‘Betraying Trust’ of Subjects is Ethical Concern of Unpublished Clinical Trial Data
EXECUTIVE SUMMARY
A growing body of research demonstrates that many completed clinical trials are not published. Ethicists call for research funders to require publication of all completed trials, or to make study data publicly available to other investigators. Ethical concerns include the following:
- Study participants are needlessly exposed to potential harm.
- The resulting knowledge can’t benefit future patients.
- Trials with favorable results are more likely to be published.
About a third of all clinical trials conducted in the United States go unpublished, a recent study reported.1 This is a serious ethical issue, according to Joseph Solomon Ross, MD, MHS, one of the study’s authors. Ross is associate professor of medicine at Yale School of Medicine’s Institute for Social and Policy Studies in New Haven, CT.
One problem is that participants exposed themselves to potential risks, at least in part, so everyone might benefit in the future. “The researchers are betraying the trust of the individuals who volunteered to participate in the trials,” Ross says.
Researchers analyzed 4,347 trials at 51 major research centers, which were completed in 2007 to 2010. Just 29% had been published two years after completion, and only 13% of the results had been submitted to ClinicalTrials.gov. As of July 2014, only 66.5% had either been published or reported on ClinicalTrials.gov.
Previous research uncovered similar poor dissemination rates. Less than half (46%) of 635 National Institutes of Health (NIH)-funded trials were published in a peer-reviewed biomedical journal within 30 months of completion, found one study.2 Another study found no results published in journals for 29% of nearly 600 trials registered on ClinicalTrials.gov.3 The study looked at only very large clinical trials. “This shows that the problem of non-publication is not just limited to small pilot studies, but affects even large-scale, resource-intensive trials,” says lead author Christopher Jones, MD. Jones, head of the division of clinical research in the department of emergency medicine at Cooper University Hospital in Camden, NJ, argues, “There is clearly an ethical obligation to make clinical trial results publicly available.”
Another recent study looked at publication rates of studies which enrolled children. The findings were in line with the previous research on adult trials.4 “This may speak to how commonplace discontinuation and non-publication are in medical research in general,” says co-author Natalie Pica, MD, PhD, a resident at Boston Children’s Hospital.
Researchers found that 19% of trials started in 2008 to 2010 that recruited children were not completed. Often, this was because researchers weren’t able to recruit enough volunteers. Of the 455 trials that were completed, 19% were discontinued early. About one-third (30%) remained unpublished in the medical literature several years later. “We believe that researchers have an ethical obligation to publish the findings of completed trials, regardless of the study findings,” says Pica.
Overall, more than 8,000 children were enrolled in trials that were never completed. Over 69,000 children were enrolled in completed trials that were never published.
Senior investigator Florence Bourgeois, MD, MPH, an assistant professor of pediatrics and emergency medicine at Boston Children’s, says, “We need to make sure that when children participate in clinical trials, their efforts are contributing to broader scientific knowledge.”
The following are ethical concerns of completed trials going unpublished:
• Part of the reason patients choose to participate in clinical research is because they hope it will improve care for future patients.
This expectation is often explicitly included during the informed consent process. “When trial results are not publicly disseminated, this knowledge cannot be used by clinicians and researchers to help improve the care of other patients,” says Jones.
• Study participants can be subjected to potential risks, inconveniences, costs, and occasional true harms.
“When investigators fail to make trial results publicly available, these consequences are not balanced by the opportunity to help improve the care of future patients,” says Jones.
• Trials which reflect positively on a particular intervention are more likely to be published than trials which are not favorable.
“This publication bias can lead patients and clinicians to make medical decisions which result in wasted time and money, as well as poor health outcomes,” says Jones.
Ideally, treatment recommendations are based on a comprehensive understanding of the existing medical research. “When trial results are not publicly disseminated, this becomes impossible,” says Jones.
• Future progress in medical research depends on the reliability of previous studies.
“When researchers do not have access to all of this foundational work, substantial time and money can be wasted pursuing research which is based on flawed assumptions,” says Jones.
Future Developments
The growing body of research on unpublished clinical trials is raising awareness of the importance of disseminating research findings, Ross says. “The question is no longer whether it’s okay for researchers not to disseminate their results, but what should be done about it,” he says. The following are some recent developments in the area and possible solutions:
• Many major pharmaceutical companies have enacted policies promoting the publication of all clinical research they fund.
“I think the next step is for other large funders to follow suit, and establish requirements that researchers publish findings from all completed clinical trials,” says Ross. This includes the NIH, CDC, and the U.S. Department of Veterans Affairs, he says.
• ClinicalTrials.gov enabled the medical community to detect and quantify the problem of non-publication.
“Unfortunately, the problem still persists,” says Jones.
• A number of regulatory agencies and funding organizations have policies on using trial registries to ensure that results are consistently publicly disseminated.
“Enforcement of these policies has been inconsistent,” notes Jones.
• The International Committee of Medical Journal Editors and the NIH continue to push for improved ways of disseminating research results.5,6
• The World Health Organization’s recent position statement calls for prompt reporting and public disclosure of interventional clinical trial results.7
“Continued progress will likely depend on more consistent enforcement of existing policies,” Jones says.
• The Restoring Invisible and Abandoned Trials (RIAT) initiative invites researchers with unpublished trials to either commit to publish within a year, or provide public access to their data.
This allows independent investigators to step in and become “restorative authors.” Pica acknowledges that it’s hard to reanalyze others’ data, “but this may be a useful mechanism to make sure that findings from completed trials are disseminated in the medical literature.”
• Groups such as AllTrials have called the public’s attention to the issue.
“As this awareness continues to grow, investigators and study sponsors will face increasing pressure to consistently release trial results,” says Jones.
REFERENCES
- Chen R, Desai NR, Ross JS. Publication and reporting of clinical trial results: cross sectional analysis across academic medical centers. BMJ 2016; 352:i637.
- Ross JS, Tse T, Zarin DA, et al. Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis. BMJ 2012; 344:d7292.
- Jones CW, Handler L, Crowell, KE, et al. Non-publication of large randomized clinical trials: cross sectional analysis. BMJ 2013; 347:f6104.
- Pica N, Bourgeois F. Discontinuation and nonpublication of randomized clinical trials conducted in children. Pediatrics 2016 Aug 4. pii: e20160223. [Epub ahead of print].
- Taichman DB, Backus J, Baethge C, et al. Sharing clinical trial data: A proposal from the International Committee of Medical Journal Editors. Ann Intern Med 2016. doi:10.7326/M15-2928.
- Institute of Medicine. Sharing clinical trial data: Maximizing benefits, minimizing risk. Washington, DC: National Academies Press; 2015.
- Moorthy VS, Karam G, Vannice KS, et al. Rationale for WHO’s new position calling for prompt reporting and public disclosure of interventional clinical trial results. PLoS Med 2015: 12(4): e1001819.
SOURCES
- Christopher Jones, MD, Head, Division of Clinical Research, Department of Emergency Medicine, Cooper University Hospital, Camden, NJ. Email: [email protected].
- Joseph Solomon Ross, MD, MHS, Associate Professor of Medicine, Institute for Social and Policy Studies, Yale School of Medicine, New Haven, CT. Phone: (203) 785-2987. Fax: (203) 737-3306. Email: [email protected].
- Natalie Pica, MD, PhD, Boston (MA) Children’s Hospital. Email: [email protected].
- Florence Bourgeois, MD, MPH, Assistant Professor, Pediatrics/Emergency Medicine, Boston Children’s Hospital. Email: [email protected].
Ethicists call for research funders to require publication of all completed trials or to make study data publicly available to other investigators.
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