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SOP MHREC 1 Sep 2019

Published by harini, 2021-11-19 01:51:19

Description: SOP MHREC 1 Sep 2019

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Chapter 3 MHREC Monitoring Procedures BOX 3.1 The classification into major or minor protocol amendments used the following criteria:  Major protocol amendments: those that may increase risk to study participants and require fullboard review. These include but are not limited to the following:  Modification of treatment – addition or reduction of treatments  Any changes in inclusion/exclusion criteria  Change in study design  Additional treatment/s or the deletion of treatment/s  Change in method of dosage formulation, such as, oral to intravenous  Significant change in the number of subjects  Significant decrease or increase in dosage amount  Any other changes that will entail more than minimal risk.  Minor protocol amendments: those which are unlikely to compromise the integrity of the research or the welfare and rights of the participants and present no new ethical issues; and changes that are administrative in nature can be expedited, i.e.  Administrative revisions, such as correction of typing errors  Addition or deletion of non-procedural items, such as the addition/change in study personnel or changes in their address or contact number, change in laboratories, and the like.  The research activity includes only minor changes from previously approved protocol.  Minor protocol amendments that do not change the risk/ benefit assessment 3.2. Review of Progress Report 3.2.1. Purpose To describe the Medical and Health Research Ethics Committee (MHREC) Faculty of Medicine, Public Health and Nursing UGM–Dr. Sardjito General Hospital review procedures for progress report for renewal of the EC approval 3.2.2. Scope This SOP provides instructions for the review of progress reports that are required by the EC to be submitted by the principal investigator to monitor the safety of the participants enrolled in a study. This SOP applies to the conduct of any continuing review of study protocols involving human subjects at intervals appropriate to the degree of risk but not less than once a year. Depending upon the degree of risk to the participants, the nature 51

Chapter 3 MHREC Monitoring Procedures of the studies, and the vulnerability of the study participants and duration of the study, the EC may require more frequent submission of progress report. 3.2.3. Responsibility It is the responsibility of the secretariat to remind investigators to submit the progress reports 30 days before the due date, to forward the reports to the primary reviewers for review, and to communicate MHREC decision to the PI. Reminder for annual progress or final report, whichever is applicable, will be automatically send one month before the expiry of the ethical approval letter, However, in case earlier progress report for certain protocol is deemed necessary by the full-board meeting, the online system is set to earlier date. It is the responsibility of the primary reviewers to review the reports to check the completeness of the information and to ensure that it is in accordance with the protocol and related documents approved by the EC. 3.2.4. Process Flow/Steps PERSON/S TIMELINE NO ACTIVITY RESPOSIBLE Secretariat staff one month before 1. Remind investigator to due date submit progress report Secretariat staff Review of protocol progress 2. Receive the online submitted Secretariat staff reports should be progress report package and Secretariat staff, completed within check its completeness primary 10 working days reviewers when 3. Identify primary reviewers The panel’s done through 4. Forward progress report to members and expedited chair review. It may primary reviewers for review take longer for Secretariat staff, full-board review 5. Discuss the progress report The panel’s chair/ depending on the or report expedited review secretary schedule of the result in the full-board Secretariat staff full-board meeting meeting 6. Communicate decision to PI 7. Update and file the protocol and all protocol related documents 3.2.5. Detailed instructions 3.2.5.1. Remind investigator to submit progress report  The online system alert investigator on the need to submit progress/ final report 30 days before the due date 52

Chapter 3 MHREC Monitoring Procedures 3.2.5.2. Receive the online submitted progress report package and check its completeness  The secretariat staff checks the completeness of the online submitted package  The Progress Report/ Continuing Review Submission package shall include the Progress Report Form and the informed consent document currently in use  For studies of long term duration (more than 3 years), the PI and the rest of the study team are required to submit evidence of updated Good Clinical Practice (GCP) Training  The secretariat staff records the submission in the protocol database. 3.2.5.3. Determine type of review & identify primary reviewers  The progress report of protocol initially reviewed at full-board is again reviewed at full-board, progress reports that were initially reviewed by expedited review and that do not deviate from approval given by the MHREC are eligible for expedited review.  The secretariat staff identifies the primary reviewers who did the initial review.  If the primary reviewers are not available to do the review, the panel chair and/or member secretary may do the review provided they do not have COI. Otherwise the panel secretary designates qualified members to do the review 3.2.5.4. Forward progress report to primary reviewers for review  The secretariat staff sends the Progress Report package linked to all relevant documents of previous review/s of the protocol such as current versions of the protocol, informed consent forms (ICF), protocol amendments, protocol deviations and on-site SAEs/SUSARs since the last progress report/ continuing review. The linked documents serve to provide the primary reviewer/s with background information to facilitate the assessment of risk-benefit ratio.  The secretariat staff sends short message reminder to the primary reviewers  Primary reviewers conduct continuing review of progress report if they are in accordance with the protocol and related documents approved by the EC.  Primary reviewers refer to the previous approved documents to check compliance with the latest MHREC approved protocol and ICF.  In the review of the progress report, there are some key evaluation points to be considered (Box 3.2)  The EC may also request the principal investigator to provide additional information, when necessary.  The primary reviewer/s or his/ her alternate must complete the review within 10 working days.  The online system tracks the timeline of the review and, reminder will be sent on day 7th in the timeline 3.2.5.5. Discuss the progress report or report expedited review result in the full-board meeting For full-board review of progress report: 53

Chapter 3 MHREC Monitoring Procedures  The secretariat staff collates the comments of the primary reviewers and includes the application for renewal of MHREC approval in the agenda.  The protocol file folder for continuing review, including relevant MHREC meeting minutes, should be made available during the meeting.  During the meeting, the primary reviewers present a summary of the progress of the research, any significant issues and their recommendation to full-board.  The MHREC members determine the need for the investigator to elaborate, explain or clarify any aspect of the progress/annual report as deemed necessary.  The following are the possible MHREC decisions for continuing review:  o Renew approval o Request additional information o Recommend modification o Suspend: - enrollment of new subjects - research procedures in currently enrolled subjects - entire study o Disapprove renewal Approval of progress report reviewed by the primary reviewers by expedited procedure is reported to the board meeting by the panel chair/ secretary. 3.2.5.6. Communicate MHREC decision to PI  The secretariat staff takes note of the decision and/or discussion during the board meeting in the meeting minutes and communicates with the PI if further action is required.  The secretariat staff prepares Notification of MHREC Decision for progress report (Form 4.7) – Progress/Annual Report for signature of the panel’s chair.  The secretariat staff sends the notification to the PI 3.2.5.7. Update and File Protocol and all Protocol’s Related Documents i 3.2.5.8. File the protocol and all protocol related documents  Refer to Chapter 4 Section 4.5 on Management of Active Study File 54

Chapter 3 MHREC Monitoring Procedures Box 3.2  Risk Assessment i. The risks to the subjects are minimized ii. The risks to the subjects are reasonable in relation to anticipated benefits, if any, and the importance of the knowledge that may be expected to be gained from the study.  Adequacy of Informed Consent i. Informed consent/Assent forms current (most recent) ii. Appropriate, new significant findings since the last continuing review that may be related to the subjects’ willingness to continue participation provided to enrolled subjects (e.g., important toxicity or adverse event information)  Local Issues i. Changes in the investigator’s situation or qualifications (e.g., suspension of hospital privileges, medical license; involvement in numerous clinical trials) ii. Evaluation, investigation and resolution of complaints related to the research, if any iii. Changes in the acceptability of the proposed research in terms of institutional commitments (e.g., personnel and financial resources, adequacy of facilities) and regulations, applicable national law, or standards of professional conduct of practice.) iv. Report from third party observation of the research (including the informed consent process) carried out v. Investigator concerns about trial conduct at the local site (e.g., study coordinator ineffectiveness, inability of subjects to understand sections of the informed consent document required by institutional policies), if any.  Trial Progress i. Start date of the study and expected duration ii. Total subject enrollment a. Expected enrollment b. Actual enrollment c. Enrollment issues iii. Subject withdrawal a. Number of subjects who withdrew b. Lost to follow-up c. Summary of reasons for withdrawal at local site 3.3. Review of Final Report 3.3.1. Purpose To describe the Medical and Health Research Ethics Committee (MHREC) Faculty of Medicine, Public Health and Nursing, UGM – Dr. Sardjito General Hospital review procedures for final reports. 55

