Editor's note: Authored by Sonia Nath, Elisabethann Wright and Natasha Leskovsek, this article was originally published in Law360.
Earlier this year, industry became more intimately familiar with the clinical trials reporting requirements in the U.S. when, on April 27, the U.S. Food and Drug Administration sent a notice of noncompliance to Acceleron Pharma Inc. identifying the company's failure to submit study results from a November 2017 trial that tested the efficacy of dalantercept and axitinib, proposed treatments for renal cell carcinoma.
As sponsors and principal investigators seek to learn from the Acceleron example, it is important for industry to consider reporting requirements not just in the U.S., but also for the European Union given the Clinical Trials Regulation, which, according to the European Medicines Agency, will go into effect in January 2022 and will impose an obligation on trials sponsors to publish amplified trial results in a database, the EU Clinical Trials Information System.
Reporting Requirements in the U.S.
ClinicalTrials.gov gives the public access to information about clinical trials, including drug and device trials, and their results. Managed by the U.S. National Institutes of Health and the National Library of Medicine, the database originally was created in 2000 primarily to include NIH-funded trials.
The site seeks to provide patients, the public and the research community with one-stop shopping for clinical trials as well as an accurate public record of study results to contribute to the collective body of medical knowledge. In 2007, Congress enacted the Food and Drug Administration Amendments Act, or FDAAA, to, among other things, address a perceived discrepancy with the website that allowed sponsors to cherry-pick data and report only favorable clinical trials.
The NIH and the U.S. Department of Health and Human Services published a final rule interpreting the FDAAA in 2017, which detailed the reporting requirements associated with ClinicalTrials.gov. Under that rule, within 21 days after the first human subject is enrolled, clinical trial sponsors or principal investigators must submit trial registration information.
This includes the study name, a summary of the study and its purpose, and recruitment information. Recruitment information delineates the eligibility criteria for study participants and provides the status of subject recruitment — e.g., not yet recruiting or enrolling by invitation — and the status of individual study sites.
The final rule also expanded the amount of information sponsors must submit about studies. For example, sponsors are now required to submit tables of adverse event information, update results as applicable and correct errors as they are identified.
Consistent with the final rule, responsible parties have one year after a study's primary completion date, defined as the day on which the final subject was examined or received an intervention for the purposes of collecting final data, to submit the results of the trial to ClinicalTrials.gov or to file a certification for delayed submission.
This applies whether the trial ends according to its protocol or if it ends early and is specific to reporting on ClinicalTrials.gov — trial results published in different public forums, such as medical journals, are not sufficient to satisfy the requirements.
In Acceleron's case, its trial of dalantercept and axitinib failed and the company stopped developing dalantercept shortly thereafter. It published the negative trial results in a peer-reviewed journal in July 2019. Nonetheless, the final rule required Acceleron to report the negative results to ClinicalTrials.gov as well.
Reporting Requirements in the EU
Similar to the U.S. framework, across the pond in the European Economic Area, the Clinical Trials Directive, which currently governs conduct of clinical trials in the EU, provides for the establishment of a clinical trials database, EudraCT.
All clinical trials of investigational medicinal products must be registered on EudraCT. Apart from the data fields for results-related information that must be completed in EudraCT there is, however, currently no obligation to publish the results of clinical trials.
Reflecting the equivalent provisions of the U.S. Public Health Service Act and with the intention of encouraging substantial disclosure of clinical data to a much larger extent than is currently the case, the Clinical Trials Regulation, which according to the European Medicines Agency will enter into application Jan. 31, 2022, will impose an obligation on trials sponsors to publish trial results in the Clinical Trials Information System database.
As a result, information concerning a clinical trial that is submitted to the EU database will be publicly accessible by default unless the information can be demonstrated to be confidential.
Article 37.4 of the regulation provides that, irrespective of the outcome of a clinical trial, within one year from the end of a clinical trial the trial sponsor must submit a summary of the results of the clinical trial to the EU database.
The content of that summary is set out in Annex IV to the regulation. The trial results must be accompanied by a summary written in a manner that is understandable to laypersons the content of which is set out in Annex V to the regulation.
In addition to the summary of the results provided in Annex IV to the regulation Article 37.4 provides that, where the clinical trial was intended to be used to support an application for marketing authorization of the product, the applicant for marketing authorization must submit a clinical study report to the EU database within 30 days after the day that either: (1) the marketing authorization has been granted; (2) the procedure for granting the marketing authorization was completed; or, (3) the applicant for marketing authorization was withdrawn.
