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.
"To avoid confusion over terminology, sponsors are encouraged to replace the phrase “protocol violation” in Annex IVa with “protocol deviation”,
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.
- 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- Those who developed withdrawal criteria during the study but were not withdrawn.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.
The FDA Office of Scientific Investigations (OSI) requests that the items described in the draft guidance for industry Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER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 majorOne 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:
trials used to support safety and efficacy in the application (i.e., phase 2/3 pivotal trials).
"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"
• 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
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.
ICH E9 Addendum also discussed the per-protocol set (PPS) and analyses based on PPS are included as supplemental analysis: