Version 3.0 Overview

The sponsor and the investigator shall keep a clinical trial master file. The clinical trial master file shall at all times contain the essential documents relating to that clinical trial which allow verification of the conduct of a clinical trial and the quality of the data generated […]. It shall be readily available, and directly accessible upon request, to the Member States.

[EU Regulation 536/2014]

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]

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

Other business records

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

Created and maintained through a group of DIA (Drug Information Association) volunteers ◦ ~450 contributors from >200 companies

June 2010: Version 1.0- 11 zones w/ associated artifacts

Feb 2011: Version 1.1-Regulator feedback

Nov 2011: Version 1.2-Investigator Site File and 1st Intro slide set

June 2012: Version 2.0- Device, Process-based metadata, and IIS

Mar 2009: 1st Meeting ~Dec 2012: Kick-

off of many Work Groups that support the TMF manage-ment process

Feb 2014:Establishment of the TMF RM Steering Committee

June 2015: Release of version 3!

11 ZonesTrial ManagementCentral Trial DocumentsRegulatory IRB/IEC and other Approvals Site ManagementIP and Trial SuppliesSafety ReportingCentralized TestingThird PartiesData ManagementStatistics

Artifact Name – document types that might be found in the TMF. Could be data files, documents, media, digitalized content, etc. There are 248 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

9

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

OCT NOV DEC JAN FEB MAR APR MAY JUN

Zone MeetingsZone Lead Meetings

v3 Final Review

v3 Draft Created

Zone Leads & Zone Members

Controllers & Steering Committee

Zone Leads & Zone Members

V3 Released

v3 zone-level drafts

v3 full draft

Steering CommitteePreparation

Adair TurnerAjitha GadangiAlan DenchAllan BukuyaAmy BirdwellAndrea PershingAndrew MitchellAnne Mette VarneyBarbara EisenhartBetsy FallenBrenda BrownBrian HarrisClaire MooneyDavid Courtney‐Rodgers David JerchowerDeb OriezDenise SturdyDina Shragay

Donna  DorozinskyDorte FrejwaldChristiansenEldin RamellElvin ThalundEric RubinsonFran RossGagandeep SinghHeather Harte‐HallJames DeSantiJamie O'KeefeJamie TothJane HickmanJane TwitchenJennifer ChoiJennifer GaskinJessica VicariJo Anna GuerraJulie Ward

Joanne MaliaJody WinkenwerderJohan PiercyJohn LazenbyJosh MyersKaren McCarthy SchauKaren RoyKaren ZuklieKarin SchneiderKathie ClarkKathleen KirbyKathy MooreKim DunmanLara NaranjoLeah RoseLinda RudolphLisa GoinesLisa MulcahyEllen LaneAnita Pudin

Lisa OchsnerLisa SiskLoretta DubrayMarie Christine PoissonMartin ThorleyMaryanne QuinnMatthew ChittickMelissa MayberryMichael RussertMichele AthertonMichele WeitzMike CzaplickiNancie CeliniPaul BychowskyPaul FentonPeter McNaneyPrianto MoeljadiSam Mowaswes

Shah AshrafSharon AmesSholeh EhdaivandSondra PepeStephen ScribnerSteve BiotySubhayan DasSuellen BigajTamika JacksonTevin PathareddyTina CipollariTodd TullisTodd TynerTricia FryerWendy TimboliYvanne EneverZiyad AbushimaPatricia O'ConnorLiza Aldridge

Adair TurnerAjitha GadangiAlan DenchAllan BukuyaAmy BirdwellAndrea PershingAndrew MitchellAnne Mette VarneyBarbara EisenhartBetsy FallenBrenda BrownBrian HarrisClaire MooneyDavid Courtney‐Rodgers David JerchowerDeb OriezDenise SturdyDina Shragay

Donna  DorozinskyDorte FrejwaldChristiansenEldin RamellElvin ThalundEric RubinsonFran RossGagandeep SinghHeather Harte‐HallJames DeSantiJamie O'KeefeJamie TothJane HickmanJane TwitchenJennifer ChoiJennifer GaskinJessica VicariJo Anna GuerraJulie Ward

