The International Council for Harmonisation (ICH) has taken another significant step toward modernizing Good Clinical Practice (GCP) guidelines with the release of the draft Annex 2 to GCP E6(R3). This latest addition is now available for public consultation and builds on the framework established by the Principles and Annex 1, which were previously released.

What Does Annex 2 Cover?

Annex 2 provides detailed guidance tailored to innovative and emerging trial designs that incorporate modern methodologies and data sources. The annex focuses on three core areas:

1. Decentralized Trial Elements: Annex 2 outlines considerations for conducting trial activities outside traditional clinical sites. This includes home visits, local healthcare centers, mobile units, or using digital health technologies (DHTs) such as wearable devices or mobile apps. The guidance emphasizes ensuring participant convenience while safeguarding data privacy and maintaining rigorous oversight. It addresses practical challenges, such as remote informed consent, investigational product distribution, and the oversight of remotely collected data.
2. Pragmatic Trial Designs: These designs aim to reflect real-world conditions by integrating routine clinical practices and streamlining protocols. Annex 2 advises on balancing simplicity with scientific robustness, ensuring data integrity while reducing participant and investigator burden. The annex also highlights the importance of selecting appropriate endpoints and ensuring that trial outcomes remain meaningful and reliable.
3. Real-World Data (RWD) Integration: Annex 2 delves into the use of secondary data sources like electronic health records (EHRs), claims data, and registries to supplement primary data collection. It discusses how RWD can serve as external controls, support endpoint determination, and enhance trial efficiency. The guidance stresses the need for rigorous data validation and harmonization to ensure reliability.

Throughout Annex 2, the importance of a Quality by Design (QbD) approach is emphasized. This ensures that trials employing decentralized, pragmatic, or RWD-based methodologies are designed to be fit for purpose, with a focus on maintaining participant safety, ethical conduct, and data reliability.

How Does Annex 2 Relate to Annex 1 and the Principles?

Annex 2 builds on the foundation laid by the Principles and Annex 1 of GCP E6(R3). Together, these documents represent a comprehensive framework for modern clinical trials:

• Principles: Serve as the overarching ethical and operational foundation, applicable to all clinical trials. They emphasize participant safety, scientific rigor, and the flexibility needed to adapt to new trial designs and technologies.
• Annex 1: Provides detailed operational guidance for traditional, site-based trials, focusing on roles and responsibilities of investigators, sponsors, and ethics committees. It emphasizes compliance with protocols, informed consent, and quality management systems.
• Annex 2: Extends this guidance to innovative trial designs, bridging traditional practices with modern methodologies. For example, while Annex 1 focuses on ensuring compliance within a physical site, Annex 2 addresses the complexities of remote monitoring, data collection, and participant engagement.

Together, these documents demonstrate how the ICH is adapting its guidelines to meet the demands of an evolving research landscape, ensuring that Good Clinical Practice remains relevant and effective in a digital and decentralized era.

What’s Next for Annex 2?

According to the ICH E6(R3) Expert Working Group Work Plan, the public consultation phase for Annex 2 will conclude in March 2025, with final adoption expected by June 2025. This timeline provides an opportunity for the clinical research community to critically evaluate and contribute to the refinement of this guidance.

Why Your Feedback Matters

Annex 2 has the potential to shape how innovative trials are conducted globally, making it essential for stakeholders to engage in the consultation process. The success of these guidelines hinges on feedback from sponsors, investigators, ethics committees, and other industry professionals.

We strongly encourage you to:

• Download the Draft Annex 2: ICH E6(R3) Annex 2 Draft Guideline
• Review the Document: Consider how it applies to your work and the broader industry.
• Submit Comments to ICH: Your input is invaluable in ensuring these guidelines address real-world challenges and support high-quality, ethical research.

A Call to Action

The release of Annex 2 marks a pivotal moment for clinical research. As the industry embraces decentralized designs, real-world data, and advanced technologies, this annex provides the roadmap for integrating these innovations while upholding the highest standards of Good Clinical Practice.

Now is the time to make your voice heard. Download Annex 2, review its contents, and contribute to shaping the future of clinical trials by submitting your feedback during this critical consultation phase. Together, we can ensure that these guidelines are practical, inclusive, and robust for the next era of clinical research.