While the regulatory regimes are similar in their reporting requirements for clinical trials, they differ in one important respect: enforcement.
In August 2020, the FDA published a guidance outlining its approach to enforcing the ClinicalTrials.gov requirements. The guidance sets forth a two-step process to encourage voluntary compliance.
Applying a risk-based framework focused on clinical trials that present a higher risk to human subjects, recidivists or sponsors that have otherwise violated the law, the FDA will first send a preliminary notice of noncompliance, which describes the potential violation and gives the sponsor 30 days to submit the study results to ClinicalTrials.gov, called the prenotice of noncompliance.
If, after 30 days, the clinical trial sponsor still has not complied, the FDA will issue and publicly post a notice of noncompliance. This second bite at the apple is public, but nonetheless affords sponsors an additional chance at voluntary compliance. While the FDA has issued more than 40 prenotices of noncompliance, the formal notice of noncompliance to Acceleron sent earlier this year was the agency's first.
Consistent with its enforcement authority, the FDA could have assessed civil money penalties against Acceleron. However, the agency's approach to voluntary compliance appears to have been successful in this instance as Acceleron appears to have voluntarily complied with the notice of noncompliance by submitting its study results on April 28, and also has corrected data for another trial that appeared to be overdue.
In contrast to the FDA, which is the agency tasked with enforcing the reporting requirements codified in the Public Health Service Act, the EU institutions have no power to impose penalties on trial sponsors who fail to publish clinical trial results in the EU database as required by Article 37.4 of the regulation. However, Article 94 of the regulation requires that EU member states establish rules concerning penalties to be imposed in these circumstances.
This obligation will also be extended to the countries in the European Free Trade Association pillar of the European Economic Area, which includes Iceland, Liechtenstein and Norway. Given the varying related approach by the individual EU member states, this may lead to a discrepancy in the penalties that sponsors who fail to fulfill related obligations will face depending on the country in which the penalty is imposed.
It remains to be seen whether EEA countries may adopt the FDA's two-bites-at-the-apple approach for voluntary compliance, or whether any states would propose civil money penalties or other tools to enforce the regulatory requirements. Additionally, time will tell whether and under what circumstances the FDA may utilize the additional civil and criminal enforcement tools available to it under the Federal Food, Drug and Cosmetic Act.
Given the increased interest by the FDA in enforcement in this area, as well as the upcoming substitution of the Clinical Trials Directive by the Clinical Trials Regulation in the EEA, drug and device sponsors and principal investigators should review their clinical trial registration and results disclosures carefully to ensure they are complying with all statutory and regulatory requirements.
 National Library of Medicine Press Release, "National Institutes of Health Launches 'ClinicalTrials.gov'" dated 2/29/2000 (available at https://www.nlm.nih.gov/archive/20040831/news/press_releases/clntrlpr00.html). Note that the Food and Drug Administration Modernization Act of 1997 (a 1997 Amendment to the Federal Food, Drug, and Cosmetic Act), required NIH to create a public registry of federally or privately-funded clinical trials conducted under an IND to test the effectiveness of experimental drugs for patients with serious or life-threatening diseases or conditions.
 See 42 C.F.R. § 11.28(a) (effective January 1, 2017); 42 U.S.C. § 282(j)(2)(A)(ii).
 See generally 42 C.F.R. Part 11.
 See 42 C.F.R. § 11.10(a).
 See 42 C.F.R. § 11.44(a); 42 U.S.C. § 282(j)(2)(C).
 Martin H.Voss, et al., A phase 2, randomized trial evaluating the combination of dalantercept plus axitinib in patients with advanced clear cell renal cell carcinoma, 125 Cancer 14 (2019) (available at https://pubmed.ncbi.nlm.nih.gov/30951193/).
 The EEA consists of the 27 EU Member States plus the three countries in the EFTA pillar of the EEA, Iceland, Liechtenstein and Norway. Switzerland is not a member country of the EEA although it is a member of EFTA.
 Food and Drug Administration Press Release, "FDA Takes Action For Failure to Submit Required Clinical Trial Results Information to ClinicalTrials.Gov" dated 4/28/2021 (available at https://www.fda.gov/news-events/press-announcements/fda-takes-action-failure-submit-required-clinical-trial-results-information-clinicaltrialsgov).
 See A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH) (PULSAR) (results last updated May 5, 2021) https://clinicaltrials.gov/ct2/show/NCT03496207.
 See 42 U.S.C. § 282(j); 42 C.F.R. § 11.44(a).