ICH E6(R3) Annex 2: Key Changes, Reflections, and How to Prepare

Designed to complement the overarching E6(R3) principles and Annex 1, Annex 2 focuses on additional considerations for non-traditional interventional trials, particularly those incorporating:

Decentralized Elements

Clinical trials today are no longer confined to traditional research sites, and the Annex 2 draft addresses this change by providing detailed guidance on remote study activities, remote informed consent and data privacy and security.

• Remote Study Activities: According to the Annex 2 draft, trial-related procedures may be performed at participants’ homes or through digital health technologies (DHTs), including telehealth visits and remote monitoring.
  
  
• Remote Informed Consent: The draft outlines secure approaches for verifying participant identity and capturing informed consent electronically.
  
  
• Data Privacy and Security: Given the increased flow of data from mobile apps, home devices, and wearables, the guideline emphasizes the importance of robust measures to protect participant information.

Pragmatic Trial Elements

Annex 2 draft acknowledges the increasing use of pragmatic trial design features, including Simplified Protocols & Broader Eligibility and Integration with Routine Care.

• Simplified Protocols & Broader Eligibility: These approaches reduce participation barriers, encourage more diverse recruitment, and align trial procedures with real-world clinical practice.

• Integration With Routine Care: Pragmatic trials blend research activities with usual care pathways, reducing operational burden and improving the generalizability of findings.

Real-World Data (RWD)

Annex 2 draft reinforces the growing role of real-world data (RWD) in clinical development, including its use as supplementary or comparative data and the importance of data quality and fitness for purpose. The draft states that sponsors must demonstrate data integrity, relevance, and suitability for regulatory decision-making. It also notes that sources such as Electronic Health Records (EHRs), registries, and health insurance claims may be used to support endpoints, external control arms, or contextual analyses.

Alignment With Annex 1 and Responsibilities of Key Stakeholders 

Annex 2 draft mirrors the structure of Annex 1, including dedicated sections on IRB/IEC, investigator, and sponsor responsibilities. This similarity means that, despite new trial models and data sources, core accountability principles remain unchanged. Central oversight obligations continue to apply to investigators even in decentralized and hybrid trial designs, with oversight extending to:

• Proper management of investigational products in remote settings

• Adapting informed consent processes to non-traditional environments

• 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. 

Critical Reflections on the Draft 

While the Annex 2 draft represents an important step toward a modernized, flexible GCP framework by embracing decentralization and digital innovation, several observations are worth highlighting, including:

• Purpose and Scope Not Yet Fully Defined

Annex 2 draft often outlines responsibilities for different stakeholders at a high level which may leave room for interpretation when it comes to implementation. Therefore, the overall purpose of Annex 2 could be clarified further to allow for greater consistency in its application in practice.

• Frequent Reference to “Applicable Local Regulatory Requirements”

The Annex 2 draft frequently refers to applicable local regulatory requirements; however, while this acknowledges regional differences, it may also undermine harmonization. Providing clearer guidance on what is meant by “regulatory requirements,” and/or offering a more standardized global interpretation could help strengthen consistency across different regions.

• Limited Patient-Centered Focus

Despite the draft's modern approach, it appears to lack a strong patient-centered focus. To enhance its practical relevance, Annex 2 could provide more explicit guidance on :

- Patient involvement in trial design

- Accessibility of consent materials

- Data transparency

- Integration of Patient-Reported Outcomes (PROs)

Notably, there is no explicit reference to PROs as part of trial assessments, including in approaches involving Real-World Data (RWD). Given the increasing emphasis on patient experience and outcome measurement in contemporary clinical research, this may represent a missed opportunity to further align the guidance with evolving industry practices.

• Limited Detail on Record Maintenance

The Annex 2 draft provides limited detail on documentation requirements in decentralized trial settings. As clinical trials increasingly involve multiple digital systems, sites, and parties, recordkeeping becomes more complex for investigators and sponsors. To ensure consistency and help maintain compliance across decentralized environments, it is critical for Annex 2 to provide clearer expectations regarding documentation standards and oversight responsibilities.

What’s Next?

The public consultation period has closed, and an overview of stakeholder comments was published in May 2025. We now await further updates to understand how ICH will address these open points and refine the guideline for final release. In the meantime, several proactive steps can help all stakeholders; sponsors, CROs, investigators, and technology partners prepare for the upcoming changes, for example:  

• Internal Readiness Assessments

By evaluating how decentralized elements, pragmatic methodologies, and real‑world data streams fit into their current operational models. Early gap assessments will help identify areas requiring process updates, staff training, or system upgrades ahead of Annex 2 finalization.

• Risk Proportionate Approaches

Annex 2 reinforces the E6(R3) shift toward proactive, risk‑based clinical operations. Companies can begin refining their risk‑assessment methodologies, data-governance structures, and oversight models, especially as responsibilities evolve under decentralized or hybrid trials.

• Enhance Documentation & Record Keeping Frameworks

Given the expected clarification around documentation requirements in remote and multi‑system environments, now is the appropriate time to harmonize documentation practices and ensure that digital systems are audit‑ready, validated, and compliant.

• Deepen Engagement with Participants & Sites

With the growing emphasis on diversity, accessibility, and patient‑centricity, sponsors should evaluate opportunities to incorporate patient input, improve transparency, simplify consent materials, and integrate PROs, even ahead of formal guidance updates.

• Prepare for Increased Regulatory Dialogue

Annex 2 encourages early and continuous interaction with health authorities, especially for decentralized, pragmatic, or RWD‑driven designs. Sponsors should prepare to bring well‑defined justifications, feasibility data, and technology partner considerations into these discussions.