ICH E6(R3) Annex 2: Decentralised Trials

Q: Does Annex 2 replace FDA’s existing decentralised clinical trials guidance?

No. FDA’s Conducting Clinical Trials With Decentralized Elements guidance for industry, finalised 18 September 2024, is a separate FDA document that predates ICH Annex 2. Annex 2 is the international ICH harmonisation counterpart; sponsors running US trials with decentralised elements should track both.

ICH E6(R3) restructured Good Clinical Practice into a core Principles & Objectives document plus two annexes: Annex 1, which covers traditional site-based interventional trials, and Annex 2, which addresses pragmatic clinical trials, decentralised clinical trials, and trials incorporating real-world data sources — territory E6(R2) never addressed as such. This page focuses specifically on Annex 2’s decentralised-trial provisions: how it frames remote and risk-based monitoring, telehealth-based visits, and direct-to-patient (DtP) investigational product shipment. For Annex 2’s place in the wider R2-to-R3 revision, see CASRAI’s ICH E6(R3): What Changed in Good Clinical Practice guide and the ICH E6(R3) dictionary entry; for how decentralised trials work operationally outside the Annex 2 framing, see Decentralized Clinical Trials (DCTs): What They Are, FDA Guidance, and Key Components.

Where Annex 2 sits, and its adoption timeline

Annex 2 is meant to be read together with the Principles document and Annex 1, not as a standalone document — it layers additional, design-specific considerations on top of the base GCP framework rather than duplicating it. Because it was developed on a separate, later track than the Principles document and Annex 1, it also has its own adoption timeline, and that timeline is not yet finished:

ICH (global Step 4): the Principles & Objectives document and Annex 1 reached ICH Step 4 on 6 January 2025. Annex 2 (pragmatic/decentralised/real-world-data trials) reached ICH Step 4 later, on 3 June 2026.
European Union (EMA/CHMP): the Principles document and Annex 1 became the operative GCP guideline in the EU on 23 July 2025. Annex 2 was adopted by CHMP on 25 June 2026 and is scheduled to take effect 15 January 2027.
United States (FDA): FDA issued final guidance implementing the Principles document (Federal Register notice of availability, 9 September 2025); as with all FDA guidance, it states current agency recommendations rather than creating a binding compliance date. As of this writing, FDA has not issued separate Annex-2-specific guidance — sponsors running US trials with decentralised elements should track this directly rather than assume a fixed date, and should also continue to work from FDA’s existing Conducting Clinical Trials With Decentralized Elements guidance for industry, finalised 18 September 2024, which predates and is separate from ICH Annex 2.

Practical consequence: a multi-region trial with decentralised elements is tracking two separate regulatory clocks — the general E6(R3) Principles/Annex 1 timeline, already in force in several jurisdictions, and Annex 2’s later, still-unsettled timeline layered on top of it. Verify current status directly against ich.org, EMA, or FDA before relying on any date above.

Remote and risk-based monitoring under Annex 2

E6(R3)’s Principles document already reframes monitoring generally: instead of uniform, resource-intensive on-site visits applied regardless of risk, sponsors are expected to identify the factors that are “critical to quality” for a given trial and scale monitoring intensity and method to match. Annex 2 extends that risk-proportionate framing specifically to trials that use decentralised elements, where a purely on-site monitoring model often doesn’t fit the trial’s design in the first place.

In practice, that means a sponsor running a trial with decentralised elements needs a written monitoring plan that does more than default to “on-site visits, full source data verification.” It should state explicitly which activities are monitored on-site, which are monitored remotely (e.g. remote source data review against an eSource or eConsent system), and which rely on centralised or statistical monitoring across the trial as a whole — and it should justify that mix against the trial’s actual risk profile, not apply it uniformly by default. This is a direct consequence of E6(R3)’s data-governance expectations being written for electronic and remote data sources from the outset, unlike R2, which assumed a largely site-based, paper-adjacent model.

Telehealth-based visits: consent, assessments, and documentation

R3 names telehealth-based visits explicitly as one of the decentralised elements R2 never contemplated, alongside remote data capture and direct-from-participant data sources. Annex 2’s decentralised-trial framing carries three practical implications for how a telehealth visit needs to be built into a trial:

Protocol specification. The protocol needs to state which visits and assessments may be conducted by telehealth and which require an in-person encounter — typically because they need equipment, a physical exam finding, or a biological sample that can’t be captured remotely. This is a design decision made per-assessment, not a blanket “this trial is remote” designation.
Informed consent. The consent process and materials need to address the remote/telehealth logistics the participant will actually experience — how a telehealth visit is conducted, what’s expected of the participant, and what happens if a remote assessment can’t substitute for an in-person one.
Documentation standard. A telehealth visit is held to the same GCP source-documentation standard as an in-person one: contemporaneous, attributable, and accurate records of what was assessed and by whom. Where a local healthcare provider or mobile-health professional performs a hands-on assessment on the investigator’s behalf during a telehealth-coordinated visit, that’s a delegated trial activity and needs the same delegation-log and training documentation any other delegated activity requires under E6(R3) — see CASRAI’s Mobile and Home Health Nursing Vendors in Decentralized Trials guide for the delegation/credentialing mechanics in depth, and Sponsor Oversight of Delegated CRO Functions Under ICH E6(R3) for the general delegation-oversight framework Annex 2 builds on.

