Group sequential design for randomized trials using “first hitting time” model

• Published in: Statistics in medicine 2022-06, Vol.41 (13), p.2375-2402
• Main Authors: Chen, Yiming, Lawrence, John, Lee, Mei‐Ling Ting
• Format: Article
• Language: English
• Subjects: Computer Simulation; group sequential design; Humans; interim analysis; Mathematical & Computational Biology; Mathematics; Medical Informatics; non‐proportional hazard; Proportional Hazards Models; Public, Environmental & Occupational Health; Randomized Controlled Trials as Topic; Research & Experimental Medicine; Research Design; Survival Analysis; threshold regression model for survival analysis
• ISSN: 0277-6715; 1097-0258
• DOI: 10.1002/sim.9360

Group sequential design (GSD) has become a popular choice in recent clinical trials as it improves trial efficiency by providing options for early termination. The implementation of traditional tests for survival analysis (eg, the log‐rank test and the Cox proportional hazard (PH) model) in the GSD setting has been widely discussed. The PH assumption is required for conventional (sequential) design, it is, however, often violated in practice. As an alternative, some generalized tests have been proposed (eg, the Max‐Combo test) and their efficacies have been established. In this article, we explore the application of a more flexible, “first hitting time” based threshold regression (TR) model to GSD. TR assumes that subjects' health status is a latent (unobservable) process, and the clinical event of interest occurs when the latent health process hits a pre‐specified boundary. The simulation results supported our findings that, in most cases, this comparable new method can successfully control type I error while providing higher early stopping opportunities in the sequential design, even when non‐proportional hazard presents.