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ICH GCP R3: Important Protocol Deviations vs. Serious Breaches—What You Need to Know


With the release of ICH GCP (Good Clinical Practice) E6(R3), sponsors and investigators are revisiting how they define and handle protocol deviations. While GCP R3 emphasizes the concept of “Important Protocol Deviations” (IPDs), it does not explicitly reference “Serious Breaches” (SBs).

However, section 3.12.2 states: “Where the sponsor identifies issues that are likely to significantly impact the rights, safety or well-being of the trial participant(s) or the reliability of trial results (i.e., serious noncompliance), the sponsor should notify the regulatory authority and/or IRB/IEC, in accordance with applicable regulatory requirements, and/or investigator, as appropriate.”

Moreover, certain jurisdictions (e.g., the UK, EU/EEA Member States under EU CTR 536/2014, Australia, Singapore, Serbia) do require sponsors to identify and promptly report Serious Breaches

Important Protocol Deviations (IPDs)
Definition (per ICH E3)
A subset of protocol deviations that might significantly affect the completeness, accuracy, and/or reliability of the study data, or might significantly affect a subject’s rights, safety, or well-being.
Purpose:
  1. Analysis: IPDs can lead to exclusion of affected subjects from certain statistical populations (e.g., Per Protocol analyses).
  2. Reporting: Summarized in the Clinical Study Report (CSR) at the end of the trial.
Examples:
  • Not meeting entry criteria (e.g., enrolling an ineligible subject)
  • Failure to follow withdrawal criteria
  • Incorrect dose or wrong treatment
  • Use of excluded concomitant medications
Serious Breaches (SBs)
Definition (common regulatory interpretation)
A breach of the conditions and principles of GCP and/or the trial protocol that is likely to significantly affect the safety, well-being, or rights of a trial subject, or the reliability and robustness of the data.
Purpose:
  1. Regulatory Oversight: Must be reported promptly (often within 7 calendar days) to relevant authorities (e.g., the MHRA in the UK, National Competent Authorities in EU/EEA) via CTIS.
  2. Protection of Subjects: Ensures quick intervention if participant safety or data integrity is compromised.
Practical Implications
Sponsor Responsibilities:
  • Define trial-specific criteria for classifying IPDs.
  • Document and track all deviations.
  • Ensure rapid reporting of any suspected SB from other parties (e.g., investigators or service providers) to the Sponsor, and then to the relevant regulatory authorities.
Investigator Responsibilities:
  • Document all deviations.
  • Implement preventive measures to avoid recurrence.
  • Collaborate with the sponsor in classifying and managing deviations.
Jurisdictional Nuances
  • United Kingdom: Serious Breaches must be reported to the MHRA within 7 calendar days.
  • EU/EEA: Under the EU Clinical Trial Regulation (536/2014), Serious Breaches must be reported to the National Competent Authority via the CTIS.
  • Other Regions: Australia, Singapore, Serbia, and others have similar or slightly varied reporting requirements.
Conclusion
While ICH GCP E6(R3) provides clarity on “Important Protocol Deviations,” the concept of “Serious Breaches”, while added to the R3 text (without using this term), remains a jurisdiction-specific requirement. Understanding the difference is crucial to ensure participant safety, data integrity, and regulatory compliance. Always stay updated on local regulations, maintain robust monitoring, and act quickly when a potential breach arises.


Practical Case Study
Scenario
A multicenter clinical trial is running in both Austria (under EU CTR 536/2014) and the UK. During a routine monitoring visit, the sponsor discovers that a subject received an incorrect dose of the Investigational Product (IP) for three consecutive days. The dose error could impact the subject’s safety and the trial’s data integrity.
Key Questions
  1. Is this an Important Protocol Deviation (IPD) or a Serious Breach (SB)?
  • IPD: If the dose error might affect data accuracy and or subject's safety but does not pose a significant risk to the subject’s safety or rights, or to the reliability of the trial data.
  • SB: If the dose error is likely to significantly affect the subject’s well-being or the trial’s data reliability—especially if it was a high-risk dosing mistake or there’s a risk of serious adverse events!!!! .
2. How to Handle This Deviation?
  • Investigator: Document the deviation, provide a detailed explanation, and outline actions to prevent recurrence.
  • Sponsor: Assess if the error meets the threshold for a Serious Breach under local regulations. If yes:
  • UK: Report to the MHRA within 7 days.
  • Austria (EU): Report to the relevant National Competent Authority under EU CTR 536/2014.
  • If classified only as an IPD, it should still be documented and may affect per-protocol analyses.
3. Reporting Timeline
  • Serious Breach: Typically within 7 calendar days to regulatory authorities.
  • IPD: Document internally and in the Clinical Study Report; no immediate external reporting unless local regulations demand it.
Learning Point: One deviation can be an IPD in some contexts but escalate to an SB if the potential harm or data impact is deemed “significant.” Jurisdiction matters—if any site is in the UK or EU/EEA (or other “SB countries”), local Serious Breach reporting rules apply.


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