Noncompletion and nonpublication of trials studying rare diseases: A cross-sectional analysis

Background Rare diseases affect as many as 60 million people in the United States and Europe. However, most rare diseases lack effective therapies and are in critical need of clinical research. Our objective was to determine the frequency of noncompletion and nonpublication of trials studying rare diseases. Methods and findings We conducted a cross-sectional analysis of randomized clinical trials studying rare diseases as defined by the Genetic and Rare Disease Information Center database that were registered in ClinicalTrials.gov between January 1, 2010, and December 31, 2012, and completed or discontinued by December 31, 2014. Our main outcome measures were the frequency of trial noncompletion and, among completed studies, frequency of trial nonpublication at 2 and 4 years following trial completion. Reasons for discontinuation were extracted from the registry, and trial sponsors were contacted for additional information, as needed. Two independent investigators performed publication searches for each trial in PubMed, EMBASE, and GoogleScholar, allowing for a minimum of 45 months between trial completion and publication. When a publication could not be identified, trial sponsors were contacted to confirm publication status. The impact of funding source on trial noncompletion was assessed with multivariable logistic regression, and the effect on time to publication was examined with Cox proportional hazards regression. Control variables included intervention type, trial phase, masking, enrollment, and study population. We analyzed 659 rare disease trials accounting for 70,305 enrolled patients. Industry was the primary funder for 327 trials (49.6%) and academic institutions for 184 trials (27.9%). There were 79 trials (12.0%) focused on pediatric populations. A total of 199 trials (30.2%) were discontinued. Lack of patient accrual (n = 64, 32.1%) and informative termination (n = 41, 20.6%) were the most common reasons for trial noncompletion. Among completed trials, 306 (66.5%) remained unpublished at 2 years and 142 (31.5%) at 4 years. In multivariable analyses, industry-funded trials were less likely to be discontinued than trials funded by healthcare centers (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.34-4.39, P = 0.003). We found no significant association between funding source and time to publication. A total of 18,148 patients were enrolled in trials that were discontinued or unpublished 4 years after completion. A potential limitation of our study is that certain interventional trials for rare diseases may not have been registered in ClinicalTrials.gov, in particular Phase 0 and Phase I trials, which are not required to be registered. Conclusions In this study, over half of clinical trials initiated for rare diseases were either discontinued or not published 4 years after completion, resulting in large numbers of patients with rare diseases exposed to interventions that did not lead to informative findings. Concerted efforts are needed to ensure that participation of patients in rare disease trials advances scientific knowledge and treatments for rare diseases. Author summaryWhy was this study done? Rare diseases are a group of 7,000 conditions affecting approximately 60 million people in the US and Europe. Many rare diseases begin in childhood and are chronic conditions but lack therapeutic options because of the challenges of conducting trials in these populations. Clinical trial activities for rare diseases, including rates of trial completion and publication, have not been well defined. What did the researchers do and find? We analyzed rare disease trials registered in a clinical trial registry from 2010 to 2012 and determined the frequencies of trial noncompletion and nonpublication through 2018. Among 659 randomized controlled trials, 199 (30.2%) were discontinued, most often because of difficulties with patient accrual. There were 306 (66.5%) trials that were not published 2 years after completion and 142 (31.5%) that remained unpublished 4 years after trial completion. What do these findings mean? In our study, over half of randomized controlled trials studying rare diseases were not completed or were left unpublished 4 years after trial completion, highlighting considerable inefficiencies in research activities for these conditions. Increased focus on establishing global initiatives and networks to coordinate recruitment efforts may be needed, as well as additional mechanisms to ensure timely dissemination of research findings.