1. Trial Master File Reference Model Supported by the DIA Document and Records Management Special Interest Area Committee
Published: 22 August 2012

2. Specific Disclaimer
In accordance with the DIA Volunteer Code of Conduct, no volunteer shall use any information provided by the Association or acquired as a consequence of volunteer's services to the Association in any manner other than in furtherance of his or her volunteer duties with DIA. Volunteers are expected to act at all times in the best interests of the Association and not for personal or third-party gain or financial enrichment. DIA reserves the right to reproduce, license, sell, display, and distribute copies of materials posted to the DIA website, in any medium or technology (including online) consistent with DIA's nonprofit and tax exempt purposes.
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3. 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]
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4. What are “Essential Documents”?
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]
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5. Why a TMF Reference Model?
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
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6. Defining the TMF Reference Model
Supporting files e.g. computer SDLC files; GMP manufacturing files; vendor selection files
Other business records
Minimum list of essential documents, as defined by ICH GCP, Chapter 8
Other trial-related records that “permit evaluation of the conduct of the trial and quality of data produced”
Usually considered outside the scope of the TMF
The Trial Master File
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© Rammell Consulting Ltd

7. Standard Contents Standard Naming Standard Structure Standard Metadata
TMF Reference Model
Standard Contents
Industry opinion on what is kept in a TMF
Standard Naming
Based on ICH E6 Sect. 8 & industry-accepted terminology
Standard Structure
To support paper and electronic systems
Standard Metadata
For eTMFs, minimum metadata at system and artifact level
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8. Who Benefits from a TMF Ref. 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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9. TMF Reference Model Facts
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
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10. Who’s been involved? 304 members on team ~200 Companies
60% US, 35% EU, 5% AP
~200 Companies
Pharma
CRO
Vendor
Regulatory agencies
MHRA
FDA
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11. Organization of the Model in 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
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12. 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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13. 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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14. eCTD Integration
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15. 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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16. Device Artifacts Adding in IDE vs IND, UADE vs SUSAR etc
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17. Investigator Initiated Study Artifacts
No or limited sponsor involvement
Need to keep list as short as possible
Challenge in variation of studies
Challenge in acceptance of Investigators
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18. Process Based Metadata
Driven by clinical trial processes
GCP-RMA support
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19. 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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20. 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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21. Support for Implementing the Model
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22. The TMF Reference Model
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23. TMF Reference Model Survey – Org Type
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24. TMF Reference Model Survey - Uptake
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25. TMF Reference Model Survey – Usage I
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26. TMF Reference Model Survey – Usage II
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27. Ways to Use the Model TMF Reference Model Referencing
Cross-referencing artifacts
Customization to Company specifics
Complete adoption
No referencing
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28. Cross-Referencing Focus is to ensure artifacts not omitted
No TMF structure change
Change artifact names
Add missing artifacts
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29. Complete Adoption The TMF Reference Model is used with no changes
Applicable to technology vendors
Applicable to start-up companies
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30. Customization Starting point is vanilla model
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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31. Identifying Artifacts
SOPs, QPs, User Manuals
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32. Managing Artifacts
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33. eTMF Areas of Assessment
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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34. TMF Reference Model Survey – Usage IV
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35. TMF Reference Model Survey - Opinion
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36. Continued Development/Activities
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)
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37. Thank you Join TMF Ref Model Team:
To stay up to date on TMF Ref Model team progress and active discussions, read the blog:
And join Linked In group “TMF Reference Model”
The TMF RM is free and available here
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