Endpoint Exposure‐Response Analyses in the Presence of Concurrent Dose Modification During Clinical Trials

Exposure‐response (E‐R) analyses are essential for dose selection in drug development, yet conventional endpoint E‐R approaches often overlook concurrent clinical events such as adverse event (AE)‐driven dose modifications (DMs), potentially leading to biased or misleading conclusions. In this study, we developed a framework to quantify the impact of AE‐driven DMs on endpoint E‐R relationships and to explore strategies to improve their accuracy. Using duvelisib as an exemplar, a drug known for frequent DMs due to Grade ≥ 3 infections, pneumonia, or transaminase elevations, we evaluated E‐R relationships under three scenarios: ground truth, conventional E‐R (based on planned dose exposures), and DM‐adjusted E‐R (accounting for AE‐induced DMs and resultant exposure changes). Our analyses showed that conventional E‐R analyses often deviated substantially from the ground truth at frequent DMs, particularly for AEs with delayed onset. Early‐onset AEs and their resultant DMs could significantly distort E‐R relationships for subsequent AEs. DM‐adjusted E‐R analyses better approximate the ground truth, especially for late‐occurring AEs, but may introduce a risk of overcorrection of early‐occurring AEs. These findings highlight the critical need to incorporate the timing and nature of AEs into E‐R analyses to ensure robust interpretation, particularly in settings where DMs are frequent.