Monitoring and Special Considerations for Multi-Center Trials

1. Monitoring and Special Considerations for Multi-Center Trials September 10, 2010 Pav Aujla, MS, CCRP, RAC Primo N. Lara, Jr. MD A Translational Innovation Forum

2. Agenda • Basic principles of: • Investigator’s Responsibilities • Sponsor’s Responsibilities • Monitor’s Responsibilities • “Sponsor – Investigator’s” Responsibilities • Investigator-Initiated Trials (IITs) • Investigator-Initiated Multi-Center Trials

3. Agenda • Types of Monitoring Visits: • Study Initiation Visit (SIV) • Periodic Monitoring Visits • Study Termination/Closeout (COV)

4. Agenda • Understand safety reporting, record retention, and FDA regulations, among other important elements

5. International Conference of Harmonization for Good Clinical Practice (E6) • A common approach to clinical research • Represents a “passport” to global use of clinical trial data • Establishes common definitions and reporting guidelines for adverse events

6. 1. Glossary 2. Principles of GCP 3. IEC/IRB Responsibilities 4. Investigator’s Responsibilities 5. Sponsor’s Responsibilities 6. Protocols and Amendments 7. Investigator’s Brochure 8. Essential Documents International Conference of Harmonization for Good Clinical Practice (E6)

7. What are GCPs? Good Clinical Practices are the ethical, scientific and regulatory standards for conducting research involving human subjects. Essential Elements • Data Integrity • Patient rights and safety

8. Is GCP training available at UCDHS? Yes, there is a GCP online training program on the CITI training site CITI homepage: http://www.citiprogram.org

9. ICH GCP Section 4Investigator • 4.1 Investigator’s Qualifications and Agreements • 4.2 Adequate Resources • 4.3 Medical Care of Trial Subjects • 4.4 Communication with IRB • 4.5 Compliance with Protocol • 4.6 Investigational Product(s) • 4.7 Randomization Procedures and Unblinding • 4.8 Informed Consent of Trial Subjects • 4.9 Records and Reports • 4.10 Progress Reports • 4.11 Safety Reporting • 4.12 Premature Termination or Suspension of a Trial • 4.13 Final Report(s) by Investigator

10. Investigator’s Responsibilities • 4.1 Investigator’s qualifications and agreements • Education, Training, Experience • Be familiar with protocol and IB • 4.2 Adequate resources • Do you have the time? • Staff and facilities • Can you recruit patients under the recruitment period? • 4.4 Medical care of subjects • Medical decisions • Adverse events

11. Investigator’s Responsibilities • 4.4 Communication with IRB • 4.5 Protocol compliance • 4.6 Investigational product(s) • Inventory, records (dates, quantities, batch/serial numbers, expiration date)

12. Investigator’s Responsibilities • 4.8 Informed consent of trial subjects • 4.9 Records and reports • 4.11 Safety reporting

13. ICH GCP Section 5Sponsor • 5.1 Quality Assurance and Quality Control • 5.2 Contract Research Organization (CRO) • 5.3 Medical Expertise • 5.4 Trial Design • 5.5 Trial Management, Data Handling, and Record Keeping • 5.6 Investigator Selection • 5.7 Allocation of Responsibilities • 5.8 Compensation to Subjects and Investigators • 5.9 Financing • 5.10 Notification/Submission to Regulatory Authority(ies) • 5.11 Confirmation of Review by IRB • 5.12 Information on Investigational Product(s) • 5.13 Manufacturing, Packaging, Labeling, and Coding Investigational Product(s)

14. ICH GCP Section 5Sponsor • 5.14 Supplying and Handling Investigational Product(s) • 5.15 Record Access • 5.16 Safety Information • 5.17 Adverse Drug Reaction Reporting • 5.18 Monitoring • 5.18.1 Purpose • 5.18.2 Selection and Qualifications of Monitors • 5.18.3 Extent and nature of Monitoring • 5.18.4 Monitor’s Responsibilities • 5.18.5 Monitoring Report • 5.19 Audit • 5.19.1 Auditing Procedures • 5.19.2 Selection and Qualification of Auditors • 5.19.3 Auditing Procedures • 5.20 Noncompliance • 5.21 Premature Termination of a Trial • 5.22 Clinical Trial/Study Reports • 5.23 Multicenter Trials

15. Sponsor’s Responsibilities • 5.3 Medical Expertise • Selects qualified investigators • 5.9 Financing • Maintains records of financial payments to investigators • 5.10 Notification/Submission to Regulatory Authority(ies) • Maintains an effective IND with respect to the investigations • Ensures compliance with IND

16. Sponsor’s Responsibilities • 5.14 Supplying and Handling Investigational Products(s) • Supplies the study drug in accordance to applicable regulations & maintains necessary records of receipt, shipment & disposition of study drug • 5.16 Safety Information • Ensures that FDA & investigators are informed of significant new adverse effects

17. ICH GCP Section 5Monitor • 5.18 Monitoring • 5.18.1 Purpose • 5.18.2 Selection and Qualifications of Monitors • 5.18.3 Extent and Nature of Monitoring • 5.18.4 Monitor’s Responsibilities • 5.18.5 Monitoring Report

