Grayling Michael J, Mander Adrian P, Wason James M S
Hub for Trials Methodology Research, MRC Biostatistics Unit, Cambridge, UK.
Institute of Health & Society, Newcastle University, Newcastle, UK.
Stat Biopharm Res. 2019;11(4):360-374. doi: 10.1080/19466315.2019.1654911. Epub 2019 Sep 6.
Bioequivalence (BE) studies are most often conducted as crossover trials, and therefore establishing their required sample size necessitates specification of the within-person variance. Given that this specification is often difficult in practice, there has been great interest in recent years in the use of adaptive designs for BE trials. However, while numerous methods for this have now been presented, their focus has been solely on two-treatment BE studies. In some instances, it will be desired to incorporate more than a single test and reference formulation into a BE trial. It would therefore be useful to establish methodology for the design of adaptive multi-treatment BE trials, to acquire the benefits in the two-treatment setting in this more complex situation. Here, we achieve this for three-treatment studies by extending previously proposed designs for two-treatment trials. First, we discuss the additional design considerations that arise when multiple comparisons are made. Next, an extensive simulation study is employed to compare the performance of the proposed procedures. With this, we demonstrate that two-stage designs with desirable statistical operating characteristics can be readily identified for three-treatment BE trials. Supplementary materials for this article are available online.
生物等效性（BE）研究大多作为交叉试验进行，因此确定其所需样本量需要明确个体内方差。鉴于在实际操作中往往难以进行这种明确，近年来人们对在BE试验中使用适应性设计产生了浓厚兴趣。然而，尽管现在已经提出了许多用于此目的的方法，但它们仅专注于双处理BE研究。在某些情况下，希望在BE试验中纳入不止一种测试制剂和参比制剂。因此，建立适应性多处理BE试验的设计方法，以便在这种更复杂的情况下获得双处理试验中的益处，将是很有用的。在此，我们通过扩展先前为双处理试验提出的设计，实现了三处理研究的这一目标。首先，我们讨论进行多重比较时出现的额外设计考虑因素。接下来，进行广泛的模拟研究以比较所提出程序的性能。通过这样做，我们证明了对于三处理BE试验，可以很容易地确定具有理想统计操作特性的两阶段设计。本文的补充材料可在线获取。
