Medical Research Council Clinical Trials Unit at University College London, 125 Kingsway, London, UK.
BMC Med Res Methodol. 2013 Nov 14;13:139. doi: 10.1186/1471-2288-13-139.
Randomised controlled trials are becoming increasingly costly and time-consuming. In 2011, Royston and colleagues proposed a particular class of multi-arm multi-stage (MAMS) designs intended to speed up the evaluation of new treatments in phase II and III clinical trials. Their design, which controls the type I error rate and power for each pairwise comparison, discontinues randomisation to poorly performing arms at interim analyses if they fail to show a pre-specified level of benefit over the control arm. Arms in which randomisation is continued to the final stage of the trial are compared against the control on a definitive time-to-event outcome measure. To increase efficiency, interim comparisons can be made on an intermediate time-to-event outcome which is on the causal pathway to the definitive outcome.
We adapt Royston's MAMS design to binary outcomes observed at the end of a fixed follow-up period and analysed using an absolute difference in proportions. We apply the design to tuberculosis (TB), an area where many new drugs are in development, and demonstrate how it can greatly accelerate the evaluation of new TB regimens. We use simulations to support the extensions to the methodology and to investigate the amount of bias in the estimated treatment effects of arms in which randomisation is ceased at the first interim analysis and arms which continue to the final stage of the trial.
The proposed seamless phase II/III TB trial designs are shown to greatly reduce sample size requirements and trial duration compared to conducting separate phase II and III trials. The bias in the estimated treatment effects for the definitive outcome is shown to be small, especially when treatment selection is based on an intermediate outcome or when a reanalysis is performed at the planned end of the trial after all recruited patients have completed follow-up.
The proposed designs are practical and could be used in a variety of disease areas. They hold considerable promise for speeding up the evaluation of new treatments particularly in TB where many new regimens will soon be available for testing in phase II and phase III trials.
随机对照试验变得越来越昂贵和耗时。2011 年，Royston 及其同事提出了一类特殊的多臂多阶段（MAMS）设计，旨在加快 II 期和 III 期临床试验中新疗法的评估。他们的设计控制了每一对比较的Ⅰ型错误率和功效，如果表现不佳的手臂在中期分析中未能显示出优于对照臂的预定水平的益处，则停止对这些手臂进行随机分组。继续进行试验最后阶段随机分组的手臂与对照臂在最终的时间到事件结果测量上进行比较。为了提高效率，可以对中间时间到事件结果进行中期比较，该结果与最终结果的因果途径相关。
我们将 Royston 的 MAMS 设计应用于固定随访期结束时观察到的二分类结局，并使用比例绝对差值进行分析。我们将该设计应用于结核病（TB）领域，该领域有许多新药正在开发中，并展示了它如何极大地加速新 TB 方案的评估。我们使用模拟来支持方法的扩展，并研究在第一次中期分析时停止随机分组的手臂和继续进行试验最后阶段的手臂中，估计的治疗效果存在的偏差量。
与单独进行 II 期和 III 期试验相比，所提出的无缝 II/III 期 TB 试验设计大大减少了样本量需求和试验持续时间。对最终结果的估计治疗效果的偏差很小，尤其是当治疗选择基于中间结果时，或者在所有招募的患者完成随访后，在计划的试验结束时进行重新分析时。
所提出的设计是实用的，可以在多种疾病领域中使用。它们在加快新疗法的评估方面具有很大的潜力，特别是在结核病领域，许多新方案很快将可用于 II 期和 III 期临床试验的测试。
