Protocol Deviations - How is the Protocol Deviation Data Analyzed and Used?

For any clinical trial, the study protocol is the blueprint of how the clinical trial should be conducted. Clinical study protocols must be conducted according to the International Council for Harmonization (ICH) guidance on good clinical practice (GCP), which, among other things, helps safeguard the rights, safety, and well-being of study participants. If conducted as designed, the associated data should be reliable and reproducible and support clear interpretation of the results, while maintaining the participants’ protection. In light of this, one might reasonably assume that deviations from this protocol could be harmful to the participant or the accuracy of the data and should therefore be avoided.

However, the reality is that within clinical trials, protocol deviations do happen, despite best efforts in designing and conducting the clinical trial. According to the ICH E3 Q&A R1, the protocol deviation is defined as: 

"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."

In the early days, the term 'protocol violation' may be used and is still used in some clinical trial documents. According to the ICH E3 Q&A R1, the term 'protocol violation' should be replaced with 'protocol deviation'

"To avoid confusion over terminology, sponsors are encouraged to replace the phrase “protocol violation” in Annex IVa with “protocol deviation”,

There is considerable variability regarding the interpretation, and classification of what an important protocol deviation is, which creates challenges in the identification, collection, and reporting of deviations - resulting in over-reporting PDs that could potentially delay the identification of important patient safety information by increasing the noise in the system or under-reporting PDs that could influence the reliability of the study results and patient safety signals.

In order to reduce the variability in what, when, how the PDs should be collected, it might be helpful to take a look at how the data about the PDs are analyzed and used. 

After the protocol deviation data is collected, the data will be mapped into the CDISC data sets (DV data set in SDTM and ADDV data set in ADaM). Then a data listing will be generated to list all protocol deviations by subjects including the date the protocol deviation occurred, the description of the protocol deviation, the category of the protocol deviation (out of visit window, informed consent issue, SAE safety reporting issue, ......), and the classification of the protocol deviations (minor, major, critical, or important).  A statistical summary table will then be generated for all protocol deviations and for major protocol deviations. 

The protocol deviation data will then be used in the following aspects: 

For the clinical study report (CSR):

CSR must include a section to describe the protocol deviations that occurred during the conduct of the study. According to  ICH E3 (Structure and Content of Clinical Study Reports), the protocol deviations section is an essential part of the CSR. 

10.2 Protocol Deviations 

All important deviations related to study inclusion or exclusion criteria, conduct of the trial, patient managements or patient assessment should be described. 

In the body of the text, protocol deviations should be appropriately summarized by center 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 center for multicenter studies. 

For FDA BIMO of NDA/BLA submission under Center for Drug Evaluation and Research (CDER):

The FDA Office of Scientific Investigations (OSI) requests that the by-site data and listing are provided for Bioresearch Monitoring (BIMO). The by-site data is used by OSI to select the investigational sites for inspections for CDER submissions.

The FDA Office of Scientific Investigations (OSI) requests that the items described in the draft guidance for industry Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions (February 2018) and the associated Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications be provided to facilitate development of clinical investigator and sponsor/monitor/CRO inspection assignments, and the background packages that are sent with those assignments to the FDA ORA investigators who conduct those inspections. This information is requested for all major
trials used to support safety and efficacy in the application (i.e., phase 2/3 pivotal trials).

One critical piece of the BIMO data is the protocol deviation data by site. The number of protocol deviations or important protocol deviations can be an indicator of protocol compliance and the study quality for specific investigational sites. According to BIORESEARCH MONITORINGTECHNICAL CONFORMANCE GUIDE Technical Specifications Document", the following protocol deviation data should be provided:

"Subject-level data line listings, by clinical site, should include consented subjects, treatment assignment, discontinuations, study population, inclusion and exclusion criteria, adverse events, important protocol deviations, efficacy endpoints, concomitant medications, and safety monitoring, as further described below"

7. Important Protocol Deviations Contains Nonbinding Recommendations 

This by-subject, by-clinical site listing should include all protocol deviations. The listing should include a description of the deviation and identify whether the sponsor considered the deviation to be an important or non-important protocol deviation.  

Clinical Site Data Elements Summary Listing

"Total number of important protocol deviations at a given site by treatment arm for subjects in the SAFPOP. A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the protocol or associated investigational plans that is not implemented or intended as a systematic change. This value should include multiple deviations per subject and all major deviation types. Important deviations are those deviations that might significantly affect the completeness, accuracy, and/or reliability of the study data or that might significantly affect a subject's rights, safety, or well-being"

"Total number of protocol deviations, excluding important protocol deviations, at a given site by treatment arm for subjects in the SAFPOP. A protocol deviation is any change, divergence, or departure from the study design or procedures defined in the protocol or associated investigational plans that is not implemented or intended as a systematic change."

FDA's Good Review Practice: Clinical Review Template listed the protocol violation information as part of the review items for assessing the GCP compliance and the impact of the protocol violations on the data quality and the safety and efficacy results. 

3.2 Compliance With Good Clinical Practices

This section should include comments on compliance with good clinical practices, including informed consent, protocol violations, site-specific issues, and whether the clinical trials were conducted in accordance with acceptable ethical standards. 

If a DSI audit process and report is not requested, provide a brief summary on the quality and nature of other methods used to audit or check the applicant’s data and/or analyses. 

For DSI-requested audits, include a brief summary of the rationale for DSI audits and site selection such as: 

• A specific safety concern at a particular site based on review of adverse events, serious adverse events, deaths, or discontinuation 

• A specific efficacy concern based on review of site-specific efficacy data

 • A specific concern for scientific misconduct at one or more particular sites based on review of financial disclosures, protocol violations, clinical trial discontinuations, or safety and efficacy results  

For defining the per-protocol population for Sensitivity or Supplemental Analyses

Efficacy analyses are usually performed in full analysis set or intention-to-treat population. However, to test the robustness of the statistical results and to assess the impact of the protocol deviations on the statistical results, additional sensitivity or supplemental analyses are usually performed on the per-protocol population. 

According to ICH E9 (Statistical Principles for Clinical Trials), the per-protocol population is defined and sensitivity analyses based on per-protocol population are suggested:  

Per protocol set (valid cases, efficacy sample, evaluable subjects sample): The set of data generated by the subset of subjects who complied with the protocol sufficiently to ensure that these data would be likely to exhibit the effects of treatment according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements, and absence of major protocol violations.

In practice, the per-protocol population is usually defined as "all randomized subjects who have no major protocol deviations" or "all randomized subjects who have no major protocol deviations that may have an impact on the efficacy assessment". The decision on the inclusion of subjects in per-protocol population needs to be decided before the database lock and study unblinding. The protocol deviation data may be reviewed at the blinded data review meeting. Subjects who are excluded from the per-protocol population need to be documented in the blinded data review report.

ICH E9 Addendum also discussed the per-protocol set (PPS) and analyses based on PPS are included as supplemental analysis: 

The meaning and role of an analysis of the per protocol set is also re-visited in this addendum; in particular whether the need to explore the impact of protocol violations and deviations can be addressed in a way that is less biased and more interpretable than naïve analysis of the per protocol set

Section 5.2.3. indicates that it is usually appropriate to plan for analyses based on both the FAS and the Per Protocol Set (PPS) so that differences between them can be the subject of explicit discussion and interpretation.

Additional Reference: Transcelerate Protocol Deviations