Navigating the latest ICH E8(R1) Guideline Revisions

Navigating the latest ICH E8(R1) Guideline Revisions: Best practices for application with increased trial variabilities

The International Conference on Harmonization (ICH) is in the final stages of publishing fresh guidance on clinical trial design, E8(R1), and is preparing a revised document covering trial conduct, E6(R3). Together, the two updates describe internationally agreed upon principles and practices that support regulatory acceptance. They’re designed to encourage trial Sponsors to develop a culture and processes that deliver repeatable quality outcomes.

Here, we outline the key principles set forth in E8(R1), which was endorsed in May, 2019, and E6(R3), which is scheduled for publication in late 2022, illustrating how Sponsors and Contract Research Organizations (CROs) can achieve compliance.

Aixial has been operating at the highest clinical research standards for over 20 years.  Our established change management processes enable us to incorporate industry advances thoroughly and maintaining our trusted provider status. Therefore, we recommend undertaking a holistic review of internal processes to ensure they’re proactive in their intent and capable of accommodating current and future trial variabilities. When selecting their CRO partners, Sponsors should take the time to understand the CRO’s approach to development, planning, and trial conduct. Ideally, the CRO will pursue a cycle of continuous improvement in quality study management that includes proactive and reactive approaches to traceability, accountability, and data integrity. 

Many Years in the Making

Undergoing its first revision since it was originally released in 1997, ICH E8 covers clinical trial design principles relating to the study population, methods for reducing bias, control groups, the intervention, response variables, and statistical analysis. The E8(R1) concept paper was endorsed in November 2019, and the revision is currently in development Step 3. The principles section and Annex-1 are currently being finalized, with Annex-2’s development timeline slightly staggered.

ICH E6 was first released in 1996 and is being revised in response to the E8 update, with the Overarching Principles and Objectives draft document having been released in March 2021. Given the dependencies between E6 and E8, ICH E6(R3) is expected to be implemented after E8(R1), and adoption is scheduled for late 2022. The update incorporates diversity in trial design, data sources and trial contexts in the facets of study conduct; training; protocol adherence; data access and management; subject eligibility and disposition; subject and study safety; committee management; and study reporting.  

Figure 1: The Approval and Adoption of ICH E8(R1) and ICH E6(R2 and R3)

A Holistic Approach to Efficacy Guidance

ICH guidelines are intended to be used holistically, meaning that any updates will also impact, and should be reflected in, other guidances. For instance, ICH E8 addresses the design elements of a study, and ICH E6, which covers study conduct, builds on this, stating that the objectives, study type, and data sources should be finalized before the start of the study.

ICH E6(R3) will provide for flexibility in study practices and will acknowledge the growing diversity in trial designs. In addition to incorporating the changes to E8, the update will also make clear that there can be a variety of approaches to conform to Good Clinical Practice (GCP) principles. The annexes will consider principles specific to interventional and non-interventional trials. 

Figure 2:  Topics Included in ICH E8(R1) and ICH E6(R3)

ICH E8(R1): A Modern Take on Quality

The modernization of ICH E8 is intended to address a broader range of clinical trial designs and data sources as well as to stress that clinical trials should embody the principles of Quality by Design (QbD). QbD relies on proactive quality management and the notion that trials must be fit for purpose.

QbD is a proactive approach, rather than a retrospective one that relies on retrospective document checking, monitoring, auditing, or inspection. In a reactive study environment, data management may discover, for example that in a first-in-human study, there is an urgent need for Safety Review Committee data that had not been entered, and what had been entered had not been cleaned. This late discovery could negatively impact the Sponsor’s ability to detect important safety signals and to meet its publication deadlines. In a proactive environment, protocols and project plans clearly state the use and plans for Safety Review Committees.  Systems are in place to compare, in real time, the forecast of data availability to the reality, such that there’s reduced opportunity for missed or surprised data needs. In an even more proactive culture, such as Aixial cultivates, the CRO has conversations with sites to understand their capabilities, and the data review algorithms are set up accordingly. And, at a level beyond that, sites are obligated via their contracts to enter data within a specific timeframe.

The new ICH E8(R1) regulation lays out the elements of a fit-for-purpose trial and makes it clear that:

• Protecting clinical study subjects is a shared responsibility between investigators, Sponsors, and Institutional Review Boards (IRBs) / Independent Ethics Committees (IECs).
• The study should flow from clear and explicit primary objectives.
• Before a study is conducted, sufficient information should be available to ensure a drug is acceptably safe for planned study in humans.
• Clinical studies should be designed, conducted, analyzed, and reported according to sound scientific principles.  Results from prior studies should inform the plan of later studies – the cardinal logic behind serially conducted studies.
• Consulting with patients and/or patient organizations in the design, planning, and conduct of clinical studies helps to ensure that all perspectives are captured and that trial designs are better tailored to patient needs.
• QbD begins with identifying critical-to-quality factors. These factors are a step beyond Key Performance Indicators (KPIs) and Quality Tolerance Limits and are defined as those that impact subject safety, affect the interpretability and reliability of data, or interfere with the reliability or ethics of decision-making.
• Sponsors must identify any risks that threaten the factors that are critical to the trial quality and calculate their potential impact. Control processes should be established to either mitigate or accept risks that arise when threats arise to the integrity of critical-to-quality factors.
• The development strategy should be modified as needed based on emerging data. For example, results of a confirmatory study may suggest the need for additional human pharmacology studies.
• Early patient and site engagement are critical to achieving patient centricity in development plans.

