Guide to ICH E6 (R3): changes and preparation
Good clinical practice, like any subset of GxP, is constantly evolving. So it wasn't surprising to see a draft of ICH 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 in 2024, it's worth familiarizing yourself with ICH GCP E6 (R3) requirements to get your clinical operation forewarned, forearmed and ready to comply.
Here's what's inside.
Table of Contents
Introduction to ICH E6 (R3)
What is ICH E6 (R3)?
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.
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.
Background of ICH guidelines
ICH E6 went live in 1996.
E6 (R2) replaced it in 2016, adding a new emphasis on both risk and quality management.
And 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.
Purpose of ICH E6 (R3)
Like any regulatory revision, ICH E6 (R3)'s purpose is to modernize, harmonize and adapt currently accepted best practice.
As ICH puts it:
"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 doesn't only want E6 (R3) to more closely align with new standards like E8 (R1), "Revision of General Considerations for Clinical Studies".
They've also pointed to a 'perceived problem' of E6 (R2) failing to keep pace with, and fully satisfy the regulatory demands of, the latest clinical trial innovations.
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
E6 (R3)'s purpose is to respond with new content around:
- Electronic systems, data, documents and integrity
- Interventional and 'non-traditional interventional' trial formats
- The underlying principles of GCP
- Risk- and quality-based considerations for the protection of patient safety and data integrity
- 'Decentralized' and 'pragmatic' clinical trial elements
When's the ICH E6 (R3) release date? That depends which part of it you mean.
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
The initial draft, released in May 2023, comprises the first two parts.
The draft of Annex 2 is expected, according to ICH, '12-18 months' after the final concept paper was unveiled in March 2023.
March-September 2024 should therefore see the entirety of ICH E6 (R3) released in its draft form for public consultation.
It's likely that the final ICH E6 (R3) release date, in live format, will then fall somewhere in 2025.
Until then, ICH E6 (R2) remains the live, valid and applicable GCP guideline for quality-focused clinical businesses to work to.
Overview of ICH E6 (R3)
With all this in mind, let's turn to what exactly ICH E6 (R3) prescribes for clinical operations, beginning with its 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.
1. 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.
2. 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.
3. Clinical trials should be subject to an independent review by an institutional review board/independent ethics committee (IRB/IEC).
4. Clinical trials should be scientifically sound for their intended purpose and based on robust and current scientific knowledge and approaches.
5. Clinical trials should be designed and conducted by qualified individuals.
6. Quality should be built into the scientific and operational design and conduct of clinical trials.
7. 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.
8. Clinical trials should be described in a clear, concise and operationally feasible protocol.
9. Clinical trials should generate reliable results.
10. Roles and responsibilities in clinical trials should be clear and documented appropriately.
11. 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.
Key updates from ICH E6 (R2)
It isn't the purpose of this article to explore the contents of ICH E6 (R2), the previous iteration of the guideline.
You can see that in our separate dedicated article below.
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.
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.
What does this mean? The other key change to R3 - deeper focus on risk, seen in Principle 7 - helps illustrate what's required.
Any critical risks and quality factors which 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 proactivity, in turn, should inform a strategy of clinical design built on measurable quality characteristics and risk metrics, underpinned 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?
E6 (R3) moves beyond the ALCOAC data integrity requirements of R2 and focuses on the broader output requirement of data reliability - 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.
Preparing your team for future developments in ICH guidelines
It's still early days for ICH E6 (R3).
Take a look at the draft and, if you have any comments, feedback or suggestions, the FDA is receiving input until September 5, 2023.
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.
Consider the current state of your processes in these areas, and their operational maturity.
Identify those areas where quality is reactive, control- and assurance-based, or an afterthought, and tackle them as areas of priority.
And take a close look at the quality management tools your operation is reliant on. Manual, admin-heavy resources like paper and spreadsheets don't only clutter and complicate your quality system - they inhibit the proactive, process-based visibility of your clinical operation that the ICH is now calling for.
Demo an electronic quality management system (eQMS) like Qualio and learn how to unite your document, training, quality event and supplier management processes in a single cloud-based platform, underpinned by powerful digital analytics.