Across various regulatory guidelines, both terms ‘protocol deviations’ and
‘protocol violations’ are used. What is the difference between a protocol
deviation and a protocol violation?
For a while, there seems to be a thinking that the protocol deviation is
less serious non-compliance and the protocol violation is more serious
non-compliance of the protocol. However, the recent documents from the
regulatory bodies suggest that both terms are the same and can be used
interchangeably. In practice, it will not be wrong if we stick to the term ‘protocol
deviation’ and avoid using the term ‘protocol violation’.
In FDA’s “Compliance
Program Guidance Manual For FDA Staff - Compliance Program 7348.811 Bioresearch
Monitoring: Clinical Investigators” in 2008. It provided a definition for ‘protocol
deviation’, however, the term ‘protocol deviation/violation’ was lumped
together and did not draw a clear distinction between protocol deviation and
protocol violation.
“Protocol deviations. A protocol deviation/violation is generally an unplanned excursion from the protocol that is not implemented or intended as a systematic change. A protocol deviation could be a limited prospective exception to the protocol (e.g. agreement between sponsor and investigator to enroll a single subject who does not meet all inclusion/exclusion criteria). Like protocol amendments, deviations initiated by the clinical investigator must be reviewed and approved by the IRB and the sponsor prior to implementation, unless the change is necessary to eliminate apparent immediate hazards to the human subjects (21 CFR 312.66), or to protect the life or physical wellbeing of the subject (21 CFR 812.35(a)(2)), and generally communicated to FDA. “Protocol deviation” is also used to refer to any other, unplanned, instance(s) of protocol noncompliance. For example, situations in which the investigator failed to perform tests or examinations as required by the protocol or failures on the part of study subjects to complete scheduled visits as required by the protocol, would be considered protocol deviations.”
In ICH E3
Guideline: Structure
and Content of Clinical Study Reports Questions & Answers in 2012, both
‘protocol deviation’ and ‘protocol violation’ were used. The document suggested
protocol violation is equivalent to important protocol deviation. In other
words, the protocol violation is a subset of all 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. The E3 Guideline provides examples of the types of deviations that are generally considered important protocol deviations and that should be described in Section 10.2 and included in the listing in Appendix 16.2.2. The definition of important protocol deviations for a particular trial is determined in part by study design, the critical procedures, study data, subject protections described in the protocol, and the planned analyses of study data. In keeping with the flexibility of the Guideline, sponsors may amend or add to the examples of important deviations provided in E3 in consideration of a trial’s requirements. Substantial additions or changes should be clearly described for the reviewer.
When protocol deviations are
documented, they are also classified into categories according to the severity
and their effect on the subject’s rights, safety, or welfare, or on the
integrity of the resultant data.
ICH E3 “STRUCTURE
AND CONTENT OF CLINICAL STUDY REPORTS” requires the important protocol
deviation to be described. It does not use the categories of critical, major,
or minor. However the descriptions In Section 10.2 suggests the important protocol
deviations are those with major or critical categories. Section 10.2 stated:All important deviations related to study inclusion or exclusion criteria, conduct of the trial, patient management or patient assessment should be described. In the body of the text, protocol deviations should be appropriately summarised by centre and grouped into different categories, such as:
− those who entered the study even though they did not satisfy the entry criteria;
− those who developed withdrawal criteria during the study but were not withdrawn;
− those who received the wrong treatment or incorrect dose;
− those who received an excluded concomitant treatment.
In appendix 16.2.2, individual patients with these protocol deviations should be listed, broken down by centre for multicentre studies.
In US, while there is no formal guidance, the
protocol deviations are usually classified as major or minor categories. For
example, in a FDA presentation about “Avoiding
Common Mistakes in Clinical Research”, the protocol deviation spectrum
contains minor (a missed lab test, a missed visit) and major (ineligible subject enrolled, safety or efficacy assessments
not done, did not report SAE to IRB • • • •).
In EU, EMA guidance “Classification
and analysis of the GCP inspection findings of GCP inspections conducted at the
request of the CHMP”, the protocol deviations are classified as Critical, Major, and Minor categories.
Critical: - Conditions, practices or processes that adversely
affect the rights, safety or well-being of the subjects and/or the quality
and integrity of data.
- Critical observations are
considered totally unacceptable.
- Possible consequences: rejection of data and/or legal
action required.
- Remarks: observations classified as
critical may include a pattern of deviations classified as major, bad quality
of the data and/or absence of source documents. Manipulation and intentional
misrepresentation of data belong to this group.
• Major: - Conditions,
practices or processes that might adversely affect the rights, safety or
well-being of the subjects and/or the quality and integrity of data.
- Major observations are serious
findings and are direct violations of GCP principles.
- Possible consequences: data may be
rejected and/or legal action required.
- Remarks:
observations classified as major, may include a pattern of deviations
and/or numerous minor observations.
•Minor: - Conditions,
practices or processes that would not be expected to adversely affect the
right, safety or well-being of the subjects and/or the quality and integrity of
data.
- Possible consequences: observations
classified as minor, indicate the need for improvement of conditions, practices
and processes.
- Remarks:
many minor observations might indicate a bad quality and the sum might
be equal
to a major finding with its consequences.
In practice, the critical and major protocol deviations may
be grouped together. At least this is how it is done in our of NIH studies. See
Protocol
Deviations CRF Module Instructions
Protocol Deviation Discussion at Firstclinical.com:
-
Protocol Deviations Discussion 1
- Protocol Deviations and Clinical Study Reports-2
- Investigator Submission of Protocol Deviations to IRB
- Prospective Protocol Waivers
- Bringing Method to the Madness: Protocol Deviation & Violation Codes
- Protocol Deviation Versus GCP Violation
- Reporting Protocol Violations to the FDA
- Question regarding Informed Consent and Major Protocol Deviations
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