Regulatory Affairs Officer 4. Review by Sponsor/Investigator if need for FDA and Med Watch UNRELATED Annual Progress Report/Continuing Review APPENDIX L Adverse Event Reporting Algorithm CONFIDENTIAL Page 94 of 102 Protocol: HERCEPTIN® + E75/GM-CSF Version 3.1 ML25749 05 March 2017 APPENDIX M FDA MedWatch 3500A Form Link http://www.fda.gov/downloads/Safety/MedWatch/DownloadForms/ucm082728.pdf CONFIDENTIAL Page 95 of 102 Protocol: HERCEPTIN® + E75/GM-CSF Version 3.1 ML25749 05 March 2017 APPENDIX N SAFETY LANGUAGE INCLUDED IN THIS DOCUMENT IS MANDATORY AND MUST BE INCLUDED IN PROTOCOL SAFETY REPORTING OF ADVERSE EVENTS ASSESSMENT OF SAFETY Specification of Safety Variables Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious adverse events (SAEs) that are considered related to {study drug}, all events of death, and any study specific issue of concern. Adverse Events An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. This includes the following: AEs not previously observed in the subject that emerge during the protocol-specified AE reporting period, including signs or symptoms associated with breast cancer that were not present prior to the AE reporting period. Complications that occur as a result of protocol-mandated interventions (e.g., invasive procedures such as cardiac catheterizations). If applicable, AEs that occur prior to assignment of study treatment associated with medication washout, no treatment run-in, or other protocol-mandated intervention. Preexisting medical conditions (other than the condition being studied) judged by the investigator to have worsened in severity or frequency or changed in character during the protocol-specified AE reporting period. Serious Adverse Events An AE should be classified as an SAE if the following criteria are met: It results in death (i.e., the AE actually causes or leads to death). It is life threatening (i.e., the AE, in the view of the investigator, places the subject at immediate risk of death. It does not include an AE that, had it occurred in a more severe form, might have caused death.). It requires or prolongs inpatient hospitalization. It results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the subject’s ability to conduct normal life functions). It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP. It is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the subject or may require medical/surgical intervention to prevent one of the outcomes listed above). METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported during the study, are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports). CONFIDENTIAL Page 96 of 102 Protocol: HERCEPTIN® + E75/GM-CSF Version 3.1 ML25749 05 March 2017 Adverse Event Reporting Period The study period during which all AEs and SAEs must be reported begins after informed consent is obtained and initiation of study treatment and ends 30 days following the last administration of study treatment or study discontinuation/termination, whichever is earlier. After this period, investigators should only report SAEs that are attributed to prior study treatment. Assessment of Adverse Events All AEs and SAEs whether volunteered by the subject, discovered by study personnel during questioning, or detected through physical examination, laboratory test, or other means will be reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected relationship to the {study drug} (see following guidance), and actions taken. To ensure consistency of AE and SAE causality assessments, investigators should apply the following general guideline: Yes There is a plausible temporal relationship between the onset of the AE and administration of the {study drug}, and the AE cannot be readily explained by the subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to the {study drug}; and/or the AE abates or resolves upon discontinuation of the {study drug} or dose reduction and, if applicable, reappears upon re-challenge. No Evidence exists that the AE has an etiology other than the {study drug} (e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal relationship to {study drug} administration (e.g., cancer diagnosed 2 days after first dose of study drug). Expected adverse events are those adverse events that are listed or characterized in the Package Insert or current Investigator Brochure. Unexpected adverse events are those not listed in the Package Insert (P.I.) or current Investigator Brochure (I.B.) or not identified. This includes adverse events for which the specificity or severity is not consistent with the description in the P.I. or I.B. For example, under this definition, hepatic necrosis would be unexpected if the P.I. or I.B.