The first version of the Good Clinical Practice (GCP) E6 guidance was released in 1996 by the International Council for Harmonisation (ICH), and it was revised in 2016. The recently released E6(R3) is the third revision, and it is a major amendment compared to the previous version.
E6(R3) impacts all the trial conduct processes and includes innovations in clinical trial design and new operational approaches that needed to be rapidly adopted during the COVID-19 pandemic. This article covers the changes to E6(R3), while sharing key insights from two of our in-house experts—Alan Yeomans, Viedoc’s Regulatory Affairs Manager, and Marialuisa Baldi, Quality Assurance Officer at Viedoc.
What is E6(R3) and why does it matter?
The ICH creates common regulations for clinical trials around the world. The ‘E’ or ‘Efficacy’ guidelines are concerned with the design, conduct, safety, and reporting of clinical trials. E6 Good Clinical Practice describes the responsibilities and expectations of all participants in clinical trials.
For this third revision, the E6 guideline has been completely revamped and some of the contents have been moved into another document, E8, that covers the higher-level aspects of running clinical trials. This allows E6 to focus on the details within clinical trials, such as flexibility, enhanced risk management, and embracing modern technologies.
The guidelines are for everyone who runs businesses involved in clinical trials, including sponsors, investigators, CROs (Contract Research Organizations), service providers, ethics committees, and Investigator Research Boards (IRBs), also known as Data and Safety Monitoring Boards (DSMBs).
The revised E6 guideline was released in January 2025 and comes into effect in the EU in July 2025. But this date varies from nation to nation as each country incorporates it into their own law.
E6(R3) is about good clinical practice, but is it just guidance or a legal requirement? Alan Yeomans, Regulatory Affairs Manager at Viedoc, clarifies “the E6 guideline is law in all the major markets, so it's not something you can decide whether you want to follow or not—you must comply with it.”
Key updates in E6(R3)
Principles
Some well-known principles that remain in E6(R3):
- Protection of rights, safety, and well-being of participants
- Informed consent
- IRB/IEC approval
- Protocol conduct by qualified individuals
- Investigational product management
New principles in E6(R3) include:
- Robust science, quality, and risk management
- Reliability of results
- Roles and responsibilities of the sponsor and investigators
Thrust on technology
The guidelines for employing different state-of-the-art technologies to manage clinical trials have been upgraded in E6(R3), with a media-neutral approach to allow the technology to be adapted according to participant attributes and specifics of the trial design.
Quest for quality
The updated E6(R3) guideline emphasizes the need for ensuring quality and recommends that quality by design should be implemented across the board. Key activities of the clinical trial, monitoring and data management, are considered essential quality control activities.
Expansion of ethics
E6(R3) includes the ethical issues described in the previous version, plus current ethical considerations based on new technologies being utilized for trial design and conduct. These fall into three main areas:
- Ensuring the participant’s rights in diverse conditions, such as emergency research and electronic consent
- Transparency of clinical trials and sharing of results
- Protecting privacy and confidentiality
Rising responsibilities
Significant changes have been made to the management of all processes throughout the trial life cycle, and E6(R3) provides clearer definitions of the roles and responsibilities of all stakeholders to ensure better collaboration and accountability. Some of the key updates include:
Ethics committee
Ensure the protection of the rights, safety, and well-being of participants in different types of trials.
Investigator
Must comply with new ethical, scientific, technological, and quality requirements, including a number of clarifications around informed consent.
Sponsor
Overarching responsibility to ensure the quality and integrity of the trial, encompassing aspects from design and conduct to data management and reporting, ultimately prioritizing participant safety and reliable results.
“It always falls to the sponsor if something goes wrong”, Alan clarifies, “which makes good sense, as it's the sponsor who loses money if the study goes badly and nothing is approved.”
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Metadata versus data
The definition of metadata and data is of key importance, as this informs how study data should be archived. In the context of E6, metadata describes the characteristics and context of data, while data specifies the structure and format of the data itself. Both are crucial for ensuring data integrity and enabling the reconstruction of trial conduct.
“So metadata is basically the audit trail”, Marialuisa Baldi, Viedoc’s Quality Assurance Officer confirms, “it's where you keep a record of who entered the data, the time and day it was first entered, if it's been changed, and in that case, who, when and why it was changed. This type of information is kept in the audit trail. But everything else, more or less, is called data now.”
In the first two versions of E6, there was a list of essential documents that had to be archived during the trial, but this was seen by many of the sponsors and pharma companies as a definitive checklist to follow. In E6(R3) this has been replaced by an updated, high-level appendix to be used more as a suggestion.
It's the sponsor’s responsibility to define the essential documents that need to be recorded for their trial, i.e. the exact information needed to be able to reenact the events of the trial. It is therefore recommended that sponsors have a pretty comprehensive list, because if inspectors can't find the information they need, the medication will not be approved, leading to huge financial loss for the sponsor.
“There is already evidence showing that DCTs can reduce recruitment timelines by up to 40% and significantly improve retention rates”, states Parul Sharma, Viedoc’s Chief Commercial Officer. Parul goes on to predict “In 2025, investments in infrastructure to support remote monitoring, particularly in emerging markets, will take center stage as sponsors strive for broader inclusivity and lower costs.”
With the growth of DCTs, ensuring robust patient safety and continuous monitoring in a decentralized setting is of paramount importance. Traditionally, trials have treated patients as sources of data only, but trial designs must consider what is most convenient for patients and provide them with benefits.
Majd Mirza, Chief Innovation Officer at Viedoc, summarizes, “ePRO and patient platforms/portals must focus on patient centricity, ensuring that patients have access to their data at all times. Patients should be able to review their progress in a trial, and benefit from participating in a trial beyond just receiving the medication. And to further ease participation in trials, there will be an increased emphasis on passive data collection using wearables and other devices, and more importantly, data collection from EHR.”
How Viedoc ensures compliance with E6(R3)
Vendor validation
One big takeaway from E6(R3) is that validation is the sponsor’s responsibility, but they can make a risk-based assessment to rely on vendor validation.
Alan explains “We do a very detailed validation of Viedoc before we release it each time, and our customers know that, so they can just write in a document that they are relying on Viedoc's validation so they don't have to validate it again. That's good for us and it's good for our customers.”
Making changes to data
Patient reported outcomes, as recorded in Viedoc Me, can be amended within Viedoc. To do this, the investigator must contact the monitor to unlock the data, and the investigator can then make the necessary changes in accordance with the patient's request. This ensures the clear documentation and traceability of any data changes as emphasized within E6(R3).
Marialuisa says “I think Viedoc was one of the first systems in the world to have the capability built in where you don't have to contact the vendor and ask them to change it in the back end, so sites and sponsors can handle it together.”
Expert knowledge
Alan has been involved with the eClinical Forum since 2003, and Marialuisa since 2023, working with inspectors on upcoming changes and necessary revisions to GCP, while also contributing to the development of several whitepapers. Much of this work has been included in the new versions of E6, first in R2 and then most recently in R3. For example, the use of contracts for vendors, with archiving and audit trail review.
“A lot of the new information in E6(R3) was already covered in the EMA’s computerized system guidelines that came out in 2023” adds Marialuisa, “so it's new compared to the previous version of GCP, but it's not new compared to the computerized system guidelines that we've already had in place for about a year and a half now.”
“Many of the things that are considered new in E6 aren't really new to us because we've been talking about them within the eClinical Forum for the last ten years or so” explains Alan. “So when the new guidance was actually released, we were already compliant with it at Viedoc, and no big changes were needed.”
Read more about how you can stay ahead of regulatory changes with Viedoc.
