欧盟指导原则 Assessing the Safety and Effectiveness of Home-Use In Vitro Diagnostic Devices IVDs Draft Points to Consider Rega

AssessingtheSafetyandEffectivenessofHome-UseInVitroDiagnosticDevicesIVDs:DraftPointstoConsiderRegardingLabelingandPremarketSubmissionsTextOnlyThisguidancewaswrittenpriortotheFebruary271997implementationofFDAsGoodGuidancePracticesGGPs.ItdoesnotcreateorconferrightsfororonanypersonanddoesnotoperatetobindFDAorthepublic.Analternativeapproachmaybeusedifsuchapproachsatisfiestherequirementsoftheapplicablestatuteregulationsorboth.Thisguidancew川beupdatedinthenextrevisiontoincludethestandardelementsofGGPs.AssessingtheSafetyandEffectivenessofHome-UseInVitroDiagnosticDevicesIVDs:DraftPointstoConsiderRegardingLabelingandPremarketSubmissionsCenterforDevicesandRadiologicalHealthOctober1988PurposeThepurposeofthisdocumentistoassistprospectivemanufacturersproducersandmarketershereinaftercalledmanufacturersofhome-useinvitrodiagnosticdevicesIVDsincomplyingwithexistinglabelingregulationse.g.21CFR

801.

5809.3aand

809.10andpremarketclearancerequirementse.g.Sections510kand515oftheFederalFoodDrugandCosmeticActtheActandregulationsincluding21CFRParts807and

814.Thisdocumentaddresseshome-usetestingkitsandhome-usemail-inspecimencollectionkits.BackgroundInvitrodiagnosticdevicesIVDsasdefinedin21CFR

