Clinical Trial Quality Management: ICH E6 (R2) Interpretations Deepen


Applied Clinical Trials

ICH E6-R2 has taken another leap forward as quality-focused personnel have shifted focus to vendor oversight plans, essential document management, and evaluating quality tolerance limits in more depth.

ICH E6-R2 has taken another leap forward as quality-focused personnel have shifted focus to vendor oversight plans, essential document management, and evaluating quality tolerance limits in more depth. In this article, we will delve into some of those areas.

ICH E6 (R2): a focus on vendor oversight plans

There has been a shift in discussion and focus of ICH E6-R2 towards vendor oversight. Liz Wool, of Wool Consulting Group, recommends that a vendor oversight plan template structure includes a cover page (necessary vendor information, such as name, address and approval signatures); study contacts (vendor, sponsor); introduction (summary of activities and duties, and governing SOPs); governance (name of governance documents, teams, and role and responsibility of clinical quality); oversight activities for the delegated duty and function (activity, sponsor responsible person, vendor responsible person, frequency of review, reference standard for review of work product, documentation and feedback to vendor, effectiveness checks of the oversight methods and documentation), which includes oversight of the computerized/electronic systems used, oversight of vendor sub-contractors, vendor risk management plan, staff qualification and selection (job functions governed by the plan, sponsor processes for vendor approval and rejection, and official authorization forms); team training (vendor on-boarding and training, master training matrix, training materials, training documentation, and sponsor staff training requirements); feedback (how feedback is provided, and who provides feedback); and communications plan (routine, escalation, reports, meeting types, and documentation). Additionally, Wool says that it is essential to include effectiveness checks of oversight plan (referencing company procedures, process, frequency, methods, and responsible parties), vendor transition (procedures for transition, sponsor responsibilities, and documentation), and procedural documents (SOPs, valid dates, and deviations). Wool emphasizes the importance of vendor quality performance metrics, such as adherence to contractual obligations, deliverables achievements, metric reporting, and allocating a sponsor person to assess metrics and takes action.

Essential documents outlined in ICH E6 (R2) §8

Michele Weitz, Senior Director of GCP Compliance Operations at Clovis Oncology, advises documents that should be included in the trial master file (TMF), pertain to what would be required during an inspection, and document retention requirements. Weitz points out that while Section 8 of the revised ICH Guideline for GCP lists many documents required as evidence of a compliant clinical trial, other documents referenced throughout the guideline are also critical. These include investigator documents evidencing investigator qualifications to conduct research; qualified personnel to whom tasks are delegated; adequate staff and facilities; informing staff about the protocol, investigational product, and trial-related duties/functions; protocol deviations; and investigational product storage specifications and documentation. Sponsors are responsible for demonstrating the ongoing safety evaluation of the investigational product; ensuring that monitors thoroughly understand the investigational product,  protocol, study consent forms, and other written information provided to subjects; and providing effective oversight of  monitoring via review or monitoring reports and follow up documentation. To be inspection ready, Weitz stressed the importance of a contemporaneous TMF with traceable alterations and added that the TMF should provide document identification, version history, and must be readily available and directly accessible upon request. Moreover, TMF documentation must adequately reconstruct trial activities undertaken, and demonstrate critical decisions made concerning the trial.  Weitz indicated that per ICH E6 (R2), sponsor and investigator documents should be retained at least two years after formal program discontinuation; however, some regulations may require document retention up to 25 years after marketing approval or trial completion. Finally, Weitz suggested that while many sponsor companies house a single study’s TMF files in a “hybrid” system that may include paper and electronic files in different departmental systems and locations, CRO systems, there is significant benefit to investing in a “single source of truth” electronic system where all users can file and/or access the documents they need to run and evidence a compliant clinical trial with reliable data.

Defining quality tolerance limits (QTLs)

Celeste Gonzalez, Principal Specialist of Clinical QA at Boston Scientific, recommends establishing QTLs that identify systematic issues impacting data integrity and safety, determining which risks to reduce and which to accept, and outlining and incorporating risk reduction activities. Gonzalez suggested that developing QTLs requires generating risk indicators (specific risk variables and data points), and risk thresholds (the level or value associated with a risk indicator that will trigger an action). Gonzalez emphasized that QTLs are set at the trial level, triggers evaluations when deviations are detected, and evaluations determine whether there is a systemic issue across an entire study. To determine which risks to reduce and which ones to accept, Gonzalez hinted to keep tolerance limits from three to five that will impact subject safety and reliability of trial results. Risk reduction activities include event-driven tolerance limits (i.e., unreported/late reported SAEs, randomization errors, and inclusion/exclusion criteria violations), distribution-driven tolerance limits (i.e., premature terminations/dropouts) and trial data (i.e., precision, accuracy and timing of clinical measurements as they relate to the importance of the variable to the trial’s objectives).


Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.

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