In 2021, FDA issued its first three official notices of noncompliance on the clinicaltrials.gov website for failure to comply with reporting obligations. Two were issued to clinical trial sponsor companies and one to an individual—a sponsor investigator.

These represent the first such warnings since the regulations for the human clinical trials database were implemented in the Code of Federal Regulations 42 CFR Part 11 in a 2016 final rule.

[Related: Find out how author Jerry Chapman used AI to identify FDA GCP inspection trends by downloading a recording of the webinar, “FDA GCP Inspection Trends Identified Using AI.”]

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What is ClinicalTrials.Gov?

ClinicalTrials.gov is a combination clinical studies registry and results database for human clinical studies run by the National Library of Medicine at the National Institutes of Health (NIH).

It was established under the FDA Modernization Act (FDAMA) of 1997. Requirements for submitting trials and results information were subsequently expanded by the FDA Amendments Act (FDAAA) of 2007 and implemented by regulation in 2016.

At the Food and Drug Law Institute (FDLI) Enforcement Conference in December 2021, FDA CDER Office of Compliance Director Donald Ashley discussed the ClinicalTrials.gov site, addressing FDA’s role and providing details about the agency’s recent compliance actions.

He described ClinicalTrials.gov as “a unique program because NIH has implementation responsibilities for the data bank itself, while FDA has the primary enforcement authority.” FDA’s primary responsibilities are to enforce the registration and results from submission requirements related to ClinicalTrials.gov and are “operationalized as an agency-wide program” (Figure 1).

Figure 1 What Are FDA Responsibilities
FIGURE 1 | What Are FDA Responsibilities?

Ashley explained that a first step in the compliance process is issuance of “pre-notices of noncompliance,” which are not publicly posted.

“We use them to give responsible parties prior notice and an opportunity to prompt voluntary compliance when they fail to register or submit required results,” the CDER Director said.

“If responsible parties fail to come into compliance after receipt of the pre-notice of noncompliance, the next step is an official notification of noncompliance, which we post publicly. And then if the responsible parties still fail to comply, we can initiate the Civil Monetary Penalty Process, though that has not happened yet.”

Compliance Case Study 1: Acceleron Pharma

The first case Ashley highlighted involves a noncompliance notice given to Acceleron Pharma, a clinical trial sponsor. FDA determined that Acceleron failed to comply with its reporting obligations and issued a pre-notice of noncompliance. The notice warned Acceleron that it had failed to submit required results information and gave the company 30 calendar days to voluntarily comply.

“We gave Acceleron ample time to address these issues,” Ashley commented. “However, they still failed to come into compliance.”

On April 27th, 2021, the agency issued an official notice of noncompliance to Acceleron for its continued failure to submit required results information to clinicaltrials.gov.

“This was the first-ever notice of noncompliance issued by the agency,” he pointed out. “We provided Acceleron 30 calendar days to remedy its noncompliance and warned that failure to do so might result in imposition of civil monetary penalties. After receipt of the notice letter, Acceleron promptly submitted results information to ClinicalTrials.gov and we are in the process of evaluating its submission right now.”

Compliance Case Study 2: Accuitis, Inc.

The second case also involved the sponsor of a trial, Accuitis, Inc. Accuitis was issued a pre-notice letter on October 26, 2020, and an official notice of noncompliance on July 26, 2021, for failure to update the primary completion date for the applicable clinical trial within 30 days after the trial had reached that date.

As with Acceleron, Accuitis promptly submitted the requested information after receipt of the official noncompliance notification. FDA notes on the clinicaltrials.gov website that Accuitis “submitted results information within the 30 calendar days of receipt of the Notice letters. Results information for these applicable clinical trials has undergone or is undergoing quality control review.”

[Related: “General Responsibilities of Investigators Conducting Study” and “Investigator Recordkeeping and Record Retention > Case Histories” were the Top 2 most common FDA 483 GCP observations for clinical investigators last year. What were the other common observations? Contact us today to learn how Redica can help you with inspection preparation when it comes to FDA GCP inspections.]

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Compliance Case Study 3: Sponsor Investigator

The third case involves a sponsor investigator—an individual rather than a company. Like the two earlier cases, FDA determined that Dr. Petrikovets failed to comply with his reporting obligations.

Ashley shared that in response to the pre-notice of noncompliance the agency sent, Dr. Petrikovets provided a copy of a published manuscript for the report of the clinical trial.

“We explained that published results in a manuscript are not sufficient to meet the requirements for submission of clinical trial results information to the ClinicalTrials.gov database. And we engaged in several conversations to help explain the requirement and provide the opportunity for voluntary compliance.”

After failure to submit the required information, Dr. Petrikovets received an official notice of noncompliance warning of the possibility of civil monetary penalties if he failed to submit results information to ClinicalTrials.gov. His subsequent submission is undergoing quality control review at the agency.

“There are some stiff penalties for responsible parties who have failed to heed warnings from FDA,” the CDER Director warned. “Beyond the official notifications of noncompliance, FDA has the authority to impose civil money penalties, and of course, we can and do refer cases to our colleagues in the Office of Criminal Investigations. There are also grant funding implications.”

He concluded by reiterating that once FDA issues a notice of noncompliance it becomes public and is posted on the ClinicalTrials.gov website, whereas the pre-notice is not, indicating an advantage to the company in resolving issues before they become public.

Additional Resources

Data Integrity and Your Clinical Investigator: What the Data Shows

The Components of “Responsibilities of the Investigator” Observations

[Related: When it comes to clinical investigator 483 observations, what can an analysis of FDA 483 observations show? Find out by downloading the recording of a recent webinar featuring author Jerry Chapman.]

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