Investigator-initiated%20Multi-center%20Trials

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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
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

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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

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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
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

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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
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

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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

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Determine Authorship Policies
Planning

• Establish policies consistent with academic
  standards
• Publication
• Presentation
• Authorship

• Source Friedman et al. Fundamentals of Clinical
  Trials, 3rd edition

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Develop the Protocol
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

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Initiate National Protocol Registration
Protocol

• Register trial with clinicaltrials.gov
• Contact the Clinical Trials Education Office
  (CTEO) for guidance
• cteo_at_dfci.harvard.edu or 617-582-8480

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Coordinate Protocol Information
Protocol

• 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

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Review and Report Deviations/Exceptions
Protocol

• Request preauthorization of deviations and
  exceptions from any site that might affect the
  riskbenefit 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

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Review and Report Violations
Protocol

• Report protocol violations from any site that
  affected the riskbenefit 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

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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

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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

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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

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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 At least annually, and when changes occur
NCI Investigator Registration Annually
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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

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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

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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 email updates

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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

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

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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.
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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

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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

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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
QACT Data Repository
Each site sends data to the QACT data
repository
Site B
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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

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Report Events to all Participating Sites
Study Conduct

• 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

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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
Site A
Local IRB A
Local IRB B
Site B
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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, email or fax

Important Reporting requirements for other
regulatory entities may differ from the DFCI IRB.
You must comply with all reporting requirements.
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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
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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

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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

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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

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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

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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)
• qcc_at_dfci.harvard.edu 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