Updated guidance for Good Clinical Practice is here. Here’s why it was needed and what it means
ICH-E6(R3) represents a shift in mindset when it comes to clinical trials. Rather than trying to control every part of a trial equally, the guideline wants researchers to focus most on factors that are critical to participant safety and the reliability of trial results. It introduces the idea of “proportionality,” meaning more control is applied to high-risk areas. It also acknowledges that technology plays a major role in today’s research, and outlines expectations for using digital systems responsibly.
TransCelerate and the Association of Clinical Research Organizations (ACRO) have been working together on various initiatives connected to clinical research since 2015. ACRO represents both CROs and technology vendors, while TransCelerate brings the sponsor perspective. Working together allows both groups to form a complete view of how the guidelines should be interpreted – and how to collectively approach implementation.
In response to this new ICH guideline, TransCelerate and ACRO have collaborated to develop a free-to-use toolkit designed to assist stakeholders in adopting ICH-E6(R3). Here, we speak with David Nickerson and Arlene Lee, who have both been involved in the TransCelerate x ACRO ICH-E6(R3) risk management team. They break down what the guideline means for clinical trials and why it was so needed in the industry.
Meet the Experts
David Nickerson, Head of Clinical Quality Management at EMD Serono, PhRMA Topic Lead on the ICH-E6(R3) Expert Working Group, and executive sponsor of TransCelerate’s ICH-E6(R3) initiative
“I’ve been in the pharmaceutical industry for nearly 40 years. Over that time, I’ve worked with three different companies and taken on a wide variety of roles. I started as a bench scientist doing drug metabolism and pharmacokinetic research and eventually moved into a broader development project management role. For the past 15 to 18 years, my focus has been on clinical quality management.”
Arlene Lee, Director of Product Management at Medidata, and member of the TransCelerate x ACRO ICH-E6(R3) sub team
“With a career spanning over 25 years in the pharmaceutical industry, I've had a diverse journey that began in preclinical drug metabolism and led me through veterinary pharmaceuticals and Quality Assurance. Subsequently, I spent over 17 years dedicated to clinical data management and centralized monitoring across multiple therapeutic areas and all phases. Most recently, my focus has been on the development of data quality and risk management solutions to ensure the integrity and success of trials”.
Why are you so passionate about clinical trials?
David Nickerson: Clinical trials are absolutely essential not only to advancing patient care and treatment availability today, but they are also critical to ensuring continued innovation and future advancements in patient care. Misspent time and effort in trials carry a cost. Any error present in the trial process has the potential to influence or bias how we interpret the results. That’s why I’ve dedicated myself to finding better, more reliable, and more holistic ways to embed quality into trial design and operational execution.
For me, this revolves around the concept of Quality by Design (QbD); identifying what matters most for participant safety and data reliability, and proactively mitigating the risks that could compromise those. The idea is to ensure our responses are proportionate to the significance of each risk.
This philosophy aligns closely with Good Clinical Practice — not just how it evolved in the E6(R2) revision, but especially with how it’s being further emphasized and expanded in the new E6(R3) guidance.
Arlene Lee: My commitment to improving clinical trials became deeply personal when a close family member was diagnosed with cancer. Like many people, I was shocked. But what really surprised me was that, despite how common the cancer was, there were no commercially available treatment options at the time. It underscored the urgency to me of accelerating clinical research and ensuring the data we generate is high quality and reliable. The drive to make trials more effective and efficient, and ultimately more impactful for participants, is what fuels me.
Clinical trials are complex and there is a lot to manage. Do you think it has been challenging for the industry to improve clinical trials?
DN: Clinical research is a far cry from a controlled manufacturing process. We can develop a beautifully crafted protocol and take every step possible to set ourselves up for success. However, that thoughtfully developed protocol and its associated operational plans are then handed off to dozens, sometimes hundreds, of clinical trial sites scattered all over the globe.
Each of those sites brings its own experience, interpretation, and understanding of how the trial should be conducted. This diversity introduces variability that makes coordination across all the sites a challenge.
AL: Having worked across CROs, small biotech companies, large pharma, and now at a technology vendor, it’s fascinating to see just how different the operational dynamics can be across organizations. Trying to standardize processes – even just aligning on how things should be done – can be incredibly difficult.
What does the new guideline ICH-E6(R3) mean for trials?
DN: ICH-E6(R3) is the latest revision of the Good Clinical Practice (GCP) guideline. It was officially adopted by the ICH in January 2025 and by EMA in July 2025. What’s important to understand is that Revision 3 isn’t just a minor update; it’s a full reorganization, rewrite, and reframing of GCP. This isn’t cosmetic. It’s foundational.
The guideline now begins with a clear set of principles that serve as the bedrock for GCP. These principles are followed by Annex 1, which provides interpretation and guidance on how to apply those principles in real-world settings.
There’s also a forthcoming Annex 2, still under development, which will offer additional direction on applying GCP in more modern, decentralized contexts, such as trials that include remote activities, pragmatic elements, or diverse data sources. It will speak to how these evolving trial designs can still fulfil the core GCP principles.
