Investigator-initiated Multi-center Trials
Jeffrey Clark, MD
DF/HCC Medical Director for Clinical Trials Operations
September 26, 2008
• 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
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
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
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
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
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
7
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
8
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
9
How Do I Fulfill My Sponsor Obligations?
• Chances for success will be highest when you
adhere to the following guidelines
10
Planning
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
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition
11
Planning
Determine Trial Feasibility
• 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
Planning
Identify Essential Centers
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
Planning
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
Source: DF/HCC SOP PM-402
14
Planning
Assess Organizational Structure
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
Planning
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
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition
16
Planning
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
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition
17
Planning
Determine Authorship Policies
• Establish policies consistent with academic
standards
• Publication
• Presentation
• Authorship
Source: Friedman et al. Fundamentals of Clinical Trials, 3rd edition
18
Planning
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
Source:
Friedman et al. Fundamentals of Clinical Trials, 3rd edition;
DF/HCC SOP PM-402
19
Protocol
Initiate National Protocol Registration
• Register trial with clinicaltrials.gov
• Contact the Clinical Trials Education Office (CTEO)
for guidance
• cteo@dfci.harvard.edu or 617-582-8480
20
Protocol
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
Protocol
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
22
Protocol
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
23
Protocol
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
24
Regulatory Requirements
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
Source: DF/HCC SOP PM-402
25
Regulatory Requirements
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
26
Regulatory Requirements
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
27
Regulatory Requirements
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
28
Study Conduct
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
Source: DF/HCC SOP PM-402
29
Study Conduct
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
30
Study Conduct
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
Source: DF/HCC SOPs PM-402, QA-712
31
Flow of Registration Procedures
Local site
Lead Site
(Coordinating Center)
QACT
32
Study Conduct
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
33
Study Conduct
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.
34
Study Conduct
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
Source: DF/HCC SOPs PM-402, QA-715
35
Study Conduct
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
Source: DF/HCC SOPs PM-402, QA-717
36
Data Management Model
Lead Site
(Coordinating Center)
Returned to Lead Site
(Coordinating Center)
Combined data from all
sites is generated by the
QACT data repository
Each site
sends data
to the
QACT data
repository
Site A
QACT
Data Repository
Site B
37
Study Conduct
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
Source: DF/HCC SOPs PM-402, PM-407, AE-601
38
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
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
Study Conduct
Report Events to Other Entities
NCI/CTEP
NIH/Office of Biotechnology
Affairs (OBA)
•
•
Trials using gene transfer
•
Submit all SAEs
•
Trials using NCI-supplied
investigational agent (s)
Use the web-based reporting
system (AdEERS) for
submission of serious and/or
unexpected events
•
•
Report by phone, email or fax
Copy OPRS on the
transmission
Important: Reporting requirements for other regulatory entities may differ from the DFCI
IRB. You must comply with all reporting requirements.
41
Study Conduct
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: 24 hours; Follow up within 7
all SAEs
days
Participating
Sites
SAEs that are related (or
possibly related) to study
After DFCI IRB review and
response
42
Oversight
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
Source: DF/HCC SOPs PM-402, QA-706
43
Oversight
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
44
Coordination
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 studyrelated activities have ended
45
Coordination
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
46
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
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
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
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