In the ever-expanding universe of clinical research, the International Council for Harmonisation (ICH) unveiled the latest iteration of E6 (R3) this January – a strategic upgrade designed to strengthen risk-based approach to the clinical trial landscape[1]. The guideline does not merely refine the past – it restructures the framework, establishing a unified standard with far clearer guidance on the implementation of risk-based methodologies than its predecessor.
The countdown has begun, withE6 (R3), under the European Medicines Agency (EMA), slated for activation on July 23, 2025. However, this is more than a regulatory milestone – it’s a foundation for practical and feasible expectations. Through the adoption of Quality by Design (QbD) and proportionate risk-based approaches to trials, it recalibrates the responsibilities of sponsors and investigators, keeping them in sync with the rapidly changing dynamics of modern clinical research.
The guideline encourages fit-for-purpose strategies and deliberate planning in trial design and execution. It extends to the management and retention of essential records, which is a central element of the new guideline and will have a profound impact on the Trial Master File (TMF) as their central repository.
It is important to consider the changes to the guideline in the context of the ICH’s other key guideline on the design and conduct of clinical studies, E8 (R1)[2]. Think of E8 as the architecture, laying the neural framework for the management of clinical trials. It introduces QbD into clinical development, emphasizes critical to quality factors, a culture of open dialogue, and stakeholder engagement. E8 encourages the identification of quality factors and determination of risk at the design level. It focuses on efficiency, relevance, and a participant-centric approach from the outset.
Running alongside E8, E6 (R3) is the machine that applies the foundations laid out by E8. It applies QbD to trial conduct and oversight and embeds risk-proportionality and fit-for-purpose systems into every phase of execution. E6 (R3) also involves some notable language changes from R2, changing “documents” to “records” – so essential records rather than essential documents – and emphasizing more of a partnership in roles and responsibilities by referring to service providers rather than vendors or contract research organizations (CROs). Even the subject has become a participant, and the investigator site has become a location. While those name changes may seem superficial, the wording is intentional and underscores the emphasis on participant engagement.
The guideline identifies 28 criteria for assessing whether a record is essential and makes clear that these records should be maintained or referred to from repositories held by sponsors and the investigator or institution, that the records are collected in a timely manner, that they remain complete, readable and readily available and accessible to regulatory authorities, and that any alteration is traceable. (See box text)
Defining the differences between R2 and R3
While there are many differences between R2 and R3, when it comes to managing the TMF, five stand out for me.
The first is the emphasis on flexibility and a risk-based approach to the management of essential records. It calls for these records to be tailored to the specific trial design and conduct, and for the application of risk-proportionate approaches.
The second emphasizes maintaining version control and ensuring traceability, including metadata such as authors, reviewers, and approvers.
The third explicitly addresses the delegation of trial activities to service providers, including direct access and management of essential records.
The fourth concerns records and data integrity and the importance of incorporating traceability, metadata, and validation of computerized systems to ensure the reliability of trial records.
And the fifth raises the issue of records retention, with no provision for the retention period for essential records, which underscores the importance of sponsors understanding regulatory requirements in the regions they are in.
ICH E6 (R3) reshapes the approach to managing essential records within TMF.
The evolution of essential records management emphasizes flexibility, transparency, and integrity. A risk-based approach tailors records to trial design, shifting from fixed checklists to adaptive matrices. Version control and metadata ensure traceability, making the transition from paper-centric to format-agnostic systems. Direct access to essential records is now prioritized, replacing the “out of sight” approach with mandated accessibility. Record integrity is reinforced through validation and metadata, moving beyond mere compliance filing to true data reliability. Lastly, record retention policies no longer follow a fixed timeline; sponsors must now align with local regulations instead of relying on a standardized two-year rule.
The Essential Records Codex: The 28 encrypted triggers that activate Essential Record status
- Regulators and ethics boards – including the decisions, approvals, and correspondence. These are the official clearances and diplomatic pings
- Plans and protocols – trial-specific procedures or plans, including amendments. This is the operational source code for the mission.
