Designing Quality Clinical Trials: Unpacking E6(R3) and E8(R1)

My colleague, Sheila Gwizdak, VP of Quality at Halloran Consulting Group, led the discussion “Designing Quality Clinical Trials: Unpacking E6(R3) and E8(R1)” during last week’s Speaker Series. Like our attendees, I was looking forward to learning about these revisions.

To place a product on the market, regardless of region, compliance with GxP regulations is required. The health authorities from each country need to ensure that the product can be reverse-engineered (traceability), all individuals contributing and involved in the development process are identified (accountability), and that the data is reliable (data integrity). These three pillars – traceability, accountability, and data integrity – were repeated throughout the presentation and are common themes in the breakdown of these revisions.

Below you’ll find these revisions in context, an understanding of how to unpack them, and how to implement them to incorporate a proactive approach to quality during trial design.

ICH E8(R1) – General Considerations for Clinical Trials

Revision in context:

E8(R1) is steering quality in a new direction:

• E8(R1) is redefining what quality looks like, focusing 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
  • The sponsor and other parties involved in designing quality into 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 can be accepted or should be mitigated

What are the updates?

• E8 was introduced years ago and has not been updated as clinical trials have progressed
• E8(R1) – revision one – focuses on designing quality into clinical studies and modernizes the following:
  • Describes internally agreed upon principles and practices to facilitate regulatory acceptance
  • Provides guidance on considerations of quality during the study design phase by identifying critical-to-quality factors to support meaningfulness and reliability of data to protect human subjects and the management of risks to those factors during study conduct
  • Addresses the broadening range of study designs and data sources
  • Cross-references other relevant ICH efficacy guidelines that should be considered during the study lifecycle

What are the key principles?

• Protection of clinical study subjects is a shared responsibility
  • Clinical studies should be designed, conducted, and analyzed according to sound scientific principles and reported appropriately
  • Consulting with patients and/or patient organizations in the design, planning and conduct of clinical studies helps to ensure that all patient perspectives are captured
    • This is a new concept in E8(R1) and ties into patient centricity

In summary, the key principles that translate to quality are good design and execution.

What are critical to quality factors?

• E8(R1) identifies quality factors for each study that ensures the quality of the study. Critical to quality equals quality by design. Critical to quality factors are attributes of a study whose integrity is fundamental to the protection of study subjects, the reliability and interpretability of the study results, and the decisions made based on the study results
• These factors are considered critical because if their integrity were to be undermined by errors of design or conduct, the reliability or ethics of the decision-making would be undermined. The critical to quality factors are identified during study design. Once identified, risks that threaten the factors’ integrity must be determined, accepted, or mitigated, and necessary control processes established

How does E8 link with E6?

• E8 and E6 will be dependent on one another as we move forward. E8 is focused on clinical trial design principles (study population, intervention, control group, response variable, methods to reduce bias, statistical analysis); all of which need to be finalized before the start of the study as required by E6
• E6 focuses on study conduct, protocol adherence, training, data management, access to interim data, subject safety, safety monitoring, withdrawal criteria, data monitoring committee, and study reporting
• E8 begins the lifecycle, while E6 concludes the lifecycle

E6(R3) – Good Clinical Practice

What are the updates?

• E6(R3) – revision three – is a response to E8(R1), which means we won’t see E6(R3) until E8(R1) is implemented. Health authorities will not adopt E6(R3) until E8(R1) is available
• E6(R3) provides flexibility, acknowledges the diversity of trial designs, data sources, and the different contexts in which clinical trials can be conducted, and also highlights that GCP principles can be satisfied in a variety of ways

What are the principles?

• E6(R3) contains 12 principles similarly to E6(R2); however, it condenses to specific points
• Six new principles have been identified:
  • Trials designed and conducted in ways that ensure the rights, safety, and well-being of participants
  • Trials are designed and conducted by qualified individuals
  • Quality built into the scientific and operational design and conduct of trials
  • Processes, measures, and approaches are proportionate to the risks to participants and reliability of results
  • Trials generate reliable results
  • Roles, tasks, and responsibilities are clear and documented appropriately

Complete implementation of E6(R2) before E6(R3)

• You need to complete implementation of E6(R2), including 5.0 Quality Management before you move on to (R3)
  • The Quality Tolerance Limit disappears in R3. Critical quality factors are deviations to your protocol that will change the integrity of the study. You should have root cause quality tolerance limits analysis

So, Now What?

Both revisions – E6 and E8 – are embedding culture and processes that repeat quality outcomes centered around the patient. To begin your journey on a proactive approach to quality, implementing early-phase initiatives is critical to drive the quality of a study through the design of the protocol.

You’ll also need to determine the critical to quality factors for each study, which should not be a large list. In fact, the less is better when identifying non-essential activities of the study, which simplifies conduct, improves study efficiency, and targets resources to critical areas.

You’ll also need to evaluate and assess your people, process, and technology to identify gaps. If there are gaps, have a plan on your next steps.

Though this is a lot to consider, keep in mind that the health authorities do not expect perfection. What they expect is your effort at a proactive approach to quality outlined in these revisions.