TITE-safety: a robust time-to-event safety monitoring approach for clinical trials.

Safety evaluation is an essential component of clinical trials. To protect study participants, these studies often implement safety stopping rules that will halt the trial if an excessive number of toxicity events occur. Existing safety monitoring methods usually treat these events as binary outcomes. A strategy that instead handles these as time-to-event (TITE) endpoints can offer higher power and a reduced time to signal of excess risk, but must manage additional complexities including censoring and competing risks. We propose the TITE-safety approach for safety monitoring, which incorporates TITE information while handling repeated analyses, censored observations, and competing risks appropriately. This strategy is applied to develop stopping rules using score tests, Bayesian beta-extended binomial models, and sequential probability ratio tests. Operating characteristics of these methods are studied via simulation for common phase 2 and 3 trial scenarios. Across simulation settings, the proposed techniques offer reductions in expected toxicities of 20% or more compared to binary data methods and maintain the type I error rate near the nominal level for various event time distributions. These methods are demonstrated through a redesign of the safety monitoring scheme for Blood and Marrow Transplant Clinical Trials Network 0601, a single arm, phase 2 trial that evaluated bone marrow transplant as treatment for sickle cell disease. Our R package "stoppingrule" offers functions to construct and evaluate these stopping rules, providing valuable tools for trial design to investigators.