6.3 T OXICITY CRITERIA The following adverse event management guidelines are intended to ensure the safety of each patient while on study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used to report AE s.All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 ). 7 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 7.1 D EFINITIONS 7.1.1 Adverse Event An adverse event is defined as any reaction, side effect, or untoward event that occurs during the course of the clinical trial associated with the use of a drug in humans, whether or not the event is considered related to the treatment or clinically significant. For this study, AEs will include events reported by the patient, as well as clinically significant abnormal findings on physical examination or laboratory evaluation. A new illness, sympt om, sign or clinically significant laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an AE. All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until satisfactory resolution. AEs should be reported up to 30 days following the last dose of study drug. An abnormal laboratory value will be considered an AE if the laboratory abnormality is characterized by any of the following: • Results in d iscontinuation from the study • Is associated with clinical signs or symptoms • Requires treatment or any other therapeutic intervention • Is associated with death or another serious adverse event, including hospitalization. • Is judged by the Investigator to be of significant clinical impact • If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient’s outcome. 7.1.2 Suspected adverse reaction Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 44 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug. 7.1.3 Unexpected adverse reaction An adverse event or suspected adv erse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application. "Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation. 7.1.4 Serious An unanticipated problem or p rotocol deviation is serious if it meets the definition of a serious adverse event or if it compromises the safety, welfare or rights of subjects or others. 7.1.5 Serious Adverse Event An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following: • Death, • A life -threatening adverse drug experience • Inpatient hospitalization or prolongation of existing hospitalization • Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions • 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 appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 7.1.6 Disability A substantial disruption of a person’s ability to conduct normal life functions. 7.1.7 Life-Thre atening Adverse Drug Exper ience Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the investigator or sponsor , at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death. 45 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential 7.1.8 Protocol Deviation (NIH Definition) Any change, divergence, or departure from the IRB -approved research protocol. 7.1.9 Non-compliance (NIH Definition) The failure to comply with applicable NIH Human Research Protection s Program ( HRPP ) policies, IRB requirements, or regulatory requirements for the protection of human research subjects . 7.1.10 Unanticipated Problem Any incident , experience, or outcome that: • Is unexpected in terms of nature, severity, or frequency in relatio n to (a) the research risks that are described in the IRB -approved research protocol and informed consent document; Investigator’s Brochure or other study documents, and (b) the characteristics of the subject population being studied; AND • Is related or po ssibly related to participation in the research; AND • Suggests that the research places subjects or others at a g reater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized. 7.2 NCI-IRB REPORTING 7.2.1 NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths The Protocol PI will report to the NCI -IRB: • All deaths, except deaths due to progressive disease • All protocol deviations • All unanticipated proble ms • All non- compliance Reports must be received by the NCI -IRB within 7 working days of PI awareness via iRIS. 7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review The protocol PI will report to the NCI- IRB: 1. A summary of all protocol deviations in a tabular format to include the date the deviation occurred, a brief description of the deviation and any corrective action. 46 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential 2. A summary of any instances of non -compliance 3. A tabular summary of the following adverse events: • All Grade 2 unexpected events that are possibly, probably or definitely related to the research; • All Grade 3 and 4 events that are possibly, probably or definitely related to the research; • All Grade 5 events regardless of attribution; • All serious ev ents regardless of attribution. NOTE : Grade 1 events are not required to be reported. 7.2.3 NCI-IRB Reporting of IND Safety Reports Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to the NCI IRB. 7.3 IND SPONSOR REPORTING CRITERIA An investigator must immediately report to the sponsor, using t he mandatory Med Watch form 3500a, any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug c aused the event . Study endpoints that are serious adverse events (e.g. all- cause mortality ) must be reported in accordance with the protocol unless there is evidence suggesting a causal relation ship between the drug and the event ( e.g. death from anaphylaxis). In that case, the investigator must immediately report the death to the sponsor. Events will be submitted to Dr. William Dahut, authorized representative for the IND Sponsor (CCR) at: William Dahut, M.D.