Bldg . 10, Room 3-2571 MSC 1206 10 Center Drive Bethesda, MD 20892 Telephone: 301-496-4251 William.Dahut@nih.gov Copy all MedWatch forms to: nciprotocolsupportoffice@mail.nih.gov 7.3.1 Reporting Pregnancy 7.3.1.1 Maternal exposure If a patient becomes p regnant during the course of the study, the study treatment should be discontinued immediately and the pregnancy reported to the Sponsor. The potential risk of 47 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential exposure of the fetus to the investigational agent(s) or chemotherapy agents (s) should be documented in box B5 of the MedWatch form “Describe Event or Problem”. Pregnancy itself is not regarded as an SAE. However, as patients who become pregnant on study risk intrauterine exposure of the fetus to agents which may be teratogenic, the CCR is requesting that pregnancy should be reported in an expedited manner as Grade 3 “Pregnancy, puerperium and perinatal conditions - Other (pregnancy) ” under the Pregnancy, puerperium and perinatal conditions SOC. Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and handled as SAEs. Elective abortions without complications should not be handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented. If any pregnancy occurs in the course of the study, then the investigator should inform the Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes aware of it. The desi gnated Sponsor representative will work with the investigator to ensure that all relevant information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies. The same timelines apply when outcome inform ation is available. 7.3.2 Paternal exposure Male patients should refrain from fathering a child or donating sperm during the study and for 4 months after the last dose of vaccine. Pregnancy of the patient’s partner is not considered to be an AE. However, the out come of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until 4 months after the last dose should, if possible, be followed up and documented. 7.4 FDA REPORTING CRITERIA 7.4.1 IND Safety Reports to the FDA (Refer to 21 CFR 312.32) The Sponsor will notify the FDA of any unexpected fatal or life -threatening suspected adverse reactions as soon as possible but no later than 7 calendar days of initial receipt of the information using the MedWatch Form 3500a. The Sponsor is also responsible for r eporting any : • suspected adverse reaction that is both serious and unexpected • any findings from clinical, epidemiological, or pooled analysis of multiple studies o r any findings from animal or in vitro testing that suggest a significant risk in humans exposed to the drug 48 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential • clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. to the FDA and to all investigators no later than 15 calendar days after determining that the information qualifies for reporting using the MedWatch Form 3500a. If FDA requests any additional data or information, the sponsor must submit it to the FDA as soon as possible, but no later than 15 calendars days after receiving the request. 7.4.2 FDA Annual Reports (Refer to 21 CFR 312.33 ) The study Sponsor will submit a brief report annually of the progress of the trial within 60 days of the anniversary date that the IND went into effect as indicated in 21CFR 312.33, and any associated FDA correspondences regarding the IND annual report. 7.4.3 Expedited Adverse Event Reporting Crite ria to the IND M anufacturer The Sponsor will notify the IND Manufacturer of any unexpected fatal or life -threatening suspected adverse reactions as soon as possible but no later than 3 calendar days of initial receipt of the information. The Sponsor will also notify the IND Manufacturer of Serious Adverse Events meeting any of the criteria defined by the bulleted list in Section 7.4.1 no later than 7 calendar days after determining that the information qualifies for reporting . A copy of the draft MedWatch Form 3500a may be used to meet these reporting requirements. Notifications will be sent to the IND Manufacturer’s Pharmacovigilance department either via email at pharmacovigilance@bavarian -nordic.com or via fax at (888) 465-1219. A listing of all other Adverse Events will be provided to the IND Manufacturer annually, e.g. via provision of a copy of the IND annual report which includes a safety summar y and Adverse Event Listings. The safety database for this study also will be shared with the IND manufacturer at the end of the study. 7.5 NIH OFFICE OF SCIENCE POLICY (OSP) /INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA 7.5.1 Serious Adverse Event Rep orts to OSP /IBC The Principal Investigator will notify OSP via email ( HGTprotocols@mail.nih.gov) and IBC of any unexpected fatal or life -threatening experience associated with the use of MVA-brachyury - TRICO M as soon as possible but in no event later than 7 calendar days of initial receipt of the information. Serious adverse events that are unexpected and associated with the use of the MVA-brachyury- TRICOM , but are not fatal or life -threatening, much be reported to NIH OSP/IBC as soon as possible, but not later than 15 calendar days after the sponsor’s initial receipt of the information. Adverse events may be reported by using the Adverse Event Reporting template available on the NIH OSP website at: http://osp.od.nih.gov/office- biotechnology- activities/biomedical-technology- assessment/hgt/gemcris or by using the FDA Form 3500a. 49 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential 7.5.2 Annual Reports to OSP /IBC The study Principal Investigator will submit to OSP via email ( HGTprotocols@mail.nih.gov) and IBC a brief report annually of the progress of the trial within 60 days of the anniversary date that the IND went into effect unless the IND sponsor has been authorized to submit this report. Within 60 days after the one-year anniversary of the date on which the investigational new drug (IND) application went into effect, and after each subsequent anniversa ry until the trial is completed, the Principal Investigator (or delegate) shall submit the information described below. Alternatively, the FDA annual report can be sent to OSP /IBC in lieu of a separate report. Please include the OSP /IBC protocol number on the annual report, and the updated clinical protocol. 7.5.2.1 Clinical Trial Information A brief summary of the status of each trial in progress and each trial completed during the previous year. The summary is required to include the following information for each trial: • the title and purpose of the trial • clinical site • the Principal Investigator • clinical protocol identifiers, including the NIH OSP/IBC protocol number, NIH grant number(s) (if applicable), and the FDA IND application number; • participant population (such as disease indication and general age group, e.g., adult or pediatric); • the total number of participants planned for inclusion in the trial; the number entered into the trial to date whose participation in the trial was completed; and the numbe r who dropped out of the trial with a brief description of the reasons • the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, or fully completed, • if the trial has been completed, a brief description of any study results. 7.5.2.2 Progress Report and Data Analysis Information obtained during the previous year's clinical and non- clinical investigations, including: • a narrative or tabular summary showing the most frequent and most serious adverse experiences by body system • a summary of all serious adverse events submitted during the past year • a summary of serious adverse events that were expected or considered to have causes not associated with the use of the gene transfer product such as disease progression or concurrent med ications • if any deaths have occurred, the number of participants who died during participation in the investigation and causes of death 50 Abbreviated Title: Phase I MVA -Brachyury -TRICOM Version Date: September 14, 2016 Confidential 7.5.2.3 a brief description of any information obtained that is pertinent to an understanding of the gene transfer product’s act ions, including, for example, information about dose- response, information from controlled trials, and information about bioavailability. 7.5.2.4 A copy of the updated clinical protocol including a technical abstract. 7.6 DATA AND SAFETY MONITORING PLAN 7.6.1 Principal I nvestigator/Research Team The clinical research team will meet on a regular basis (at least every other week) when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if appli cable will be made based on the toxi city data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator.