the regulatory binder/trial master file: essential records...
TRANSCRIPT
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Clinical Research Operations &
Regulatory Support (CRORS)
Ann Glasse, RN, BSN, MBA
Director-CRORS
The Regulatory Binder/Trial Master File:
Essential Records for the Conduct of a Clinical Trial
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Objectives
To understand:
• The definition and purpose of the Regulatory Binder/Trial
Master File (TMF)
• The required essential documents
• Maintenance of the Regulatory Binder/Trial Master File
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Definition
International Conference On Harmonization-
Good Clinical Practice (E-6) (ICH-GCP 8.1)
Defines Essential Documents as:
• Documents that individually and collectively permit evaluation of
the conduct of a trial and the quality of the data produced.
ICH-GCP E-6 website:
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf
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Purpose
These documents serve to demonstrate:
• Compliance of the investigator, sponsor and monitor with the standards
of GCP and with all applicable regulatory requirements.
• Management of a trial when documents are filed in timely manner.
• Documents are available for review by study monitors, auditors and
regulatory authorities to demonstrate validity of study conduct and data
integrity.
**The regulatory binder/trial master file should be established at the
beginning of the trial and maintained throughout.
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IRB Essential Documents
IRB initial submissions & approvals• IRB submission form
• IRB approval letter
• IRB approved documents
• Study Protocol
– Version # and date
– Signed & dated
• IRB communications
Amendments submissions & approvals• Modification submission form
• Protocol Revisions
• Revision date and/or version number
• Signed & dated
• IRB approval letter
• Other IRB approved documents
• IRB communications
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IRB Essential DocumentsReportable New Information (RNI)
[SAEs, Deviation/Violation, Exception, Unanticipated Problems, etc.]
• RNI submission form
• IRB approved documents, if applicable
• IRB acknowledgement letter
• IRB communications
Continuing Report submissions & approvals• IRB continuing review report
• AE logs and deviation logs
• IRB approval letter
• IRB approved documents
• IRB communications
Final study report • Final study report submission (all applicable logs/reports)
• IRB acknowledgment of study closure
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IRB Essential Documents
Informed Consent Forms (ICFs)
• UM-ICFs, JHS-ICFs, any translated versions and certificate of
translation
• Initial approved version and all applicable revisions
HIPAA Research Authorization Form B
• Translated versions
• Initial approved version and all applicable revisions
Information provided to or seen by (potential) subjects
• Advertisement for subject recruitment, web postings
• Letters, telephone scripts
• Diaries, Assessments, Questionnaires
• Instructions for subjects (study-specific instructions not individual
instructions such as appt. reminders, etc.)
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IRB Essential Documents
Investigator’s Brochure
• To document that relevant & current scientific info about the investigational
product has been provided to the investigator
• Maintain all revisions
Deviation Reports
• Assessment of the cause of the deviation
• Ensure it does not happen again: training, change process, Corrective
Action & Preventative Action (CAPA) Plans , etc.
• Ensure correct assignment of major/minor classification
Serious Adverse Events submitted to the IRB and sponsor
• Initial submission, follow up submission, IRB acknowledgment letters
IRB Committee Composition List (spanning duration of review of study)
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FDA Essential Documents
For drugs or biologics studies:• Copy of Form FDA 1571
• Cover sheet for all initial FDA submission and amendments to the IND
• Signed and dated by Sponsor-Investigator
• Start with serial number “0000” and then sequentially thereafter
• Copies of Form FDA 1572
• Signed and dated by PI
• Updated as needed: PI & Sub-Investigator names, IRB, clinical sites, clinical
labs
• Keep all revisions
For device studies:• Copies of Investigator’s Agreement (every 6 months)
• Signed and dated by PI
• Updated as needed (as above)
• Keep all revisions
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FDA Documents
For drugs, biologics and device studies:
• Copies of Financial Disclosures provided to Sponsor
• Disclosures for PI and all Sub-Investigators
Form FDA 3454 (Certification):
• To attest to the absence of financial interests and arrangements
Form FDA 3455 (Disclosure):
• Disclosure of financial arrangements between investigator and sponsor,
or investigator interest in tested product, etc.
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JHS and UMH Essential Documents
JHS Clinical Research Review Committee (CRRC) at the JHS Clinical
Trial Office (CTO) approval documents:
• Studies testing a drug, device or biologic at JHS
• Procedures, lab tests (including blood draws) at JHS
• Review of JHS patient records
• Recruitment or referral of JHS patients
• Use of JHS research pharmacy or other JHS facilities
University of Miami Hospital (UMH) Quality Department :
• Same as above but at UMH
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Additional Essential DocumentsQualification documents for PI and all key research personnel
• CITI Certifications (UM requirement is every 2 years)
• Medical licenses for physicians and nurses
• Current CVs for all study team members
• Certifications such as ACRP, SOCRA, Phlebotomy, etc.
• Study-specific training: Documentation of protocol review with study team, in-service
• Research-related training documentation
• Spanning duration of study or assignment to study
• Maybe maintained in a separate “credential binder(s)” with a documentation of
where to locate these.
