ICH GCP E6 R3 Glossary: summary of changes in Good Clinical Practice

Some existing terms got major updates. Here’s what you need to know:

• ADVERSE EVENTS AND ADVERSE REACTION-RELATED DEFINITIONS: Enhanced definition: “Adverse Event (AE): Any unfavourable medical occurrence in a trial participant administered the investigational product. The adverse event does not necessarily have a causal relationship with the treatment”.
  • What are the key updates:
    • Adverse Event: Clearer distinction between events occurring during trial participation vs. those related to the investigational product.
    • Adverse Reaction: Enhanced definition emphasizing causal relationship assessment.
    • Serious Adverse Event: Expanded criteria including persistent or significant disability/incapacity.
    • Unexpected Adverse Reaction: Refined definition linking to Reference Safety Information (RSI)

• • Why these changes matter:
    • More precise safety reporting requirements.
    • Better alignment with pharmacovigilance regulations
    • Clearer guidance for causality assessment
    • Standardized approach across global regions
  • What you should know:
    • Learn updated reporting timelines
    • Understand new causality criteria
    • Practice with revised case studies
    • Master RSI-based expectedness assessment

• AUDIT TRAIL: Formally defined to address computerized system requirements, an audit trail is now recognized as a secure, computer-generated, time-stamped electronic record that allows reconstruction of the course of events relating to the creation, modification, or deletion of an electronic record. So basically, electronic records should show who changed data and when. “Metadata records that allow the appropriate evaluation of the course of events by capturing details on actions (manual or automated) performed relating to information and data collection and, where applicable, to activities in computerised systems. The audit trail should show activities, initial entry and changes to data fields or records, by whom, when and, where applicable, why. In computerised systems, the audit trail should be secure, computer-generated and time stamped”.
  • • Rationale: The inclusion of this term reflects the widespread adoption of electronic data capture systems and the regulatory need for comprehensive data integrity measures.
    • Why it’s critical: Data integrity is everything in clinical trials. Regulatory inspectors always check audit trails.
    • What you should know:
      • Must be computer-generated
      • Cannot be changed or deleted
      • Shows complete history of data changes
      • Required for all electronic systems
    • Training tip: Practice reading audit trail reports. 

• GOOD CLINICAL PRACTICE (GCP): Updated definition: “A standard for the planning, initiating, performing, recording, oversight, evaluation, analysis and reporting of clinical trials that provides assurance that the data and reported results are reliable and that the rights, safety and well-being of trial participants are protected”.
  More precisely, the ICH E6 R3 guideline describes standards that apply to sponsors, investigators, IRBs/IECs, and service providers involved in the planning, conduct, and reporting of clinical trials involving human participants. This new definition has been expanded to emphasize that GCP is “an international, ethical, scientific, and quality standard,” with a stronger emphasis on quality by design principles. The previous definition (R2) was based on ethical and quality standards; however, the new definition emphasizes that it is an “international, ethical, scientific, AND quality standard with risk-based approaches.” This means that GCP isn’t just about following rules. It’s about building quality into every aspect of trials.

• INSTITUTIONAL REVIEW BOARD  (IRB)/INDEPENDENT ETHICS COMMITTEE (IEC): Enhanced definition: “An independent body (a review board or a committee, institutional, regional, national or supranational) constituted of medical professionals and non-medical members whose responsibility it is to ensure the protection of the rights, safety and well-being of human participants involved in a trial and to provide public assurance of that protection by, among other things, reviewing and approving/providing favourable opinion on the trial protocol, the suitability of the investigator(s), the facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial participants. The legal status, composition, function, operations and regulatory requirements pertaining to IRBs/IECs may differ among countries but should allow the IRB/IEC to act in agreement with GCP as described in this guideline”.
  • Major updates:
    • Expanded composition requirements: More specific guidance on member qualifications and independence
    • Digital review processes: Acceptance of electronic submissions and virtual meetings
    • Risk-based review: Tailored review frequency based on trial risk assessment
    • Continuing review: More flexible approaches for low-risk studies
  • New responsibilities:
    • Review of digital consent processes
    • Assessment of data governance plans
    • Evaluation of computerized systems
    • Oversight of decentralized trial elements

• ESSENTIAL RECORDS: Expanded Definition: “Essential records are the documents and data (and relevant metadata), in any format, associated with a clinical trial that facilitate the ongoing management of the trial and collectively allow the evaluation of the methods used, the factors affecting a trial and the actions taken during the trial conduct to determine the reliability of the trial results produced and the verification that the trial was conducted in accordance with GCP and applicable regulatory requirements (see Appendix C)”. The definition has been broadened to encompass various media formats and emphasizes the concept of “fitness for purpose” rather than prescriptive record-keeping requirements.
  • Key changes:
    • Includes all media formats (paper, electronic, digital)
    • Emphasizes “fitness for purpose”
    • Covers modern storage methods
  • Why it matters: Electronic records are now fully equal to paper records. Your Good Clinical Practice certification must cover both.

• INVESTIGATOR: Expanded responsibilities: “A person responsible for the conduct of the clinical trial, including the trial participants for whom that person has responsibility during the conduct of the trial. If a trial is conducted by a team of individuals, the investigator is the responsible leader of the team and may be called the principal investigator.
  Where an investigator/institution is referenced in this guideline, it describes expectations that may be applicable to the investigator and/or the institution in some regions. Where required by the applicable regulatory requirements, the “investigator” should be read as “investigator and/or the institution”.
  • The enhanced definition now includes:
    • Digital oversight: Responsibility for computerized systems used at their site
    • Data governance: Active role in ensuring data integrity throughout trial
    • Service provider management: Oversight of delegated activities to external parties
    • Technology validation: Understanding and approval of electronic systems
  • What you should know:
    • Basic computerized systems validation knowledge
    • Data integrity assessment capabilities
    • Electronic signature authorization
    • Digital monitoring participation

• INVESTIGATOR SITE: Modernized definition: “The location(s) where trial-related activities are conducted and/or coordinated under the investigator’s/institution’s oversight”.
  • The expanded concept:
    • is adapted for clinical trial operations in decentralised settings
    • Technology infrastructure: Digital capabilities and system requirements
    • Multiple locations: Satellite sites and mobile units
  • New site requirements:
    • Computerized system validation capability
    • Data integrity compliance infrastructure
    • Service provider coordination systems
    • Digital patient engagement platforms

• SPONSOR: enhanced responsibilities: “An individual, company, institution or organisation 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 of a sponsor 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”.
  • Expanded definition now includes:
    • Digital transformation leadership: Overall responsibility for trial digitalization
    • Data governance: Comprehensive data integrity framework implementation
    • Service provider ecosystem: Management of complex outsourcing relationships
    • Technology validation: Oversight of all computerized systems validation
  • New sponsor obligations:
    • Risk-based quality management system implementation
    • Comprehensive service provider qualification and oversight
    • Data integrity assurance throughout trial lifecycle
    • Computerized systems validation program leadership