January 16, 2020
Study Shows More Than Half of United States Clinical Trials Fail to Comply With Law on Reporting Results
January 17, 2020—The Lancet announced the publication of a study finding that only 41% of clinical trial results are reported promptly onto the United States trial registry, and one in three trials remain unreported. The journal advised that this is the first comprehensive study of compliance since new United States regulations went into effect in January 2017. The study by Nicholas J. DeVito, MPH, et al is available online ahead of print in The Lancet.
According to the announcement, the findings indicate that trials with nonindustry sponsors (eg, universities, hospitals, and governments) are far more likely to breach the rules than trials sponsored by industry, with United States government–sponsored trials the least likely to post results on time via the world’s largest clinical trial registry, the FDA’s ClinicalTrials.gov.
The background of the study is that it has been known for several decades that the results of clinical trials are often not fully reported. The US Food and Drug Administration Amendment Act (FDAAA) of 2007 was legislated to improve public disclosure and limit selective publishing of results by requiring sponsors of most FDA-regulated clinical trials to register and report results on ClinicalTrials.gov within 12 months of primary completion, irrespective of whether the results are positive or negative.
A subsequent “Final Rule” to the Act took effect in January 2017, which introduced clearer reporting requirements including fines of up to $10,000 per day for noncompliance (now $12,103 with adjusted inflation). Leaders at the National Institutes of Health said that the Final Rule would result in “rapid increases” in the percentage of trials registered and shared on the United States registry, reported The Lancet.
The authors of the study advised that the high rates of noncompliance found in the new study likely reflect the lack of enforcement by regulators, and they call for trial sponsors to be held to account by the FDA.
Ben Goldacre, MBBS, who led the study, commented in The Lancet announcement, “Patients and clinicians cannot make informed choices about which treatments work best when trial results are routinely withheld. Clinical trials are not abstract research projects: they are large, expensive, practical evaluations that directly impact on patient care by informing treatment guidelines and evidence reviews.” He continued, “Sponsors are breaching their legal obligations, but also their ethical obligations to the patients who generously participate in clinical trials. Our study has identified over 2,400 trials breaching the rules, but to our knowledge the FDA has never levied a single fine or other enforcement action, despite all the levers available to them. Compliance will only improve when action is taken.”
The announcement further noted that nonreporting of clinical trial results has been well documented since the 1980s, especially those trials finding no evidence of effectiveness for the treatment being tested. However, failing to disclose trial results threatens the integrity of the evidence base of all clinical medicine, breaches participants’ trust, and wastes valuable research resources.
As summarized in The Lancet press release, the first trials covered by the Final Rule were due to report in January 2018. To investigate the extent of compliance with these new reporting requirements, the investigators examined all 4,209 trials registered on ClinicalTrials.gov that were legally required to report results between March 2018 and September 2019. They also assessed trends in compliance, factors associated with compliance, and ranked individual sponsors according to their level of compliance.
Of the completed trials included in the study, approximately half (52%; 2,178) had nonindustry sponsors, most involved a drug intervention (71%; 2,968), and most were solely conducted in the United States (71%; 3,000). Analyses found that only 41% (1,722/4,209) of completed clinical trials reported results within the 1-year legal deadline, whereas 36% (1,523/4,209) still had not been reported by September 16, 2019. Moreover, progress has stalled—the proportion of compliant trials has remained stable since July 2018. The median delay from completion to submitting results was 424 days, which is 59 days longer than the legal reporting requirement of 1 year. Trials with an industry sponsor were much more likely to comply with the law than those with a nonindustry or United States government sponsor (50% vs 34% vs 31%, respectively).
Better performance was also seen among sponsors with more experience in running large numbers of trials, when compared with those who have only run a very small number of projects (66% vs 21%). The authors noted that this suggests that “research experience and robust internal governance processes can contribute to improved performance.”
Further analyses estimate that had the law been strictly enforced, over $4 billion in fines could have been collected up to the end of September 2019. Dr. DeVito, who is from Oxford University in Oxford, United Kingdom, stated, “Over 4 decades since nonreporting of clinical trials was first reported, it is disappointing to see that we have only progressed to legislation being passed, and then largely ignored. The fact that the United States government cannot comply with its own laws is particularly concerning.” He continued, “Until effective enforcement action is taken, public audit may help. We have established an openly accessible public website at fdaaa.trialstracker.net where fresh data on compliance with FDAAA will be posted every day, identifying each individual overdue trial, and compliance statistics for each individual sponsor. We hope this will help to incentivize sponsors and provide useful targeted information for all those who aim to comply with the law.” The authors noted that they only examine the availability of results on ClinicalTrials.gov as required by the law and not the quality of the results or their availability elsewhere.
The study is accompanied by a commentary in The Lancet, "Trial Results Reporting: FDA Amendments Act Final Rule Needs Enforcement," by Erik von Elm, MD, from Cochrane Switzerland, Center for Primary Care and Public Health at University of Lausanne in Lausanne, Switzerland, and and Joerg J. Meerpohl, MD, with Cochrane Germany, Cochrane Germany Foundation in Freiburg, Germany. Dr. von Elm stated, “Any law is only as good as its enforcement.” He added, “If this rule were to be enforced, academic sponsors would probably make substantial efforts to reduce the number of non- or late-reported trials and to improve data quality. Training, auditing and incentive mechanisms could be overseen by dedicated staff. A senior ‘transparency officer’ versed in trial conduct and reporting could take a proactive mentoring role and help investigators overcome barriers that currently prevent them from timely reporting of trial results in registries. If completeness of reporting was a criterion in individual academic evaluations, this could have a considerable ‘signaling effect’ within the local research community.”