1. Trial Master File Reference Model Supported by the DIA Document and Records Management Special Interest Area Committee Karen Redding, Co-Chair

2. 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. Specific Disclaimer 2

3. 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?

4. 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”?

5. 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? 5

6. 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 6

7. 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 7

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 8

9. 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 9

10. Who’s been involved? 304 members on team –60% US, 35% EU, 5% AP c200 Companies –Pharma –CRO –Vendor Regulatory agencies –MHRA –FDA 10

11. Organization of the Model in Zones 11

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 12

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 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

14. eCTD Integration

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. 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

16. Adding in IDE vs IND, UADE vs SUSAR etc Device Artifacts 16

17. 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 17

18. Process Based Metadata Driven by clinical trial processes GCP-RMA support Driven by clinical trial processes GCP-RMA support

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 19

20. Paper TMF Application To create a paper TMF, split the Model out to 3 spreadsheets, filtering for trial, country and site on each 20

21. Support for Implementing the Model Drug Information Associationwww.diahome.org21

22. The TMF Reference Model 22

23. TMF Reference Model Survey – Org Type 23

24. TMF Reference Model Survey - Uptake 24

25. 25 TMF Reference Model Survey – Usage I

26. 26 TMF Reference Model Survey – Usage II

27. Ways to Use the Model TMF Reference Model Referencing Cross- referencing artifacts Customization to Company specifics Complete adoption No referencing 27

28. Focus is to ensure artifacts not omitted No TMF structure change Change artifact names Add missing artifacts Cross-Referencing Drug Information Associationwww.diahome.org28

29. The TMF Reference Model is used with no changes Applicable to technology vendors Applicable to start-up companies Complete Adoption

30. 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 30

31. Identifying Artifacts SOPs, QPs, User Manuals 31

32. Managing Artifacts 32

33. eTMF Areas of Assessment Drug Information Associationwww.diahome.org33

34. 34 TMF Reference Model Survey – Usage IV

35. TMF Reference Model Survey - Opinion 35

36. 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 25 th June –Link on DIA EDM corner (website) Continued Development/Activities

37. Thank you Contact co-chairs to join TMF Ref Model Team: –Karen Redding, kredding@phlexglobal.comkredding@phlexglobal.com –Lisa Mulcahy, mulcahy67@comcast.netmulcahy67@comcast.net To stay up to date TMF Ref Model team progress and active discussions, read the blog: http://tmfrefmodel.blogspot.com/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 37