ICH E6(R3) Annex 2 is the good clinical practice guidance for trials that run partly outside the site: visits at home or at a local clinic, video calls, wearables and apps, investigational product shipped to the participant, and data drawn from health records. The ICH adopted the final text on June 3, 2026. The European Medicines Agency lists it as coming into effect on January 15, 2027; in the United States, the FDA's page for Annex 2 still shows the December 2024 draft at the time of writing. Most of the document is addressed to sponsors, but section 2 is written to the investigator, and it keeps the investigator responsible for four things that now happen away from the site: confirming who is consenting, knowing where the drug went and who received it, overseeing the local clinicians doing trial work, and seeing the safety information those channels produce. A site that works with sponsors running decentralised elements should be able to show, for each of those four, what it checked and where the record is.
In short
- Annex 2 final text adopted by the ICH on June 3, 2026; in the EU, CHMP adoption June 25, 2026, effective January 15, 2027 (EMA).
- The FDA published final guidance on the E6(R3) Principles and Annex 1 on September 8, 2025; its Annex 2 page still lists the December 2024 draft.
- Section 2.3.1 lists 5 things to consider before shipping investigational product to a participant's home.
- Section 2 of Annex 2, the investigator's part, has 5 subsections: IRB communication, consent, product, oversight, and safety.
What ICH E6(R3) Annex 2 asks of the investigator
Annex 2 defines decentralised elements as "trial-related activities conducted outside the investigator's location." It defines pragmatic elements as those that "integrate aspects of usual clinical practice into the design and conduct of the trial," and real-world data as health data "collected from a variety of sources outside of clinical trials," such as health records, registries and claims. The table sets out the investigator-facing provisions and the record a site would expect to hold for each.
| Section | What Annex 2 says | What the site keeps |
|---|---|---|
| 2.2.1 | Remote consent: assure yourself of identity, for example an ID checked on a video call; method and privacy measures pre-specified | The pre-specified method, and a note of the check for each participant |
| 2.2.2 | Offer a paper or in-person consent option where feasible | The option offered, and what the participant chose |
| 2.2.3 | Consent materials say who can see personal details such as a home address | The approved consent version that says so |
| 2.3.1 | Shipping product to a home: privacy, intended recipient, receipt to disposal, blinding, support tools | Shipping and receipt records per participant |
| 2.3.2 | Sponsor ships directly: investigator keeps responsibility and stays informed | The documented split of roles, and receipt and issue reports |
| 2.4.1 | Local clinicians doing usual-practice activities: arrangements to get their records to you | How records reach the site, as certified copies where relevant |
| 2.5 | Safety information from home nursing, remote visits and devices reaches the investigator | Where that information arrives, and who reviews it |
Two lines carry most of the weight. On shipping by the sponsor, section 2.3.2 says "the investigator/institution retains responsibility for the safe and appropriate use of the investigational product for participants under their care." On home nursing the sponsor arranges, section 3.8 says "the investigator retains the ability to make the decision on the appropriateness of the proposed service provider and is responsible for the oversight of their activities."
Why the manual way struggles with this
A traditional study keeps most of its evidence in one building: the consent was signed in the exam room, the product was dispensed from the site's pharmacy, and the coordinator saw the participant. Annex 2 moves each of those out of the building without moving the responsibility. The evidence now arrives from a courier, a home nursing company, a patient's local clinic and a device platform, each on its own schedule and in its own format.
The Annex is explicit that oversight can be proportionate. Section 2.4 says it "may range from direct supervision to less intensive oversight, whether in person or via remote communication methods (e.g., video, telephone or email), to only the review of essential records (including source records)." That flexibility is only useful if the site can say which level it chose for each activity and show the records it reviewed. Without a place where those records land and a person who checks them, the oversight exists in the plan and nowhere else.
How a site prepares for Annex 2
- List the decentralised and pragmatic elements in each active protocol. Home visits, remote consent, direct-to-participant shipping, devices and record extraction. Section 3.2.1 requires the protocol to describe them, so start from the protocol.
- Write down the remote consent identity check. Section 2.2.1 wants the method pre-specified. Decide what counts as an official document, who checks it and where the note goes. Offer a paper or in-person route where feasible, as section 2.2.2 suggests.
- Map the product's route for every participant who doses at home. Who ships, who receives, how receipt is confirmed, how blinding is protected and how returns come back. Section 2.3.1 lists those points; section 2.3.4 says the investigator oversees receipt, use and return.
- Sort local clinicians into the two groups section 2.4.1 describes. Those doing usual-practice activities that need no protocol knowledge need an arrangement for getting their records to you. Those whose work requires the protocol or investigator's brochure are delegated and trained, and belong on the delegation log.
- Decide where safety information from outside the site arrives. Section 2.5 wants information from home nursing, remote visits and devices provided in a way that lets the investigator act. Name the inbox, the review frequency and the person.
- Ask the sponsor for the vendor details before activation. Section 3.8 leaves the investigator able to judge a sponsor-arranged provider. That judgement needs the provider's name, scope and contact before the first home visit.
The mistake most sites make at step 4
They treat a sponsor's home nursing vendor as the sponsor's problem. Annex 2 does not. The sponsor must ensure the provider is suitable, but the investigator "is responsible for the oversight of their activities," and anyone whose work depends on the protocol has to be trained and delegated like site staff. A home nurse who is not on the delegation log, or whose training record the site has never seen, is a gap in the investigator's oversight wherever that nurse works. The regulatory binder guide sets out the documents that expire, and the same calendar applies to people working outside the site.
Remote visits raise the same question for reminders and missed appointments, which the patient retention post covers, and the FDA's thinking on AI in drug development is set out in FDA AI principles for research sites. The systems we build for sites, including document tracking and visit reminders, are on the clinical research industry page. None of them decides eligibility, obtains consent or certifies compliance; the investigator's oversight stays the investigator's.
