Wake Forest School of Medicine

Wake Forest School of Medicine Guidance Document on Protocol Deviations

Purpose As outlined in the Wake Forest School of Medicine HRPP policies, investigators are responsible for conducting research in accordance with the IRB-approved protocol, HRPP Policies and Procedures, and applicable federal and state regulations. The purpose of this guidance document is to provide guidance to investigators for circumstances in which events, actions, or activities associated with the conduct or oversight of a human subject research study do not follow and/or comply with the protocol, HRPP Policies and Procedures, or federal and state regulations.

Please note that planned changes to a protocol should always be submitted to the IRB as a protocol amendment and should be approved prior to implementation, unless the changes are necessary to eliminate apparent immediate hazards to the human subjects [(DHHS 45 CFR § 46.103(b)(4); (FDA 21 CFR § 56.108(a)(4)]. Failure to do so will cause a protocol deviation, and may result in administrative actions, up to and including suspension of the study.

Definitions: Protocol Deviation: Any event, action, or activity associated with the conduct or oversight of a human subject research study that diverges from those described in the IRB approved protocol and/or fails to comply with IRB Policies and procedures, Federal agency regulations, or other applicable regulatory policies governing such research, regardless of whether or not it causes harm of any kind to research subjects, increases the risk of harm, or otherwise negatively impacts their safety, rights, welfare, or privacy.

Unanticipated Problem: Any event, action, or activity related to the conduct or oversight of a human subject research study - not articulated in the study protocol or consent or expected as a consequence of the natural history of a disease under study - that causes physical, psychological, economic, or social harm to a human subject; increases the risk of harm of any kind; or otherwise compromises subject's safety, rights, welfare, or privacy. Please note that many protocol deviations are not unanticipated problems (UAPs) and that not all UAPs are protocol deviations.

Serious Noncompliance: Any single protocol deviation that causes, or a series of repeated protocol deviations that increases the risk of harm of any kind to a research subject; adversely affects subjects' safety, rights, welfare, or privacy; or compromises the scientific integrity of the study

Corrective Action Plan: A written document which acknowledges that a protocol deviation and/or unanticipated problem has occurred, provides an analysis of the factors that led to its occurrence, and outlines the steps which will be taken to prevent a re-occurrence in the future.

1/9/12 When and how should a PI report a protocol deviation to the IRB? Protocol deviations that meet the definition of an unanticipated problem or serious noncompliance must be reported to the IRB within 7 days of the time at which the investigator or other member of the study team first became aware of the event. Reports should be submitted via eIRB using the Safety Event reporting process. All reports must include a corrective action plan outlining the safeguards/steps that have been taken to prevent the deviation from recurring.

Protocol deviations that do not meet the definition of an unanticipated problem or serious noncompliance should be entered into a Protocol Deviation Log and submitted to the IRB at the time of annual continuing review. A Protocol Deviation Log template is available on the Monitoring and Oversight website (http://www.wakehealth.edu/IC_Office-of-Research/Human- Research-Oversight.htm). If the study sponsor provides a study-specific deviation log, then this log may be used to record deviations. All studies, regardless of funding, should maintain a Protocol Deviation Log.

Examples of deviations reportable to the IRB within 7 days: This list of examples is intended as a guide and is not-all inclusive:  Failure to obtain informed consent  Changes made to the protocol taken without prior IRB review to prevent an apparent immediate hazard to a subject  Conducting human subjects research without IRB approval  Recruiting subjects, conducting study interventions, or collecting data after IRB approval has expired  Enrollment of a subject who does not meet eligibility criteria (e.g. enrolling a subject with decreased renal function in a trial in which decreased function is exclusionary because the drug may be nephrotoxic)  Prior failure to report protocol deviations or unanticipated problems per institutional policy  Conducting a study visit outside of the protocol window that, in the opinion of the investigator, affects subject safety or data integrity.  Performing study procedures not outlined in the IRB approved protocol  Failure to perform a required test that, in the opinion of the investigator, may affect subject safety or data integrity. (e.g. missed CBC for an oncology study in which a known side effect of the drug is neutropenia)  Study medication errors  Enrollment of a subject from a federally defined “vulnerable population,” i.e. children, prisoners, pregnant women and fetuses, without prior IRB approval

Examples of deviations that should be recorded on a Protocol Deviation Log and reported to the IRB at continuing review: This list of examples is intended as a guide and is not-all inclusive:  Failure to initial the bottom page(s) of the consent form

1/9/12  Conducting a study visit outside of the protocol window that, in the opinion of the investigator, does not affect subject safety or data integrity  Obtaining blood samples at times close to but not precisely at the time points specified in the protocol  Failure to perform a required test that, in the opinion of the investigator, does not affect subject safety or data integrity (ex. Temperature not obtained from subject. Study does not involve treatment of infections, and the investigational product has no known affect on the body’s immune system.)  Conducting a study procedure out of sequence that does not affect subject safety or data integrity  Failure to complete a QOL survey  Failure of subject to return unused study drug  Failure to complete a subject diary card  Failure to show up for a study appointment that results in missing a visit or procedure that, in the opinion of the investigator, does not affect subject safety or data integrity (Missed urinalysis, questionnaire, etc.)

How can the study team avoid protocol deviations? While many deviations may be outside of the study team’s control, the recommendations below can help prevent or reduce the likelihood of protocol deviations occurring during the conduct of the study.  Ensure that each member of the study team is familiar with both the protocol, and his/her specific study related tasks. Every study should establish a site Signature and Responsibility Log that clearly outlines each study team member’s delegated tasks. A template log is available on the Monitoring and Oversight website under “Study Management Tools.” (http://www.wakehealth.edu/IC_Office-of-Research/Human- Research-Oversight.htm).  Submit study amendments to the IRB in a timely fashion for review before planned or anticipated changes are implemented.  Add all key study personnel to the IRB application for approval before authorizing them to perform any study-related activities.  Consider withdrawing a subject from the study if subject-specific deviations become too numerous or too severe/extensive for the subject’s safety or data validity.

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