Direct-to-participant investigational product shipment: sponsor oversight obligations

Under E6(R2) Section 5.14 (“Supplying and Handling Investigational Product(s)”), sponsor obligations already covered confirming approvals before shipment, ensuring site-level written procedures for receipt, storage, dispensing, retrieval, return and destruction, and maintaining systems and records for delivery, shipment/receipt/disposition tracking, and retrieval including recall — but that framework assumed investigational product moved to an investigator site, not to a participant directly. E6(R3) restates the general investigational-product-management responsibility at Section 2.10.1, resting with the investigator (accountability, handling, dispensing, administration, return), with specific activities delegable. Cross-referenced regulatory-consulting sources report that Annex 2 additionally, and specifically, addresses direct-to-participant IMP shipment — product shipped to a participant’s home or a local care setting rather than dispensed only at the investigator site — as an area E6(R2) did not contemplate at all.

What that means operationally, building on what CASRAI’s Decentralized Clinical Trials guide already covers for DtP shipment generally: the sponsor’s chain-of-custody, temperature-control, and accountability obligations don’t relax just because the destination changed. In practice that means:

Chain-of-custody documentation tracking the product from depot or pharmacy, through the courier, to confirmed receipt by the participant (or the local provider administering it) — not just confirmation that a package was shipped.
Temperature/cold-chain monitoring through transit, with a defined excursion-handling procedure, since a home delivery doesn’t have a site pharmacist checking the shipment on arrival the way an investigator site does.
Accountability and reconciliation records equivalent in rigor to site-dispensed product — what was shipped, to whom, in what quantity, and what was returned, destroyed, or accounted for as used.
Identity and eligibility verification before administration, since routine checks a site pharmacist or coordinator would normally perform are no longer automatically part of the hand-off.
Coordination with any local or home healthcare provider administering the product, including their training and delegation records, per the telehealth/delegation point above.

Treat “Annex 2 addresses direct-to-participant shipment” as the general, cross-referenced position rather than a verbatim quote of Annex 2’s text — verify the exact clause language against the primary ICH/regional document before citing it in a compliance filing.

How this page differs from CASRAI’s other ICH E6(R3) and DCT content

Several CASRAI pages touch adjacent ground, and it’s worth being explicit about the boundaries:

ICH E6(R3): What Changed in Good Clinical Practice covers the full R2-to-R3 revision at a survey level — Annex 1 as the operational replacement for R2, Annex 2’s existence and adoption dates, and the general shift to risk-based quality management. It names remote monitoring, telehealth visits, and decentralised elements in passing as examples of what R3 was written to accommodate; it does not work through their specific operational provisions, which is what this page does.
ICH E6(R3) Definitions: Audit, Inspection, Monitoring and Quality Assurance covers the R2-to-R3 definitional cross-walk for those four terms specifically, independent of Annex 2.
Decentralized Clinical Trials (DCTs) is the general operational guide to how DCTs work — eConsent, remote monitoring, direct-to-participant shipment, and IRB considerations — anchored in FDA’s decentralised-trials guidance for industry. This page instead anchors the same three decentralised-element categories specifically in the ICH E6(R3) Annex 2 regulatory framework and its adoption timeline.

Practical checklist for trials with decentralised elements

Confirm whether your trial(s) use decentralised, pragmatic, or real-world-data elements at all — Annex 2 applies only where they do; a fully traditional site-based interventional trial is governed by Annex 1.
Revise the monitoring plan to explicitly justify the on-site/remote/centralised mix per activity, rather than defaulting to a single approach.
Update the protocol and informed consent materials to specify which visits and assessments may occur by telehealth and which require in-person attendance.
Write or update a direct-to-participant shipment SOP covering chain of custody, temperature monitoring and excursion handling, accountability/reconciliation, and identity/eligibility verification at the point of receipt.
Update delegation logs and training records for any local healthcare provider or mobile-nursing personnel performing telehealth-coordinated assessments or administering shipped product.
Track Annex 2’s adoption status separately from the Principles/Annex 1 timeline for every region the trial runs in — they are not on the same clock.

Frequently asked questions

Does ICH E6(R3) Annex 2 apply to every clinical trial?

No. Annex 2 applies to trials that incorporate pragmatic, decentralised, or real-world-data elements. A traditional, fully site-based interventional trial is governed by Annex 1 and the Principles document, not Annex 2.

When does Annex 2 take effect?

Annex 2 reached ICH Step 4 on 3 June 2026 and was adopted by CHMP on 25 June 2026, with an EU effective date of 15 January 2027. As of this writing, FDA has not issued separate Annex-2-specific guidance. Because adoption is still in progress in several regions, verify current status directly against ICH, EMA, or FDA rather than relying on a fixed date.

Does Annex 2 replace FDA’s existing decentralised clinical trials guidance?

No. FDA’s Conducting Clinical Trials With Decentralized Elements guidance for industry, finalised 18 September 2024, is a separate FDA document that predates ICH Annex 2. Annex 2 is the international ICH harmonisation counterpart; sponsors running US trials with decentralised elements should track both.

Can a trial use telehealth visits or direct-to-participant shipment without being labelled a “decentralised trial”?

Yes. Annex 2’s decentralised-element provisions apply to any trial incorporating remote monitoring, telehealth visits, or direct-to-participant shipment for specific activities, whether the trial overall is described as fully decentralised, hybrid, or traditional with limited decentralised elements.

Primary sources

ICH (International Council for Harmonisation) — official source for E6(R3) Principles, Annex 1, and Annex 2 text and Step 4 status.
FDA — E6(R3) implementation guidance and Conducting Clinical Trials With Decentralized Elements (final guidance, 18 September 2024).

ICH E6(R3) Annex 2: Remote Monitoring, Telehealth Visits, and Direct-to-Patient Shipment Oversight

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