Supported by the DIA Documentand Records Management

Special Interest Area Committee

Trial Master File Reference Model

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What is the Trial Master File?

The documentation referred to in Article 15(5) of Directive 2001/20/EC as the trial master file shall consist of essential documents, which enable both the conduct of a clinical trial and the quality of the data produced to be evaluated

[European Directive 2005/28/EC]

Essential documents are those documents that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements.

[ICH GCP, Section 8.1]

What are “Essential Documents”?

ICH GCP Section 8.2 – 8.4“The minimum list of essential documents that has been developed.....”ICH GCP does NOT provide a comprehensive contents list for the TMF– Examples of missing documentation:

• Electronic systems• Data management and statistical methodology• Safety monitoring

Why a TMF Reference Model?

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Other business records

Defining the TMF Reference ModelSupporting files e.g. computer SDLC files; GMP manufacturing files; vendor selection files

Usually considered outside the scope of the TMF

Other trial-related records that “permit evaluation of the conduct of the trial and quality of data produced”

Minimum list of essential documents, as defined by ICH GCP, Chapter 8

The Trial Master File

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TMF Reference Model

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Standard ContentsIndustry opinion on

what is kept in a TMF

Standard NamingBased on ICH E6 Sect. 8 & industry-

accepted terminology

Standard StructureTo support paper and

electronic systems

Standard MetadataFor eTMFs, minimum metadata at system

and artifact level

Who Benefits from a TMF Reference Model?

Sponsors

Investigators

Collaborators

Technical Vendors

Reg. Authorities

Including during mergers and joint ventures

Who conduct our trials and their own

CROs and other vendors outsourced by sponsors

System & TMF Application developers

Consistency across sites and sponsors would lead to more efficient, quicker audits and approvals

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A reference - not intended to be a regulatory standardExtension of the EDM Reference Model Reviewed by Regulatory Authorities to gain the benefit of the agency’s inputPositive Regulator feedback– ‘I am impressed of all the hard work and thinking that has gone into this

project’ MPA - Sweden– Congratulations on the interest’ FDA - USA– ‘Wonderful work, congratulations’ BfArM - Germany

Team meetings commenced in March of 2009

TMF Reference Model Facts

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Version 1.0 June 2010

Version 1.1 February 2011

Version 1.2 November 2011 (Includes ISF)

Version 2.0 June 2012

Who has been involved?

304 members on team– 60% US, 35% EU, 5% AP

c200 Companies– Pharma– CRO– Vendor

Regulatory agencies– MHRA– FDA

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Organization of the Model in Zones 11 Zones

Trial Management

Central Trial Documents

Regulatory

IRB/IEC and other Approvals

Site Management

IP and Trial Supplies

Safety Reporting

Centralized Testing

Third Parties

Data Management

Statistics 11

Artifact name, Alternate names, Definition/Purpose

Artifact Name: Document types that might

be found in the TMF. Could be data files, documents, media,

digitalized content, etc. There are 245 artifacts defined in the model.

Alternate names: Other names that our industry has used for the artifact.

Definition/Purpose: Text explaining the content or the use of the artifact

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Inclusion in TMF and ICH CodeCore: (if applicable to the study) must be in the TMF as dictated by the ICH Guidelines, regulations, or by the TMF Ref Model Team

Recommended: Does not have to be in the TMF, but if it is collected or created, it is recommended to be in the TMF

ICH Code: Reference to the ICH GCP Guidelines. Notice that other sections beyond E6 Section 8 are quoted.

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eCTD Integration

TMF Zone Section Artifact nameSponsor

DocumentInvestigator Document

02 Central Trial Documents 02.01 Trial Documents 02.01.01 Investigator Brochure X XG

02 Central Trial Documents 02.01 Trial Documents 02.01.02 Protocol X XG

02 Central Trial Documents 02.01 Trial Documents 02.01.03 Protocol Synopsis XNO-CS (if

applicable)

02 Central Trial Documents 02.01 Trial Documents 02.01.04 Protocol Amendment XXG or XS (if applicable)

02 Central Trial Documents 02.01 Trial Documents 02.01.05 Financial Disclosure Summary X NO

02 Central Trial Documents 02.01 Trial Documents 02.01.06 Insurance X XG (if applicable)

02 Central Trial Documents 02.01 Trial Documents 02.01.07 Sample Case Report Form X XG

02 Central Trial Documents 02.01 Trial Documents 02.01.10 Report of Prior Investigations NO NO

02 Central Trial Documents 02.02 Subject Documents 02.02.01 Subject Diary X XG (if applicable)

02 Central Trial Documents 02.02 Subject Documents 02.02.02 Subject Questionnaire X XG (if applicable)

Investigator Site File Artifacts

Investigator vs Sponsor Documents• Assessing relevance of artifact to ISF• XS refers to artifact specific for one site• XG refers to general artifact for all sites• NO-CS is generally not for ISF apart from for limited countries

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Adding in IDE vs IND, UADE vs SUSAR etc

