1. RIHES-II: H ANDLING A UDITS AND I NSPECTIONS E FFECTIVE D ATE 25 D ECEMBER 2006 V ERSION : 3.0 บุญเหลือ พรึงลำภู 15 มกราคม 2557

2. Purpose: Provides procedures to be followed when RIHES research is audited by the sponsor or sponsor’s representative, by the United States Food and Drug Administration (U.S. FDA) or by other regulatory authorities. วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.02

3. Applies to: All internationally-funded RIHES projects, researchers participating in those projects, and particularly to projects carried out under New Drug Applications. วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.03

4. Definitions: Good Clinical Practice. A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentially of trial subjects are protected. Non-Compliance: (GCP 5.20.1) with the protocol, SOP, GCP and /or applicable regulatory requirements by an investigator/institution will lead to prompt action that can be as severe as terminating the investigator/institution participation in the trial. วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.04

5. 4.3 Monitoring ( การกำกับดูแล ): (GCP 5.18) the purpose of trial monitoring are to: 4.3.1 verify that the rights and wellbeing of human subjects are protected 4.3.2 the reported trial data are accurate, complete and verifiable from source documents 4.3.3 the conduct of the trial is in compliance with the currently approved protocol/amendments, GCP and applicable regulatory requirements 4.3.4 Monitor: the monitor is appointed by the sponsor 4.3.5 Monitors at RIHES include PPD, MSD Inc. and other sponsor appointed monitors วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.05

6. 4.4 Audit( การตรวจสอบ ): (GCP 5.19) independent audits are separate from routine monitoring or quality control/quality assurance and is conducted to evaluate compliance with the protocol, SOP, GCP and applicable regulations 4.4.1 Auditors are independent of the trial/systems and auditor qualifications should be documented 4.4.2 sponsor ensures the auditing is in compliance with sponsor SOP 4.4.3 audit plan is guided by the importance of the trial, type and complexity 4.4.4 all observations/findings are documented 4.4.5 regulatory authorities do not request audit reports but can request these reports on the basis of serious GCP or protocol non-compliance. 4.4.6 When required by law, the sponsor can require an auditors certificate 4.4.7 Possible auditors of NIH studies at RIHES are the United States Food and Drug Administration (FDA), the Thai FDA, the Thai Ministry of Public Health วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.06

7. 4.5 Quality Management Plan (QMP) 4.5.1 Sponsor approved site quality management plan to ensure continual quality monitoring in addition to periodic sponsor appointed monitoring and independent auditing 4.5.2 Frequency and intensity of regulatory, clinical and safety monitoring is protocol specific and detailed in the QMP. 4.6 Monitoring Log: Daily record of monitor and auditor visits to the site. Maintained in the Regulatory Compliance Unit with monitoring records. Must be signed by the monitor and counter signed by at least one RIHES staff who met with the monitor/auditor on that date. วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.07

8. Procedures 1.Pre-monitoring/audit 2.On the day(s) of the monitoring/audit 3.After the Monitoring/Audit 4. Monitoring/audit Report 5.Non-compliance/significant findings 6.Protocol Close Out วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.08

9. Procedures 1.Pre-monitoring/audit The monitor or auditor will contact the PI in writing ~ 10 days prior to the audit to explain the audit process/requirements and confirm the audit date. When a RIHES PI or other staff receive a letter announcing or confirming monitoring/audit, the official will immediately inform: 1. RIHES Director 2. Project staffs 3. RCU 4. Related Unit staffs at RIHES If necessary, the SC and/or RCU head will convene a meeting to prepare for the monitoring/audit and review past reports – QA records for chart review and regulatory files will be reviewed to ensure all outstanding issues have been resolved – RCU staffs will conduct a targeted QA if necessary Work space will be provided for the monitoring/auditor(s) in the RCU. Access to a fax machine email and outside telephone line will be provided upon request. วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.09

10. Procedures 2. On the day(s) of the monitoring/audit – all requested records and other materials will be available for the monitoring/auditor in the designated workspace. – Only the items intended to be reviewed will be presented upon request. – This will usually include IRB/EC Approval(s), documentation and SOPs concerning the informed consent process, investigational drug dispensing records, and other documentation about the conduct of the trial (Title 21 CFR, Part 312.57-312.68). วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.010

