1. Investigator-initiated Multi-center Trials
Jeffrey Clark, MD DF/HCC Medical Director for Clinical Trials Operations
September 26, 2008

2. Whether a company, organization, or single individual, the entity initiating the research project is directly responsible for the overall conduct of the entire study. 2

3. Overview
Responsibilities of the sponsoring investigator when conducting a multi-center trial
Requirements for planning and conducting a multi-center trial
Strategies for managing a multi-center trial 3 3

4. Investigator-initiated Defined
Investigator conceives the concept to be researched, develops the protocol and, as an investigator acting as a sponsor, takes responsibility for the initiation, conduct, and management of the trial
Protocol development
Study coordination
Regulatory sponsor
Source: ICH GCP Guidelines 1.53, 1.54 4

5. Multi-center Trial Defined
Single protocol conducted at more than one location
Locations external to DF/HCC or DF/PCC Network Affiliates
Source: ICH GCP Guidelines 1.40; DF/HCC SOP PM-402 5

6. Why Conduct a Multi-center Trial?
Recruit appropriate number of participants
Address research question in reasonable time period
Evaluate feasibility of conducting a protocol therapy at multiple sites
Complex/higher risk regimens 6

7. What Is My Role?
When you initiate a multi-center trial, you become a Sponsor
Regulatory responsibility for entire trial at all sites and for maintaining protocol in accordance with all regulations
Your site (Lead Site) becomes the DF/HCC coordinating center
Source: DF/HCC SOP PM-402

8. Sponsor Responsibilities (1)
Plan the study
Develop and manage the protocol
Register the trial with clinicaltrials.gov
Perform all regulatory requirements
Single liaison with regulatory agencies, review and oversight authorities, and all participating sites
File applications/revisions/amendments
Maintain records
Review and report adverse events

9. Sponsor Responsibilities (2)
Select and train all site personnel
Protocol, study procedures, SAE reporting, and data collection
Coordinate conduct of the study at all sites
Protocol adherence, appropriate drug handling/dispensing, adverse event reporting
Review and report all Serious Adverse Events (SAEs)
Monitor the study at all sites
Assure complete and accurate data collection, analysis and reporting
Close the study

10. How Do I Fulfill My Sponsor Obligations?
Chances for success will be highest when you adhere to the following guidelines 10

11. Establish a Team that will
Planning
Plan/organize the study
Recruit participating sites
Oversee aspects of the study
Perform data analysis
Write study reports and/or papers
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition 11

12. Determine Trial Feasibility
Planning
Review literature/preclinical data
Calculate sample size
Estimate trial cost
Evaluate availability of participants and/or investigators
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition 12

13. Identify Essential Centers
Planning
Participating Sites
Base decision on population, experience, and research infrastructure
Coordinating Center
Assign this function to the Lead Site staff
Necessary to manage the trial and provide ongoing communication to participating sites
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition 13

14. Initiate Inter-institutional Agreements
Planning
Work with Research Administration to develop a formal agreement/contract in situations where:
Information/samples will be sent by or between participating sites and the Lead Site
Financial arrangements must be made
No other agreements exist between the institutions
Must be reviewed and approved by DF/HCC Research Administration Office prior to study activation
Source: DF/HCC SOP PM-402 14

15. Assess Organizational Structure
Planning
Data and Safety Monitoring
Use the DF/HCC Data and Safety Monitoring Committee (DSMC) for periodic data review
Group independent of sponsor and investigators preserves study integrity
Committees/individuals for “housekeeping tasks
Assign this function to the Lead Site staff or a Contract Research Organization (CRO)
Necessary to handle routine problems
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition 15

16. Establish Quality Assurance Standards
Planning
Develop consistent procedures for protocol training and data collection
Discuss common problems
Review proper ways to collect data and complete forms
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition 16

17. Develop the Data and Safety Monitoring Plan
Planning
Set up procedures to review performance at all sites
Recruitment, data collection, protocol adherence, regulatory requirements
Determine the nature and frequency of site monitoring
Base decision on complexity and risk level of trial
Identify what will be monitored
Consider plans for remediation and adjustment
Select site monitor (s)
Refer to DF/HCC Guidelines for Monitoring Multi-center Trials
See DF/HCC website under QACT → Multi-center Trials
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition 17

18. Determine Authorship Policies
Planning
Establish policies consistent with academic standards
Publication
Presentation
Authorship
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition 18

19. Develop the Protocol Involve participating sites as much as possible
Planning
Involve participating sites as much as possible
Include in the protocol document:
Name of each participating site and site PI
Multi-center data and safety monitoring plan
Procedures for central participant registration
Data submission schedule and method of transmittal
Reporting policy for AEs, SAEs and unexpected problems
Plan for site monitoring
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition; DF/HCC SOP PM-402 19

