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2012-12-16
NIDCR National Institute of Dental and Craniofacial ResearchNational Institutes of Health
CROMS Clinical Research Operations and Management SupportRho, Inc., Federal Division
Sponsor Responsibilities ICH E6 Good Clinical Practice Guidance
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An individual, company, institution, or organization which takes responsibility for the initiation, management and/or financing of a clinical trial
Sponsor
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Implement and maintain QA and QC systems with written SOPs to ensure GCP compliance
Secure agreements from all sites for monitoring, auditing, and inspections
QC of data handling◦ Reliable
◦ Processed correctly All agreements should be in writing
Quality Assurance /Quality Control (ICH 5.1)
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A person or an organization contracted by the sponsor to perform one of more of a sponsor’s trial related duties and functions◦ Commercial◦ Academic◦ Other
Contract Research Organization (CRO)
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Sponsor may transfer all or some trial duties/functions to a CRO
Ultimate responsibility lies with the sponsor Transferred duties should be specified in writing
◦ Not specified = retained by sponsor References to sponsor apply to CRO for duties that
are transferred
Contract Research Organization (CRO) (ICH 5.2)
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Designate qualified medical personnel to advise on trial questions or problems
Outside consultants may be appointed if needed
Medical Expertise (ICH 5.3)
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Utilize qualified individuals: Biostatisticians, Clinical pharmacologists, Physicians
Use as appropriate through all trial stages◦ Protocol design◦ CRF development◦ Analysis (planning/preparing study reports)
For further guidance:◦ Clinical Trial Protocol and Protocol Amendments (Sec. 6)
Trial Design (ICH 5.4)
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Utilize qualified individuals to supervise conduct of trial, handle and verify data, conduct statistical analysis, and prepare trial reports
Can create independent data monitoring committee (IDMC) to assess progress◦ Safety data and critical efficacy endpoints◦ Recommendations to sponsor: continue, modify or stop trial◦ IDMC should have SOPs and maintain written records of
meetings
Trial Management, Data Handling, and Recordkeeping (ICH 5.5)
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When handling electronic trial data:◦Data processing system should conform to sponsor
requirements◦Maintain SOPs◦Permit changes that are documented(audit trail)◦Maintain a security system to prevent unauthorized
access◦Maintain list of individuals authorized to make changes◦Maintain data backup◦Safeguard blinding (if applicable) during data
entry/processing
Trial Management, Data Handling, and Recordkeeping (ICH 5.5)
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Possible to compare original data to processed data Use an unambiguous subject identification code Retain all essential documents pertaining to trial and regulatory
requirements If clinical development of an investigational product is
discontinued:◦ Retain essential documents for up to 2 years◦ Notify site investigators and appropriate regulatory authorities
Transfer of ownership of data should be reported to appropriate authorities, as per applicable regulatory requirements
Trial Management, Data Handling, and Recordkeeping (ICH 5.5)
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Retain sponsor-specific essential documents until:◦ At least 2 years after the last approval of a marketing application in
an ICH region , and until there are no pending or contemplated marketing applications in an ICH region, OR
◦ At least 2 years after formal discontinuation of clinical development of the investigational product
◦ Retain longer if required by applicable regulatory requirements or needed by the sponsor
Sponsor should communicate in writing to investigator/institutions:◦ Inform of the need for record retention◦ Notify when the trial-related records are no longer needed
Trial Management, Data Handling, and Recordkeeping (ICH 5.5)
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Sponsor selects investigators and/or institutions Provide protocol and up-to-date Investigator’s
Brochure◦ Ensure time to review before agreement
Obtain agreement to:◦ Conduct trial in compliance with GCP◦ Comply with data recording procedures◦ Permit monitoring, auditing and inspection◦ Retain essential documents
Investigator Selection (ICH 5.6)
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Before the trial begins, ensure that all duties and functions are:◦ Defined◦ Established◦ Allocated
Allocation of Duties and Functions (ICH 5.7)
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Provide insurance or indemnify the investigator/institution (if required)
Policies and procedures should address costs of treatment for trial-related injuries
Method and manner of compensation should comply with regulatory requirements
Compensation of Subjects and Investigators (ICH 5.8)
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Documented in agreement between sponsor and investigator/institution
Financing (ICH 5.9)
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Before initiating trial, the sponsor (or sponsor & investigator) should submit required applications to appropriate authorities for:
Review Acceptance Permission
Any submission should be dated and include protocol identifiers
Notification/Submission to Regulatory Authority(ies) (ICH 5.10)
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Obtain IRB/IEC documentation from investigator◦ IRB/IEC name and address
◦ Statement that IRB/IEC is organized and compliant with GCP and applicable regulations
◦ Documented approval to begin study
◦ If requested by the sponsor: Copy of protocol, written informed consent and other written
information to be provided to subjects Subject recruiting procedures Documents related to subject payment
Confirmation of Review by IRB/IEC (ICH 5.11)
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Obtain copy of modifications made and date of IRB/IEC approval :◦ Modification to protocol
◦ Written informed consent
◦ Other written information to subjects Obtain documentation and dates of re-approvals/re-
evaluations or withdrawals/suspensions
Confirmation of Review by IRB/IEC continued (ICH 5.11)
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During planning, ensure that safety and efficacy data are available to support human exposure◦ By the route
◦ At the dosages
◦ For the duration
◦ In the trial population Update Investigator’s Brochure as new information
becomes available
Information on Investigational Products (IP) (ICH 5.12)
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Manufactured in accordance with applicable GMP Coded and labeled to protect blinding, if applicable Labeling complies with regulatory requirements Determine acceptable storage temperatures and
conditions and inform involved parties
Manufacturing, Packaging, Labeling, and Coding IP (ICH 5.13)
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Product packaged to prevent contamination and unacceptable deterioration
Blinded trials should include a mechanism for rapid product identification (in case of medical emergency)◦ Should not permit undetectable breaks
Results of studies on significant formulation changes should be assessed before new clinical trials
Manufacturing, Packaging, Labeling, and Coding IP (ICH 5.13)
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Obtain all required documentation Supply investigator/institution with the products Ensure that written procedures include instructions for
handling and storage of IP Ensure timely delivery Maintain records of IP shipment receipt, disposition,
return, and destruction Maintain system for disposition of unused product Ensure that product is stable over period of use
Supplying and Handling Investigational Products (IP) (ICH 5.14)
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Protocol or other written agreement should state that investigator will provide direct access to source data for monitoring, audits, IRB review and regulatory inspection
Verify that each subject consented to direct access to medical records◦ Must be in writing
Record Access (ICH 5.15)
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Responsible for ongoing safety evaluation of the IP Should promptly notify all investigators/institutions
and regulatory authorities of findings that could:◦ adversely affect safety of subjects
◦ impact conduct of trial
◦ alter IRB approval
Safety Information (ICH 5.16)
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Expedite reporting of adverse drug reactions to:◦ Concerned investigators/institutions,
◦ IRBs/IECs
◦ Regulatory authorities Expedited reports should comply with applicable
regulatory requirements and ICH Guidance Submit to regulatory authorities required safety
updates and reports
Adverse Drug Reaction Reporting (ICH 5.17)
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Verify that:◦ The rights and well-being of human subjects are protected
◦ The reported trial data are accurate, complete, and verifiable from source documents
◦ Conduct of trial is in compliance with: Approved protocol/amendments GCP Applicable regulatory requirements
Monitoring: Purpose (ICH 5.18)
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Monitors should be appointed by sponsor Appropriately trained; have the needed scientific and/or
clinical knowledge◦ Qualifications should be documented
Familiar with:◦ Investigational product◦ Protocol, written informed consent form, and other written
information for subjects◦ SOPs ◦ GCP and applicable regulatory requirements
Monitoring: Selection and Qualification of Monitors (ICH 5.18)
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Ensure trials are adequately monitored Determine extent and nature of monitoring based
on:◦ Objective , Purpose and Endpoints
◦ Size, Design and Complexity
◦ Blinding On-site monitoring before, during, and after the trial
◦ Central monitoring in exceptional circumstances
Monitoring: Extent and Nature of Monitoring (ICH 5.18)
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Main line of communication between sponsor and investigator Verify investigator qualifications & resources Verify staff and facilities are adequate to safely and properly
conduct the trial Verify investigational products
◦ Acceptable storage times and conditions and sufficient supplies ◦ Supplied only to eligible subjects and at protocol-specified dose◦ Subjects provided with instruction before use◦ IP receipt, use and return is controlled and documented◦ Disposition of unused product complies with requirements
Monitoring: Monitor’s Responsibilities (ICH 5.18)
