Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biometry and Clinical Epidemiology, Charitéplatz 1, Berlin, 10117, Germany.
RPACT GbR, Am Rodenkathen 11, Sereetz, 23611, Germany.
BMC Med Res Methodol. 2024 Oct 17;24(1):242. doi: 10.1186/s12874-024-02363-7.
In group-sequential designs, it is typically assumed that there is no time gap between patient enrollment and outcome measurement in clinical trials. However, in practice, there is usually a lag between the two time points. This can affect the statistical analysis of the data, especially in trials with interim analyses. One approach to address delayed responses has been introduced by Hampson and Jennison (J R Stat Soc Ser B Stat Methodol 75:3-54, 2013), who proposed the use of error-spending stopping boundaries for patient enrollment, followed by critical values to reject the null hypothesis if the stopping boundaries are crossed beforehand. Regarding the choice of a trial design, it is important to consider the efficiency of trial designs, e.g. in terms of the probability of trial success (power) and required resources (sample size and time).
This article aims to shed more light on the performance comparison of group sequential clinical trial designs that account for delayed responses and designs that do not. Suitable performance measures are described and designs are evaluated using the R package rpact. By doing so, we provide insight into global performance measures, discuss the applicability of conditional performance characteristics, and finally whether performance gain justifies the use of complex trial designs that incorporate delayed responses.
We investigated how the delayed response group sequential test (DR-GSD) design proposed by Hampson and Jennison (J R Stat Soc Ser B Stat Methodol 75:3-54, 2013) can be extended to include nonbinding lower recruitment stopping boundaries, illustrating that their original design framework can accommodate both binding and nonbinding rules when additional constraints are imposed. Our findings indicate that the performance enhancements from methods incorporating delayed responses heavily rely on the sample size at interim and the volume of data in the pipeline, with overall performance gains being limited.
This research extends existing literature on group-sequential designs by offering insights into differences in performance. We conclude that, given the overall marginal differences, discussions regarding appropriate trial designs can pivot towards practical considerations of operational feasibility.
在分组序贯设计中，通常假设临床试验中患者入组和结局测量之间没有时间间隔。然而，在实践中，这两个时间点之间通常存在滞后。这会影响数据的统计分析，特别是在具有中期分析的试验中。Hampson 和 Jennison（J R Stat Soc Ser B Stat Methodol 75:3-54, 2013）提出了一种解决延迟反应的方法，他们建议在患者入组时使用误差消耗停止边界，然后在停止边界提前越过时使用临界值拒绝零假设。关于试验设计的选择，重要的是要考虑试验设计的效率，例如试验成功的概率（功效）和所需的资源（样本量和时间）。
本文旨在更深入地了解考虑延迟反应的分组序贯临床试验设计和不考虑延迟反应的设计的性能比较。描述了合适的性能指标，并使用 R 包 rpact 对设计进行了评估。通过这样做，我们深入了解了全局性能指标，讨论了条件性能特征的适用性，最后是否值得使用包含延迟反应的复杂试验设计来提高性能。
我们研究了如何扩展 Hampson 和 Jennison（J R Stat Soc Ser B Stat Methodol 75:3-54, 2013）提出的延迟反应分组序贯检验（DR-GSD）设计，以包括非绑定的较低招募停止边界，说明他们最初的设计框架可以在施加额外约束时容纳绑定和非绑定规则。我们的研究结果表明，包含延迟反应的方法的性能提高在很大程度上取决于中期的样本量和管道中的数据量，总体性能提高有限。
本研究通过提供对性能差异的深入了解，扩展了分组序贯设计的现有文献。我们的结论是，考虑到总体边际差异，关于适当试验设计的讨论可以转向操作可行性的实际考虑。
