Key Takeaways from Arkivum’s Expert Panel on Navigating the New ICH E6 R3 Guidelines

On Tuesday, 22nd October 2024, Arkivum hosted a panel discussion exploring various perspectives on the upcoming ICH E6 R3 guidelines. The panel included Sara Thuresson, Head of Clinical Operations at Guard Therapeutics; Suzanne Turner, Trial Master File (TMF) Consultant and owner of ICE Consulting; and Matthew Addis, CTO and co-founder of Arkivum. Together, they shared their thoughts on the implications and challenges that these new guidelines will bring to the pharma and life sciences sectors.

Navigating the Shift from Documents to Records

The transition from using the term “documents” to “records” in clinical trials and regulatory processes marked a significant shift in the pharma and life sciences industries. Suzanne noted that this shift was positive, as the term “records” better captured the variety of information types being managed.

She also highlighted that this change raised important questions around record formats and storage. The industry had to consider whether all records could fit into standard eTMF systems or if alternative solutions were needed to accommodate non-traditional formats. This shift pushed the industry to rethink what constituted a “complete record” while ensuring compliance without sacrificing flexibility.

Sara mentioned that the focus was now on the information gathered and the process behind it, rather than just the document itself. This required continuous improvement in digital record-keeping systems to capture information reliably and consistently. She emphasised the need for people with technical expertise to ensure proper validation, as well as the challenge of transferring records with the precision required by varying technical solutions. Nevertheless, the shift from documents to records leads to better insight into trial conduct, aiding risk management and improving inspection readiness.

From an archiving and long-term retention perspective, Matthew saw the shift as encouraging a move away from the “paper” mindset, promoting active records management via online archives during the retention period. He compared ICH E6 R3 with R2, noting that the new guidelines abandoned the tick-list mentality in favour of a risk-based approach that emphasised critical thinking around what records were ‘essential’, for example to reconstruct a trial. The scope of records includes not just documents but also data, metadata, audit trails, including source data and data in data acquisition tools, among others.  This in turn means that data retention and archiving needs careful consideration right upfront in a trial, not just at the end.

Retention of Records: The Long-Term View

The panel discussion moved on to the topic of retention of records under ICH E6 R3. Suzanne highlighted that the guideline made sponsors responsible for ensuring that investigators, institutions, and service providers were aware of the need for record retention and were notified when the records were no longer required. This language shifted accountability to the sponsor, making it an essential part of vendor qualification and collaboration. Suzanne also emphasised the importance of long-term accessibility, as records might need to remain accessible for up to 25 years or more—a challenge as technology and formats continually evolved.

Sara agreed, mentioning the 25-year minimum retention period mandated by the EU Clinical Trials Regulation (CTR) and the sponsor’s responsibility to notify sites and service providers when retention was no longer needed. This underscored the importance of having a well-documented chain of custody, especially for smaller sponsors who might face difficulties managing such long-term requirements.

Matthew expressed concern that many organisations are unprepared for the complexity of retaining data for such extended periods. He emphasised that retention covered not just documents but source data, datasets, and metadata. The guidelines emphasise maintaining data integrity using ALCOA+ principles throughout the lifecycle, including during the retention period. However, Matthew pointed out that the guidelines lacked practical details on how to achieve this, particularly in terms of digital preservation techniques. He advocated for greater awareness of good practices from the digital preservation community to help organisations maintain compliance over long timeframes.

Embracing a Risk-Based Approach

The new ICH E6 R3 guidelines encouraged the adoption of risk-based tools and decision-making strategies throughout the lifecycle of clinical trials. Suzanne recommended organisations take a holistic view, incorporating risk assessments from the outset of a study. By identifying historical risks and staying current with industry trends, companies could prioritise areas of focus and tailor their strategies. Suzanne also stressed the importance of continuous monitoring and feedback to evaluate the effectiveness of risk-based strategies.

