What is ICH E6(R3)? The 2025 GCP Update Explained

If you work in clinical research, you have almost certainly heard about ICH E6(R3) — the most significant update to Good Clinical Practice, GCP, guidelines in decades. The final guideline was adopted in 2025, replacing ICH E6(R2), which had been in place since 2016.

For clinical trial sponsors, CROs, investigators, and monitors, ICH E6(R3) is not just a document update — it represents a fundamental shift in how clinical trials are designed, conducted, and overseen. Understanding what changed, why it changed, and what it means for your GCP training obligations is essential for anyone working in clinical research today.

This guide explains ICH E6(R3) clearly — what it is, what the key changes are, who is affected, and what you need to do now.

What is ICH E6?

ICH E6 is the International Council for Harmonisation, ICH, guideline on Good Clinical Practice, GCP — the international ethical and scientific quality standard for designing, conducting, recording, and reporting clinical trials that involve human subjects.

To understand where GCP fits within the broader compliance landscape, see our guide on What is GxP?

ICH E6 was first published in 1996 and became the global standard for GCP. It defines the responsibilities of sponsors, investigators, ethics committees, and monitors in clinical trials. Regulatory authorities in the US, FDA, EU, EMA, UK, MHRA, Japan, PMDA, Canada, Health Canada, and over 50 other countries have adopted ICH E6 as the basis for their GCP requirements.

The version history:

• ICH E6(R1) — 1996. Original guideline. Established GCP principles for paper-based trials.
• ICH E6(R2) — 2016. Added Annex on risk-based approaches and electronic systems.
• ICH E6(R3) — 2025. Complete restructure. Addresses modern clinical trial models including decentralised trials, risk-based quality management, and digital data.

Why Was ICH E6 Updated to R3?

ICH E6(R2) was a partial update — it added an annex to the existing 1996 document rather than fully rewriting it. By the time work on R3 began, clinical trials had changed dramatically:

• Decentralised clinical trials, DCTs — remote visits, wearables, home nursing, electronic patient-reported outcomes
• Risk-based monitoring, RBM — moving away from 100% source data verification to targeted, risk-proportionate oversight
• Electronic systems — EDC, eConsent, CTMS, eTMF all standard; paper records now the exception
• Complex trial designs — adaptive trials, platform trials, basket trials, master protocols
• Data integrity — increasing regulatory focus on audit trails, access controls, and data provenance

The 1996 framework — even with the 2016 annex — was not built for this environment. ICH E6(R3) is a complete rewrite designed to be fit for modern clinical research.

Key Changes in ICH E6(R3)

1. Complete Restructure — Two Parts Instead of One

ICH E6(R3) is structured differently from previous versions. It is divided into:

Part I — General Principles
The overarching GCP principles that apply to all clinical trials regardless of design, setting, or technology. These are the non-negotiable ethical and quality standards.

Part II — Annexes
Specific guidance for particular trial types and contexts:

• Annex 1 — Interventional clinical trials, the main annex covering traditional and hybrid trial models
• Annex 2 — Decentralised elements in clinical trials
• Annex 3 — Investigational medicinal products

This modular structure means guidance can be updated for specific contexts without rewriting the entire document — an important design choice for a rapidly evolving field.

2. Risk-Based Quality Management, RBQM, is Now Central

In ICH E6(R2), risk-based approaches were in an annex — essentially optional guidance. In ICH E6(R3), Risk-Based Quality Management, RBQM, is embedded throughout the core guideline as the expected standard of practice.

RBQM requires sponsors to:

• Identify what is critical to trial quality — the data and processes that directly affect participant safety and the reliability of trial results
• Assess the risks to those critical elements
• Implement proportionate controls — focusing oversight resources where the risk is highest
• Monitor continuously and adapt when risks materialise

This means traditional 100% source data verification, SDV, is no longer the default expectation. Sponsors must instead demonstrate that their monitoring approach is justified by a formal risk assessment.