Chapter 3 MHREC Monitoring Procedures 3.3.2. Scope This SOP provides instructions for the review of final reports that are required by the EC to be submitted by the principal investigator when the approved study is completed or when the study site is closed. The final report when approved by the EC becomes the basis for initiation of the archiving procedure. This SOP applies to the review of final/closure report of a study protocol approved by the EC. 3.3.3. Responsibility It is the responsibility of the secretariat staffs to identify study protocols whose final reports are due. Reminder for final report will be automatically send 30 days before due date together with reminder for annual progress report, whichever is applicable. It is the responsibility of the primary reviewers to review the reports to check completeness of information and to ensure that the data are in accordance with the protocol and other related documents approved by the EC. 3.3.4. Process Flow/Steps PERSON/S TIMELINE NO ACTIVITY RESPOSIBLE Secretariat staff Review of final 1 Receive the online submitted final/ report should closure report package and check its Secretariat staff take place completeness Secretariat staff, within 10 primary reviewer working days 2 Identify primary reviewers The panel’s except when 3 Forward final/closure report to member, chair and there is a delay secretary in the due to primary reviewers for review Secretariat staff, the schedule of 4 Approved the final/closure report the panel’s chair the full-board Secretariat staff meeting during full-board meeting 5 Communicate MHREC decision to PI 6 File documents & update protocol file index and protocol database 3.3.5. Detailed instructions 3.3.5.1. Receive the online submitted final/ closure report package and check its completeness  The submission shall include the Final Report forms.  The secretariat staffs verifies the completeness of the submission 3.3.5.2. Identify primary reviewers  The secretariat staff identifies the original primary reviewers of the protocol from the protocol database.  If the primary reviewer is not available, the review is done either by the panel’s chair/ secretary, or qualified member/s designated by the panel’s secretary 56

Chapter 3 MHREC Monitoring Procedures 3.3.5.3. Forward final/closure report to primary reviewers for review  The Closure/Final Report package is forwarded to the appropriate panel, i.e. the panel of the primary reviewer  The primary reviewer/s accomplish the review by commenting and recommending appropriate action on the Closure/Final Report form.  The online system tracks the time of review to be within the timeline, i.e. 10 working days for expedited review. Reminder will be automatically send on day 7th of the timeline 3.3.5.4. Approve the final/closure report during full-board meeting  The primary reviewer presents the results of the review.  The MHREC decision can be any of the following: ▪ Acknowledged/accepted ▪ Request for further information, specify ▪ Recommend further action, specify ▪ Pending, if major clarifications are required before a decision can be made 3.3.5.5. Communicate MHREC decision to PI  The secretariat staff takes note of the decision and/or discussion during the board meeting in the meeting minutes and communicates with the PI if further action is required.  The secretariat staff prepares Notification of MHREC Decision for closure of final report – Review of Closure/Final Report for signature of the panel’s chair.  The secretariat staff sends the notification to the PI 3.3.5.6. File the protocol and all protocol related documents  Refer to Chapter 4 (4.5) on Management of Active Study File 3.4. Review of Serious Adverse Event 3.4.1. Purpose To describe the Medical and Health Research Ethics Committee (MHREC) Faculty of Medicine, Public Health and Nursing, UGM – Dr. Sardjito General Hospital review procedures for serious adverse events 3.4.2. Scope This SOP applies to the review of SAE and SUSAR reports submitted by investigators and sponsors to the MHREC to comply with ICH GCP. The MHREC reviews such reports to determine appropriate action to protect the safety of participants in an approved study. ICH-GCP E6 defines a serious adverse event (SAE) or a serious adverse drug reaction (ADR) as any untoward medical occurrence that at any dose  results in death,  is life threatening, 57

Chapter 3 MHREC Monitoring Procedures  requires hospitalization or prolongation of existing hospitalization,  results in persistent or significant disability or incapacity, or  results in a congenital anomaly or birth defect. A suspected unexpected serious adverse reaction (SUSAR) is a serious event the nature and severity of which is not consistent with the applicable product information. In the case of an unapproved investigational product, the event is not consistent with the Investigator’s Brochure (IB). In the case of a licensed product, the event is not consistent with the approved package insert or summary of product characteristics 3.4.3. Responsibility The primary responsibility of the MHREC is to conduct an appropriate review of onsite SAE and SUSAR reports to ensure oversight over the safety of participants enrolled in the study. The MHREC should also:  Make sure that researchers are made aware of its policies and procedures concerning SAE reporting.  Set up the necessary mechanisms to receive SAE and SUSAR reports from investigators of researches that it has approved.  Review SAE and SUSAR reports from other sites within and outside the country to be updated about safety issues related to the protocols that it has approved. 3.4.4. Process Flow/Steps PERSON/S TIMELINE NO ACTIVITY RESPOSIBLE Secretariat staffs 10 working 1 Receive SAE/SUSAR Report Secretariat staffs days 2 Determine type of review and Primary reviewers/ forward SAE Reports to Designated members appropriate reviewers The panel’s members, 3 Review on-site and off-site chair and secretary SAEs 4 Discuss on-site SAE reports at Secretariat staffs, chair full-board to ensure patient Secretariat staff safety 5 Communicate decision to PI 6 File the documents and update the SAE database 3.4.5. Detailed instructions 3.4.5.1. Receive SAE/SUSAR Report  The PI submit SAE/ SUSAR Report according to whether it is on-site or off- site (within or outside the country)  The secretariat staff checks submitted documents for completeness and whether Protocol Code Number and form used are correct. 58

Chapter 3 MHREC Monitoring Procedures 3.4.5.2. Determine type of review and forward SAE Reports to appropriate reviewers  On-site SAEs and SUSARs are reviewed by the primary reviewer/s or by SAE Committee or by suitable members designated by the chair/ secretary if the primary reviewer is not available to do the review.  Off-site SAEs are reviewed through expedited process by an MHREC designated member (preferably, a pharmacist or a pharmacologist) or SAE Committee to note the trends in SAE occurrence, provided these are not SUSARs.  The secretariat staff identifies the primary reviewer of the protocol and prepares the SAE Report package.  The secretariat staff forwards the SAE Report to the primary reviewer/s or designated member/s  Primary reviewer or designated member recommends appropriate action to be done by the EC. 3.4.5.3. Review on-site and off-site SAEs  The MHREC should adopt appropriate response depending on the site where the SAE/SUSAR happened.  For SAEs that occur on-site, the MHREC secretariat staffs should analyze the investigator/sponsor’s assessment (related, unexpected):  Assessment of the SAE is unlikely or unrelated to the study drug or article: the report is forwarded to the MHREC designated member for review and determination if the report should be reviewed at the convened full-board meeting.  Assessment of the SAE is definitely, possibly, or probably related to the study drug or article: the report is added to the agenda for review at a convened full-board meeting.  Assessment of the SAE is unexpected/unanticipated and definitely, possibly, or probably related to the study drug or article: the report is added to the agenda for review at a convened full-board meeting.  For multicenter, international studies, note the trend of occurrence of SAE/ SUSAR in study sites in foreign counties and other local sites. For multicenter, national studies, note the nature (related or expected) of the SAE/ SUSAR 3.4.5.4. Discuss on-site SAE reports at full-board to ensure patient safety  Primary reviewers or designated member/s present the results of review to full- board.  Full-board discusses on-site SAEs and its impact to patient safety.  After deliberation, MHREC decides on appropriate action as follows:  Request an amendment to the protocol or consent form  Request further information  Suspension of:  Enrollment of new research participants until further review by the MHREC 59

Chapter 3 MHREC Monitoring Procedures  All trial-related procedures (except those intended for the safety and well-being of the participants) until further review by the MHREC  Termination of the study  Take note and continue monitoring  Conduct Study Site Visit. Designated member reports trends in off-site SAEs for full-board information. 3.4.5.5. Communicate decision to PI  The secretariat staff prepares notification of MHREC Decision about SAE Report  Forward the notice to the PI 3.4.5.6. File the documents and update the SAE database  Record the SAE report in the SAE database to facilitate tracking of repetitive SAE of the same nature. 3.5. Review of Protocol Violation/Deviation 3.5.1. Purpose To describe the Medical and Health Research Ethics Committee (MHREC) Faculty of Medicine, Public Health and Nursing, UGM – Dr. Sardjito General Hospital review procedures for protocol violation/deviation 3.5.2. Scope This SOP provides instructions for taking action and maintaining records of various types of protocol deviation or violations:  It includes investigators who fail to comply with the procedures in the approved protocol or to comply with national/ international guidelines for the conduct of human research, including those who fail to respond to the EC’s requests.  It also covers action taken by the MHREC related to protocol violation/ deviation reports submitted by the PI related to any event at the site that is not in compliance with the protocol documents previously approved by the EC 3.5.3. Responsibility It is the responsibility of the secretariat staffs to receive protocol violation/deviation reports submitted to the MHREC. It is the responsibility of the panel’s chair, secretary and primary reviewer to take action related to protocol violation/deviation 60

