Noninferiority trial design with survival outcome for nonproportional hazards with Relative Time

Music City Center 

Non-inferiority (NI) clinical trials are designed to determine whether a new treatment is not substantially worse than an existing standard treatment by a small, predefined margin. These trials are important when the new intervention offers other advantages, such as improved safety, fewer side effects, greater convenience, or cost-effectiveness, while maintaining comparable efficacy to the standard treatment. While extensive methodologies exist for sample size determination in NI trials with continuous or binary outcomes, approaches for time-to-event (TTE) outcomes have traditionally relied on the assumptions of proportional hazards or exponentially distributed survival times. Among these, the fixed margin method is commonly implemented in statistical software, whereas the synthesis method remains underutilized due to its complexity. In this paper, we develop sample size calculation techniques for both the fixed margin and synthesis methods within a non-proportional hazard framework, employing the concept of proportional time for two independent arms following Weibull distributions. Comprehensive simulation studies support the validity and robustness of our proposed approaches.

Non-interiority

Non-proportional hazards

Relative time

Time-to-event

Weibull

Clinical trials 

Biopharmaceutical Section