809.3aarethosereagentsinstrumentsandsystemsintendedforuseinthediagnosisofdiseaseorotherconditionsincludingadeterminationofthestateofhealthinordertocuremitigatetreatorpreventassessingthesafetyandeffectivenessofhome-useIVDs.Consequentlythefollowingadditionalsuggestionsareofferedwithrespecttothegoalsconductandanalysisofsuchstudies.Theprimarygoaloftheconsumerfieldevaluationshouldbetoestablishcomparablelevelsoftestperformanceforaparticularhome-useIVDwhencomparison-testedbybothintendedusersandtrainedlaboratorypersonnel.Itissuggestedthatsplitclinicalsamplesbetestedbybothlayusersandtrainedlaboratorypersonnelwithbothgroupsusingthehome-useIVD.Suchtestingwillsimultaneouslyvalidatethetechnicalperformancecharacteristicsofthedeviceandthedeviceslabelingbasedonuserexperience.InordertoassesstheabilityoflayuserstoproperlyperformandinterprettestresultsCDRHrecommendsthatmanufacturersprovidesimplequestionnairestostudyparticipantsaspartoftheconsumerfieldevaluationtodetermineiflayuserscanreadandunderstandthelabeling.Forexampleaquestionnairecouldbeusedtodetermineiftheuserunderstandsthepurposeofthetesttheconditionsforitsusethetestslimitationsthemeaningoftheresultsandappropriatefollow-upItisrecommendedthatsamplesofsuchquestionnairesbeincludedinapremarketsubmissionaswellasatabulationofallstudyparticipantsresponsestoeachquestion.Layusersselectedforstudyshouldberepresentativeoftargetusersforwhichatestisintended.Arepresentativestudypopulationmayrequiretheselectionofindividualsofvariedbackgroundeducationlevelsandagegroups.Consequentlysubjectsshouldbeselectedfortestingbasedoncarefullydevelopedselectioncriteria.ThebasisforestablishingtheselectioncriteriashouldbesubmittedtoCDRHalongwiththestudyprotocolandtestresults.Thenumberofsubjectsselectedfortestingshouldbesufficienttosubstantiatethatalltargetedlayuserpopulationscanperformandinterpretthetest.Itishighlyrecommendedthatthenumberofsubjectsselectedforstudybebasedonastatisticallyvalidsamplingofrelevantlayusersandshouldtakeintoaccountappropriatedemographicfactors.Moreovertestresultsshouldbeanalyzedusingappropriatestatisticalmethodstodemonstratecorrelationbetweenlayusersandtrainedtechnologistsperformingthetest.Ideallytoavoidpotentialproblemsofbiasduringdatacollectionandevaluationoftheconsumerfieldstudyadoubleblinddesignshouldbeused.Howeverinstudieswheresuchadesignisimpossibleorimpracticalasingleblindapproachandothermeasurestoreducepotentialbiasmaybeacceptable.Themanufacturershouldbecarefultoselecttheappropriatetypeofstudytoensurethatthestudywillprovideappropriateinformation.CDRHbelievesthatbothprospectivemanufacturersofhome-useIVDsandCDRHreviewerswillbebetterabletoevaluatethesafetyandeffectivenessofthesedeviceswhensupportinginformationbasedontheaboveconsiderationsissubmittedtoCDRHinanappropriatepremarketsubmission.MoreoverCDRHbelievesthatasaresultoftheseconsiderationsthegeneralpublichealthwillbebetterservedbytheavailabilityofmeaningfulandreliablehome-useIVDs.10/5/88diseaseoritssequelae.Theseproductsareintendedforuseinthecollectionpreparationandexaminationofspecimenstakenfromthehumanbody.TraditionallyIVDshavebeenusedprimarilybyhospitalsclinicallaboratoriesandphysiciansoffices.Inrecentyearshowevertherehasbeenincreasinginterestinhome-useIVDswherenophysicianisinvolvedtointerpretthetestresults.BecauseofthisgrowinginterestFDAsCenterforDevicesandRadiologicalHealthCDRHanticipatesreceivinganincreasingnumberofpremarketproductsubmissionsi.e.premarketnotificationsorpremarketapprovalapplicationsforthesedevices.ConsequentlyCDRHbelievesthatuniformevaluationcriteriaforhome-useIVDsareneededtobetterensurethatthesedevicesareregulatedinaconsistentfashionandthatconsumersareprovidedwithreliableusefulandadequatelylabeledproducts.Tothisendinthespringof1985CDRHsolicitedviewsfromvariousindustryconsumerandhealthprofessionalorganizationstohelpidentifytheissuestoberesolvedbyCDRHindevelopingevaluationcriteriaforhome-useIVDs.TnadditiononSeptember91985CDRHconvenedapublicmeetingofthechairpersonstheconsumerrepresentativesandtheindustryrepresentativesoftheImmunologyDevicesPaneltheMicrobiologyDevicesPaneltheHematologyandPathologyDevicesPanelandtheClinicalChemistryandClinicalToxicologyDevicesPanel.Thepurposeofthismeetingwastosolicittheviewsoftheseindividualsandotherinterestedpersonsregardinggeneralissuesofthesafetyandeffectivenessofhome-useIVDs.ThepresentdocumentreflectsCDRH，sviewsonkeypointstobeconsideredinestablishingthesafeandeffectiveuseofhome-useIVDs.TheseviewsaresignificantlybasedontheinputCDRHhasreceivedfromtheaforementionedoutreachactivities.FactorsCDRHwillConsiderinEvaluatingtheSafetyandEffectivenessofHome-useIVDsPerformanceConsiderationsAkeyfactorCDRHmustconsiderinassessingthesafetyandeffectivenessofhome-useIVDsistestperformance.Becausethegreatmajorityofproposedhome-useIVDsarelikelytobederivedfromprofessional-useIVDsitisexpectedthattherewillbeaclearandestablishedrelationshipbetweentheanalytetobetestedusingthehome-useIVDandaspecificmedicaldisorderorcondition.Becausehome-useIVDsfunctionessentiallythesameasprofessional-useIVDstheirperformancecharacteristicscanbedefinedintermsoftraditionalperformanceparameterssuchassensitivityspecificityaccuracyandreproducibilityoftestresults.Neverthelesstheperformanceofthedeviceinthehandsofskilledusersmaynotreflectthedevicesperformanceinthehandsoflayusers.Consequentlymanufacturersofhome-useTVDsshouldfocustheirattentiononthefollowingperformanceconsiderations:Foragivenintendedusetheabilityofthehome-useIVDtodetectand/ormeasureaparticularanalyteofinterestanalyticalperformanceshouldbecomparabletotheperformanceofIVDsintendedforthesamepurposethatareusedbyprofessionalsinclinicalsettings;Home-useIVDsshouldbedesignedwithaviewtoensuringthatthedevice*sperformancewillnotbeappreciablyaffectedbyanticipatedvariationinusertechnique;andHome-useIVDsshouldincludeasimplemethodbywhichtheusercanreasonablyverifythattheproduct*sperformancemeetsitsdesignspecificationsatthetimeofuse.Ideallyauserqualitycontroltestshouldbeprovidedor“builtintoeachhome-useIVDsee21CFR