- Decisions and discussions – correspondence and meeting records tied to key decisions. This is the evidence of when, how, and why you altered the path.
- Trial execution logs – records of trial procedures being performed, such as the database lock checklist produced from following data management standard operating procedures. Consider this the ‘black box’ flight recorder for GCP compliance
- Contracts and agreements – the arrangements between parties and insurance/indemnity arrangements. In common parlance, this is “shields up: legal protection enabled.”
- Compliance records – proof of meeting conditions from authorities/ethics boards. This shows you followed orders and have the logs to prove it.
- Committee oversight – membership, actions, decisions of oversight committees, in other words, who watched the watchers.
- System validation – validation of trial-specific systems and assessment of non-trial systems. What this means is all tech must be trial-ready. No rogue code.
- Authorized signatures – signed approvals by the sponsor and/or investigator to confirm review or approval. These are the fingerprints in the digital vault.
- Authorized signatures – staff initials tied to critical trial-related tasks
- Informed consent evidence – documents what participants were told and how consent was obtained
- Qualifications and training – records demonstrating sponsor personnel involved in the trial conduct and individuals performing significant trial-related activities on their behalf are skilled, trained, and certified. Here’s the proof that only qualified operatives touch the system.
- Qualifications and training – records demonstrating that investigators and other delegated staff are skilled, trained, and certified
- Metadata and raw data – contains the data and metadata that are needed for the appropriate evaluation of the trial. Here you’re demonstrating the full chain of custody for every data point.
- Safety monitoring – oversight of participant safety, reporting, and communication, or colloquially speaking, the surveillance grid for harm detection.
- Vendor vetting – proof that service providers are qualified to handle trial activities, or as we might say: No shadow agents. Everyone must be vetted.
- Lab and test fitness – certification and validation of diagnostic/test platforms. In other words, calibrate the scanners before scanning the genome.
- Oversight of sites – documents sponsor oversight of site selection, monitoring, and audits, and provides information on any deviations and implementation of corrective and preventive actions. These are the remote oversight logs: you saw the glitch and you patched it.
- Data handling and analysis – evidence of proper data analysis and production of reports. In other words, algorithms deployed per spec and output verified
- Biological sample tracking – documents the collection, storage, analysis, and destruction of biosamples. This is the DNA chain of custody. Nothing leaks. Nothing gets reused in the dark.
- Product control – as it relates to labeling. From factory to vein, every molecule is accounted for.
- Product control – as it relates to the supply chain
- Product control – as it relates to traceability and accountability across the supply chain
- Product control – as it relates to the identity and quality of the investigational product used in a clinical trial
- Unblinding – documents all related processes and activities
- Participant lifecycle – recruitment, screening and consent – documents these processes with participants. The digital ghosts given form or the who, when, and why of every subject.
- Trial participants, source, data, and history – documents the existence of trial participants and substantiates the integrity of trial data collected. This is the underlying script – not just what happened but what really happened.
- Data security – defines processes and practices to protect participants and data during a security breach. Consider this the intrusion protocol: how you will shut the doors when the alarms go red.
About the author:
Marcin Hernik is Associate Director of TMF Study Resourcing and Consulting, for Cencora clinical services. With a degree in methodology, organization, and management of clinical trials, Marcin has spent nearly a decade working across various TMF roles, gaining experience from both sponsor and CRO perspectives. He has worked with pharmaceutical companies of all sizes, helping to refine TMF processes and support teams by leveraging people, process and technology. At PharmaLex, he has continued to focus on practical solutions that make clinical trial documentation smoother and more effective.
[1] ICH guideline E6 (R3) on good clinical practice, January 2025. ICH. https://database.ich.org/sites/default/files/ICH_E6%28R3%29_Step4_FinalGuideline_2025_0106.pdf
[2] ICH guideline E8 (R1) on general considerations for clinical studies, October 2021. ICH. https://database.ich.org/sites/default/files/E8-R1_Guideline_Step4_2021_1006.pdf