20. Initiate National Protocol Registration
Register trial with clinicaltrials.gov
Contact the Clinical Trials Education Office (CTEO) for guidance or 20 20 20

21. Coordinate Protocol Information
Distribute protocol and subsequent amendments to all participating sites
Assure each site is using and following correct version of the protocol
Report any new information to DFCI IRB
Include adverse events, protocol deviations/violation, and unanticipated problems occurring at all participating sites
Source: DF/HCC SOPs PM-402, PM-407 21

22. Review and Report Deviations/Exceptions
Protocol
Request preauthorization of deviations and exceptions from any site that might affect the risk:benefit ratio or impact study integrity
Submit to DFCI IRB prior to initiation at any site
Forward DFCI IRB written response to appropriate site for submission to the local IRB
Submit other deviations on the deviation/violation log at the time of continuing review 22

23. Review and Report Violations
Protocol
Report protocol violations from any site that affected the risk:benefit ratio or impacted study integrity per the DFCI IRB reporting policy
Submit to local IRB and then forward to DFCI IRB the local IRB determination using OPRS forms
Submit other violations on the deviation/violation log at the time of continuing review 23

24. Draft and File Amendments
Protocol
Pay attention to the frequency and nature of deviations, exception and violations filed for the protocol
Multiple deviations, exceptions or violations associated with a specific aspect of the protocol should elicit a protocol amendment
Submit amendments to DFCI IRB prior to implementation at any site
Forward DFCI IRB written response and revised documents to sites for submission to local IRB 24

25. Oversee Essential Regulatory Documents
Regulatory Requirements
Obtain and maintain the following documents from each participating site:
Federal wide assurance (FWA) number
IRB approval letters for the protocol, amendments, informed consent, and other protocol-related approvals
Study-specific Form FDA 1572 accompanied by the current and corresponding CVs
Delegation of Authority and/or Training logs
Source: DF/HCC SOP PM-402 25

26. Manage Additional Regulatory Documents
Regulatory Requirements
Obtain and retain the following documents when appropriate for the study:
Approvals from other entities
NCI, FDA
Study-related correspondence
Confirmation of NCI investigator registration
NCI/CTEP supported trial only
Form FDA 1571
Investigator-held IND trial only 26

27. Summary of Regulatory Document Updates
Regulatory Requirements
Document
Update
FWA Assurance
Upon expiration, and when changes occur
IRB approval
At least annually, and when changes occur
Study-specific Form FDA 1572
When changes occur at a site CV
Every 2 years
Delegation of Authority Log
When changes occur
Form FDA 1571
NCI Investigator Registration
Annually 27

28. Observe Regulatory Reporting Requirements
Regulatory Requirements
Report adverse events for all sites to DFCI IRB and oversight authorities
Submit final reports at study completion to DFCI IRB and oversight authorities

29. Train Investigators and Staff
Study Conduct
Train at the beginning and at intervals during the trial
DF/HCC Standard Operating Procedures
DFCI IRB Reporting requirements
Study protocol and study-specific procedures
Data collection
Adverse event reporting
Establish procedures for training new investigators and study staff
Document training
Source: DF/HCC SOP PM-402 29

30. Establish Routine Progress Reports
Study Conduct
Schedule progress reports with each participating site
Suggested timelines
Weekly (phase I)
Monthly (phase II)
At least every 3-6 months (phase III)
Documentation
Minutes from face-to-face meetings and teleconferences, or updates 30

31. Register all Participants with QACT
Study Conduct
Make sure all participants are registered with QACT prior to initiation of the protocol intervention
Submit eligibility checklist and signed/dated consent form
QACT will review for completeness and confirm registration
Notify participating site when registration is complete
Source: DF/HCC SOPs PM-402, QA-712

32. Flow of Registration Procedures
Lead Site
(Coordinating Center)
QACT
Local site 32

33. Maintain Direct Drug Ordering
Study Conduct
Non-DFCI sites should order any study drug (s) directly from the supplier, except in unusual circumstances
Make arrangement prior to the study
Order after initial IRB approval for the site has been forwarded to the Lead Site and/or supplier 33

34. Monitor Drug Dispensing
Study Conduct
Ensure implementation of local pharmacy and dispensing procedures
Secure storage area
No unauthorized access
Dispense only for study use
Accurate accountability records
Helpful hint: In the case of NCI-supplied drug (s), monitor the status of NCI investigator registrations. Drug shipments may be delayed until participating investigators are registered with NCI. 34

35. Develop Data Collection Procedures
Study Conduct
Work with QACT to develop standardized case report forms (CRFs)
eDC when appropriate
Establish procedures to capture follow-up data if long-term follow-up for toxicities and response is needed
Source: DF/HCC SOPs PM-402, QA-715 35

36. Oversee Data Accuracy
Study Conduct
Monitor ongoing data submissions from all sites to QACT
Submission schedule described in protocol and/or multi-center data and safety monitoring plan
Respond to validity and accuracy checks (data queries) within two weeks
Source: DF/HCC SOPs PM-402, QA-717