Sara highlighted the importance of using and further developing existing tools like risk-based quality management and monitoring plans, vendor oversight, and defined key risk indicators (KRIs) and key performance indicators (KPIs). These tools helped ensure that organisations were well-equipped to manage the complexities of modern clinical trials.

From an archiving perspective, Matthew reiterated the need for solutions that were “fit for purpose” across the entire retention period, which could extend for decades. He advocated for the application of a risk-based approach using digital preservation techniques to mitigate long-term risks to data integrity, including the use of suitably designed and validated systems and the use of qualified suppliers.  Matthew mentioned that proper archiving solutions needed to be set up at the outset of a study to manage essential records effectively, and this required careful planning and awareness of digital preservation practices, which is something many organisations need support with, for example small biotechs.

Adopting Computerised Systems: Progress and Challenges

As clinical trials increasingly relied on computerised systems, the adoption of these technologies varied widely across organisations. Suzanne observed that while companies made progress in adopting these systems, especially in streamlining trials and ensuring system qualification and validation, gaps remained. Many organisations not dealing with eTMFs were unprepared when auditors requested access to audit trails during inspections. Suzanne emphasised the need for better preparation to ensure smooth inspections and compliance.

Sara noted that smaller biotechs may struggle with integrating different computerised systems, especially when relying on multiple vendors. These organisations sometimes lacked the technical resources needed for validation and security, making audits more challenging. On the other hand, larger organisations were generally better positioned but still needed to evolve their technologies and systems to meet regulatory requirements.

Matthew added that the sheer number and diversity of computerised systems used in modern trials posed challenges. These systems were distributed across different stakeholders, including sites, sponsors, and CROs, and were increasingly cloud-hosted. As trials moved towards decentralised models, data management became more complex. Matthew advocated for planned migrations and consolidation of data into dedicated archiving environments to simplify long-term retention and inspection readiness.

Sponsor Responsibility for Data Retention

The R3 guidelines place more responsibility on sponsors to guide sites in retaining data appropriately. Sara expressed concerns about the practicality of this increased accountability, especially for smaller sponsors. While the guidelines aimed to create consistency and ensure data integrity, implementing them at every site with varying electronic systems and security measures remained a significant challenge. Sara suggested that harmonisation in guidance across sponsors could help address these issues.

Matthew agreed, highlighting that many organisations were ill-equipped to handle the long-term data integrity risks outlined in the R3 guidelines. He suggested looking outside the GCP framework to the Research Data Management community, where Data Management Plans and Trusted Digital Repositories were used to ensure long-term data stewardship. Matthew proposed that similar models could benefit the life sciences community by providing trusted and sustainable archives for study outputs to help Sites and Sponsors meet their responsibilities.

AI in Clinical Trials: Can ICH Keep Up?

As AI continued to make its mark on clinical trials, the question arose: Could ICH keep up with these changes? Suzanne acknowledged that AI in clinical trials was still in its early stages, making it difficult for ICH to address all potential risks and considerations. In the meantime, she believed the responsibility lay with organisations to ensure that AI tools were used within compliance boundaries, with appropriate oversight.

Sara noted that while guidelines like GCP R3 left room for evolution, any updates needed to be coordinated with regulators like the EMA and FDA to maintain confidence in the data provided. AI’s potential for driving change in trial design and data collection was undeniable, but the foundational principles of ethical and scientifically sound trials remained unchanged.

Matthew added that while ICH E6 R3 didn’t preclude advancements like AI, there were already guidelines available from regulatory bodies, including the FDA and EMA. He believed that over time, the ICH would incorporate AI into its framework, using Cloud Computing as an example of how regulators have incorporated other technological advancements into their guidelines. For now, R3 provides a framework within which AI can be used, but full automation and reliance on AI were still on the horizon, and the rules on taking a risk-based approach and focussing on patient safety still apply.

If you would like more information on ICH E6 (R3) we have an eBook available on our website, here.