Strengthening the FDA’s Enforcement of ClinicalTrials.gov Reporting Requirements

However, reporting of results information remains limited despite the legal mandate and clear instructions from DHHS and the NIH Final Rule. Recent estimates suggest that approximately 60% of trials fail to report results on time and more than 30% (almost 3000 clinical trials with primary completion dates between January 18, 2017, and January 18, 2021) have not yet reported results. 3 Among 3951 trials sponsored by industry, 43.2% complied fully with the FDAAA results reporting requirements. 3 Among the top 40 US research universities (by number of trials subject to the FDAAA), only 17 complied fully with reporting of trial results. 4 The FDA and NIH share responsibility for enforcing FDAAA. The NIH has independent authority and obligations under the FDAAA to withhold grant money from grantees who do not comply with their FDAAA reporting requirements, yet the NIH has historically declined to take any enforcement action on its own. 5 However, when the FDA issued its Notice of Noncom-pliancetoAcceleron,theNIHupdatedtheClinicalTrials.gov entry for the Acceleron trial with a public notice of "FDAAA 801 Violation." 6 This constituted, to our knowledge, the NIH's first public acknowledgment of a specific trial out of compliance with the FDAAA. Further Notices of Noncompliance from the FDA may trigger, or even require, the NIH to take separate enforcement actions, including withholding grant money from noncompliant grantees.

For its part, the FDA has stated that it identifies potential violations of the FDAAA through investigations conducted as part of the agency's BIMO (Bioresearch Monitoring) program as well as third-party complaints. 7 The FDA then takes a "risk-based approach" "consistent with FDA's public health mission" and, at its discretion, may issue a Preliminary Notice of Noncompliance (hereafter referred to as Pre-Notice) informing responsible parties of potential FDAAA violations. 7 Pre-Notices alert responsible parties that the agency plans to check on the potential missing trial results information (including study protocol and statistical analysis plan) 30 days after receipt of the Pre-Notice. Only after Pre-Notices are sent will the FDA issue a Notice of Noncompliance if results information remains missing. Pre-Notices also warn responsible parties that if the required information is not submitted, the FDA may take enforcement action, potentially levying civil monetary penalties of more than $10 000 for each day of violation or opening criminal prosecution should the party continue to fail to submit required information.

Through an ongoing Freedom of Information Actbased investigation, all 58 Pre-Notices that the FDA issued from2013throughApril29,2021,wereobtained.Ofthese, 57 described potential missing trial results information and 1 described missing registration information. Three trends stand out. First, the 57 Pre-Notices represent a tiny fraction of the thou-sandsofFDAAA-applicableclinicaltrialsidentifiedasnoncompliantwith results information reporting requirements as of January 2021. 3 Second, the FDA sent no Pre-Notices to any federal agencies, including the NIH, even though the NIH is the responsible party for many trials that havenotsubmittedmandatedresultstoClinicalTrials.gov.Instead,most Pre-Notices were sent to industry, with a smaller number sent to academia and other organizations (Supplement). Third, Pre-Notices may be effective at improving compliance: as of August 17, 2021, more than 90% of the 57 Pre-Notice recipients had reported missing information to ClinicalTrials.gov. Among recipients who submitted missing results information after receiving a Pre-Notice, the median time for submission was approximately 3 weeks.

The FDA has since taken additional action to enforce FDAAA compliance. In July and August 2021, it issued 2 additional Notices of Noncompliance 1 -onetoAccuitisforaphase2trialofatopicaltreatment for acne rosacea 8 and another to an academic investigator for a phase 4 trial of a postoperative combination ice and analgesic treatment. 9 But the FDA's enforcement efforts could be strengthened substantially. First, the FDA could send more Pre-Notices. 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. Moreover, in lieu of relying on inconsistent BIMO investigations and third-party complaints to identify noncompliant trials, the FDA could instead use a continually updated list of FDAAA 801 problems 10 maintained by the NIH to quickly identify potential noncompliant trials and issue Pre-Notices as appropriate.

Second, the FDA could publicize all Pre-Notices it issues, as opposed to sharing them only with responsible parties. As with Notices of Noncompliance, Pre-Notices could be posted on the FDA website and cross-linked on ClinicalTrials.gov. Such transparency would improve public accountability and encourage prompt submission of missing information.

Third, the FDA could ensure that Pre-Notices present clear timelinesforfurtherenforcementactionsifresultsremainunreported.Within Pre-Notices, the FDA does not currently state specifically when subse-quentenforcementactionswilloccuriftheFDAdeterminestheresponsible party is noncompliant, including when a Notice of Noncompliance willbeissued.Additionally,whentheFDAdeterminesaresponsibleparty is noncompliant, the FDA could immediately send a Notice of Noncompliance that establishes a clear timeline for escalating consequences of continued noncompliance, including civil monetary penalties. Notices may succeed even where Pre-Notices fail: within a month of receiving their Notices of Noncompliance, all 3 sponsors reported their missing results information to ClinicalTrials.gov. 6,8,9 Fourth, if FDA resources or personnel remain constrained, the agency could set and consistently apply objective criteria for prioritization of enforcement efforts. These might be based on the "riskbased" approach outlined in the FDA's issued guidance 7 and include duration of noncompliance, trial size, patient population affected, severity of disease, and availability of alternative treatments.

The NIH could support the FDA and improve its own enforcement efforts. Rather than wait for the FDA to send Pre-Notices and Notices, the NIH could use its own list of FDAAA 801 problems 10 to identify noncompliant trials and send reminders to the responsible parties. If a responsible party is an NIH grantee, the NIH could also warn that future grant funds may be withheld until the trial comes into compliance. Additionally, Congress could act by explicitly allocating funding for FDAAA enforcement efforts by the NIH and FDA, because the FDAAA imposed new regulatory obligations on both without allocating new funds.

The FDA can and should harness its enforcement tools to ensure timely submission of trial results information to ClinicalTrials.gov. By doing so, the FDA could bring important missing results to light and demonstrate its commitment to protecting patients through clinical trial transparency.