News Updates

New regulations cause a scramble to understand them, their impacts, and the timelines required to move from words in a document to compliance with daily activities. Many face this daunting task with a healthy dose of anxiety and uncertainty surrounding the interpretation of the new requirements and questions that naturally arise whenever current processes need an adjustment.

In September 2016, the Global Clinical Trial Disclosure Community was in such a position when the US Department of Health and Human Services (HHS) issued 42 CFR Part 11 for Clinical Trials Registration and Results Information Submission, commonly referred to within the disclosure community as the “Final Rule.” The Final Rule was a required update to Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA). It clarifies and expands requirements for registering clinical trials and disclosing clinical trial results. Studies and results are made publicly available on the ClinicalTrials.gov website.

Understanding the Final Rule

The Final Rule is an evolution of FDAAA (Food and Drug Administration Amendments Act) requirements. Because of this, it is important to understand not only the requirements for the Final Rule, but how they differ from the previous requirements.

Effective Dates

The Final Rule became effective on January 18, 2017. Studies subject to the Final Rule must comply with the new protocol registration requirements if they started enrolling participants on or after this date, and the new results requirements must be followed if they complete data collection for the primary outcome measure(s) on or after this date. Studies for which these milestone dates are earlier than January 18, 2017 are subject to the protocol and results requirements in FDAAA.

Applicable Clinical Trials

Applicable Clinical Trials (ACT) are defined as studies that are subject to the Final Rule. Under FDAAA, there was some ambiguity when attempting to identify studies that were subject to the regulation and those that were not. Under the Final Rule, ACTs can be definitively identified through the required data elements collected for each study. ACTs can be summarized as follows:

• Interventional studies
• Phase 2-4 studies (for drug studies), or where the primary purpose is not a feasibility study (for device studies)
• With one or more pre-specified arms
• Studies a drug, biologic, or device product regulated by the FDA;

And one or more of the following are true:

• One or more sites in the US or US territory
• Conducted under an US IND or IDE, or
• One or more products being studied is manufactured in the US or a US territory and exported.

Results Required for All ACTs

Under FDAAA, results were required for studies of approved products or indications. Under the Final Rule, this requirement expands to results for all ACTs, including those for unapproved or uncleared products or indications. Although the Final Rule went into effect on January 18, 2017, results for ACTs are due one year after the Primary Completion Date, thus the results records must meet the new results requirements starting on January 18, 2018.

Expanded Access

Expanded access, sometimes referred to as compassionate use, makes an unapproved medical product available to patients outside a clinical trial. Providing information on expanded access programs was optional prior to the Final Rule. Now, sponsors who are also manufacturers of the investigational product are required to provide information about expanded access programs and link relevant studies to the expanded access record.

Updates to Registration and Results Data

Under FDAAA, studies needed to be updated every 12 months, unless there was a change to the overall status of the study, which required an update within 30 days (all deadlines are denoted in calendar days). The Final Rule increases the number of data elements where a change triggers an update on a more frequent basis.

The approval or clearance status of a device must be updated within 15 days of approval or clearance and the following data elements must be updated within 30 days of change:

• Study dates (study start date, primary completion date, study completion date)
• Enrollment status
• Overall study recruitment status
• Individual site status changes (including for sites outside the US)
• Human Subject Review Board status
• Intervention name, once a non-proprietary name is issued
• Availability or changes to expanded access
• Linking relevant studies to the expanded access record
• Responsible party.

In addition, a complete review of the submitted study data must be done every 12 months with an update to the verification date.

Correcting Data

Each record is reviewed by a member of the ClinicalTrials.gov team prior to publication on the website. The Final Rule defines that sponsors must address issues raised by this quality review within 15 days for protocol registration data, and within 25 days for results data. Records that have outstanding issues will be published on the ClinicalTrials.gov website with a notification that the data do not meet the quality standards.

Identifying Challenges

As with any new regulation, there are several challenges to operationalize the new requirements and bring an organization into compliance.

One challenge is achieving a general understanding of the regulation. In the case of the Final Rule, the Federal Register publication results in a 177-page document when converted to a PDF document. A large portion of this document is the preamble, which includes a summarized history of the disclosure regulations, discussion of public comments, and explanations of what was included in the final regulation.

Another challenge is understanding how the regulation fits in the context of your organization. Which existing policies or procedures are affected and does the regulation require the creation of new ones? Finally, how are daily practices impacted by the new regulation? Which groups or departments within the organization need to be informed of the new requirements and trained on new processes?

Sharing Perspectives

DIA has a Clinical Trial Disclosure (CTD) Community for clinical trial disclosure specialists. The CTD Community has over 325 very active members that include various Life Sciences organizations from biopharmaceutical and device to academia, to government agencies, and solution providers. In order to start digesting the Final Rule, the CTD Community quickly organized a working group with facilitator Francine Lane. This working group met several times between September and November 2016 to read and discuss the Final Rule.

Each participant read the Final Rule individually and had discussions with their internal regulatory and legal teams. The working group provided an opportunity to bring together our different perspectives and interpretations and if possible, come to a collective understanding of the Final Rule. We documented our issues, questions, and ideas in a shared Final Rule Q&A document. This document was shared with the larger CTD Community and with representatives from the National Institutes of Health (NIH) who are responsible for the ClinicalTrials.gov website where ACTs are registered and results are disclosed.

Benefiting the Community

The CTD Community realized several benefits from the working group. Foremost was the exposure to different perspectives, interpretations, and questions that community members could take back to their own organizations to inform the decision-making process. Tab Hoda (Senior Manager, Clinical Data Management, Amgen) felt that the working group helped create a sense of camaraderie, that you weren’t alone trying to figure out how to do the right thing.

The working group continues to provide a central point of contact for the community to triage emerging challenges and questions and update the living Final Rule Q&A document. One unexpected benefit noted by CTD Community Chair Bob Paarlberg was the coordination between the working group and the team at the NIH to identify and prioritize questions to address. Many of these topics are making their way into a general FAQ shared on the public ClinicalTrials.gov website.

Moving Forward

The Final Rule Q&A document continues to be a valuable resource for the CTD Community. Despite the effective date being months in the past and nearly a year after the publication of the Final Rule, it is rare that a week goes by without an addition to the Final Rule Q&A document. The working group hasn’t even started on the nuances regarding results disclosure. Results disclosure requirements for studies applicable to the final rule will become effective in January 2018. The working group is taking the summer off and will start meeting again in the fall to discuss the complexities relating to results. We hope you can join us! You can do so by joining the Clinical Trial Disclosure Community or the Final Rule Working Group.

This article originally appeared in the August 2017 Global Forum.