January 22, 2020
Three years after a federal deadline was clarified, mandating that clinical trial sponsors report results to ClinicalTrials.gov within 1 year of the primary completion date, most researchers still miss the deadline, a new analysis has found.
Nicholas J. DeVito, MPH, of The DataLab at University of Oxford in the United Kingdom, and colleagues downloaded all registered trials due to report between March 2018 and September 2019 and found that of those 4209 trials, only 40.9% made the 1-year deadline; only 63.8% reported results at any time.
The researchers report their findings in an article published online January 17 in The Lancet.
A related investigation in the journal Science published on the same day found similar results.
The Science article gave a glimpse of some of what is at stake. "In one long-overdue trial, researchers compared the efficacy of different chemotherapy regimens in 200 patients with advanced lymphoma; another — nearly 2 years late — tests immunotherapy against conventional chemotherapy in about 600 people with late-stage lung cancer," author Charles Piller, an investigative journalist, writes.
No improvement is in sight and the compliance level has not increased since July 2018, Piller explains.
The US Food and Drug Administration (FDA) in January of 2017 issued the Final Rule on reporting and set fines for up to $10,000 a day ($12,103 a day today) for noncompliance.
But the researchers say the rule is not being enforced.
"To our knowledge, there have been no fines imposed by the FDA to date; indeed we are unable to find any public record of any enforcement action by the FDA on any aspect of the Final Rule," DeVito and colleagues write.
They estimate that strict enforcement of the Final Rule could have resulted in $4 billion in fines as of September 2019.
US Government Is a Big Offender
The researchers also found that US government-sponsored trials are the least likely class to report results on time. Only 31.4% of those trials made the deadline.
"The fact that the US Government cannot comply with its own laws is especially concerning," the authors write.
Trials that had an industry sponsor were much more likely to meet the reporting deadline (50%) than those with a non-industry (34%) or US government sponsor (31%) (odds ratio [OR], 3.08).
Sponsors who had experience with a large number of trials were much more likely to submit on time than were those who had sponsored a small number of trials (66% vs 21%; OR, 11.84).
The average time from primary ending of the trial to reporting was 424 days — almost 2 months past the 1-year deadline.
The overall effect of the lapses is clear, the researchers say: "Patients and clinicians cannot make informed choices when the results of clinical trials [positive or negative] are routinely withheld."
Trouble for Decades
The lack of reporting has been documented for decades.
DeVito and colleagues point out, "The importance of addressing the bias from non-publication of clinical trials has been (emphasized) since at least the 1980s."
The 2017 Final Rule was issued to clarify confusion over the Food and Drug Administration Amendments Act (FDAAA) passed 10 years before in 2007.
The Science article quotes Patrick McNeilly, an FDA official who handles trial enforcement matters, as saying recently at an industry conference session in regard to the reporting lapses: "FDA has limited resources, and we encourage voluntary compliance."
Erik von Elm, a senior researcher at the University of Lausanne in Switzerland, and Joerg J. Meerpohl, MD, with the Institute for Evidence in Medicine at the University of Freiburg in Germany, write in an accompanying commentary that enforcement is paramount.
They suggest adding training, auditing, and incentive mechanisms to increase compliance.
"A senior transparency officer versed in trial conduct and reporting could take a proactive mentoring role and help investigators overcome barriers that prevent them from timely reporting," they write.
Including completed reporting in academic evaluations could also be a strong motivator, they suggest.
"Results reporting of all trials is an achievable goal that should be high on the agenda of anybody involved in the funding, conduct, or regulation of clinical research," von Elm and Meerpohl write.
For their part, DeVito and colleagues say, they set up a publicly viewable website where data on compliance will be posted every day. "The FDA are not publicly tracking compliance. So we are, here," the top of the page reads.
It flags overdue trials and compliance statistics for each sponsor.
"We hope this will help to (incentivize) sponsors, and provide useful targeted information for all those who aim to comply with the law," DeVito said in a news release.
Deborah Zarin, MD, a physician at Brigham and Women's Hospital and Harvard Medical School in Boston, who led ClinicalTrials.gov between 2005 and 2018, said in the Science article that one of three things will likely happen from here.
"One possibility is that FDA and NIH will be shamed into enforcing the law," she said. "Another possibility is that sponsors will be shamed into doing a better job. A third possibility is that ClinicalTrials.gov will never fully achieve its vital aspirations."
Study funding was provided by the Laura and John Arnold Foundation. DeVito is employed under a grant from the Laura and John Arnold Foundation and is supported in his doctoral studies through a Naji Foundation Scholarship. He has previously been employed on grants from the Open Society Foundation and the State Attorney General Consumer and Prescriber Education Grant Program. Coauthors have also received funding from the Arnold Foundation, Wellcome Trust, Oxford Biomedical Research Centre, NHS National Institute for Health Research School of Primary Care Research, Health Foundation, the World Health Organization, and the Open Prescribing project.
Coauthor Ben Goldacre, MBBS, also receives personal income from speaking and writing for lay audiences on the misuse of science. As of 2020 the TrialsTracker is funded by the Good Thinking Society.
The editorialists have disclosed no relevant financial relationships.