Annex-1 of ICH E8(R1) recommends that studies be classified by their objective, rather than by their phase.

Quality by Design: A Real-Life Example  

In 2018, Aixial began working with a biotech company that was developing a complex radiolabeled gene therapy for use in a rare disease with the intent to market in multiple regions. The Sponsor company had invested heavily in the program to determine the safety of the Investigational Medicinal Product (IMP) and was nearing the end of the pre-clinical phase.

Aixial collaborated with the Sponsor to design the study and write the protocol. Due to the complexities of rare diseases and the nuances of regional standards of care, it was important to build in feedback gathered from physicians, key opinion leaders, patients, and advocacy groups before submitting the protocol to the regional and local regulatory bodies. Feedback from these stakeholders was incorporated into the study design, all the while, considering the patient and the effects on operationalizing the study.  Given the disease and product type, the information-collection phase did extend typical protocol development timelines. However, this due diligence and understanding of the patient perspective allowed the Sponsor to remain realistic about the study design as the treatment moved from the bench to the clinic. The thoroughness in design has facilitated committee approvals and also site adoption of this complex trial across the multiple departments involved.

This study is now in the enrollment phase with a robust and carefully considered protocol that is thorough yet accommodates sites and patients in ways that ensure the best possible outcome and meet the study objectives.  

Aixial Practices for Applying these Guidelines

When assisting clients in developing or executing their trial plan, Aixial takes a cross-functional approach. Our aim in the trial design is to find a balance between acceptable risks, practicalities, and financial responsibility. Our Risk-Based Quality Management (RBQM) and Trial Operations Planning Standard Operating Procedures (SOPs) outline the framework for these tradeoffs.

The text related to these processes is not prescriptive, as every trial is unique and requires that team members use their experience and a holistic understanding of the ICH and regulatory guidances to understand the data and take any actions accordingly. It’s not uncommon for our strategists to gather around a virtual conference table to create a program design or project plan while also cross checking and managing risk from their respective functional angles.

Table 1 outlines at a high level a small sampling of frequent discussion points from such sessions and lists how they relate to ICH E8(R1) planning guidance and ICH E6(R3) conduct guidance.

Table 1: Considerations to Ensure Holistic Trial Strategies

Recommended Next Steps for Sponsors

It is helpful to recognize that becoming fully compliant with the latest and soon-to-be released ICH guidance documents is necessarily a journey – a journey that organizations are traversing at their own pace. The maturity model in Figure 3 describes the conditions that companies move through as they progress from non-compliance (Level 1) to compliance with E2 (Level 2) and compliance with E8(R1) (Level 3). By the time they reach Level 4, companies have moved beyond mere compliance with the minimal standards to active adoption of the principles and best practices that lead to quality. They then are able to optimize those processes in Level 5.

At Aixial, our E6(R2) and E8(R1) readiness aligns with Level 4. Our Level 5 automation is in active development between our Technology, Operations, and Risk teams, and centralized, interim processes are in place. Because flexibility underpins our philosophy, we can minimize any process updates expected as part of E6(R3).

Figure 3: Maturity Model for Adoption of ICH E8(R1) and ICH E6(R3)

As Sponsors embark on this journey with the goal of achieving greater compliance maturity, we recommend that they:

1. Systematically evaluate internal processes to ensure full adoption of E6(R2). After completing a gap analysis, outline the necessary actions, activity owners, and timelines required for full adoption and application of E6(R3). The exact approach is case dependent, and some companies may be far enough along in adopting E6(R2) that they can easily include E6(R3) in their final process documents.
   
   
2. Evaluate CROs in part on their processes related to E8(R1) and their adoption of E6(R2) as this will indicate their readiness to accommodate E6(R3). Sponsors should probe on such points as:
   
   
   1. If the CRO hasn’t fully embraced E6(R3) and E8(R1), what are the associated risks to their performance?
   1. How will the CRO ensure a cyclical review of project quality spanning trial planning through execution?
   1. How and where are such evaluations conducted?
   1. What would be the Sponsor’s level of visibility to the results of such quality reviews?
   1. Will the CRO entertain entering a risk-sharing agreement as a guarantee that their process adoption will not negatively impact the trial?

The release of ICH E8(R1) and E6(R3) represents an important step in our collective progress toward delivering quality outcomes in clinical trials. Becoming compliant with international standards is a process – especially as recommendations evolve – and requires flexibility, forethought, and determination. The rewards of adopting a logical, patient-focused, and quality-driven approach to planning and conducting clinical trials as outlined in the new guidelines extend from Sponsors and CROs to sites and patients. Aixial has invested across the board in order to reach E8(R1) and E6(R3) compliance, and we’re committed to supporting our Sponsors to reap the benefits of working under these guidelines. 

Reach out to us at info@aixial.com