One Third of Connective Tissue Diseases Trials Go Unpublished

Heidi Splete

January 21, 2022

Approximately one-third of registered randomized, controlled trials for connective tissue diseases are incomplete or unpublished, based on data from 175 studies.

"The failure to complete a trial is a waste of time and money, and a missed opportunity to contribute to patient's health," Alejandro Brigante, MD, of the Internal Medicine–Rheumatology service at Güemes Sanitorium in Buenos Aires, and colleagues wrote.

Patients with connective tissue diseases (CTDs) experience high levels of disability, poor quality of life, and poor survival, and more randomized, controlled trials are needed to explore treatment options, they said.

In a study published in Arthritis Care & Research, the researchers examined factors leading to the failure of CTD studies. They identified 175 studies of CTDs registered at clinicaltrials.gov since 2000. Most of the studies were phase 3, placebo-controlled trials involving pharmacologic treatments; 117 (67%) were identified as completed, 58 (33%) were identified as discontinued. Approximately half (51%) of the studies involved systemic lupus erythematosus, and half were funded by industry. The median sample size planned for the studies was 101 patients, and 83 studies stated a plan to recruit less than 100 patients.

Of the 58 discontinued trials, 12 were withdrawn, 33 were terminated, and 13 had an unknown status. These trials represented a potential enrollment of 11,389 patients, 31% of the estimated number of patients across all 175 studies.

The researchers found identified reasons for discontinuation for 39 of the 58 discontinued trials. The main reasons included insufficient patient accrual in 11 trials, interim results showing futility (8 trials), safety concerns (5 trials), funding issues (5 trials), conduct problems (4 trials), company decisions (2 trials), administrative reasons (2 trials), and departure of the principal investigator (1 trial); the reason for discontinuation was unclear in 1 trial. Discontinuation rates were not significantly different across disease types.

"By subtracting from the 58 discontinued trials the 13 studies for which early termination was justified (e.g., discontinuation for futility or safety concerns), we considered 45 (26%) trials prematurely terminated," the researchers wrote. Overall, completed studies were less likely than discontinued studies to have a placebo group, and they had longer treatment periods to evaluate primary outcomes. A sample size of less than 100 patients was the only factor significantly associated with early study termination (odds ratio, 2.1), after controlling for multiple variables.

The researchers checked the publication status of 130 studies, including 94 completed and 36 discontinued randomized, controlled trials. Of these, 44 were unpublished and 86 were published in a peer-reviewed journal at a median of 24 months after study completion. The publication rate was significantly higher for completed studies, compared with discontinued studies (81% vs. 22%), and the rates were not significantly different among diseases. The main reasons for nonpublication included poor recruitment, study rejection and preparation for resubmission, lack of time, low priority, and the fact that the study was ongoing. A sample size of less than 100 patients was the main barrier to publication for completed studies.

The study findings were limited by several factors including selection bias and inability to study factors, such as study complexity or the nature of interventions that might have affected trial completion, the researchers noted. Other limitations include a lack of data on negative results and the possible missed publication of some of the studies.

However, the results illustrate the waste of resources in CTD trials, which are needed to identify effective treatments for these patients, the researchers said. "A better understanding of the factors leading to waste will guide future allocation of resources and could help to maximize the successful conduct of RCTs."

More research is needed to determine the most effective interventions and reduce the risk of trial noncompletion and nonpublication, they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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