CE 临床数据评估 官方指南

CE临床数据评估官方指南onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECNB-MED/2.7/Rec3Title:EvaluationofclinicaldataChapter:2.7Clinicalinvestigations,clinicalevaluationText:...Keywords:Clinicaldata,EvaluationArationaleandhistorysheetisavailable;pleasecontactTechnicalSecretariat.ReferencetoDirectives:Article/Annex:Referencetostandards:AIMDAnnex1(I.1,I.2,I.5),Annex7MDDAnnexI(I.1,I.3,I.6),AnnexXIVDStageproposedbyRev.-Nr.Rev.dateacceptedamendedwithdrawnPage3taskforce511.05.9908.06.991/141.IntroductionandpurposeItistheprimarypurposeofthisdocumenttoprovideguidancetoNotifiedBodieswhenreviewingthemanufacturersevaluationofclinicaldataaspartoftheconfor-mityassessmentproceduresrequiredby90/385/EEC(AIMD)[1]and93/42/EEC(MDD)[2].Thisdocumentwillalsoassistmanufacturers,byprovidingguidanceonwhatisex-pected.Itisnotthepurposeofthisdocumenttodefinethecircumstancesunderwhichclini-caldataareprovidedandtheextentofclinicaldataneededinrelationtoaparticularmedicaldevice.2.BackgroundThemanufacturermustdemonstratethathisintendedpurpose(s)andclaim(s)madeinrelationtosafetyandperformanceareachieved,asreferredtointheDirectives.Asageneralrule,suchdemonstrationwillrequireclinicaldata(seeAnnexX,1.1ofMDD).EvaluationofclinicaldataasdescribedinAnnexXoftheMDDandAnnex7oftheAIMDisparticularlyrelevanttoassessmentofconformitywithessentialrequirementsgiveninMDD,AnnexI,IGeneralrequirements,sections1and3andAIMDAnnex1,NB-MED/2.7/Rec3onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECTitle:EvaluationofclinicaldataIGeneralrequirements,sections1and2.AttentionshouldalsobepaidtoAnnexI,I.6(MDD)andAnnex1,I.5(AIMD).3.ExplanationoftermsForthepurposeofthisdocument:3.1.Clinicaldataisdatawhichisrelevanttothevariousaspectsoftheclinicalsafetyandperformanceofthedevice.Thismayincludedatafromprospectiveandretrospectiveclinicalinvestigationsofthedeviceconcernedaswellasmarketexperienceofthesameorsimilardevicesandmedicalproceduresandinformationfromthescientificliterature.3.2.TheEvaluationofclinicaldataistheprocessbywhichclinicaldatafromallse-lectedsources(literature,resultsofclinicalinvestigationsandother)isas-sessedtoestablishconformityofthedevicewiththepertinentessentialre-quirementsoftheDirective,andtodemonstratethatthedeviceperformsasintendedbythemanufacturer.Theoutcomeofthisprocessisareportwhichincludesaconclusionontheacceptabilityofrisksandsideeffectswhenweighedagainsttheintendedbenefitsofthedevice.4.ClinicaldatatobeprovidedbythemanufacturerAsageneralrule,andinparticularinthecaseofimplantabledevicesanddevicesinClassIII,evidenceoftheclinicalperformanceandsafetyofamedicaldeviceispro-videdbymeansofclinicaldata,whichissuppliedbythemanufacturerinaccordancewithAnnexX(MDD)orAnnex7(AIMD).Alltheconformityassessmentproceduresleadingto”CE”markingaddresstheissueofclinicalevaluationbythemanufacturer.InthecaseofAnnexesIIandIII,theNotifiedBodyisinvolved.Clinicalevaluationisbasedontheassessmentoftherisksandthebenefits,associ-atedwithuseofthedevice,througheither1.Acompilationofrelevantscientificliterature,thatiscurrentlyavailableaswellas,whereappropriate,awrittenreportcontainingacriticalevaluationofthiscompilation(the"literatureroute")or2.Theresultsofalltheclinicalinvestigationsmade(the"clinicalinvestigationroute"),orNB-MED/2.7/Rec3onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECTitle:Evaluationofclinicaldata3.acombinationof1and2above.