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Trial Master File Reference Model
Supported by the DIA Documentand Records Management Special Interest Area Committee
Karen Redding, Co-Chair
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Specific Disclaimer
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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]
What is the Trial Master File?
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 Model
Supporting 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
Standard ContentsStandard Contents
Industry opinion on what is kept in a TMF
Standard NamingStandard Naming
Based on ICH E6 Sect. 8 & industry-accepted
terminology
Standard StructureStandard Structure
To support paper and electronic systems
Standard MetadataStandard Metadata
For eTMFs, minimum metadata at system and
artifact level
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Who Benefits from a TMF Ref. Model?
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 standard• Extension of the EDM Reference Model • Reviewed by Regulatory Authorities to gain the benefit of
the agency’s input• Positive 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• Version 1.0 June 2010; Version 1.1 February 2011• Version 1.2 November 2011 (Includes ISF)• Version 2.0 June 2012
TMF Reference Model Facts
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Who’s 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
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Artifact name, Alternate names, and 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 Code
Core – (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 name
Sponsor Document
Investigator 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. 15
Adding in IDE vs IND, UADE vs SUSAR etc
Device Artifacts
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TMF Zone Section Artifact name
Sponsor Document
Investigator 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) X
NO-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 involvement
• Need to keep list as short as possible
• Challenge in variation of studies
• Challenge 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 name
Process 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 name
Trial 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 name
Trial 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
Drug Information Association www.diahome.org 21
Artifact name
Current Artifact Name Artifact Owner Artifact Location
Wet Ink Signature SOP Reference
Translation Required
Dating Convention Additional Metadata
05.03.02 Site Training Material
05.03.03 Site Training Documentation
05.04.01 Subject Log
05.04.02 Source Data Verif ication
05.04.03 Monitoring Visit Report
05.04.04 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 Model
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• Focus is to ensure artifacts not omitted• No TMF structure change• Change artifact names• Add missing artifacts
Cross-Referencing
Drug Information Association www.diahome.org 28
• The TMF Reference Model is used with no changes
• Applicable to technology vendors• Applicable to start-up companies
Complete Adoption
• Starting point is vanilla model
Customization
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Identifying Artifacts
SOPs, QPs, User ManualsSOPs, QPs, User Manuals
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Managing Artifacts
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eTMF Areas of Assessment
Drug Information Association www.diahome.org 33
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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 youContact co-chairs to join TMF Ref Model Team:
– Karen Redding, [email protected]– Lisa Mulcahy, [email protected]
To stay up to date TMF Ref Model team progress and active discussions, read the blog: http://tmfrefmodel.blogspot.com/
join Linked In group “TMF Reference Model”
The TMF RM is free and available here <http://www.diahome.org/en/News-and-Publications/Publications-and-Research/EDM-Corner.aspx>.
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