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1、MEDDEV2.7/1revision4MEDDEV2.7/1revision4page of65MEDDEV2.7/1revision4MEDDEV2.7/1revision4page3Oof65Itisimportantthatthereportoutlinesthedifferentstagesoftheclinicalevaluation:StageO,scopeoftheclinicalevaluation:explainsthescopeandcontextoftheevaluation,includingwhichproducts/models/sizes/settingsare

2、coveredbytheclinicalevaluationreport,thetechnologyonwhichthemedicaldeviceisbased,theconditionsofuseandtheintendedpurposeofthedevice;documentsanyclaimsmadeaboutthedevicesclinicpaelrformanceorclinicalsafety.Stage1,identificationofpertinentdata:explainstheliteraturesearchstrategy;presentsthenatureandex

3、tentoftheclinicaldataandrelevantpre-clinicaldatathathavebeenidentified.Stage2,appraisalofpertinentdata:explainsthecriteriausedbytheevaluatorsforappraisingdatasets;summarisesthepertinentdatasets(methods,results,conclusionsoftheauthors);evaluatestheirmethodologicalquality,scientificvalidity,therelevan

4、cefortheevaluation,theweightingattributedtotheevidence,andanylimitations;presentsjustificationsforrejectingcertaindataordocuments.Stage3,analysisoftheclinicaldata:explainsifandhowthereferencedinformation,suchasconfirmationofcompliancewithclinicaldatarequirementfromapplicableharmonisedstandardsandthe

5、clinicaldata,constitutesufficientclinicalevidencefordemonstrationoftheclinicalperformanceandclinicalsafetyofthedeviceunderevaluation;explainswhetherthereareadequatedataforallaspectsoftheintendedpurposeandforallproducts/models/sizes/settingscoveredbytheclinicalevaluation.describesthebenefitsandriskso

6、fthedevice(theirnature,probability,extent,durationandfrequency);explainstheacceptabilityofthebenefit/riskprofileaccordingtocurrentknowledge/thestateoftheartinthemedicalfieldsconcerned,withreferencetoapplicablestandardsandguidancedocuments,availablemedicalalternatives,andtheanalysisandconclusionsofth

7、eevaluatorsonfulfilmentofallEssentialRequirementspertainingtoclinicalpropertiesofthedevice(MDDER1,ER3,ER6;AIMDDER1,ER2,ER5);analysesifthereisconsistencybetweentheclinicaldata,theinformationmaterialssuppliedbythemanufacturer,theriskmanagementdocumentationforthedeviceunderevaluation;whetherthereiscons

8、istencybetweenthesedocumentsandthecurrentknowledge/thestateoftheart;identifiesanygapsanddiscrepancies;identifiesresidualrisksanduncertaintiesorunansweredquestions(suchasrarecomplications,uncertaintiesregardingmedium-andlongtermperformance,safetyunderwide-spreaduse)thatshouldbefurtherevaluatedduringP

9、MS,includinginPMCFstudies.Theevaluatorsshouldchecktheclinicalevaluationreport,provideverificationthatitincludesanaccuratestatementoftheiranalysisandopinions,andsignthereport.TheyshouldprovidetheirCVandtheirdeclarationofintereststothemanufacturer.Theclinicalevaluationreportshouldbedatedandversioncont

10、rolled.AsuggestedformatfortheclinicalevaluationreportislocatedatAppendixA9(Clinicalevaluationreport-proposedtableofcontents,examplesofcontents).SuggestionsforaspectsthatshouldbecheckedforthereleaseofaclinicalevaluationreportaresummarisedinAppendixA1O(Proposedchecklistforthereleaseoftheclinicalevalua

11、tionreport).InformationondeclarationofinterestscanbefoundinAppendixA11(Informationondeclarationsofinterests).TheroleofthenotifiedbodyintheassessmentofclinicalevaluationreportsThenotifiedbodyplaysakeyroleintheassessmentandverificationofclinicalevaluationreportsandsupportingdocumentationprovidedbymedi

12、caldevicemanufacturerstosupportdemonstrationofconformityofadevicewiththeEssentialRequirementsoftherelevantDirective.DetailedrecommendationsfornotifiedbodiesaregiveninAppendixA12(Activitiesofnotifiedbodies).Theseinclude:guidancefornotifiedbodiesontheassessmentofclinicalevaluationreportsprovidedbymedi

