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

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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] Drug Information Association www.diahome.org

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] Drug Information Association www.diahome.org

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 Drug Information Association www.diahome.org

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 Drug Information Association www.diahome.org © Rammell Consulting Ltd

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 Drug Information Association www.diahome.org 7

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 Drug Information Association www.diahome.org

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 Drug Information Association www.diahome.org

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 Drug Information Association www.diahome.org 10

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 Drug Information Association www.diahome.org

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 Drug Information Association www.diahome.org

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. Drug Information Association www.diahome.org

eCTD Integration Drug Information Association www.diahome.org

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. Drug Information Association www.diahome.org

Device Artifacts Adding in IDE vs IND, UADE vs SUSAR etc Drug Information Association www.diahome.org

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 Drug Information Association www.diahome.org

Process Based Metadata Driven by clinical trial processes GCP-RMA support Drug Information Association www.diahome.org

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 Drug Information Association www.diahome.org

Paper TMF Application To create a paper TMF, split the Model out to 3 spreadsheets, filtering for trial, country and site on each Drug Information Association www.diahome.org

Support for Implementing the Model Drug Information Association www.diahome.org

The TMF Reference Model Drug Information Association www.diahome.org

TMF Reference Model Survey – Org Type Drug Information Association www.diahome.org

TMF Reference Model Survey - Uptake Drug Information Association www.diahome.org

TMF Reference Model Survey – Usage I Drug Information Association www.diahome.org

TMF Reference Model Survey – Usage II Drug Information Association www.diahome.org

Ways to Use the Model TMF Reference Model Referencing Cross-referencing artifacts Customization to Company specifics Complete adoption No referencing Drug Information Association www.diahome.org

Cross-Referencing Focus is to ensure artifacts not omitted No TMF structure change Change artifact names Add missing artifacts Drug Information Association www.diahome.org

Complete Adoption The TMF Reference Model is used with no changes Applicable to technology vendors Applicable to start-up companies Drug Information Association www.diahome.org

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 Drug Information Association www.diahome.org

Identifying Artifacts SOPs, QPs, User Manuals Drug Information Association www.diahome.org

Managing Artifacts Drug Information Association www.diahome.org

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..) Drug Information Association www.diahome.org

TMF Reference Model Survey – Usage IV Drug Information Association www.diahome.org

TMF Reference Model Survey - Opinion Drug Information Association www.diahome.org

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) Drug Information Association www.diahome.org

Thank you Join TMF Ref Model Team: http://tmfrefmodel.com/join/join-here/ To stay up to date on TMF Ref Model team progress and active discussions, read the blog: http://tmfrefmodel.com/ And 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. Drug Information Association www.diahome.org