FDA could do more to enforce ClinicalTrials.gov reporting requirements

Regulatory NewsRegulatory News | 15 November 2021 |  By 

Reshma Ramachandran. Credit: Yale School of Medicine

The US Food and Drug Administration (FDA) hasn’t been notifying most clinical trial sponsors they are in violation of reporting requirements.
That’s according to results of a Freedom of Information Act (FOIA) investigation by Reshma Ramachandran, of the Yale School of Medicine in New Haven, CT, and colleagues in a recent Viewpoint published in JAMA.
In January 2017, a final rule issued by the National Institutes of Health (NIH) determining ClinicalTrials.gov trial submission and reporting requirements went into effect, clarifying requirements outlined in Section 801 of the FDA Amendments Act (FDAAA) of 2007. The final rule directs the sponsor or designated principal investigator of an applicable clinical trial to submit timely registration of clinical trials as well as results information within 12 months of a trial’s primary completion date. FDAAA enforcement falls under the purview of both FDA and NIH.
Although nearly 5 years has passed since the final rule took effect, FDA seems to have only recently started to take action against clinical trials not meeting FDAAA reporting requirements. Out of thousands of clinical trials identified as being out of compliance, Ramachandran and her colleagues received 58 preliminary notices of noncompliance (pre-notices) in their FOIA investigation issued by FDA between 2013 and April 2021. One pre-notice described missing registration information, while the remaining 57 pre-notices alerted sponsors to missing trial information.
April 2021 also marked the first time a notice of noncompliance for clinical trial reporting was sent by FDA, “an important, if long overdue, step by the agency toward fulfilling its responsibility to enforce the federal law that requires clinical trial sponsors to disclose trial results information to the public via ClinicalTrials.gov,” Ramachandran and colleagues wrote. The company, Acceleron Pharma, Inc., had failed to submit results for a trial that was completed in June 2017, and ignored a pre-notice the agency sent as a warning in July 2020. FDA has since sent two additional notices in July and August 2021 to Accuitis, Inc., and to an academic investigator.
The timeline raises questions about what FDA and NIH will do next to enforce clinical trial reporting requirements, the authors said.
In an interview, Ramachandran told Focus the pre-notices were sent by FDA in waves, with an initial wave in 2013-2014 that subsided before picking up again in 2020. “There’s this huge gap in between,” she said.
One clue about the gap in enforcement can be found in FDA’s final guidance document on assessing civil money penalties for submissions to the ClinicalTrials.gov data bank. “In that guidance, they basically made clear that they’re pursuing their own process that seems to be independent of what ClinicalTrials.gov might report,” Ramachandran said. “They’re not really using the database to really identify which trials might be out of compliance, but instead are taking this risk-based approach.”
It is unclear why FDA and NIH don’t appear to be working together when identifying non-compliant trials. Why FDA is targeting specific trial sponsors with pre-notices, and following up by sending Notices to some sponsors but not others is also unclear, Ramachandran said.
“There really wasn’t any kind of rhyme or reason for why these trials were chosen,” she said. “Why pursue these three? Why were these the first three? It's really not clear because it doesn't really seem to concur with the guidance that they put out in August 2020.”
Another notable finding is that FDA did not send pre-notices to federal agencies, including trials sponsored by NIH. While it is possible the agencies are communicating behind the scenes, Ramachandran said the results of the FOIA investigation did not turn up documentation of interagency communication or internal enforcement. NIH did follow FDA’s notice to Acceleron by publicly updating the sponsor’s ClinicalTrial.gov’s listing as being in violation of FDAAA. However, the degree of interagency communication is still unclear, Ramachandran explained.
“It’s still very much a black box,” she said.
Improving enforcement efforts
What is clear is that the pre-notices seem to be effective at getting sponsors to comply with reporting requirements. Of the 57 Pre-notices sent by FDA alerting sponsors to missing trial information, the median time to submitting missing information was 22 days, Ramachandran and colleagues found.
To ramp up enforcement efforts, the authors recommended FDA send more pre-notices to sponsors with non-compliant trials and make those pre-notices public with clear timelines for enforcement actions. The agency could also use ClinicalTrials.gov to identify FDAAA 801 problems instead of performing their own independent investigations, they said.
“At least in our preliminary FOIA findings, there doesn’t seem to be a concerted effort to use the ClinicalTrials.gov database to its full potential in terms of enforcement activity,” Ramachandran said. “[We want to] understand why the NIH hasn't done so, not just for its own trials that they sponsor, but really for any NIH-funded trials by other sponsors as well.”
If resourcing is a concern, FDA could set a prioritization framework “to make sure that trials that are of clinical importance for patients—that really matter for making sure that what we prescribe them is actually safe and effective—that the FDA actually addresses those first and foremost out of the thousands that are non-compliant,” she said.
Ramachandran said she hopes this uptick in pre-notices signals an intention on FDA’s part to begin taking action against trials out of compliance with FDAAA. If recent nominee Robert M. Califf is confirmed as FDA commissioner, she said, his interest in clinical trial reporting may also lead to a shift by the agency in enforcement of trial reporting requirements.
“[T]he bottom line is that the FDA has this enforcement capability and it’s really a policy choice for them or whether or not they're going to be able to actually carry it forward,” Ramachandran explained. “They’re not really complying with their responsibility or obligation to do so under the law.”
“There is a legal mandate to ensure clinical trials results reporting, and it’s incredibly important for patients,” she said. “The FDA really hasn’t done enough, and we want them to do much more.”
JAMA Ramachandran R et al.


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