37. Data Management Model Lead Site (Coordinating Center) Site A QACT
Returned to Lead Site
(Coordinating Center)
Lead Site
(Coordinating Center)
Combined data from all
sites is generated by the
QACT data repository
Site A
Each site
sends data
to the
QACT data
repository
QACT
Data Repository
Site B 37

38. Promptly Report Adverse Events to DFCI IRB
Study Conduct
Review safety evaluations from each site
Report AEs and SAEs from any site
Use the appropriate internal or external event report form
Determine if any corrective actions should be taken as a result of the event
Amend the protocol and/or revise the consent form as necessary
Source: DF/HCC SOPs PM-402, PM-407, AE-601 38

39. Report Events to all Participating Sites
Study Conduct
Report Events to all Participating Sites
Notify participating investigators of all SAEs and request reporting to the local IRB
Events that are unexpected and related (or possibly related) to the study
Forward any corrective actions that must be taken as a result of the event
Amended protocol and/or revised consent form
Source: DF/HCC SOP PM-402 39 39 39

40. Flow of Adverse Event Reporting
Step 1:
Sponsor
reviews safety
information from each
site to determine if
any event requires
expedited reporting
Sponsor
DFCI IRB
Step 2:
SAEs and any
corrective actions
are shared with
participating sites
Local IRB A
Site A
Site B
Local IRB B 40

41. Report Events to Other Entities
Study Conduct
NCI/CTEP
NIH/Office of Biotechnology Affairs (OBA)
Trials using NCI-supplied investigational agent (s)
Use the web-based reporting system (AdEERS) for submission of serious and/or unexpected events
Copy OPRS on the transmission
Trials using gene transfer
Submit all SAEs
Report by phone, or fax
Important: Reporting requirements for other regulatory entities may differ from the DFCI IRB. You must comply with all reporting requirements. 41 41

42. Summary of AE Notification
Study Conduct
Who
Circumstance
Timeline
DFCI IRB
Reportable event from any site
Within 10 days of notification
NCI
Agent under CTEP IND
24 hours; Follow up within 5 days
OBA
Human gene transfer study: all SAEs
24 hours; Follow up within 7 days
Participating Sites
SAEs that are related (or possibly related) to study
After DFCI IRB review and response 42

43. Initiate Procedures for Site Monitoring
Oversight
Inform sites they may be audited by DF/HCC
Examine site monitoring results/reports
Adequacy of informed consent process
Protocol adherence
Appropriate adverse event reporting
Verification that data matches the original source documents
Submit to QACT copies of any external audit reports
Source: DF/HCC SOPs PM-402, QA-706 43

44. File Data and Safety Monitoring Reports
Oversight
Submit information requested by the DF/HCC Data and Safety Monitoring Committee (DSMC) in a timely manner
Quarterly review 44

45. Coordinate Study Closure Procedures
Coordination
Notify DFCI IRB and all sites when trial closes to accrual
Participating sites must notify their IRBs as local policy requires
Notify all sites when study-related activities have ended
Participating sites must file study termination reports with their IRBs as local policy requires
Report study completion to DFCI IRB and applicable regulatory entities once all study-related activities have ended 45

46. Notify Sites of Record Retention Policy
Coordination
Inform sites to store data in locked, restricted access, or password-protected location
Advise sites to retain all study-related documents according to federal or institutional policy, whichever is more stringent
HIPAA requires document retention for 6 years following study completion 46

47. What Your Coordinating Center Can Do
Provide administrative support
Confirm initial and ongoing IRB approvals for each site
Manage regulatory documents
Including study-specific Form FDA 1572 and CVs from each site
Facilitate study participant registration
Prepare information for oversight entities
For example DFCI IRB forms or DSMB/DSMC reports
Provide organizational support
Organize investigator and staff training
Keep an eye on data flow from each site
Craft procedures for communicating with all applicable parties
Coordinate monitoring or auditing visits 47 47 47

48. How DF/HCC Can Help
Supply templates for investigator-initiated research
Protocol template
Multi-center data and safety monitoring plan template
Provide guidance about conducting a multi-center trial
Multi-center Coordinating Committee
Offer limited site monitoring services
Funding and approval from QACT Director is required 48 48 48

49. For More Information Templates Guidance or monitoring requests
Visit the Clinical Investigator Toolkit
Clinical Trials Portal or directly at
Guidance or monitoring requests
Contact the Quality Assurance Office for Clinical Trials (QACT) or 49 49

50. Summary Initiating a multi-center trial is a complex undertaking
Understand your responsibilities as sponsor
Think carefully before accepting responsibility for a study at external sites
If a multi-center trial is appropriate and you wish to proceed, make sure the necessary support mechanisms are in place to ensure proper conduct of the study at each site 50