Summary of Key Changes in the ICH E6 (R3) Guidelines

Summary of Key Changes in the ICH E6 (R3) Guidelines

The final version of ICH E6 (R3) (.PDF) Good Clinical Practice (GCP) Guidelines was published on 6^th January, 25 and recommended for adoption by regulatory bodies. The changes reflect advancements in trial design, technology and the digital ecosystem for trials, with expanded content on data governance and computerised systems. 

There is also an emphasis on Quality-by-Design - a methodology that proactively designs quality into a trial to prevent errors that could significantly impact patient safety and data reliability (see CTTI Guidance). Additional content supports the implementation of key trial design principles, with a strong emphasis on proportionality and fitness-for-purpose, aiming to improve trial efficiency and extend the applicability of GCP to a broader range of trials. Transparency in the trial process is also emphasised. For teams conducting trials that incorporate decentralised, pragmatic or real-world elements, additional considerations are outlined in the draft Annex 2 of ICH E6 (R3 (.PDF)).

This document updates the summary of the draft ICH E6 (R3) published on the CT Toolkit in August 2024, incorporating the latest changes from the final version. While this summary highlights key updates, it is not exhaustive. New sections, particularly Section 3.16 and Section 4 (relating to data governance), warrant thorough review. 

ICH E6 R3 SCOPE

As with all previous versions, ICH E6 (R3) applies specifically for investigational product (IP) trials (medicines and biologicals) intended for regulatory submission. The guideline now clarifies that the principles of GCP may apply to other IP trials, rather than the full guidelines.

SUMMARY OF KEY CHANGES

• The guideline is now organised into: An introduction, GCP Principles, Annex 1 (covering IRB/IEC, investigator and sponsor responsibilities and a new Data Governance section, three appendices (Investigator’s Brochure, Protocol and Essential Records) and a Glossary at the end.
• Proportionality is now a GCP principle. There is emphasis on a ‘fit-for-purpose’ approach to trial conduct – data does not have to be error-free if it supports conclusions equivalent to those drawn from error-free data.
• The introduction of the ‘Quality by Design’ concept, which includes the identification of critical-to-quality factors to prevent errors that could compromise patient safety and data reliability.
• Expanded content supporting the management of critical activities, such as randomisation, blinding/masking and participant retention, with reference to ICH E8 (R1) for additional guidance.
• Removal of the requirement for all SUSARs to be expedited to investigators and IRBs/IECs and introduction of alternative arrangements for safety reporting to regulatory authorities.
• Content reflecting the growth of novel trial designs and technology, such as trials with decentralised elements (e.g., remote consent/monitoring/audit, home nurses).
• References to public involvement and participant diversity, including the requirement for sponsors to clearly describe the rationale for exclusion of participants.
• Expanded data governance requirements, including a new sponsor section covering data and records (Section 3.6) and a new stand-alone section for Data Governance (Section 4).
• Removal of any explicit references to non-therapeutic trials.

THE PRINCIPLES OF GCP

The 13 principles of ICH E6 (R2) have been rearranged to produce 11 more detailed principles consisting of a statement and sub-points designed to provide a flexible framework for trial conduct.

SELECTED STAKEHOLDER-SPECIFIC CHANGES

IRB/IEC SECTION: NEW, REVISED OR MORE EXPLICIT CONTENT 

• Confirmation that the review by an ethics committee and regulatory authority can be combined. (1.1)
• Requirement to review assent materials for trials involving minors. (1.2.2.b)
• Confirmation that the IRBs/IECs should receive an alternative document (e.g. a Summary of Product Characteristics) when an Investigator’s Brochure is not required. (1.2.2 c)
• Confirmation that reasonable participant reimbursement (e.g., travel/lodging) is not coercive. (1.2.8)
• Broadened definition of a lay member, which can now be anyone not in medical sciences. (1.3.1 b)

INVESTIGATOR SECTION: EXAMPLES OF NEW/MORE EXPLICIT CONTENT

Responsibilities

• Clarification that investigators retain the final decision on whether a service provider contracted by the sponsor is appropriate for trial support. (2.3.1)
• Confirmation that training (e.g., GCP) for those assisting in the trial should align with the delegated activities that go beyond their usual training and experience. (2.3.2)  
• Removal of the requirement to include individuals who perform activities ‘as part of clinical practice’ on the delegation log. (2.3.3)

Participant Medical Care and Safety Reporting

• Confirmation that health professionals other than doctors and dentists can have overall responsibility for trial-related medical care and decisions. (2.7.1)
• Clarification that unfavourable medical events occurring before Investigational Product (IP) administration should be reported to the sponsor. (2.7.2a) 

Informed Consent 

• Confirmation of the need to establish the identity of participants. (2.8.1e)
• Confirmation that electronic methods can be used to obtain informed consent. (2.8.7)
• Flexibility in tailoring consent elements, allowing specific items in the Participant Information Sheet to be included “as applicable.” Three consent elements (points m, n, and v) have been added. (2.8.10)
• Clarification that minors should provide assent where appropriate. (2.8.12)

End of Trial Participation 

• Suggestion for protocols to include instructions to avoid loss of already collected data when participants withdraw, thereby preventing bias. (2.9.1)
• Guidance for participant withdrawal requiring investigators to explore ways to resolve issues and encourage participants (without undue influence) to reconsider withdrawal, (2.9.2)
• Emphasis on trial transparency, encouraging investigators to inform participants about trial results and the treatment received, if appropriate. (2.9.3)

Investigational Product (IP) Management and Unblinding

• Confirmation that sponsors may facilitate IP management, such as arranging distribution. (2.10.1)
• Clarity that the level of oversight for delegated IP management will depend on the IP’s characteristics. (2.10.3)
• Support for alternative approaches to IP management and accountability in authorised trials. (2.10.4)
• Confirmation that IP may be shipped to participants and administered by investigator site staff, participants, caregivers, or health professionals. (2.10.8)

