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November 12, 2021

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

Author Affiliations
  • 1National Clinician Scholars Program, Yale School of Medicine, Department of Internal Medicine, New Haven, Connecticut
  • 2Veterans Affairs Connecticut Healthcare System and Yale University, West Haven, Connecticut
  • 3Columbia Law School, New York, New York
  • 4Global Health Justice Partnership, Yale Law School, New Haven, Connecticut
  • 5Section of General Internal Medicine, Yale School of Medicine, New Haven, Connecticut
JAMA. Published online November 12, 2021. doi:10.1001/jama.2021.19773

On April 28, 2021, the US Food and Drug Administration (FDA) announced that it “issued its first Notice of Noncompliance to Acceleron Pharma, Inc. (Acceleron) for failing to submit required summary results information to ClinicalTrials.gov.”1 These results were based on a phase 2 trial that reached its primary completion date in June 2017. The trial examined the safety and efficacy of the candidate drug dalantercept in combination with an FDA-approved drug, axitinib, in patients with advanced renal cell carcinoma. Acceleron not only missed its 2018 deadline for submitting results to ClinicalTrials.gov, but also ignored an initial warning (Pre-Notice of Noncompliance) that the FDA sent the company in July 2020.1 The FDA’s first Notice of Noncompliance was recognized as 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 to the public via ClinicalTrials.gov. But, the Notice of Noncompliance also prompts a key question: what comes next for noncompliant trial sponsors and the FDA?

Under Section 801 of the FDA Amendments Act (FDAAA) of 2007, “responsible parties” (typically trial sponsors) of “applicable clinical trials” of FDA-regulated products are mandated to first register (within 21 days of initiating enrollment) and subsequently submit summary results information to ClinicalTrials.gov within 12 months after the trial’s primary completion date.2 However, responsible parties may legally delay submission of results information under certain conditions, such as if the product studied has not yet been approved, cleared, or licensed by the manufacturer and is still under development or if approval will be sought within 1 year of the primary completion date of the trial for a new use of an already marketed product. A subset of trials is exempt from the FDAAA mandate, including phase 1 drug trials, smaller feasibility studies of devices, and trials completed before January 18, 2017, of drugs and devices not approved, licensed, or cleared by the FDA. For trials with a primary completion date on or after January 18, 2017, responsible parties are also required to submit the protocol and statistical analysis plan when results information is due.

The FDAAA reporting requirements were implemented to make detailed information regarding testing and evaluation of FDA-regulated products available to support trial enrollment, inform clinical care decisions, and accelerate future research. The requirements have proven effective: a Final Rule issued by the National Institutes of Health (NIH) and the US Department of Health and Human Services (DHHS), which came into effect in January 2017, elaborated and expanded the FDAAA reporting requirements and prompted increases in registration of trials and submission of protocols.2

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 Noncompliance to Acceleron, the NIH updated the ClinicalTrials.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 Act–based investigation, all 58 Pre-Notices that the FDA issued from 2013 through April 29, 2021, were obtained. Of these, 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 thousands of FDAAA-applicable clinical trials identified as noncompliant with 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 have not submitted mandated results to ClinicalTrials.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 Noncompliance1—one to Accuitis for a phase 2 trial of a topical treatment for acne rosacea8 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 problems10 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 timelines for further enforcement actions if results remain unreported. Within Pre-Notices, the FDA does not currently state specifically when subsequent enforcement actions will occur if the FDA determines the responsible party is noncompliant, including when a Notice of Noncompliance will be issued. Additionally, when the FDA determines a responsible party 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 “risk-based” approach outlined in the FDA’s issued guidance7 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 problems10 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.

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Article Information

Corresponding Author: Reshma Ramachandran, MD, MPP, Yale School of Medicine, 333 Cedar St, SHM IE-68, New Haven, CT 06510 (reshma.ramachandran@yale.edu).

