Inspections are anticipated to begin in the near future and the risk of non-compliance will have a financial impact.

In 2007, the Food and Drug Administration Amendments Act (FDAAA) was passed. Title VIII of this act requires sponsors to register and provide results for Applicable Clinical Trials (ACTs) on a public database.

Responsibility for implementation was given to the National Library of Medicines (NLM), which used the existing ClinicalTrials.gov database and website to fulfill their obligation. In September of 2012 the Food and Drug Administration (FDA) was given the authority to enforce compliance with FDAAA. 

In September 2016, two disclosure-related items made the news in the U.S. The first was the issuance of “42 CFR Part 11, Clinical Trials Registration and Results Information Submission,” commonly referred to as the “Final Rule.” Anticipated since 2009, the Final Rule clarifies and enhances requirements for registering clinical trials and disclosing results. 

Concurrently to the Final Rule, the National Institutes of Health (NIH) issued the “NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information.” This policy requires that all clinical trials that are conducted with NIH funding must be registered and results must be disclosed on ClinicalTrials.gov, irrespective of whether the study is applicable to other legal obligations, such as FDAAA or the Final Rule.

Penalties

Penalties for non-disclosure or submitting false or misleading information includes criminal and civil judiciary action, civil monetary penalties, and grant funding penalties. Fines of $10,000 for each infraction and $10,000 per day until the issue is resolved can be levied for non-compliance.

To date, there has been no specific enforcement of FDAAA, and no fines levied, although some sponsors may have disclosure-related language included in Corporate Integrity Agreements (CIA).

Additionally, certain regulatory submissions such as IND, NDA, BLA, PMA, etc. require the inclusion of Form 3674, which certifies that the submitting organization has complied with trial disclosure regulations. A representative of the organization must sign this form and is personally liable for the accuracy of the information since making a willfully and knowingly false statement is a criminal offense.

With the publication of the Final Rule in September 2016, ambiguities with identifying ACTs under FDAAA have largely been resolved. It is widely anticipated within industry that the issuance of the Final Rule opens the door to FDA enforcement activities.

What actions can clinical trial sponsors take now to ensure they are prepared for a possible inspection?

Review Your Studies on ClinicalTrials.gov

Review the studies that you have registered on ClinicalTrials.gov and make sure that the information registered is up-to-date and correct. As part of this review, be sure to consult the problem studies identified in the Protocol Registration and Results System (PRS) data entry system.

This selection of problem records helps to identify, among other things, if required data is missing and if the study is late submitting results according to regulation. Review this list carefully and try to address the issues causing the study to land on the report. The FDA is likely to focus on studies that show up on the report.

Review Corporate Policies

Review your corporate or organization’s policies to determine if the Declaration of Helsinki, the World Health Organization, or trade organizations such as PhRMA, EFPIA, or BIO are referenced. These organizations have statements related to the publication of clinical trial data.

The FDA could find that you are not in compliance with your corporate policies if you do not adhere to the standards published by these external organizations. These references might not be included in disclosure-specific policies, so a review of all corporate policies may be necessary to identify unexpected obligations.

Review SOPs

Review your disclosure Standard Operating Procedures (SOPs) and Work Instructions (WIs) to determine if they reflect your current disclosure practices. Are they written in a way that is flexible enough to accommodate the current regulatory changes, or do they need frequent updates when changes occur? 

Do they align with your corporate policies and public disclosure stance? If there are gaps between your current practices and your SOPs and WIs, make a plan to close the gap. The FDA Inspector will take a close look at how you perform against these important documents.

Conduct an Internal Audit

Once you have cleaned up your studies on ClinicalTrials.gov, acknowledged external corporate commitments, and aligned your SOPs and WIs with current practices and obligations, it is a good idea to schedule and internal audit. The internal audit should identify areas of concern before they are found by an FDA Inspector. It will also give you a test-run of how you can provide the data to an inspector.

Will you allow the inspector to look directly into your Clinical Trial Management System (CTMS) or your disclosure system, or do you need to print out various pages for review? How long does it take to collate the information for an inspection and how many people does it take?  Can you make this process more efficient by building reports that will help provide the information that an auditor needs without disrupting the team?

Create a Remediation Plan

Use the findings from your internal audit to create a remediation plan to resolve any issues.   Include priorities, timelines, and responsibilities in the remediation plan to instill a sense of urgency and accountability.  Have key stakeholders agree on the plan because you may need to account for additional time and resources to remediate.

Remediate the Issues

Once you have a plan, start remediating the issues. Meet with the key stakeholders on a regular basis to monitor progress and alleviate roadblocks.

Develop a Plan for Demonstrating Compliance to Inspectors

Consider how you will respond to questions from the FDA inspectors and what evidence you will provide. 

In responding to a question about the disclosure history and compliance for a specific study, this might be a report that includes a summary of the study, a list of stakeholders that participated in the disclosure processes, the dates that protocol or results forms were submitted or updated, and a document version history for each submitted form.

Conclusion

FDA inspections of clinical trial disclosure practices are anticipated to begin in the near future. The current rash of articles and publications criticizing the perceived lack of clinical trial disclosure have focused on large pharma and biotech companies.

FDA inspectors are less likely to focus their inspections on one sector of the industry. They can and probably will select organizations of varying sizes, number of studies, and number of products.

Because of the increased publicity of clinical trial disclosure, compliance is a corporate concern that has risen to the C-suite. The risk of non-compliance will have financial impacts and can become a public relations issue that directly influences your brand integrity in the marketplace. Prepare your team and your clinical trial disclosure data early for a successful inspection.

It is worth the investment.

(TrialScope, based in Jersey City, NJ, assists clinical trial sponsors with improving their disclosure capabilities and gaining control over clinical trials registration and reporting processes.)

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