809.10a

6.Omissionofsuchatestorotherreasonablemeansofverifyingproductperformanceshouldbejustifiedbasedonscientificmerit.Risk/BenefitConsiderationsHome-useIVDsaredifferentfromclinicallaboratorydevicesinfourimportantways:1thepersonperformingthetestorreviewingtheresultsreturnedfromaclinicallaboratorylikelylacksthenecessarymedicaltrainingtoevaluateotherrelatedmedicalinformationsuchaspertinentpersonalorfamilymedicalhistoryotheranalytelevelsandtheresultsofacompletephysicalexamination;2thepersonperformingthetestmaylackthetechnicaltrainingoflaboratorytechnologistswhotraditionallyhaveperformedlaboratorytestsandmaynotinterpretdirectionscarefully;3thepersonperformingthetestmayormaynotcarryoutnecessaryfollow-upactionsonthebasisoftestresults;and4thepersoncollectingasampleofabodyspecimenandmailingittoaclinicallaboratorygenerallylacksthetechnicaltrainingofpersonswhotraditionallyhavecollectedorsupervisedthecollectionofbodyspecimensandsupervisedthetransportofthespecimenstothetestlaboratory.Thusthepersonmaynotensurethatthespecimenthatarrivesattheclinicallaboratoryisinthesameconditionasitwaswhenitwascollectede.g.ensuringthattheanalytetobemeasureddoesnotdegradebecauseofpassageofalongperiodoftimefromspecimencollectionuntilanalysisorensuringthataspecimenisnotexposedtoextremesofhotorcoldtemperaturesorotherenvironmentalhazardsthatmayaffectthetestresults.Henceinevaluatinghome-useIVDsCDRHmustconsiderprobablehealthbenefitstobegainedintheuseofsuchdevicescomparedtotheprobablerisksassociatedwiththeiruse.Inthiscontextconsiderationofbenefitandriskisinherentintheevaluationofsafetyandeffectiveness.Whentheuseofanin-homeIVDcanbedemonstratedtobesubstantiallyequivalentintermsofsafetyandeffectivenesstoaclinicallaboratorydevicewhenusedbyahealthprofessionalandthedevicemeetsalllabelingandotherregulatoryandstatutoryrequirementsitwillgenerallysatisfyrequirementsformarketclearance.WhenuniqueissuesofsafetyandeffectivenessariseandsubstantialequivalencecannotbedemonstratedCDRHwillnonethelessevaluatebenefitandriskfactorsinmakingdeterminationswithrespecttothemarketabilityofin-homeIVDs.ForpurposeofassessingthesebenefitandriskfactorsCDRHwillconsiderthefollowingquestionsandencourageapplicantstoproviderelevantinformationintheirsubmissions.BenefitsWhatistheclinicalbenefitofthetesttothepatientorsocietypublichealthintermsofscreeningdiagnosingormonitoringaparticulardiseaseconditionorriskfactorWhatarethebenefitstothepatientorsocietyofhavingthetestavailableforhome-useasopposedtohavingthetestperformedonlybyhealthcareprofessionalsRisksWhatistheimpactontheuserortosocietyofafalse-positiveorfalse-negativetestresulte.g.intermsofuserfollow-uporadversemedicalconditionsWhataretheriskstotheuserorsocietyintermsofdelayinobtainingaprofessionalexaminationifaproposedhome-useIVDthatisintendedforuseonsymptomaticsubjectsgivesafalseorequivocalresultCDRHrecognizesthatforevaluationpurposesresponsestothesequestionscanvarybasedonthetypeofproductbeingconsidered.C.LabelingConsiderationsAcceptabilityofhome-useIVDlabelingwilldependuponwhethersuchlabelingmeetsthecriteriaforadequatedirectionsforuseasprovidedforinsection502f1oftheActanddefinedby21CFR

801.5andtherequirementsofSubpartCof21CFRPart

801.Inadditionhome-useIVDswillbedeemedtobeincompliancewiththerequirementsforadequatedirectionsforuseiftheymeettherequirementsof21CFR

809.10-LabelingforInVitroDiagnosticProducts.Inherentintheconceptof“adequatedirectionsforuse“istheneedforthelabelingofhome-useIVDstobesimpleconciseeasytounderstandmake1iberaluseofillustrationsanddrawingsuseboldprintorothermethodstohighlightwarningsandprecautionsandprovidecolorcodingofreagentcontainerswheneverpracticable.LabelingforIVDsintendedforhomeandprofessionalusearecoveredby21CFR

809.

10.Thefollowingelaboratesontheapplicationoftheregulationtothehome-usesituationandsuggestsmeansofaccomplishingcompliance:Section

809.10aTheintendedusestatementsection

809.10a2shouldclearlyindicateontheoutsidepackagingcontainerthetypeofprocedurethatisofferedi.e.screeningmonitoringordiagnosticandthespecificdisorderconditionorriskfactorofinterestforwhichthetestisintended.Inadditionastatementalsoshouldbepresentedindicatingwhoshouldusethetestandtheconditionsforitsusefollowedbyacontraindicationstatementsifnecessary.Thequantityproportionconcentrationoractivityofeachreactiveingredientincludedwiththetestkitneedonlybepresentedasspecifiedbysection

