When the International Council for Harmonisation (ICH) introduced its comprehensive revision to the E6 guideline for Good Clinical Practice (GCP) – E6 (R3) — it recognized the imperative to respond to rapidly changing trends in clinical research with clearer governance and oversight[1].
Since it was first released in 1996, E6 has been focused on monitoring and reporting, as well as establishing the roles and responsibilities of key stakeholders. As the clinical trial landscape has evolved, so too has E6 – starting in 2016 with R2, which sought to encourage more efficient processes and to update standards to account for electronic records while ensuring the safety of trial participants[2].
Now, nearly a decade later, R3 introduces further rigor to oversight and governance. While E6 (R3) is very broad in its objective of tightening the conduct of clinical trials, two areas that deserve particular focus in a changing environment are the guideline’s emphasis on quality by design (QbD) and a heightened focus on digital provenance.
QbD and data-based oversight
Over the past decade, there has been a growing focus on using data and analytics to support clinical trials, initially with the objective of supporting remote in place of onsite monitoring to improve efficiency. This has given rise to risk-based monitoring (RBM), where, rather than relying on source data verification, monitoring is based on an assessment and analysis of the data to identify specific risks and take steps to mitigate these[3].
With the release of E6 (R3), which fosters the key principles of clinical study design established in ICH E8[4], the ICH heightens the emphasis on incorporating a culture of quality-based systemic management throughout the lifecycle of a clinical trial. Adopting the practice of QbD ensures the guideline is razor-focused on identifying quality-related parameters and risk mitigation approaches that are critical to protecting rights, safety and wellbeing of trial participants and assuring reliability and interpretability of the trial results. Specifically, R3 emphasizes the importance of adopting a proportionate approach to the identification and monitoring of risk. The ultimate objective of this QbD approach is to maximize the achievement of trial objectives and reduce occurrence of non-compliance.
One of the key points to consider with QbD is risk analysis, leveraging predictive analytics or modelling to assess various activities related to the operation of a trial, such as data quality, primary endpoints, trial outcomes, and data governance. This analysis can help investigators or sponsors act earlier on any potential signals to modify the trial – for example, signals on enrolment, on trial dropouts, assay findings, and so on.
By introducing centralized monitoring to the analysis of data and bringing together clinicians, statisticians, data managers, and clinical trial operators, sponsors can start to look at their trials holistically and infuse QbD into the whole process.
What E6 (R3) does is to enforce that concept of QbD across all stages of a clinical trial, applicable to all stakeholders, with the objective of ensuring efficiency, effectiveness and reliability while observing safety and ethical standards. R3 also extends governance to include documents, data, and relevant metadata (now collectively referred to as records) to determine the reliability and reproducibility of data.
It requires the sponsor to ensure they have a proper risk assessment or procedural document as part of the study plan and to maintain and constantly update that document throughout the study. It requires the sponsor to answer questions such as, how are you carrying out remote monitoring? If you are assessing risk, how are you measuring that? And what measures do you have in place to respond to a risk if it reaches amber or red status? If there are signals, can you find trends that explain what those signals mean for the molecule or indication or trial population? R3 is much more explicit about what is expected of sponsors or whoever is handling the trial on the sponsor’s behalf.
E6 in a digital world
In parallel with the emphasis on risk proportionality and QbD is the growth of digital technologies and integration of platforms such as e-consent and tools such as wearables in clinical trials.
Digital tools play an integral role not only in influencing the clinical trial process but also in helping to support data and quality governance. At the same time, as these tools add significantly to the datasets available, there is an imperative to remove the noise.
Now, for the first time with E6 (R3), a guideline speaks directly to the use of digital tools to manage clinical trials and data and emphasizes the imperative of chain of custody and data traceability. Data traceability/reproducibility is a significant issue in clinical trials, and very often clinical trials fail due to issues with data traceability, reproducibility, or not achieving endpoints[5]. The new guideline expands on the objectives laid out by the US Food and Drug Administration (FDA) in 21 CFR Part 11 on ensuring data integrity across the chain of custody.
Regulators have made clear they expect sponsors and investigators to have full traceability across the entire process. For example, when using e-consent, can the sponsor demonstrate proper management of the entire consent process? What R3 does is to emphasize compliance with digital system requirements, including electronic signatures.
Equally, the concept of digital traceability in clinical trials concerns patient-centric at-home models designed to better support patient outcomes and reduce the risk of patient drop out. That raises questions such as, how is the data collected? If a nurse is required to be in attendance, how can the trial investigator and sponsor be sure they were there? The ability to track the process becomes paramount.
Technologies such as lab-on-a-chip with incorporated barcodes unite all those principles of traceability by enabling time and date stamps. Full compliance with E6 (R3) will require that such data can be managed and traced across the entire lifecycle.
Stakeholder responsibility
The new guideline gives clinical trial stakeholders clarity as to what is expected of them and why traceability, chain of custody, and QbD are imperative to good clinical practice (GCP). It clearly lays out the responsibilities of investigators and ethics committees to not only ensure protocols are written in a way that assures patients’ well-being and safety, but also that they have properly reviewed and understood the use of tools such as e-consent. Has the sponsor provided them the adequate information on validation of the signature platforms? Can they be sure there is proper oversight of the process?
Technology shifts the dynamic but also paves the way for greater oversight if properly managed. E6 (R3) provides the clarity needed for all stakeholders. These stakeholders will need to ensure they understand what is expected of them and make sure the proper oversight and governance is achieved to adhere to the principles of safeguarding the rights, well-being and safety of all trial participants.
The way forward
The technology adoption component of ICH E6 R3 reflects the harmonization body’s intent to modernize trial conduct, making studies more efficient, patient-friendly, and robust, while maintaining high standards for data quality, security, and regulatory compliance.
About the author:
Rajesh Jain, MBBS is VP, operations India, and global lead for clinical services solutions, at PharmaLex. He has three decades of expertise in clinical research outsourcing and combines domain knowledge with strategic foresight to drive transformative initiatives that foster innovation, efficiency, and growth in global business operations. Before joining PharmaLex, Rajesh cofounded a life sciences tech startup delivering patient-centric digital trial management solutions and has also established successful CRO operations in India and the United States.
[1] Guideline for Good Clinical Practice, E6 (R3), ICH, Jan 2025. https://database.ich.org/sites/default/files/ICH_E6%28R3%29_Step4_FinalGuideline_2025_0106.pdf
[2] Integrated addendum to ICH E6 (R1), Guideline for Good Clinical Practice, E6 (R2), ICH, Nov 2016. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf
[3] Risk-Based Monitoring in Clinical Trials: Past, Present, and Future, Ther Innov Regul Sci. 2021 Jul;55(4):899-906. doi: 10.1007/s43441-021-00295-8. Epub 2021 Apr 29. PMID: 33914298; PMCID: PMC8082746.
[4] General considerations for clinical studies, E8 (R1), ICH, Oct 2021. https://database.ich.org/sites/default/files/E8-R1_Guideline_Step4_2021_1006.pdf
[5] Why Most Published Research Findings Are False, PLOS Medicine, 2005. https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0020124
