Table 1. Adverse event reporting Expected Expected Unexpected Unexpected Non-Serious Serious Non-Serious Serious (including grade 4 & 5 toxicity) Attribution* (Possible, Probable, Definite) Attribution * (Possible, Probable, Definite) Attribution * (Possible, Probable, Definite) Attribution * (Possible, Probable, Definite) FHCRC – IRB Continuation Review Report Continuation Review Report Continuation Review Report FHCRC Adverse Event Expedited 7866/135 08/23/2021 Page 36 of 39 Expected Expected Unexpected Unexpected Non-Serious Serious Non-Serious Serious (including grade 4 & 5 toxicity) Attribution* (Possible, Probable, Definite) Attribution * (Possible, Probable, Definite) Attribution * (Possible, Probable, Definite) Attribution * (Possible, Probable, Definite) Reporting Form – ASAP but within 7 days FDA Annual Progress Report Annual Progress Report Annual Progress Report FDA Form 3500A – ASAP but within 7 days NCCAM Annual Review Annual Review Annual Review Notify Program Officer within 24 hours of FDA notification FDA Form 3500A – ASAP but within 7 - 15 days UW Clinical Research Center (CRC) Copy of Continuation Review Report Copy of Continuation Review Report Copy of Continuation Review Report Copy of FHCRC Adverse Event Expedited Reporting Form Medical Monitor Bi-annual Meeting (twice a year) Bi-annual Meeting (twice a year) Bi-annual Meeting (twice a year) Copy of FHCRC Adverse Event Expedited Reporting Form 6. Procedure for reporting serious adverse events: a. Identify the classification/attribution of the AE as defined above using CTCAE v4 . b. After appropriate medical intervention has been instituted, the P.I. or his/her designee will be notified within 24 hours. c. File appropriate reports immediately by phone/fax with appropriate agencies, as descri bed in Table 1. d. Notify the patient’s primary physician or referring physician within a medically appropriate timefr ame, depending on the classification of the adverse event. e. Submit written reports to appropriate agencies. f. Document the AE in the patient’s research file, using a progress note to describe the event and treatment, if appropriate. g. File copies of all forms /correspondence relating to the AE in the patient’s research file. D. Clinical trials monitoring operational procedures (Table 2) 1. Clinical data documentation a. Internal study monitoring: All patients actively enrolled in the study are seen monthly during the treatment period and one month following the final vaccine administration. Clinical labs are evaluated at baseline, before each vaccination and 1 month after the 3rd vaccine for the development of toxicity (adverse events) related to the vaccine. Any clinically significant abnormal lab values may be faxed to the patient’s physician. The Research Physician, physician extender or P.I. sees each study participant at each visit and the following evaluations are completed: toxicity evaluation, physi cal assessment and AE summary (these 7866/135 08/23/2021 Page 37 of 39 evaluations are part of the source documentation that is filled out at each visit). Grade 3 and 4 non- serious and expected AEs will be reviewed with the P.I. regularly at clinical meetings. All other AEs will be repor ted to the P.I. at the time they become known and reported as outlined above in Section C. Each patient research file is audited for completeness. Audits may be conducted by a designated clinical research staff member on an ongoing basis and the results may be presented clinical meetings. Patient’s research files are audited for completeness, legibility, and accuracy. Clinical research staff members will review all patient research files for patient recruitment and retention, protocol adherence, follow -up, data quality, and participant risk versus benefit. Additionally, correspondence with primary physicians and patients is maintained in the patient research file. Copies of email communications and of verbal communications are maintained. b. Biannual review with the independent Medical Monitor : The Medical Monitor will meet/or conference call with the P.I. or designee, and other members of the clinical team, approximately every 6 months. All patients are reviewed for AEs. Conduct of the study is review ed for any practice changes and documentation of proper notification of changes as appropriate to the IRB and FDA. c. Biannual study audit: An independent Study Monitor will be assigned by the CTSO of the FHCRC/ UW Division of Oncology and an independent stud y audit may be performed two times a year (approximately every 6 months). This audit will be conducted on a select percentage of enrolled patients. Patient research files will be formally audited for completeness, accuracy and compliance to protocol. In addition, a certain percentage of all computer data entry will also be reviewed. In addition to the routine visit of the UW IDS pharmacy, the monitor will also confirm the correct randomized product (PSK/Placebo) was dispensed to the patient. 