Preparing for ICH E6(R3) GCP When You’re Still Struggling with (R2)

The first version of the International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP) Guideline was finalized in 1996 describing the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, sponsors, and Institutional Review Boards. GCP covers all aspects of initiating, monitoring, reporting, and archiving of clinical trials, and incorporates guidance on the requirements for Essential Documents and the Trial Master File.

ICH guidelines are important as they provide standards to ensure that biotech and pharmaceutical products are safe, meet their intended use, and adhere to quality processes during manufacturing, control, storage, and distribution. ICH E6 outlines the standards for Good Clinical Practices (GCP) in clinical trials to ensure the rights, safety, well-being, and confidentiality of human participants are protected and that the data collected during the trials is accurate and credible. Health Authorities from each country define, oversee, and enforce compliance with these standards through country-specific regulations.

The ICH E6 GCP Guideline was amended in 2016 with an integrated addendum to encourage the implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting, while continuing to ensure human subject protection and reliability of trial results. There were also standards added regarding electronic records and essential documents intended to increase clinical trial quality and efficiency.

Even in 2022 clinical trial sponsors are still struggling with the revision. But with another draft revision – (R3) – released in March 2021, clinical trial sponsors are grappling with preparing for (R3) expectations when they haven’t addressed the expectations from (R2).

In this blog post, we will share tactics to move forward with the new revision in confidence.

E6(R3) Updates and The Connection to E8(R1)

E6(R3) is intended to align with the recent revision to ICH E8, General Considerations for Clinical Trials. E8(R1) is steering quality in an entirely new direction, and this is the first major revision to this guideline in 25 years. Yes, you didn’t misread that.

For example:

• E8(R1) is redefining what quality looks like with a focus on a proactive approach rather than a retrospective reaction. Quality should rely on good design and its execution rather than overreliance on retrospective document checking, monitoring, auditing, or inspection
• Critical to Quality factors are essential. The sponsor and other parties involved in designing quality in a clinical study should identify the critical quality factors. By identifying the critical quality factors, it’s important to determine the risks that threaten their integrity, the probability, and the impact on those risks, and to decide whether those risks should be accepted or should be mitigated

The overarching principles and objects for (R3) include:

• A risk-based approach
• Reference to E8
• Reference to Critical to Quality Factors
  • These factors are attributes of a study whose integrity is fundamental to the protection of study subjects, the reliability, and the interpretability of the study results, and the decisions made based on the study results
  • They are considered to be critical because, if their integrity were to be undermined by errors of design or conduct, the reliability or ethics of decision-making would also be undermined
  • These factors are identified during study design, and once identified, risks that threaten integrity must be determined, accepted, or mitigated, and necessary controls processes are established
• Trial design and objectives strongly influence Critical to Quality Factors

How to Move Through the Updates with Success

A clinical trial sponsor is successful in implementing the guideline principles if they have a robust risk identification and management strategy that includes policies, procedures, templates, and risk libraries. Success is also displayed when Critical to Quality Factors and Quality Tolerance Limits are identified by compound, indication, and study. And lastly, there is a Quality by Design (QBD) strategy in place with QBD principles applied in clinical trial protocol development.

Adopting a proactive approach to quality isn’t easy, but it certainly offers flexibility. As trial sponsors prepare for E6(R3) and E8(R1), there are three essential components to evaluate in order to make the right changes that will enable compliance.

People

• Do you have the right people with the right skill sets?
• Do you have the right people involved during study planning and design?
• Are you deploying your resources upfront rather than at the end?

Processes

• Have you modified your protocol design processes?
• Have you evaluated your timelines to allow for quality study design and planning?
• Have you changed a key metric from protocol approval or first patient into more meaningful metrics?
• Have you shared your expectations for quality with your vendors?

Technology

• Does your technology enable risk management and risk detection?
• Are you able to track and report deviations and trends?
• Does your technology support Quality Events, Root Cause Analysis, and Corrective and Preventative Actions?

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Halloran’s Quality Team helps its clients through harmonization plans to help them become streamlined and fit-for-purpose quality organizations.

Please contact our team to learn more.