Final Concept Paper
ICH E6 (R3) Guideline for Good Clinical PracticeAnnex-230 March 2023

Endorsed by the Management Committee on 28 April 2023
Type of Harmonisation Action Proposed
The action proposed is the development of the new Annex 2 of ICH E6(R3) Guideline entitledGood Clinical Practice (GCP). When complete, E6(R3) will be composed of an overarching
principles document, Annex 1 (considerations for interventional clinical trials), and Annex 2(additional considerations for interventional clinical trials).1 This document complies with theICH MC request to review and approve Annex 2 Concept Paper once the updated ICH E6(R3)Principles and Annex 1 are on the verge of entering Step 1 of the ICH development process.
The original Concept Paper stated that before the drafting of Annex 2, its scope would be further
clarified, to define the nature of trials involved, in an update to the concept paper. Although theinitial perspective was to update the original Concept Paper with Annex 2 details, the EWG
determined that a separate Concept Paper (this document) is preferred for Annex 2.
Statement of the Perceived Problem
In the two decades since ICH E6 was first drafted, clinical trials have become more complex
with respect to trial design, use of technology, quantity of data collected, and involvement ofcentral testing facilities or other service providers. ICH E6(R2) was developed with multiple
addenda to address the emerging use of electronic data sources and risk management processes.
Nonetheless, since the development of E6(R2), clinical trials have continued to evolve withnew designs and technological innovations. It was also noted that while E6(R2) provided agreat deal of details, it did not address many aspects of modern clinical trials. Advances intechnologies used in clinical practice provide opportunities to integrate clinical research andclinical care. The trend of growing interoperability of technology across the data life cycle
serves as a new vehicle for data exchange among multiple stakeholders in the clinical trial
enterprise, including patients, researchers, and caregivers. The richness of these multiple data
sources and the growing exploration and use of artificial intelligence offers the potential tosignificantly enhance evidence generation in clinical trials. Annex 2 provides additionalconsideration that are based on the foundation established in Annex 1. Annex 2 should be readand implemented with E6(R3) principles and Annex 1.
Issues to be Resolved
Thoughtful design of clinical trials is critical and it should consider available design elements
and data sources that may make a trial more efficient and more accessible, while helping toensure participants’ safety and the reliability of the trial results.
1 In the original concept paper, E6(R3) Annex 1 was described as providing considerations for traditional interventional

clinical trials, while and Annex 2 was described as providing considerations for non-traditional interventional clinical trials.

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E6(R3) Annex 2 Concept Paper

Endorsed: XXThe proposed development of Annex 2 will include additional considerations on how GCP
principles may be applied across a variety of trial designs and data sources, where applicable.
This will include:
1- Decentralised elements, where some or all trial-related activities occur at locations
other than traditional clinical trial sites, such as patient homes, mobile trial units,
or local clinics, and data collection may occur remotely.
2- Pragmatic elements, reflecting trials that closely resemble routine clinical practice.
3- Real-world data (RWD) sources2, for example, the use of registries, electronic
health records (EHR), hospital data, pharmacy and medical claims data orwearables.
As the work on Annex 2 proceeds, this concept paper will be updated as necessary toincorporate new learning and ideas that are not described above.
Background to the Proposal••••ICH Reflection on “GCP Renovation:” Modernization of ICH E8 and Subsequent
Renovation of ICH E6, 2017.
Draft version ICH E6(R3) Principles – Published on the ICH website on 19 April
2021
ICH E6(R2) Good Clinical Practice
ICH E8(R1) General Considerations for Clinical Studies

Type of Working Group and Resources
The working group (WG) that will be tasked with developing Annex 2 will include certain
members from the E6(R3) EWG with specific overarching expertise relevant to the scope of
this Annex. New members will also be considered to ensure the scope of expertise isrepresented. The Annex 2 WG may include experts from various disciplines including clinical,statistical, data science, clinical outcomes assessment, regulatory compliance, ethics andpotentially others. The Annex 2 WG will involve engagement with stakeholders including
academia throughout the development process.
To ensure efficiency membership will be designed to be representative, but limited in size tobe efficient. This will help ensure concurrent development of Annex 2 while the full EWG
continues to work on addressing the development of Annex 1. Direct and frequent interactions,as well as continuity of leadership between the groups will help ensure that Annex 1 and Annex
2 are well connected and synergistic while avoiding redundancies.
TimingWe expect approximately 12-18 months are needed to develop a draft that will be subject topublic consultation.

2 This does not include observational studies.

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