EnhancingLaboratoryDataInfrastructuretoAccessReal-WorldEvidence(RWE)forinvitro

Diagnostics(IVDs):ThreeModelsforRWEUse

MichaelWaters,Ph.D.Michael.Waters@fda.hhs.gov

OfficeofInVitroDiagnosticsandRadiologicalHealth(OIR)CenterforDevicesandRadiologicalHealth(CDRH)

FoodandDrugAdministration(FDA)

MDEpiNet AnnualMeetingThursday,October19th,2017

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Supporteffortstoharnessnon-traditionalinvitrodiagnostic(IVD)datasourcesto:• supportregulatorydecisionsforIVDsandmorethroughouttheTotalProductLifeCycle(TPLC),

• reduceburdenstothehealthcareecosystemand

• promotedevelopmentofinnovativesolutionstopublichealthchallenges.

SHIELDMission(SystemicHarmonization&InteroperabilityEnhancementforLabData)

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WhatIVDsDo?

• Invitrodiagnostics(IVDs)productsare…intendedforuseindiagnosisofdiseaseorotherconditions...[21CFR809.3]

• Fundamentally,IVDs‘ask’aquestionofaspecimentakenfromahumanbody.

• Theresultthatfollowsisthe‘answer’tothatquestion.

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Registries/EHRs:AccessingRWE

RWD≠‘bad/sketchy’dataRWE≠ lessevidence

‘FitforPurpose’Datamustbecomplete,consistent,accurate,andcontainallcriticaldata

elementsneededtoevaluateamedicaldeviceanditsclaims.

KEY:Coordination/Harmonization(Interoperability)

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Multi-StakeholderIVDSemanticInteroperabilityEfforts

FDAengagedCDISCtoadvocateforLOINCinclusioninIVDsdevice

2013

2015

2016

• DraftGuidances:RWE,Interoperability,NGSDatabase• FDA/CDC/NLM/ONC/CMSLabDataInteroperabilityWkshp• LIVDLaunch• UDIforClassIIDevices

2017

• FinalGuidances:RWE,Interoperability,NGSDatabase• DraftofHL7&FHIRimplementationguide

2014

• Assemblyofmulti-stakeholderconsensusforumforlabdatasemanticinteroperability• UDIforClassIIIdevices

CDISC:ClinicalDataInterchangeStandardsConsortiumLOINC:LogicalObservationsIdentifiersNamesandCodesSNOMED:SystematizedNomenclatureofMedicineLIVD:IVDStructuredDataFormatCDC:CentersforDiseaseControlNLM:Nat’lLibraryofMedicineONC:OfficeoftheNat’lCoordinatorCMS:CenterforMedicareandMedicaidServicesNGS:NextGenerationSequencingHL7:Health-Level7FHIR:FastHealthcareInterchangeResource

• FDA/CDC/NLMLabDataInteroperabilityWkshp•WhitepaperforHarmonizationoflabdata• RecognizedStandards:LOINC,SNOMED• DraftofLIVD

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SHIELDInfrastructure

Function Candidate Coding Elements (partiallist) Transmission Format

DescribeIVDdevice/methodtype

LOINC(LogicalObservationsIdentifiersNamesandCodes)

ComponentPropertyTimeSystemScaleMethod

Structured DataFormat-LIVD

DescribeIVDdevice/methodresult

SNOMED-CT(SystematizedNomenclatureofMedicine– ClinicalTerms)

DetectedNotDetectedInconclusiveTest NotCompleted

Structured DataFormat–LIVDII

UCUM(UnifiedCodeforUnitsofMeasure)

UnitsofMeasures(e.g.grams,etc.)

Structured DataFormat–LIVDII

Unique DeviceIdentification

UDI(FDA UniqueDeviceIdentificationSystem)

Device IdentifierElementsofUDI

Structured DataFormat-LIVD

AssociateddatapopulatedintoLaboratoryInformationSystems(LISs)canbequeried.FastHealthcareInterchangeResource(FHIR)implementationguideisnearcompletion.

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OngoingSHIELDEfforts1. Developingtoolsfortheapplicationofsemanticstandardsin

structureddataformatsthrough:

• step-by-stepmanualdefininghowtomapLOINCtoIVDdevices

• Government/Industry/LaboratoryClinicalIVDSemanticInteroperabilityMeeting– ValueSets(LIVDII)

2. FDAisdevelopingregulatoryguidanceandinter-Office/Centerinfrastructuretodeterminehow/whenregulatorygradeReal-WorldEvidence(RWE)canbeleveragedinregulatorydecisions.

InvolvedStakeholders:FDA(CDRH,CDER,CBER),CDC,NIH,ONC,CMS,IVDManufacturers,EHRVendors,Laboratories,CAP,StandardsDevelopers,Academia

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• LabsoperateundertheClinicalLaboratoryImprovementAmendments(CLIA)regulations

• CMSoverseeslabsthroughtheCollegeofAmericanPathologists(CAP)labaccreditationprogramLabsregularlyconductproficiencytestingofCAPpanelsandsubmitresultstoCAP(formosttests)

• LabsconformtoGoodLaboratoryPractices(GLP;21CFR58&42CFR493)

• Labshavetovalidateoff-labeluseandLaboratoryDevelopedTests(LDTs)

SomeNuancesUniquetoIVDs

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• Lowprevalenceanalytes/patientpopulationsubgroups/rareendpoints/long-termoutcomes(e.g.,patient/healthcareproviderexperience)

• Bringingoff-labeluseon-labelandunderaQualitySystem(leveragingEHRdata;ObservationalStudies)

• LeveragingdatageneratedexternaltotheUnitedStates(leveragingOUSdatathatisfitforUS)

ThreeRWEUseCasesforIVDs*

*Existingexamplesandmodelsforfuture…

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Real-WorldExperience

RWE Use Examples

Modificationofclaimsfromadjunctivetonon-adjunctivetousediagnosticfortreatmentdecisions

RWEExamples

EHR,SurveillanceData

RWEusedtosupportfalsenegativeratecalculations.

