Abstract

The use of multiregional clinical trials (MRCTs) in clinical developments increased to accelerate patients’ access to new drugs globally. MRCTs inherently assume that the treatment effect is consistent across regions; therefore, we generally estimate the overall treatment effect using a weighted mean of regional estimates with the proportions of enrolled patients as a weight. However, recent MRCTs occasionally encountered an inconsistency in treatment effect among regions. This study was motivated by two actual MRCTs showing the inconsistency of the treatment effects. In these trials, inconsistent treatment effects were observed in a few regions and the estimates in these regions impacted the overall treatment effect estimate. In this study, we propose an exploratory analysis to estimate the overall treatment effect based on robust estimation. The proposed estimator adaptively changes the weights for each region by minimizing the weighted jackknife-based mean squared error of the proposed estimator. We examined the utility of the proposed method through simulation studies. We found that the proposed estimators were less biased and more statistically powerful compared with other ordinary estimators when inconsistent regions existed. We also illustrated estimation of the overall treatment effect by applying the proposed estimators to the two MRCTs.

摘要

在临床开发中越来越多地使用多区域临床试验（MRCT），以加速患者在全球范围内获得新药的机会。MRCT固有地认为治疗效果在各个地区是一致的。因此，我们通常使用区域估计值的加权平均数（以入组患者的比例作为权重）来估计总体治疗效果。但是，最近的MRCT偶尔会遇到区域间治疗效果不一致的情况。这项研究是受两个实际的MRCT的启发而来的，这些MRCT显示出治疗效果的不一致。在这些试验中，在几个地区观察到不一致的治疗效果，这些地区的估计值影响了整体治疗效果的估计值。在这项研究中，我们提出了一项探索性分析，以基于稳健估计来估计总体治疗效果。所提出的估计器通过最小化所提出的估计器的基于加权折刀的均方误差来自适应地改变每个区域的权重。我们通过仿真研究检查了该方法的实用性。我们发现，在存在不一致区域的情况下，与其他普通估计量相比，拟议的估计量具有较小的偏倚且在统计上更有效。我们还通过将建议的估算器应用于两个MRCT来说明总体治疗效果的估算。我们发现，在存在不一致区域的情况下，与其他普通估计量相比，拟议的估计量具有较小的偏倚且在统计上更有效。我们还通过将建议的估算器应用于两个MRCT来说明总体治疗效果的估算。我们发现，在存在不一致区域的情况下，与其他普通估计量相比，拟议的估计量具有较小的偏倚且在统计上更有效。我们还通过将建议的估算器应用于两个MRCT来说明总体治疗效果的估算。