Trial Master File
Reference Model
Supported by the DIA Document
and Records Management
Special Interest Area Committee
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2
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]
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]
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
5
Defining the TMF Reference Model
Supporting files e.g.
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”
computer SDLC files; GMP
manufacturing files; vendor
selection files
Usually
considered
outside the
scope of the
TMF
The Trial Master File
Other business records
6
TMF Reference Model
Standard Contents
Industry opinion on
what is kept in a TMF
Standard Naming
Based on ICH E6
Sect. 8 & industryaccepted terminology
Standard Structure
To support paper and
electronic systems
Standard Metadata
For eTMFs, minimum
metadata at system
and artifact level
7
Who Benefits from a TMF Reference Model?
Sponsors
Including during mergers
and joint ventures
Investigators
Who conduct our trials and
their own
Collaborators
CROs and other vendors
outsourced by sponsors
Technical Vendors
Reg. Authorities
System & TMF Application
developers
Consistency across sites
and sponsors would lead
to more efficient, quicker
audits and approvals
8
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
9
Who has been involved?
304 members on team
– 60% US, 35% EU, 5% AP
c200 Companies
– Pharma
– CRO
– Vendor
Regulatory agencies
– MHRA
– FDA
10
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
12
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.
13
eCTD Integration
Investigator Site File Artifacts
TMF Zone
Section
Artifact nam e
Sponsor
Docum ent
Investigator
Docum ent
XG
02 Central Trial Documents
02.01
Trial Documents
02.01.01
Investigator Brochure
X
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
X
NO-CS (if
applicable)
02 Central Trial Documents
02.01
Trial Documents
02.01.04
Protocol Amendment
X
XG 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 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
Device Artifacts
Adding in IDE vs IND, UADE vs SUSAR etc
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 lim ited countries
TMF Artifacts (Non-device)
TMF Zone
Section
Artifact nam e
TMF Artifacts (Device)
Sponsor
Docum ent
Investigator
Docum ent
Sponsor
Docum ent
Investigator
Docum ent
XG
X
XG
02 Central Trial Documents
02.01
Trial Documents
02.01.01
Investigator Brochure
X
02 Central Trial Documents
02.01
Trial Documents
02.01.02
Protocol
X
XG
X
XG
X
NO-CS (if
applicable)
02 Central Trial Documents
02.01
Trial Documents
02.01.03
Protocol Synopsis
X
NO-CS (if
applicable)
02 Central Trial Documents
02.01
Trial Documents
02.01.04
Protocol Amendment
X
XG 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)
16
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
TMF Zone
Section
Investigator Initiated Study
Artifacts
M: m andatory, D: dependent
upon the type of study, R:
recom m ended
Artifact nam e
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
D
02 Central Trial Documents
02.01
Trial Documents
02.01.05
Financial Disclosure
Summary
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
17
Process Based Metadata
Process Based Metadata
TMF Zone
Artifact nam e
Process
Num ber
Process Nam e
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
05 Site Management
05.04
Site Management
05.04.01
Subject Log
17
Set up site(s)
Recruit Subjects &
Obtain Consent
05 Site Management
05.04
Site Management
05.04.02
Source Data Verification
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
05 Site Management
05.04
Site Management
05.04.07
Financial Documentation
24
Monitor Site(s)
Manage Project /
Manage Budget
05 Site Management
05.04
Site Management
05.04.08
Final Trial Close Out
Monitoring Report
34
Close Site(s) /
Close Site
05.04.09
Notification to Investigators
of Safety Information
28
05.04.10
Subject Identification Log
17
05 Site Management
•
Section
05.04
Site Management
05 Site Management
05.04
Site Management
Driven
by clinical trial
processes
• GCP-RMA support
Manage Subject
Risk / Report
Safety Issue(s)
Recruit Subjects &
Obtain Consent
Using the Reference Model for Paper TMFs
Used to define paper TMF form at and
electronic m etadata
TMF Zone
Section
Trial Level
Docum ent
Artifact nam e
Country/ Region Site Level
Level Docum ent Docum ent
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
05 Site Management
05.01
Site Selection
05.01.04
Pre Trial Monitoring Report
05 Site Management
05.01
Site Selection
05.01.05
Sites Evaluated but not
Selected
05 Site Management
05.02
Site Set-up Documentation
05.02.01
Acceptance of Investigator
Brochure
05 Site Management
05.02
Site Set-up Documentation
05.02.02
05 Site Management
05.02
Site Set-up Documentation
05.02.03
Protocol Signature Page
Protocol Amendment
Signature Page
05 Site Management
05.02
Site Set-up Documentation
05.02.04
Principal Investigator
Curriculum Vitae
X
Identical artifacts can exist
across each level e.g.