ObservationalStudies

Metaanalysis ofobservationalstudiesallowedacomparisonofsubjectdevicetoasimilardevice.

RWEcouldbeusedtosupportlowprevalenceanalyteclaims

EHRData

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• Panelist’sclinicalexperiencewithcurrentoff-labelnon-adjunctiveuseofthemarketeddevice.

• Adiagnosticdevicewasapprovedbasedontraditionalclinicaltrialsandanalyticalstudies. • Directcommentsfromcurrentusersregarding

theirexperiencewithoff-labelnon-adjunctiveuseofthemarketeddeviceincluding:

− publiccommentsfrompatients,caregiversandothermembersofthecommunityimpactedbythedisease.

• PragmaticClinicalTrialwithpatientsusingtheadjunctiveandnon-adjunctivemethods.

• Sponsorsoughtshiftfrom: adjunctive usefollowedbyaninvasivemonitoringprocedureto: non-adjunctive use—whereCGMinformationcanbeuseddirectlytomakediabetestreatmentdecisions.

Real-WorldExperience

RWE Use Examples

Modificationofclaimsfromadjunctivetonon-adjunctivetousediagnosticfortreatmentdecisions

RWEExample1Background/Claim RWE

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EHR,SurveillanceData

RWEusedtosupportfalsenegativeratecalculations.

RWE Use Examples

• LaboratoriesdevelopedandconductedscreeningtestsintheabsenceofanyFDAclearedorapprovedassay.

• Somestatesmandatediseasescreeningtestsduetothehighdiseasemortalityrate.

• Sponsorsoughtdenovoscreeningclaimtoaidinthediagnosisofdisease.

• Atraditionalpivotalstudywasconductedwiththenewdeviceincomparisontotheroutinelaboratoryscreeningtodeterminetruepositives.

• Itwasimpracticaltoperformconfirmatorytesting(orothersuitablefollow-up)onallnegativepatients.

• Thefalsenegative resultratewascalculatedbasedontheclinicalstatusofallpatientswhotestednegative.Publichealthlabsworkedwithdiagnosticcenterstocollectsurveillanceinformationtofollowuponallpatientsintheclinicalstudythatwerediagnosedwithanyofthescreenedconditionsandparticipated(falsenegatives).Therewerenofalsenegatives.

Background/Claim RWE

RWEExample2

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• Clinicalperformanceforthistestwasassessedusingpublisheddata.Meta-analysesofpublishedstudiesofawiderangeofpatientpopulationsforseveraldiseaseswereconductedtocalculatelikelihoodratios(anestimateofhowthetestresultaffectsthechancesofacondition).

• Traditionalanalyticalstudieswereconductedalongwithstudiestodemonstrateusercomprehensionofthelabelingandtestresults.

• Sponsorsoughtdenovoclaimassesstheprobabilitythatapatientisatriskofdevelopingaseriesofdifferentdiseases.

Examples

Metaanalysis ofobservationalstudiesallowedacomparisonofsubjectdevicetoasimilardevice.

RWEExample3

ObservationalStudies

Background/Claim RWE

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Examples

• Forsomeassays,thereisroutineclinicalfollow-upregardlessoftheresultsofthetest.

• Itmaybepossibletoreleasethedevicetomarketwithawell-qualifiedpresumptiveclaimforthedetectionofresistancegenesbasedonanalyticalstudiesandminimalclinicalinformationcollectedintrials.

• post-marketsusceptibility/resistancedataforalldetectedorganismscouldbecollectedalongwiththeobligatereferencemethodtobesubmittedinasecondapplicationtoremovethepresumptivequalifications.

RWEMockExample• Traditionalclinicaltrials

showthatgenestoidentifyaninfectiousorganismcanbedetected,butgenestoinferantibioticresistancearetoolowprevalence.

• Lowprevalenceanalytes/patientpopulationsubgroups/rareendpoints/long-termoutcomes canallbedifficultclaimstoattainanddramaticallyincreasethesizeofaclinicaltrial.

RWEcouldbeusedtosupportlowprevalenceanalyteclaims

EHRData

Background/Claim RWE

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PotentialUseCaseCollaborations

Title: “AddingLightningSpeedtoClinicalLaboratoryDataAssessmentTools- ImplementationofAdd-OnToolsthatwillGenerateSemanticInteroperableLaboratoryDataOutputsfromClinicalTrials(CTs)andElectronicHealthRecords(EHRs)toexpediteanalyticalprocessesusingAcuteKidneyInjury(AKI)asaCaseStudy”Lead: FDA/CDER

Title: “EmergencyMedicineOpioidDataInfrastructure:KeyVenuetoAddressOpioidMorbidityandMortality”Lead: NIH/NIDA

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Conclusions/Requests

• SHIELDimplementationcanunlockRWEsiloedindatarepositorieswhichmaybeleveragedinregulatorydecisions.

• OIRisengagingincross-centerandmulti-stakeholdereffortstoassistintheadoptionofsemanticinteroperabilitystandardsandstructureddataformats.

• Collaborationandsupportiscriticaltorealizingthebenefitsoftheseefforts.