NEW YORK (Reuters Health)—Results from a substantial proportion of large, registered, randomized controlled trials (RCTs) can go unpublished for years after their completion, researchers report.
“These unpublished and unreported trials include a vast number of patients, about 90,000,” Dr. John P. A. Ioannidis from Stanford University in California told Reuters Health. “Many people think that trials that are not reported are small ones, but here we found many very large trials which are still not communicated.”
Dr. Ioannidis and colleagues sought to identify the largest preregistered RCTs that were completed before June 1, 2012 and were still both unpublished and lacked reported results at ClinicalTrials.gov as of April 22, 2016. They selected the largest 500 trials in terms of participant enrollment.
Among these 500 trials, 146 did not have main publications listed or results posted, although 60 had in fact been published by that time and two additional trials had duplicate ClinicalTrials.gov records, leaving 84 trials that were unreported as of April 2016.
Of these 84 unreported trials, 14 (17%) were published in the ensuing 32 months, by January 2019.
The researchers contacted 29 researchers whose email addresses they found: 15 replied, and two responded that their RCT was published in 2011.
Results of only 3 of the 70 long-unreported studies were posted on ClinicalTrials.gov as of January 2019. The 67 long-unreported trials had a median enrollment of 765 patients and were unreported for a median 9 years after completion, according to the May 7th Annals of Internal Medicine online report.
Among 10 trials randomly selected from these 70, the researchers found larger studies for only one treatment for the same disease and condition (eplivanserin for insomnia), and that study had negative results and led to a licensing application withdrawal.
“For medical areas and interventions where large trials remain unpublished, one should be very skeptical about what the published results mean, since the missing part may be a large share of the evidence,” Dr. Ioannidis said in an email.
“Physicians should be sensitized to the existence of this dark side of the moon,” he said. “When they read meta-analyses or guidelines based on them, they should see whether these meta-analyses and guidelines have explored and reported on the existence of such unpublished trials.”
“We need more transparency to build our trust on evidence,” Dr. Ioannidis said.
Dr. Harlan M. Krumholz from Yale School of Medicine, Yale School of Public Health, and Yale-New Haven Hospital, New Haven, Connecticut, who co-authored an editorial related to this report, told Reuters Health by email, “I am hopeful that we are getting to a tipping point – many trials, large and small, across academia and industry, involving NIH and non-NIH funded efforts, do not have their results in the public domain – even many years after their completion. This is wasteful of research dollars, disrespectful of patients, unfaithful to the ethics of science, and a threat to the integrity of the medical literature. The moment is ripe for change.”
“In reviews of the literature, [physicians] should be looking for information about what research was done but never reported,” he said. “The registration of studies at least provides the ability to have a sense of the magnitude of what is kept from the public eye.”
The editorial, co-authored by Dr. Joshua D. Wallach, suggests, “Several potential approaches may be taken to ensure that clinical trial results become publicly available. First and foremost, nonreporting should be considered academic misconduct. Institutions should suspend investigators who do not report results within a year of finishing a trial, unless extenuating circumstances exist that impede reporting. These institutions also should consider lack of reporting in the academic promotion process.”
“Funding agencies, such as the NIH, should withhold support from researchers who fail to report results,” they write. “Investigators who have completed clinical trials without reported results should be prohibited from applying for additional grants, and their current grants should be suspended. An even stronger incentive would be to hold institutions accountable for reporting results.”
“Lastly,” they conclude, “the public must be made aware of the ongoing gaps in the reporting of clinical trial results by dissemination of a list of completed clinical trials without reported results. Together, these efforts may ensure that all stakeholders in clinical research fulfill their ethical obligations to trial participants.”
References
- Tatsioni A, Karassa FB, Goodman SN, et al. Lost Evidence From Registered Large Long-Unpublished Randomized Controlled Trials: A Survey. Ann Intern Med. 2019 May 7. [Epub ahead of print]
- Wallach JD, Krumholz HM. Not Reporting Results of a Clinical Trial Is Academic Misconduct. Ann Intern Med. 2019 May 7. [Epub ahead of print]