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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. Basic principles of: Investigator’s Responsibilities Sponsor’s Responsibilities Monitor’s Responsibilities

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monitoring and special considerations for multi center trials

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
Agenda
  • Basic principles of:
    • Investigator’s Responsibilities
    • Sponsor’s Responsibilities
    • Monitor’s Responsibilities
    • “Sponsor – Investigator’s” Responsibilities
  • Investigator-Initiated Trials (IITs)
  • Investigator-Initiated Multi-Center Trials
agenda1
Agenda
  • Types of Monitoring Visits:
      • Study Initiation Visit (SIV)
      • Periodic Monitoring Visits
      • Study Termination/Closeout (COV)
agenda2
Agenda
  • Understand safety reporting, record retention, and FDA regulations, among other important elements
international conference of harmonization for good clinical practice e6
International Conference of Harmonization for Good Clinical Practice (E6)
  • 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 e61
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

International Conference of Harmonization for Good Clinical Practice (E6)
what are gcps
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
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
ICH GCP Section 4Investigator
  • 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
Investigator’s Responsibilities
  • 4.1 Investigator’s qualifications and agreements
    • Education, Training, Experience
    • Be familiar with protocol and IB
  • 4.2 Adequate resources
    • 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
investigator s responsibilities1
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)
investigator s responsibilities2
Investigator’s Responsibilities
  • 4.8 Informed consent of trial subjects
  • 4.9 Records and reports
  • 4.11 Safety reporting
ich gcp section 5 sponsor
ICH GCP Section 5Sponsor
  • 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 sponsor1
ICH GCP Section 5Sponsor
  • 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
Sponsor’s Responsibilities
  • 5.3 Medical Expertise
    • Selects qualified investigators
  • 5.9 Financing
    • 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 responsibilities1
Sponsor’s Responsibilities
  • 5.14 Supplying and Handling Investigational Products(s)
    • Supplies the study drug in accordance to applicable regulations & maintains necessary records of receipt, shipment & disposition of study drug
  • 5.16 Safety Information
    • Ensures that FDA & investigators are informed of significant new adverse effects
ich gcp section 5 monitor
ICH GCP Section 5Monitor
  • 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
Monitor’s Responsibilities
  • 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)
  • Ensures that the rights and well being of human subjects are protected
  • Confirms reported trial data are accurate, complete, and verifiable from source documents
common deficiencies when gcps are not followed
Common Deficiencies (when GCPs are not followed)
  • 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
Investigator-Initiated Trials (IITs)
  • Investigator comes up with the concept and designs the protocol
    • Review literature/preclinical data
    • Calculate sample size
    • Trial cost
  • Investigator gets the study “up and going”
investigator initiated trials iits1
Investigator-Initiated Trials (IITs)
  • Highest priority studies within the Cancer Center
  • Viewed as of higher academic value
  • Typically, the investigator serves as both investigator and sponsor roles
    • 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
    • Ensure that this is accounted for in the IIT budget!!!
investigator initiated trials iits2
Investigator-Initiated Trials (IITs)
  • 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
Investigator-Initiated Multi-center Trials
  • 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 trials1
Investigator-Initiated Multi-center Trials
  • Active to Accrual studies
    • 5 IITs/Multi-Center
      • 4 with Pharmaceutical Industry Support
      • 1 with UCDCC support only
types of monitoring visits
Types of Monitoring Visits
  • Study Initiation Visit (SIV)
  • Periodic Monitoring Visits
  • Study Termination/Closeout (COV)
study initiation visit siv
Study Initiation Visit (SIV)
  • 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:
    • Review the study protocol
      • Eligibility Criteria
      • Treatment Procedures
periodic monitoring visits
Periodic Monitoring Visits
  • Verify informed consent for each subject enrolled
  • Assess IRB status
  • Review study files
    • Check source documents
    • Identify deviations and protocol violations
study closeout termination
Study Closeout/Termination
  • The following activities are performed when a trial is completed as planned (close-out) or prematurely (termination). 
    • 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 termination1
Study Closeout/Termination
  • 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
Safety Reporting
  • Definitions (21 CFR §314.80)
    • Serious Adverse Experience
  • Reporting Requirements
sae processing for ucd patients
SAE Processing for UCD Patients

SAE is identified by CTSU Staff

Study Coordinator completes “UCDCC Serious Adverse Event Cover Sheet”

Study Coordinator submits ‘”Report of Unanticipated Problems Involving Risk to Participants or Others” to IRB

Study Coordinator completes SAE Report per protocol

Fax MedWatch Form to FDA

Study Coordinator and PI determine event was unanticipated, related and increase risk

“Acknowledgement of Receipt” Letter from FDA

[SAE Report = IND Safety Report or

MedWatch Form]

UCDCC Serious Adverse Event Cover and SAE report submitted to CC Database

safety reporting1
Safety Reporting
  • Document and report all adverse events
  • Report Serious Adverse Events to IRB per IRB SOPs
  • Document all information regarding adverse events in the source document
clinical trial documentation
Clinical Trial Documentation
  • Communications with subjects
  • Shipping records
  • Accountability logs
clinical trial documentation1
Clinical Trial Documentation
  • 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
Record Retention
  • Clinical trial data records (GCP)

At least 2 years after

    • 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
Summary
  • 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
References
  • 21 CFR 50, 54, 56, 312
  • Friedman et al. Fundamentals of Clinical Trials, 3rd Edition 1999
  • FDA Guidance for Industry:
    • ICH E6 Good Clinical Practice
    • Guideline for the Monitoring of Clinical Investigations
helpful links
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/5965CB14C2506914

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