2022-05-09 TMF Reference Model General Meeting, 09 May 2022

This video provides an in-depth exploration of the TMF Reference Model's general meeting from May 2022, primarily focusing on its strategic affiliation with CDISC (Clinical Data Interchange Standards Consortium) and the anticipated impact of the EU Clinical Trials Regulation (EU CTR) on Trial Master File (TMF) content and processes. The meeting, attended by a large community of TMF professionals, featured presentations from Dave Evans, President and CEO of CDISC, and Mary from Pfizer, alongside updates from Karen, representing the TMF Reference Model. The overarching theme was the critical need for standardization, interoperability, and regulatory compliance in clinical research documentation.

Dave Evans' presentation detailed CDISC's mission to develop and support global, platform-independent data standards that enhance information system interoperability in medical research. He outlined CDISC's 20-year history as a non-profit standards development organization, emphasizing its evolution into a "standards governance organization" that maintains and governs existing standards. Evans highlighted CDISC's extensive volunteer network, diverse membership (from small biotech to large pharma and regulatory agencies), and its widely adopted, freely available clinical research data standards. A key aspect of CDISC's strategy is moving beyond traditional documents and spreadsheets to machine-readable formats, facilitated by its innovative open-source technology for standards library metadata management, which allows for consumption by both humans and machines and integration via APIs.

The affiliation of the TMF Reference Model with CDISC is positioned as a significant step towards formalizing TMF standards within the broader clinical research ecosystem. This collaboration aims to leverage CDISC's established global standing, expertise in promoting interoperability, and capabilities in developing machine-readable metadata and implementation guidance. The goal is to elevate the TMF to a recognized standard, akin to CDISC's data standards that are mandated by regulatory bodies like the FDA and PMDA. This move is expected to bring the TMF "right out center in front with the regulators," ensuring that TMF considerations are integrated into broader regulatory discussions and fostering greater efficiency, data reuse, and quality across the industry.

The latter part of the meeting focused on the impact of the EU CTR on TMF content and process. While the EU CTR itself provides limited explicit guidance on TMF, it mandates that relevant documentation allows for effective supervision, is readily available, and directly accessible, with a new 25-year archiving requirement. The EU CTR represents a fundamental shift in clinical trial approvals in Europe, centralizing processes and introducing extensive event reporting. This leads to a significant increase in documentation generated during the submission and approval phases. A major implication for TMF is the management of "redacted" versus "non-redacted" documents, as information submitted to the CTIS (Clinical Trials Information System) will be publicly published, necessitating careful handling of commercially confidential or personal data. The discussion also touched upon potential new sub-artifacts for the TMF, such as protocol synopses and clinical trial summary reports for laypersons, and the challenges of avoiding duplication when integrating CTIS-generated documents into the TMF.

Key Takeaways:

• Strategic Affiliation with CDISC: The TMF Reference Model's affiliation with CDISC is a pivotal move to formalize TMF standards, gain global regulatory recognition, and integrate TMF documentation into the broader clinical research data standards ecosystem.
• CDISC's Evolving Role: CDISC is transitioning from solely developing standards to actively promoting their implementation, automation, and interoperability, aiming to make clinical research data and documentation more efficient and usable across the industry.
• Machine-Readable Standards: CDISC emphasizes the importance of moving beyond traditional documents to machine-readable formats for standards, utilizing metadata repositories and APIs to enable digital data processes and enhance interoperability between systems.
• Benefits of Standardization: Standards are crucial for achieving semantic clarity, organizing clinical information, facilitating efficient sharing among stakeholders (vendors, sponsors, regulators), and supporting new scientific advancements, ethics, safety, and overall data quality.
• EU CTR's Transformative Impact: The EU Clinical Trials Regulation (EU CTR) marks the most significant regulatory change in European clinical trials in a long time, centralizing approval processes and introducing a new paradigm for documentation and public disclosure.
• Increased Documentation Volume: The EU CTR's event-based reporting and centralized submission process via CTIS will generate a substantially higher volume of regulatory and submission-related documentation that needs to be managed within the TMF.
• Redacted vs. Non-Redacted Documents: A major challenge under EU CTR is managing both redacted (for public disclosure via CTIS) and non-redacted (for TMF and regulatory review) versions of documents, requiring clear strategies to avoid duplication and ensure the correct version is accessible.
• Archiving Requirements: The EU CTR extends the archiving period for clinical trial essential documents to 25 years, a significant increase that necessitates robust long-term archiving strategies and consideration of different media types.
• TMF Content Adaptation: While the core types of documents remain similar, the EU CTR necessitates new sub-artifacts (e.g., protocol synopsis for laypersons, clinical trial summary report for laypersons) and careful consideration of how to incorporate CTIS-generated submission evidence and notifications.
• Interoperability with CTIS: The lack of an API for CTIS means manual data entry and challenges in integrating CTIS outputs (e.g., downloaded submission packages) into the TMF without creating unnecessary duplication.
• Proactive Impact Assessment: Companies conducting trials in Europe must proactively assess the EU CTR's impact on their TMF processes, document management systems, and overall regulatory compliance strategy, including decisions on where to collate documents (eTMF, regulatory systems, or both).
• Ongoing Implementation Work: The TMF Reference Model and CDISC have established an implementation team focused on transitioning membership, communication, events, standards alignment, and technology integration to ensure a smooth affiliation.
• Free Access to TMF Reference Model: Despite the affiliation with CDISC, the TMF Reference Model and its content will remain freely available to the industry, promoting widespread adoption and standardization.

Tools/Resources Mentioned:

• CDISC Library: An innovative technology platform serving as a metadata repository and registry for CDISC standards, designed for machine-readable consumption and API integration.
• CTIS (Clinical Trials Information System): The European database for regulatory submissions under the EU CTR.
• Mailchimp: Used for launching the TMF Reference Model survey.
• YouTube: Platform for hosting webinar recordings.

Key Concepts:

• TMF Reference Model: A standardized, hierarchical model for organizing and filing essential documents of a clinical trial, crucial for regulatory compliance.
• CDISC (Clinical Data Interchange Standards Consortium): A global non-profit organization that develops and supports data standards for medical research to improve data exchange and interoperability.
• EU CTR (EU Clinical Trials Regulation): A European Union regulation that harmonizes the assessment and supervision processes for clinical trials throughout the EU, replacing the previous Clinical Trials Directive.
• Interoperability: The ability of different information systems, devices, or applications to connect, communicate, and exchange data in a coordinated manner, without special effort from the end user.
• Machine-Readable Standards: Data standards that can be automatically processed and understood by computer systems, enabling automation and seamless data exchange, as opposed to human-readable documents.
• Metadata Repository: A database that stores information about data (metadata), such as its structure, meaning, and relationships, facilitating data management and understanding.
• Redacted/Non-Redacted Documents: Versions of documents where sensitive information (commercial confidentiality, personal data) is obscured for public release (redacted) versus the full, original version (non-redacted).