Device Artifacts

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TMF Zone Section Artifact nameSponsor

DocumentInvestigator Document

Sponsor Document

Investigator Document

02 Central Trial Documents 02.01 Trial Documents 02.01.01 Investigator Brochure X XG X XG

02 Central Trial Documents 02.01 Trial Documents 02.01.02 Protocol X XG X XG

02 Central Trial Documents 02.01 Trial Documents 02.01.03 Protocol Synopsis XNO-CS (if

applicable) XNO-CS (if

applicable)

02 Central Trial Documents 02.01 Trial Documents 02.01.04 Protocol Amendment XXG or XS (if applicable) X

XG or XS (if applicable)

02 Central Trial Documents 02.01 Trial Documents 02.01.05 Financial Disclosure Summary X NO X NO

02 Central Trial Documents 02.01 Trial Documents 02.01.06 Insurance X XG (if applicable) X XG (if applicable)

02 Central Trial Documents 02.01 Trial Documents 02.01.07 Sample Case Report Form X XG X XG

02 Central Trial Documents 02.01 Trial Documents 02.01.10 Report of Prior Investigations NO NO X XG

02 Central Trial Documents 02.02 Subject Documents 02.02.01 Subject Diary X XG (if applicable) X XG (if applicable)

02 Central Trial Documents 02.02 Subject Documents 02.02.02 Subject Questionnaire X XG (if applicable) X XG (if applicable)

TMF Artifacts (Device)TMF Artifacts (Non-device)

TMF Reference Model Sponsor Files - X: applicable; NO - Not applicable

Investigator Site Files - XS: artifact specific for one site; XG: general artifact for all sites; NO: not for ISF; NO-CS: generally

not for ISF apart from for limited countries

No or limited sponsor involvementNeed to keep list as short as possibleChallenge in variation of studiesChallenge in acceptance of Investigators

Investigator Initiated Study Artifacts

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TMF Zone Section Artifact name

02 Central Trial Documents 02.01 Trial Documents 02.01.01 Investigator Brochure M

02 Central Trial Documents 02.01 Trial Documents 02.01.02 Protocol M

02 Central Trial Documents 02.01 Trial Documents 02.01.03 Protocol Synopsis M

02 Central Trial Documents 02.01 Trial Documents 02.01.04 Protocol Amendment M

02 Central Trial Documents 02.01 Trial Documents 02.01.05Financial Disclosure Summary D

02 Central Trial Documents 02.01 Trial Documents 02.01.06 Insurance M

02 Central Trial Documents 02.01 Trial Documents 02.01.07 Sample Case Report Form M

02 Central Trial Documents 02.01 Trial Documents 02.01.10 Report of Prior Investigations M

02 Central Trial Documents 02.02 Subject Documents 02.02.01 Subject Diary D

02 Central Trial Documents 02.02 Subject Documents 02.02.02 Subject Questionnaire D

Investigator Initiated Study Artifacts

M: mandatory, D: dependent upon the type of study, R:

recommended

TMF Zone Section Artifact nameProcess Number Process Name

05 Site Management 05.03 Site Initiation 05.03.02 Site Training Material 16 Set up site(s)

05 Site Management 05.03 Site Initiation 05.03.03 Site Training Documentation 16 Set up site(s)

05 Site Management 05.04 Site Management 05.04.01 Subject Log 17Recruit Subjects & Obtain Consent

05 Site Management 05.04 Site Management 05.04.02 Source Data Verif ication 20 Manage Project

05 Site Management 05.04 Site Management 05.04.03 Monitoring Visit Report 19 Monitor Site(s)05 Site Management 05.04 Site Management 05.04.04 Visit Log 19 Monitor Site(s)

05 Site Management 05.04 Site Management 05.04.05 Additional Monitoring Activity 19 Monitor Site(s)

05 Site Management 05.04 Site Management 05.04.06 Protocol Deviations 19 Monitor Site(s)

05 Site Management 05.04 Site Management 05.04.07 Financial Documentation 24Manage Project / Manage Budget

05 Site Management 05.04 Site Management 05.04.08Final Trial Close Out Monitoring Report 34

Close Site(s) / Close Site

05 Site Management 05.04 Site Management 05.04.09Notif ication to Investigators of Safety Information 28

Manage Subject Risk / Report Safety Issue(s)

