Trial master file - Wikipedia

In a clinical trial involving human subjects, a set of content known as a trial master file (TMF) must be produced in accordance with applicable international ... Trialmasterfile FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch Inordertocomplywithgovernmentregulatoryrequirementspertinenttoclinicaltrials,everyorganizationinvolvedinclinicaltrialsmustmaintainandstorecertaindocuments,imagesandcontentrelatedtotheclinicaltrial.Dependingontheregulatoryjurisdiction,thisinformationmaybestoredinthetrialmasterfileorTMF,whichtodaytakestheformofanelectronictrialmasterfile(eTMF).TheInternationalConferenceonHarmonization(ICH)publishedaconsolidatedguidanceforindustryonGoodClinicalPracticein1996withtheobjectiveofprovidingaunifiedstandardfortheEuropeanUnion,Japan,andtheUnitedStatesofAmericatofacilitatemutualacceptanceofclinicaldatabytheregulatoryauthoritiesinthosejurisdictions.ThisguidancedocumentestablishedtherequirementacrossallICHregionstoestablishtrialmasterfilescontainingessentialdocumentsthatindividuallyandcollectivelypermitevaluationoftheconductofatrialandthequalityofthedataproduced.[2]Insomejurisdictions,forexampletheUSA,thereisnospecificrequirementforatrialmasterfile.However,iftheregulatoryauthorityrequiresICHGCPtobefollowed,thenthereisconsequentlyarequirementtocreateandmaintainatrialmasterfile.[2] Contents 1History 2TMFdefinition 3TMFcontent 4TMFcontentclassificationefforts 5TMFrecentdevelopments 6Companies 7References History[edit] Inaclinicaltrialinvolvinghumansubjects,asetofcontentknownasatrialmasterfile(TMF)mustbeproducedinaccordancewithapplicableinternationalandlocalregulations.TMFsareacollectionofdocumentsandotherartifactswhich"individuallyandcollectivelypermitevaluationoftheconductofatrialandthequalityofthedataproduced.Thesedocumentsservetodemonstratethecomplianceoftheinvestigator,sponsorandmonitorwiththestandardsofGoodClinicalPracticeandwithallapplicableregulatoryrequirements."[1] Historically,TMFshavebeenpaper-basedcontentsetsstoredinphysicalfilecabinets,centralfilerooms,orshelvedinbinders.ThesizeandcomplexityofaTMFisindirectproportiontothelengthandcomplexityofthetrial.[citationneeded]TheTMFisactivelybuiltduringatrial,andmustbemaintainedduringapost-trialperiodforpossibleregulatoryagencyinspectioninalignmentwithGCPandlocalcountryregulations.Traditionally,theTMFcontentnamesandrequirementsvariesfromsponsortosponsor,creatingahighdegreeofvariabilityandinconsistency. TMFdefinition[edit] Atrialmasterfilecontainsessentialdocumentsforaclinicaltrialthatmaybesubjecttoregulatoryagencyoversight.IntheEuropeanUnion(EU),TMFshaveadifferentdefinitionandsetofrequirementsthanintheUS.TheEUCommission'sDirective2005/28/EC63Chapter4states'thetrialmasterfileshallconsistofessentialdocuments,whichenableboththeconductofaclinicaltrialandthequalityofthedataproducedtobeevaluated.Thosedocumentsshallshowwhethertheinvestigatorandthesponsorhavecompliedwiththeprinciplesandguidelinesofgoodclinicalpracticeandwiththeapplicablerequirements.'TheUSFDArecognizestheuseofTMFsasasignificantpieceofinformationbutunliketheEUwithitsTMFregulation,thereisnoformalrequirementformaintenanceofessentialdocumentsinaTMFinUS-basedclinicaltrialsintheU.S.CodeofFederalRegulations.However,sincetheU.S.FDArequiretrialstobeconductedincompliancewithICHGCP,thereisanexpectationthatatrialmasterfilewillbecreatedandmaintainedinaccordancewiththoseguidelines. TMFcontent[edit] TheUnitedStates,theEUandJapansupporttheInternationalConferenceonHarmonisationorICH.TheICHhaspublishedaminimumsetofessentialdocumentsfortheTMF.Theminimumessentialdocumentsthatarerequiredfortheregistrationofpharmaceuticalproductsdesignedforhumanusearespecifiedinthedocument'ICHGoodClinicalPractices,'publishedin1997bytheICH[2]ExampleICHessentialdocumentsthatwouldberequiredinanyUS,EUorJapanbasedclinicaltrialwouldinclude:signedprotocol,auditcertificate,subjectenrollmentlog.AlthoughtheICHguidelinesareapplicabletothethreenamedICHregions,manyothercountrieshaveagreedtofollowtheguidelinesandhaveincorporatedtheprinciplesintotheirnationalmedicineslegislation.CreationofaTMFandinclusionofICHessentialdocumentsisbasedonthediscretionoftheregulatoryagencyforthecountryinwhichtheclinicaltrialisconducted.Inaddition,thesubmissionofamarketingapplicationwillnormallyrequirecompliancewiththeregulatoryrequirementsofthatcountry,includingrequirementsspecifictoTMFcontent. TMFcontentclassificationefforts[edit] SincetherequirementtomaintainaTMFcontainingessentialrecordswasdocumentedintheICHGCPE6ConsolidatedGuidelinein1996,trialsponsorshavestruggledtoidentifyexactlywhatcontenttheTMFshouldcontain.ICHE6includesdetailsofonlyaminimumlistofcontentsandnootherregulationorguidelineprovidesacomprehensivelistofTMFcontent.Asaresultoftheinconsistenciesthatweredevelopingacrossthesector,anindustrygroupcomprisingabout20membersfromtheDrugInformationAssociation(DIA)decidedtodevelopastandardcontentslistfortheTMF.TheTMFReferenceModelteamwasformedin2009withintheDocumentandRecordsManagementCommunityoftheDIA. ThefirstversionoftheTMFReferenceModel(TMFRM)[5]wasreleasedinJune2010andwasupdatedinFebruary,2011(v1.1)basedonfeedbackprovidedbyRegulators,andagaininDecember,2011(v1.2),basedonfeedbackprovidedbyusersofthemodelastheyuseditwithintheirrespectiveorganizationstostructuretheirpaperandelectronicTMFs.v2.0inJune2012andincludedexpansionstothereferencemodel.Artifacts,thetermusedforcontenttypes,wereaddedforInvestigatorSiteFiles,Devicetrials,andInvestigatorInitiatedStudies.Thescopeofmetadatawithinthemodelwasalsoextendedinv2.0toincludethetrialprocesswithwhicheachTMFartifactisassociated.InJune2015v3.0[3]oftheTMFReferenceModelwaspublished.v3.0includesprovisionforsub-classificationofartifacts;identifiedassub-artifacts.Section01.03(TrialCommittees)wasrevisedtoprovideadditionalflexibility,allowingforlimitlessnumbersofcommitteestobemanagedwithinaTMFwithacommonclassificationstructure.Italsoincluded12newartifacts,8removedartifactsand1re-classifiedartifact. TheDIAstatesontheirwebsite'TheTMFReferenceModelprovidesanopportunityforstandardizationacrosstheindustry,andcanbeusedbyanycompanyinanelectronicorpaperformat'.[5]WhilsttheDIAdoesn'thaveaformal,publicandopenstandardseffortinplacetodevelopaformal,publishedstandard,theuseoftheReferenceModelishelpingindustrytostandardizeonthecontentofthetrialmasterfile,onthenomenclaturefortrialmasterfileartifactsandonthetaxonomyused.Forclarificationpurposes,thereisnointentionbytheDIAorthemembersoftheReferenceModelProjectfortheTMFReferenceModeltobeconsideredaformalstandard. InSeptember2013non-profitCareLexinitiatedaneTMFstandardsinitiativeundertheOASISstandardsorganizationtodevelopaconsistent,machine-readablecontentclassificationmodelforeTMFs.[8] RationaleforthecreationoftheTMFReferenceModelThisinitiativedidnotreceiveindustrysupportandisnoweffectivelydismantled. TheTMFcontainsthetrialsponsor’sandparticipatinginvestigators’setofcontentwhichindividuallyandcollectivelypermittheevaluationoftheconductofaclinicaltrialandthequalityofthedataproduced.ThesedocumentsservetodemonstratecompliancewiththestandardsofGCPandwithallapplicableregulatoryrequirements.