Chapter 3 MHREC Monitoring Procedures 3.5.4. Process Flow/Steps PERSON/S TIMELINE NO ACTIVITY RESPOSIBLE Secretariat staff 10 working 1 Receive protocol days violation/deviation report Secretariat staff, primary reviewers 2 Forward Protocol Violation/Deviation Report to The panel’s primary reviewers members, chair and secretary 3 Discuss/report during full-board Secretariat staff, the meeting for decision/information panel’s chair Secretariat staff 4 Communicate decision to PI 5 File the documents and update the protocol deviation/violation database 3.5.5. Detailed instructions 3.5.5.1. Receive protocol violation/deviation report  Reports of protocol deviation/violation may come directly from the PI, or as result of study site monitoring by the Clinical Monitor/Sponsor or the MHREC Site Visit Team, or from related documents received by the MHREC.  The MHREC members performing monitoring of the research study at the trial site may detect protocol violation/deviation if the implementation of the research is not conducted as per approved protocol or institutional, national or international standards.  It is the responsibility of the Principal Investigator to determine whether a protocol violation/deviation is major or minor, and ensure proper reporting to MHREC. If the PI is unsure whether the variance is a violation or deviation s/he should seek advice from the sponsor to ensure appropriate action is taken.  The secretariat staff checks submitted documents for completeness and whether Protocol Code Number and form used are correct. 3.5.5.2. Forward Protocol Violation/Deviation Report to primary reviewers  Major protocol violation/deviation is a persistent protocol noncompliance with potentially serious consequences that could put patients’ safety at risk or critically affect data analysis  Minor protocol deviation is a nonsystematic protocol noncompliance with minor consequences, in terms of its effect on the participant’s/subject’s rights, safety or welfare, or the integrity of study data; includes deviations that are administrative in nature  Protocol violation in a research study should be discussed at full-board meeting.  The secretariat staff includes the Protocol Violation/Deviation Report in the meeting agenda for the month  The secretariat staffs refers the Protocol Violation/Deviation Report to the primary reviewers 61

Chapter 3 MHREC Monitoring Procedures 3.5.5.3. Forward Protocol Violation/Deviation Report to appropriate MHREC Member/s  The secretariat staffs records the report and forwards the package to the primary reviewer/s  Primary reviewer/s assess if the protocol violation/deviation impacts on patient safety or the integrity of the data.  The assigned primary reviewer/s complete their review and recommend corrective actions, if any within 10 working days after receipt.  Forward their assessment to the secretariat staffs.  The result of the review decision is reported to full-board for discussion 3.5.5.4. Discuss/report to full-board for information or appropriate action  The primary reviewers present the result of their assessment to full-board that deliberates on effects of the protocol violation/ deviation on the rights and safety or research participants or integrity of data.  Possible decisions are as follows:  Acknowledged – no further information or action required  Additional information required – additional information is needed in order to properly evaluate the violation  Correction and/or corrective actions are required. The MHREC must specify the corrective measures to prevent harm to current and future research participants  Site visit needed 3.5.5.5. Communicate decision to PI  The secretariat staff prepares notification of MHREC decision.  If correction and/or corrective action are required from the PI, the PI is requested to provide the information within 10 working days.  A site visit may also be required by the MHREC 3.5.5.6. File the Documents and Update the Protocol Deviation/ Violation Database  Record the protocol violation/deviation in the protocol violation/deviation database to facilitate tracking of repetitive violations/deviations of the same nature. 3.6. Responding to Participant’s Request/Query 3.6.1. Purpose To describe the Medical and Health Research Ethics Committee (MHREC) Faculty of Medicine, Public Health and Nursing, UGM – Dr. Sardjito General Hospital procedures related to research participants requests and/or queries 3.6.2. Scope This SOP applies to all queries and requests related to the rights and well-being of the research participants in studies approved by the EC 62

Chapter 3 MHREC Monitoring Procedures 3.6.3. Responsibility A designated member of the secretariat is responsible for receiving participant queries and requests related to their participation, refers relevant issues to the panel’s chair to take appropriate action. The secretariat keeps records of all action taken by the MHREC 3.6.4. Process Flow/Steps PERSON/S TIMELINE NO ACTIVITY RESPOSIBLE 10 working 1 Receive the complaint or injury days 2 Review the complaint/inquiry Secretariat staff The panel’s chair/ 3 Discuss in convened meeting or report the decision/action taken to full-board member/ secretary The panel’s members, 4 Communicate MHREC’s response chair and secretary 5 File the documents Secretariat, the panel’s chair/ secretary Secretariat staff 3.6.5. Detailed instructions 3.6.5.1. Receive the complaint or injury  Study protocol-related complaints and inquiries may come from research participants, or other parties.  The secretariat staff receives the complaint.  The secretariat staff may assist to put the complaint in writing especially if the complainant or inquiring party is a research participant.  The secretariat staff responds to inquiry, if it is within his/ her authority to do so or refers the complaint or inquiry to the chair/secretary for appropriate action.  The secretariat staff records the submitted document in the Log of Incoming Documents. 3.6.5.2. Review the complaint/inquiry  The panel’s chair or secretary reviews the complaint.  The PI may be contacted to provide clarification or further information 3.6.5.3. Discuss in a convened meeting or report the decision/action taken to full-board  The panel’s chair presents a serious complaint to full-board for discussion.  The panel’s members discuss to take appropriate actions 3.6.5.4. Communicate MHREC’s response  Secretariat staff prepares response to inquiry complaint within 10 working days. 3.6.5.5. File the documents 63

Chapter 3 MHREC Monitoring Procedures  The secretariat staff files the completed Form 3.7 together with the letter of inquiry/complaint and excerpts of the meeting minutes when this was deliberated or reported in the protocol file folder.  The secretariat staff updates the protocol file index 3.7. Site Visit 3.7.1. Purpose To describe Medical and Health Research Ethics Committee (MHREC) Faculty of Medicine, Public Health and Nursing, UGM – Dr. Sardjito General Hospital procedures related to the conduct of site visits 3.7.2. Scope This SOP applies to any visit made in any study site, on behalf of the EC, to check compliance with the EC’s approved protocol and related documents, and national and international standards. 3.7.3. Responsibility It is the responsibility of the EC to conduct study site monitoring for cause or routine. MHREC members may recommend that a particular study site be visited. The chair/ secretary selects members of the study site visit team. 3.7.4. Process Flow/Steps PERSON/S TIMELIN NO ACTIVITY RESPOSIBLE E MHREC members 10 working 1 Select study site to visit Chair/ secretary days 2 Create Study Site Visit Team Study site visit team 3 Prepare study site visit plan Chair/ secretary 10 working 4 Notify PI of date of site visit Study site visit team days 5 Conduct site visit and debrief MHREC Members study team 6 Present findings during full- Secretariat staff board meeting Secretariat staff 7 Communicate results of site visit and recommended actions, if any to PI 8 File the documents 3.7.5. Detailed instructions 3.7.5.1. Select study site to visit  The MHREC members may recommend to visit study sites for any of the following reasons: frequent occurrence of SAE, protocol violations, failure to submit progress reports, complaints about PI performance.  Visits may also be conducted to monitor implementation of risky protocols, PI with many ongoing studies or inexperienced PIs.  Study site visit may be conducted upon recommendation of primary reviewers 64

Chapter 3 MHREC Monitoring Procedures 3.7.5.2. Create Study Site Visit Team  The MHREC Chair/ secretary selects members of Study Site Visit Team and designates the Team Leader. Members should include the primary reviewers.  The Site Visit Team members are formally informed of their assignment.  The secretariat staff prepares the Study Site Visit package consisting of the latest version of the approved protocol and informed consent documents, and other relevant documents (like protocol deviation reports, on-site SAEs/SUSARs - initial and follow-up reports) and a copy of the Study Site Visit Report Form 3.7.5.3. Prepare Study Site Visit Plan  The Study Site Visit Team prepares the Study Site Visit Plan that includes the following:  Date and time of the planned visit  Members of the Study Site Visit Team  Objectives of the Visit  Documents to be reviewed  Persons to be interviewed  The Study Site Visit Team, in consultation with the MHREC chair, is given access to documents in the protocol file folder of a study for monitoring. The Team may also photocopy some parts of the files (like advertisement materials, the informed consent form (ICF), case report form) for comparison with the documents used in the study site 3.7.5.4. Notify PI of the date of the site visit  The secretariat staff prepares the letter informing the PI of the planned study site visit for signature by the MHREC chair. Attached to the letter is the Study Site Visit Plan and the Study Site Visit Report form 3.7.5.5. Conduct site visit and debrief study team  The Study Site Visit Team conducts the site visit as per the Study Site Visit Plan. Additional guide in the conduct of the visit is the Study Site Visit Report Form  At the end of the visit, the Study Site Visit Team presents the findings to the Study Team and solicits feedback.  The Study Site Visit Team completes the Study Site Visit Report Form  Conflicting findings should be resolved by consensus.  The report is submitted to the secretariat staff within 10 working days from the date of the visit.  The secretariat staff logs the submission in the Log of Incoming Documents.  The secretariat staff includes the presentation of the study site visit report in the meeting agenda 3.7.5.6. Present findings during full-board meeting  The Study Site Visit Team presents the report during the full-board meeting. 65

