International Council for Harmonisation (ICH) E3 Guideline: Structure and Content of Clinical Study Reports Questions & Answers (R1) (2012) provided the definition for protocol deviation and important protocol deviation. The term "protocol violation" should be avoided and replaced with "protocol deviations" :
A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the protocol.
Important protocol deviations are a subset of protocol deviations that may significantly impact the completeness, accuracy, and/or reliability of the study data or that may significantly affect a subject's rights, safety, or well-being. For example, important protocol deviations may include enrolling subjects in violation of key eligibility criteria designed to ensure a specific subject population or failing to collect data necessary to interpret primary endpoints, as this may compromise the scientific value of the trial.
Protocol violation and important protocol deviation are sometimes used interchangeably to refer to a significant departure from protocol requirements. The word “violation” may also have other meanings in a regulatory context. However, in Annex IVa, Subject Disposition of the ICH E3 Guideline, the term protocol violation was intended to mean only a change, divergence, or departure from the study requirements, whether by the subject or investigator, that resulted in a subject’s withdrawal from study participation. (Whether such subjects should be included in the study analysis is a separate question.)
To avoid confusion over terminology, sponsors are encouraged to replace the phrase “protocol violation” in Annex IVa with “protocol deviation”, as shown in the example flowchart below. Sponsors may also choose to use another descriptor, provided that that the information presented is generally consistent with the definition of protocol violation provided above.
In adopting and implementing the ICH E3 guidelines, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) differ in certain respects. In particular, the EMA guidelines introduce a new term: “serious breach.” While the concept of a “serious breach” overlaps with that of an “important protocol deviation,” subtle distinctions remain between the two terms.
The EMA’s clinical trial protocol breach guideline (CTR Article 52) uses the term “serious breach” to mean a protocol or regulation violation with significant impact on a trial. In contrast, FDA’s protocol deviations guidance (Draft version, December 2024) adopts ICH definitions and uses “important protocol deviation” for critical departures from the protocol. We compare these terms by definition, thresholds, reporting, examples, and implications.
|
Serious Breach (EMA/CTR) |
Important Protocol Deviation (FDA/ICH) |
|
|
Definition |
Any deviation of the approved protocol (or EU CTR)
likely to affect subject safety, rights, or data reliability to a
significant degree. This is a legal term under EU CTR
(Art. 52). |
A subset of protocol deviations that might significantly
affect data completeness, accuracy, or reliability or significantly
affect a subject’s rights, safety, or well‑being. (FDA guidance aligns with ICH E3(R1)). |
|
Criteria/Threshold |
Threshold is “likely to affect to a significant degree” at
least one of: safety, rights, or data integrity. The impact must be substantial (regulatory
text: “significant degree”). In practice, breaches that systematically
endanger participants or core data are serious. |
Threshold is “might significantly affect” key trial
aspects. Important deviations are those that could undermine data
quality or subject welfare – for example, affecting critical‑to‑quality
factors (ICH E8(R1)) such as eligibility, endpoint collection,
randomization, or safety monitoring. Deviations not reaching “significant” impact are
considered minor. |
|
Reporting Obligations |
Mandatory notification to regulators: The sponsor
must report via CTIS (EU portal) without undue delay, and within 7
calendar days of becoming aware. The sponsor is responsible for the report
(it may delegate CTIS submission). All serious breaches must be entered into
the EU database (CTIS). Investigators and CROs must promptly inform the
sponsor of any suspected serious breach. Failure to report can trigger GCP
inspection findings. |
No direct mandatory FDA notification: FDA does not
require sponsors to notify FDA of individual protocol deviations. Instead,
FDA recommends that investigators promptly report important deviations
to the sponsor and IRB, and sponsors document them. Specifically,
investigators should report all deviations to the sponsor (highlighting the
important ones), and device trials must report emergency
deviations to sponsor/IRB within ~5 days. Sponsors should capture important deviations in
oversight and include them in regulatory submissions: FDA guidance
advises sponsors to discuss important deviations in the Clinical Study Report
(NDA/BLA) and list all deviations in the Study Data Tabulation Model (SDTM)
(with an indicator of importance). |
|
Examples |
EMA guideline Appendix I (non‑exhaustive)
includes situations like: dosing a subject with the wrong drug or dose
(e.g. incorrect IMP, wrong frequency); giving IMP to a pregnant subject without
protocol-required test; systematically failing to administer
required therapy. Other examples: temperature excursions
unverified by corrective action, severe informed consent lapses, etc. These
all have significant safety/data impact. |
FDA guidance examples highlight failures that
impair safety or data. For instance: skipping key safety assessments (e.g.
missing lab tests or not administering study drug per spec); giving a prohibited concomitant treatment; failure to obtain valid informed consent or protect private data; dosing errors (wrong treatment or dose); non‑adherence to randomization; enrolling
ineligible subjects or missing primary endpoint data; or unblinding inappropriately. These deviations affect subject protection or
critical data (as listed in the FDA document). |
|
Consequences/Implications |
Regulatory action: Reporting a serious breach
obligates Member States to evaluate it. Some breaches may require corrective
actions overseen by regulators; others may trigger inspections or trial
suspension. Failure to have a proper breach‐reporting
system can itself be a GCP inspection finding. If serious breaches reveal fundamental
trial defects (e.g. safety is compromised), the trial approval or application
may be withdrawn. In summary, a serious breach can lead to heightened
regulatory scrutiny, mandatory CAPA plans, or more severe sanctions. |
Data validity risks: The FDA guidance notes that
frequent or severe important deviations can compromise a trial’s validity.
Reviewers may judge a study “not adequate and well‑controlled” if key
deviations occur (e.g. wrong enrollment or missing data). As a result, sponsors are urged to design
protocols to minimize these issues (via “quality‑by‑design”). Important deviations do not immediately
trigger FDA enforcement, but they must be documented; pervasive deviations
could lead FDA to question the reliability of submitted data. Investigators/IRBs also review important
deviations for participant safety. |
Key differences: A serious breach is a legal CT
regulation concept requiring prompt notification to EU authorities; by
contrast, an important protocol deviation is a statistical/GCP concept from
FDA/ICH guidance, focused on documenting major protocol departures in the trial
record. The EMA rule imposes timely reporting to regulators (CTIS) for
serious breaches, whereas the FDA guidance places emphasis on internal
reporting and documentation (investigator→sponsor/IRB, sponsor→study
report) rather than immediate FDA notification.
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