--- title: "ICH E6(R3) Annex 2: Key Changes, Reflections, and How to Prepare" description: ICH E6(R3) Annex 2 reshapes GCP for decentralized and real-world data–driven trials. image: https://blog.pqegroup.com/hubfs/ICH%20E6_Blog-1.jpg --- [![Logo PQE Group - azzurro - 2024](https://blog.pqegroup.com/hs-fs/hubfs/Logo%20PQE%20Group%20-%20azzurro%20-%202024.png?width=2000&height=721&name=Logo%20PQE%20Group%20-%20azzurro%20-%202024.png "Logo PQE Group - azzurro - 2024")](https://www2.pqegroup.com) - [Home](https://www2.pqegroup.com/) - [Industry](https://www2.pqegroup.com/industry/) - [Pharma & API](https://www2.pqegroup.com/pharma-api/) - [Medical Device](https://www2.pqegroup.com/medical-device/) - [Biotech](https://www2.pqegroup.com/biotech/) - [Startup](https://www2.pqegroup.com/startup/) - [Veterinary](https://www2.pqegroup.com/veterinary/) - [Services](https://www2.pqegroup.com/services/) - [Data Integrity](https://www2.pqegroup.com/data-integrity/) - [Digital Governance](https://www2.pqegroup.com/digital-governance/) - [Engineering](https://www2.pqegroup.com/engineering/) - [Commissioning, Qualification and Validation (CQV)](https://www2.pqegroup.com/commissioning-qualification-validation/) - [Quality Compliance](https://www2.pqegroup.com/quality-compliance/) - [Laboratory Excellence](https://www2.pqegroup.com/laboratory-excellence/) - [Regulatory Affairs](https://www2.pqegroup.com/regulatory-affairs/) - [Audits](https://www2.pqegroup.com/audits/) - [Training](https://www2.pqegroup.com/training/) - [Clinical Research](https://www2.pqegroup.com/clinical-research-services/) - [Pharmacovigilance](https://www2.pqegroup.com/pharmacovigilance/) - About - [About Us](https://www2.pqegroup.com/about/) - [ESG](https://www2.pqegroup.com/about/csr/) - [Women in STEM](https://www2.pqegroup.com/about/women-in-stem/) - Resources - [News & Press](https://www2.pqegroup.com/news/) - [Webinars](https://www2.pqegroup.com/webinars/) - [Blog](https://blog.pqegroup.com/) - [Careers](https://www2.pqegroup.com/careers/) - [Contact Us](https://www2.pqegroup.com/contact-us/) ![Marianna Esposito](https://blog.pqegroup.com/hubfs/Marianna%20Esposito.jpg) Marianna Esposito Clinical Compliance Director @PQE Group # **ICH E6(R3) Annex 2: Key Changes, Reflections, and How to Prepare** [Regulatory Affairs](https://blog.pqegroup.com/tag/regulatory-affairs) With the adoption of Annex 2, the ICH E6(R3) revision is now complete. More importantly, the guideline formally recognizes that modern clinical research is no longer limited to traditional site-based models. Decentralized approaches, pragmatic trial designs, and the use of real-world data have become integral components of clinical development, and Annex 2 provides the GCP framework needed to govern them. It clarifies expectations for decentralized activities, the use of digital technologies, integration with routine healthcare, and the governance of real-world data sources. *Annex 2 reached Step 4 following ICH adoption on 3 June 2026 and CHMP adoption on 25 June 2026 and will come into effect on 15 January 2027.* Designed to complement the overarching E6(R3) principles and Annex 1, Annex 2 focuses on the following considerations for non-traditional interventional trials: ### **Decentralized Elements** Clinical trials today are no longer confined to traditional research sites, and Annex 2 addresses this change by providing detailed guidance on remote study activities, remote informed consent and data privacy and security.   - **Remote Study Activities & Digital Health Technologies (DHT)** Trial-related procedures may be performed at participants' homes or through Digital Health Technologies (DHTs), including telemedicine visits, remote data collection, home healthcare services, and remote monitoring activities. These approaches may improve participant access and reduce barriers to trial participation. Annex 2 acknowledges the increasing use of DHTs to support trial conduct and data collection and highlights the need for appropriate oversight, governance, cybersecurity, and fitness-for-purpose assessments. - **Remote Informed Consent** Annex 2 recognizes that informed consent may be obtained through electronic and remote processes, provided that participants identity verification, adequate interaction with study personnel, participant understanding, proper documentation, and compliance with applicable regulatory requirements are ensured. - **Data Privacy and Security** The increasing use of mobile applications, wearable devices, electronic platforms, and remote data collection technologies creates additional challenges related to privacy and cybersecurity. Annex 2 therefore emphasizes the need for robust controls to ensure data integrity, confidentiality, traceability, and protection of participant information throughout the data lifecycle. ### **Pragmatic Trial Elements** Annex 2 acknowledges the growing use of pragmatic trial methodologies designed to generate evidence under conditions that more closely reflect routine clinical practice.  - **Simplified Protocols & Broader Eligibility Criteria** These approaches reduce participation barriers, encourage more diverse recruitment, and align trial procedures with real-world clinical practice. - **Integration with Routine Clinical Care** Pragmatic trials may integrate research activities within standard healthcare pathways, reducing operational burden while enhancing the relevance of clinical evidence in real-world settings. ### **Real-World Data (RWD)** Annex 2 reinforces the growing role of Real-World Data (RWD) in clinical development. RWD may be used as supplementary, comparative, or supportive evidence and may originate from sources such as Electronic Health Records (EHRs), disease registries, claims databases, digital health technologies, and other healthcare data repositories. The guideline emphasizes that sponsors should demonstrate that RWD is fit for purpose, appropriate access and oversight are in place, and that use of such data complies with applicable privacy and data protection requirements, including consent and permission. Although Annex 2 encourages the use of RWD, it does not lower expectations regarding data reliability. Sponsors remain responsible for demonstrating that data sources are sufficiently complete, accurate, traceable, and suitable to support the intended regulatory or scientific objectives. Beyond the specific trial design elements addressed above, Annex 2 also clarifies how established GCP (Good Clinical Practice) responsibilities apply within decentralized, pragmatic, and RWD-enabled trial environments.   ## **Alignment With Annex 1 and Responsibilities of Key Stakeholders** Annex 2 closely mirrors the structure of Annex 1 and includes dedicated sections addressing the responsibilities of IRBs/IECs, investigators, and sponsors. While the operational environment may differ significantly from traditional site-based trials, the underlying accountability framework remains unchanged.  - Proper management of investigational products in remote settings - Adapting informed consent processes to non-traditional environmen - Safeguarding participant safety regardless of trial decentralization For sponsors, the draft introduces broader expectations and promotes a proactive, stakeholder-engaged approach. This includes collaboration with regulators, patients, and technology partners to ensure feasibility, accessibility, and compliance.  Given the complexities associated with real-world data and emerging methodologies, the draft also emphasizes the importance of early and ongoing regulatory dialogue.  ### **Investigator Responsibilities** Investigators retain overall responsibility for participant protection, protocol compliance, medical oversight, and data reliability, regardless of where trial activities are performed. Particular attention should be given to: - Oversight of delegated activities performed remotely, including activities conducted by healthcare professionals as part of routine clinical practice; - Oversight of home healthcare providers and third-party services; - Proper management of investigational products in decentralized settings; - Adaptation of informed consent procedures to non-traditional environments; - Protection of participant safety throughout the trial.  The use of decentralized approaches does not diminish the investigator's accountability for trial conduct.  ### **Sponsor Responsibilities** Sponsors are expected to implement proportionate oversight strategies reflecting the complexity, risks, technologies, operational models, and data sources used within a study. One of the key messages of Annex 2 is that oversight, monitoring, documentation, and quality management activities should be proportionate to the risks and criticality of the trial design, rather than applying a one-size-fits-all approach. Key areas of focus include: - Oversight of third parties and service providers; - Governance of digital technologies and trial data; - Risk-based quality management; - Data governance and cybersecurity. Annex 2 further reinforces the concepts of quality by design, fitness for purpose, and risk proportionality introduced within the broader E6(R3) framework.   ## **Critical Reflections** While Annex 2 represents an important step toward modernizing GCP and enabling innovative clinical trial models, several practical considerations remain relevant.  ### **Global Consistency Versus Local Requirements** Although the final version provides greater clarity than the public consultation draft, implementation will continue to depend on local regulatory requirements. Organizations operating globally may therefore encounter regional differences in the acceptance and application of decentralized procedures, electronic informed consent models, digital technologies, and RWD methodologies. ### **Documentation and Record Management Remain Challenging** Annex 2 provides additional considerations regarding data governance and documentation in decentralized environments. However, organizations will still need to develop detailed internal procedures defining: - Source data ownership; - Record retention responsibilities; - System interfaces and data transfers; - Documentation standards across multiple platforms; - Oversight responsibilities among sponsors, investigators, and service providers. As trial ecosystems become increasingly digital and distributed, documentation and data governance will remain critical areas for inspection and audit readiness. ### **Technology and Vendor Dependency** As decentralized trials increasingly rely on external technology providers, home healthcare organizations, and data aggregators, sponsors and investigators may face greater challenges in maintaining effective oversight and ensuring clear accountability across complex service networks.   ## **Preparing for ICH E6(R3) Annex 2** With Annex 2 now finalized, organizations should focus on practical implementation activities to ensure readiness before its effective date. ### **Considerations for Sponsors When Implementing Annex 2** - Review Trial Designs and Operational Models: Evaluate whether decentralized elements, pragmatic design features, Digital Health Technologies (DHTs), or Real-World Data (RWD) sources introduce additional considerations regarding oversight, data quality, participant protection, and trial conduct. - Ensure Proportionate Risk-Based Quality Management: Confirm that quality management activities are proportionate to the risks, complexity, data sources, technologies, and operational models used within the trial. - Evaluate Oversight of Service Providers and Third Parties: Ensure appropriate oversight arrangements are in place for vendors, home healthcare providers, laboratories, technology providers, and other third parties involved in trial-related activities. - Assess Data Governance and Data Reliability: Establish appropriate arrangements for data traceability, integrity, confidentiality, accessibility, and management throughout the data lifecycle, particularly when multiple systems and external data sources are involved. - Evaluate the Use of Digital Health Technologies: Ensure that digital technologies used to support trial activities are fit for their intended purpose and supported by appropriate governance, training, and operational controls. - Assess the Suitability of Real-World Data Sources: When RWD is used, ensure that data sources are fit for purpose and that appropriate access, oversight, and data protection arrangements are established. - Review Organizational Procedures and Training: Evaluate whether existing procedures, roles, responsibilities, and training programs adequately support decentralized activities, remote processes, and the use of digital technologies. ### **Considerations for Investigators When Implementing Annex 2** - Review oversight arrangements for delegated activities performed remotely, including activities conducted by third parties and healthcare professionals involved in routine care. - Ensure informed consent processes remain appropriate when electronic or remote methods are used. - Verify procedures for investigational product management in decentralized settings. - Evaluate documentation practices and source data management across multiple systems and locations. - Ensure study personnel are adequately trained and supervised for decentralized trial activities. - Assess whether local processes adequately support participant safety, communication, and medical oversight throughout the study.   ## **Conclusion** ICH E6(R3) Annex 2 does not introduce a completely new regulatory framework. Instead, it extends established GCP principles to accommodate modern clinical trial methodologies, including decentralized trial elements, pragmatic study designs, and the use of Real-World Data. Organizations that proactively strengthen risk-based quality management, data governance, investigator oversight, vendor management, and technology governance will be best positioned not only to achieve compliance but also to take full advantage of the opportunities offered by more flexible and patient-accessible clinical trial models. ![ICH E6\_Blog](https://blog.pqegroup.com/hs-fs/hubfs/ICH%20E6_Blog.jpg?width=2000&name=ICH%20E6_Blog.jpg) ## Want to know more? Visit our [Regulatory Affairs](https://www2.pqegroup.com/regulatory-affairs/) dedicated page Bring your product into the next generation. Risking inspection failures is a cost no company can afford: get in touch with us and learn more together with our experts. 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