Chapter 3 MHREC Monitoring Procedures  The MHREC makes a determination whether the rights, safety and welfare of research participants are compromised and appropriate recommendations to the PI, if any 3.7.5.7. Communicate results of site visit and recommended actions, if any to PI  Based on the minutes of the meeting, the secretariat staff prepares the Notification Letter – Study Site Visit for signature of the chair.  The PI may be requested to provide additional information or documents or implement corrective actions 3.7.5.8. File pertinent documents The secretariat staff files the Study Site Visit Report, excerpt of the minutes of the meeting when report was discussed and the Notification Letter (including the response from the PI, if any) in the protocol file folder and update the protocol file index 3.8. Review of Early Protocol Termination 3.8.1. Purpose To describe the Medical and Health Research Ethics Committee (MHREC) Faculty of Medicine, Public Health and Nursing, UGM – Dr. Sardjito General Hospital procedures related to early termination of protocol implementation 3.8.2. Scope This procedure describes how the EC proceeds and manages the premature or early termination of a protocol when subject enrollment is discontinued before the scheduled end of the study. Protocols are usually terminated at the recommendation of the Data Safety Monitoring Board (DSMB), the Scientific Director, sponsor, PI, by the MHREC itself or other authorized bodies 3.8.3. Responsibility It is the responsibility of the EC to act on any early protocol termination application. It is also the responsibility of the EC to withdraw approval for any previously approved protocol when the safety or benefit of the study participants is doubtful or at risk. All applications are reviewed at full-board for appropriate action. The secretariat is responsible for the receipt and management of the termination documentation. The primary reviewers review the reasons for early termination and make a recommendation to full-board. 3.8.4. Process Flow/Steps PERSON/S TIMELINE NO ACTIVITY RESPOSIBLE 66

Chapter 3 MHREC Monitoring Procedures 1. Receive application for early study Secretariat staffs 10 working days study termination or to the next 2. Refer Notice of Early termination to Secretariat staffs, full-board meeting primary reviewers The panel’s chair/ secretary or primary 3. Deliberate decision during full- reviewers The panel’s chair and 5 working days board meeting members days 4. Communicate MHREC decision to The panel’s chair and PI secretariat staff 5. File the documents Secretariat staffs 3.8.5. Detailed instructions 3.8.5.1. Receive application or recommendation for early study termination  An application for early termination is submitted when an MHREC-approved study protocol is being recommended for termination before its scheduled completion. This is done when the rights, safety and welfare of participants are threatened or upon the request of the PI or sponsor due to operational problems.  Recommendation for early termination may come from the Sponsor, DSMB, Scientific Director, MHREC members, or other authorized bodies.  The secretariat staff receives the study protocol termination package prepared and submitted by the principal investigator and verifies whether the Protocol Code Number and form used are correct, and the completeness of the Early Study Termination Form  Check approval given by the MHREC and type of review from the protocol data base 3.8.5.2. Forward Notice of Early Termination to Primary Reviewers The secretariat staff forwards the document package to the primary reviewer/s 3.8.5.3. Review the submission  Assess the termination issues and make recommendation. The primary reviewers review the safety data. It is important for the termination package to contain a plan to follow up the participants who are still active in the study.  For submission to full-board review, the secretariat includes the review of the study for early termination in the meeting agenda. 3.8.5.4. Discuss decision during full-board meeting  The panel’s chair/ secretary deliberates on the effects of the early study termination on the safety and welfare of study participants.  Final decision of the application are as follows:  Approval  Acknowledgment  Further information required 3.8.5.5. Communicate MHREC decision to PI 67

Chapter 3 MHREC Monitoring Procedures Based on the minutes of the meeting, the secretariat staff prepares the Notification Letter – Early Study Termination for signature of the panel’s chair The PI may be requested to provide additional information or documents or implement actions to ensure the safety and welfare of subjects still active in the study 3.8.5.6. File the documents  Refer to Chapter 4 Section 4.6 on Management of Inactive Study Files 68

Chapter 3 MHREC Monitoring Procedures APPENDIX C MHREC Monitoring Procedures Form 3.1 Protocol Amendment Submission Form Form 3.2 Progress Report (Continuing Review) Submission Form Form 3.3 Closure/Final Report Submission Form Form 3.4 Onsite Serious Adverse Event Report Form 3.5 Off-site Serious Adverse Event Report Form 3.6 Protocol Violation/Deviation Report Form 3.7 Query/Complaint Record Form 3.8 Study Visit Site Report Form 3.9 Early Study Termination Application 69

Chapter 3 MHREC Monitoring Procedures FORM 3.1 PROTOCOL AMENDMENT SUBMISSION FORM To be filled up by the Principal Investigator MHREC Protocol no. : automatically assigned Sponsor Protocol no. (if : automatically assigned applicable) Submission Date : automatically assigned when the secretariat send Document Received Form Date of Initial Approval : automatically assigned Protocol Title : automatically assigned Principle Investigator : automatically assigned Items to be amended List of amendments Reasons Protocol Informed Consent Form Other documents: Upload Amended Documents: Protocol Informed Consent Others, specify: PI Signature: Date (automatically assigned) Received by MHREC Secretariat Date (automatically assigned) 70

Chapter 3 MHREC Monitoring Procedures FOR MHREC USE Assessment by Primary Reviewers: Type of amendments: ○ Major (for Full Board review) ○ Minor (for Expedited review) Does the amendment increase the risks to participants? ○ Yes ○ No Does the amendment increase the benefit to participants? ○ Yes ○ No Is there favorable benefit/risk ratio ○ No ○ Yes Comments: Decision: Date: (automatically assigned o Approved after verified by reviewer) o Minor Revision o Major Revision o Disapproved o Request additional information, i.e.: Reviewer’s Name and Signature (automatically assigned) 71

Chapter 3 MHREC Monitoring Procedures FORM 3.2 PROGRESS REPORT (CONTINUING REVIEW) SUBMISSION FORM To be filled up by the Principal Investigator MHREC Protocol no. : automatically assigned Sponsor Protocol no. (if : automatically assigned applicable) Submission Date : automatically assigned when the secretariat send Document Received Form Date of Initial Approval : automatically assigned Protocol Title : automatically assigned Principle Investigator : automatically assigned Summary of recruitment: (in number) Accrual ceiling set by EC : New participants accrued since last review : Total participants accrued since protocol began : No. of participants who are lost to follow up : No. of participants withdrawn from the study : No. of participants who experienced SAEs/ SUSARs : 1. Any amendment since the last review? (Describe briefly.) ○ No ○ Yes 2. Any change in participant population, recruitment or selection criteria since the last review? (Explain the changes.) ○ No ○ Yes 3. Any change in the Informed Consent process or documentation since the last review? (Please explain.) ○ Yes ○ No 4. Is there any new information in recent literature or similar research that may change the risk/ benefit ratio for participants in this study? (Summarize) ○ No ○ Yes 5. Any unexpected complication or side effect noted since the last review?(Summarize) ○ No ○ Yes 6. Were there protocol deviation/ violation reports? Summarize What corrective actions were taken? ○ No ○ Yes 7. Any new investigator that has been added to or removed from the research team since the last review? (Please identify them and submit the CVs of new investigators.) ○ No ○ Yes 72

Chapter 3 MHREC Monitoring Procedures 8. Are there any new collaborating sites that have been added or deleted since the last review? Please identify the sites and note the addition or deletion □ No □ Yes For MHREC USE Assessment by the primary reviewer: Yes No Comment Do the risks to the study participants remain reasonable in relation to anticipated benefits Are there new findings in the Investigator brochure or literature (e.g. important toxicity or adverse event information) that need to be included in the informed consent? Is there need to revise the ICF? Is the need to reconsent subjects enrolled in the study? Are there concerns about conduct of the research team (e.g suspension of medical license, frequents protocol violation, patients or third party complaints, etc) or institutional commitment that may affect patients safety Are there concerns about patient safety, inability to comply with the protocol, high dropout rate that affect study implementation Check the protocol file to ensure consistency of the progress report with actual reports (SAE, protocol deviation/violation, etc) submitted by the PI Decision: □ Renew approval □ Request additional information □ Recommend modification □ Suspend: □ enrollment of new subjects □ research procedures in currently enrolled subjects □ entire study □ Disapprove renewal Reviewer’s Name and Signature Date: (automatically assigned (automatically assigned) after verified by reviewer) 73

Chapter 3 MHREC Monitoring Procedures FORM 3.3 CLOSURE/ FINAL REPORT MHREC Protocol no. : automatically assigned Sponsor Protocol no. (if : automatically assigned applicable) Submission Date : automatically assigned when the secretariat send Document Received Form Date of Initial Approval : automatically assigned Protocol Title : automatically assigned Principle Investigator : automatically assigned Summary of recruitment: (in number): : Accrual ceiling set by EC : New participants accrued since last review : Total participants accrued since protocol began : No. of participants who are lost to follow up : No. of participants withdrawn from the study : No. of participants who experienced SAEs/ SUSARs : Duration of the study (months)  Informed consent form used (with version no./date) and attach most recent version: filled automatically  Amendments to the original protocol (including date of approval) filled automatically  Progress reports submitted (with date of approval): filled automatically  Summary of on site SAEs reported:  Summary of participants complaints or grievances documented regarding conduct of study:  Summary of benefits to participants:  Summary of indemnifications of study related injury (if applicable)  If terminated early, specify reason for termination:  Study objectives and summary of results: 74

