Trial Master File (TMF) Quality Review: Identify and Mitigate Compliance Risk with PhlexTMF

This video provides an in-depth exploration of Trial Master File (TMF) Quality Review, demonstrating how Phlexglobal's PhlexTMF software facilitates a systematic and compliant approach. The main purpose of the video is to showcase the exclusive quality review functionality within PhlexTMF, which enables periodic review of TMF content to identify and mitigate compliance risks. The presenter begins by establishing the crucial role of periodic or milestone-based reviews in ensuring a well-formed TMF and robust oversight processes. The core idea is to ensure the TMF tells a clear, collective, and accurate story of the clinical trial, as intended by regulatory guidelines.

The video details how reviews are conducted through "packages," which allow for the sampling of documents. The selection of documents for review and the sampling methodology are automated through "review templates." These templates are designed to operationalize an organization's Standard Operating Procedures (SOPs), thereby ensuring that study teams consistently comply with predefined review parameters. The demonstration walks through the process from the perspective of a study manager creating a quarterly review package, naming it, accepting default settings, and then assigning different parts of the review to various members of the study team. This assignment process includes automated notifications, eliminating the need for manual email correspondence and establishing the package as a central command center for tracking review completion.

Further into the demonstration, the video shifts to the reviewer's perspective, illustrating how they receive alerts or emails prompting them to complete a review. Upon accessing the review, the system presents a list of selected documents. A specific example involves reviewing a Form 1572 (Statement of Investigator). The system provides built-in checks tailored to the document type, ensuring completeness, correct filing location, and accurate listing of relevant information, such as IRB details. A key feature highlighted is the cross-checking capability, where the system compares information within the document (e.g., sub-investigators listed on the 1572) against existing system records. This allows reviewers to easily identify discrepancies, such as an investigator listed on the form but not known to the system or the TMF. In such cases, the system enables the reviewer to "raise an event" directly, which automatically triggers the collection of required documents for the newly identified individual, streamlining remediation efforts. The video concludes by emphasizing that all review work and findings are collected into package findings reports, providing transparent and reportable remediation efforts, trend identification, and, most importantly, clear, simple evidence for auditors or inspectors that the quality review process is being followed.

Key Takeaways:

• Systematic TMF Quality Review: The video underscores the critical importance of periodic or milestone-based quality reviews of the Trial Master File (TMF) content to ensure consistency, completeness, and accuracy, which are vital for regulatory compliance and telling a clear story of the clinical trial.
• Automation via Review Templates: PhlexTMF automates the document sampling and review process through configurable "review templates." These templates operationalize an organization's SOPs, ensuring that review parameters are consistently applied and compliance is maintained.
• Centralized Review Management: The system allows study managers to create "review packages," assign specific review tasks to team members, and track progress from a central command center, significantly improving oversight and reducing manual communication efforts.
• Enhanced Efficiency and Productivity: By managing all aspects of quality review within a single system, organizations can achieve greater efficiency and productivity, replacing manual processes and spreadsheets with built-in workflows and best practices.
• Risk-Based Approach to Compliance: The solution facilitates a risk-based approach to TMF Quality Review, aligning with industry guidelines such as ICH E6 (R2), by enabling early identification and resolution of potential issues.
• Early Issue Identification and Mitigation: The system helps identify and resolve potential TMF issues early in the study lifecycle, thereby eliminating the significant cost and effort associated with rework during inspection preparation or at the end of the study.
• Intelligent Cross-Checking Capabilities: PhlexTMF offers intelligent cross-checking features, allowing reviewers to compare information within documents (e.g., investigator lists on Form 1572) against system records to identify discrepancies and ensure data consistency.
• Streamlined Discrepancy Resolution: When discrepancies are found, reviewers can easily "raise an event" within the system, which automatically initiates the process of collecting necessary supporting documents, ensuring prompt and compliant remediation.
• Transparent Reporting and Audit Readiness: All review findings, queries, and remediation efforts are transparently collected and reported, providing clear, simple evidence to auditors and inspectors that the organization is diligently following its quality review processes.
• Reduced TMF Finalization Effort: The systematic approach and early issue resolution significantly reduce the time and effort required to finalize and close the TMF for new applications or study completion.
• Configurable Review Rules: The review rules and checks within the system are configurable, allowing organizations to tailor the quality review process to their specific needs and pertinent regulatory agencies.

Tools/Resources Mentioned:

• PhlexTMF: Phlexglobal's eTMF software solution.
• Review Templates: Automated configurations for document sampling and review parameters.
• Review Packages: System-generated containers for organizing and assigning TMF review tasks.
• Event Raising Functionality: A feature within PhlexTMF to log and manage discrepancies or missing information.

Key Concepts:

• Trial Master File (TMF): A collection of essential documents that individually and collectively permit the evaluation of the conduct of a clinical trial and the quality of the data produced.
• TMF Quality Review (QR): The systematic process of checking TMF documents for completeness, accuracy, and compliance with regulatory requirements and internal SOPs.
• ICH E6 (R2): The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) E6 (R2), which provides a unified standard for clinical trial conduct.
• Form 1572 (Statement of Investigator): A form used in clinical trials in the United States to provide information about the investigator and site, committing to comply with FDA regulations.
• SOPs (Standard Operating Procedures): Detailed, written instructions to achieve uniformity of the performance of a specific function.
• Risk-Based Approach: A strategy that prioritizes activities based on their potential impact on data integrity, patient safety, and regulatory compliance.

Examples/Case Studies:

• Reviewing a Form 1572: The demonstration specifically shows a reviewer checking a Form 1572 for completeness, correct filing, and accurate listing of IRB information.
• Cross-checking Investigator Lists: An example is provided where the system cross-checks investigators listed on the 1572 form against those recorded in the system. When a discrepancy is found (e.g., Dr. Paul Newton is listed on the form but not in the system), an "event" is raised.
• Automated Document Collection: Raising an "event" for a missing investigator automatically triggers the collection of all required documents for that individual, demonstrating how the system streamlines the remediation process.