13、caldevicemanufacturersaspartoftechnicaldocumentation(includingdesigndossiers)andguidancefornotifiedbodyindevelopmentoftheirinternalproceduresforassessmentofclinicalaspectsrelatingtomedicaldevices.Inaddition,documentsoftheNotifiedBodiesOperationsGroup(NBOG)shouldalsobeconsulted.NBOGdocumentsincludebe

14、stpracticeguides,checklistsandforms.Pursuanttosection6aofAnnexIMDDandtosection5aofAnnex1AIMDD,thedemonstrationofconformitywiththeEssentialRequirementsmustincludeaclinicalevaluationconductedinaccordancewithAnnexXofDirective93/42/EECorwithAnnex7AIMDD.Thisisapplicableforallclassesofmedicaldevice.Whered

15、emonstrationofconformitywithEssentialRequirementsbasedonclinicaldataisnotdeemedappropriatethismustbeadequatelyjustifiedbythemanufacturerandbasedontheoutputoftheriskmanagementprocess.Thedevice-bodyinteraction,theintendedpurposeandtheclaimsofthemanufacturerhavetobespecificallyconsidered.Theadequacyofd

16、emonstrationofconformitybasedonperformanceevaluation,benchtestingandpre-clinicalevaluationintheabsenceofclinicaldatamustbedulysubstantiated.Thenotifiedbodymustreviewthemanufacturerjusstification,theadequacyofdatapresentedandwhetherornotconformityisdemonstrated.Neverthelessaclinicalevaluationisstillr

17、equiredandtheaboveinformationandanevidencedjustificationshouldbepresentedastheclinicalevaluationforthedeviceinquestion.AppendicesA1.DemonstrationofequivalencePursuanttoAnnexXofDirectiveMDDandAnnex7AIMDD,theevaluationofclinicaldata(i.e.theclinicalevaluation),whereappropriatetakingaccountofanyrelevant

18、harmonisedstandards,mustfollowadefinedandmethodologicallysoundprocedurebasedon:eitheracriticalevaluationoftherelevantscientificliteraturecurrentlyavailablerelatingtothesafety,performance,designcharacteristicsandintendedpurposeofthedevice,where:-thereisdemonstrationofequivalenceofthedevicetothedevice

19、towhichthedatarelates,and-thedataadequatelydemonstratecompliancewiththerelevantEssentialRequirements.oracriticalevaluationoftheresultsofallclinicalinvestigationsmade.oracriticalevaluationofthecombinedclinicaldataprovidedfrom1and2.Clinical,technicalandbiologicalcharacteristicsshallbetakenintoconsider

20、ationforthedemonstrationofequivalence:Clinical:usedforthesameclinicalcondition(includingwhenapplicablesimilarseverityandstageofdisease,samemedicalindication),andusedforthesameintendedpurpose,andusedatthesamesiteinthebody,andusedinasimilarpopulation(thismayrelatetoage,gender,anatomy,physiology,possib

21、lyotheraspects),andnotforeseentodeliversignificantlydifferentperformances(intherelevantcriticalperformancessuchastheexpectedclinicaleffect,thespecificintendedpurpose,thedurationofuse,etc.).Technical:beofsimilardesign,andusedunderthesameconditionsofuse,andhavesimilarspecificationsandproperties(e.g.ph

22、ysicochemicalpropertiessuchastypeandintensityofenergy,tensilestrength,viscosity,surfacecharacteristics,wavelength,surfacetexture,porosity,particlesize,nanotechnology,specificmass,atomicinclusionssuchasnitrocarburising,oxidability),andusesimilardeploymentmethods(ifrelevant),andhavesimilarprinciplesof

23、operationandcriticalperformancerequirements.Biological:Usethesamematerialsorsubstancesincontactwiththesamehumantissuesorbodyfluids.Exceptionscanbeforeseenfordevicesincontactwithintactskinandminorcomponentsofdevices;inthesecasesriskanalysisresultsmayallowtheuseofsimilarmaterialstakingintoaccountthero

24、leandnatureofthesimilarmaterial.DifferentaspectsofequivalenceandcompliancetodifferentEssentialRequirementscanbeaffectedbymaterials.Evaluatorsshouldconsiderbiologicalsafety(e.g.incompliancetoISO10993)aswellasotheraspectsnecessaryforacomprehensivedemonstrationofequivalence.Ajustificationexplainingthes