Chapter 3 MHREC Monitoring Procedures MHREC USE Decision: □ Acknowledged/Accepted □ Request for further information, specify □ Recommend further action, specify □ Pending, if major clarifications are required before a decision can be made Comments: (i.e compliance with the terms of the approved protocol including post – approval review requirements and overall assessment of risks against benefits in the conduct of study) Reviewer’s Name and Signature Date: (automatically assigned (automatically assigned) after verified by reviewer) 75

Chapter 3 MHREC Monitoring Procedures FORM 3.4 ON-SITE SERIOUS ADVERSE EVENT REPORT Report No. (automatically assigned: numbered consecutively by the system - On-Site/ MHREC Protocol No.) Report Date (automatically assigned when the secretariat send Document Received Form) ○ Initial ○ Follow up (only item no. 7,8,9) 1. Patient Initials : 2. Country : 3. Date of Birth : 4. Age : 5. Sex : 6. Onset Date : 7. Describe the events: 8. Seriousness: o Patient Died o Involved or Prolonged in patient hospitalization o Involved persistent or significant disability or incapatity o Life threatening o Congenital anomaly o Other medically important condition 9. Outcome ○ resolved ○ on-going 10. Suspect Drug(s) (include generic name): 11. Daily Dose(s) : 12. Indication(s) for use : 13. Route(s) of administration : 14. Therapy dates (from/to) : 15. Therapy duration : 16. Did reaction abate after stopping drug? : ○ Yes ○ No ○ Not Applicable 17. Did reaction reappear after reintroduction: ○ Yes ○ No ○ Not Applicable 18. Concomitant drug(s) and dates of Administration (exclude those used to treat reaction): 19. Other relevant history (e.g. diagnoses, allergies, pregnancy with last menstrual period, etc): 20. Name and address of Manufacturer : 21. MFR Control No : 76

Chapter 3 MHREC Monitoring Procedures 22. Name and address of reporter (include ZIP code): 23. Date Received by manufacturer : 24. Report source : ○ Study ○ Literature ○ Health professional ○ Regulator authority ○ Other: For MHREC USE □ No □ Yes Assessment by the primary reviewer: □ No □ Yes Changes to the protocol recommended? Comments: Changes to the informed consent form recommended? Comments: Recommendation: □ Request an amendment to the protocol or the consent form □ Request further information □ Suspend enrollment of new research participant ____________ □ Suspend all trial-related procedures □ Termination of the study □ Take note and continue monitoring □ Conduct study site visit □ Others Reviewer’s Name and Signature Date: (automatically assigned (automatically assigned) after verified by reviewer) 77

Chapter 3 MHREC Monitoring Procedures MHREC Final Action (to be communicated with the PI): To be used for either On-site or Off-site SAE Report No. (automatically assigned) Report Date (automatically assigned) SAE type : □ On-site □ Off-site □ Initial □ Follow up Type of review : □ Expedited review □ Full board review Date of Meeting :_ Recommendation: □ Request an amendment to the protocol or the consent form □ Request further information □ Suspend enrollment of new research participant ____________ □ Suspend all trial-related procedures □ Termination of the study □ Take note and continue monitoring □ Conduct study site visit □ Others Comments: 78

Chapter 3 MHREC Monitoring Procedures FORM 3.5 OFF-SITE SERIOUS ADVERSE EVENT REPORT Report No. (automatically assigned: numbered consecutively by the system - Off-Site/ MHREC Protocol No.) Report Date (automatically assigned when the secretariat send Document Received Form) Seriousness of SAE : o Patient died o Involved or prolonged in patient hospitalization o Involved persistent or significant disability or incapacity o Life threatening o Congenital anomaly o Other medically important condition Country : Upload Document(s) : For MHREC USE □ No □ Yes Assessment by the SAE point person: □ No □ Yes Changes to the protocol recommended? Comments: Changes to the informed consent form recommended? Comments: Recommendation: □ Request an amendment to the protocol or the consent form □ Request further information □ Suspend enrollment of new research participant ____________ □ Suspend all trial-related procedures □ Termination of the study □ Take note and continue monitoring □ Conduct study site visit □ Others Reviewer’s Name and Signature Date: (automatically assigned (automatically assigned) after verified by reviewer) 79

Chapter 3 MHREC Monitoring Procedures FORM 3.6 PROTOCOL VIOLATION/ DEVIATION REPORT MHREC Protocol no. : automatically assigned Sponsor Protocol no. (if : automatically assigned applicable) Submission Date : automatically assigned when the secretariat send Document Received Form Date of Initial Approval : automatically assigned Protocol Title : automatically assigned Principle Investigator : automatically assigned Reported by : Description : For MHREC USE Assessment by the primary reviewer: o Major PI Deviation from the protocol o Minor PI Deviation from the protocol o Participant Non-Compliance Comments: Reviewer’s Name and Signature Date: (automatically assigned (automatically assigned) after verified by reviewer) MHREC Final Action (to be communicated with the PI): □ Acknowledged– no further information or action required □ Additional information required – additional information is needed in order to properly evaluate the violation □ Correction and/or corrective actions are required. The MHREC must specify the corrective measures to prevent harm to current and future research participants □ Site visit needed Required corrective action: Please provide further information within 10 working days. 80

Chapter 3 MHREC Monitoring Procedures Date received : FORM 3.7 Received by : QUERY/COMPLAINT RECORD Request from : : Telephone call number : Mailed letter/Date : Email/Date : Walk-in/Date/Time : Other, specify Participant’s name : Contact Address : Phone : Title of the participating study : : Starting date of participation What are requested? Action taken: Outcome : MHREC Chair/Secretary : Name/signature : Date : 81

Chapter 3 MHREC Monitoring Procedures FORM 3.8 STUDY SITE VISIT REPORT Date of the Visit : MHREC Protocol No. : Protocol Title : Principal Investigator : Phone : Sponsor : Site : Reason for site visit : Persons interviewed : Total number of expected subjects : : Total subjects enrolled : : Duration of visit hours (from …. to ….) Names of MHREC visitors 1…. 2…. etc YES NO Comments Are site facilities appropriate Is confidentiality of documents maintained (e.g. cabinets with lock and keys) Are the test articles properly kept and maintained? Are informed consent forms complete? Are approved ICF versions used? Are copes of the approved versions of the protocol documents kept in the site? Are files of all communication with the MHREC found in the site? Does the site keep copies of all communication with the MHRE in the site? Are copies of adverse event report kept? Are investigator functions properly delegated to qualified research personnel? Is there appropriate documentation of qualifications of personnel? Are all case record forms up to date? Are copies of protocol deviation/violation reports kept in the site Is there evidence of appropriate corrective action taken as recommended by the MHRC 82

Chapter 3 MHREC Monitoring Procedures Summary of findings: Recommendations: Report prepared by : Name/signature : Date : MHREC Chair/Secretary : Name/signature : Date : 83

Chapter 3 MHREC Monitoring Procedures FORM 3.9 EARLY STUDY TERMINATION APPLICATION MHREC Protocol No. : Sponsor Protocol No. : Protocol Title : Principal Investigator : Phone : Email : Institution : Sponsor : MHREC Approval Date: Date of Last Report : Starting Date : Termination Date : Total No. of Participants approved: No. enrolled : Reason for early termination: Summary of Results : Accrual data : How many have completed the study? How many are still active? Plans for Those who are still active in the study? PI Signature Date For MHREC USE Assessment by primary Reviewer (any issue related to participant safety?) Recommendations: Final MHREC Decision Date of Full Board meeting 84

Chapter 4 Meeting conduct, Documentation, and Archiving Supersedes: Previous MHREC SOPs Prepared by: Reviewed by: MHREC SOP Team MHREC Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada – Dr. Sardjito General Hospitalal Approved by: Dean of Faculty of Medicine, Public Health and Nursing, Effective date: Universitas Gadjah Mada and Director of Dr. Sardjito General Hospitalal 1 September 2019 4. Meeting Conduct, Documentation and Archiving 4.1. Preparation of Meeting Agenda 4.2. Conduct of a Full Board Meeting 4.3. Preparation of Meeting Minutes 4.4. Communicating EC Decision to PI 4.5. Management of Active Study Files 4.6. Archiving of Inactive Study Files 4.7. Maintenance of Confidentiality of Study Files and EC Documents Appendix D Form 4.1 Template of Meeting Agenda Form 4.2 Template of Meeting Minutes Form 4.3 MHREC Decision and notification for initial protocol submission, Form 4.4 MHREC Decision and notification for resubmission submission Form 4.5 MHREC Decision and notification for amandment submission Form 4.6 MHREC Decision for Progres report Form 4.7 MHREC Decision for Final report Form 4.8 Notification MHREC Decision (review of progress report) Form 4.9 Notification MHREC Decision (review of final report) Form 4.10 Template of Approval Letter Form 4.11 Template of Exemption Letter Form 4.12 Template of Amendment Approval letter Form 4.13 Template of Continuing Review Approval letter Form 4.14 Template of Document Request Form 4.15 Table of contents of protocol related documents files Form 4.16 Log of Requested MHREC Documents 85