Wheretheclinicalevaluationisbasedonsuchacombinationof1and2,itshouldincludeanoverallassessment.Itisimportantthatthemanufacturerrelatesthedatatothespecificdevice,havingregardtothehazardsidentified(see4.1).Themanufacturermustdecidewhethertheavailabledataissufficienttodemon-strateconformitywiththeDirective,havingregardto(a)thesimilarityofthecharac-teristicsofthedevice(s)towhichthedatarelatesandthedevice(s)forwhichcon-formityisbeingassessed,andsotheapplicabilityofthefindingstothedevicesbeingassessed,and(b)theadequacyofthedatainaddressingtherelevantaspectsofDirectiveconformity.NOTEIftheavailableliteratureissufficienttodemonstrateconformitywiththeDirective,therewillbeethicalconsiderationsassociatedwithperformingfurtherclinicalinvestigations(e.g.delayinavailabilityofagivendeviceleadingtothelossofbenefitofthisdevice).4.1.IdentificationofaspectsofsafetyandperformancetobeaddressedthroughclinicaldataThemanufacturerisrequiredbytheDirectivetoperformariskanalysis.Ariskanalysisisimportantinhelpingthemanufactureridentifyknownorreasonablyfore-seeablehazardsassociatedwithuseofthedevice,anddecidehowbesttoestimatetherisksassociatedwitheachhazard1.Fromtheresultsoftheriskanalysis,themanufacturerlaysouthoweachriskisaddressedanddecidesontheacceptabilityofriskswhenweighedagainsttheintendedbenefits.Theriskanalysisincludestechnicalandclinicalaspectsrelatingtotheparticulardeviceconcerned.1Theloss/absenceoftheperformanceofagivendeviceasclaimedbythemanufacturerandwhichcouldresultinthelossofbenefitofatreatmentmaybeconsideredahazard.NB-MED/2.7/Rec3onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECTitle:EvaluationofclinicaldataItshoulddistinguishbetweenaspectsassociatedwith(i)themedicalprocedureforwhichthedeviceisintended,Forexample,therisksversusbenefitsassociatedwithextracorporeallithotripsyascomparedwithconventional(surgicalandnotsurgical)methodsofkidneystoneremoval.(ii)thetechnicalsolutionsadopted,Forexampletherisksversusbenefitsassociatedwithdifferenttechnologiesofextracorporeallithotripsysuchasthoseinvolvinggeneratingshock-waveswithelectricsparks(electrohydraulicmethod),withanelectromagneticgeneratororapiezoelectricsystem.(iii)aspectsspecifictothedesignanduseoftheparticulardeviceconcerned.Forexampletherisksversusbenefitsassociatedwiththeshockwavecouplingmethod,sizeofthefocalzone,thestonelocalisationandtargetingsystem(X-ray,ultrasound)andthetriggermethodThisdistinctionshouldbeusedtoidentifythetypeandspecificityofclinicaldataneeded.Wheretheavailabledataisnotsufficienttoaddresstheidentifiedclinicalhazardsrelatingtooneormoreoftheaboveaspects,aclinicalinvestigationwillbeneeded(seealsosection4.3.1).Theobjectivesoftheclinicalinvestigationshouldfocusonthoseaspectsnotsufficientlyaddressedbytheavailabledata.route4.2.LiteratureIfthemanufacturer'sclinicalevaluationtobesubmittedtotheNotifiedBodytakestheformofareviewoftherelevantscientificliterature,thefollowingrequirementsshouldbefulfilled:4.2.1.Compilationoftherelevantliteraturea)Thecompilationshouldberelatedtothehazardsidentifiedintheclinicalpartoftheriskanalysis(see4.1.),andsupporttheargumentssetoutinthereport.b)Publishedliteratureshouldbetakenfromrecognizedscientificpublicationsin-cludingunfavourableaswellasfavourabledata.NB-MED/2.7/Rec3onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECTitle:EvaluationofclinicaldataFactorswhichmayinfluencethescientificvalidityofthepublishedliteraturein-clude:i)whetherornottheauthor'sconclusionsaresubstantiatedbytheavailabledata;ii)theextenttowhichthepublishedliteratureistheoutcomeofastudy,fol-lowingscientificprinciplesforexample,inhavingdemonstrableandap-propriateendpoints,inclusionandexclusioncriteriaandanappropriateandvalidatednumberofpatientssubmitted.iii)whetherornottheliteraturestillreflectsthe“generallyacknowledged”stateoftheart;iv)therelevanceoftheauthor'sbackgroundandexpertiseinrelationtotheparticulardeviceand/ormedicalprocedureinvolved;andv)lackofimpartiality.c)Otherscientificdata,suchasthedocumentedresultsofthemanufacturersbenchtesting,includinginvitrotestingandanimalstudies,andanassessmentofcompliancewithrelevanttechnicalstandards,maybenecessaryto(i)alone,orincombinationwithotherdata,demonstratecompliancewithrele-vantessentialrequirementsoftheDirectives;(ii)establishtheextentofsimilaritybetweendevice(s)andmedicalprocedure(s)coveredbythescientificliteratureandthecharacteristicsofthedevicebeingassessed.d)Forwell-establishedorsimpledevices,documentedexpertopinionswithra-tionalefromdulyqualifiedmedicalpractitioner(s)orotherexpert(s)suitablyqualifiedintheareaconcernedcanalsobeusedtodemonstratesafetyandperformance.Inselectingsuchexpert(s),themanufacturershouldgiveduere-gardtotheirbackgroundandexpertiseinrelationtotheareaconcernedandanyconflictofinterestwhichmaycompromiseimpartiality.Suchanexpertopinionshouldbesignedanddatedbytheauthor.report4.2.2.Writtena)Awrittenreportcontainingacriticalevaluationisrequired,unlessajustificationforitsabsenceisgiven,e.g.iftheparticulardeviceitselfisthesubjectofthepublicationandthecriticalevaluationofrisksandintendedbenefitsisalreadyadequatelycoveredbythepublication.b)Thereportshouldbewrittenbyapersonsuitablyqualifiedintherelevantfieldandknowledgeableinthestate-of-the-art.NB-MED/2.7/Rec3onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECTitle:Evaluationofclinicaldatac)Thereportshouldbebasedonthescientificliteratureconsidered,andshouldbeaccompaniedbyalistingandcopyofthepublicationsquoted.d)Thereportshouldberelateddirectlytothedeviceundercertification.e)Thereportshoulddiscussallthereferencedscientificliteratureandshouldad-dressunfavourableaswellasfavourabledataf)Thereportshouldcontainashortdescriptionofthemedicaldeviceanditsin-tendedfunctions,adescriptionoftheintendedpurposeandtheapplicationofthedeviceaswellastheindicationsandcontraindicationsforitsuse.g)Thereportshouldclearlyestablishtheextenttowhichtheliteraturerelatestothespecificcharacteristicsandfeaturesofthedevicebeingassessed.Thisshouldtakedueaccountoftheextentofsimilaritybetweenthedevice(s)cov-eredbytheliteratureandthedevicenowbeingassessed,andthereforerele-vanceintheareasof,forexample,design,technology,principlesofoperation,criticalperformancecharacteristics,specifiedconditionsforuseetc.h)Thereportshoulddemonstratethatthoseaspectsofuseofthedevice,includ-ingperformance,addressedintheclinicalpartoftheriskanalysisaremetasclaimedbythemanufacturer,andthatthedevicefulfilsitsintendedpurposeasamedicaldevice.i)Theidentifiedhazards,theassociatedrisksandtheappropriatesafetymeas-uresforpatients,medicalstaffandthirdpartiesshouldbecoveredinthereport,forexamplebyreferencetothemanufacturer’sriskanalysis.j)Arisk/benefitassessment,whichjustifiestheacceptabilityofeachremainingriskwhenweighedagainsttheintendedbenefitsfromuseofthedevice,shouldbeincluded.k)Thereportshouldcontainappropriatecross-referencestotheattachedpubli-cations.l)Marketexperienceofthesameorsimilardevicescanformpartofthereport.m)Resultsoflaboratorytesting,biocompatibilityandcompliancewithtechnicalstandards,orreferencetotheseresults,ifavailable,canadditionallybeusedinthereporttodemonstratecompliancewithcertainessentialrequirementsandtherelevanceofthescientificliteraturethatisreferredto.NB-MED/2.7/Rec3onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECTitle:Evaluationofclinicaldatan)Statementsconcerningthefieldofuseofthedeviceanditsindications,con-traindications,effectsandsideeffectsshouldbeconsistentwiththeinstructionsforuse.o)Thereportshouldgiveaconcludingopinionwithrationale.p)Thereportshouldbesignedanddatedbytheauthor.4.3.Clinicalinvestigationsroute4.3.1.NeedforclinicalinvestigationsWhenreviewingthemanufacturer’sevaluationofclinicaldataandwhetherornotaclinicalinvestigationisneededaspartofthis,dueregardshouldbepaidtoNB-MED/2.7/R1[5].4.3.2.ConductofclinicalinvestigationsWheretheresultsofclinicalinvestigationsformpartoftheclinicaldata,theclinicalinvestigationsshouldcomplywiththerelevantsectionsofAnnexXMDDorAnnex7AIMD.CompliancewiththeEN540[3]carriesthepresumptionthatthedesignandconductandmonitoringoftheclinicalinvestigationconformswiththerequirementsoftheseAnnexes.Whilstnotcarryingsuchapresumptionofconformity,otherequivalentstandardsmaybeused.2[4]4.3.3.TheresultsandfinalreportoftheclinicalinvestigationThedocumentationonaclinicalinvestigationshouldinclude:1.Theidentificationofthemedicaldevicewhichisthesubjectoftheclinicalin-vestigation,consistingofshortdescriptionofthedevice.Thisdescriptionshouldbesufficienttoaddressalltheaspectsrelevanttotheclinicalinvestigation.Itshouldincludeinparticular:-normaluse,intendedpurpose,indications,contraindications-performanceasclaimedbythemanufacturer2.Acleardefinitionoftheobjectivesoftheclinicalinvestigation2Wherejustified,theNotifiedBodymayrequirefurtherinformationtoassessthemanufacturersclinicalinvestigationdata.NB-MED/2.7/Rec3onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECTitle:Evaluationofclinicaldata3.Methodology-enrolmentofsubjects,includinginclusionandexclusioncriteria,rateofen-rolment,numbersandgrouping-studystartandcompletiondates-medicalproceduresinvolved-appropriate,objectiveendpointswhich,ifachieved,demonstratetherequiredsafetyandperformances-parametersassessed,withfrequencyandmethodsofassessmentanddataacquisition-statisticalmethods4.Resultsandconclusion-detailsofanydeviationsfromtheagreedClinicalInvestigationPlan,withthereasonsandanyresultingamendmentstotheClinicalInvestigationPlanfortheremainderoftheClinicalInvestigation,togetherwiththeimplicationsforinterpretationofresults.NOTEInthecaseofmulti-centreinvestigations,itshouldbemadeclearwhetherdeviationsandanysubsequentamendmentsand/oradditionalordifferenttreatmentofresultsapplytoalloronlyparticularcentres-criticalevaluationofallthedatacollectedduringtheclinicalinvestigation-appraisalofclinicalrelevance-demonstrationthattheobjectivesoftheclinicalinvestigationhavebeenmetinthecontextoftheoverallassessmentofthedevice'ssafetyandperform-ance.5.Dateandsignatureoftheresponsibleinvestigator.NB-MED/2.7/Rec3onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECTitle:Evaluationofclinicaldata5.TheroleoftheNotifiedBodyWithregardtotheevaluationofclinicaldatatheNotifiedBodyhasdifferentrolesdependingontheconformityassessmentprocedurefollowed.Aspartofthedesign/typeexaminationunderAnnexesII.4orIII,theNotifiedBodyassessestheclinicaldataassembledbythemanufacturerandthemanufacturer’sevaluationandthevalidityoftheconclusionsdrawn.