2. Data validit y/integrity Systems to insure data integrity have been put into place to provide multiple checks to data entry. Patient eligibility is initially reviewed by the Research Coordinator/Research Nurse at screening, by the Research MD prior to enrollment in select cases, approved by the P.I. before enrollment, and biannually by the Independent Study Monitor of a certain percentage of charts. Source documents are initially reviewed by the Research Nurse and/or any clinical research staff member involved with recruitment for completeness. Clinical laboratory monitoring data is reviewed by a qualified clinician (Research MD, physician extender, Research Nurse and/or P.I.) and any abnormalities are assessed. All patients’ records are kept in the patient’s research file and reviewed at biannual monitoring visits. All toxicity scoring is done by a study clinician . Data is taken from the patient’s source documentation, the patient’s research file, and entered into a databas e which links data to patient by a Unique Patient Identifier and is accessible by password code only. Data entry is made by the Research Coordinator/designated clinical research staff member and is verified at end of study by the Research Nurse/designated clinical research staff member reviewing source documents and case report forms ; and reconciling them to the study database. A percentage of all data entry is reviewed by a clinical research team member and the Independent Study Monitor. At the time of study reports or publications , print outs of all data from the database are reviewed by the P.I. Table 2. Operational procedures Study Event Specific Action Performed By Screen Screening of interested patients Research Coordinator/physician extender/Research Nurse/other designated clinical research staff member assigned by PI Eligibility Initial review w/interested patient Research Coordinator/physician extender/Research Nurse/other designated clinical research staff member assigned by PI 7866/135 08/23/2021 Page 38 of 39 Study Event Specific Action Performed By Obtain source documents to determine eligibility Research Coordinator/Research Nurse/other designated clinical research staff member assigned by PI 2nd review of eligibility with final approval from the PI Research MD/P.I. Biannual review Independent Study and Medical Monitor s Consent Obtain Informed Consent P.I/ Research MD/physician extender Monthly Visits Blood draw/ Urine Collection Research Nurse (including nurses from CRC)/physician extender Physical assessment/toxicity evaluation P.I/ Research MD/physician extender Vaccination Research Nurse (including nurses from CRC)/physician extender Monitor for immediate reactions Research Nurse (including nurses from CRC), Study Physician Toxicity Monitoring Monitoring of AEs with patient at each visit Review of non serious and grade 2 expected AEs regularly Research MD/P.I./physician extender P.I. Biannual review of documentation of AEs Independent Study and Medical Monitor s Report of serious adverse events See sections B and C of DSMP Research Nurse/P.I./Physician Extender/Research MD/ Research Coordinator Immunologic Monitoring - Research data Performed at specified timepoints for each patient Immunologic Monitoring Lab Technologist(s) Review of immunologic data PI /Research MD Computer entry of immunologic data Research Coordinator/physician extender/other designated clinical research staff member assigned by PI Study review with P.I. Regularly scheduled meeting to report study status/evaluate eligibility, patient recruitment and retention, protocol adherence, and AE evaluations. Daily on an as needed basis for all unexpected grade 3 -5 AEs P.I./Research MD/Physician Extender/Research Nurse/Research Coordinator Study Review by Medical Monitor Biannual evaluation of patient recruitment and retention, protocol adherence, AEs and participant risk versus benefit. Medical Monitor, P.I., Research MD, Research Nurse, and Research Coordinator Twice yearly chart audits Biannual evaluation of patient recruitment and retention, protocol adherence, AEs and participant ri sk versus benefit. Validation of computer data entry from the source document. Independent Study Monitor w/ wrap up meeting with t he P.I./Study physician/physician extender/Research Nurse/Research Coordinator(s) Assurance of Data Accuracy and Integrity Validation of computer data entry for clinical data Research Nurse and Research Coordinator(s) 7866/135 08/23/2021 Page 39 of 39 Study Event Specific Action Performed By Validation of data entry for immunologic monitoring - research data Independent Study and Medical Monitor s/P.I. Annual reports to: IRB PI with Research Coordinator(s)/Research Nurse FDA PI with Research Coordinator(s)/Research Nurse CRC PI with Research Coordinator(s)/Research Nurse NCCAM PI with Research Coordinator(s)/Research Nurse