ICH E6 R3 Guideline on GCP - Summary of Proposed Changes

The “renovation” of Good Clinical Practice (GCP) began in 2017 with the publication of a reflection paper[1]. It was prompted by calls from the clinical trials sector for a more flexible and evidence-based guideline, based on scientific principles relevant to a broader range of trial designs and data sources. The highly anticipated draft of the International Council for Harmonisation (ICH) E6 R3 Guideline has now been published. In the knowledge that some content may be revised, here is a summary of the changes.

Key changes

• A revised layout. Key sections include: GCP Principles, Annex 1 comprising of the previous sections for the IRB/IEC, investigator and sponsor, a new section Data Governance, a glossary and three appendices (Investigator’s Brochure, Protocol and Essential Records).

• Stronger emphasis on proportionality, which is now embedded as a GCP principle. This includes the adoption of a ‘fit-for-purpose’ approach to trial conduct – i.e., data does not have to be error-free if it still supports conclusions/interpretations equivalent to those derived from error-free data.

• Incorporation of the ‘Quality by Design’ concept, including the key factors impacting trial quality (critical to quality factors) to prevent errors that could undermine the reliability of trial results. Quality by Design principles[2] can be found on the Trials Management and Monitoring Content to support the management of critical activities, such as randomisation, blinding/masking, retention 2.9.2), has also been added. lCH E8 R1, is frequently referenced as a source of additional guidance to support data reliability.

• More proportionate requirements for safety reporting. Removal of the strict requirement for all suspected unexpected serious adverse events (SUSARs) to be individually expedited to investigators and IRBs/IECs.

• Additional content relevant to decentralised trials (e.g., the acceptability of remote consent, a definition for data acquisition tool, a reference to home nurses and confirmation that secure, a reference to remote monitoring and audit).

• A reference to public involvement and trial diversity, including the requirement for sponsors to clearly describe the rationale for inclusion/exclusion of participants to improve trial generalisability.

• A reference to other annexes. Annexe 2 will outline ‘additional considerations’ for trials with new designs and technological innovations, including pragmatic and real-world trials.

• Essential records section lists records applicable to all trials and records applicable to some trials.

Scope

As with ICH E6 R2, the stated scope of the draft ICH E6 R3 Guideline is investigational product trials (medicines and biologicals) intended for regulatory submission. In the UK, the principles of GCP still apply to trials both intended regulatory submission and not intended for regulatory submission.

The Principles of GCP

The thirteen principles of ICH E6 R2 have been rearranged to produce eleven more detailed principles consisting of a statement and sub-points.

The eleven principles of GCP:

Key changes to the IRB/IEC section (now Section 1 of Annex 1)

• Clarity that IRBs/IECs should receive the Summary of Product Characteristic when an Investigator’s Brochure is not required.
• Acknowledgement that combined ethics committee-regulatory authority submission may be adopted in some regions.

Key changes to the Investigator section (now Section 2 of Annex 1)

• Clarity that the submission to the IRB/IEC can be made by the sponsor, in addition to investigators and institutions.
• The specific requirement for investigators to provide an up-to-date curriculum vitae has been removed and replaced with a more general requirement to provide evidence of qualification.
• Confirmation that persons conducting activities performed in accordance with routine care may not need to be on the delegation log.
• Flexibility in the content of the Participant Information Sheet, with the addition of the phrase ‘as applicable’ to the section listing the elements of consent (2.8.11). Two other elements have been added to this section:
• 8.11 (m) - Data handling, including after participant withdrawal.
• 8.11 (u) - Making available to participants the trial’s results and, if appropriate, information on the participant’s actual treatment.

• Examples of proportionality include confirmation that:
• A person’s trial-related training should be necessary to fulfill their delegated activities ‘beyond their usual training and experience’.
• Alternative approaches to the management of ‘authorised medicinal products’ are acceptable.
• An extension to the groups of health professionals who can have overall responsibility for trial-related medical care and decisions (currently physicians and dentists).
• A new section on computerised systems.

Key changes to the Sponsor section (now Section 3 of Annex 1)

• Additional requirements for trial design (e.g., identifying critical to quality factors, consulting with appropriate stakeholders).
• New examples of proportionality, including confirmation that:
• There is no requirement for delegation of duty documentation for those performing trial activities in accordance with routine clinical care.
• Trial related training should focus on the delegated activities that go beyond the person’s usual training/experience. There may be no requirement for some to be included on a delegation log.
• The addition of guidance relating to service providers, including the need for
• Confirmation that a trial can have more than one sponsor.
• The need to determine trial-specific criteria for classifying deviations as important (i.e., serious breaches).
• The timelines for SUSAR reporting to investigators and IRBs/IECs no longer need to comply with ICH E2A (7/15-day reporting).
• The requirement to describe the quality management approach adopted in the clinical trial report.
• The requirement to have adequate resources to conduct the trial.
• Confirmation that centralised monitoring could be used on its own.
• The removal of a specific retention time for essential records.
• Recognition that for trials using marketed investigational product (IP), some requirements for the management IP may not be required.

Changes to the Glossary (now near the end of the Guideline)

New, removed and amended terms are summarised below.

In addition to these changes, the descriptions in many unchanged terms have been reworded and extended.

Author: Tanya Symons: T Symons Associates Pty Ltd

[1] ICH. ICH Reflection on “GCP Renovation”: Modernization of ICH E8 and Subsequent Renovation of ICH E6 2017.

[2] Critical to Quality (CTQ) factors Principles Document from the Clinical Trials Transformation Initiative