ICH E6(R3) Annex 2 adopted to support decentralized clinical trials and real-world data use

The International Council for Harmonisation (ICH) has adopted E6(R3) Annex 2, introducing additional Good Clinical Practice (GCP) guidance for clinical trials incorporating decentralized elements, pragmatic elements, and real-world data (RWD), reflecting the continued evolution of clinical research methodologies and digital technologies.

The Baseline

• ICH has adopted E6(R3) Annex 2, providing new Good Clinical Practice guidance for clinical trials incorporating decentralized elements, pragmatic elements, and real-world data.
• The annex introduces recommendations for applying proportionate risk-based approaches and Quality by Design principles to modern trial designs while maintaining participant protection and data reliability.
• The guidance provides greater regulatory clarity on the use of decentralized trial methods, digital health technologies, and real-world data in clinical research.

The annex was formally adopted under Step 4 of the ICH harmonization process during the organization's biannual Assembly meeting in Rio de Janeiro, Brazil, on June 3, 2026. It complements the E6(R3) Principles and Annex 1 by providing additional guidance on applying GCP to modern trial designs and alternative approaches to evidence generation while maintaining participant protection and data reliability.

According to the guideline, GCP remains applicable across all clinical trial types and settings, but “the application of GCP should be tailored to the trial design and technologies utilized.” It further explains that a proportionate risk-based approach can support evolving trial designs “without compromising the rights, safety and well-being of the participants and the reliability of the trial results.”

Annex 2 focuses on studies incorporating decentralized elements, pragmatic elements, and/or RWD. It defines decentralized elements as trial-related activities conducted outside the investigator's location, including home visits, local healthcare centers, mobile medical units, and remote interactions supported by digital health technologies (DHTs). Pragmatic elements include aspects of trial design that integrate routine clinical practice, such as streamlined data collection and procedures aligned with standard healthcare delivery.

The guideline also formally describes DHTs including mobile applications, wearable devices and sensors, as technologies used to collect, measure, or monitor health-related data from participants and patients. It recognizes their growing role in modern clinical trials, including supporting remote visits, protocol-related procedures, and data collection outside traditional investigator sites. Throughout the document, there is a continued emphasis on Quality by Design (QbD) principles and a proportionate risk-based approach to ensure that innovative methodologies remain fit-for-purpose while protecting participants and supporting reliable evidence generation.

Reflecting on the publication, Andrew Thomson, owner and lead consultant at Regnitio and former Regulatory Chair for the Annex 2 development work at the European Medicines Agency, described the guideline as "enabling," saying that:

“It gives medicines' developers the confidence that trials using decentralized and pragmatic elements and RWD sources will still be considered 'GCP compliant'.”

He added that it also gives inspectors confidence that they can assess “the data underpinning these trials and ensure they are indeed fit-for-purpose.”

The annex provides detailed considerations covering remote informed consent, investigational product management, investigator and sponsor oversight, safety assessment and reporting, participant privacy, and data governance. It also addresses participant-centered trial design, noting that sponsors should consider factors such as digital literacy, access to technology, and participant burden when implementing decentralized approaches.

A substantial section of the annex is dedicated to the incorporation of RWD into interventional clinical trials. The guidance distinguishes between trial-specific primary data collection and the secondary use of healthcare data originally collected for other purposes, noting that different considerations apply to data quality, governance, and regulatory acceptability. It states that sponsors should ensure RWD are fit-for-purpose by assessing both their reliability and relevance, including “accuracy, completeness, provenance and traceability.” The annex also highlights considerations relating to data quality, source verification, data linkage, privacy protection, consent, regulatory access, and governance arrangements when RWD are used to support trial endpoints or external controls.

Commenting on the adoption, Agrim Jain, Clinical Research Associate at the Translational Health Science and Technology Institute, suggested the adoption provides greater regulatory clarity for these approaches. Reflecting on the use of decentralized trials, wearable technologies, and electronic health data, he said researchers had often been “operating in a regulatory grey zone,” adding that “that grey zone officially closed on June 3, 2026.”