Understanding late-stage clinical trial failure in multiple sclerosis: insights from ClinicalTrials.gov

INTRODUCTION: Clinical trial failure -when a study is withdrawn or terminated for reasons unrelated to safety or efficacy- wastes resources and exposes patients to unnecessary risks. We examined such failures in the field of multiple sclerosis (MS). METHODS: We searched ClinicalTrials.gov for phase III and IV MS drug trials conducted in 2008-2024. Trials were classified as normally ended or failed based on recruitment status and reported reasons. When information was missing, we reviewed publications and contacted principal investigators (PIs). Kaplan-Meier method was used to assess time to trial end and multivariate logistic regression was used to identify factors associated with failure. RESULTS: The 282 clinical trials included in our analysis involved 62 experimental drugs, primarily disease-modifying therapies (n=213 trials). Most studies aimed to evaluate drug efficacy (n=197 trials). Overall, 74.8% of trials ended normally while 25.2% failed. On average, failed trials ended ten months earlier than the rest of studies (trial actual duration: 17.8 vs. 28.2 months, p<0.001). Main reasons for failure were low recruitment (28.2%), unspecified business decisions (26.8%), and logistical problems (12.7%). In 28.2% of occasions it remained undisclosed. Trials evaluating drug safety (OR 0.35, 95%CI 0.13-0.94) and those with ≥50 participating centres (OR 0.10, 95%CI 0.02-0.38) seemed to have a lower risk of failure. Failure was not significantly associated with other factors such as study start date, PI location, or industry involvement. CONCLUSION: One out of four late-stage MS clinical trials fails. Increasing the number of study sites and improving recruitment strategies could enhance their success rates.