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

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:

9. ICH GCP Section 4 Investigator
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 5 Sponsor
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 5 Sponsor
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
Purpose
Selection and Qualifications of Monitors
Extent and nature of Monitoring
Monitor’s Responsibilities
Monitoring Report
5.19 Audit
Auditing Procedures
Selection and Qualification of Auditors
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 5 Monitor
5.18 Monitoring
Purpose
Selection and Qualifications of Monitors
Extent and Nature of Monitoring
Monitor’s Responsibilities
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) Reporting Requirements
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
investigators_handbook.htm
ICH website
US Department of Health and Human Services

41. Questions? Clarifications?