Liu J P
Biostatistics Department, Berlex Laboratories, Inc., Wayne, NJ 07066, USA.
Stat Med. 1995;14(9-10):1067-78; discussion 1079-80. doi: 10.1002/sim.4780140926.
We consider applications of the repeated 2 x 2 cross-over design to evaluating bioequivalence between the two formulations. The repeated 2 x 2 cross-over design allows us not only to assess bioequivalence on average bioavailability and to examine the subject-by-formulation interaction but also to obtain independent unbiased estimates of intrasubject variability. One consequence of unequal intrasubject variabilities is that the sum of squares of intersubject residuals and the sum of squares of subject-by-formulation residuals are not independent. We also discuss the relative merits of this design as compared to the standard 2 x 2 cross-over design without repeated measurements in terms of precision and sample size with respect to the ratio of the number of subjects to the repeated measurements per subject. We investigate other uses of the 2 x 2 cross-over in examining the bioequivalence between the two different dosing regimens. Possible applications of other repeated cross-over designs to bioequivalence for more than two formulations are explored. A numerical example illustrates the proposed procedure.
我们考虑将重复的2×2交叉设计应用于评估两种制剂之间的生物等效性。重复的2×2交叉设计不仅使我们能够评估平均生物利用度的生物等效性并检验制剂与受试者之间的相互作用，还能获得个体内变异性的独立无偏估计。个体内变异性不相等的一个结果是，个体间残差平方和与制剂与受试者间残差平方和不独立。我们还讨论了与无重复测量的标准2×2交叉设计相比，该设计在精度和样本量方面（相对于受试者数量与每个受试者重复测量次数的比率）的相对优点。我们研究了2×2交叉设计在检验两种不同给药方案之间生物等效性方面的其他用途。探讨了其他重复交叉设计在两种以上制剂生物等效性方面的可能应用。一个数值例子说明了所提出的程序。
