TMF Risk Base Quality Control

This video provides an in-depth exploration of Trial Master File (TMF) risk-based quality control (QC), addressing the persistent challenges faced by clinical trial sponsors and Contract Research Organizations (CROs in achieving TMF health and inspection readiness. The presenter begins by highlighting the omnipresence of TMF QC discussions at conferences, underscoring the industry's struggle to efficiently implement quality control and review activities. Drawing upon ICH E6 R2 guidelines, the video defines quality control as operational techniques and activities within a quality assurance system designed to verify that trial-related activities meet quality requirements. This foundational definition emphasizes the need for QC to be embedded under a predefined, documented regime and executed according to specific quality level requirements, including a crucial verification step often misunderstood.

The core of the discussion revolves around how to effectively meet these QC requirements, particularly in the context of a TMF. ICH E6 R2 advocates for QC activities to focus on aspects essential for human subject protection and trial result reliability, acknowledging that not all TMF management aspects directly impact subject safety or data integrity. This principle of proportionality is further reinforced by EMA guidelines, which explicitly recommend implementing risk-based quality checks or review processes. The video then introduces a structured, four-step risk-based approach: identification of critical processes and data, identification and assessment of risks, implementation of risk controls through tailored quality review, and robust risk communication, review, and reporting.

The first step, identification of critical processes and data, involves assessing TMF content to pinpoint documents or artifacts with the potential to adversely impact subject protection and data reliability. The video notes the absence of an industry standard classification, necessitating each sponsor to make its own determination, suggesting categorization into criticality groups (e.g., high, medium, low) or assigning impact scores. The second step focuses on identifying and assessing risks, outlining three primary TMF management risks: poor document quality (not meeting GCP/internal requirements), incorrect filing (poor indexing), and missing documents. Risk assessment can involve evaluating the effort required to demonstrate compliance in case of quality issues, or, more effectively, leveraging empirical data from eTMF systems. A purpose-built eTMF can provide metadata on document availability, due dates, and study milestones, allowing organizations to identify artifacts frequently filed late or incorrectly and assign them to appropriate risk groups.

The final two steps detail risk controls and communication. Step three, risk controls, advocates for implementing tailored quality review processes rather than a one-size-fits-all approach. Based on risk categorization, some artifacts may require no review, others 100% review, and many can be managed through sampling. A critical warning is issued against using spreadsheets for managing QC activities, citing their resource intensiveness, error proneness, and potential to contribute to inspection findings. Instead, the video stresses that eTMF systems should be capable of identifying artifacts due for QC, tracking issues, and ensuring resolution. Step four, risk communication, review, and reporting, highlights the eTMF's role in efficiently communicating TMF status, outcomes, and trends. It emphasizes that a TMF quality regime should be cyclical, with QC failure data feeding back into future review activities, enabling continuous improvement and allowing high-risk artifacts to potentially become low-risk over time through timely escalation and user education.

Key Takeaways:

