Abstract

Background Intercurrent events in clinical trials can disrupt the interpretation and/or measurement of clinical endpoints. This article focuses on terminal intercurrent events that preclude complete measurement of a longitudinal outcome. When such events are related to the underlying outcome, particularly for physical signs, analyses based only on the available measurements can yield biased estimates. Consequently, a principled methodology is needed to effectively handle these intercurrent events.

Methods We propose a Bayesian joint modeling approach to account for terminal intercurrent events. Our model jointly analyzes longitudinal outcomes and terminal events using shared random effects. We employ multiple discrete-time survival submodels to accommodate different event types and evaluate operating characteristics through extensive simulations that resemble a clinical trial with recovery and death as competing events.

Results The proposed Bayesian joint modeling strategy demonstrates higher power than models that do not account for intercurrent events. Specifically, power increases by approximately 15% when bias due to intercurrent events is substantial and can be reduced by joint modeling.

Conclusion Our Bayesian joint modeling approach effectively addresses terminal intercurrent events in both the design and analysis phases of clinical trials. By explicitly accounting for event-related truncation of longitudinal follow-up, it improves the precision and reliability of treatment effect estimation when outcome measurement is incomplete.