809.10a3wheninformationisnecessaryforproperlayuseofthetest.Section

809.10bTheorderandscopeoftheinformationspecifiedbythissectionshouldbeasfollows:Theintendedusestatementshouldreiteratetheinformationrequiredundersection80910a.Section

809.10b3summaryandexplanationofthetestmaybecombinedwithsection

809.10b4principlesoftheprocedure.Thiscombinationofsectionsshouldincludeadiscussionofboththemedicalbenefitsandlimitationsofthetestwithrespecttoitsintendeduseinadditiontoprovidingasimpleexplanationofhowthetestworks.Presentationofchemicalreactionsorformulasarenotnecessarybutmaybereferencedinthebibliographysection

809.10b

13.Aseparateinformationsectionrelatingtointerpretationoftestresultsshouldbepresentedandincludeinformationspecifiedbysection

809.10b10limitationsoftheprocedure.Thissectionshouldindicatethesignificanceofthetestresultsinlightofthetestsintendeduseandprovidespecificinformationastowhatappropriatefollow-upactionshouldbetakenbytheuser.Additionallythissectionshouldexplainthemeaningoffalse-positiveandfalse-negativetestresultsandcitepossiblesourcesandimplicationsoffalseresults.Aseparateinformationsectionshouldbepresentedwhichidentifiesanyfoodsmedicationsorotherpossibleinterferingsubstancesthatwouldaffecttestresults.Suchinformationshouldspecifywhatsubstancesshouldbeavoidedandforhowlongpriortotesting.Informationspecifiedinsections

809.10b567and8maybecombinedintoasingleinformationsectioni.e.testprocedure.Allinformationspecifiedbytheseindividualsectionsshouldbepresentedinthecombinedsectionifapplicableinadditiontothefollowing:aspreviouslystatedthequantityproportionconcentrationoractivityofeachreactiveingredientincludedinthetestkitneednotbepresentedunlessthisinformationisnecessaryforproperuseofthetest.HoweversuchinformationshouldbepresentedelsewhereinapremarketsubmissionforCDRHreview.discussionofspecimencollectionpreparationandanalysisstepsshouldbeenhancedbytheuseofpicturesandillustrationspreferablyincolor.Informationspecifiedbysection

809.10b9testresultsshouldbepresented.Thissectionalsoshouldincludetrouble-shootinginformationwhereapplicable.Informationspecifiedbysections

809.10b11and12maybecombinedintoasingleinformationsectioni.e.testperformancecharacteristicsmissectionshouldsummarizethedataseparatelyfromboththelaboratoryevaluationandtheconsumerfieldevaluationseeITIPremarketEvaluationConsiderationsandshouldincludeaconcisediscussionofthestudyprotocolsusedtoevaluatethetest，sperformance.Alsodiscussionand/orpresentationofdatarelativetothetestsaccuracyshouldbepresentedandincludefalse-positiveandfalse-negativelevels.Suchinformationshouldbepresentedforboththelaboratoryandtheconsumerfieldevaluations.Sections

809.10b1314and15shouldbeaddressedinthesamemannerasotherIVDs.InadditionCDRHrecommendsthatmanufacturersprovideuserswithatoll-freetelephonenumberoranaddresstowritetoshouldquestionsoccurconcerningtheuseofthedevice.FinallyCDRHisconcernedthatconsumersbeawareofsignificantchangesinhome-useIVDlabeling;particularlylabelingaccompanyinghighfrequencyusedevicessuchashome-useglucosetestdevices.CDRHadvisesmanufacturerstoalertconsumersofsignificantlabelingchangesbyincludingspecialinsertswithdevicepackagingwhichhighlightkeylabelingchanges.MoreoverCDRHadvisesmanufacturersthatlabelingchangesthatsignificantlyimpactonadevicessafeandeffectiveusemayrequirepremarketreviewandclearancebyCDRHbeforecommercialdistributionofdevicesbearingsuchlabeling.D.PremarketEvaluationConsiderationsGiventheaboveconsiderationsCDRHrecommendsthatprospectivemanufacturersofhome-useIVDsconductthefollowingperformancestudiesandsubmitresultstoCDRHforreviewinanappropriatepremarketsubmission:A.Alaboratoryevaluationoftheanalyticalperformanceofthedevicee.g.analyticalsensitivityanalyticalspecificityaccuracyandreproducibilityshouldbedonebyperformingstandardlaboratorymeasurementsusingappropriatereferencetests.Thepurposeofthisevaluationistoestablishthetrueperformancecharacteristicsofthedeviceasdeterminedundercontrolledlaboratoryconditions;andAconsumerfieldevaluationofthedeviceshouldbeconductedtodeterminethedcvice，sperformancewhenusedbylayusersunassistedfollowinginstructionsprovidedinthelabeling.CDRHplacesconsiderableimportanceontheoutcomeoftheconsumerfieldevaluationitemBabovein。