ICH GCP E6 (R3) Annex 2 training

ICH GCP Annex 2 is the third component of the ICH E6(R3) guideline — alongside the overarching Principles and Annex 1 — and provides GCP considerations specifically for clinical trials that go beyond the traditional site-based model. It addresses trials that incorporate decentralised elements (e.g. home visits, remote monitoring), pragmatic designs (e.g. embedding trial activities within usual clinical practice), and real-world data (RWD) sources such as electronic health records, registries, and claims databases.

Rather than prescribing rigid rules, Annex 2 offers a flexible, principle-based framework built on three core ideas: Quality by Design (QbD), fitness-for-purpose, and risk-proportionate oversight.

Annex 1 provides GCP guidance for traditional interventional clinical trials, the type of study most clinical research professionals are already familiar with, conducted primarily at investigator sites with standard monitoring and data collection practices.

Annex 2 builds on Annex 1 and addresses what happens when trials incorporate modern methodologies. It covers scenarios such as shipping an investigational product directly to a participant’s home, obtaining informed consent via video call, collecting safety data from wearable devices, or using electronic health records as a primary data source. Both annexes must be read together,  Annex 2 does not replace or stand alone from Annex 1.

The ICH E6(R3) Principles and Annex 1 came into effect in the EU on 23 July 2025. The FDA released final guidance on ICH E6(R3) in September 2025. Annex 2 was under public consultation through February 2025 and was expected to be finalised in late 2025 or early 2026.
As with Annex 1, regulatory adoption timelines vary by region and are subject to local implementation. Organisations should monitor announcements from the EMA, FDA, MHRA, and other relevant authorities for the specific effective date for Annex 2 in their jurisdiction.

Yes, if your work involves trials that use any of the methodologies Annex 2 covers. Standard GCP E6(R3) training is built around Annex 1,  traditional interventional trials. Annex 2 introduces a separate set of considerations for decentralised, pragmatic, and RWD-driven trials that are not addressed in Annex 1.

If you are working on (or planning to work on) a decentralised clinical trial, a pragmatic study, a trial using EHR or registry data, or any design that involves digital health technologies (DHTs), dedicated Annex 2 training ensures you understand the specific GCP requirements that apply.

A decentralised clinical trial (DCT) is one where some or all trial-related activities take place outside the traditional investigator site, for example, at a participant’s home, a local healthcare centre, or via remote digital interaction. Annex 2 provides GCP guidance on how to conduct these activities compliantly, covering areas such as:

• Remote informed consent and participant identity verification
• Direct-to-participant investigational product shipment and accountability
• Oversight of home nursing and other third-party service providers
• Safety monitoring using digital health technologies (wearables, mobile apps)
• Data privacy and cybersecurity requirements for remote data collection

In the context of ICH E6(R3) Annex 2, real-world data (RWD) refers to data relating to patient health status collected from sources outside traditional clinical trials — such as electronic health records (EHRs), insurance claims databases, and disease registries — that is incorporated into an interventional clinical trial.

Annex 2 requires sponsors to ensure RWD is “fit for purpose,” which means demonstrating that it is both reliable (accurate, complete, traceable) and relevant (containing the data elements needed to answer the trial question). Sponsors must also establish appropriate consent and data governance arrangements, including third-party data access agreements for regulatory inspections.

Fitness-for-purpose is one of the central concepts running through Annex 2. It means that every operational approach, design element, data source, and technology used in a trial must be demonstrably appropriate and adequate for achieving the trial’s specific objectives, not merely technically available or commercially convenient.

In practice, this applies to everything from choosing a digital health technology for data collection, to deciding whether existing pharmacy records are sufficient for investigational product accountability, to assessing whether a real-world data source contains the right variables to support a trial endpoint.

Annex 2 explicitly permits remote informed consent when appropriate. It allows for varied approaches including text, images, videos, and interactive digital tools. However, investigators must:

• Verify the participant’s identity before obtaining consent (for example, by checking an official ID document during a video call)
• Pre-specify the identity verification process and the data privacy measures in the protocol
• Ensure the consent materials clearly disclose what data will be collected, how it will be used, and who will have access, including data collected via digital health technologies or at home
• Offer a paper-based or in-person alternative where feasible, particularly for participants who are less familiar with digital tools

The investigator retains ultimate responsibility for the safe and appropriate use of the investigational product (IP), regardless of where it is delivered. Even when a sponsor arranges direct-to-participant shipment, the investigator must remain informed of shipping arrangements, stay aware of receipt and usage, and maintain oversight of any participant-reported issues.

Roles and responsibilities between the sponsor, investigator, and any service providers (such as home nurses or local pharmacists) must be clearly documented before shipment begins. IP management, including accountability, blinding, storage, and return or destruction, must follow the sponsor’s documented instructions and applicable regulatory requirements.

Anyone whose work involves clinical trials that incorporate decentralised elements, pragmatic designs, or real-world data. This includes:

• CRAs and Monitors at pharmaceutical companies and CROs overseeing modern or hybrid trial designs
• Sponsors and Clinical Operations teams designing trials with DHTs, home-based IP delivery, or RWD integration
• Investigators and Site Coordinators running trials with remote visits or remote consent
• Clinical Data Managers working with EHRs, registries, or claims data in a trial context
• Regulatory Affairs and Quality professionals preparing for inspections under ICH E6(R3)
• Any GCP-trained professional whose current or upcoming trials go beyond the traditional site-based model

Yes. Upon completing the course and passing the final exam with a score of 80% or above, you will receive a downloadable training certificate. The exam consists of 20 multiple-choice questions and can be retaken if needed.

It is strongly recommended. Annex 2 is explicitly designed to be read and applied together with Annex 1 and the ICH GCP Principles, it does not replace foundational GCP training. If you do not yet hold a current GCP E6(R3) certification, we recommend completing our ICH GCP E6(R3) Good Clinical Practice training first.