[1]Itispartoftheevidenceprovidedforregulatoryinspectionthatverifiesthatthemembersofthetrialteam:ensuredsubjectprotection,compliancewithregulations/GoodClinicalPractice,andthatscientificallyrobustbenefit-riskdatawasproduced.WhileICHGCPE6detailstheminimumessentialdocuments,itaddressesonlyasub-setofTMFcontentthatisrequiredtobecreatedandavailableforinspection.Documentationrequirementsfortheset-upandmaintenanceofqualitysystems,electronicsystems,safetymonitoring,andproofofanadequateandwell-controlledtrial,tonameafew,existinvariousregulationsacrossmanycountriesorregions,butarenotexplicitlydescribedinICHGCPE6.Sincetherewasnocomprehensive,commonindustrymodelorbestpracticeforaTMF,theobjectiveoftheTMFRMistoprovideasingle,unifiedinterpretationoftheregulationsoftheICHregionsasadocument-typelistingwhichwouldbeacceptedbyallclinicaltrialstakeholdersandwhichcanbeadoptedoradaptedbyanycompany,institutionororganization.Itdoesnotprovideguidanceontheprocessbywhichthecontentiscreated,managedorretained. TMFReferenceModelshortcomings AsofMay2013,theTMFRMv2.0wasmadeavailableinanelectronicspreadsheetformatwhichissuitableforhumanviewing.WhiletheTMFRMisacceptableforpaperTMFs,thereisnosupportforTMFcontentexchangebetweencomputersystems.AstheTMFRMisnotastandardandisthereforenotfixed,theTMFModelallowsforflexibilityinapproachandanyaspectofthemodelcanbechangedtosuitanindividualuser'sneeds.Whilstthisbenefitstheindividualuser,itresultsinvariancesinuseandinterpretationfromonecompanytoanother. OneissuewiththeuseoftheTMFRMasaneTMFclassificationmodelrelatestoduplicateartifactnamesintheTMFRM.ThecurrentreleaseoftheTMFRMv3.0containsseveralduplicateartifactnamessuchas'Communications'or'General',eachwithdifferentcontextsandusesbutthesamename,whichmakestheTMFartifactnamesmorechallengingtoimplementineTMFsearchandretrievalwhereauniquesetofsearchresultsisdesired.[9]AsecondissuewiththeTMFRMrelatestothelengthoftheTMFRMartifactnames-oneartifactnameismorethan64characters.Differentfilesystemshavedifferentlimitsonthedepthofthefilenamepath,creatingpotentialproblemsandlimitationsbasedonthefilesystemhierarchyinuse.[10]Thirdly,withrespecttotheuseoftheTMFReferenceModelasadatabaseschema,theTMFRMv3.0spreadsheetcannotbeusedwithoutmanualmodificationasaclassificationtaxonomyinanelectronicdatabase.[11]Electronicsystemswhicharenotbasedoninteroperabilitystandardsareoftenunabletocommunicatewithothersystemsorapplications.[12]TheTMFRMcurrentlylacksacontrolledvocabularybasedonpublishedstandards,whichmeansthatcontentindexedwiththeTMFRMartifactnamesandtermscouldreturnduplicaterecords,incorrectrecordsorpossiblynorecordsatallifthemodelisnotimplementedappropriately.[13]TheTMFRMdoesn'tprovidestandards-basedmethodstoexchangetheTMFmodelexceptforexchangingspreadsheetcopiesofTMFmodels.TodayinternetstandardssuchasthosepromotedbytheW3Careutilizedforinteroperableelectronicexchangeoverlegacymanualinformationexchangeapproaches. DevelopmentofeTMFContentExchangeStandardsandProtocols InanefforttoassureinteroperabilityofeTMFdataamongclinicaltrialstakeholders,inSeptember2013non-profitCareLexinitiatedaneTMFstandardsinitiativeundertheOASISOpenstandardsdevelopmentorganizationforthedevelopmentofaglobaleTMFISOstandardsupportingseamlesseTMFcontentexchangeandportability.CareLexandSureClinicalIncarethefoundingsponsorsoftheeTMFstandardsinitiative,withparticipationonthecurationofacontrolledvocabularybytheNationalCancerInstitute.[4][5]ThestatedobjectiveoftheeTMFstandardsinitiativeisto"defineanopen,internationallyrecognizedstandardthatwillassureinformationinteroperabilityamongclinicaltrialstakeholdersintheBioPharmaindustry."AccordingtominutesfromtheOASISeTMFstandardTechnicalCommittee,thestandardsinitiativeiscoordinatingtheeffortsofclinicaltrialsponsors,CRO’s,researchorganizations,andvendorstodevelopanISOstandard.[6]ThiseffortdidnotreceiveindustrysupportandhasnowbeendismantledandreplacedbytheTMFReferenceModelExchangeMechanism.[7] AsofFebruary2014,apartiallistofmembersintheOASISeTMFStandardTechnicalCommitteeincludesCareLex,EMC,ForteResearch,HL7,MayoClinic,Oracle,ParagonSolutions,Safe-BioPharma,SterlingBio,andSureClinical.NationalCancerInstituteworkedwiththeOASISteamtocurateeTMFterms.TheTechnicalCommitteewasclosedbyTCAdministrationwithoutpublicationofastandardon17November2017andisnolongeractive.