What this means for monitors and CRAs:
Risk-based monitoring skills — including central monitoring, data review, and risk signal identification — are now core competencies, not advanced skills. See our GCP Training course for full coverage of RBQM requirements

3. Explicit Guidance on Decentralised Clinical Trials, DCTs

ICH E6(R3) Annex 2 provides the first dedicated ICH guidance on decentralised clinical trial elements — aspects of a trial conducted outside a traditional clinical site:

• Remote participant visits — telemedicine consultations, video calls with investigators
• Home nursing visits — assessments conducted at participants’ homes
• Direct-to-participant drug shipment — investigational product sent directly to participants
• Wearables and digital health technologies — continuous remote data collection
• Electronic patient-reported outcomes, ePRO — participant data collected via apps or devices

The annex addresses how GCP principles apply to these settings — including how to obtain informed consent remotely, how to qualify home nurses as trial personnel, how to maintain the audit trail for remotely collected data, and how sponsors retain oversight when trial activities are distributed across multiple locations.

What this means for clinical teams:
Anyone working on hybrid or fully decentralised trials needs updated training on DCT-specific GCP requirements. ICH E6(R2) did not address these scenarios. Learn more about GxP training requirements for clinical teams.

4. Strengthened Sponsor Oversight Requirements

ICH E6(R3) significantly strengthens the requirements for sponsor oversight — particularly for activities delegated to CROs or other third parties.

Key changes:

• Sponsors must maintain ultimate responsibility for all delegated activities — oversight cannot be delegated
• Quality agreements between sponsors and CROs must clearly define responsibilities
• Sponsors must have systems to oversee CRO performance — not just rely on CRO self-reporting
• The Trial Master File, TMF requirements are more detailed, with clearer guidance on what must be in the sponsor TMF vs the investigator site file

For CROs, this means clients will demand stronger oversight evidence. For sponsors, it means more rigorous vendor qualification and ongoing performance monitoring.

5. Updated Informed Consent Requirements

ICH E6(R3) modernises informed consent to reflect current trial practices:

• eConsent — electronic informed consent is explicitly recognised as acceptable, with requirements for audit trails and participant comprehension verification
• Remote consent — guidance on obtaining consent via telemedicine or video call
• Ongoing consent — clearer requirements for re-consenting participants when new information emerges during a trial
• Vulnerable populations — strengthened protections for participants who may have difficulty understanding trial information

The principle remains the same — consent must be freely given, informed, and documented — but the mechanisms for obtaining and recording it have been updated for the digital age.

6. Data Integrity and Electronic Systems

ICH E6(R3) integrates data integrity requirements throughout — rather than treating electronic systems as a special case:

• All GxP data — whether paper or electronic — must meet ALCOA+ principles: Attributable, Legible, Contemporaneous, Original, Accurate, plus Complete, Consistent, Enduring, and Available, the same principles that apply across all GxP frameworks
• Electronic systems used in clinical trials must have validated audit trails
• Access controls must prevent unauthorised data changes
• System validation is required for all GxP computerised systems
• Guidance on data transfer between systems — ensuring data integrity is maintained when data moves between EDC, CTMS, and sponsor databases

7. Investigator Responsibilities Clarified

ICH E6(R3) clarifies and strengthens several investigator obligations:

• Investigators must ensure adequate resources — not just sign off on a delegation log
• Sub-investigator oversight — investigators remain responsible for all trial-related activities at their site, even when delegated
• Protocol adherence — clearer requirements for documenting and managing protocol deviations
• Safety reporting — updated requirements aligned with current regulatory expectations for expedited reporting of serious adverse events

Who Does ICH E6(R3) Affect?

ICH E6(R3) applies to everyone involved in the design, conduct, oversight, and reporting of clinical trials:

ICH E6(R3) vs ICH E6(R2) — Key Differences

GCP Training Obligations Under ICH E6(R3)

ICH E6(R3) Section 5, Sponsor responsibilities, and Section 4, Investigator responsibilities, both require that all trial personnel are qualified by education, training, and experience to perform their roles.

This means:

1. All existing GCP-trained personnel need updated training

Anyone trained on ICH E6(R2) — or earlier — does not have current GCP knowledge. ICH E6(R3) introduces enough new requirements that R2 training is no longer sufficient.