Feasibility documentation
X
X
X
X
X
X
X
X
X
Trial, country and site level
represent the 3 traditional
paper groupings – used to
define electronic metadata too
05 Site Management
05.02
Site Set-up Documentation
05.02.05
Sub-Investigator Curriculum
Vitae
X
05 Site Management
05.02
Site Set-up Documentation
05.02.06
Other Curriculum Vitae
X
19
Paper TMF Application
Used to define paper TMF form at and
electronic m etadata
TMF Zone
Section
Artifact nam e
Trial Level
Docum ent
Country/ Region Site Level
Level Docum ent Docum ent
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
05 Site Management
05.01
Site Selection
05.01.04
Pre Trial Monitoring Report
05 Site Management
05.01
Site Selection
05.01.05
Sites Evaluated but not
Selected
Acceptance of Investigator
Brochure
X
X
X
X
X
X
05 Site Management
05.02
Site Set-up Documentation
05.02.01
05 Site Management
05.02
Site Set-up Documentation
05.02.02
05 Site Management
05.02
Site Set-up Documentation
05.02.03
Protocol Signature Page
Protocol Amendment
Signature Page
05 Site Management
05.02
Site Set-up Documentation
05.02.04
Principal Investigator
Curriculum Vitae
X
X
X
05 Site Management
05.02
Site Set-up Documentation
05.02.05
Sub-Investigator Curriculum
Vitae
05 Site Management
05.02
Site Set-up Documentation
05.02.06
Other Curriculum Vitae
X
X
X
To create a paper TMF, split the Model out to 3 spreadsheets, filtering
for trial, country and site on each
20
Support for Implementing the Model
Suggested Colum ns for Im plem enting the TMF Reference Model
Artifact nam e
05.03.02
Site Training Material
05.03.03
Site Training Documentation
05.04.01
Subject Log
05.04.02
Source Data Verification
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
05.04.08
Final Trial Close Out
Monitoring Report
05.04.09
Notification to Investigators
of Safety Information
05.04.10
Subject Identification Log
Current Artifact
Nam e
Artifact Ow ner Artifact Location
Wet Ink
Signature
SOP Reference
Translation
Required
21
Dating
Convention
Additional Metadata
The TMF Reference Model
22
TMF Reference Model Survey – Org Type
23
TMF Reference Model Survey - Uptake
24
TMF Reference Model Survey – Usage I
25
TMF Reference Model Survey – Usage II
26
Ways to Use the Model
TMF
Reference
Model
Crossreferencing
artifacts
Referencing
No
referencing
Customization
to Company
specifics
Complete
adoption
27
Cross-Referencing
Focus is to ensure artifacts not omitted
No TMF structure change
Change artifact names
Add missing artifacts
28
Complete Adoption
The TMF Reference Model is used with no changes
Applicable to technology vendors
Applicable to start-up companies
Customization
Starting point is vanilla model
Initial crossfunctional
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
Consolidated
amended TMF
Reference Model
produced and
into feedback
cycle
Clinical
department to
consolidate
meeting
feedback
30
Identifying Artifacts
SOPs, QPs, User Manuals
31
Managing Artifacts
32
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..)
33
TMF Reference Model Survey – Usage IV
34
TMF Reference Model Survey - Opinion
35
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)
Thank You
Contact DIA Community Members
• Karen Redding, kredding@phlexglobal.com
• Lisa Mulcahy, mulcahy67@comcast.net
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