The International Council for Harmonization of Technical Requirements for Pharmaceuticals (ICH) is updating the ICH E6(R2) Good Clinical Practice (GCP) guideline to address evolving trial designs and technological innovations for risk-based approaches.
The ICH is a global organization that brings together regulatory authorities and the pharma industry to develop and promote harmonized guidelines for the development, registration and post-approval of pharmaceutical products. The main purpose of ICH E6(R2) is to ensure the protection of human subjects involved in clinical trials and to provide consistent and reliable clinical trial data to support the registration and marketing authorization of new drugs and medical treatments.
The 2016 version of ICH E6 (R2) introduced important updates to enhance clinical trial quality and integrity, including a risk-based approach, clarifying responsibilities, and emphasizing data integrity and electronic systems. The new updated 2023 ICH E6(R3) guidelines, first endorsed in May of 2023, prioritize trial quality, patient safety, flexibility in planning, and alignment with standard medical care.
Here are some notable changes, which were discussed at length in a blog post from a senior GCP inspector at the UK's MHRA.
Institutional review board / Independent ethics committee:
- Restructuring information to be reviewed, including innovative methods and electronic consent
- Expanding investigational product information
- Addressing trials without prior consent and review of assent materials for minors
- Reimbursing travel expenses is not considered coercive
- Inclusion of a non-medical sciences member in reviewing IRB/IEC
- Adjustments to meet regulatory requirements
Investigator:
- Ammendments to curriculum vitae (CV) requirements for sponsors
- Including the sponsor's role in service provider agreements and the investigator's decision-making authority
- Simplifying serious adverse event (SAE) reporting
- Removing 'Suspected Unexpected Serious Adverse Reaction' reporting to the regulatory authority and IRB/IEC
- New text on communication with IRB/IEC and frequency of progress report submission
- New requirements for minors' assent and consent for adults with impaired decision-making
- Exceptional circumstances for alternative consent methods
- Expanding withdrawal guidance and follow-up measures
- Updates for decentralized trials and alternative accountability approaches
- Requirement for unblinding processes in emergencies
Summary of III Annex 1:
- Emphasis on data integrity and avoiding unnecessary data transcription
- Timely access to relevant data for participant eligibility, treatment, and safety
- Compliance with sponsor instructions for data acquisition tools and systems
- Endorsement of clinical trial data by the investigator at agreed milestones
- Protecting participant privacy and confidentiality, especially in electronic systems
- Traceability and training for trial participants using electronic equipment
- Reporting incidents impacting trial data in computerized systems
- Removing certain text covered elsewhere in the guidance
Sponsor:
- Removing references to other sections and including stakeholder input
- Recognizing delegated activities but not responsibility
- Ensuring sufficient resources for trial conduct
- Utilizing appropriately qualified individuals and assessing service providers
- Documenting agreements and providing information about service providers to investigators
- Ensuring service providers comply with applicable Good Clinical Practice aspects
- Documenting responsibilities in case of multiple sponsors
- Reorganizing and updating various sections related to trial management, oversight and quality
Safety assessment and reporting:
- Emphasizing periodic review and update of the Investigator's Brochure
- Reporting urgent safety issues and managing immediate hazards
- Considering alternative safety reporting arrangements
- Requiring safety reporting to regulatory authorities, IRB/IEC and investigators
Data handling and computerized systems:
- Focusing on data reliability and quality for generating reliable results
- Ensuring data integrity, security, and confidentiality
- Providing clarity on data collection and flow in the trial
- Offering guidance for data life cycle management for investigators, participants, and service providers
- Ensuring investigator access to relevant data
- Documenting data management processes, changes, and access restrictions
- Requiring sponsor reporting of incidents and meeting data system requirements
Essential records:
- Simplifying retention times based on applicable regulatory requirements
Reports:
- Adding requirements for clinical trial/study reports, interim analysis, results provision to investigators, and layperson-friendly summaries
Data governance (new section):
- Emphasizing the importance of data quality and integrity throughout the trial
- Focusing on maintaining blinding, data protection, and risk assessment
- Covering data capture, verification, corrections, transfers and finalization
- Providing guidance on computerized systems, including validation and security
Glossary:
- Updating definitions and terms, using 'trial participant' instead of 'trial subject'
- Combining 'documentation' and 'essential documents' into 'essential records'
- Introducing new terms like 'data acquisition tool,' 'metadata,' and 'signature'
Investigator's brochure (Appendix A):
- Restructuring with clarification of sponsor responsibility
- Including information on reference safety data for expedited reporting
Protocol (Appendix B):
- Encouraging stakeholder involvement in protocol development
- Emphasizing concise and feasible protocols, reducing unnecessary complexity
- Adding information on data monitoring committees, quality factors and non-compliance
Essential records (Appendix C):
- Broadening the concept of records to include data
- Retaining requirements for filing, retention, access, and certified copies
- Providing updated tables with essential records, eliminating duplication
- Offering guidance on record assessment, use of new technology, and version control
What the industry is saying
The FDA has initiated the standard public comment period of 60 days for this draft guidance. The ICH Expert Working Group will then review and take into account feedback from ICH member countries before finalizing the guideline.
One comment suggested the inclusion of electronic health record (EHR)-to-electronic data capture (EDC) streaming, aligning with FDA guidelines on the use of EHR data in clinical investigations. This streaming, which refers to the process of seamlessly transferring relevant data from EHRs to EDC systems used in clinical trials, offers an opportunity to enhance data accuracy, improve clinical trial efficiency and maintain patient rights.
Another comment raised concerns about the wording of certain sections, particularly regarding the investigator's obligation to permit monitoring, auditing, and inspections. They argue the use of "should" in these sections may imply optional rather than mandatory requirements, leaving room for ambiguity.
One of the commenters highlighted the need for clarity regarding laboratories performing analytical testing of human biological samples in clinical trials, often referred to as "GCLP" labs. Defining the scope of central laboratories and their inclusion in the monitoring plan would ensure effective communication and documentation of any errors that may impact sample integrity and data quality.
The exclusion of medical devices from the definition of investigational products is questioned in one comment. The commenter suggests referring to specific guidelines for device trials to avoid confusion and establish the primary focus of the ICH E6 guidelines on pharmaceuticals and drugs.
Lastly, there is a call for a comprehensive definition of "protocol deviation." "A broad definition that encompasses any deviation from the approved investigational plan, regardless of the cause or originator, would bring clarity and facilitate a common understanding," said the commenter.
