Good Clinical Practice (GCP) affects a variety of entities, including sponsors, contract research organisations (CROs), and investigator sites. It’s essential for maintaining ethical standards, high-quality outcomes and facilitating global standardisation, enabling multi-center and multinational studies, thereby streamlining the development and approval process for new medical treatments, and maintaining public trust in clinical research. But in order to keep in line with the ever-evolving field of drug development, GCP is also subject to changes. In our article we look into the potential implications of E6(R3) for the future of clinical studies and how organisations can best prepare for these changes.
Overview of the ICH E6(R3) GCP update
In May 2023, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) made the ICH E6(R3) draft guideline available for public consultation. This update, in cooperation with global health authorities like the FDA, revises the previous ICH E6(R2) update from 2016 by steering committee. Currently, regulatory bodies are considering feedback from the public and are expected to initiate public discussions on Annex II in 2024, with the final guidelines projected for release in 2025.
The goal of E6(R3) is to build upon the foundations set by E6(R2), emphasizing adaptability, sustainability, and a risk-balanced approach. These updates aim to nurture a quality-oriented culture that supports continuous innovation in the field.
Moreover, the E6(R3) enhances the principles laid out in the newly adopted ICH E8(R1), which revises the general considerations for clinical studies. This integration fosters a comprehensive approach, ensuring clinical trials are designed and conducted with utmost efficacy from start to finish.
What are the 4 main categories of ICH E6?
The ICH E6 guideline on GCP provides a unified standard for designing, conducting, recording, and reporting human life sciences clinical trials. Adherence to these guidelines ensures the ethical and scientific quality, safeguarding of participants, whilst also generating credible data. The ICH E6 guidance is divided into 4 main categories, which collectively cover the essential aspects of clinical trial conduct:
- Ethical Principles and Responsibilities: The includes the ethical considerations and practices that must be followed throughout a clinical trial, ensuring the protection of trial participants rights, safety, and well-being.
- Clinical Trial Protocol and Amendments: This covers everything from content and design through to amendments. The protocol is a crucial document outlining the objectives, design, methodology, statistical considerations, as well as the organisation and administration of the trial.
- Investigator and Sponsor Responsibilities: Detailed descriptions of their roles, qualifications, and duties must be included to ensure compliance with GCP and the integrity of the trial.
- Essential Documents: This category lists the essential documents that must be prepared, maintained, and retained to demonstrate compliance with GCP and make certain the quality and integrity of the data collected. These documents include the trial protocol, investigator’s brochure, case report forms (CRFs), and consent forms.
The Key Concepts and Potential Changes
A significant critique of E6(R2) is its tendency towards excessive specificity, leading to a rigid compliance mindset. In contrast, E6(R3) seeks to dismantle these rigidities, promoting a more agile and adaptable framework, which in turn will help studies adapt their trial design by utilising apportionate risk-based tools/decision making.
A notable change is the transformation of "Quality Tolerance Limits" (QTLs) into "Acceptable Ranges." This adjustment broadens the scope of control measures and aligns with the continuous need for vigilance and scientific thoroughness, without the pressure for perfection.
The revisions in both E6(R3) and E8(R1) emphasises a risk-balanced approach to quality management throughout the lifecycle of clinical trials. This method focuses more on essential processes and data that significantly impact participant safety and study outcomes.
E6(R3) also redefines the term "error(s)" from E6(R2) to "harms/hazards," indicating a shift in focus. Not every error necessitates intense scrutiny; only those posing real risks require detailed investigation and preventive measures.
The update challenges the industry to differentiate between errors that affect data quality and participant safety and those that do not warrant severe interventions.
With the new update, there looks to be an increased focus on patient centricity, placing an emphasis on the patients’ considerations and perspective of the trial and design. This could lead to the increase in decentralised trials to lessen the burden on patients, further increasing the adoption of real world data (RWD).
Heightened requirements to ensure the accurate handling of both electronic and manual records to ensure that efficiency and flexibility is adopted while maintaining the rigid requirements of data integrity and patient safety.
Implications for Innovation
E6(R3) adapts to the rapidly advancing technology capabilities and the increasing data volumes in clinical studies. For instance, a typical Phase III study now manages millions more data points than a decade ago, often from multiple sources. This complexity necessitates a proportionate approach to data management, now highlighted in a new section on data governance within the guidelines.
As technologies like machine learning (ML) and artificial intelligence (AI) evolve, E6(R3) prompts a reconsideration of the demands of data collection, ensuring that every aspect of data management adheres to validated systems and prioritises compliance and data integrity.
There will also be the need to have a fully validated Quality Management System (QMS) which will assist the evolution of the trial allowing the stakeholders to continuously monitor the data via the agreed KPIs and QTLs to make decisions on the trial design.
Practical Impacts
The adoption of Risk-Based Quality Management (RBQM) marks a major shift in mindset, evidenced by the swift development and deployment of COVID-19 vaccines. To embrace this approach, organisations are encouraged to simplify processes, enhance technological integration, and foster critical thinking to assess risks effectively and make informed decisions.
The movement to enhance patients experience via the inclusion and adoption of digital tools lending themselves to decentralised and virtual trials, allowing the patients to have a better clinical trial experience.
E6(R3) also promotes collaboration among all stakeholders involved in a clinical trial, from design through ongoing assessments and adjustments.
Looking Forward
E6(R3) acknowledges the impracticality of perfect data and flawless clinical trials. It advocates for a thoughtful, risk-aware approach to clinical study management, prioritising safety and efficiency over unattainable perfection.
The advancement of technology will not only play an important role in our day to day lives but the evolution of clinical trials, E6(R3) opens up the industry to become innovative, flexible and data focused with its clinical trials, while still maintaining that core value of data integrity.
This shift toward a more flexible and patient-centered methodology not only reduces the burden on all parties involved, but also enhances the overall participant experience and expedites the drug development process. By recognising the reality of errors and fostering a cooperative environment, E6(R3) contributes to the overarching goal of improving patient outcomes.
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