I have previously discussed the protocol deviation issues in clinical trials.
- Inclusion/exclusion violations, protocol deviations, protocol deviation waiver, rescreening, and others
- Protocol Deviation versus Protocol Violation and its Classifications (minor, major, critical, important)
After the study, when a clinical study report (CSR) is prepared, there should be a section to describe the protocol deviations. ICH guideline E3 STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS stated the following:
Protocol deviations also have an impact on the statistical analysis side. Protocol deviation will not result in excluding the subjects from full analysis set (usually the intention-to-treat population), however, the important protocol deviations may result in subjects being excluded from the per-protocol population. For pivotal studies, analyses using the per-protocol population will always be performed as one type of sensitivity analyses to evaluate the robustness of the study results.
If the results from the main analyses (usually based on intention-to-treatment population) are negative, the analyses on the per-protocol population may not be very meaningful. If the results from the main study are positive, the analyses on the per-protocol population will be important. If there are a lot of protocol deviations in a study, it may trigger the regulatory reviewer’s scrutiny and damp the confidence about the study results.
The CDISC’s CDASH (the guidelines for case report form design) and SDTM (the guidelines for standardized tabulation data structure) have the detail discussions about the protocol deviations. While violation of inclusion/exclusion criteria (or study entry criteria or eligibility criteria) may also be considered as part of the protocol deviations, the CDISC discussions are only for protocol deviations occurred after the study start (subjects randomized into the study and/or received the first dose of the study drug). Violation of Inclusion/exclusion should be collected separately in IE form (domain).
CDASH recommends identifying the protocol deviation (DV domain) through other sources, not from the case report form. It stated:
5.14.1 Considerations Regarding Usage of a Protocol Deviations CRF
The general recommendation is to avoid the creation of a Protocol Deviations CRF (individual sponsors can determine whether it is needed for their particular company), as this information can usually be determined from other sources or derived from other data. As with all domains, Highly Recommended fields are included only if the domain is used. The DV domain table was developed as a guide that clinical teams could use for designing a Protocol Deviations CRF and study database should they choose to do so.
In practice, the protocol deviations are usually collected and maintained by the clinical team either in CTMS (clinical trial management system) or excel spreadsheet even though there are examples (maybe the future trend) of collecting the protocol deviations through the electronic data capture (EDC).
If the sponsor decides to use a case report form (paper or electronic) to capture the protocol deviations, CDASH recommends the following:
If a sponsor decides to use a Protocol Deviations CRF, the sponsor should not rely on this CRF as the only source of protocol deviation information for a study. Rather, they should also utilize monitoring, data review and programming tools to assess whether there were protocol deviations in the study that may affect the usefulness of the datasets for analysis of efficacy and safety.
SDTM requires a protocol deviation (DV) domain for tabulation data set (dv.xpt) no matter how the original protocol deviation data is collected.
In ADAM, whether or not creating an analysis data set for protocol deviation is up to each individual's decision. It is not required. If a summary table for protocol deviation is needed, it can be programmed from the SDTM DV data set and ADAM ADSL data set.