What Annex 2 Covers and When It Applies

Part of ICH E6(R3) Annex 2 for Site Staff: Annex 2 and Decentralized Elements.

About 5 minutes. Free, in your language, no account needed.

Expert review pending. CRLN wrote this lesson against the ICH E6(R3) Annex 2 text adopted on 3 June 2026. It has not yet been reviewed by a subject matter expert. Always follow your protocol, your sponsor and your regulator.

Why this matters

More of a trial now happens away from the site. A nurse visits a participant at home. Study drug arrives by courier. A consent discussion happens on a video call. Outcome data come straight from a hospital's electronic health record (EHR). ICH E6(R3) Annex 2 is the part of the Good Clinical Practice guideline written for exactly these situations. If your site runs studies like this, Annex 2 describes what is expected of you.

What Annex 2 is

ICH E6(R3) is the international Good Clinical Practice guideline. It has three parts you will hear about:

Annex 2 does not replace Annex 1. The Annex says it should be read together with the Principles and Annex 1. It also says it is not an endorsement of any particular method. It does not tell a sponsor to run a decentralized trial. It says what Good Clinical Practice looks like when a trial does use these methods.

The three methodologies

Annex 2 groups three kinds of approach together and calls them methodologies. A trial may use one, two or all three.

Decentralized elements are trial activities done outside the investigator's location. Examples in the Annex include visits or procedures at the participant's home, at a local healthcare center or in a mobile medical unit, and remote interactions such as video calls or the use of digital health technologies (DHTs). DHTs include mobile apps, wearables and sensors. When a DHT collects participant data for a trial, it counts as a data acquisition tool.

Pragmatic elements bring parts of usual clinical practice into the trial. That can mean eligibility and procedures that look like routine care, care given where patients normally receive it, such as primary care, and streamlined data collection: collecting only the minimum data needed, at the times routine care already produces it.

Real-world data (RWD) are data about patients' health collected outside clinical trials, for example from EHRs, registries and claims databases. When those data are reused in a trial, Annex 2 calls this secondary use, and the data must be fit for their purpose in that trial.

Key dates

ICH adopted Annex 2 at Step 4 on 3 June 2026. Step 4 means the text is final and recommended to regulators for adoption.

Each regulator then decides when it applies. The European Medicines Agency states that Annex 2 comes into effect in the EU on 15 January 2027. In the United States, the FDA guidance page for Annex 2 still listed the December 2024 draft when this lesson was written in November 2026. Other regulators set their own dates. Always check what your own regulator and your sponsor require for a given study.

How Annex 2 thinks

Two ideas run through the whole Annex.

Proportionality. Annex 2 repeats the risk-based approach of the Principles and Annex 1. The amount of oversight, checking and documentation should match how much a task matters for participant safety and for the reliability of the results. Not every remote task needs the same control.

Fit for the participant. When planning decentralized and pragmatic elements, the Annex asks teams to consider participants' needs. That includes whether people have, and are comfortable with, the technology involved, and whether a remote option actually adds burden for some of them.

For the IRB or ethics committee, Annex 2 section 1 points back to the existing ethical standards and asks for particular attention to participants' rights, safety and well-being, to privacy and confidentiality, and to the security of their data. Section 2.1 asks the investigator to give the IRB or ethics committee the information it needs to judge whether the methods are appropriate.

In practice

When a new study arrives at your site, ask three questions:

  1. Will any trial activity happen outside our site? If yes, decentralized elements apply.
  2. Will any trial data come from routine care or from local doctors who are not on our study team? If yes, pragmatic elements may apply.
  3. Will any data come from an EHR, a registry or another source built for something other than this trial? If yes, RWD considerations apply.

Each yes points you to a different part of Annex 2, and the rest of this course works through them.

Key takeaways