25、ituationshouldbeprovidedforanydifference.Forassumingequivalence,equivalencecanonlybebasedonasingledevice4allthreecharacteristics(clinical,technical,biological)needtobefulfilled;similarmeansthatnoclinicallysignificantdifferenceintheperformanceandsafetyofthedevicewouldbetriggeredbythedifferencesbetwee

26、nthedeviceunderevaluationandthedevicepresumedtobeequivalent;thedifferencesbetweenthedeviceunderevaluationandthedevicepresumedtobeequivalentneedtobeidentified,fullydisclosed,andevaluated;explanationsshouldbegivenwhythedifferencesarenotexpectedtosignificantlyaffecttheclinicalperformanceandclinicalsafe

27、tyofthedeviceunderevaluation;themanufacturershouldinvestigateifthemedicaldevicepresumedtobeequivalenthasbeenmanufacturedviaaspecialtreatment(e.g.asurfacemodification,aprocessthatmodifiesmaterialcharacteristics);ifthisisthecase,thetreatmentcouldcausedifferencesinrespecttotechnicalandbiologicalcharact

28、eristics;thisshouldbetakenintoaccountforthedemonstrationofequivalenceanddocumentedintheCER;ifmeasurementsarepossible,clinicallyrelevantspecificationsandpropertiesshouldbemeasuredbothinthedeviceunderevaluationandthedevicepresumedtobeequivalent,andpresentedincomparativetabulations;comparativedrawingso

29、rpicturesshouldbeincludedinordertocompareshapesandsizesofelementsthatareincontactwiththebody;themanufacturerisexpectedto:includethesupportingnon-clinicalinformation(e.g.pre-clinicalstudyreports)inthetechnicaldocumentationofthedevice,andintheclinicalevaluationreport,summarisetheinformationandciteitsl

30、ocationinthetechnicaldocumentation;fortheevaluationofthetechnicalcharacteristics,devicesthatachievethesametherapeuticresultbydifferentmeanscannotbeconsideredequivalent;fortheevaluationofthebiologicalcharacteristics:whenadetailedchemicalcharacterisationofmaterialsincontactwiththebodyisneeded,ISO10993

31、-18AnnexCcanbeusedtoshowtoxicologicalequivalencebutthisisjustapartoftheevaluationofthebiologicalcriteria;sourcingandmanufacturingproceduresmayadverselyaffectimpurityprofiles;analyticalmethodschosentocharacterisemedicaldevicesshouldappropriatelytakeintoconsiderationknowledgeconcerningexpectedimpurity

32、profiles(testsmayhavetoberepeatedwhenproductionmethodsorsourcingarechanged);itmaybenecessarytoshowfromhistopathologicalstudiesthatthesamehostresponseisachievedinvivointheintendedapplicationandtheintendeddurationofcontact;foranimaltests,differencesbetweenspeciesmaylimitthepredictivevalueofthetest;the

33、choiceofthetestanditspredictivevalueshouldbejustified;abrasion,ifrelevant,andhostresponsetoparticlesmayalsoneedtobeconsidered.theonlyclinicaldatathatareconsideredasrelevantarethedataobtainedwhentheequivalentdeviceisaCE-markedmedicaldeviceusedinaccordancewithitsintendedpurposeasdocumentedintheIFU.14E

34、valuatorsmaywishtorefertoseveraldevicesthatareequivalent.Insuchasituation,equivalenceofeverysingledevicetothedeviceunderevaluationshouldbefullyinvestigated,demonstrated,anddescribedintheclinicalevaluationreport.Note:Exceptionscanbeconsidered.WhentheequivalentdeviceisnotaCE-markeddevice,informationco

35、ncerningtheregulatorystatusoftheequivalentdeviceandajustificationfortheuseofitsdatashouldbeincludedintheclinicalevaluationreport.ThejustificationshouldexplainiftheclinicaldataistransferrabletotheEuropeanpopulation,andananalysisofanygapstogoodclinicalpractices(suchasISO14155)andrelevantharmonisedstan

36、dards.A2.Whenshouldadditionalclinicalinvestigationsbecarriedout?Howshouldmanufacturersandevaluatorsdecideifthereissufficientclinicalevidence?WhenclinicaldataarerequiredinordertodrawconclusionsastotheconformityofadevicetotheEssentialRequirements,thedataneedtobeinlinewithcurrentknowledge/thestateofthe

