Hartung Joachim, Knapp Guido
Department of Statistics, University of Dortmund, 44221 Dortmund, Germany.
Biom J. 2006 Aug;48(4):697-709. doi: 10.1002/bimj.200510213.
In self-designing clinical trials, repeated confidence intervals are derived for the parameter of interest where the results of the independent study stages are combined using the generalized inverse chi-square-method. The confidence intervals can be calculated at each interim analysis and always hold the predefined overall nominal confidence level. Moreover, the confidence intervals calculated during the course of the trial are nested in the sense that a calculated interval is completely contained in all the previously calculated intervals. During the course of the self-designing trial the sample sizes as well as the number of study stages can be determined simultaneously in a completely adaptive way. The adaptive procedure allows an early stop for significance. The clinical trial may be originally designed either to show noninferiority or superiority. However, in each interim analysis, it is possible to change the planning from showing superiority to showing noninferiority or vice versa. Since the repeated confidence intervals are nested, there is no risk to loose the noninferiority once showed when, after an interim analysis, the trial is continued in an attempt to reach superiority. A simulation study investigates the behavior of the considered confidence intervals. The performance of the derived nested repeated confidence intervals is also demonstrated in examples showing both kinds of switching during an ongoing trial.
在自行设计的临床试验中，针对感兴趣的参数得出重复的置信区间，其中独立研究阶段的结果使用广义逆卡方方法进行合并。可以在每次期中分析时计算置信区间，并且始终保持预定义的总体名义置信水平。此外，在试验过程中计算的置信区间具有嵌套性，即计算出的区间完全包含在所有先前计算的区间内。在自行设计的试验过程中，可以以完全自适应的方式同时确定样本量和研究阶段数。自适应程序允许提前停止以判定显著性。临床试验最初可以设计为显示非劣效性或优效性。然而，在每次期中分析时，可以将计划从显示优效性改为显示非劣效性，反之亦然。由于重复的置信区间是嵌套的，因此在期中分析后继续试验以试图达到优效性时，一旦显示出非劣效性，就不存在失去非劣效性的风险。一项模拟研究调查了所考虑的置信区间的行为。在正在进行的试验中显示两种转换类型的示例中，也展示了所推导的嵌套重复置信区间的性能。
