A simple and flexible graphical approach for adaptive group-sequential clinical trials.
In this article, we introduce a graphical approach to testing multiple hypotheses in group-sequential clinical trials allowing for midterm design modifications. It is intended for structured study objectives in adaptive clinical trials and extends the graphical group-sequential designs from Maurer and Bretz (Statistics in Biopharmaceutical Research 2013; 5: 311-320) to adaptive trial designs. The resulting test strategies can be visualized graphically and performed iteratively. We illustrate the methodology with two examples from our clinical trial practice. First, we consider a three-armed gold-standard trial with the option to reallocate patients to either the test drug or the active control group, while stopping the recruitment of patients to placebo, after having demonstrated superiority of the test drug over placebo at an interim analysis. Second, we consider a confirmatory two-stage adaptive design with treatment selection at interim.
a Section for Medical Statistics, Medical University of Vienna , Vienna , Austria.
Toshifumi
T
Sugitani
b Novartis Pharma AG , Basel , Switzerland.|c Shanghai University of Finance and Economics , Shanghai , Peoples Republic of China.
Frank
F
Bretz
b Novartis Pharma AG , Basel , Switzerland.
Willi
W
Maurer
D000465:Algorithms; D002986:Clinical Trials as Topic / Q000379:methods / Q000706:statistics & numerical data; D003196:Computer Graphics; D006801:Humans; D015233:Models, Statistical; D012107:Research Design / Q000706:statistics & numerical data*; D018401:Sample Size
Adaptive design; closed test procedure; group-sequential design; inverse normal combination test; sample size reassessment