Department of Health Statistics and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Preventative Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China.
PLoS One. 2012;7(9):e44013. doi: 10.1371/journal.pone.0044013. Epub 2012 Sep 5.
Group sequential design has been widely applied in clinical trials in the past few decades. The sample size estimation is a vital concern of sponsors and investigators. Especially in the survival group sequential trials, it is a thorny question because of its ambiguous distributional form, censored data and different definition of information time. A practical and easy-to-use simulation-based method is proposed for multi-stage two-arm survival group sequential design in the article and its SAS program is available. Besides the exponential distribution, which is usually assumed for survival data, the Weibull distribution is considered here. The incorporation of the probability of discontinuation in the simulation leads to the more accurate estimate. The assessment indexes calculated in the simulation are helpful to the determination of number and timing of the interim analysis. The use of the method in the survival group sequential trials is illustrated and the effects of the varied shape parameter on the sample size under the Weibull distribution are explored by employing an example. According to the simulation results, a method to estimate the shape parameter of the Weibull distribution is proposed based on the median survival time of the test drug and the hazard ratio, which are prespecified by the investigators and other participants. 10+ simulations are recommended to achieve the robust estimate of the sample size. Furthermore, the method is still applicable in adaptive design if the strategy of sample size scheme determination is adopted when designing or the minor modifications on the program are made.
在过去的几十年中，群组序贯设计已在临床试验中得到广泛应用。样本量估计是赞助商和研究者关注的重要问题。特别是在生存群组序贯试验中，由于其分布形式不明确、存在删失数据以及信息时间的不同定义，这是一个棘手的问题。本文提出了一种实用且易于使用的基于模拟的多阶段两臂生存群组序贯设计方法，并提供了其 SAS 程序。除了通常假设生存数据服从指数分布外，这里还考虑了威布尔分布。在模拟中纳入中断概率会导致更准确的估计。模拟中计算的评估指标有助于确定中间分析的次数和时间。通过一个实例说明了该方法在生存群组序贯试验中的应用，并探讨了不同形状参数对威布尔分布下样本量的影响。根据模拟结果，提出了一种基于受试药物的中位生存时间和风险比（由研究者和其他参与者预先指定）来估计威布尔分布形状参数的方法。建议进行 10 次以上的模拟以实现样本量的稳健估计。此外，如果在设计时采用样本量方案确定策略或对程序进行较小的修改，那么该方法在适应性设计中仍然适用。