11. Procedures Monitoring/Audit Process at the site: An initial interview with the PI, SC and any other applicable site personnel will be conducted to determine the level of control the PI maintained over the study, delegation of authority, and general procedures the site had in place for subject safety and to control and maintain data integrity and validity. – The monitor/auditor will review the schedule and requirements of the visit. Each unit will be informed of the schedule in advance. – The PI, investigators and/or SC will give a study status report and inform the monitor/auditor of any issues – The monitor/auditor is required to sign the monitoring log daily. This must be verified with RIHES staff signature. Essential documents reviewed – Copies made will be duplicated and/or logged and signed by the monitor/auditor and RIHES staff. These duplicates and/or logs will be kept with monitoring/audit records at RCU – each unit will be notified prior to monitoring/audit of the scheduled visit to the unit The monitor/auditor will first review regulatory and essential documents at RCU วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.011

12. Procedures The monitor/auditor will then proceed to review clinical charts with the SC or designee and clinic staff - Source Data Verification (SDV) may be performed on a random sample of subject case report forms (CRFs) to assess the validity and reliability of data captured. The auditor will request that all records provided are original documents. - Monitoring of all or a random sample of signed and dated ICF will be conducted to confirm that all subjects signed and dated the consent prior to study procedures being performed, and that the appropriate version of the ICF, approved by the IRB/EC was used. The monitor/auditor will assess if additional versions exist apart from the original IRB/IEC approved ICF. - A review of the study Adverse Events (AE), Serious Adverse Events (SAE) and Expedited Adverse Event (DAIDS EAE) วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.012

13. Procedures Discussions with the site pharmacist (if applicable), and a review of study drug storage, dispensing, and accountability procedures and documentation will be conducted. A review of the site laboratory facilities (if applicable) to assess their ability to perform the required protocol procedures will be conducted. วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.013

14. Procedures Exit Interview an exit interview will be conducted with the PI, SC, RCU and any applicable site staff to address the monitoring/audit findings and to summarize the overall monitoring/audit results. Any significant and/or critical monitoring/audit observations should be discussed with the PI at the close of the visit. These must be documented Meeting rosters are kept on site with a copy given to the monitor/auditor If the monitor/auditor requests the PI to sign any documents, they must first be reviewed by the SC and/or relevant study staff. A copy must be left at the site. วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.014

15. Procedures 3. After the Monitoring/Audit Once the monitoring/audit is over, the RCU will coordinate with the PI and study team to ensure that answers are obtained to any unresolved questions that the monitor/auditor had, and communicated in writing to the monitor/auditor and/or his office, as per the monitor/auditor’s request. If the monitor/auditor contacts study staff after leaving the site, this must be documented by email with a copy sent to: 1. PI; 2. SC; 3. RCU. วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.015

16. Procedures 4.Monitoring/audit Report – Monitoring/audit Report: (GCP5.18.6) A written report will be submitted to the sponsor and will include a summary of what the monitor/auditor reviewed and the monitor’s/auditor’s statements concerning significant findings, deviations, conclusions and actions taken and/or recommended.. the sponsor will contact the PI with the report and request clarifications and explanations of any reported findings. a copy of the monitoring report should be sent to the RCU to be filed with essential documents The RCU will coordinate any requested/necessary response to the monitoring/audit report which will be verified by the PI before being sent to the sponsor วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.016

17. Procedures 5. Non-compliance/significant findings – Non-compliance/significant findings: (GCP 5.20) any report of non-compliance and/or significant findings or deviations must be reported immediately to the PI and RIHES director. 6.Protocol Close Out If the protocol is no longer open to accrual or if significant members of the original team have left, attempts will be made to contact those individuals to participate in the preparation for the monitoring/audit and to be present on the days of the monitoring/audit itself, if possible. If any documents or patient charts form the study have been placed in storage, the RIHES Secretary’s Office will arrange to retrieve them from storage วันพุธที่ 15 มกราคม พ. ศ. 2557 RIHES-II Version 3.017