Handling site level protocol deviations

In previous post, the CDISC data structure for protocol deviations was discussed. The protocol deviation data set (DV domain) is an event data set (just like how we record the adverse event). The tabulation data set should contain one record per protocol deviation per subject. In other words, each protocol deviation is always tied to each individual subject. In DV data set, each record of the protocol deviations should have an unique identifier for subject ID (usubjid).

There are situations where the protocol deviations are on the site level, not the subject level. For example, many study protocols have a specific requirement for handling the study drugs (or IP - investigational products). The study drug must be stored under the required temperatures. An temperature excursion occurs when a time temperature sensitive pharmaceutical product is exposed to temperature outside the ranges prescribed for storage. The temperature excursion may result in inactivation of the study drug efficacy or cause safety concern. If there are multiple subjects enrolled in the problematic site, the protocol deviation associated with temperature excursion will have impact on all subjects at this site - this is called the site level protocol deviation.

There is no specific discussion about documenting and handling site level protocol deviations in ICH and CDISC guidelines.

According to CDISC SDTM, Protocol Deviations should be captured in DV domain. According to current SDTM standard, all tabulation data sets including DV are designed for subject data (with the only exception of Trial Design info).

For site level deviations, the deviations are not associated with any specific subjects, they can not be directly included in the DV data set. There may be two ways to handle the site level protocol deviations:

• Document the site level protocol deviations separately from the subject level protocol deviations. Then document them in Clinical Study Report (CSR) and in Study Data Reviewer's Guide (SDRG) if applicable.
• If any site level deviation has impact on all or multiple subjects enrolled at that site, the specific deviation can be repeated for each affected subject

It is advisable to pre-specify the instructions for handling the site level protocol deviations so that the site level protocol deviations are recorded appropriately.

Identifying and recording the protocol deviations including site level protocol deviations should be an ongoing process during the conduct of the clinical trials. If we wait until the end of the study, we may have difficulties to determine if a specific site level deviation has impact on all subjects or partial subjects at that site.