Monitoring and Special
Considerations for
Multi-Center Trials
September 10, 2010
Pav Aujla, MS, CCRP, RAC
Primo N. Lara, Jr. MD
A Translational Innovation Forum
Agenda
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Basic principles of:
• Investigator’s Responsibilities
• Sponsor’s Responsibilities
• Monitor’s Responsibilities
• “Sponsor – Investigator’s” Responsibilities
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Investigator-Initiated Trials (IITs)
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Investigator-Initiated Multi-Center Trials
Agenda
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Types of Monitoring Visits:
Study Initiation Visit (SIV)
• Periodic Monitoring Visits
• Study Termination/Closeout (COV)
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Agenda
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Understand safety reporting, record retention,
and FDA regulations, among other important
elements
International Conference of Harmonization
for Good Clinical Practice (E6)
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A common approach to clinical research
Represents a “passport” to global use of clinical
trial data
Establishes common definitions and reporting
guidelines for adverse events
International Conference of Harmonization
for Good Clinical Practice (E6)
1. Glossary
2. Principles of GCP
3. IEC/IRB
Responsibilities
4. Investigator’s
Responsibilities
5. Sponsor’s
Responsibilities
6. Protocols and
Amendments
7. Investigator’s
Brochure
8. Essential Documents
What are GCPs?
Good Clinical Practices are the ethical, scientific and
regulatory standards for conducting research
involving human subjects.
Essential Elements
- Data Integrity
- Patient rights and safety
Is GCP training available at UCDHS?
Yes, there is a GCP online training program on the
CITI training site
CITI homepage: http://www.citiprogram.org
ICH GCP Section 4
Investigator
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4.1 Investigator’s Qualifications and Agreements
4.2 Adequate Resources
4.3 Medical Care of Trial Subjects
4.4 Communication with IRB
4.5 Compliance with Protocol
4.6 Investigational Product(s)
4.7 Randomization Procedures and Unblinding
4.8 Informed Consent of Trial Subjects
4.9 Records and Reports
4.10 Progress Reports
4.11 Safety Reporting
4.12 Premature Termination or Suspension of a Trial
4.13 Final Report(s) by Investigator
Investigator’s Responsibilities
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4.1 Investigator’s qualifications and agreements
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4.2 Adequate resources
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Education, Training, Experience
Be familiar with protocol and IB
Do you have the time?
Staff and facilities
Can you recruit patients under the recruitment period?
4.4 Medical care of subjects
Medical decisions
• Adverse events
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Investigator’s Responsibilities
4.4 Communication with IRB
• 4.5 Protocol compliance
• 4.6 Investigational product(s)
• Inventory, records (dates, quantities, batch/serial
numbers, expiration date)
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Investigator’s Responsibilities
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4.8 Informed consent of trial subjects
4.9 Records and reports
4.11 Safety reporting
ICH GCP Section 5
Sponsor
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5.1 Quality Assurance and Quality Control
5.2 Contract Research Organization (CRO)
5.3 Medical Expertise
5.4 Trial Design
5.5 Trial Management, Data Handling, and Record Keeping
5.6 Investigator Selection
5.7 Allocation of Responsibilities
5.8 Compensation to Subjects and Investigators
5.9 Financing
5.10 Notification/Submission to Regulatory Authority(ies)
5.11 Confirmation of Review by IRB
5.12 Information on Investigational Product(s)
5.13 Manufacturing, Packaging, Labeling, and Coding Investigational
Product(s)
ICH GCP Section 5
Sponsor
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5.14 Supplying and Handling Investigational Product(s)
5.15 Record Access
5.16 Safety Information
5.17 Adverse Drug Reaction Reporting
5.18 Monitoring
5.18.1 Purpose
5.18.2 Selection and Qualifications of Monitors
5.18.3 Extent and nature of Monitoring
5.18.4 Monitor’s Responsibilities
5.18.5 Monitoring Report
5.19 Audit
5.19.1 Auditing Procedures
5.19.2 Selection and Qualification of Auditors
5.19.3 Auditing Procedures
5.20 Noncompliance
5.21 Premature Termination of a Trial
5.22 Clinical Trial/Study Reports
5.23 Multicenter Trials
Sponsor’s Responsibilities
• 5.3 Medical Expertise
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Selects qualified investigators
• 5.9 Financing
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Maintains records of financial payments to investigators
• 5.10 Notification/Submission to Regulatory Authority(ies)
• Maintains an effective IND with respect to the
investigations
• Ensures compliance with IND
Sponsor’s Responsibilities
• 5.14 Supplying and Handling Investigational Products(s)
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Supplies the study drug in accordance to applicable regulations &
maintains necessary records of receipt, shipment & disposition of
study drug
• 5.16 Safety Information
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Ensures that FDA & investigators are informed of significant new
adverse effects
ICH GCP Section 5
Monitor
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5.18 Monitoring
5.18.1 Purpose
5.18.2 Selection and Qualifications of
Monitors
5.18.3 Extent and Nature of Monitoring
5.18.4 Monitor’s Responsibilities
5.18.5 Monitoring Report
Monitor’s Responsibilities
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Ensures clinical studies are conducted and reported in compliance
with the approved protocol, SOPs, GCPs, and with applicable
country and state-specific regulatory requirement(s)
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Ensures that the rights and well being of human subjects are
protected
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Confirms reported trial data are accurate, complete, and verifiable
from source documents
Common Deficiencies
(when GCPs are not followed)
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Failure to follow protocol
Inadequate informed consent process, record
keeping, drug accountability
Failure to report adverse events in a timely
manner
Inadequate monitoring
Failure to submit IND amendment/progress
reports
Investigator-Initiated Trials (IITs):
“Sponsor – Investigator”
Investigator-Initiated Trials (IITs)
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Investigator comes up with the concept and
designs the protocol
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Review literature/preclinical data
Calculate sample size
Trial cost
Investigator gets the study “up and going”
Investigator-Initiated Trials (IITs)
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Highest priority studies within the Cancer Center
Viewed as of higher academic value
Typically, the investigator serves as both investigator and
sponsor roles
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Preferred UC Davis term: “Sponsor-Investigator”
Most IITs are single institution; however, some may
require multi-institution involvement
Monitoring of multi-institutional IITs are more resource
demanding
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Ensure that this is accounted for in the IIT budget!!!