Chapter 4 Meeting conduct, Documentation, and Archiving 4.1. Preparation of Meeting Agenda 4.1.1. Purpose To describe the procedures involved in agenda preparation before the conduct of the full board meeting of the EC 4.1.2. Scope This SOP provides instructions related the preparation of meeting agenda before a full board meeting. 4.1.3. Responsibility It is the responsibility of EC Secretariat, composed of the EC Secretariat Staff under the supervision of the Member-Secretary to prepare the meeting agenda before an EC full board meeting. 4.1.4. Process Flow/Steps PERSON(S) TIMELINE No ACTIVITY RESPONSIBLE 5 working days Panel’s Secretary 1 Prepare and finalize the meeting agenda Panel’s Secretary 2 Make arrangements for Secretariat Staff the meeting Secretariat Staff 3 Distribute notice of meeting 4 File a copy of the agenda after the meeting 4.1.5.1. 4.1.5. Detail instructions Prepare and finalize the meeting agenda  One week before the scheduled meeting date, the EC Secretariat Staff checks the submissions since the last full board meeting and prepares a list of items for review during the next full board meeting.  The EC Secretariat Staff uses the Meeting Agenda template to classify the items for review.  The EC Secretariat Staff forwards the draft meeting agenda to the EC Panel’s Secretary to review and finalize.  The EC Panel’s Secretary reviews the draft meeting agenda and makes changes, if needed, then it will be presented to the EC Panel’s Chair for approval and comments and it becomes the provisional meeting agenda. The provisional meeting agenda is presented at beginning of the full board meeting and EC members are given the chance to suggest additional items to finalize the meeting agenda.  Investigators will be invited when reviewers need to clarify protocols submitted to the Ethics Committee 4.1.5.2. Make arrangements for the meeting  EC Secretariat Staff contacts EC members to check who will be available to attend the meeting to ensure quorum. 86

Chapter 4 Meeting conduct, Documentation, and Archiving  The EC Secretariat Staff makes the necessary arrangements:  for reservation of meeting room on the scheduled meeting date and time  for snacks or meals of meeting attendees  Prepares relevant documents to be distributed to EC Members who confirmed to attend the meeting. 4.1.5.3. Distribute notice of meeting EC Secretariat Staff distributes the Notice of Meeting (with the provisional meeting agenda) together with the relevant documents for review during the meeting to REC Members within 5 working days prior to meeting date. 4.1.5.4. File a copy of the agenda after the meeting  EC Secretariat Staff takes note of changes in the provisional meeting agenda after this is presented for approval to the EC members. If there are no changes, the provisional meeting agenda becomes the final meeting agenda.  EC Secretariat Staff files a copy of the provisional meeting agenda in a folder of Meeting Agenda for the year 4.2. Conduct of a Full Board Meeting 4.2.1. Purpose To describe the procedures of Medical and Health Research Ethic Committee (MHREC) of Faculty of Medicine, Public Health and Nursing, UGM - Dr. Sardjito General Hospital when it conducts a full board meeting to review protocol submission 4.2.2. Scope This SOP describes the various steps the EC follows to review various types of protocol submissions, the types of decision and action taken as well as necessary documentation to record its proceedings. 4.2.3. Responsibility  It is the responsibility of the EC Panel’s Chair to preside over the meeting and exercise leadership to enable the EC members and EC Secretariat Staff to fulfill their designated roles in the review of protocol related documents submitted to the EC in an efficient and effective manner.  It is the responsibility of the Panel’s Secretary to ensure that quorum will be met, that the required documents needed are available, to supervise the secretariat staff taking real time minutes of the proceedings and to report the results of expedited review.  It is the responsibility of EC Members to prepare and participate in EC full board meetings to enable the EC to conduct good review and take appropriate action related to documents submitted to the EC.  It is the responsibility of the EC Secretariat Staff to prepare and make available all documents needed during the meeting and to take down minutes of the proceedings 87

Chapter 4 Meeting conduct, Documentation, and Archiving 4.2.4. Process Flow/Steps No ACTIVITY PERSON(S) RESPONSIBLE 1. Call the Meeting to order Panel’s Chair 2. Determine Quorum Panel’s secretary 3. Declare Conflict of Interest EC Members 4. Approved the minutes of the EC Members previous full board meeting and discuss business arising from the minutes 5. Approved or modify the agenda EC Members 6. Discuss and decide on protocols Primary Reviewers for initial review EC Members a. Reviewers present summary of the protocol b. Discussion of scientific issues c. Discussion of ethical issues, d. Discussion of informed consent 7. Decide on protocol document Primary Reviewers resubmission EC Members 8. Discuss and decide on major Primary Reviewers protocol amendments EC Members 9. Discuss and decide on progress Primary Reviewers reports for full board review EC Members 10. Approve final reports Primary Reviewers EC Members 11. Discuss protocol deviation/ Primary Reviewers violation reports for appropriate EC Members action 12. Reports onsite SAEs for Designated EC Member appropriate action EC Members 13. Report expedited review results Panel’s secretary 14. Report/discuss other matters for EC Panel’s Chair/Panel’s Secretary full board action/information EC Members 15. Formally close the Full Board EC Panel’s Chair Meeting 4.2.5. Detail instructions 4.2.5.1. Call the Meeting to order The Panel’s Chair declares the formal opening of the Meeting at the appointed time and place once majority of the members are present 4.2.5.2. Determine Quorum 88

Chapter 4 Meeting conduct, Documentation, and Archiving The Panel’s Secretary checks and reports if the quorum requirements are met to enable the meeting to start. EC Quorum requirements should comply with national and international requirements and as defined in these SOPs. Quorum should be maintained throughout the duration of the meeting when members are required to vote to arrive at a decision. The following should be met to constitute quorum in a full board meeting of EC:  50%+ 1 of panel membership but not less than 5  presence of medical/ scientific and non- medical/ non-scientific members  presence of non-affiliated member When reviewing clinical trials involving children or pediatric patients, a pediatrician or child development specialist shall be present during its board meeting 4.2.5.3. Declare Conflict of Interest  The Panel’s Chair asks the EC members to declare their conflict of interest related to any protocols to be discussed.  The EC members checks the agenda and declares their COI related to any protocol to be reviewed. They should be asked to leave the room during the discussion of such protocols, unless they are asked to reply to questions for clarification. Quorum should be maintained when conflicted members leave the room. They return to the room after discussion of their protocol 4.2.5.4. Approve the Minutes of the previous Full Board Meeting and discuss business arising from the Minutes  The Minutes of the previous meeting should have been sent to all members before the meeting for comments. The Chair asks the members to approve the Minutes of the last meeting and ask the members to voice out their comments, if any.  The Panel Chair also ask the members to comment about issues arising from the Minutes and the discussions are recorded in the current minutes by the Secretariat. 4.2.5.5. Approve or modify the agenda  The Panel’s Chair asks the Members to examine and approve the items in the Meeting Agenda.  EC members may suggest additional items for discussion and the meeting agenda may be modified to include additional items for discussion 4.2.5.6. Discuss and decide on protocols for initial review The list of protocols for initial review are discussed according to the following procedures: • The primary medical reviewer summarizes the protocol to enable the members to understand it. • He/she uses the assessment form to comment on the technical and ethical issues in the protocol and makes recommendations about clarification, 89

Chapter 4 Meeting conduct, Documentation, and Archiving modification or approval. He/she also comments on the qualifications of the researchers and the sites • The Panel’s Chair opens the protocol for discussion of EC members taking note of additional and contradictory comments. • The PI is called to enter the room to answer questions and clarify certain protocol related matters, after which, he/she is asked to leave the room. • The Panel’s Chair summarizes the points raised and notes different views among members that should be resolved. The Chair asks the members to vote based on the decision points in the SOPs  Approved (no further revision of the documents is required)  Minor Revision  Major Revision  Disapproved • The Non Medical/ Non Scientific Reviewer presents his/her assessment of the Patient Information Sheet and Informed Consent Form making use of the ICF Assessment Form. The comments should note the discrepancies between the protocol and the information sheet, the correct consent or assent is enclosed, and provisions for proper signatures in the form. • The Panel’s Secretary takes note of voting results, records them and includes them in the Minutes of the meeting. • Once the protocol documents are approved, the EC should agree on the frequency of continuing review 4.2.5.7. Decide on protocol document resubmission • The Secretariat includes in the Meeting Agenda resubmissions required for Major revision for full board discussion. • The Primary Reviewers check if the researchers complied with the EC requirements and recommends appropriate decision. The EC members vote to approve the resubmission. 4.2.5.8. Discuss and decide on Major Protocol Amendments • The Panel’s Secretary screens amendments to determine Major Protocol Amendments that require full board review and to ensure inclusion in the Meeting Agenda. • The Primary Reviewers review the amendment and presents their assessment to full board. • The MHREC members vote to approve the Major Amendment 4.2.5.9. Discuss and decide on Progress Reports for full board review • The EC Staff/Panel’s Secretary screens Progress Reports that require full board review to ensure inclusion in the Meeting Agenda. 90

