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Monitoring and Special Considerations for Multi-Center Trials
September 10, 2010
Pav Aujla, MS, CCRP, RACPrimo N. Lara, Jr. MD
A Translational Innovation Forum
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
Agenda• Types of Monitoring Visits:
• Study Initiation Visit (SIV)• Periodic Monitoring Visits• Study Termination/Closeout (COV)
Agenda Understand safety reporting, record retention,
and FDA regulations, among other important elements
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 (E6)
1. Glossary2. Principles of GCP3. IEC/IRBResponsibilities4. Investigator’sResponsibilities
5. Sponsor’sResponsibilities6. Protocols andAmendments7. Investigator’sBrochure8. Essential Documents
What are GCPs?
Good Clinical Practices are the ethical, scientific andregulatory 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 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• 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 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 Responsibilities
• 4.8 Informed consent of trial subjects• 4.9 Records and reports• 4.11 Safety reporting
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 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• 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 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 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
• 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)
• 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)
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 (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 (IITs)
Active to Accrual studies 10 IITs/Single Institution
4 with Pharmaceutical Industry Support2 with Lawrence Livermore National
Laboratory4 with UCDCC support only
Investigator-Initiated Multi-center Trials:
“Sponsor – Investigator”
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 Trials Active to Accrual studies
5 IITs/Multi-Center4 with Pharmaceutical Industry Support1 with UCDCC support only
Types of Monitoring Visits
• Study Initiation Visit (SIV)• Periodic Monitoring Visits• Study Termination/Closeout (COV)
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
Verify informed consent for each subject enrolled Assess IRB status Review study files
Check source documents Identify deviations and protocol violations
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/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
• Definitions (21 CFR §314.80)• Serious Adverse Experience
• Reporting Requirements
SAE Processing for UCD Patients
Study Coordinator completes SAE Report
per protocol
Study Coordinator completes “UCDCC
Serious Adverse Event Cover Sheet”
SAE is identified by CTSU Staff
Fax MedWatch Form to FDA
“Acknowledgement of Receipt” Letter from
FDA
Study Coordinator and PI determine
event was unanticipated, related
and increase risk
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
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
Communications with subjects Shipping records Accountability logs
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
Clinical Trial Documentation
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 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
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
Investigator’s Handbookhttp://ctep.cancer.gov/investigatorResources/investigators_handbook.htm• ICH websitehttp://www.ich.org• US Department of Health and Human Serviceshttp://www.youtube.com/user/USGOVHHS#g/c/
5965CB14C2506914
Questions? Clarifications?