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Protocol Deviations and Serious Breach Expedited Reporting

Posted on May 19th, 2017 by in Pharmacovigilance


Protocol deviations will occur even with the best designed clinical trial protocols and investigator training. Although minimizing such protocol breaches is an absolute mandate for Clinical Trial Sponsors, there are specific deviations (usually qualified as “major”) which require expedited reporting if they impact patient safety.

Regulation 29A of the Medicines for Human Use in the UK, effective since 2006, requires a 7-day report of “Serious Breach” during clinical trials implemented in UK, when it is “likely to effect to a significant degree the safety or physical or mental integrity of the subjects of the trial (…)”. The MHRA Serious Breach and Good Clinical Practice Reporting guideline provides several examples of such reportable “Serious Breaches”.

Article 52 of the Directive 536/2014/EC, effective with transition phase in 2018/2019, has similar requirements for 7-day reporting.

In the US, even if the term Serious Breach is not used, the Sponsors are responsible for reporting and taking actions following identification of “unanticipated problems involving risk to human subjects or others”, as per 21CFR312.56 and 21CFR312.66.

Reporting a Serious Breach (SB) is only the beginning of an urgent and critical process. All SBs and Major Deviations should always be promptly investigated, corrected and prevented, applying a formalized Deviation Management or CAPA process. Then the company needs to identify what risk minimization measures should be implemented ASAP and what should be communicated to the Health Authorities. This triggers another short reporting timeline between 5 days (study hold), or 7 to 15 calendar days (depending on the regions). Now would be a good time to conduct a checkup of your organization before a Serious Breach (SB) pushes you into crisis mode. For example, do you have in place:

  • A clear definition of when the clock starts (Day 0) for SB identification? It is at the site level (during the CRA visit)? Is it when the Site Visit Report (SVR) is read by a Project Manager or Medical Monitor at the Sponsor or CRO site?
  • How quick is the review of a Site Visit Report (SVR) which might contain a suspected SB? Are all the SVRs reviewed within a short timeline allowing the reporting of a confirmed SB?
  • Do you have a Protocol Deviation Review process in place for all trials? How frequent is this review happening? Is there a connection with the drug safety signal detection activities?
  • Do you have a clear escalation path between the CRO and the Sponsor, allowing the Sponsor to make the final decision for the confirmation of a Serious Breach?
  • Do you have a definition of major versus minor deviations?
  • Do you have a process to recognize when a pattern of minor or major deviations become a risk for the patients?
  • Who makes the final decision to confirm a Serious Breach?
  • Have you trained your CRAs and Project Managers to recognize a Serious Breach?
  • Once a Serious Breach is identified, do you have SOPs describing the process and responsibilities for identifying, implementing and notifying the authorities of Urgent Safety Measures?

Like any situation, the best is to anticipate and design the adequate process before the first Serious Breach occurs. There are significant liabilities associated with non-compliance to these regulations, and the Sponsor’s obligation to prevent harm to the patients should always be the ultimate driver. Be prepared and well-organized.

JP Clement

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All opinions shared in this post are the author’s own.

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J.-P. Clement MD

Executive Pharmacovigilance Consulting

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