"vaccination of high risk breast
18. adverse events

Following consent, safety will be measured by assessment of adverse events through the duration of the study, which is approximately 16 months post first vaccination.  
a. **Adverse Event (AE):** Any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or procedure. Each AE is a unique representation of a specific event used for medical documentation and scientific analysis. *[ICH E6 1.2]*
b. **Serious Adverse Event (SAE):** Any adverse drug experience occurring at any dose that results in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization, prolongation of existing hospitalization, a persistent or significant disability/incapacity or a congenital anomaly/birth defect. Important medical events that may not result in death, be life threatening or require hospitalization may be considered a serious adverse drug experience when, based upon medical judgment, they may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. FDA requires IND sponsors to report qualified AEs and SAEs through the expedited reporting system. [21CFR312.32 (a)]  
Version 21 06/02/2022 Page 55 of 59 To avoid confusion, as the terms "serious" and "severe" are not synonymous, the following clarification is given: The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, moderate or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as severe headache). This is not the same as "serious,"
which is based on subject/event outcome or *action* usually associated with events that pose a threat to a subject's life or functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. *[ICH-E2A(II)(B)]*
c. **Related**: An event is related if more likely than not it was caused by the research activity. d. **Unexpected**: An event is unexpected when its specificity, nature, severity or incidence is not accurately reflected in the consent form, protocol, or investigator's brochure previously reviewed and approved by the IRB. Examples include a lower rate of response to treatment or a side effect that is more severe than initially expected.  
e. **Monitoring, Recording and Reporting of AEs:** All subjects will be monitored for AEs during the study. Assessments may include monitoring the subject's clinical symptoms; laboratory, pathological, radiological, or surgical findings; physical examination; or other appropriate tests and procedures.
Any condition, laboratory abnormality, or physical finding with an onset date prior to the subject signing consent for study participation is considered to be pre-existing in nature and part of the subject's medical history. All relevant historical medical conditions that are known/diagnosed prior to the administration of study vaccine are to be recorded. All AEs, which completely resolve and then recur, should be recorded as a new AE, regardless of whether it is related or not. In addition to new events, any increase in the severity or frequency of a pre-existing condition that occurs after the administration of the first vaccine is considered an AE.  
All AEs occurring during the study period must be recorded. The clinical course of each event should be followed until resolution, stabilization, or until it has been determined that the study treatment or participation is not the cause. SAEs that are still ongoing at the end of the study period must be followed for up to 30 days to determine the final outcome. Any SAE that occurs after the study period and is considered to be possibly related to the study treatment or study participation should be recorded and reported immediately to the Sponsor.  
All AEs and SAEs must be recorded in the appropriate section of the CRF. The report should include, whenever possible, the investigator's written medical judgment as to the relationship of the AE/SAE to the vaccine and/or to the study (not the chemotherapy) (i.e., "definite", "probable", "possible" or "unrelated").  
Expedited Reporting: *Any instance of a Guillain-Barre Syndrome event will require expedited* reporting *to the FDA, IRB, and IND Sponsor.*
AEs that are serious, unanticipated/unexpected, and possibly related to the vaccine qualify for expedited reporting. Any adverse experience that meets expedited reporting guidelines for SAEs must be reported immediately to the Sponsor. The CRA will follow AE reporting plans per institutional policies and applicable regulations. All qualified AEs will be reported to the Investigators, FDA, IRB, Medical Monitor, and the UAMS Office of Research Regulatory Affairs (Sponsor) according to this plan. The Sponsor will report all events that meet expedited reporting requirements to FDA in accordance with 21CFR312. All other AEs will be reported to the Sponsor and FDA in the Annual Progress Report.  
Version 21 06/02/2022 Page 56 of 59 Only AEs meeting UPIRTSO (Unanticipated Problem Involving Risks to Subjects or Others) will be reported to the UAMS IRB within the required 10-day allotment of being notified of the event.  
UPIRTSO requires that an unanticipated problem meet the following qualifications: a)
unanticipated or unexpected; b) related to the research; and c) involves new or increased risk to the subject(s). All other AEs should be recorded and reported to the UAMS IRB at continuing review.  
Deaths that are related to research will be reported to the Sponsor immediately upon Investigator notification. A death due to a terminal condition of the research participant would be considered anticipated and not related to the research and will be reported at continuing review and the Annual Progress Report.
"vaccination of high risk breast
19. clinical site monitoring

Clinical site monitoring will be conducted by the UAMS Office of Research Regulatory Affairs (ORRA) to ensure that the rights and well-being of human subjects are protected, that the reported trial data are accurate, complete, and verifiable from source documents, and that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), ICH GCP, and applicable regulatory requirements.  
Monitoring specialists from ORRA will conduct periodic on-site, comprehensive monitoring as determined by a protocol specific monitoring plan, which will be provided by the ORRA Monitoring Unit to the Investigator.
"vaccination of high risk breast
20. deviations and violations

a. Protocol Deviation: A deviation is any unintentional change, divergence, or departure from the study design or procedures defined in the protocol. Protocol deviations will be tracked and compiled in a Protocol Deviation Log. Deviations that potentially cause concern for the subject health, safety, or rights will be reported to the Sponsor as soon as possible for guidance on reporting.  
b. Protocol Violation: A violation is a change to, or non-compliance with, the IRB-approved procedures without prior Sponsor and IRB approval (excluding changes made to eliminate apparent immediate hazard to subjects). A violation may affect health, safety, or rights of a subject. Any violation will be reported immediately to the Sponsor for guidance on reporting.
If the protocol deviation/protocol violation does not represent a significant alteration in the approved protocol and/or affect the safety or welfare of the subject, it will be reported to the UAMS IRB at the time of Continuing Review. If the protocol deviation/violation represents a significant alteration in the approved protocol and/or if it affects the safety or welfare of the subject, it must be reported to the Sponsor and UAMS IRB immediately.
"vaccination of high risk breast
21. bibliography

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