37、art,bescientificallysound,coverallaspectsoftheintendedpurpose,andallproducts/models/sizes/settingsforeseenbythemanufacturer.Ifgapsarepresentthatcannotbeaddressedbyothermeans,clinicalinvestigationsshouldbeplannedandcarriedout.ConsiderationsImplantsandhigh-riskdevices,thosebasedontechnologieswherether

38、eislittleornoexperience,andthosethatextendtheintendedpurposeofanexistingtechnology(i.e.anewclinicaluse)aremostlikelytorequireclinicalinvestigationdata.ForcompliancewithAnnexXsection1.1.aMDDandAnnex7AIMDD,clinicalinvestigationswiththedeviceunderevaluationarerequiredforimplantableandclassIIIdevicesunl

39、essitcanbedulyjustifiedtorelyonexistingclinicaldataalone.Theneedforclinicalinvestigationsdependsontheabilityoftheexistingdatatoadequatelyaddressthebenefit/riskprofile,claims,andside-effectsinordertocomplywiththeapplicableEssentialRequirements.Clinicalinvestigationsmaythereforealsoberequiredforotherd

40、evices,includingfordevicesinclassIandclassIIa,andforclassIIbdevicesthatarenotimplantable.Whendecidingifadditionalclinicalinvestigationsneedtobecarriedout,themanufacturershouldperformadetailedgapanalysis.Thegapanalysisshoulddeterminewhethertheexistingdataaresufficienttoverifythatthedeviceisinconformi

41、tywithalltheEssentialRequirementspertainingtoclinicalperformanceandclinicalsafety.Specialattentionshouldbegiventoaspectssuchas:newdesignfeatures,includingnewmaterials,newintendedpurposes,includingnewmedicalindications,newtargetpopulations(age,gender,etc.),newclaimsthemanufacturerintendstouse,newtype

42、sofusers(e.g.laypersons),seriousnessofdirectand/orindirectrisks,contactwithmucosalmembranesorinvasiveness,increasingdurationofuseornumbersofre-applications,incorporationofmedicinalsubstances,useofanimaltissues(otherthanincontactwithintactskin),-issuesraisedwhenmedicalalternativeswithlowerrisksormore

43、extensivebenefitstopatientsareavailableorhavebecomenewlyavailableSeeAppendixA7.2(Conformityassessmentwithrequirementonacceptablebenefit/riskprofile),SeeAppendixA7.2(Conformityassessmentwithrequirementonacceptablebenefit/riskprofile)-issuesraisedwhennewrisksarerecognised(includingduetoprogressinmedic

44、ine,scienceandtechnology)-whetherthedataofconcernareamenabletoevaluationthroughaclinicalinvestigation,-etc.Dataonthesafetyandperformanceofotherdevicesandalternativetherapies,includingbenchmarkdevicesandequivalentdevices,shouldbeusedtodefinethestateoftheartoridentifyhazardsduetosubstancesandtechnolog

45、ies.Thiswillallowtheclinicaldatarequirementstobeestablishedmorepreciselyinrelationtotheintendedpurposeofadevice.Precisioninthisanalysisandthechoiceofselectedmedicalindicationsandtargetpopulationsmayreducetheamountofclinicaldataneededfromadditionalclinicalinvestigations.A3.Devicedescription-typicalco

46、ntentsThedescriptionshouldbedetailedenoughtoallowforavalidevaluationofthestateofcompliancewithEssentialRequirements,theretrievalofmeaningfulliteraturedataand,ifapplicable,theassessmentofequivalencetootherdevicesdescribedinthescientificliterature:name,models,sizes,componentsofthedevice,includingsoftw

47、areandaccessoriesdevicegrouptowhichthedevicebelongs(e.g.biologicalartificialaorticvalve)whetherthedeviceisbeingdeveloped/undergoinginitialCE-marking/isCE-markedwhetherthedeviceiscurrentlyonthemarketinEuropeorinothercountries,sincewhen,numberofdevicesplacedonthemarketintendedpurposeofthedeviceexactme

48、dicalindications(ifapplicable)nameofdiseaseorcondition/clinicalform,stage,severity/symptomsoraspectstobetreated,managedordiagnosedpatientpopulations(adults/children/infants,otheraspects)intendeduser(usebyhealthcareprofessional/layperson)organs/partsofthebody/tissuesorbodyfluidscontactedbythedevicedu