Investigator-Initiated Trials (IITs)
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Active to Accrual studies
 10 IITs/Single Institution
 4 with Pharmaceutical Industry Support
 2 with Lawrence Livermore National
Laboratory
 4 with UCDCC support only
Investigator-Initiated
Multi-center Trials:
“Sponsor – Investigator”
Investigator-Initiated
Multi-center Trials
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Single protocol conducted at more than one location
Inter-Institutional Agreements
Determine Authorship Policies
Register trial with clinicaltrials.gov
Oversee regulatory documents
Adverse Events Reporting - Central Monitoring Body
Site Monitoring ?? CC does not have the funds to do this
Investigator-Initiated
Multi-center Trials
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Active to Accrual studies
 5 IITs/Multi-Center
 4 with Pharmaceutical Industry Support
 1 with UCDCC support only
Types of Monitoring Visits
Study Initiation Visit (SIV)
• Periodic Monitoring Visits
• Study Termination/Closeout (COV)
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Study Initiation Visit (SIV)
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Verify that all required documents and supplies
are available at the site, and that the study team
is ready to enroll patients.
Some items discussed at Site Initiation Visit:
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Review the study protocol
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Eligibility Criteria
Treatment Procedures
Periodic Monitoring Visits
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Verify informed consent for each subject enrolled
Assess IRB status
Review study files
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Check source documents
Identify deviations and protocol violations
Study Closeout/Termination
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The following activities are performed when a trial
is completed as planned (close-out) or prematurely
(termination).
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Final review of all study documents
Inventory, itemize, return or destroy unused supplies
and/or study treatment
Obtain copies of any source documents only available in
the medical records or ensure that medical records are
not destroyed in the event of subject’s death
Study Closeout/Termination
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Ensure that the regulatory files are complete and current
Provide the sponsor with a summary overview of the
study documenting official close
Once all study activities are completed, submit the final
report to the IRB
Prepare a quick reference file including subject
identification code list, sponsor contacts and document
storage location for future reference
Maintain study records according to long-term storage
requirements
Safety Reporting
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Definitions (21 CFR §314.80)
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Serious Adverse Experience
Reporting Requirements
SAE Processing for UCD Patients
SAE is identified
by CTSU Staff
Study Coordinator
completes SAE Report
per protocol
Study Coordinator
completes “UCDCC
Serious Adverse
Event Cover Sheet”
Fax MedWatch Form
to FDA
Study Coordinator
and PI determine
event was
unanticipated, related
and increase risk
“Acknowledgement of
Receipt” Letter from
FDA
UCDCC Serious
Adverse Event Cover
and SAE report
submitted to CC
Database
Study Coordinator submits
‘”Report of Unanticipated
Problems Involving Risk to
Participants or Others” to
IRB
[SAE Report = IND Safety Report or
MedWatch Form]
Safety Reporting
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Document and report all adverse events
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Report Serious Adverse Events to IRB per IRB
SOPs
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Document all information regarding adverse
events in the source document
Clinical Trial Documentation
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Communications with subjects
Shipping records
Accountability logs
Clinical Trial Documentation
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Documentation of used and unused drug supply
returned to the Sponsor
IRB approvals for study protocol and all amendments
All source documents and laboratory records
Essential regulatory documents (ie. FDA form 1572s)
Any other pertinent study document
Record Retention
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Clinical trial data records (GCP)
At least 2 years after
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The IND is discontinued (If no NDA is submitted)
5 years after submission of an NDA
May have to keep the documents for a longer period
of time
Summary
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Be familiar with GCPs!
Know your responsibilities as the “Sponsor-Investigator”
Initiating a multi-center trial is complex
Research whether the trial can be conducted at external
sites
Establish excellent communication with external sites
Have the resources to provide administrative and other
support to ensure proper conduct of the study
References
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21 CFR 50, 54, 56, 312
Friedman et al. Fundamentals of Clinical Trials, 3rd
Edition 1999
FDA Guidance for Industry:
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ICH E6 Good Clinical Practice
Guideline for the Monitoring of Clinical Investigations
Helpful Links
Investigator’s Handbook
http://ctep.cancer.gov/investigatorResources/
investigators_handbook.htm
• ICH website
http://www.ich.org
• US Department of Health and Human Services
http://www.youtube.com/user/USGOVHHS#g/c/59
65CB14C2506914
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Questions? Clarifications?