Randomisation

• Emphasis that systems for unblinding should be established at the start of the trial to ensure readiness if unblinding becomes necessary. (2.11)

Records*

• Emphasis on site computerised systems including a requirement to:
  • Notify the sponsor when system access needs to be revoked. (2.12.10b)
  • Validate systems specifically for clinical trials that are deployed by the investigator, as described in Section 4. (2.12.10c)    
• Requirement for participant-facing equipment to be traceable and its use supported with appropriate training. (2.12.10.d)
• Additional requirements for investigators to:
  • Define source records and data capture methods before starting the trial. (2.12.2)
  • Conduct timely reviews of all relevant data, including data from external sources affecting participant eligibility, treatment, or safety. (2.12.3)
  • Identify a person responsible for maintaining essential records during the retention period and notify the sponsor of their name. (2.12.13)

         *Additional requirement for investigator/institution in Section 4.

SPONSOR SECTION: EXAMPLES OF NEW/MORE EXPLICIT CONTENT

Trial Design and Conduct

• Requirement to incorporate Quality-by-Design by identifying critical-to-quality factors and implementing proactive risk management. (3.1.2)
• Encouragement for stakeholder input (e.g. patients, healthcare professionals) during trial planning. (3.1.3)
• Requirement to minimise unnecessary burden on participants and investigators. (3.1.4)

Sponsor Resources

• Confirmation that the sponsor requires sufficient resources for appropriate trial conduct. (3.2)

Agreements

• Confirmation that service providers should agree to report incidents impacting safety and data reliability. (3.6.6)
• Clarification that services provider quality management processes should be fit-for-purpose, but not necessarily designed to be GCP compliant. (3.6.10)
• Confirmation that a trial may have more than one sponsor and should have documented agreements relating to their respective responsibilities. (3.6.11)

Sponsor Oversight

• Requirement for trial-specific criteria for classifying deviations as important. (3.9.3)
• Confirmation that issues arising from a trial require timely escalation and follow-up. (3.9.6)
• Consideration for establishing endpoint assessment/adjudication committees, which should typically be blinded. (3.9.8)

Monitoring

• Reference to the independence of monitoring. (3.11.4)
• Further clarity that centralised monitoring can be used as the sole monitoring approach (3.11.4.2.b)
• Requirement for monitoring reports to include findings requiring escalation, along with actions and resolutions. (3.11.4.6 c)

Safety Monitoring/Reporting

• Clarity that the sponsor should aggregate relevant safety information, when appropriate, and include unfavourable medical events occurring before IP administration. (3.13.1)
• Emphasis on the expectedness assessment and introduction of the term reference safety information. (3.13.2.c)
• Replacement of the 7/15-day timeline for SUSARs reporting to investigators/IRBs/IECs (ICH E2A) with the requirement to report SUSARs in a timeframe that ‘reflects the urgency of the action required.’ (3.13.2.d)
• Confirmation that alternative arrangements for safety reporting to regulatory authorities, IRB/IECs and investigators are permitted, including selective safety reporting in late-stage trials. (3.13.2 f)

Investigational Product 

• Confirmation that risk-based approaches to shipping and dispensing IP are acceptable. (3.15.3 a)
• Removal of the requirement for sponsors to retain samples of unmodified authorised IP. (3.15.3 c vi)

Data and Records 

An extensive section outlining expectations for data handling and management, including:

• A new 24-point list for data handling expectations, including:

Pre-specification of data to be collected and the collection method. (3.16.1.c)

Clearly outlined data flow, e.g. with data flow diagrams. (3.16.1.c) 

Validation of data acquisition tools before their required use. (3.16.1.d) 

Investigator training on the use of computerised systems. (3.16.1.n)

Investigator endorsement of data at pre-determined milestones. (3.16.1.o)

Documentation of data management steps prior to data analysis. (3.16.1.p)

Processes to report incidents with significant impact (e.g. security breaches). (3.16.1.w)

• Clarification of expectations when computer systems are deployed by sponsors and sites. (3.16.1.x)
• Clarification of expectations for statistical programming and data analysis. (3.16.2)
• Confirmation that the timeline for retention of sponsor-specific essential records is now in accordance with the applicable regulatory requirements. (3.16.3.a)
• Requirement to report transfer of ownership of essential records. (3.16.3 c)
• Consideration for the coordinating investigator as a signatory on the clinical study report. (3.17.2 b)
• Expectations for trial transparency, including providing investigators with trial results and for blinded trials, information about the treatment taken by their participants. (3.17.2.c)

OVERVIEW OF THE REMAINING SECTIONS

Section 4: Data Governance 

• A new section providing comprehensive guidance on data integrity, traceability, security, and computer systems, addressing both investigator and sponsor-deployed systems.

Appendix A: Investigator’s Brochure

• New heading to describe the Reference Safety Information, its purpose and content. (A.1.2)

Appendix B: Protocol/Protocol Amendments 

• A broadly unchanged structure. Includes a reference to a wider range of trial designs, such as adaptive and umbrella trials. (B 4.2)

Appendix C: Essential Records 

• Removal of a specific retention time for essential records held by the investigator/institution. (C.1.3)
• Requirement, where appropriate, for essential records to include details of authors, reviewers and approvers. (C.2.1)
• Expanded content on digital data requirements, including clarification on which party retains original records and a new framework for determining the essentiality of trial records. (C.3)

Glossary

• New, removed and amended terms, which are summarised below. 

Author: Tanya Symons: T Symons Associates Pty Ltd