Gao Ping, Liu Lingyun, Mehta Cyrus
The Medicines Company, Parsippany, New Jersey 07054, USA.
Stat Med. 2013 Oct 15;32(23):3991-4005. doi: 10.1002/sim.5847. Epub 2013 May 19.
Methods for controlling the type-1 error of an adaptive group sequential trial were developed in seminal papers by Cui, Hung, and Wang (Biometrics, 1999), Lehmacher and Wassmer (Biometrics, 1999), and Müller and Schäfer (Biometrics, 2001). However, corresponding solutions for the equally important and related problem of parameter estimation at the end of the adaptive trial have not been completely satisfactory. In this paper, a method is provided for computing a two-sided confidence interval having exact coverage, along with a point estimate that is median unbiased for the primary efficacy parameter in a two-arm adaptive group sequential design. The possible adaptations are not only confined to sample size alterations but also include data-dependent changes in the number and spacing of interim looks and changes in the error spending function. The procedure is based on mapping the final test statistic obtained in the modified trial into a corresponding backward image in the original trial. This is an advance on previously available methods, which either produced conservative coverage and no point estimates or provided exact coverage for one-sided intervals only.
崔、洪和王（《生物统计学》，1999年）、莱马赫和瓦斯默（《生物统计学》，1999年）以及米勒和舍费尔（《生物统计学》，2001年）在开创性论文中提出了控制适应性成组序贯试验I型错误的方法。然而，对于适应性试验结束时同样重要且相关的参数估计问题，相应的解决方案并不完全令人满意。本文提供了一种方法，用于计算具有精确覆盖率的双侧置信区间，以及在双臂适应性成组序贯设计中对主要疗效参数中位数无偏的点估计。可能的调整不仅限于样本量的改变，还包括中期观察次数和间隔的数据依赖变化以及误差消耗函数的变化。该程序基于将修改后的试验中获得的最终检验统计量映射到原始试验中的相应反向图像。这是对先前可用方法的改进，先前的方法要么产生保守的覆盖率且无点估计，要么仅为单侧区间提供精确覆盖率。
