What's New in ICH GCP E6 R3?
A Comprehensive Guide to ICH GCP E6 R3 Compliance and Readiness
Good clinical practice, like any subset of GxP, is constantly evolving. So it wasn’t surprising to see a draft of ICH GCP E6 (R3) unveiled in May 2023 to replace R2, which was itself the second revision of the E6 guidelines.
ICH E6 (R3) maps out the latest expectations for modern good clinical practice, keeping most of the components of R1 and R2 preceding it, then refining them in a few key areas.
Although still in draft, with its final Annex 2 expected by the end of 2024, it’s worth familiarizing yourself with ICH GCP E6 (R3) requirements to get your clinical operation forewarned, and ready to comply.
Here’s what’s inside
A Legacy of Evolution: ICH E6 background
The story of ICH E6 dates back to 1996, when the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) established the first set of internationally recognized GCP standards. This groundbreaking document laid the foundation for ethical and scientifically sound clinical research, ensuring participant protection and reliable research data.
Moving forward to 2016, the E6 (R2) placed a strong emphasis on both risk management and quality management, reflecting the ever-changing clinical research landscape. However, the rate of change in clinical trials is unstoppable, thanks to technological advancements, innovative trial designs, and a growing emphasis on patient-centricity.
ICH E6 (R3) aims to move the needle again, updating and evolving the ICH’s expectations for how modern clinical trials are operated.
The evolution of the E6 guidelines has run in parallel with the broader changes taking place in the clinical sphere, such as the adoption of new technology and the cross-fertilization of other ICH concepts from the pharma world, like quality by design (QbD).
All three iterations have good clinical practice (GCP) at their core.
The protection of subject rights and safety, married with the output of robust, trustworthy clinical data, is the key objective of GCP, and both sponsors and investigators have their own set of responsibilities within ICH’s E6 GCP framework.
What is ICH GCP E6 R3?: A Response to a Dynamic World
It’s the third revision of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E6 guideline, an internationally recognized standard of ‘good’ practice for the entire clinical trial lifecycle – from design and conduct to monitoring, recording, and reporting.
This revision isn’t just a minor update; it’s a comprehensive transformation designed to address the complexities of modern clinical trials.
It’s optional, non-binding, and non-mandatory, but since R2 is widely recognized as the leading international structure for modern GCP R3 will assume that mantle when it goes live, and planning for compliance is therefore strongly recommended if you’re a quality-conscious clinical operation.
Why is ICH GCP E6 R3 important? This is what ICH GCP E6 R3 brings to the table:
Purpose of ICH GCP E6 R3
As with any regulatory update, ICH E6 (R3) focuses on three key objectives:
• Modernization: Aligning with the latest advancements in technology, trial designs, and data capture methods.
• Harmonization: Ensuring consistency and streamlined processes across different regulatory bodies worldwide.
• Adaptability: Addressing the growing complexities of clinical research while prioritizing participant safety and data integrity
On this regards, ICH states: “The development of E6(R3) will address the complexities of clinical trials in the current global regulatory climate…” – ICH E6 (R3) Final Concept Paper
ICH highlights the need for E6 (R3) to better reflect current best practices, including those outlined in the ICH E8 (R1) Revision “General Considerations for Clinical Studies” guideline.
Additionally, they acknowledge the need for ICH E6 R3 to address “perceived problems” where E6 R2 may not fully meet the demands of new clinical trial innovations.
ICH GCP key changes since 2016 include:
• New trial designs
• Further technological advancement
• Breadth and depth of data capture and sources
• New types of testing facilities
Proliferation of outsourced service providers and more complex clinical supply chains
ICH GCP E6 R3’s purpose is to respond with new content around:
• Electronic Systems, Data, Documents, and Integrity: E6 (R3) places significant emphasis on data governance, emphasizing the importance of secure electronic systems and processes to ensure data integrity throughout the trial lifecycle.
• Interventional and “Non-Traditional Interventional” Trial Formats: The guideline acknowledges the increasing use of novel trial designs, including decentralized and pragmatic trials, and provides updated guidance for conducting them ethically and efficiently.
• Underlying Principles of GCP: While the core principles of GCP remain at the heart of E6 (R3), the revision streamlines and clarifies some existing principles, making them more readily applicable to the current research environment.
• Risk- and Quality-Based Considerations: ICH E6 (R3) promotes a proactive approach to risk management and quality assurance. By identifying critical risks and quality factors at the outset of the trial, sponsors and investigators can design protocols and processes that prioritize patient safety and data reliability.
• “Decentralized” and “Pragmatic” Clinical Trial Elements: The guideline addresses the growing popularity of decentralized and pragmatic trials, offering specific guidance on conducting them while adhering to GCP principles.
