Shun Zhenming, Lan K K Gordon, Soo Yuhwen
Sanofi-Aventis, Bridgewater, NJ 08807, USA.
Stat Med. 2008 Feb 20;27(4):597-618. doi: 10.1002/sim.2990.
We consider a study starting with two treatment groups and a control group with a planned interim analysis. The inferior treatment group will be dropped after the interim analysis, and only the winning treatment and the control will continue to the end of the study. This 'Two-Stage Winner Design' is based on the concepts of multiple comparison, adaptive design, and winner selection. In a study with such a design, there is less multiplicity, but more adaptability if the interim selection is performed at an early stage. If the interim selection is performed close to the end of the study, the situation becomes the conventional multiple comparison where Dunnett's method may be applied. The unconditional distribution of the final test statistic from the 'winner' treatment is no longer normal, the exact distribution of which is provided in this paper, but numerical integration is needed for its calculation. To avoid complex computations, we propose a normal approximation approach to calculate the type I error, the power, the point estimate, and the confidence intervals. Due to the well understood and attractive properties of the normal distribution, the 'Winner Design' can be easily planned and adequately executed, which is demonstrated by an example. We also provide detailed discussion on how the proposed design should be practically implemented by optimizing the timing of the interim look and the probability of winner selection.
我们考虑一项研究，该研究从两个治疗组和一个对照组开始，并计划进行中期分析。在中期分析后，较差的治疗组将被淘汰，只有胜出的治疗组和对照组将继续到研究结束。这种“两阶段胜者设计”基于多重比较、适应性设计和胜者选择的概念。在具有这种设计的研究中，如果在早期阶段进行中期选择，多重性会降低，但适应性会更强。如果在研究接近结束时进行中期选择，情况就会变成传统的多重比较，此时可以应用邓尼特方法。来自“胜者”治疗组的最终检验统计量的无条件分布不再是正态分布，本文给出了其精确分布，但计算需要数值积分。为避免复杂计算，我们提出一种正态近似方法来计算I型错误、检验效能、点估计和置信区间。由于正态分布具有广为人知且吸引人的性质，“胜者设计”可以很容易地进行规划和充分实施，本文通过一个例子进行了说明。我们还详细讨论了如何通过优化中期查看的时间和胜者选择的概率来实际实施所提出的设计。