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More Essential Documents…Laboratory Credentials
For all labs listed in protocol and on the 1572 (if applicable)
• Current and updated laboratory certifications (e.g. CLIA or CAP)
• Current and updated lab Director’s CV & medical license(s)
• Normal values/ranges for all tests included in protocol
Delegation of Authority
• Typically a table listing all study personnel and their assigned responsibilities as
delegated by the PI:
– Required by ICH-GCP, strongly recommended by FDA (mentioned in guidance
and audits)
– Lists all key personnel and Sub-Investigators
– Duties & responsibilities assigned by PI
– Informed Consent, physical exams, data entry, etc.
– Start date & end date for all personnel
– Include creation date
– Signed by PI: at start date and at end date for all study personnel
Note: This is an active document that should be continuously updated to reflect personnel
being added and removed from study.
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More Essential Documents…• Subject screening & enrollment log: Required by ICH-GCP
• Randomization list
• Decoding procedure for blinded trials
» In case of emergency, identity of blinded
investigational product can be revealed without
breaking blind of remaining subjects
• Monitoring
• Trial initiation monitoring report
• Monitor follow up letters - documents monitor site visits,
deviations, action items
• Monitoring visit log(s)
• Corrective Actions Preventive Actions (CAPA), if any
• Correspondence (emails, etc.) with monitors
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More Essential Documents…• DSMB plan (if applicable): including committee members
• DSMB reports:
• Determination of subject safety and continuation of trial
• Notification of SAEs
• From investigator to sponsor
– Include Documentation of submission within required timeframe
• From sponsor to investigator (External SAEs/IND Safety
Reports)
• Findings that could adversely affect subject safety
• Findings that could impact the conduct of the trial or impact the
IRB’s favorable opinion to continue the trial
See 21 CFR 312.32 and 812.46 for safety reporting
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf
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More Essential Documents…
• Adverse Event Log (s) (recommended)
• Running log of SAEs, AEs and unanticipated problems
• Helps monitor the safety of subjects
• Helps to compile Continuing Reports
• Sponsor correspondences and/or communications: amendments,
requests, queries
• Correspondences: with IRB, medical monitor, relevant emails
• Research team meeting minutes (including agendas and sign in sheets)
• Case Report Forms (blank template)
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More Essential Documents…
Investigational Product
• IP includes drugs, devices and biologics
• Instructions for handling investigational product (if not included in protocol or
Investigator’s Brochure)
• Includes instructions for storage, packaging,
dispensing and disposition
If the study team dispenses IP: Suggest to create a SOP on dispensing IP
Must meet pharmacy requirements; includes:
• Procedures on handling, storage, dispensing
and disposition of IP
• Record keeping of accountability logs
• Storage requirements: locked, limited access
• Temperature controlled environment
» Calibrated thermometers
» Temp logs or charts
» Emergency back-up power
• Destruction of IP
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More Essential Documents…
• Investigational Product Shipping Records
• Shipment dates
• Lot/Batch numbers
• Method of shipment
• Shipping conditions
• Investigational Product Accountability Logs
• Amount dispensed
• Date dispensed
• Lot/batch number
• Name of personnel dispensing
• Name of recipient & date received
• Amount returned & date returned
• Disposition
• Investigational Product Temperature logs
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Agreements/Contracts
To document financial agreements:
• Grant proposal & award letter – May list conditions for clinical trial
• Investigator/institution agreement with trial sponsor
Recommendation to maintain in a separate binder
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Maintaining the Regulatory Binder
Organize binder with:
• Labeled cover: study # and title, PI name, volume #, etc.
• Sections: with labeled tabs
• Chronological order within sections
Maintain a schedule for:
• Continuing Reports
• CITI re-certification due dates
Update on a regular basis:
• Delegation of Authority Log
• Qualification documentation: CITI, medical licenses, CVs
• Subject Enrollment/Disenrollment Log
*Keep all documents throughout the life of the study
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Investigator held IND/IDE Studies:
Sponsor-Investigator Responsibilities
Investigators holding an IND/IDE have sponsor
responsibilities in addition to investigator
responsibilities…
• Separate “sponsor” binder(s) containing IND/IDE
submissions, annual reports, amendments, FDA
correspondence, etc.
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Recommended SOPs
For research teams:
• Maintaining the Regulatory Binder
• Storage, handling and dispensing IP (if applicable)
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Final Words…
Organize the regulatory/TMF binders:
• Chronological order
• Tell the story of your study such that an outside reviewer
or new study team member can read it and understand
what happened
• Maintain documentation of all approvals and re-approvals
• Update documents as needed: Form FDA1572, DOA log, training
records, etc.
The regulatory/TMF binders are continuously evolving
throughout the study…
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Questions?
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How to Contact us
Office of Clinical Research Operations & Regulatory Support
• http://www.uresearch.miami.edu
• Telephone: (305) 243-6381
• E-mail:
To report a problem or concern:
https://canewatch.ethicspoint.com
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