在本文中，所有推导均基于这一特定设计。假设对于基础统计模型，在原始测量尺度上满足正态性和可加性的通常假设，并且希望基于试验制剂和参比制剂未知总体均值的比值来评估平均生物利用度。本文的目的是说明，对于两阶段交叉设计假设一个均匀协方差结构是合理的，这是因为除了平均生物利用度相等之外，参比制剂和试验制剂在生物利用度方面具有相等变异性的要求使得均匀协方差结构的假设非常现实，还因为基于均匀协方差结构下的菲勒置信区间的决策规则的性质与基于一般协方差结构的相应规则的性质具有竞争力。
