ICH E6 (R3) is Here – What You Need to Know

Implementation timelines are set by the regional regulatory authority. The European Medicines Agency (EMA) implementation date is Jul. 23, 2025. The U.S. Food and Drug Administration (FDA) has not yet set a date.

ICH E6 (R3) final principles and Annex 1 were adopted in January 2025. Annex 2 is still draft and currently open for public consultation. Once Annex 2 is adopted, it will be included in the ICH E6 (R3) final document.

ICH training materials are planned to be developed (with use-cases) and will be publicly available for free at www.ich.org/page/training-library. There is no confirmed timeline for release at this time.

The ICH E6 (R3) glossary defines a service provider as a person or organization (commercial, academic, or other) providing a service used by either the sponsor or the investigator to fulfil trial-related activities. Examples may include central lab, central imaging reading facility, interactive response technology (IRT) provider, and home nursing providers.

The ICH E6 (R3) glossary defines sponsor as an individual, company, institution, or organization that takes responsibility for the initiation, management, and arrangement of the financing of a clinical trial. A clinical trial may have one or several sponsors where permitted under regulatory requirements. All sponsors have the responsibilities set out in this guideline. In accordance with applicable regulatory requirements, sponsors may decide in a documented agreement setting out their respective responsibilities. Where the documented agreement does not specify to which sponsor a given responsibility is attributed, that responsibility lies with all sponsors.

ICH E6 (R3) Appendix C highlights the expectation for a risk-proportionate approach to essential records, noting that the nature and extent of the records generated and maintained should be dependent on the trial design, its conduct, and the importance and relevance of the record to the trial. Additionally, a few key changes in C.2 “Management of Essential Records” include that records should be identifiable and version controlled, protection of the blind and privacy should be considered when sharing records across stakeholders, and some essential records that may not be specific to the trial such as standard operating procedures (SOPs), validation records, or master service agreements (MSAs), may be retained outside of the TMF.

ICH E6 (R3) 4.2.3 “Review of Data and Metadata” outlines that the review of trial-specific data, including audit trails should be planned activity. The extent and nature of the reviews should be risk-based, and procedures should be documented.

ICH E6 (R3) 2.3.3 states that the investigator should ensure a record is maintained of the persons/parties to whom the investigator has delegated trial-related activities, and that documentation of delegation should be proportionate to the significance of the trial-related activities. ICH E6 (R3) does not distinguish between site staff and non-site staff in this section.

ICH E6 (R3) 2.12.12 notes that the investigator should retain the essential records for the required retention period in accordance with applicable regulatory requirements (e.g., EU requires 25 years) or until the sponsor informs the investigator that the records are no longer needed, whichever is the longest.

ICH E6 (R3) 2.1.1 states that investigators should be qualified by education, training, and experience and should provide evidence of those qualifications. A CV may be an example of “evidence of qualifications.” It is likely that a medical license would not sufficiently evidence experience.

ICH E6 (R3) 2.3.1 notes that the investigator may delegate trial-related activities to other persons or parties. 2.7 addresses participant medical care and safety reporting, noting that that an investigator or sub-investigator should have responsibility for trial-related medical care and decisions (2.7.1(a)) and that the investigator can delegate activities for safety reporting to qualified investigator site staff but retains overall responsibility (2.7.2(d)). Similarly, 2.10.2 notes that the investigator may delegate some or all of their activities for investigational product management.

ICH E6 (R3) notes in 2.10.1 that responsibility for investigational product(s) management, including accountability, handling, dispensing, administration, and return, rests with the investigator. The sponsor may facilitate aspects of investigational product management (e.g., by providing forms and technical solutions, such as computerized systems, and arranging distribution of investigational product to trial participants).

ICH E6 (R3) notes in 2.8.5 that the consent process should be conducted by the investigator or other investigator site staff delegated by the investigator, in accordance with applicable regulatory requirements. This depends on local regulatory/state requirements.

Most of the IRB expectations in ICH E6 (R3) Section 1 IRB/IEC are similar to ICH E6 (R2) with a few new expectations including (but not limited to) a restructuring the of responsibilities section with expanded list of documents that the IRB should review including informed consent process and assent, annual review has been replaced with a risk proportionate approach to continuing review appropriate to the degree of risk to participants, and a shift in safety reporting from all adverse drug reactions (ADRs) that are both serious and unexpected to reporting all suspected unexpected serious adverse reactions (SUSARs).