49、rationofuseorcontactwiththebodyrepeatapplications,includinganyrestrictionsastothenumberordurationofreapplicationscontactwithmucosalmembranes/invasiveness/implantationcontraindicationsprecautionsrequiredbythemanufacturersingleuse/reusableotheraspectsgeneraldescriptionofthemedicaldeviceincludingaconci

50、sephysicalandchemicaldescriptionthetechnicalspecifications,mechanicalcharacteristicssterilityradioactivity-howthedeviceachievesitsintendedpurpose-principlesofoperation-materialsusedinthedevicewithfocusonmaterialscomingincontact(directlyorindirectly)withthepatient/user,descriptionofbodypartsconcerned

51、-whetheritincorporatesamedicinalsubstance(alreadyonthemarketornew),animaltissues,orbloodcomponents,thepurposeofthecomponent-otheraspectswhetherthedeviceisintendedtocovermedicalneedsthatareotherwiseunmet/iftherearemedicalalternativestothedevice/ifthedeviceisequivalenttoanexistingdevice,withadescripti

52、onofthesituationandanynewfeaturesifthedeviceisintendedtoenterthemarketbasedonequivalence:name,models,sizes,settingscomponentsofthedevicepresumedtobeequivalent,includingsoftwareandaccessorieswhetherequivalencehasalreadybeendemonstratedIntendedperformance,includingthetechnicalperformanceofthedeviceint

53、endedbythemanufacturer,theintendedclinicalbenefits,claimsregardingclinicalperformanceandclinicalsafetythatthemanufacturerintendstouseFordevicesbasedonpredecessordevices:Name,models,sizesofthepredecessordevice,whetherthepredecessordeviceisstillonthemarket,descriptionofthemodifications,dateofthemodifi

54、cations.Thecurrentversionnumberordateoftheinformationmaterialssuppliedbythemanufacturer(label,IFU,availablepromotionalmaterialsandaccompanyingdocumentspossiblyforeseenbythemanufacturer).A4.SourcesofliteratureTherearedifferentsourcesofclinicalliteraturethatcanbesearchedforclinicalevaluation.Acomprehe

55、nsivesearchstrategyisrequired,normallyinvolvingmultipledatabases.Thesearchstrategyshouldbedocumentedandjustified.Importantsourcesincludethefollowing:ScientificliteraturedatabasesMEDLINEorPubmedcanprovideagoodstartingpointforasearch.However,withpossiblyincompletecoverageofEuropeanJournalsandreducedse

56、archfeatures,comprehensivenessmaynotnecessarilybeguaranteed.AdditionaldatabasesmayneedtobeusedtoensureadequatecoverageofdevicesandtherapiesinuseinEurope,toidentifyrelevantclinicaltrialsandpublicationsofuserexperienceStudiesyieldingnegativeresultsoruserexperience(suchaspublicationsaboutrisksthatareba

57、sedonacaseoracaseseries)maynotqualifyforpublicationinhighimpactmedicaljournals.LowimpactjournalsavailabletoEuropeanusersandothersourcesmaythereforeneedtobesearched.,andtofacilitatesearchesbydevicenameandmanufacturer(e.g.EMBASE/ExcerptaMedica,theCochraneCENTRALtrialsregister,etc.).Studiesyieldingnega

58、tiveresultsoruserexperience(suchaspublicationsaboutrisksthatarebasedonacaseoracaseseries)maynotqualifyforpublicationinhighimpactmedicaljournals.LowimpactjournalsavailabletoEuropeanusersandothersourcesmaythereforeneedtobesearched.Informationcoverageandsearchfeaturesavailableinscientificdatabasescanch

59、angewithtime.Criteriaforselectingadequatedatabasesthereforeneedtobedefinedandre-evaluatedonaregularbasis.InternetsearchesSearchesprovideimportantdata,examplesincludeinformationon:-harmonisedstandardsandotherstandardsapplicabletothedeviceinquestionandcontaininginformationonclinicalperformanceandclini

60、calsafety.-Fieldsafetycorrectiveactionsfortheequivalentand/orotherdevices.Thesecanbefoundonmanufacturerswebsitienste,rnetsitesofEuropeanCompetentauthorities,theU.S.FoodandDrugAdministration(FDA),possiblyothersites.-Implantregistryreports.-Documentsavailableinsystematicreviewdatabases(e.g.theCochrane