(see5.1)AspartofqualitysystemapprovalunderAnnexII.3,theNotifiedBodyassessesthemanufacturer’sprocedureforclinicaldataevaluation.Thismayincludeareviewofexamplesofsuchevaluations.(see5.2)5.1.Examinationofadesigndossier(AnnexII.4)orofatypeexaminationdossier(AnnexIII)TheNotifiedBody(NB)examinesthedocumentationsubmittedaccordingtothepre-cedingsections.Inordertodoso,theNBshouldpossessenoughknowledgeandexperienceinclinicalevaluationasstatedinsection6ofthisdocument.making5.1.1.DecisionInreviewingtheevaluationofclinicaldatasubmittedbythemanufacturer,theNotifiedBodydecideswhetherornotthemanufacturerhasadequately:a)describedandverifiedtheintendedcharacteristicsandperformancesrelatedtoclinicalaspects.b)performedariskanalysisandestimatedtheundesirablesideeffects.c)concludedonthebasisofdocumentedjustificationthattherisksareacceptablewhenweighedagainsttheintendedbenefits.TheassessmentcarriedoutbytheNotifiedBodywilltypicallycoverthefollowingaspectsofthemanufacturer’sclinicaldataevaluation:1.Thelistingandcharacterisationoftheclinicalperformanceofthedevicein-tendedbythemanufacturerandtheexpectedbenefitsforthepatient2.Theuseofthelistofidentifiedhazardstobeaddressedthroughevaluationofclinicaldataasdescribedinparagraph4.1.ofthisdocumentNB-MED/2.7/Rec3onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECTitle:Evaluationofclinicaldata3.Theadequateestimationoftheassociatedrisksforeachidentifiedhazardby:a)characterisingtheseverityofthehazardb)estimatingandcharacterisingtheprobabilityofoccurrenceoftheharm(orhealthimpairmentorlossofbenefitofthetreatment)(documentwithra-tionale)4.Thedecisionontheacceptabilityofrisksinrelationtoeachidentifiedhazard,basedonthecombinationof1,3a,and3busingtheALARP3philosophy[6,7],andcharacterisationofthecorrespondingrisk/benefitratioas:-unacceptableor-broadlyacceptableor-acceptableunderspecifiedconditions4(seeISO/IECGuide51[9])5.1.2.ThereportoftheNotifiedBodyTheNotifiedBodywritesareportonitsassessmentofthesubmittedclinicaldocu-mentation.ThereportmaybeaseparatereportorpartoftheNotifiedBody’soverallreport.Inthelattercasetheclinicalpartshouldbeclearlyidentified.TheNotifiedBody’sreportshouldinclude:-Identificationofthemanufacturer-Identificationofthemedicaldevice-Basisofevaluation(whichDirectiveandwhichAnnex(es))-Submitteddocuments-Descriptionofthedevice-Assessmentofclinicalsafetyandperformance-Conclusion.TheNBshouldjustifyanddocumenteachstepofthedecisionmakingprocessreferredin5.1.1.Onesingle“unacceptablerisk/benefitratio”leadstoanegativeconclusion.53ALARPmeans"AsLowAsReasonablyPracticable"4Theassessmentofarisk/benefitratioas”acceptableunderspecifiedconditions”impliesthedeterminationofthosespecifiedconditionsunderwhichitcanbeaccepted.Atthestageofassessment,theexpectedbenefittothepatient,aswellastherisk,hastotakeaccountofthegenerallyacknowledgedstateoftheart.5Insomecases,thecombinationoftheconditionsspecifiedinordertocharacterisedifferentRisk/benefitratiosasacceptablemaybecontradictoryorimpracticable,andsoalsoleadstoanegativeconclusion.NB-MED/2.7/Rec3onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECTitle:Evaluationofclinicaldata-thenamesofallNBinternalassessorsandexternalexpertsinvolvedintheas-sessmentofthemanufacturersdocumentation,togetherwithdetailsoftheas-pectsassessedbyeach-Dateandsignatureoftheresponsibleassessor5.2.Evaluationaspartofqualitysystemrelatedprocedures(AnnexII.3)5.2.1.ReviewoftheproceduresWhenthemanufacturerselectsthisprocedure,theNotifiedBodyshould,aspartofthereviewofthemanufacturer’squalitysystem,assesstheestablishment,mainte-nanceandapplicationofthemanufacturer’sproceduresforthedocumentedevalua-tionofclinicaldata.Thisshouldcover:a)theresponsibilityfortheevaluationoftheclinicaldatabyasuitablyqualifiedperson;b)theidentificationofclinicaldata,bothunpublished(forexamplecontainedinthemanufacturersfilese.g.thecomplaintshistory)andpublished.c)therelevanceoftheclinicaldataidentifiedasdemonstratingcompliancewithparticularrequirementsoftheDirectiveorcitedinparticularaspectsoftheriskanalysis6.d)assuringthatclinicalinvestigationsareperformedincompliancewiththeappli-cableregulationsandtheclinicalinvestigationplan,withasuitablejustificationforanydeviationse)identificationandevaluationofundesirableside-effects.Thislatterpointinvolvesidentificationofknownorreasonablyforeseeablehazards,qualificationoftheirseverityandoftheirprobabilityofoccurrence.Itispartofthemanufacturer’sdocumentedriskanalysisbasedonbothfavourableandunfavourabledataidentifiedasrelevantinordertogiveabalancedview.5.2.2.Reviewofsamples6Therecordofthismaytaketheformofrelevantentriesinthe“ERChecklist”ortheriskanalysisdocumentwithinthemanufacturer’stechnicaldocumentation(checkwith“Explanationofterms”)NB-MED/2.7/Rec3onCouncilDirectives90/385/EEC,93/42/EECand98/79/ECTitle:EvaluationofclinicaldataTheNotifiedBody,whenreviewingsamplesofthemanufacturer’sclinicaldataevaluation,shouldpayspecialattentiontothefollowing:(a)whetherornotthedataisrelevanttothedeviceormedicalprocedureinvolved;(b)wherethemanufacturer,intheselectedsample,haschosenthe“literatureroute”(see4.2.),whetherthecriteriadefinedin4.2.havebeenapplied;(c)wherethemanufacturer,intheselectedsample,hasselectedthe“clinicalin-vestigationsroute”(see.4.3.),whetherthecriteriadefinedin4.3.havebeenapplied.Whenperformingtheassessmentonsamplesofamanufacturersrisk/benefitas-sessment,theNotifiedBodywillfollowthestepsindicatedin5.1.1.,1-4.6.NotifiedBodySpecificProceduresandExpertiseNotifiedBodiesshouldestablishandimplementinternalpoliciesandproceduresfortheassessmentofclinicaldatainorderto:a)Ensurethatsuitableresources,especiallyrelevantknowledgeandcompetencenecessaryforsuchevaluation,areavailablewithintheNotifiedBodyand/orbycontractingexternalexperts.Suchexpertiseshouldbesufficienttoidentifyandestimatetherisksandbenefitsassociatedwiththeuseofthemedicaldevices.Theevaluationteamshouldbeabletoevaluateariskanalysisandtheriskmanagementstrategyperformedbythemanufacturer.Theevaluationteamshouldunderstandthedevicetechnologyaswellasthemedicalprocedure[8].Suchanevaluationmayrequireinputfromaqualifiedmedicalpractitioner(forexamplephysician,dentist,nurse),asappropriatefortheparticulardevice,whohasclinicalexperience.Whenexaminingtheresultsofclinicalinvestigations,theevaluationteamshouldhaveknowledgeinplanning,conductandinterpretationofclinicalinvestigations.Allevaluatorsshouldbetrainedandqualified.Particularattentionshouldbedrawntotrainingofexternalexpertswithregardtotheconformityassessmentprocedure