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

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


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Identify Essential Centers

Planning


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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


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Assess Organizational Structure

Planning


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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


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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


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Determine Authorship Policies

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

Planning


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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