2. Training must be documented

As with all GxP training, ICH E6(R3) training must be documented with the individual’s name, course content, date, and assessment result. A certificate compliant with 21 CFR Part 11 serves as the training record during regulatory inspections.

Read our guide on GxP Certification: Which One Do You Need? for more on certification requirements.

3. Role-specific training

Sponsors, monitors, investigators, and site coordinators have different ICH E6(R3) obligations. Training should reflect the specific requirements of each role.

4. Annual refresher training

GCP refresher training should now cover ICH E6(R3) content — not the superseded R2 version. For organisations training multiple staff, our Corporate GxP Training packages include progress tracking and automated refresher reminders.

When Does ICH E6(R3) Apply?

ICH E6(R3) was adopted by ICH in 2025. Implementation timelines vary by regulatory authority:

• FDA — Has indicated alignment with ICH E6(R3). Check FDA guidance for specific implementation dates for US-regulated trials.
• EMA — ICH E6(R3) is being integrated into EU clinical trial regulation. Trials under EU CTR 536/2014 should align with R3.
• MHRA — UK GCP guidance is being updated to reflect ICH E6(R3).

For new trials initiated after adoption, ICH E6(R3) applies. For ongoing trials, sponsors should assess whether protocol amendments or updated SOPs are needed to align with R3 requirements.

Frequently Asked Questions

Is ICH E6(R2) still valid?

ICH E6(R2) has been superseded by ICH E6(R3). Trials that were designed and initiated under R2 may continue under R2 requirements in some jurisdictions — but sponsors should check with their regulatory authorities. New trials should be designed to ICH E6(R3).

Do I need to redo my GCP training for ICH E6(R3)?

Yes. If your GCP training was based on ICH E6(R2) or earlier, you need updated training on ICH E6(R3). The changes are significant enough that R2 training does not cover the new requirements.

Does ICH E6(R3) apply to all clinical trials?

ICH E6(R3) applies to interventional clinical trials of investigational medicinal products in humans. Non-interventional studies, observational research, and post-marketing studies may have different requirements depending on the regulatory jurisdiction.

What is the difference between ICH E6(R3) Part I and Part II?

Part I contains the general GCP principles that apply to all trials. Part II contains the annexes with specific guidance for particular trial types — including Annex 1 for interventional trials, Annex 2 for decentralised elements, and Annex 3 for investigational medicinal products.

How does ICH E6(R3) affect investigator-initiated trials?

Investigator-initiated trials, IITs, are subject to the same GCP requirements as industry-sponsored trials. When the investigator acts as the sponsor, they assume all sponsor responsibilities under ICH E6(R3) in addition to their investigator obligations.

Does ICH E6(R3) require new SOPs?

Yes. Sponsors and sites will need to review and update SOPs to reflect ICH E6(R3) requirements — particularly for risk-based monitoring, decentralised trial elements, eConsent, and sponsor oversight of CROs. All affected personnel must be trained on the updated SOPs.

Conclusion

ICH E6(R3) is the most significant update to GCP in nearly 30 years. It reflects how clinical trials actually work in 2025 — with risk-based quality management at the core, decentralised trial elements explicitly addressed, and data integrity requirements integrated throughout.

For clinical trial professionals, the message is clear: ICH E6(R2) training is no longer current. Everyone working in clinical research needs updated GCP training aligned with ICH E6(R3) — and that training needs to be documented.

Whether you are a sponsor building a new monitoring strategy, a CRA adapting to risk-based approaches, or an investigator running a hybrid decentralised trial, ICH E6(R3) defines your obligations. Structured, up-to-date GCP training is the most efficient way to build that knowledge and generate the documented training records regulators require.

Get ICH E6(R3) GCP Training Online

GxP Trainings offers GCP training aligned with ICH E6(R3) — covering risk-based quality management, decentralised clinical trials, sponsor oversight, and updated investigator responsibilities. Self-paced. 21 CFR Part 11 compliant certificates. Trusted by clinical research professionals worldwide.

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