Joanne MaliaJody WinkenwerderJohan PiercyJohn LazenbyJosh MyersKaren McCarthy SchauKaren RoyKaren ZuklieKarin SchneiderKathie ClarkKathleen KirbyKathy MooreKim DunmanLara NaranjoLeah RoseLinda RudolphLisa GoinesLisa MulcahyEllen LaneAnita Pudin

Lisa OchsnerLisa SiskLoretta DubrayMarie Christine PoissonMartin ThorleyMaryanne QuinnMatthew ChittickMelissa MayberryMichael RussertMichele AthertonMichele WeitzMike CzaplickiNancie CeliniPaul BychowskyPaul FentonPeter McNaneyPrianto MoeljadiSam Mowaswes

Shah AshrafSharon AmesSholeh EhdaivandSondra PepeStephen ScribnerSteve BiotySubhayan DasSuellen BigajTamika JacksonTevin PathareddyTina CipollariTodd TullisTodd TynerTricia FryerWendy TimboliYvanne EneverZiyad AbushimaPatricia O'ConnorLiza Aldridge

40 BioPharma20 Vendor16 Consultant7 CRO6 Investigator Site 4 Device

Completely reviewed by 100’s of peopleUpdated artifacts – added, deleted, consolidated, split out, left the sameUpdated zones – reassessed for artifact belongingUpdated definitionsSubartifact facilitationImproved presentationTMF Reference Model User GuideCommunication plan!

Complete map from V2 to V3 for traceability ‘V3 Mark-up’Subartifacts – just examples

Specific records within an artifact

Company specificities Examples provided Essentially a 4th level Zone Section Artifact Sub artifact

New Artifacts Moved ArtifactsZone 011. Transfer of Regulatory Obligations2. Operational Oversight3. Committee Member CV4. Committee Member FDF5. Committee Member Contract6. Committee Member CDA 7. Trial Team Evidence of Training8. Marketed Product Material

Zone 059. Coordinating Investigator Documentation10. Subject Eligibility Verification Forms and

Worksheets

Zone 0911. Third Party CV12. Ongoing Third Party Oversight

1. Roles and Responsibility Matrix (moved from Zone 09 to Zone 01)

Removed Artifacts1. Adjudication Committee Document 2. Other Trial Committee Document3. Dose Escalation 4. Device Review Committee5. Clinical Study Report Synopsis6. Local Lab Certification or Accreditation7. Local Lab Normal Ranges 8. Completed CRFs

Zone 08 is now “Central and Local Testing”

Re-mapped artifacts to EDM Reference Model 1.4

Replaced “&” and “/” with “and” and “or” (respectively)

Final eTMF transfer to sponsor from CRO for archiving

Interim transfer of eTMF content to central eTMFor other trial management system

Migration of eTMF content following merger and acquisition

Migration of eTMF content following upgrade or change of eTMF system

Long term archiving of eTMF content and associated metadata

Study #Process Zone

Section

Section

Section

Artifact

Artifact

Content Export XML Inventory

Part of Technical Team (with Interoperability)Aim: • Defining alternative forms for consuming the data

produced by the TMF team • Provide these outputs in digital formats that do not

require specialized software to read the content, assuming all consumers have access to Microsoft Office, Adobe PDF and HTML

Added attributes for each artifact

Attributes allow for searching / narrowing of artifacts presented e.g. “Show all the core artifacts required by a drug sponsor”:

PDF Version allows for navigation and searching without Mindjet Mind Manager license

Two webinars – June and July (Recording)Press releasesLetters to RegulatorsWord of mouthhttp://tmfrefmodel.comLinked In: TMF Reference Model

Join the TMF Reference Model Yahoo! Group

http://tmfrefmodel.com/join• Knowledge sharing• Networking• Too Much Fun!

QUESTIONS?