08/11/2026

On June 3rd, 2026, the International Council of Harmonisation’s final ICH GUIDELINE FOR GOOD CLINICAL PRACTICE (GCP) E6(R3) Annex 2 was adopted in step 4 of the ICH formal procedure. A reminder of ICH’s standardized 5-step Formal Procedure of developing, adopting, and implementing of guidelines can be reviewed.

Step 5 is implementation which timing varies from country to country as each nation undergoes the process of changing their rules and regulations to comply with the guidelines. For example, ICH E6(R3) and Annex 1 reached step 4 on January 6th, 2025 (see our previous blog entry on the topic), the European Medicines Agency (EMA), Switzerland, and the USA had implemented the guidelines into national law in the same year whereas countries like Canada and the UK implemented them in April of 2026. Often Members of ICH prepare draft guidelines announcing their plans for adoption, like FDA did in December of 2024 for Annex 2 (see the FDA’s draft guidance here). Overall, it will vary when Members adopt Annex 2, but it is likely that implementation of Annex 2 across ICH Members will be seen around the end of 2026 and throughout 2027.

Annex 2 provides additional GCP considerations for trials that incorporate real-world data (RWD), decentralized elements, and/or pragmatic elements. Each of these components are prominent innovations to clinical trials in recent years and are the subject of multiple FDA guidance and projects (see Real-World Evidence, Conducting Clinical Trials With Decentralized Elements, and Project Pragmatica).

RWD refers to the use of a patient health status from sources outside the trial such as electronic health records, registries, or claims data bases (note the intentional use of “patient” as opposed to “participant” as it is data generated outside of the individual’s participation in the trial).
Decentralized elements are trial-related activities outside of the investigator’s location such as a participant’s home, local healthcare centers, or mobile medical units. Remote interactions or use of digital health technology such as mobile applications, wearables like smart watches, or sensors like heart monitors are all considered decentralized elements.
Pragmatic elements integrate usual clinical practice into the design and conduct of a trial. Examples of pragmatic elements include broader eligibility criteria that reflect a more naturally occurring patient population as opposed to more selective criteria, routine visits to a healthcare provider as opposed to scheduled site visits or streamlined data collection that uses minimal data that is generated from usual clinical practices.

Overarching concepts that tie Annex 2 to the rest of E6(R3) and Annex 1 include implementation of proportionate risk-based approaches to the design, planning, and conduct of trials that support evolving trial designs and technologies without compromising the rights, safety and well-being of participants or the reliability of the data. Quality by design (QbD) is another connecting concept within E6(R3). The principles of QbD are explained best in ICH E8(R1) General Considerations for Clinical Studies (see the full guideline here and our E8 blog). Implementing QbD involves identifying critical to quality factors (CtQ) that ensure the protection of participant’s rights, safety, and wellbeing as well as the generation of reliable and meaningful data and managing risks associated using a risk-proportionate approach. An example to highlight the importance of QbD is the process of informed consent. In section 2.2.1 of Annex 2, it states that informed consent may be done remotely making it a decentralized element. The CtQ risk of this scenario, that the annex raises, is the potential of misidentifying the participant or legally acceptable representative. The QbD approach would be to have a process in place for the investigator to ascertain the identity of who is giving consent. The example that the annex gives on how to manage this risk is by verification of an official identification document via a video call.

The format of Annex 2 is similar to E6(R3) Annex 1 with an introduction followed by the 3 major sections being for the IRBs, Investigators, and Sponsors. Each stakeholder is being asked to focus on the unique aspects of RWD, pragmatic and decentralized trials, and apply QbD to their responsibilities and processes that support them, for example:

§ IRBs are encouraged to evaluate trial designs that include RWD, pragmatic and decentralized elements with participant’s rights, safety, and well-being being the foremost concern.

§ For the Investigator, a focus on investigator oversight activities related to the investigation product management as well as healthcare professionals (HCP) conducting trial activities within usual clinical practice are both emphasized for trials that have decentralized and pragmatic elements.

§ Much of the document is dedicated to the Sponsor’s section as RWD, pragmatic and decentralized elements pertain to the protocol and trial design. Considerations for the Sponsor include access and obtaining permission or consent for use of RWD, communication with regulatory authorities early in the design and planning phase, and security of privacy and confidentiality.

A key takeaway from Annex 2 is that the standards and principles of GCP cannot be reduced under any circumstances, regardless of trial design or innovative approach. Therefore, data generated from RWD, pragmatic and decentralized trials must be held to the same level of scrutiny as traditional trial elements and require justification for the risk they may pose to the quality and safety of the trial.

The use of RWD and other external data needing to be fit for purpose as described in section 3.5 of Annex 2. This means it must be both reliable and relevant, reliable meaning the data is accurate, complete, and has provenance and traceability, and relevant meaning that the data must be capable of answering, in part, the study question with the specific method. RWD that is either inaccurate or irrelevant to the study question will undermine the integrity of the trial results which go against the QbD principles of E6(R3).

For Sponsors, this may require them to explain and justify the use of innovative trial designs and components and answer questions such as:

Where did the data come from?
What purpose does the data have?
What oversight measures are required/in place?
What are potential risks to data integrity and participant rights safety and wellbeing?

Organizations need to assess if and how their current structure, processes and vendor relationships can support the innovative designs for all stages of their programs and trials. The implications are different for sponsors, sites, IRBs/ECs, and vendors. For example, decentralized trial elements, how these remote activities will be conducted and/or overseen. Management of the changes in risks to IT security for trials shift towards digital media increases the risk of cyberattacks, loss or alteration of data during transfers, and breaches of protected health information.

Annex 2 is important for the industry’s swifter shift to QbD. This takes Culture Shift toward rewarding Critical Thinking, Open Dialogue, Focus on What Matters, and fresh focus to relationships, and of course training. Clinical Pathways provides consulting services to support this journey, and Clinical Pathways has training to support Critical Thinking, including eLearning courses and comparison tools. Have a look at our online store and course catalog to see if any of our other services could benefit you or your company, and while you are there sign up for our free newsletter and blog to stay up to date on trial-related news such as this.

-The Clinical Pathways Team

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