In a Long-Awaited Move, FDA Enforces Trial Result Transparency
Once a clinical trial is completed, the clock is supposed to start ticking. For certain trials, researchers have one year to upload the results of their study to a public database maintained by the National Library of Medicine. If they fail to do so, the U.S. Food and Drug Administration may send out warnings, letters, and, if researchers and companies are still noncompliant, impose a fine.
The rule applies to trials that test drug or medical devices as an intervention, involve drugs or products manufactured in the United States, or that have at least one study facility in the U.S., which fall under the FDA Amendments Act of 2007. A little less than a quarter of all clinical trials are considered to fall under this law, according to a 2021 estimate based on FDA approvals of certain drugs and therapeutics in 2016 and 2017. Yet for about 30 percent of trials, sponsors — the companies, universities, hospitals, and other organizations responsible for overseeing studies — appear to be failing to comply with the law, the FDA noted in an April announcement after conducting an internal analysis. That number may be even higher, with one analysis finding that as many as 59 percent of applicable trials missed the legal deadline for reporting results.
“There’s a rampant disregard,” said Jennifer Miller, co-director of the program for biomedical ethics at Yale School of Medicine. Without that data out there, researchers may be duplicating studies or following dead ends. And selective reporting of results can bias the field. “You need all the evidence out there.”
Despite data showing this ongoing issue, historically, the FDA has done little to mitigate it; since 2017, when the final rule clarifying reporting requirements took effect, the agency has only sent out eight notices of noncompliance and have never fined a sponsor. “The law is not monitored and enforced consistently,” Miller said. In their stead, researchers have stepped in to fill the transparency gap, monitoring non-compliance through clinical trial trackers.
Now, experts say the FDA is finally acting: In March, the agency sent notices to 2,200 companies and researchers overseeing more than 3,000 clinical trials that do not appear to have submitted required results to ClinicalTrials.gov, the official public database for clinical research studies, or may not have completed the National Library of Medicine’s quality control review process.
This represents a long-awaited move on behalf of regulators that academics hope will continue improving transparency. “That’s kind of what we’ve been asking for all along,” said Nicholas DeVito, a research integrity researcher at the Bennett Institute for Applied Data Science. “You don’t need to threaten to sue them; you don’t need to make the notices public. Just start letting people know, and that might scare enough people into reporting that we can really get the numbers up.”
In the early 2000s, the world saw the consequences of a company suppressing clinical trial results. SmithKline Beecham (now GlaxoSmithKline) concealed results showing that paroxetine, its drug for depression, anxiety, and PTSD, had no benefit in treating adolescents and that the drug also increased suicidal thoughts and behaviors. The FDA issued safety warnings and later directed the manufacturers of certain antidepressants, including paroxetine, to include a black box warning — the agency’s strongest caution to consumers — about the increased risk of suicidal thoughts for children and adolescents.
Publicly listed companies have incentive to hide unfavorable negative findings, or results showing no benefit from a drug or device, said Till Bruckner, a scientist at the Karolinska Institute in Sweden. “Why would you want to make public evidence that shows that your medicines are less safe or less effective than previously thought?”
“The law is not monitored and enforced consistently.”
In other cases, reporting study results can simply fall through the cracks, he added. For example, companies sometimes end their investment in a drug or medical device for commercial reasons, and in academia, researchers can move labs without writing up the results. Sponsors may also be too optimistic about how many participants they will be able to recruit for the trial and end up with a small study with limited power.
Studies that show no effect of an intervention are typically harder to publish in top-ranked academic journals, said Bruckner. Some researchers may even think that their negative or small studies do not contribute much to the community, so they see no reason to post the results. But researchers can glean insights by pooling small studies, which can provide helpful information for the community, Bruckner pointed out. “Your little drop of evidence actually does influence the final color of the sea of evidence.”
Sponsors also have an ethical obligation to share the results, said Miller, since clinical trials are justified by their potential to benefit society: “If you don’t generalize the knowledge by sharing the results, the whole ethics of the trial comes into question.”
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However, regulators have historically failed to enforce the law, she said. So academics stepped up to fill this need, establishing clinical trial trackers. For example, the Good Pharma Scorecard, led by Miller, ranks pharmaceutical companies on many factors, including clinical research transparency. The FDAAA Trials Tracker, co-developed and maintained by DeVito, estimates that around 20 percent of sponsors have not published results from the clinical trials and that, under the law, the FDA could have collected more than $120 billion by fining the sponsors. Buckner, who also started a trial transparency effort called TranspariMED, found in a study that has yet to be peer reviewed that about half of clinical trials conducted in Europe do not report results to the European Clinical Trial Information System in the required timeframe.
Although there are some companies increasing transparency and improving their compliance, Miller’s work suggests that transparency might be worsening. The trend may underscore how limited enforcement has been despite years of efforts by researchers and advocates to improve compliance.
Researchers who track clinical trial reporting argue that the FDA has had the tools to address the problem but rarely used them. And, DeVito said, how the FDA decided to prioritize which companies to scrutinize and which to send notices of non-compliance was opaque.
“While the agency has previously utilized other forms of outreach, including webinars and press releases, this is the first time FDA has conducted broad, targeted email outreach,” the FDA noted in an unattributed email to Undark. To do this, the agency said they conducted an internal analysis by searching ClinicalTrials.gov for trials that would likely fall under the law that were more than one year past their primary completion date and had not yet submitted results, the email noted.
“This outreach effort was designed to maximize impact with existing resources by utilizing broad, automated email rather than the more resource-intensive, case-by-case review process associated with formal compliance actions,” the email read.
“Your little drop of evidence actually does influence the final color of the sea of evidence.”
The warnings sent to researchers and companies signal that regulators are paying attention to reporting requirements that, for years, appeared to receive little oversight. Those 2,200 notices were a good start, said Miller.
But whether the effort marks a lasting shift remains unclear. DeVito worries that they may represent a rare one-off event instead of a consistent shift towards ongoing monitoring. There would need to be a follow-up to make sure that the results that they were targeting actually do get reported, Miller said, and if warranted, they should implement the $10,000-a-day penalty they are allowed to impose on companies. The FDA has not indicated whether it plans to conduct similar reviews regularly, and did not respond to specific questions about future outreach. It has never imposed the financial penalties authorized under the law..
“Just doing it once cross-sectionally, while laudable and good, sort of leaves a lot that ongoing monitoring can offer on the table,” DeVito said. “Having an established program of doing this, I think, could be good for everyone.”
The warning notices have put thousands of companies and researchers on notice. Whether the FDA’s enforcement will have a lasting impact remains to be seen, and researchers like DeVito will be watching closely.