Table 1.

Protocol deviation classification and categorization examples

Category	Protocol deviation classification examples
	Important	Non-important	Not a protocol deviation
Informed consent	• Clinical study procedures conducted prior to obtaining initial informed consent • New clinical study procedures performed before participant was re-consented • Re-consent containing updated risk language or important safety information not signed	• If required by local regulation or IRB/EC, participant did not initial all pages	• Administrative items such as: participant did not use requested date format, participant did not sign on requested line, etc
Inclusion/exclusion	• Participant entered the clinical study without satisfying entry criteria
Study intervention	• Participant received wrong study treatment • Participant received the incorrect dose unit, route of administration, and/or inaccurate frequency of administration or expired product • Participant was non-compliant with study medication/treatment (e.g., above or below protocol-specified threshold, overdose) • Participant received and took study medication which underwent a temperature excursion and was deemed unacceptable for use	• Participant was dispensed study medication which underwent a temperature excursion and was not taken or was taken but deemed acceptable prior to use • Stratification error/missed stratification	• Investigational product underwent a temperature excursion but was never dispensed to a participant • NOTE: May be considered a GCP issue for resolution outside of PD process • Investigational product had a temperature excursion which was determined to be within acceptable range before it was provided to a participant
Prohibited concomitant medication	• Participant took an excluded concomitant medication during the clinical study • Participant took a specific class of medication within X days before a specific procedure [outside the window, taking the medication may be considered non-important]	• Instructional text for windows of analysis in the protocol may result in non-important deviations • Participant took a single dose of a class of medication [repeated use may be considered important]
Trial procedures	• Missed safety or efficacy assessments related to primary or key secondary endpoints • Key safety or efficacy endpoint data collected on equipment which was not properly calibrated at protocol defined time points • Specific personnel for key or critical protocol specific procedures did not complete specific training (e.g., in a neuroscience therapy area, the rater was not trained on how to assess a key study endpoint)	• Procedures not directly related to participant safety (e.g., outcomes research) • Repeat efficacy measures not performed after predefined endpoints • Missed procedures that have no impact on reliability of study results (e.g., exploratory analysis) • Missed laboratory measurements that are not part of key or critical safety or efficacy endpoints • Non-critical procedures performed out of a specified window • Failure to calibrate equipment relating to non-key safety or efficacy endpoints, at protocol defined time points	• Anticipated quantity of lab collection kits not on-site • Not calibrating a piece of equipment on a day it was not used to obtain participant data • Training of CRAs or other sponsor personnel • Note: In general, training is not a PD. It is an issue that does need corrective action and appropriate follow-up
Safety reporting	• Serious Adverse Events (SAEs) or Pregnancy not reported within required reporting timeframe (e.g. 24 h from awareness) • Events of Special Interest (e.g., potential drug induced liver injury [DILI], Hy's Law, major adverse cardiac event) not reported within protocol specified timeframe	• Non-serious AEs (NSAEs) not reported within predefined protocol timelines	• Site appropriately reported an SAE. Later, the sponsor data management team asked for the SAE to be split and recorded as multiple events. The time stamp of the new data entry made it appear that the site was delayed, but they were not
Discontinuation	• Participant developed withdrawal criteria during the clinical study but was not withdrawn • Participant developed withdrawal criteria for study treatment but was not withdrawn from study treatment

This table offers examples of PD classification and categorization to guide stakeholders in defining important and non-important PDs including ICH E3 Guideline examples. This list is not intended to be all-inclusive or exhaustive. All users are responsible for ensuring compliance with relevant laws and regulations