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

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:

aglasse@med.miami.edu

CRORS@med.miami.edu

To report a problem or concern:

https://canewatch.ethicspoint.com

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