18. Monitor’s Responsibilities • Ensures clinical studies are conducted and reported in compliance with the approved protocol, SOPs, GCPs, and with applicable country and state-specific regulatory requirement(s) • Ensures that the rights and well being of human subjects are protected • Confirms reported trial data are accurate, complete, and verifiable from source documents

19. Common Deficiencies (when GCPs are not followed) • Failure to follow protocol • Inadequate informed consent process, record keeping, drug accountability • Failure to report adverse events in a timely manner • Inadequate monitoring • Failure to submit IND amendment/progress reports

20. Investigator-Initiated Trials (IITs): “Sponsor – Investigator”

21. Investigator-Initiated Trials (IITs) • Investigator comes up with the concept and designs the protocol • Review literature/preclinical data • Calculate sample size • Trial cost • Investigator gets the study “up and going”

22. Investigator-Initiated Trials (IITs) • Highest priority studies within the Cancer Center • Viewed as of higher academic value • Typically, the investigator serves as both investigator and sponsor roles • Preferred UC Davis term: “Sponsor-Investigator” • Most IITs are single institution; however, some may require multi-institution involvement • Monitoring of multi-institutional IITs are more resource demanding • Ensure that this is accounted for in the IIT budget!!!

23. Investigator-Initiated Trials (IITs) • Active to Accrual studies • 10 IITs/Single Institution • 4 with Pharmaceutical Industry Support • 2 with Lawrence Livermore National Laboratory • 4 with UCDCC support only

24. Investigator-Initiated Multi-center Trials:“Sponsor – Investigator”

25. Investigator-Initiated Multi-center Trials • Single protocol conducted at more than one location • Inter-Institutional Agreements • Determine Authorship Policies • Register trial with clinicaltrials.gov • Oversee regulatory documents • Adverse Events Reporting - Central Monitoring Body • Site Monitoring ?? CC does not have the funds to do this

26. Investigator-Initiated Multi-center Trials • Active to Accrual studies • 5 IITs/Multi-Center • 4 with Pharmaceutical Industry Support • 1 with UCDCC support only

27. Types of Monitoring Visits • Study Initiation Visit (SIV) • Periodic Monitoring Visits • Study Termination/Closeout (COV)

28. Study Initiation Visit (SIV) • Verify that all required documents and supplies are available at the site, and that the study team is ready to enroll patients. • Some items discussed at Site Initiation Visit: • Review the study protocol • Eligibility Criteria • Treatment Procedures

29. Periodic Monitoring Visits • Verify informed consent for each subject enrolled • Assess IRB status • Review study files • Check source documents • Identify deviations and protocol violations

30. Study Closeout/Termination • The following activities are performed when a trial is completed as planned (close-out) or prematurely (termination).  • Final review of all study documents • Inventory, itemize, return or destroy unused supplies and/or study treatment • Obtain copies of any source documents only available in the medical records or ensure that medical records are not destroyed in the event of subject’s death

31. Study Closeout/Termination • Ensure that the regulatory files are complete and current • Provide the sponsor with a summary overview of the study documenting  official close • Once all study activities are completed, submit the final report to the IRB • Prepare a quick reference file including subject identification code list, sponsor contacts and document storage location for future reference • Maintain study records according to long-term storage requirements

32. Safety Reporting • Definitions (21 CFR §314.80) • Serious Adverse Experience • Reporting Requirements

33. SAE Processing for UCD Patients SAE is identified by CTSU Staff Study Coordinator completes “UCDCC Serious Adverse Event Cover Sheet” Study Coordinator submits ‘”Report of Unanticipated Problems Involving Risk to Participants or Others” to IRB Study Coordinator completes SAE Report per protocol Fax MedWatch Form to FDA Study Coordinator and PI determine event was unanticipated, related and increase risk “Acknowledgement of Receipt” Letter from FDA [SAE Report = IND Safety Report or MedWatch Form] UCDCC Serious Adverse Event Cover and SAE report submitted to CC Database

34. Safety Reporting • Document and report all adverse events • Report Serious Adverse Events to IRB per IRB SOPs • Document all information regarding adverse events in the source document

35. Clinical Trial Documentation • Communications with subjects • Shipping records • Accountability logs

36. Clinical Trial Documentation • Documentation of used and unused drug supply returned to the Sponsor • IRB approvals for study protocol and all amendments • All source documents and laboratory records • Essential regulatory documents (ie. FDA form 1572s) • Any other pertinent study document

37. Record Retention • Clinical trial data records (GCP) At least 2 years after • The IND is discontinued (If no NDA is submitted) • 5 years after submission of an NDA • May have to keep the documents for a longer period of time

38. Summary • Be familiar with GCPs! • Know your responsibilities as the “Sponsor-Investigator” • Initiating a multi-center trial is complex • Research whether the trial can be conducted at external sites • Establish excellent communication with external sites • Have the resources to provide administrative and other support to ensure proper conduct of the study

39. References • 21 CFR 50, 54, 56, 312 • Friedman et al. Fundamentals of Clinical Trials, 3rd Edition 1999 • FDA Guidance for Industry: • ICH E6 Good Clinical Practice • Guideline for the Monitoring of Clinical Investigations

40. Helpful Links • Investigator’s Handbook http://ctep.cancer.gov/investigatorResources/ investigators_handbook.htm • ICH website http://www.ich.org • US Department of Health and Human Services http://www.youtube.com/user/USGOVHHS#g/c/5965CB14C2506914

41. Questions? Clarifications?