When developing E6(R3), the ICH expert working group had a few key goals that really shaped the document.
Flexibility. The previous guideline was seen as very rigid in terms of a “you must do this, and never do that” framework. With R3, the goal was to introduce much greater flexibility and put GCP principles at the heart of decision-making.
Emphasis on QbD. That idea of QbD was introduced in ICH-E8(R1), and now it’s been fully integrated into E6(R3). The message is: don’t try to control everything equally – put your energy into the aspects of the trial that are most critical.
Collaboration. The guideline promotes collaboration and input from interested parties, particularly participants, advocacy groups, investigators, and site staff. Their voices are key to ensuring that trial designs are not just scientifically sound, but also operationally feasible and free from unnecessary complexity.
Proportionality. Finally – and I think this may be the most important concept – the idea of proportionality is threaded throughout the entire document. It’s about ensuring that the actions you take to manage quality are appropriate to the importance of the data and processes involved. If a process is critical to participant safety or data reliability, you apply more control. If it’s less critical, you apply less. That risk-based mindset is central to effective quality management.
What is the history behind the new guideline?
DN: E6(R1) was introduced in 1996. Since then, new methodologies, technologies, and data types have completely reshaped the landscape.
The first formal effort to address these changes came with ICH-E6(R2), which was adopted in 2016. This version kept all the original content intact but added short, targeted updates designed to address some of the more significant developments in trial conduct that had emerged over the years.
I was part of the R2 working group at the time. Even as R2 was being released, we were already hearing feedback from stakeholders saying that it didn’t go far enough; that the additions were too limited and didn’t offer the flexibility needed to accommodate new trial designs, novel data sources, or emerging digital health technologies. Essentially, the world had moved forward and R2 hadn’t caught up.
That feedback sparked a broader initiative known as the GCP Renovation effort. The first phase of this effort included a revision of ICH-E8, which provides general considerations for clinical trials. E8(R1) introduced and reinforced ideas like QbD and the importance of gathering input from diverse stakeholders to improve how trials are designed and executed.
The second phase focused on E6, which brings us to E6(R3). This was no overnight task. It took over 5 years.
I think it’s fair to say that the industry and the broader clinical research community have responded with significant interest. When E6(R3) was released for public consultation, it generated around 7,000 comments. That kind of volume really speaks to the global significance of the guideline and how much is riding on getting it right.
AL: Based on my observations, the industry’s reaction has generally been optimistic, but also cautious, which is typical in a field where change is always approached carefully.
When E6(R2) came out in 2016, it wasn’t embraced quickly. I was working in centralized monitoring around 2018–2019, and while we were utilizing the concepts, it was still limited in nature. It wasn’t until the COVID-19 era that I saw a real shift in accepting the risk-based quality management (RBQM) concepts. With sites shutting down, centralized monitoring became absolutely essential for sponsors and study teams to understand what was happening with participants and site operations. That’s when the industry seemed to collectively realize, "Hey, this is really useful — we probably should have been doing this all along." And from there, the momentum grew.
What challenges may companies face in following the new guideline?
DN: The challenges really boil down to critical thinking. Critical thinking is essential when it comes to designing and conducting clinical trials in a way that protects participant safety and ensures data reliability.
What the new guideline asks of us is to step back and ask:
What is truly fit for purpose?
What does that mean in the context of the specific trial we’re planning?
What matters most from a safety and data reliability standpoint in this protocol?
Once we’ve answered those questions, we then have to decide what kind of risk management actions are needed and, just as importantly, whether those actions are proportionate to the significance of the risks involved.
To really benefit from the flexibility E6(R3) offers, we need to resist the urge to always default to the most conservative, risk-averse interpretation and move beyond this mindset which has been prevalent in the industry for a long time.
The real challenge ahead is not just technical, but also cultural.
AL: Continued implementation of RBQM is fundamental to ensuring both trial efficiency and data integrity. Many companies started that journey during COVID-19 but have struggled to truly integrate RBQM into their everyday operations. They often lack the tools, processes, or data visibility needed to assess risks in real time.
This has been highlighted by ACRO’s RBQM Working Group, which brings together industry experts to assess how RBQM practices are evolving. One of the working group’s current areas of focus is centralized monitoring. Today’s trials generate a huge volume of complex data and centralized monitoring is a critical tool in managing that data. It allows for more targeted oversight by helping teams detect risk signals early and focus resources and attention on what truly matters.
Beyond RBQM, another key area raised in E6(R3) is technology. The guideline assumes a certain level of digital maturity, however, not all sponsors or sites are equipped with the systems needed for real-time oversight, traceability, and centralized monitoring.
Sponsors also need to ensure that both they and their vendors – whether they are CROs or technology providers – are aligned with the new expectations, especially when it comes to quality and risk. Successful implementation will depend on alignment.
Working in partnership with ACRO, TransCelerate has released a free-to-use toolkit to help stakeholders understand and implement ICH-E6(R3). In part 2 of this discussion released on October 1, find out more about the tools and why they were developed.
Newsletters
Receive the latest pharmaceutical news, personalities, education, and career development – weekly to your inbox.
