When the FDA gets tough on clinical trial transparency, the industry listens. The problem is the FDA doesn’t get tough with enough regularity.

That’s the upshot of research published in the Journal of the American Medical Association (JAMA), which showed that 90 percent of those conducting clinical trials who got preliminary warnings from the FDA about overdue clinical trial results promptly provided the requested information.

The researchers argue that the FDA should be more aggressive at pushing drugmakers, universities and National Institutes of Health grantees for transparency in their trial results. “The FDA can and should harness its enforcement tools to ensure timely submission of trial results information to ClinicalTrials.gov,” they wrote.

The researchers used Freedom of Information Act requests to obtain 58 preliminary warnings — called pre-notices — that the FDA sent to sponsors from 2013 through April 2021. Fifty-seven of the 58 pre-notices obtained described potential missing trial results and one referred to missing information about registering a clinical trial. The median time trial sponsors took to post results after getting these notices from the FDA was three weeks, the researchers found.

The FDA Amendments Act (FDAAA) — which requires trial sponsors to register trials on ClinicalTrials.gov within 21 days after the first human subject is enrolled and submit summary results information to the database within 12 months after the trial’s completion date — took effect in 2007. And in 2017, a rule strengthening its reporting requirements was added.

Recent estimates cited by the researchers suggest that approximately 60 percent of trials fail to report results on time and more than 30 percent (almost 3,000 clinical trials with primary completion dates between Jan. 18, 2017, and Jan. 18, 2021) have not yet reported results.

Among 3,951 trials sponsored by industry, just 43.2 percent complied fully with the FDAAA results reporting requirements. Among the top 40 U.S. research universities (by number of trials subject to the FDAAA), only 17 complied fully with reporting of trial results, said the researchers.

In April of this year — 14 years after the law was passed — the FDA issued its first-ever notice of noncompliance with the FDAAA to Acceleron Pharma for failing to submit required summary results information on candidate drug dalantercept in combination with an FDA-approved drug, axitinib. These results were based on a phase 2 trial that reached its primary completion date in June 2017.

Acceleron not only missed its 2018 deadline for submitting results to ClinicalTrials.gov, but also ignored an initial warning that the FDA sent the company in July 2020, the researchers said.

Since then the FDA has issued two more notices of noncompliance — one to Accuitis for a phase 2 trial of a topical treatment for acne rosacea and another to an academic investigator for a phase 4 trial of a postoperative combination ice and analgesic treatment.

In addition to not communicating nearly enough with trial sponsors about missing trial information, the researchers found that the FDA also did not communicate with other agencies such as the National Institutes of Health (NIH), even though the NIH and FDA share responsibility for enforcing FDAAA.

Rather than wait for the FDA to send pre-notices and notices, the NIH could use its own list of FDAAA 801 problems to identify noncompliant trials and send reminders to the responsible parties, the researchers said.

Additionally, if a responsible party is an NIH grantee, the NIH could also warn them that future grant funds may be withheld until the trial comes into compliance.

The researchers suggested that the FDA send more pre-notices, adding, “The FDA has yet to send Pre-Notices (or Notices) to thousands of responsible parties that have not reported results, including government sponsors such as the NIH.”

In lieu of relying on inconsistent on-site inspection investigations and third-party complaints to identify noncompliant trials, the researchers suggest that the FDA instead use a continually updated list of FDAAA 801 problems maintained by the NIH to quickly identify potential noncompliant trials and issue pre-notices as appropriate.

The FDA could also get more compliance by publicizing all pre-notices it issues, as opposed to sharing them only with the responsible parties. “Such transparency would improve public accountability and encourage prompt submission of missing information,” the researchers wrote.

Also, the pre-notices could show more teeth. The researchers suggest that the FDA include clear timelines for further enforcement actions if results remain unreported. Currently, pre-notices don’t say anything about when any enforcement actions will take place.

The researchers anticipate that the FDA’s response to these suggestions will be that they don’t have the necessary staff — to which the researchers suggest taking a risk-based approach to identifying where the enforcement efforts should be rather than not enforcing anything at all.

The FDA did not respond to a request for comment by press time.

Access the JAMA report here: https://bit.ly/3cgF3ws.