Friday, July 03, 2015

Protocol Deviation versus Protocol Violation and its Classifications (minor, major, critical, important)

Every clinical trial will have a study protocol. The investigator is required to follow the study protocol to conduct the study. However, during the clinical trial, there will always be planned or unplanned deviations from the protocol. ICH GCP requires that these protocol deviations are documented. ICH E6 (section 4.5.3) states “the investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol.” At the end of the study, statistical analysis will include a listing for all protocol deviations and a summary table for protocol deviations by category.

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

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