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Trial Master File Reference Model Supported by the DIA Document and Records Management Special Interest Area Committee Karen Redding, Co-Chair 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 thirdparty 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. 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 Standard Naming Industry opinion on what is kept in a TMF Based on ICH E6 Sect. 8 & industry-accepted terminology Standard Structure Standard Metadata To support paper and electronic systems For eTMFs, minimum metadata at system and artifact level 7 Who Benefits from a TMF Ref. 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’s 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, 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 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 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 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 Artifact nam e Investigator Initiated Study Artifacts M: m andatory, D: dependent upon the type of study, R: recom m ended 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 02.01.05 Financial 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 17 Process Based Metadata Process Based Metadata TMF Zone Section 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 28 17 05 Site Management 05.04 Site Management 05.04.09 Notification to Investigators of Safety Information 05 Site Management 05.04 Site Management 05.04.10 Subject Identification Log • 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 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 Identical artifacts can exist across each level e.g. Feasibility documentation 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 Drug Information Association Artifact Ow ner Artifact Location Wet Ink Signature www.diahome.org SOP Reference Translation Required Dating Convention Additional Metadata 21 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 Referencing Crossreferencing artifacts Customization to Company specifics No referencing Complete adoption 27 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 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 Clinical department to consolidate meeting feedback Consolidated amended TMF Reference Model produced and into feedback cycle 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..) Drug Information Association www.diahome.org 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 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/Publicationsand-Research/EDM-Corner.aspx>. 37