September 19 , 2018 Page | 71 Protocol Version 8.0. September 19 , 2018 Page | 72 11.6 BMS Guidelines for Adverse Event Reporting • All Serious Adverse Events (SAEs) that occur following the subject’s written consent to participate in the study through 90 days of discontinuation of dosing must be reported to BMS Worldwide Safety. • If the BMS safety address is not included in the protocol document (e.g. multicenter studies where events are reported centrally), the procedure for safety reporting must be reviewed/approved by the BMS Protocol Manager. Procedures for such repor ting must be reviewed and approved by BMS prior to study activation. • The BMS SAE form should be used to report SAEs. If the BMS form cannot be used, another acceptable form (i.e CIOMS or Medwatch) must be reviewed and approved by BMS. The BMS protocol ID number must be included on whatever form is submitted by the Sponsor/Investigator. • Following the subject’s written consent to participate in the study, all SAEs, whether related or not related to study drug, are collected, including those thought to be associated with protocol -specified procedures. The investigator should report any SAE occurring after these time periods that is believed to be related to study drug or protocol-specified procedure. • • In accordance with local regulations, BMS will noti fy investigators of all reported SAEs that are suspected (related to the investigational product) and unexpected (i.e., not previously described in the IB). In the European Union (EU), an event meeting these criteria is termed a Suspected, Unexpected Serio us Adverse Reaction (SUSAR). Investigator notification of these events will be in the form of an expedited safety report (ESR). o Other important findings which may be reported by the as an ESR include: increased frequency of a clinically significant expected SAE, an SAE considered associated with study procedures that could modify the conduct of the study, lack of efficacy that poses significant hazard to study subjects, clinically significant safety finding from a nonclinical (eg, animal) study, important safety recommendations from a study data monitoring committee, or sponsor decision to end or temporarily halt a clinical study for safety reasons. o Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the IB. Where required by local regulations or when there is a central IRB/IEC for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will determine if the Protocol Version 8.0. September 19 , 2018 Page | 73 informed consent requires revision. The investigator should also comply wit h the IRB/IEC procedures for reporting any other safety information. o In addition, suspected serious adverse reactions (whether expected or unexpected) shall be reported by BMS to the relevant competent health authorities in all concerned countries accordi ng to local regulations (either as expedited and/or in aggregate reports). Serious Adverse Event Collection and Reporting Following the subject’s written consent to participate in the study, all SAEs, whether related or not related to study drug, must be collected, including those thought to be associated with protocol- specified procedures. All SAEs must be collected that occur within 90 days of discontinuation of dosing. All SAEs must be collected that occur during the screening period. If applicable, SAE s must be collected that relate to any protocol -specified procedure (eg, a follow -up skin biopsy). The investigator should report any SAE that occurs after these time periods that is believed to be related to study drug or protocol-specified procedure. SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies on a Pregnancy Surveillance Form. SAE Email Address: Worldwide.Safety@BMS.com SAE Fac simile Number: 609-818-3804 If only limited information is initially available, follow -up reports are required. (Note: Follow-up SAE reports should include the same investigator term(s) initially reported.) If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes available, a follow -up SAE report should be sent within 24 hours to the BMS (or designee) using the same procedure used for transmitting the initial SAE report. All SAEs should be followed to resolution or stabilization. The Sponsor/Investigator will ensure that all SAEs in the clinical database are reported to BMS and any applicable health authority during the conduct of the study including periodic reconciliation. For studies conducted under an Investigator IND in the US include the following timelines or text: For studies conducted under an Investigator IND in the US, any event that is both serious and unexpected must be reported to the Food and Drug Administration (FDA) as soon as possible and no later than 7 days (for a death or life -threatening event) or 15 days (for all other SAEs) after the investigator’s or institution’s initial receipt of the information. BMS will be provided with a simultaneous copy of all adverse events filed with the FDA. Protocol Version 8.0. September 19 , 2018 Page | 74 SAEs should be reported on MedWatch Form 3500A, which can be accessed at: http://www.accessdata.fda.gov/scripts/medwatch/. MedWatch SAE forms should be sent to the FDA at: MEDWATCH 5600 Fishers Lane Rockville, MD 20852-9787 Fax: 1 -800- FDA -0178 (1 -800-332-0178) http://www.accessdata.fda.gov/scripts/medwatch/ All SAEs should simultaneously be faxed or e- mailed to BMS at: Global Pharmacovigilance & Epidemiology Bristol-Myers Squibb Company Fax Number: 609-818-3804 Email: Worldwide.safety@bms.com • An SAE report should be completed for any event where doubt exists regarding its seriousness. • For studies with long -term follow -up periods in w hich safety data are being reported, include the timing of SAE collection in the protocol. • If the investigator believes that an SAE is not related to study drug, but is potentially related to the conditions of the study (such as withdrawal of previous ther apy or a complication of a study procedure), the relationship should be specified in the narrative section of the SAE Report Form. • If only limited information is initially available, follow -up reports are required. (Note: Follow- up SAE reports should include the same investigator term(s) initially reported.) • If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes available, a follow -up SAE report should be sent within 24 hours to BMS using the same procedure us ed for transmitting the initial SAE report. All SAEs should be followed to resolution or stabilization. All SAEs should be followed to resolution or stabilization. DEFINITIONS The protocol must include a definition for Serious Adverse Events (SAE) SERIOUS ADVERSE EVENTS Protocol Version 8.0. September 19 , 2018 Page | 75 A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: • results in death • is life -threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe) • requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE below) • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • is an important medical event (defined as a medical event(s) that may not be immediately life -threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or m ay require intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.) • Potential drug induced liver injury (DILI) is also considered an important medical event. • Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study drug is an SAE. • Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these events must be handled as SAEs. NOTE : (PI - determines if this information should be included. This is provided as supplemental information that is included in BMS-sponsored trials) The following hospitalizations are not considered SAEs in BMS clinical studies: − a visit to the emergency room or other hospital department < 24 hours, that does not result in admission (unless considered an im portant medical or life -threatening event) − elective surgery, planned prior to signing consent − admissions as per protocol for a planned medical/surgical procedure − routine health assessment requiring admission for baseline/trending of health status (eg, routine colonoscopy) − Medical/surgical admission other than to remedy ill health and planned prior to entry into the study. Appropriate documentation is required in these cases − Admission encountered for another life circumstance that carries no bearing on healt h status and requires no medical/surgical intervention (eg, lack of housing, Protocol Version 8.0.