Enforcing Reporting Requirements for Clinical Trials

(A version of this column appeared in the November 2023 issue of Public Citizen’s Health Letter.)

In the United States, sponsors of clinical trials covered by the legal requirements are required to register the trials and report the results to ClinicalTrials.gov at the National Institutes of Health (NIH). Under the Food and Drug Administration (FDA) Amendments Act of 2007 (FDAAA) and clarifying regulations effective in 2017 (the Final Rule), the FDA and the NIH share responsibility for enforcing the reporting of clinical trial results.[1] Timely and complete trial registration and results reporting are essential for patients, clinicians and researchers. As Deborah Zarin, a former director of ClinicalTrials.gov, and Robert Califf, the FDA Commissioner, wrote in 2021, “the goal [of trial registration and results reporting] is to ensure that each trial contributes accurate and complete information to the medical evidence base — eliminating “secret trials” or biased reports with misleading conclusions.”[2]

Although most covered clinical trials comply with the legal requirements, many do not. In 2017, when the Final Rule became effective, problems with compliance were understandable. Six years later, they are not. According to the FDAAA Trials Tracker, as updated in October 2023, only 15,095 (77.7%) of 19,429 trials in their database complied.[3]

One reason that noncompliance is so frequent is because the FDA’s enforcement has been seriously deficient. The FDA has sent few pre-notices and notices of noncompliance to trials sponsors. Moreover, it has never imposed any fines on a trial sponsor who is noncompliant, even though it has the legal authority to do so. The FDA has issued only five notices of noncompliance; four of the sponsors have addressed the issues.[4]

In February 2023, the Universities Allied for Essential Medicines North America filed a Citizen’s petition with the FDA to increase enforcement of the ClinicalTrials.gov reporting requirements and to impose fines when appropriate.[5] Among the specific requests were that the agency send a minimum of 250 pre-notices of noncompliance each year (as of April 2021 it had issued less than 60)[6] and that it issue updated guidance with a new framework for prioritizing enforcement. The petition asked that enforcement be prioritized for trials of high relevance to how patients are cared for, including NIH-funded trials of FDA-approved medical products, trials that provided data that the FDA relied upon when making decisions to approve products and required post-marketing trials. Finally, the petition called for increasing transparency and demonstrating the agency’s efforts to comply with federal regulations by creating “a public dashboard of all enforcement actions taken,” including pre-notices of noncompliance.

In August 2023, the FDA sent an interim response, which, however, was effectively a non-response.[7] The agency said that it “will require additional time to issue its final response…because of the complexity of issues raised.” The basic requirement to register clinical trials and report the results to ClinicalTrials.gov is not complex. The FDA has had more than six years to get enforcement right. Further delay is not a path forward.
 

References

[1] Zarin DA, Tse T, Williams RJ, et al. Trial reporting in ClinicalTrials.govthe final rule. N Engl J Med. 2016:375(20):1998-2004. doi:10.1056/NEJMsr1611785

[2] Zarin DA, Califf RM. Trial reporting and the clinical trials enterprise. JAMA Intern Med. 2021;181(8):1131-1132. doi:10.1001/jamainternmed.2021.2041

[3] FDAAA Trials Tracker https://fdaaa.trialstracker.net Accessed October 23, 2023.

[4] Food and Drug Administration ClinicalTrials.gov – notices of noncompliance and civil money penalty actions. https://www.fda.gov/science-research/fdas-role-clinicaltrialsgov-information/clinicaltrialsgov-notices-noncompliance-and-civil-money-penalty-actions. Accessed October 23, 2023.

[5] Citizens Petition from Morningside Heights Legal Services, Inc. (on behalf of Universities Allied for Essential Medicines North America) to the Food & Drug Administration for increased enforcement of the ClinicalTrials.gov reporting requirements in the Food and Drug Administration Amendments Act of 2007. February 27, 2023. https://www.regulations.gov/document/FDA-2023-P-0660-0001 Accessed October 23, 2023.

[6] Ramachandran R, Morten CJ, Ross, JS. Strengthening the FDA’s enforcement of ClinicalTrials.gov reporting requirements. JAMA 2021;326(21):2131-2132. doi:10.1001/jama.2021.19773.

[7] Interim response letter from FDA OC to Morningside Heights Legal Services, Inc. (on behalf of Universities Allied for Essential Medicines North America). August 23, 2023.https://www.regulations.gov/document/FDA-2023-P-0660-0016 Accessed October 23, 2023.