05 Site Management 05.04 Site Management 05.04.10 Subject Identif ication Log 17Recruit Subjects & Obtain Consent

Process Based Metadata

Process Based Metadata

• Driven by clinical trial processes• GCP-RMA support

TMF Zone Section Artifact nameTrial Level Document

Country/ Region Level Document

Site Level Document

05 Site Management 05.01 Site Selection 05.01.01 Site Contact Details X

05 Site Management 05.01 Site Selection 05.01.02 Confidentiality Agreement X

05 Site Management 05.01 Site Selection 05.01.03 Feasibility Documentation X X X

05 Site Management 05.01 Site Selection 05.01.04 Pre Trial Monitoring Report X

05 Site Management 05.01 Site Selection 05.01.05Sites Evaluated but not Selected X X

05 Site Management 05.02 Site Set-up Documentation 05.02.01Acceptance of Investigator Brochure X

05 Site Management 05.02 Site Set-up Documentation 05.02.02 Protocol Signature Page X

05 Site Management 05.02 Site Set-up Documentation 05.02.03Protocol Amendment Signature Page X

05 Site Management 05.02 Site Set-up Documentation 05.02.04Principal Investigator Curriculum Vitae X

05 Site Management 05.02 Site Set-up Documentation 05.02.05Sub-Investigator Curriculum Vitae X

05 Site Management 05.02 Site Set-up Documentation 05.02.06 Other Curriculum Vitae X

Used to define paper TMF format and electronic metadata

Using the Reference Model for Paper TMFs

Trial, country and site level represent the 3 traditional paper groupings – used to define electronic metadata too

Identical artifacts can exist across each level e.g. Feasibility documentation

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TMF Zone Section Artifact nameTrial Level Document

Country/ Region Level Document

Site Level Document

05 Site Management 05.01 Site Selection 05.01.01 Site Contact Details X

05 Site Management 05.01 Site Selection 05.01.02 Confidentiality Agreement X

05 Site Management 05.01 Site Selection 05.01.03 Feasibility Documentation X X X

05 Site Management 05.01 Site Selection 05.01.04 Pre Trial Monitoring Report X

05 Site Management 05.01 Site Selection 05.01.05Sites Evaluated but not Selected X X

05 Site Management 05.02 Site Set-up Documentation 05.02.01Acceptance of Investigator Brochure X

05 Site Management 05.02 Site Set-up Documentation 05.02.02 Protocol Signature Page X

05 Site Management 05.02 Site Set-up Documentation 05.02.03Protocol Amendment Signature Page X

05 Site Management 05.02 Site Set-up Documentation 05.02.04Principal Investigator Curriculum Vitae X

05 Site Management 05.02 Site Set-up Documentation 05.02.05Sub-Investigator Curriculum Vitae X

05 Site Management 05.02 Site Set-up Documentation 05.02.06 Other Curriculum Vitae X

Used to define paper TMF format and electronic metadata

Paper TMF Application

To create a paper TMF, split the Model out to 3 spreadsheets, filtering for trial, country and site on each

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Support for Implementing the Model

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Artifact nameCurrent Artifact

Name Artifact Owner Artifact LocationWet Ink

Signature SOP ReferenceTranslation

RequiredDating

Convention Additional Metadata

05.03.02 Site Training Material

05.03.03 Site Training Documentation

05.04.01 Subject Log05.04.02 Source Data Verif ication

05.04.03 Monitoring Visit Report05.04.04 Visit Log

05.04.05 Additional Monitoring Activity

05.04.06 Protocol Deviations

05.04.07 Financial Documentation

05.04.08Final Trial Close Out Monitoring Report

05.04.09Notif ication to Investigators of Safety Information

05.04.10 Subject Identif ication Log

Suggested Columns for Implementing the TMF Reference Model

The TMF Reference Model

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TMF Reference Model Survey – Org Type

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TMF Reference Model Survey - Uptake

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TMF Reference Model Survey – Usage I

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TMF Reference Model Survey – Usage II

Ways to Use the ModelTMF

Reference Model

Referencing

Cross-referencing

artifacts

Customization to Company

specifics

Complete adoption

No referencing

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Focus is to ensure artifacts not omittedNo TMF structure changeChange artifact namesAdd missing artifacts

Cross-Referencing

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The TMF Reference Model is used with no changesApplicable to technology vendorsApplicable to start-up companies

Complete Adoption

Starting point is vanilla model

Customization

Initial cross-functional meeting to

present TMF Ref Model

Zones allocated to functional

areas – homework is to

review with teams

Chaired functional

meetings to address all

relevant zones

Clinical department to

consolidate meeting feedback

Consolidated amended TMF

Reference Model produced

and into feedback cycle

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Identifying Artifacts

SOPs, QPs, User Manuals

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Managing Artifacts

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eTMF Areas of Assessment

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Paper or Electronic format (note wet-ink signatures)

Milestone-driven

Compound document

Grouping conventions

Expedited processing required

Extra Metadata required

Should Artifact/ document have restricted access (CROs etc..)

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TMF Reference Model Survey – Usage IV

TMF Reference Model Survey - Opinion

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Quality Control– Processing QC - scan, index etc

– Document QC – cross-checking and ordering

Look, feel and usage of the TMF Ref Model

Metadata

Intra operability– On hold

Destruction of scanned paper originals – Version 1.0 was released 25th June

– Link on DIA EDM corner (website)

Continued Development/Activities

Thank You

Contact DIA Community Members• Karen Redding, kredding@phlexglobal.com• Lisa Mulcahy, mulcahy67@comcast.netDownload the TMF (scroll down) Stay up to date on TMF Reference Model team progress and active discussions on our blogJoin the DIA Documents & Records Management Community Join our Linked In group (NEED HYPERLINK)

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