[8] InJune2018,theTMFReferenceModelprojectteampublishedaspecification[9]andanexampleXMLexchangefile[10]foraneTMFExchangeMechanismStandard[11]attheDIAGlobalMeetinginBoston,USA.UseofthisstandardwillhelpfacilitatetheexchangeofTMFcontentbetweensystems. TMFrecentdevelopments[edit] InFebruary2013,theEMA(EuropeanMedicinesAgency)createdadraftguidelinedocumentthatrecognizestheimportanceandlegalequivalenceoftheTMFandtheeTMF,andprovidedguidancetoorganizationsimplementingTMFsandeTMFsystems.Intheguidelinedocument,EMAinspectorsstatethatpaperTMFdocumentsmaybestoredinelectroniceTMFsystems,andafterthisprocess,thatthepapermaybedestroyed.TheuseofeTMFsystemsforelectronicstorageisfullysupportedbytheEMAinclinicaltrialsasareplacementforpaper.Inacautionarystatement,theagencycitesqualityproblemswithTMFsandeTMFsduetodocumentqualityanddiscrepanciessuchasmissingpages,improperlabellingormissingdocuments.[16] InApril2014,theEuropeanParliamentapprovedRegulation(EU)No536/2014onclinicaltrialsonmedicinalproductsforhumanuse,repealingDirective2001/20/EC.[17]Article57oftheRegulationrequiresthattheTMF"shallatalltimescontaintheessentialdocumentsrelatingtothatclinicaltrialwhichallowverificationoftheconductofaclinicaltrialandthequalityofthedatagenerated",confirmingthatthetrialmasterfileshouldbemaintainedcontemporaneously.Article58requiresthat"thesponsorandinvestigatorshallarchivethecontentoftheclinicaltrialmasterfileforatleast25yearsaftertheendoftheclinicaltrial."ThisrequirementdefinesaminimumretentionperiodacrosstheEUforallclinicaltrialmasterfiles,irrespectiveofwhetherthedatasubsequentlysupportsamarketingauthorizationapproval. Companies[edit] Manycontractresearchorganizations(CROs)providedocumentmanagementservicestosupporttrialmasterfilemanagement.Inaddition,thereareasmallnumberofnichecompaniesthatfocusspecificallyonthetrialmasterfile.Theirservicesincludeprocessandqualityconsultancy,managementandfilingoftrialmasterfilecontentandprovisionoftrialmasterfiledocumentmanagementtechnologysolutions(eTMFs). References[edit] ^"ICHGuidelines"(PDF).Archivedfromtheoriginal(PDF)on2011-05-15.Retrieved2013-06-14. ^ICHGoodClinicalPracticeP.47 ^https://tmfrefmodel.files.wordpress.com/2016/03/tmf-reference-model-version-3-0_16-june-20153.xlsx ^"CareLexBuildsSupportforDevelopingInteroperabilityStandardforClinicalTrialDataExchange". ^"TheStartofaNewEraforClinicalTrials".7October2019. ^"OASISOpen:Committees". ^"ExchangeMechanismStandard–TrialMasterFileReferenceModel". ^"OASISOpen:Committees". ^https://tmfrefmodel.files.wordpress.com/2018/06/etmf-ems-v1-0.pdf[bareURLPDF] ^"Exchange-framework".GitHub.7January2022. ^"Archivedcopy".Archivedfromtheoriginalon2018-07-19.Retrieved2018-07-19.{{citeweb}}:CS1maint:archivedcopyastitle(link) 1. TMFReferenceModel 2. EUParliamentDirective2005/28/EC63Chapter4 3. USFDAGuidanceforIndustry 4. TMFReferenceModel2.0 5. EuropeanMedicinesAgency,9.ProblemsfoundwithTrialMasterFilesfromGCPinspections,Jan2013 6. EuropeanECRegulations Retrievedfrom"https://en.wikipedia.org/w/index.php?title=Trial_master_file&oldid=1076972711" Categories:ClinicaltrialsHiddencategories:AllarticleswithbareURLsforcitationsArticleswithbareURLsforcitationsfromMarch2022ArticleswithPDFformatbareURLsforcitationsCS1maint:archivedcopyastitleAllarticleswithunsourcedstatementsArticleswithunsourcedstatementsfromMay2013 Navigationmenu Personaltools NotloggedinTalkContributionsCreateaccountLogin Namespaces ArticleTalk English Views ReadEditViewhistory More Search Navigation MainpageContentsCurrenteventsRandomarticleAboutWikipediaContactusDonate Contribute HelpLearntoeditCommunityportalRecentchangesUploadfile Tools WhatlinkshereRelatedchangesUploadfileSpecialpagesPermanentlinkPageinformationCitethispageWikidataitem Print/export DownloadasPDFPrintableversion Languages Deutsch Editlinks