The ICH E6(R3) guideline was formally adopted on January 6, 2025, introducing reinforced principles for clinical trial conduct. This final version builds on its draft with clarified expectations and some notable revisions. Let’s explore the highlights and the implications for stakeholders.

Key Updates in ICH E6(R3)

Risk Management

The final guideline provides detailed steps for evaluating risks, emphasizing their alignment with existing controls. Sponsors are required to consider the likelihood of risks, the extent to which they are detectable, and their potential impact on trial participants and data reliability (Section 3.10.1.2).

Harm and Hazard Language

New terminology, such as the focus on “harm” and “hazard,” highlights participant safety but introduces stricter definitions that could limit operational flexibility. Sponsors must account for these terms when assessing risks and designing mitigation strategies (Section 3.10.1.2 and 3.10.1.3).

Quality Tolerance Limits (QTLs)

QTLs are now explicitly defined as “pre-specified acceptable ranges” that support risk control. When deviations occur, sponsors must evaluate systemic issues and implement corrective actions, underscoring the role of QTLs in maintaining trial quality (Section 3.10.1.3).

This update ensures greater consistency in trial oversight and enhances documentation standards for regulatory compliance.

Download the final version: GOOD CLINICAL PRACTICE E6(R3)

What Has Changed Since the Draft?

The final version sharpens its focus in several areas:

Risk Assessments:
What does this mean?
Sponsors and trial teams must evaluate risks by considering what safeguards are already in place. For example, if a site’s data collection process shows recurring discrepancies, the focus shifts to identifying and addressing gaps in training or workflow to prevent future errors.

Terminology Adjustments:
What does this mean?
Specific words now make safety and quality expectations clearer, leaving little room for varied interpretations. This encourages consistent practices across all trials.

Documentation Expectations:
What does this mean?
Sponsors are now required to maintain detailed records of their decisions and risk evaluations, ensuring transparency and accountability throughout the trial.

Implications for Stakeholders:

Stakeholder What this means
Sponsors
  • Must retain full responsibility, even with delegation.
  • Need to implement proactive monitoring and detailed risk reviews.
CROs
  • Expected to validate their processes and meet stricter sponsor oversight requirements.
Trial Sites
  • Require training on using QTLs and improved documentation practices.
  • Need more assertive communication with sponsors.
Trial Participants
  • Gain better access to data and improved safety protections.
  • Benefit from clearer informed consent processes.

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