Assessing the impact of safety monitoring on the efficacy analysis in large Phase III group sequential trials with non-trivial safety event rate

作者：Weng Yanqiu^*; Palesch Yuko Y; DeSantis Stacia M; Zhao Wenle

来源：Journal of Biopharmaceutical Statistics, 2016, 26(4): 672-685.

DOI：10.1080/10543406.2015.1052473

• Data and safety monitoring committee
• efficacy
• group sequential design
• power
• safety
• Type I error

In Phase III clinical trials for life-threatening conditions, some serious but expected adverse events, such as early deaths or congestive heart failure, are often treated as the secondary or co-primary endpoint, and are closely monitored by the Data and Safety Monitoring Committee (DSMC). A naive group sequential design (GSD) for such a study is to specify univariate statistical boundaries for the efficacy and safety endpoints separately, and then implement the two boundaries during the study, even though the two endpoints are typically correlated. One problem with this naive design, which has been noted in the statistical literature, is the potential loss of power. In this article, we develop an analytical tool to evaluate this negative impact for trials with non-trivial safety event rates, particularly when the safety monitoring is informal. Using a bivariate binary power function for the GSD with a random-effect component to account for subjective decision-making in safety monitoring, we demonstrate how, under common conditions, the power loss in the naive design can be substantial. This tool may be helpful to entities such as the DSMCs when they wish to deviate from the prespecified stopping boundaries based on safety measures.

• 出版日期2016