'Waste of energy': One-third of connective tissue disease RCTs never completed, published
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One out of three registered randomized controlled trials on connective tissue diseases are never completed or published, representing a “waste of energy or resources” that may skew meta-analyses, according to researchers.
“Everybody should be aware about the importance of making publicly available the results of randomized controlled trials,” Michele Iudici, MD, PhD, MPH, of Geneva University Hospitals and the University of Geneva, in Switzerland, told Healio. “This is a matter of public health.
“When results are not published researchers cannot aggregate data in meta-analysis, safety concerns about the tested interventions can be hidden, and patient’s participation — that implies generosity form patients who take risks in order to contribute to scientific advancement — is made unfruitful,” Iudici added. “Moreover, since there is the tendency to publish more ‘positive’ — ie, showing treatment is useful against a comparator — than ‘negative’ results, the overall efficacy of treatments whose trials are published is emphasized when data are aggregated in meta-analyses.”
To examine the proportion of randomized controlled trials on connective tissue diseases that are never completed or published, as well as the reasons and factors associated with discontinuation or nonpublication, Iudici and colleagues conducted a search of trials registered in Clinicaltrials.gov since 2000. The researchers included trials on undifferentiated connective tissue disease, systemic sclerosis, systemic lupus erythematosus, Sjögren’s syndrome, dermatomyositis/polymyositis/inclusion body myositis, mixed connective tissue disease and antiphospholipid syndrome.
Inclusion criteria for studies were interventional randomized trials in phase 2/3, 3 or 4, with a completed, suspended, terminated, withdrawn or unknown status. Trial status was defined through the Clinicaltrials.gov glossary. The researchers categorized all studies labeled as terminated, withdrawn or suspended as “discontinued.” Those labeled “unknown” were categorized as completed or discontinued based on whether results were posted on Clinicaltrials.gov or in a peer-reviewed publication. Non-randomized trials and those in recruitment or pre-recruitment status were excluded.
In all, the researchers included 175 trials in their analysis. Most were phase 3, placebo-controlled studies on pharmacologic treatments, enrolling patients with SLE (51%), SSc (20%), Sjögren’s syndrome (12%) or other connective tissue diseases.
When reasons for trial discontinuation were not specified, or when the researchers could not find any publication, they attempted to contact the corresponding author identified in Clinicaltrials.gov directly. If no response was given within 8 weeks, or an email was returned as inactive, the author was deemed uncontactable. Trials were categorized as unpublished if the search process and the email contact failed to provide evidence of publication in a peer-reviewed journal.
According to the researchers, who published their findings in Arthritis Care & Research, 33% of the included studies were discontinued, largely due to insufficient patient accrual, with no differences in discontinuation rates across specific connective tissue diseases (P > .5).
Among the 130 studies with at least one patient, 35% were unpublished, while 65% were published in a peer-reviewed journal following a median of 24 months from completion. There was a significantly higher publication rate among completed studies, at 81%, compared with discontinued studies, at 22% (P < .001).
The researchers were able to obtain reasons for nonpublication for one-third of cases. Among them, small sample size — defined as fewer than 100 participants — was the only factor associated with noncompletion and nonpublication.
“There is an urgent need to identify efficacious treatment for [connective tissue diseases],” Iudici and colleagues wrote. “The failure to complete [randomized controlled trials (RCTs)] represents not only a waste of energy or resources, but negatively impacts on patient’s health. 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.
“Studies with larger patient numbers were more likely to be completed and published, so investment in their delivery is advisable,” they added. “Further research is necessary to determine the optimal interventions to minimize the waste of time and resources due to trial noncompletion and nonpublication.”
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