US FDA Inspection at Clinical Investigator Site Sharing of Lessons Learned

1. US FDA Inspection at Clinical Investigator Site Sharing of Lessons Learned Presenter: Nattharat Laemlukvorakul CPO Development Quality Manager Date: 01-Mar-13

2. Pre-announced Inspection – Preliminary Info & Assistance • Clinical Investigator Site Inspection pre-announced through sponsor regulatory affairs (for non-US clinical investigator sites) • Notification Timeline – approx. 3 weeks notice in advance • Inspection Period: approx. 5 days • Administrative support: • Hotel booking • Transportation to site • Translator • Internet access at site | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

3. Inspection Preparation • Identify and Generate a list of the inspection team - Role & Responsibility • Confirmation of Inspection dates – Letter from Principal Investigator (PI) • Notify local EC and Health Authorities • Inform all relevant study team members (Sponsor and CRO) • Onsite visit preparation – Meeting with PI, staff and IRB members, training, document reviews and facilities check • Get to know the FDA inspector | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

4. Inspection Preparation – 5. Onsite Visit • Tips during interview: • Be Honest  Look confident • Answer what’s being asked • Factual answers • Inspector has their manual/instruction  check and go through all questions • It’s OK to say “I cannot remember” since the study already took place long time ago • Refer back to documents for evidence or memory recall • Don’t rush into answering • If the questions are not understandable, re-address the question again, or repeat the questions in your own words to ensure the same understanding. | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

5. Inspection Preparation – 5. Onsite Visit | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only Logistics – Inspection Room, Back-up Room and equipment

6. Inspection Preparation – 5. Onsite Visit: Facilities | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only Logistics – Inspection Room, Back-up Room and equipment

7. Inspection Preparation - 6. US FDA Inspector | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

8. INSPECTION BEGINS | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

9. US FDA Inspection – Preliminary Activities Meeting with PI and Site Staff • Questions will be addressed at the end of the day/upon PI’s availability • Any issues will be highlighted immediately • Mini-close-out at the end of each day • Agenda discussion • Protocols, Protocol Signature page, FDF, Screening/Enrollment log, Site MV Log, Visit Schedule • AE/SAE Listing, Protocol Deviation Listing and Concomitant Medication Listing used at site or by the monitor • IRB Approval letters • CSR Line Listing Copies of Documents requested | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

10. US FDA Inspection – Interview Questions PI and Site Staff • How was the training during Investigator Meeting? What was trained? • Who gave you the training of the study? • Who do you contact when there are issues? • How often does the monitor come to the site? • Study specific procedures – who does what? • What is the unblindingprocedure? • Who has access to eCRF and study specific systems? • Investigational Medicinal Product (IMP) Management – explain who does what and storage location • IMP Return from patients – any problems? • Lab technicians – what were their involvement with Investigational Medicinal Products management? | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

11. US FDA Inspection – Interview Questions CRA and Sponsor • Monitoring Frequency • # of Patient Screened, # of Screen failures, # of Completed Patients, # of re-screened Patients, # of SAEs • Visit Window • Vendors used in the study – e.g. Monitoring, IXRS, IMP Supply • Double Enrollment – same patient but enrolled into 2 sites • Transfer of data from different systems to clinical Database • Training of eCRFCompletion | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

12. US FDA Inspection – Review of Source Data VS. Clinical Study Report Line Listing Process & Document Review • ICF Dates and Process • Eligibility Criteria from all sources (e.g. OPD cards) • Lab Results – all • Study procedure/examination results (e.g. ECG, MRI) • AE/SAE cases • Concomitant Medication Protocol Deviations Review Paper-based Review • List of impacted patients • Review of Dates – • Date of deviation • Amendment approval dates • ICF approval dates • Visit Dates • ICF re-consented dates • IRB/IEC Notification dates | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

13. US FDA Inspection – Investigational Medicinal Product (IMP) Management • Document Review: • Monitoring Log • Temperature Log • IMP Accountability Log “Do not do shaded area on the log  bad copy when photocopying” “Comment box should be bigger, and empty space at the end of the page should be smaller” • IMP Inventory Log • Identify the total # of shipments, IMPs arrived, dispensed and returned • Verification ofIVRS Fax vsDrug Accountability Log vsOPD Cards vsDrug Dispensing Log • Each patient, Date Dispensed and Date Returned , Medication no. and its dosage | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

14. US FDA Inspection – Finding and Discussion points Failure to obtain an updated Informed Consent prior to implementing a change in the protocol • General Discussion • Proof-read protocol (error or ambiguous language) – both sponsor & PI • Amendment – No implementation until IRB approval given • Compliance to visit window (especially safety visits) • Monitoring should be more robust – monitors must be on top of the study – understanding all site issues and closely follow-up with all issues • IMP Inventory – Total no. of IMPs received ≠ Total no. of IMPs returned for destruction • Late re-consenting | Presentation Title | Presenter Name | Date | Subject | Business Use Only

15. US FDA Inspection – Lessons Learned • FDA inspector working style and expertise • “What is done cannot be undone” – make it correct at the first time • Great inspection team coordination is the key • PI/Study Nurse/CRA must be well prepared for interview. Be confident, precise, and accurate in your answers. Ensure there is a good collaborative relationship. • Full oversight of the study, understand your role and responsibilities • Clear, accurate, comprehensive documentation is critical (e.g. OPD cards) • Good document filing management (Site Files) • Sites must understand their existing issues, identify root causes and address the corrective actions promptly | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

16. After US FDA Inspection The following types of letters is typically sent from the FDA  INV • A letter - FDA observed basic compliance with pertinent regulations. The letter might not be sent when FDA observes no significant deviations. • An “Informational or Untitled Letter” – deviations from statutes and regulations that do not meet the threshold of regulatory significance for a Warning Letter. A response from INV is normally required. • A “Warning Letter” – Serious deviations to statutes and regulations (may lead to enforcement action if not promptly and adequately corrected). Request for correction and a written response. • A Notice of Initiation of Disqualification Proceeding and Opportunity to Explain – may disqualify the INV from receiving IMP | US FDA Inspection | Nattharat Laemlukvorakul | 01-Mar-13 | Business Use Only

17. | Presentation Title | Presenter Name | Date | Subject | Business Use Only