Insights from ICH Draft Revision E6(R3), Risk-Based Approaches, and Quality Systems in GCP Compliance
The International Council on Harmonisation (ICH) E6 Good Clinical Practice (GCP) Guideline was first finalized in 1996 and described the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, sponsors, and Institutional Review Boards (IRBs). Subsequent revisions encouraged the implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, and recording and reporting, while continuing to ensure human subject protection and reliability of trial results.
On May 19, 2023, the ICH released draft revision E6(R3) with updated regulatory and quality standards for a more modernized and adaptive risk-based approach to planning, designing, conducting, recording, and reporting clinical trials. The major areas of focus in ICH E6(R3) Draft remain concise:
“Fostering a quality culture and proactively (versus retrospectively) designing quality into clinical trials and drug development planning, identifying factors critical to trial quality, and engaging stakeholders, as appropriate, using a proportionate risk-based approach.”
Beaufort is adept at advising sponsors in the application of GCP guiding principles throughout the clinical trial process
Beaufort is adept at advising sponsors in the application of GCP guiding principles throughout the clinical trial process. Our team has thoroughly reviewed E6(R3) and was asked to be a contributing author to the 2024/2025 edition of Barnett’s Good Clinical Practice: A Question and Answer Reference Guide.
Our team addressed over 70 questions related to Study Sponsors and Investigator Site Monitoring, and below are several key takeaways and important issues covered:
What are the key messages for Monitoring of Trials (Section 3.11.4) in ICH GCP E6(R3) Draft?
- Sponsor should use a risk-based approach to determine appropriate nature and extent of monitoring
- Monitoring plan development should consider objective, design, complexity, size, investigational product, safety profile, and trial endpoints
- The identified potential safety risks, risks to data quality, and any other risks impacting the reliability of trial results should guide the nature and the extent of the monitoring strategy selected.
- The monitoring plan that is developed should be focused on aspects that are critical to quality
Should sponsors have their site monitors monitor against the FDA’s GCP regulations/guidelines or the ICH GCP guideline, or both?
- FDA views ICH E6(R3) as entirely consistent with FDA GCP regulations and standards
- FDA BIMO inspections are focused on finding deviations from FDA GCP guidelines
- Some believe that adhering to ICH guidelines in addition to FDA guidelines increase FDA’s comfort level with site and sponsor performance
What is Adaptive Monitoring?
- Adaptive trial monitoring has a flexible study design, allowing for real-time adjustments to various aspects of the protocol as data is collected
- It is often utilized in situations where the optimal treatment regimen may be uncertain at the trial outset, or where there are resource allocation challenges
- Some key components are interim data analyses, reallocation of participants, dose adjustments, re-evaluation of sample size, enrollment and treatment adjustments, predefined stopping rules
Is there any guidance on how risk-based monitoring plans should be developed and what elements should be included?
- The primary principles of quality risk management as stated by the FDA in Q9(R1) Quality Risk Management Guidance for Industry (May 2023) are: (1) the evaluation of the risk to quality should be based on scientific knowledge and linking to patient protection, and (2) the intensity of the response to identified risks should be proportionate to the assigned risk level
- Prospectively identify the data and processes that are critical to trial quality, and then perform a risk-assessment to identify and understand the risks to those critical factors
- The monitoring plan should then be developed to focus on the prevention and/or mitigation of the most important and likely risks to critical data and processes
- Per ICH, the Sponsor should determine the appropriate extent and nature of monitoring based on the identified risks. The monitoring plan should be tailored to the identified potential safety risks, the risks to data quality and/or other risks to the reliability of the trial results
- In addition to describing and justifying the monitoring strategy, activities, methodologies, and tools, the plan should put emphasis on participant safety and trial endpoints and should focus on aspects that are critical to quality
How should sponsors determine monitoring frequency for clinical studies?
- A risk-based approach to monitoring where the frequency of monitoring visits and the types of other activities to support monitoring is based on the study design and a risk assessment of the plan
- Factors to consider when determining the extent, frequency, and method of monitoring activities include: the complexity of study design, types of study endpoints, clinical complexity of the study population, geography, relative experience of the CI and of the sponsor with the CI, electronic data capture, relative safety of the investigational product, stage of the study, and the quantity of data
- Sites that enroll a large number of patients in a short period of time need to be monitored far more frequently than sites that are low, slow enrollers
FDA compliance officials increasingly are speaking about the importance of sponsors’ quality systems in clinical research, and of the shifting expectations for sponsor’s clinical trial oversight, to a quality risk management approach in trial oversight. What do they mean by this?
- FDA acknowledges that the previous model for compliance and managing the quality of trials was simply not sustainable, and recent technological advancements have created opportunities for more efficient trial management without impacting quality
- FDA’s current guidance advises sponsors to maintain trial participant protection and ensure the quality of clinical data by emphasizing oversight on the aspects of conduct and reporting that have been identified as the most critical to quality
- Prospectively identifying the data and processes that are critical to trial quality, and then perform a risk-assessment to identify and understand the risks to those critical factors
- Trial oversight will then focus on the prevention and/or mitigation of the most important and likely risks to critical data and processes
What implications does the FDA’s “fitness for use” definition and approach to high-quality data have for clinical trial monitoring, acceptable error rates, source data verification, and related issues?
- Fitness-for-use can be thought of as the suitability and appropriateness of data or materials for their intended purpose within the trial
- “High-quality data” can be thought of as data that effectively and efficiently demonstrates the clinical benefits and risks of a medical product while assuring the protection of trial participants
- There is not going to be one set standard for monitoring approaches, acceptable error rates, source data verification (SDV) strategies, and other trial design specifications
- The study protocol, patient population, investigational product and intended use are all going to impact what ‘high-quality data’ needs to look like for any given study in order to effectively support the evaluation of the safety and efficacy of the drug being studied
What kinds of alternate monitoring practices exist if a sponsor is not going to conduct 100% verification through extensive on-site visits?
- Sponsors using centralized monitoring should ensure that site processes and expectations for record keeping, data entry, and reporting are well-defined and support the ability to access trial data in a timely manner
- Remote monitoring activities that can be performed as well as or better than on-site activities include routinely reviewing the quality of submitted data, conducting statistical analyses, analyzing site performance metrics, and completing administrative and regulatory tasks
- Methods to securely and accurately validate source data include through electronic data capture (EDC) systems, electronic health records (EHRs), and remote access to site data systems
- There is evidence to suggest that centralized monitoring techniques may in some cases be even more efficient at detecting certain types of data anomalies, including fraud, fabrication of data, and other non-random data distributions.
How Beaufort can Help
As the clinical research landscape continues to evolve with ICH E6(R3) Draft, Beaufort stands as a trusted partner, bringing a wealth of GCP expertise to meet the latest industry standards. Our team is dedicated to guiding sponsors through the intricacies of risk-based monitoring, ensuring a proactive approach to quality in clinical trials. Beaufort’s provides a seamless integration of cutting-edge strategies, compliance assurance, and a commitment to unlocking the full potential of your research programs.
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