Chapter 4 Meeting conduct, Documentation, and Archiving • The Primary Reviewers review Progress Reports and present their assessment to full board. • The EC members vote to approve the Progress Reports 4.2.5.10. Approve Final Reports • The EC Secretariat Staff submits a list of Final Reports to full board review and includes them in the Meeting Agenda. • The Primary Reviewers review Final Reports and presents their assessment to full board. • The EC members vote to approve the Final Reports 4.2.5.11. Discuss Protocol Deviation/ Violation Reports for appropriate action • The EC secretariat Staff includes all Protocol Deviation/ Violation Reports in the Meeting Agenda. • The Primary Reviewers review the Reports and present their assessment and recommendation for appropriate action to full board. • The EC members vote to take corresponding action on the Protocol Deviation/ Violation Reports 4.2.5.12. Report Onsite SAEs for appropriate action • The EC secretariat Staff prepares a list of onsite SAEs/ SUSARs and • submits them to full board for appropriate action. The Designated EC Reviewer reviews the onsite SAE/SUSAR Reports and • present their assessment and recommendation for appropriate action to full board. The MHREC members vote to take corresponding action on the Onsite SAE/ SUSAR Reports 4.2.5.13. Report Expedited Review results • The EC secretariat Staff prepares a list of all Expedited Review results approved by the Member Secretary and submits them to full board to inform the MHREC members. • MHREC Members may comment on the Report 4.2.5.14. Report/ Discuss other matters for full board action/ information • The Panel Chair/Panel’s Secretary or any EC Members may suggest items or other matters for the information or discussion by full board. • The Panel’s Chair/Panel’s Secretary or any EC Members may report queries and complaints that may need board discussion for appropriate action 4.2.5.15. Formally close the Full Board Meeting The Panel’s Chair formally closes the full board meeting after determination that all the Meeting Agenda items have been discussed 91

Chapter 4 Meeting conduct, Documentation, and Archiving 4.3. Preparation of Meeting Minutes 4.3.1. Purpose To describe procedures for the preparation and approval of the minutes of the Medical and Health Research Ethic Committee (MHREC) of Faculty of Medicine, Public Health and Nursing, UGM - Dr. Sardjito General Hospital full board meeting 4.3.2. Scope This SOP provides instructions related to the preparation of the EC full board meeting minutes and its approval by the MEC members 4.3.3. Responsibility It is the responsibility of the Secretariat, composed of the EC secretariat Staff under the supervision of the Member- Secretary, to document the conduct of the full board meeting, including the issues discussed, the decisions and recommendations made in accordance with the items in the EC meeting agenda. 4.3.4. Process Flow/Steps PERSON(S) TIMELINE No ACTIVITY RESPONSIBLE 5 working days EC Secretariat 1. Prepare template of Minutes of EC Secretariat Meeting EC Members 2. Preparation/Correction/ EC secretariat Staff Finalization of minutes of the meeting 3. Approve minutes of the meeting 4. File minutes of the meeting 4.3.5. Detail instructions 4.3.5.1. Prepare template of Minutes of Meeting • The EC secretariat Staff fills up the basic information about each protocol submission for review of the EC Meeting Minutes template with identifying information (Protocol number, title, PI, sponsor, etc.) before the meeting date. • MHREC Secretariat uses this prepared template to document the proceedings during the full board meeting. 4.3.5.2. Prepare minutes of the meeting • As the MHREC meeting proceeds, the EC Secretariat takes minutes of the meeting on real time according to the prescribed format and projects this on the multimedia screen to enable the EC Members to closely follow the proceedings, and to facilitate the recapitulation of discussion points by the EC Panel’s Chair. • The EC decisions and recommendations are collective in nature. No attribution to specific EC member is stated in the minutes. • The meeting minutes should include the following items: 92

Chapter 4 Meeting conduct, Documentation, and Archiving  Date and venue of the meeting  Member attendance  Attendance of Researchers/PI, Independent Consultant and guest or observer, if any  Presiding Officer  Time when the meeting was called to order  Status of quorum at the start of the meeting and before every decision making  Members who declared COI and the protocol concerned  Discussion of items based on the order in meeting agenda  Summary of technical and ethical discussion points and recommendations  EC decision and voting results according to decision categories, abstention and votes for disapproval with reasons given. • If the review decision (for initial and continuing reviews) is “approved”, the frequency of submission of progress report are determined. • If the review decision is disapproved, the reasons for the disapproval are stated. • If the review decision (for initial and continuing reviews) is “minor revision or major revision”, the items to be revised are identified and the type of review for the resubmission is defined. • Attach the list of submission approved through expedited review for the information of EC members. • Name and signature of the person who prepared the minutes o Name and signature of the Panel’s Secretary to indicate the contents have been verified and corrected o Name and signature of the Panel’s Chair who approved the minutes with the date of approval • The EC secretariat Staff who prepared the draft of the Meeting Minutes submits it to the Member-Secretary for correction and finalization within 3 working days from the date of the meeting. • The MHREC secretariat Staff group-e-mails the copy of the provisional meeting minutes to the MHREC Members for their review and comments within 7 days from the meeting date. The EC Members are expected to e-mail their corrections to the group. • The EC Secretariat finalizes minutes of the meeting incorporating corrections from the EC Members. • The EC Staff distributes the final version of the minutes of the meeting together with the Notice of Meeting for the next MHREC meeting 93

Chapter 4 Meeting conduct, Documentation, and Archiving 4.3.5.3. Approve minutes of the meeting • During the next full board meeting, the Chair asks the members to approve the Minutes. • The MHREC members may suggest further corrections. • The MHREC members approve the Minutes. • The Chair signs approval after the meeting 4.3.5.4. File minutes of the meeting • The MHREC Staff files approved meeting minutes in the folder for Meeting Minutes. • Excerpts of meeting minutes may be extracted and filed in specific protocol file folder, and the protocol file index is updated 4.4.Communicating MHREC Decision to PI 4.4.1. Purpose To describe the procedure for communicating Medical and Health Research Ethic Commitee (MHREC) of Faculty of Medicine, Public Health and Nursing, UGM - Dr. Sardjito General Hospital to the PI. 4.4.2. Scope This SOP provides instructions related to the preparation of MHREC communication to the PI and the management of such documents 4.4.3. Responsibility It is the responsibility of the EC Secretariat to prepare the Approval or Notification Letter to the PI to be signed by the MHREC Chair. 4.4.4. Process Flow/Steps PERSON(S) TIMELINE No ACTIVITY RESPONSIBLE 7 days EC Secretariat, Chair Prepare Notification/ Approval Letter to PI EC Staff Send Notification/ Approval Letter to PI EC Staff File Notification/ Approval Letter to PI EC Staff Update protocol database 4.4.5. Detail instructions 4.4.5.1. Prepare Notification/Certificate of Approval to PI • Based on the final version of the Meeting Minutes, the EC secretariat Staff prepares the EC communication to the PI in duplicate copies using the standard SOP template. • For the Notification Letter, the EC secretariat Staff copies the list of EC Recommendations from the meeting minutes to communicate them to the PI. • The EC Chair signs and dates the Notification/ Certificate of Approval. 94

Chapter 4 Meeting conduct, Documentation, and Archiving • All Notification/ Certificate of Approval should be ready within 7 days after the meeting date for full board or 7 days after receipt of expedited review results 4.4.5.2. Send Notification/Certificate of Approval to PI • The EC secretariat Staff informs the PI/Research Assistant that the original copy of the Notification or Certificate of Approval is ready for pick-up. • The EC secretariat Staff emails a scanned copy of the Notification/ Certificate of Approval to the PI. • EC secretariat Staff logs the Notification/ Approval in the Log of Outgoing Document when the original copies are released 4.4.5.3. File Notification/Approval Letter to PI The MHREC Staff files a duplicate copy of the Notification/ Approval Certificate in the protocol file folder and updates the Protocol File Index. 4.4.5.4. Update protocol data base The EC Staff updates the protocol data base 95