Overview of ICH GCP E6 R3
With all this in mind, let’s turn to what exactly ICH E6 (R3) prescribes for clinical operations, beginning with its scope.
Scope
The draft itself states that the guideline applies to ‘interventional clinical trials of investigational products that are intended to be submitted to regulatory authorities’.
And even for clinical trials that aren’t connected to marketing authorization, the guideline could still be applicable.
In short, E6 (R3) intends to offer a shared GCP framework connecting sponsors, IRBs, investigators and their regulators from clinical trial design through to final data analysis.
If you’re conducting any kind of interventional (clinical) trial, ICH E6 R3 will be applicable to you.
If you’re operating an observational trial, it won’t be.
Principles for clinical research
The guideline kicks off by mapping out 11 core principles of good clinical practice. Interestingly, that’s two fewer than in E6 (R2).
They’re a good place to start as you make your compliance preparations.
They are:
- Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with GCP and applicable regulatory requirement(s). Clinical trials should be designed and conducted in ways that ensure the rights, safety and wellbeing of participants.
- Informed consent is an integral feature of the ethical conduct of a trial. Clinical trial participation should be voluntary and based on a consent process that ensures participants (or their legally acceptable representatives, where applicable) are well-informed.
- Clinical trials should be subject to an independent review by an institutional review board/independent ethics committee (IRB/IEC).
- Clinical trials should be scientifically sound for their intended purpose and based on robust and current scientific knowledge and approaches.
- Clinical trials should be designed and conducted by qualified individuals.
- Quality should be built into the scientific and operational design and conduct of clinical trials.
- Clinical trial processes, measures and approaches should be implemented in a way that is proportionate to the risks to participants and to the importance of the data collected.
- Clinical trials should be described in a clear, concise and operationally feasible protocol.
- Clinical trials should generate reliable results.
- Roles and responsibilities in clinical trials should be clear and documented appropriately.
- Investigational products used in a clinical trial should be manufactured in accordance with applicable Good Manufacturing Practice (GMP) standards and be stored, shipped, handled and disposed of in accordance with the product specifications and the trial protocol.
What are the main differences between R2 and R3? Key updates from ICH E6 (R2)
But it’s worth taking a look at how R3 differs from R2. After all, ICH wouldn’t bother drafting a fresh guideline if they didn’t feel certain changes had to be made to its content.
It’s important to note, though, that R3 tweaks and tinkers with R2’s content rather than representing a dramatic overhaul. For clinical teams planning to make the transition, that’s good news.
- Principles: The first change from ICH E6 (R2) to ICH E6 (R3) can be gleaned from the principles listed above. Principle 6, about building quality into clinical trials with a quality-by-design approach, takes the quality focus of R2 and builds on it.
Where R2 wants clinical teams to ‘ensure the quality of every aspect of the trial’ with an assurance approach, R3 seems to be pushing for a more proactive, forward-thinking, and considered approach to quality, where it’s baked into the very fabric of the trial design and operation.
That means training procedures, protocols, SOPs, and your wider document stack should only be constructed after a clear quality-based focus has been established.
- Proportionality and Efficiency: The other key change to R3—a deeper focus on risk, seen in Principle 7—helps illustrate what’s required. ICH E6 (R3) advocates for a risk-based approach, focusing resources on processes and data points with the most significant impact on patient safety and trial outcomes. This lean and efficient approach aims to accelerate evidence generation without compromising quality.
Any critical risks and quality factors that could threaten either of those two main GCP goals of patient safety and data integrity should be pinpointed as your very first set of work.
This proactive approach should then inform a clinical design strategy based on measurable quality characteristics and risk metrics, supported by multivariate analysis and clear lines of communication.
And your risk-based thinking should drive proportionality, with maximum planning effort focused on the processes and data streams with the greatest impact on patient safety and the outcome of the trial.
The final outcome of this quality and risk approach?
- Data Reliability Takes Center Stage: Moving beyond the ALCOAC data integrity focus of E6 (R2), ICH E6 (R3) emphasizes the need for reliable data that can be confidently used to make critical decisions that impact healthcare—”results”should be able to be accepted with ‘confidence’, and in turn’support good decision-making’.
A beneficial side-effect of this lean, proportional risk-based focus is the acceleration of evidence generation, and ICH hopes the new emphases of R3 will help steer IPs through efficient, optimized trials faster than ever.
- Future-Proof Framework: Recognizing the rise of data-driven technologies, decentralized trials, and “non-traditional interventional” designs, ICH E6 (R3) offers a future-proof framework for conducting ethical and reliable clinical research.
Enhanced Focus on Quality and Risk: Building on the foundation laid by E6 (R2), the new revision prioritizes quality by design (QbD) principles. This proactive approach encourages risk management strategies to safeguard patient safety and data integrity from the very beginning.
Beyond Compliance: Embracing the Transformative Power
While achieving compliance with ICH E6 (R3) is crucial, the true power lies in embracing its transformative spirit. This means:
- Shifting from reactive to proactive risk management: Instead of simply mitigating risks that arise, QbD principles encourage proactive identification and mitigation strategies throughout the entire trial lifecycle.
- Optimizing clinical trial design: Risk-based thinking allows for more streamlined protocols by focusing resources on critical aspects while minimizing unnecessary burdens on investigators and participants.
- Enhanced collaboration and communication: The emphasis on data reliability necessitates clear communication and collaboration between sponsors, investigators, and regulatory bodies.
When will ICH GCP E6 R3 be implemented? - Timeline for ICH GCP E6 R3 Implementation:
ICH E6 (R3), in its finished form, will comprise 3 sections:
1) Overarching ‘principles’ document
2) Annex 1: considerations for interventional trials
3) Annex 2: further considerations for ‘non-traditional interventional’ trials
Here’s a breakdown of the release schedule:
- Initial Draft (May 2023): Released, comprising the core principles document and Annex 1 related to interventional trials.
- Draft Annex 2 (expected end-2024): This annex will address considerations for “non-traditional interventional” trials.
- Final Draft for Public Consultation (expected end-2024): Once both Annexes are drafted, the entire guideline will be released for public feedback.
- Final Live Version (Estimated 2025): Following public consultation, the final ICH GCP E6 R3 release date is expected to be sometime in 2025.
Until then, ICH E6 (R2) remains the live, valid and applicable GCP guideline for quality-focused clinical businesses to work to.
Preparing Your Team for the Future
While the final release of ICH E6 (R3) is anticipated in 2025, proactive steps can be taken today:
- Familiarize your team with the draft: Familiarize yourself with the current draft of E6 (R3) and Annex 1 (interventional trials). A thorough understanding of the core principles and proposed changes will allow you to identify areas where your current practices may need adjustments. Consider how the revisions might impact your clinical operations.
- Conduct a Risk Assessment: Identify critical risks specific to your trials that could jeopardize patient safety or data integrity. Develop risk mitigation strategies aligned with the principles of E6 (R3). Develop strategies to mitigate these risks based on the principles of QbD
- Conduct a QbD-based risk assessment: Quality by design is well and truly migrating from the pharmaceutical world into the realm of the clinical trial—ICH E6 (R3) is testament to that. Effective quality and risk management should therefore be your primary focus as you prepare to keep pace with ICH E6 developments. Identify those areas where quality is reactive, control- and assurance-based, or an afterthought, and tackle them as areas of priority.
- Review and update SOPs and protocols: Revise standard operating procedures (SOPs) to reflect the emphasis on quality by design, risk management, and data governance.
- Ensure your Standard Operating Procedures (SOPs) and clinical trial protocols are aligned with the evolving principles of ICH E6 (R3).
- Update GCP Training and SOPs: Ensure your team receives training on the key updates of E6 (R3). Revise standard operating procedures (SOPs) to reflect the emphasis on quality by design, risk management, and data governance.
- Invest in GCP training: Ensure your team receives Good Clinical Practice training on the key updates of E6 (R3). Equip them with the knowledge and skills necessary to implement the new requirements effectively. GCP Training on risk management, data integrity, and QbD principles is crucial.
- Embrace New Technologies: Explore and implement technology solutions that can enhance data management, risk mitigation, and overall trial efficiency.
It is recommended that key stakeholders review the draft and understand the major updates. Even though the paper has not been adopted yet, this is a good time to begin organizing and putting changes into practice.
While you wait, keep in mind that ICH GCP E6 (R2) is still in effect, so make sure your staff completes up-to-date Good Clinical Practice training and holds a valid GCP certification. Remember that GCP training should be updated every three years.
PharmaEduCenter understands how busy research professionals are and the value of effective, high-quality online training. Because the next ICH GCP R3 release will feature a significant upgrade to the ICH GCP guidance, we want to ensure you can register for our GCP training right away. CLICK HERE TO REGISTER!
All of our GCP trainings are comprehensive, practical, online, and convenient, allowing you to earn your GCP certification at your own pace.
The Future of Clinical Research is Here
The arrival of ICH E6 (R3) marks a significant turning point in clinical research towards safer, more ethical, and efficient clinical research.
By embracing this transformative framework, we can pave the way for better healthcare solutions and improved patient outcomes.
By embracing the new framework, we can usher in a new era of safe, ethical, and efficient clinical trials that pave the way for better healthcare solutions and improved patient outcomes.
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