The next phase of the ICH GCP E6 (R3) modernisation is on its way, and Annex 2 is set to reshape how sponsors, CROs and investigators approach decentralised, pragmatic, and real-world data-enabled trials. While Annex 1 covers traditional interventional studies, Annex 2 introduces additional considerations for trial designs that go beyond the conventional site-based model.
Annex 2 of ICH GCP E6(R3) will provide long-awaited guidance for the design and conduct of decentralised, hybrid and real-world data-enabled trials. It reflects how clinical research is evolving, with technology, remote assessments and data integration transforming how trials are carried out around the world.
Annex 2 explains how the core principles of E6(R3) apply to non-traditional trial designs while maintaining participant safety, data integrity and ethical standards. It promotes flexibility and innovation, supported by clear justification, documentation and proportionate risk management. The focus is on embedding quality into the design and conduct of the trial, rather than relying solely on retrospective checks.
Annex 2 gives clearer direction on the practical implementation of decentralised and pragmatic trial elements such as telemedicine, electronic informed consent, wearable devices, home healthcare visits and the inclusion of external data sources like electronic health records, registries and claims databases. It will also strengthen expectations around sponsor oversight of third-party providers, ensuring responsibilities are well defined and that quality is maintained across all partners.
Quality by design and proportionality remain central themes. Sponsors and investigators will be expected to identify what is critical to quality, apply oversight and monitoring in a risk-proportionate manner, and document the rationale behind operational decisions. This represents a cultural shift from rigid compliance to a more thoughtful, participant-centred approach that balances flexibility with accountability.
The final version of Annex 2 is anticipated in late 2025, with implementation expected to follow in 2026 as regulatory authorities across ICH regions adopt the updated guideline. Now is the time to prepare by reviewing existing procedures, updating protocols and monitoring strategies, assessing digital readiness and ensuring teams are trained to operate confidently under the modernised framework.
Annex 2 moves GCP toward being more flexible. This can reduce burdens in some cases and make diverse trial types more feasible. It combines flexibility with responsibility, ensuring that innovation never comes at the expense of quality or participant safety. Understanding its principles early will help organisations adapt effectively, maintaining high standards of participant protection, data reliability and ethical integrity while embracing more efficient and innovative ways to conduct trials.
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