investigator-initiated multi-center trials jeffrey clark, md df/hcc medical director for clinical...
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Investigator-initiated Multi-center Trials
Jeffrey Clark, MDDF/HCC Medical Director for Clinical Trials Operations
September 26, 2008
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• Whether a company, organization, or single individual, the entity initiating the research project is directly responsible for the overall conduct of the entire study.
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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
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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
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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
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Why Conduct a Multi-center Trial?
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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
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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
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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
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How Do I Fulfill My Sponsor Obligations?
• Chances for success will be highest when you adhere to the following guidelines
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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
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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
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Identify Essential Centers
Planning
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition
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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
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Assess Organizational Structure
Planning
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition
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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
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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
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Determine Authorship Policies
• Establish policies consistent with academic standards• Publication• Presentation• Authorship
Planning
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition
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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
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Initiate National Protocol Registration
• Register trial with clinicaltrials.gov
• Contact the Clinical Trials Education Office (CTEO)
for guidance• [email protected] or 617-582-8480
Protocol
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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
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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
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Review and Report Violations
• 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
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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
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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
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Manage Additional Regulatory 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
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Summary of Regulatory Document Updates
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 At least annually, and when changes occur
NCI Investigator Registration
Annually
Regulatory Requirements
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Observe Regulatory Reporting 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
Regulatory Requirements
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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
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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
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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
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Flow of Registration Procedures
Local site QACT Lead Site (Coordinating Center)
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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
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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
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.
Study Conduct
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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
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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
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Data Management Model
Site AQACT
Data RepositorySite B
Lead Site (Coordinating Center)
Combined data from all sites is generated by the
QACT data repository
Returned to Lead Site(Coordinating Center)
Each site sends data
to the QACT data repository
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Promptly Report Adverse 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
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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
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Flow of Adverse Event Reporting
Sponsor
Site ALocal IRB A Local IRB BSite B
DFCI IRB
Step 1:Sponsor
reviews safety information from each
site to determine if any event requiresexpedited reporting
Step 2:SAEs and any
corrective actions are shared with
participating sites
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)
• Trials using gene transfer
• Submit all SAEs
• Report by phone, email or fax
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Important: Reporting requirements for other regulatory entities may differ from the DFCI IRB. You must comply with all reporting requirements.
Study Conduct
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Summary of AE Notification
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
Study Conduct
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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
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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
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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
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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
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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
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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
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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)• [email protected] or 617-632-3761
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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