When introduced in 2017, ICH E6 (R2) represented the most significant change to international clinical research in eighteen years. Developed in response to the rising complexity of studies and the Industry’s increasing reliance on electronic data management, the addendum provides core guidance for clinical research management. The updates incorporate a clear expectation for Risk-Based Quality Management (RBQM) methods, reinforcing the need for risk planning, Quality Tolerance Limits (QTLs), and Centralized Monitoring, including statistical data monitoring. It also supports the need to document centralized monitoring activities and ensure the sponsor oversees CRO services in managing studies.
Another significant update to this ICH guidance – ICH E6 (R3) – is now in the final stages of development with an expectation to publish in 2024. The updated guidance incorporates principles of Quality by Design (QbD) included in the ICH E8 (R1) guidance and, in doing so, ensures that QbD and RBQM are recognized as part of the same holistic, end-to-end risk-based approach to providing high-quality clinical research. Based on the final draft of the R3 guidance, nothing essential has changed concerning RBQM expectations, and more than anything, it’s reinforcing and refining the importance of risk-based approaches. Language has been updated in specific areas related to RBQM to better align with QbD concepts incorporated into ICH E8 (R1). One notable update is the replacement of the term “quality tolerance limits” with the term “acceptable ranges.” However, the essential expectations for the concept remain in place.
ICH guidance is generally adopted by the major regulatory authorities such as FDA, EMA, PMDA, etc.
- The responsibility for the quality and integrity of trial data resides with the sponsor, even if trial duties are outsourced to a Clinical Research Organization (CRO).
- Quality assurance systems should focus on human subject protection and the reliability of trial results.
- Sponsors should implement a quality management system from trial design through close out.
- Sponsors should use a risk-based approach to develop the study protocol and materials.
- Sponsors should perform a root-cause analysis and implement and document corrective and preventative actions for all issues.
- Every study requires a monitoring plan that includes information on the potential risk of harm to participants, critical data and processes, etc.
In the spring of 2018, the FDA published its updated thinking on regulatory standards for clinical trials, which took the form of a document produced collaboratively with the International Council for Harmonisation (ICH): E6 (R2) Good Clinical Practice: Integrated Addendum to ICH E6 (R1). This document represents the FDA’s current thinking on ethical and scientific considerations for designing, conducting, recording, and reporting trials that involve human subjects.
- Sponsors should implement quality systems to manage quality throughout the trial process, including design, protocol, tools, procedures, data collection, decision making, etc.
- The quality management system should utilize a risk-based approach regarding critical processes, data identification, and risk identification, evaluation, control, communication, review, and reporting.
- For the risk control aspect, the FDA recommends that the sponsor decide which risks to reduce and/or which risks to accept, using risk reduction approaches proportionate to the risks’ significance.
- QTLs should be established and evaluated upon detecting deviations from pre-defined limits to decide if action is required.
- Sponsors may choose onsite monitoring, centralized monitoring, or a combination of both.
- The guidance should be read in conjunction with other relevant ICH guidance.
- ICH E6 (R2) – sections 5.0 (Quality Management), 5.2 (CRO), and 5.18 (Monitoring)
- FDA extends CRADA with CluePoints to further explore a data-driven approach to quality oversight in clinical trials
- A Data Anomaly Tool for Site Selection at FDA [FDA-Published Poster]
- Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring
MCC is a trusted partner in the clinical trials industry—identifies what to measure and how to assess the critical components of what is changing and how the industry is responding to address the changes to make improvements. MCC continually brings new insights into the leading trends within the industry.
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ICH E6 (R2)
Created in conjunction with our peers at TUFTS Center for the Study of Drug Development, this paper provides insights on how companies are responding to ICH E6 (R2) and information on the key themes on adoption.
ICH E6 (R2)
This recorded webinar covers all of the frequently asked Questions about ICH E6 (R2), Risk-Based Study Execution (RBx) and what’s required from a people, process & technology standpoint.