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Verify that investigator follows approved protocol and amendments
Verify that written informed consent is obtained before participation
Ensure that investigator receives current Investigator’s Brochure and all documents/supplies needed
Ensure that investigator and trial staff are informed about the trial
Monitoring: Monitor’s Responsibilities (continued) (ICH 5.18)
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Verify that trial staff are performing specified trial functions in accordance with protocol
Verify that only eligible subjects are being enrolled
Report the subject recruitment rate Verify documents and records are complete and up-to-
date Verify that investigator provides all reports,
notifications, applications and submissions
Monitoring: Monitor’s Responsibilities (continued) (ICH 5.18)
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Check accuracy and completeness of CRF entries◦ Data required by protocol are reported accurately
◦ Dose/therapy modifications are well-documented
◦ Adverse events, concomitant medications, and intercurrent are reported
◦ Missed visits, tests, and examinations are reported
◦ Withdrawals and dropouts are reported
Monitoring: Monitor’s Responsibilities (continued) (ICH 5.18)
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Inform investigator of CRF entry error, omission, or illegibility◦ Ensure that corrections, additions, or deletions are made,
dated, explained, and initialed
Determine if adverse events are reported appropriately
Determine if the investigator is maintaining essential documents
Monitoring: Monitor’s Responsibilities (continued) (ICH 5.18)
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Communicate deviations from the protocol, SOPs, GCP, and regulatory requirements to the investigator
Take appropriate action designed to prevent recurrence of the detected deviations.
Monitoring: Monitor’s Responsibilities (continued) (ICH 5.18)
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Follow the sponsor’s written SOPs and procedures set by the sponsor for a specific trial
Monitoring: Monitoring Procedures (ICH 5.18)
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Submit written report to sponsor after each trial-related visit/communication◦ Date, site, name of monitor, name of investigator
◦ Summary of review, monitor statements on findings, facts, deviations, deficiencies, conclusions, actions taken, and actions recommended
Review and follow up of the report should be documented by sponsor’s designated representative
Monitoring: Monitoring Report (ICH 5.18)
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An audit is independent of and separate from routine monitoring or quality control functions
Evaluate trial conduct and compliance with the protocol, SOPs, GCP, and regulatory requirements
Audit: Purpose (ICH 5.19)
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Sponsor appoints individuals, independent of the clinical trial
Ensure auditors are qualified by training and experience◦ Qualifications should be documented
Audit: Selection and Qualification of Auditors (ICH 5.19)
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Conducted in accordance with sponsor’s written procedures ◦ What to audit◦ How to audit◦ Frequency, form, and content
Audit: Auditing Procedures (ICH 5.19)
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Audit plan and procedures should be guided by:◦ Importance of trial to submission to regulatory authorities◦ Number of subjects◦ Type and complexity ◦ Levels of risks◦ Any identified problems
Observations and findings should be documented When required, provide and audit certificate
Audit: Auditing Procedures (continued )(ICH 5.19)
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Defined as noncompliance with protocol, SOPs, GCP, and/or regulatory requirements
Should lead to prompt action by the sponsor to secure compliance
If monitoring or auditing identifies serious or persistent noncompliance, sponsor should terminate participate in the trial and notify regulatory authorities
Noncompliance (ICH 5.20)
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Inform and provide reasons◦ Investigators/institutions, and regulatory authorities◦ IRB/IEC
Premature Termination or Suspension of a Trial (ICH 5.21)
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Ensure clinical trial/study reports are prepared and provided to regulatory agencies as required
Reports in marketing applications should meet the standards of the ICH Guidance for Structure and Content of Clinical Study Reports
Clinical Trial/Study Reports (ICH 5.22)
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All investigators conduct the trial in strict compliance with protocol
CRFs are designed to capture data at all multicenter sites
Supplemental CRFs should be provided for investigators who are collecting additional information
Responsibilities of coordinating investigators are documented prior to start of trial
Multicenter Trials (ICH 5.23)
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All investigators are given instructions on following:◦ The protocol ◦ Compliance with uniform standards for the assessment of
clinical and laboratory findings◦ Completing the CRFs
Facilitate communication between investigators
Multicenter Trials (continued)(ICH 5.23)
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Questions?
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