Published Online: November 12, 2021. doi:10.1001/jama.2021.19773

Conflict of Interest Disclosures: Dr Ramachandran reported being a board member of Universities Allied for Essential Medicines North America, the nonprofit organization that filed the Freedom of Information Act (FOIA) requests with the FDA from which the 58 Pre-Notices described were obtained. Dr Morten reported receiving personal fees from New York University School of Law; personal fees from Yale University's Collaboration for Research Integrity and Transparency, which has received grant funds from Arnold Ventures, outside the submitted work; being employed as staff attorney at the Collaboration for Research Integrity and Transparency from 2018 to 2019; and legally representing Universities Allied for Essential Medicines North America and serving as the organization's lawyer in connection with its FOIA requests. Dr Ross reported receiving grants from the FDA, Johnson & Johnson, Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, the National Institutes of Health/National Heart, Lung, and Blood Institute, and the Laura and John Arnold Foundation, outside the submitted work.

Disclaimer: The views expressed herein are those of the authors and do not necessarily reflect views of the US Department of Veterans Affairs or the US government.

References
1.
ClinicalTrials.gov: Notices of Noncompliance and civil money penalty actions. US FDA. Published September 1, 2021. Accessed October 8, 2021. https://www.fda.gov/science-research/fdas-role-clinicaltrialsgov-information/clinicaltrialsgov-notices-noncompliance-and-civil-money-penalty-actions
2.
Zarin  DA, Fain  KM, Dobbins  HD,  et al.  10-Year update on study results submitted to ClinicalTrials.gov.   N Engl J Med. 2019;381(20):1966-1974.PubMedGoogle ScholarCrossref
3.
DeVito  NJ, Goldacre  B.  Evaluation of compliance with legal requirements under the FDA Amendments Act of 2007 for timely registration of clinical trials, data verification, delayed reporting, and trial document submission.   JAMA Intern Med. 2021;181(8):1128-1130.PubMedGoogle ScholarCrossref
4.
Clinical trials transparency at US universities. Universities Allied for Essential Medicines. Published May 26, 2021. Accessed November 4, 2021. http://www.altreroute.com/clinicaltrials/assets/download/Clinical_Trials_Transparency_Report_UAEM_v5.pdf
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Memorandum of law in further support of defendants’ motion to dismiss or, in the alternative, for summary judgment, and in opposition to plaintiffs’ cross-motion for summary judgment. US District Court. July 26, 2019. Accessed November 11, 2021. https://www.law.columbia.edu/sites/default/files/2021-08/Seife%20v%20HHS%20DI%2050%20USG%20Reply%20Brief.pdf
6.
Study of dalantercept and axitinib compared to placebo and axitinib in patients with advanced renal cell carcinoma. ClinicalTrials.gov identifier: NCT01727336. Updated September 23, 2021. Accessed November 4, 2021. https://clinicaltrials.gov/ct2/show/results/NCT01727336
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Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank. US Food and Drug Administration; 2020.
8.
Safety and efficacy of ACU-D1 in the treatment of acne rosacea. ClinicalTrials.gov identifier: NCT03064438. Updated August 23, 2021. Accessed October 7, 2021. https://clinicaltrials.gov/ct2/show/study/NCT03064438
9.
Ice T postoperative multimodal pain regimen in FPMRS Surgery (ICET). ClinicalTrials.gov identifier: NCT03052816. Updated October 6, 2021. Accessed October 7, 2021. https://clinicaltrials.gov/ct2/show/NCT03052816
10.
PRS user’s guide section 8.1.2: FDAAA 801 problems. ClinicalTrials.gov. Published June 28, 2021. Accessed August 18, 2021. https://prsinfo.clinicaltrials.gov/prs-users-guide.html#fdaaa801problems
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    1 Comment for this article
    EXPAND ALL
    Quick But Incomplete Fixes
    Bob Roehr, MS | Freelance biomedical Journalist; Past member two NIH advisory committees
    Growing up my father taught me the job isn't done until the paperwork is completed. That should certainly apply to clinical trials where volunteer patients take on the risks of participating. 

    For academic studies, the NIH should certify that reporting requirements are current, and if such reporting is not current, the the NIH should not release any new funds. Researchers and institutions habitually delinquent in reporting should not be allowed to file new grant applications.

    There is no such financial stick to use with industry. However if a drug is approved and the required information has not
    been published in a journal then the FDA should make public the voluminous information the sponsor has filed for that approval. Most companies would prefer that the public record consist of papers it has vetted and spun rather than the far larger mass of raw data.

    Such changes would greatly enhance compliance.
    CONFLICT OF INTEREST: None Reported
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