Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
Stat Methods Med Res. 2019 Jul;28(7):2179-2195. doi: 10.1177/0962280217751277. Epub 2018 Jan 22.
Multiregional clinical trials have been accepted in recent years as a useful means of accelerating the development of new drugs and abridging their approval time. The statistical properties of multiregional clinical trials are being widely discussed. In practice, variance of a continuous response may be different from region to region, but it leads to the assessment of the efficacy response falling into a Behrens-Fisher problem-there is no exact testing or interval estimator for mean difference with unequal variances. As a solution, this study applies interval estimations of the efficacy response based on Howe's, Cochran-Cox's, and Satterthwaite's approximations, which have been shown to have well-controlled type I error rates. However, the traditional sample size determination cannot be applied to the interval estimators. The sample size determination to achieve a desired power based on these interval estimators is then presented. Moreover, the consistency criteria suggested by the Japanese Ministry of Health, Labour and Welfare guidance to decide whether the overall results from the multiregional clinical trial obtained via the proposed interval estimation were also applied. A real example is used to illustrate the proposed method. The results of simulation studies indicate that the proposed method can correctly determine the required sample size and evaluate the assurance probability of the consistency criteria.
近年来，多区域临床试验已被接受为加速新药开发和缩短其批准时间的有用手段。多区域临床试验的统计特性正在被广泛讨论。在实践中，连续反应的方差可能因地区而异，但这导致疗效反应的评估陷入了 Behrens-Fisher 问题——对于不等方差的均值差异，没有精确的检验或区间估计。作为一种解决方案，本研究应用了基于 Howe、Cochran-Cox 和 Satterthwaite 逼近的疗效反应区间估计，这些估计已被证明具有良好控制的Ⅰ类错误率。然而，传统的样本量确定方法不能应用于区间估计。然后提出了基于这些区间估计来实现所需功效的样本量确定。此外，日本厚生劳动省指南中建议的一致性标准也被用于决定通过拟议的区间估计获得的多区域临床试验的总体结果是否也适用。实际示例用于说明所提出的方法。模拟研究的结果表明，所提出的方法可以正确确定所需的样本量并评估一致性标准的保证概率。
