Traceability, proportionality, and flexibility: Strategies for operationalizing ICH E6(R3)

Earlier this year, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) released revision 3 of the ICH E6 Guideline for Good Clinical Practice (GCP). ICH E6 is the international standard for conducting clinical research. It’s critical, therefore, that sponsors, CROs, investigators, site staff, and other partners understand the updates in this latest revision, known as ICH E6(R3). The EU EMA will implement the new guidelines on July 23, 2025. The U.S. FDA is also expected to implement ICH E6(R3) in coming months.

What changes are included in ICH E6(R3)?

This revision aims to modernize GCP guidelines, addressing recent developments in the technology and approaches used to conduct clinical research. The most notable updates emphasize:

• Transparency in data governance. Data must be traceable from the point of collection onward. This includes data flows, systems integrations, and the associated audit trail data.
• Quality by design (QbD), in which sponsors address critical-to-quality (CtQ) factors early in the study design process. Sponsors should identify and mitigate risks as part of protocol development, which helps ensure patient safety and data reliability. This aspect of ICH E6(R3) builds on other guidelines outlined in ICH E8.
• Risk-based approaches, which align with QbD. Rather than treating all data equally, sponsors should implement risk-based trial operations (RBTO) processes. With RBTO, sponsors focus most of their cleaning, monitoring, and mitigation efforts on the data most critical to the study. While the previous version of ICH E6 addressed risk-based quality monitoring, the latest version advocates for broader risk-based approaches, calling on sponsors to use proportional risk management in all aspects of clinical operations.
• Patient-guided trial design. ICH E6(R3) encourages sponsors and their development partners to consider patient perspectives when developing protocols in order to reduce the burden of participation. 

To comply with the updated guidelines and improve efficiency, we recommend sponsors focus on three key areas: data traceability, proportionality in risk management, and flexibility in study design.   

Traceability: Have a clear understanding of the data path

For the greatest possible transparency in a trial, sponsors must be able to trace data from capture through submission, fully documenting its end-to-end path. ICH E6(R3) strongly recommends that path now be documented via a data flow diagram, which identifies all systems, integrations, and data repositories that are part of the process. 

Because studies generate vast amounts of data through numerous sources, creating a comprehensive data flow diagram can be complex.  As a starting point, sponsors might tap into resources available through TransCelerate’s Digital Data Flow initiative. 

For all data points, sponsors need to make sure they know:

• The origin of capture, such as the EDC system or a wearable device with data delivered via vendor portal. In our experience, at least half of all critical data is   captured outside of the EDC system.
• How and why the data is cleaned.
• How data is stored, such as in data warehouses and/or data lakes.
• What roles query the data and for what purpose.
• What data is used for evidence generation and how that evidence is ultimately submitted or otherwise presented.
• What integrations are required among systems to facilitate data flow.

By answering these questions, sponsors also create an audit trail that demonstrates the accuracy and trustworthiness of their evidence packages. Additionally, diagramming the data flow is an opportunity to pinpoint and mitigate risks, such as data leaks that could occur as data is transferred between platforms.

Because much of a study’s data will be collected and first managed by vendors, as in the earlier example of wearable devices, sponsors should state explicitly in their vendor specifications their requirements for data traceability. Unfortunately, some vendors’ systems do not allow for easy exportation of data in a consumable format or for access to audit trails, and sponsor often realize this too late. Additionally, vendors should agree to send sponsors only required data variables, not every data point collected. This will reduce the amount of data tracing, auditing, and cleaning that must be conducted.

Proportionality: Prioritize the critical data 

In encouraging the use of QbD principles, ICH E6(R3) directs sponsors and their partners to maximize their use of risk-based data cleaning and monitoring, focusing most of their time and resources on the data that is most critical to the study rather than treating all data equally. Risk-based approaches, which leverage the concept of proportionality, should be informed by comprehensive initial risk assessments, illustrated by data flow diagrams and risk controls, and supported by ongoing risk management and centralized monitoring, including aggregated statistical data analysis.  

While all data should be treated with care, peripheral and exploratory data don’t demand the same level of cleaning rigor as is necessary for critical data. With critical data, for example, a sponsor might use automated edit checks and centralized statistical monitoring while for exploratory data, automated edit checks might be enough. Allowing sponsors to relax oversight of less risky study elements, such as exploratory data not required for efficacy and safety analysis, leads to greater overall operational efficiency.

In relation to RBQM, ICH E6(R3) has introduced new terminology: acceptable ranges. This expands on previous standards regarding quality tolerance limits (QTLs) — deviations from which would indicate possible systemic safety or reliability issues within a study. An acceptable range extends from the Key Risk Indicator (KRI) threshold to the QTL. Each acceptable range, particularly those that could impact patient safety or the ability to perform analysis, should be set with input from biostatisticians and medical experts and based on previous-phase research data whenever possible.

Flexibility: Adapt to what patients are asking for

ICH E6(R3) promotes flexibility in both protocol design and study activities to make participation as easy and simple as possible for patients. In particular, the guideline recommends the use of decentralized clinical trial (DCT) elements.  This could include at-home digital technologies such as wearables that enable remote participation, but it also encompasses telehealth, in-home nursing, and visits to community-based or satellite sites.

As much as possible, sponsors should allow patient perspectives to guide protocol design. This might mean, for example, reducing exploratory endpoints in a study to correspondingly reduce the number of visits patients must attend and/or the length of those visits. Sponsors should also ensure that compliance and data integrity are built into every decentralized element, as even the most innovative process or technology cannot create value if it doesn’t deliver consistent, reliable, and trustworthy data.

A thorough understanding of ICH E6(R3) is important for anyone involved in clinical trials but particularly so for sponsors and CROs, who will be responsible for guaranteeing that study designs and conduct comply with the latest implemented guidelines. Compliance demonstrates that sponsors are holding themselves to the highest possible standards for participant and patient safety and data quality and reliability. And with its emphasis on traceability, proportionality, and patient-guided study design, ICH E6(R3) can also lead to greater efficiency so critical therapies can reach patients faster.

Disclaimer:
Parexel provides the information contained in this document for educational purposes only. The information does not constitute legal or regulatory advice. Readers should not act upon this information without seeking advice from professional advisers. 
 

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