Chapter 4 Meeting conduct, Documentation, and Archiving 4.5. Management of Active Study Files 4.5.1. Purpose To describe the Medical and Health Research Ethic Committee (MHREC) of Faculty of Medicine, Public Health and Nursing, UGM - Dr. Sardjito General Hospital procedures related to the management of active study files. 4.5.2. Scope This SOP provides instructions related to the management of active study files that include protocol submissions, all documents that reflect all actions taken by the EC before completion of the study. It also provides instructions for the maintenance and storage of other EC documents that include SOPs, EC membership files, agenda and meeting minutes, relevant international and national regulations and guidelines, etc. 4.5.3. Responsibility It is the responsibility of EC Secretariat to manage all protocol submissions and documents that reflect all EC actions and organize them in an orderly manner. The EC Secretariat also manages the maintenance and storage of all EC documents and records 4.5.4. Process Flow/Steps PERSON(S) No ACTIVITY RESPONSIBLE EC secretariat Staff 1. File printout of some documents in an organized manner EC secretariat Staff 2. Update protocol related documents file folder EC secretariat Staff regularly as documents come or are produced 3. Create an electronic protocol database and update it regularly 4.5.5. Detail instructions 4.5.5.1. File printout of some documents in an organized manner. • protocol related documents Protocol related documents consist of Institution Letter, Protocol, Patient information form, Informed consent form, Advertisement, Investigator brochure, Case report forms (CRF), Tools to be used for data collection, Research team list, CVs, GCP certificates, Study budget • Printout of some documents: 1. Document receipt form 2. Protocol summary sheet 2. Assessment of reviewer 3. Approval letter keep in document folder use a unique identifier or code referred to protocol number for efficient file management and retrieval. • Study Protocols are identified using a unique identification number known as Protocol Code No. given by the MHREC as described in Chapter 2 (2.1.5.2) on Initial Review Procedures. • File in a durable binder with table of contents sheet at first page. Update the table of contents whenever a new document is filled. Stick a protocol file 96

Chapter 4 Meeting conduct, Documentation, and Archiving label (Protocol code no., title of the protocol, name of PI, sponsor on the front cover of the file binder. Stick a label with the Protocol No. and color for type of review on the side of the file binder. 4.5.5.2. Update protocol related documents file folder regularly as documents come or are produced • The MHREC Staff logs every protocol-related document received. This log should contain at least the following items: o Date/Time received o Protocol Code No. o Study Title o Principal Investigator o Initial of Person who received the document o Type of Submission (eg. Protocol for Initial Review, resubmitted Protocol, Application for Protocol Amendment, Protocol  Violation/Deviation Report, SAE Report, etc.) • o EC Action Required. The EC secretariat Staff also logs protocol and protocol-related documents when they are forwarded to EC members for review. This log should contain the following items: o Date/Time Sent o Sending Person o Mode (eg. e-mail, courier, etc.) o Receiving Person o Content of Document  o Remarks • Protocol-related documents are added to the protocol file folder on the day that they are submitted or accomplished (assessment forms, EC decision letters). The binders are kept in locked cabinets. 4.5.5.3. Create an electronic protocol database and update it regularly • Create an electronic database to contain a list of all protocols received by the EC with sufficient columns to contain all protocol related information, PI submissions and action taken by the EC from initial review to final report approval. • The Study Protocol or related document is first entered into the EC protocol database using its protocol code number, title, names of PI and sponsor, etc. • Create a secure protocol database to facilitate protocol monitoring including due dates of reports and determining active protocol status. The database should use an electronic format and password protected. It should have at least the following fields:  Protocol Code  Protocol title  Department  PI and details  Submission date  Full board or Expedited Review date  Primary Reviewers 97

Chapter 4 Meeting conduct, Documentation, and Archiving  Review decision  Full Committee review meeting date  Approval date and expiration date  Due date for progress report  Date of approval  Date of final report • The EC secretariat Staff should also maintain a back-up copy of the protocol database in an external drive that is updated every 1st day of the month, or the following day if the day falls on a non-working day. • All data keeps in server at Library building Faculty of Medicine, Public Health and Nursing UGM. 4.5.5.4. Keep other EC files that include the SOPs, Membership Files, international and national guidelines and regulations, etc. in the office cabinets and regularly update them for reference of the EC members. 4.6. Archiving of Inactive Study Files 4.6.1. Purpose To describe Medical and Health Research Ethic Committee (MHREC) of Faculty of Medicine, Public Health and Nursing, UGM - Dr. Sardjito General Hospital procedures related to archiving of terminated, inactive and completed studies 4.6.2. Scope This SOP provides instructions to the Secretariat related to requirements for archiving completed study protocols after the final report or other relevant documents have been received. 4.6.3. Responsibility It is the responsibility of EC secretariat Staff, under the supervision of the Member- Secretary, to archive in an orderly manner all protocol files that have been terminated completed or are no longer active. They are kept together in a designated place in the hospital where confidentiality and security of the documents can be maintained. 4.6.4. Process Flow/Steps PERSON(S) RESPONSIBLE TIMELINE No ACTIVITY EC Secretariat Staff 7 days 1. Identify inactive EC Secretariat Staff protocol files EC Secretariat Staff 2. Affix appropriate label to EC Secretariat Staff files for archiving & record in Database of Archived Documents 3. Transfer files to the archiving room 4. Update protocol database 4.6.5. Detail instructions 4.6.5.1. Identify inactive protocol files 98

Chapter 4 Meeting conduct, Documentation, and Archiving • Studies are considered to be completed and inactive when the closure/final report of the study has been reviewed and approved by the EC. • Studies are also classified as inactive when no further communication has been received by the EC after two years. • Studies that underwent early termination are subsequently categorized as inactive upon receipt of relevant information about termination. 4.6.5.2. Affix appropriate label to files for archiving & record in Database of Archived Documents • The EC secretariat Staff labels protocol file as inactive by attaching a orange sticker and adding the year the study is declared inactive. • The EC secretariat Staff logs the protocol number and other protocol identifiers in the Database of Archived Documents. 4.6.5.3. Transfer files to the archiving room • The EC secretariat Staff transfers the protocol file to the designated secure archive room. • As in active study files, protocol files in the secure storage cabinet for inactive studies are arranged sequentially. The storage cabinet is properly labeled with the year in the original protocol code. • Protocols are archived for at least 5 years. Archived protocols can be accessed in accordance with the SOP 4.6 on Maintaining Confidentiality of Study Files and EC Documents. • After 5 years in the archive, the protocol files may be transferred to the Faculty archive or shredded. 4.6.5.4. Update protocol database • The archiving data should be entered accordingly in the protocol database. • MHREC secretariat Staff reviews entries in the protocol data base for the protocol for archiving, to check if all fields are completely filled 4.7. Maintenance of Confidentiality of Study Files and MHREC Documents 4.7.1. Purpose Describe Medical and Health Research Ethic Committee (MHREC) of Faculty of Medicine, Public Health and Nursing, UGM - Dr. Sardjito General Hospital Procedures related to maintaining the confidentiality of the study files and other MHREC documents 4.7.2. Scope This SOP provides instructions to the EC Secretariat related to maintaining the confidentiality of all study files and documents 99

Chapter 4 Meeting conduct, Documentation, and Archiving 4.7.3. Responsibility It is the responsibility of the EC Secretariat to ensure that confidentiality is maintained in the management of all study files and records and to follow the confidentiality procedures when requests to access the files are granted 4.7.4. Process Flow/Steps PERSON(S) No ACTIVITY RESPONSIBLE EC Secretariat Staff 1 Properly manage all active and inactive EC files EC secretariat Staff 2 Receive request to access confidential files EC Secretariat Staff 3 Approve and log in requests for access and retrieval EC Secretariat Staff of documents EC Secretariat Staff 4 Supervise the use of retrieved confidential document 5 Return document to the protocol file folder 4.7.5. Detail instructions 4.7.5.1. Properly manage all active and inactive EC files. • Properly handle original documents and copies of these documents during the day-to-day operation of the EC to protect the confidentiality of study files and related documents. Proper handling also involves proper control and care in the distribution and storage of confidential documents of the EC. • Study files submitted to the EC and related documents are considered confidential, such as: Study protocols and related documents (case report forms) 4.7.5.2. Receive request to access EC confidential files • Access to EC confidential documents is subject to the following limitations: o EC members and staff with a signed Confidentiality Agreement and Conflict of Interest Disclosure can access confidential documents outside of regular protocol review access, upon request. o Non-members can access specific documents by submitting a formal request. The Secretariat will require a Confidentiality Agreement Form for Non-Members to be signed by the person making the request, and approved by the EC Chair or Vice-Chair or designated EC Member in the absence of the EC Chair. o Regulatory authorities can have full access to EC documents provided it is within their mandate (e.g. Indonesian National Agency of Drug and Food Control), and within a reasonable notice to make the files available. o The Secretariat records all transactions whenever any document of the MHREC is accessed as described above. 4.7.5.3. Receive request to access EC confidential files • A separate log is kept in the protocol folder to record access as described above. It contains the following information: o Study file code 100


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