Investigator-initiated Multi-center Trials

1. Investigator-initiated Multi-center Trials Jeffrey Clark, MDDF/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

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

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

6. Why Conduct a Multi-center Trial?

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

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

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

13. Identify Essential Centers Planning Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition

14. Initiate Inter-institutional Agreements 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 Planning Source: DF/HCC SOP PM-402

15. Assess Organizational Structure Planning Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition

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

17. Develop the Data and Safety Monitoring Plan 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 Planning Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition

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

19. Develop the Protocol 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 Planning Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition; DF/HCC SOP PM-402

20. InitiateNational Protocol Registration Register trial with clinicaltrials.gov Contact the Clinical Trials Education Office (CTEO) for guidance cteo@dfci.harvard.edu or 617-582-8480 Protocol 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 Protocol Source: DF/HCC SOPs PM-402, PM-407

22. Review and Report Deviations/Exceptions 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 Protocol

23. Review and ReportViolations 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 Protocol

24. Draft and File Amendments 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 Protocol

25. Oversee Essential Regulatory Documents 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 Regulatory Requirements Source: DF/HCC SOP PM-402

26. Manage AdditionalRegulatory Documents 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 Regulatory Requirements

27. Summary of Regulatory Document Updates Regulatory Requirements

28. ObserveRegulatory ReportingRequirements 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 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 Study Conduct Source: DF/HCC SOP PM-402

30. Establish Routine Progress Reports 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 email updates Study Conduct

31. Register all Participants with QACT 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 Study Conduct 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 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 Study Conduct

34. Monitor Drug Dispensing Ensure implementation of local pharmacy and dispensing procedures Secure storage area No unauthorized access Dispense only for study use Accurate accountability records Study Conduct • 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.

35. Develop Data Collection Procedures 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 Study Conduct Source: DF/HCC SOPs PM-402, QA-715

36. Oversee Data Accuracy 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 Study Conduct Source: DF/HCC SOPs PM-402, QA-717

37. Data Management Model 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 ReportAdverse Events to DFCI IRB 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 Study Conduct Source: DF/HCC SOPs PM-402, PM-407, AE-601

39. 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 Study Conduct Source: DF/HCC SOP PM-402 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 NCI/CTEP 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 NIH/Office of Biotechnology Affairs (OBA) Study Conduct • Important: Reporting requirements for other regulatory entities may differ from the DFCI IRB. You must comply with all reporting requirements. 41 • Trials using gene transfer • Submit all SAEs • Report by phone, email or fax

42. Summary of AE Notification Study Conduct

43. Initiate Procedures for Site Monitoring 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 Oversight Source: DF/HCC SOPs PM-402, QA-706

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

45. Coordinate Study Closure Procedures 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 Coordination

46. Notify Sites of Record Retention Policy 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 Coordination

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

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

49. For More Information Templates Visit the Clinical Investigator Toolkit Clinical Trials Portal or directly at www.dfhcc.harvard.edu/toolkit Guidance or monitoring requests Contact the Quality Assurance Office for Clinical Trials (QACT) qcc@dfci.harvard.edu or 617-632-3761 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