Barriers to completion: Investigating determinants of premature discontinuation in biliary tract cancer clinical trials.

28 Background: Biliary tract cancers (BTC) are a rare and deadly group of malignancies with a rising incidence globally. Despite diagnostic and therapeutic advances, outcomes among patients with BTC remain suboptimal. As with other rare cancers, conducting clinical trials in BTC poses several challenges, including limited patient populations, complex trial logistics, and constrained resources across multiple sites. Here, we sought to investigate premature discontinuation in BTC clinical trials to better understand the challenges associated with studying BTC. Methods: We conducted a comprehensive search of the ClinicalTrials.gov registry to identify all clinical trials investigating BTC (1/1/2000-12/31/2024). These were classified by design allocation, intervention, location, phase, sponsor, single vs. multicenter, date of initiation, enrollment, and duration. Trials with premature discontinuation were analyzed for reasons for termination. Univariate and multivariate logistic regression was used to compare completed and terminated clinical trials to identify factors associated with early termination. A p-value < 0.05 was considered statistically significant. Results: Among 160 trials identified, 46 (28.8%) were terminated prematurely. Of these, the majority were phase 2 (28, 60.9%) followed by phase 3 (11, 23.9%) and phase 1 (4, 8.7%). Leading funding sources for terminated trials were industry (20, 43.5%) followed by academic (17, 37%) and National Cancer Institute (6, 13%). The leading reasons for termination were poor accrual (21, 45.7%), followed by futility (7, 15.2%) and sponsor decision (6, 13.0%). We did not identify a trend in trial termination by year (2000-2024, p = 0.58) or sponsor (p = 0.54). On univariate logistic regression, phase 3 trials were less likely to be completed than phase 1/2 trials (OR = 0.36, CI: 0.14 - 0.93, p < 0.05). International trials excluding the US were more likely to be completed than international trials including the US (OR = 5.51, CI: 1.99 - 15.96, p < 0.01). US only trials were more likely to be completed than international trials including the US (OR = 3.02, CI: 1.10 - 8.59, p < 0.05). On multivariate logistic regression, the only statistically significant predictor of trial completion was trials that recruited internationally excluding the US (OR = 3.59, CI: 1.22 - 10.83, p < 0.05). Conclusions: Premature discontinuation impacts nearly a third of BTC clinical trials with poor accrual as the leading cause. Phase 3 trials and those enrolling patients internationally, particularly with U.S. involvement, were associated with risk for early termination. These results highlight persistent structural challenges in conducting clinical trials in rare cancers. Our findings may inform implementation science frameworks and support systems-level changes aimed at optimizing trial design and improving research efficiency in BTC.