• Definition of Quality Control (QC): According to ICH E6 R2, QC involves operational techniques and activities within a quality assurance system to verify that trial-related activities fulfill quality requirements, necessitating a predefined, documented regime and specific quality level understanding.
• Requirements for Effective QC: Effective TMF quality control requires embedding activities within a quality assurance system under a predefined and documented regime, and executing them according to specific quality level requirements, including a verification step (quality review).
• Principle of Risk-Based QC: QC activities should be proportionate to the risks inherent in the trial and the importance of the information collected, focusing on aspects essential for human subject protection and reliability of trial results, as mandated by ICH E6 R2 and EMA guidelines.
• Four-Step Risk-Based Approach: A comprehensive risk-based TMF QC strategy involves (1) identification of critical processes and data, (2) identification and assessment of risks, (3) implementation of risk controls (quality review), and (4) risk communication, review, and reporting.
• Criticality Assessment: Identifying critical TMF artifacts requires assessing their potential to adversely impact subject protection and data reliability. There is no industry standard classification, so sponsors must determine their own, often categorizing documents into high, medium, or low criticality groups or assigning impact scores.
• Primary TMF Management Risks: The three main risks in TMF management are documents not meeting GCP/internal requirements (poor quality), incorrect filing (poor indexing), and documents missing from the TMF.
• Empirical Data for Risk Assessment: Leveraging eTMF system metadata is crucial for identifying risks. Data on document availability compared to due dates or study milestones can reveal artifacts frequently filed late or not at all, allowing for data-driven risk grouping.
• eTMF for Quality Issue Tracking: Purpose-built eTMF solutions with embedded quality review workflows can capture QC rejections and reasons (e.g., missing signatures, page numbers), providing empirical data to identify artifacts most frequently indexed incorrectly or containing content errors.
• Impact of Document Lifecycle and Active Use: Documents undergoing content review and inline approval workflows in the eTMF are likely to have fewer quality issues. Similarly, documents actively referenced by study team members tend to have quality issues highlighted sooner, making unreferenced documents higher risk.
• Defining a Comprehensive QC Strategy: An effective QC strategy considers four factors: artifact impact on patient safety/rights/data integrity, effort to demonstrate compliance where quality issues exist, likelihood of quality issues based on empirical data, and robustness of document review processes.
• Tailored Quality Review: Risk controls involve configuring different review activities based on risk categorization. Some low-risk, non-critical artifacts may not need review, while high-risk ones might require 100% review, and others can use sampling.
• Warning Against Spreadsheets for QC: Managing quality review activities with spreadsheets is highly discouraged due to being resource-intensive, error-prone, and confusing. A sponsor's root cause analysis revealed Excel use for tracking periodic reviews as a major contributor to critical inspection findings.
• Importance of Purpose-Built eTMF: A dedicated eTMF built on TMF best practices is essential for efficient risk communication, review, and reporting, enabling easy surfacing, reporting, and escalation of TMF status, outcomes, and trends, which general document management systems or spreadsheets cannot do well.
• Cyclical Quality Improvement: A TMF quality regime should be cyclical, with data on QC failures feeding back into future quality review activities. This continuous feedback loop, combined with timely escalation and user education, can lead to ongoing productivity and quality improvements.

Tools/Resources Mentioned:

• eTMF Systems: Purpose-built electronic Trial Master File solutions are highlighted as critical for managing metadata, workflows, tracking QC issues, and generating empirical data for risk assessment and reporting.
• Anonymized Data Warehouse of eTMF Metadata: A select few eTMF providers can offer access to anonymized data warehouses, enabling organizations without sufficient historical data to identify quality trends across numerous sponsors.

Key Concepts:

• Trial Master File (TMF): A collection of essential documents that individually and collectively permit evaluation of the conduct of a clinical trial and the quality of the data produced.
• Quality Control (QC): Operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.
• Quality Assurance (QA): The overall system that ensures the quality of the trial.
• ICH E6 R2: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Guideline for Good Clinical Practice (GCP), an internationally accepted standard for clinical trials.
• EMA Guidelines: European Medicines Agency guidelines, specifically on the content, management, and archiving of the clinical trial master file.
• Good Clinical Practice (GCP): An international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects.
• Risk-Based Quality Control: An approach to QC that focuses resources and efforts on the aspects of a trial that are most critical to human subject protection and data reliability, proportionate to the risks involved.
• Critical Process/Data: Elements within the TMF whose potential failure or inaccuracy could significantly impact subject protection, data reliability, or regulatory compliance.
• Risk Control: The implementation of tailored quality review processes and other measures to mitigate identified risks.
• Risk Communication, Review, and Reporting: The systematic process of sharing information about TMF risks, monitoring their status, and reporting on their management and outcomes.

Examples/Case Studies:

• Excel for QC Tracking Pitfall: A sponsor at a TMF Summit in Orlando (January 2019) performed a root cause analysis for critical inspection findings and discovered that a major contributing factor was the use of Excel spreadsheets for tracking their periodic reviews, highlighting the dangers of inadequate system support for QC.