Investigators are required to submit results to ClinicalTrials.gov within 12 months of completion for National Institutes of Health (NIH)-funded trials. Not all do.
A central reason the law requires researchers to report all trial results is that medical journals tend to publish studies in which the investigational intervention is shown to be superior to the control, according to Carl H. Coleman, JD, professor of law at Seton Hall University.
The ethical concern is researchers, as well as the general public, mostly hear about studies with positive findings. They may not realize there were other studies that showed negative results. “There has been increasing attention to this problem among both ethicists and policymakers,” Coleman says.
A publicly accessible database that includes all study results, both positive and negative, gives the public a more accurate understanding of the current state of scientific knowledge. “Sponsors that fail to report study results undermine this important public health goal,” Coleman says.
While conducting a study on NIH funding of pediatric research and how it aligns with disease burden, Chris A. Rees, MD, MPH, and colleagues read hundreds of grant applications.1 Some of those clinical trials piqued their curiosity, spurring the researchers to look for the published findings. For some of those studies, the results were nowhere to be found. “We were seeing some really cutting-edge work, but the results never got published. That made us wonder how often it happens,” says Rees, research director for the Pediatric Emergency Medicine Fellowship at Emory University School of Medicine.
Rees and colleagues decided to quantify how often NIH-funded pediatric research goes unpublished. The researchers analyzed 413 NIH-funded pediatric clinical trials. They found that lack of prospective trial registration was common.2 Most (85.7%) of the trials were registered on ClinicalTrials.gov, but only 64.1% were prospectively registered.
Many of the researchers failed to submit their study results to ClinicalTrials.gov in a timely manner. Almost half the clinical trial results remain unpublished four years after the study was completed. Of the 323 trials that were completed, 13% of results were submitted to ClinicalTrials.gov within one year. Four years after grant completion, only 54% of the results were published. “Unfortunately, oftentimes investigators aren’t always up to date with registration of their trials,” Rees says. “Very rarely are they posting results in a timely fashion.” The Office of Inspector General conducted its own audit, with similar findings.3
The NIH mandates all clinical trials to be registered on ClinicalTrials.gov. “This provides the opportunity for anybody to go see what type of work is going on for any given disease,” Rees says.
The NIH RePORTER website (https://reporter.nih.gov) provides information on all NIH-funded research. “The NIH does a wonderful job with transparency on what they fund — and also with having policies in place to promote the dissemination of findings of clinical trials in general,” Rees says.
Some policymakers are calling for the NIH to enforce ClinicalTrials.gov reporting requirements.4 “The NIH is aware of this problem and is creating a better system for monitoring if funded trials are being registered and published,” Rees reports.
Although they did not look at the reasons the findings were not reported, Rees says studies with negative findings are harder to publish. But that is changing, according to Rees. “Many journals are doing a good job publishing studies with negative findings,” he observes.
For researchers, it is an ethical imperative to know whether a drug or treatment is beneficial. “You don’t want to waste people’s time, money, and effort — and potentially expose participants to things that are harmful — if we’ve already learned that it doesn’t work in the past,” Rees says.
The publication of results helps fulfill researchers’ ethical obligations to study participants, says Barbara DeCausey, MPH, MBA, director of Virginia Tech’s human research protection program. “Research participants should have access to the results of the study as soon as they are available,” DeCausey argues.
Publishing the results on ClinicalTrials.gov gives researchers a mechanism to do this, without waiting for the results to be published in a journal, to which study participants may not have access. Publishing research results also is a way to instill trust in the research enterprise. “Not reporting compromises that trust,” DeCausey underscores. “Allowing research results to go unreported may send the message that we are not willing to hold researchers accountable.”
Why do researchers fail to submit their clinical trials results in a timely manner? “The ClinicalTrials.gov system is not user-friendly, and not very intuitive,” DeCausey offers.
Researchers often struggle to navigate the system and have to work with the Protocol Registration and Results System administrator to resolve any problems. While there are civil money penalties for failure to report, only four notices of noncompliance have been issued to date.5 None have resulted in financial penalties.
“Lack of enforcement of the requirement also contributes to the problem,” DeCausey adds.
Failure to make study findings publicly available in a timely fashion can contribute to bias in the scientific knowledge base, warns Nora Hutchinson, MDCM, MPhil, a postdoctoral research fellow at The Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard. If studies with a positive result on the primary outcome are more likely to be published than studies with a negative result, this can lead to an overestimation of treatment effects.
“In addition, failure to report study results promptly can limit the ability of future investigators to build upon knowledge generated from prior research,” Hutchinson adds.
This leads to duplication of research efforts and misuse of scarce resources. “While the deposition of study results on ClinicalTrials.gov may be seen as an administrative burden by researchers, it should be hailed as an important contribution to science that improves the robustness and health of the scientific enterprise,” Hutchinson argues.
REFERENCES
1. Rees CA, Monuteaux MC, Herdell V, et al. Correlation between National Institutes of Health funding for pediatric research and pediatric disease burden in the US. JAMA Pediatr 2021;175:1236-1243.
2. Rees CA, Narang C, Westbrook A, Bourgeois FT. Dissemination of the results of pediatric clinical trials funded by the US National Institutes of Health. JAMA 2023;329:590-592.
3. Office of Inspector General. The National Institutes of Health did not ensure that all clinical trials were reported in accordance with federal requirements. Aug. 12, 2022.
4. House Committee on Energy and Commerce. Letter to the Food & Drug Administration and the National Institutes of Health. Jan. 19, 2023.
5. U.S. Food & Drug Administration. ClinicalTrials.gov - Notices of noncompliance and civil money penalty actions. Content current as of Aug. 2, 2022.
Further, this can contribute to bias in the scientific knowledge base, limit the ability of future investigators to build on knowledge generated from prior research, and lead to duplication of research efforts and misuse of scarce resources.
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