MEDDEV2.5_7 rev1 乳房植入物指南

RuedelaLoi200,B-1049Bruxelles/Wetstraat200,B-1049Brussel–Belgium–Office:SC153/133Telephone:directline(+32/2)295.93.39,switchboard299.11.11.Fax:296.70.13Telex:COMEUB21877.Telegraphicaddress:COMEURBrusselsEUROPEANCOMMISSIONDGENTERPRISEDirectorateGUnit4-PressureEquipment,MedicalDevices,MetrologyMEDICALDEVICES:GuidancedocumentMEDDEV2.5-7rev1(Entiredocument)July1998GUIDELINESFORCONFORMITYASSESSMENTOFBREASTIMPLANTSACCORDINGTODIRECTIVE93/42/EECRELATINGTOMEDICALDEVICESTheseguidelinesaimatpromotingacommonapproachbythemanufacturersofbreastimplants,theNotifiedBodiesinvolvedintheconformityassessmentproceduresaccordingtotherelevantannexesoftheMDDandbytheCompetentAuthoritieschargedwithsafeguardingPublicHealth.Theyhavebeencarefullydraftedthroughaprocessofconsultationwithvariousinterestedpartiesduringwhichintermediatedraftswerecirculatedandcommentsweretakenupinthedocument.Therefore,thisdocumentreflectspositionstakeninparticularbyrepresentativesofCompetentAuthoritiesandCommissionServices,NotifiedBodies,industryandotherinterestedpartiesinthemedicaldevicessector.Theseguidelinesarenotlegallybinding.Itisrecognisedthatundergivencircumstances,forexample,asaresultofscientificdevelopments,analternativeapproachmaybepossibleorappropriatetocomplywiththelegalrequirements.DuetotheparticipationoftheaforementionedinterestedpartiesandofexpertsfromCompetentAuthorities,itisanticipatedthattheseguidelineswillbefollowedwithintheMemberStatesand,therefore,ensureuniformapplicationofrelevantDirectiveprovisions.Ref.Ares(2015)2030338-13/05/2015-2–TABLEOFCONTENTSPAGES1.INTRODUCTION.............................................................................32.GUIDELINES2.1Tableofhazardsassociatedwiththedesignandmanufactureofthedevicewiththerelatedguidelines....................................................2.2Useofanimalstudiesforestimatingrisks......................................2.3Clinicalevaluation........................................................................2.4Post-marketingsurveillance..........................................................2.5Hazardsassociatedwiththesurgeryandinherenthazardsassociatedwiththeclinicaluseofbreastimplants..........................355663.REFERENCES3.1Standards...................................................................................3.2Report........................................................................................77ANNEXESAnnexIA:informativeannexrelatingtopre-clinicalinvestigation............AnnexIB:informativeannexrelatingtoclinicalevaluation......................AnnexIC:informativeannexrelatingtoevaluationandacceptabilitycriteriatobeusedfortheclinicalevaluation............................................AnnexII:EQUAMInformativeannexrelatingtoinformationtobeprovidedtopatients–patientquestionnaireanddeclarationofconsent...8162027-3–1.INTRODUCTIONBreastimplantsareusuallyClassIIbproducts,insomecasestheyareclassIIIaccordingtoMDD,AnnexIX,Rules8,13or17.Theproductrelatedhazardsofbreastimplantscanbedividedintothefollowingcategories:-hazardsassociatedwiththedesignandmanufactureofthedevice(see2.1,2.2,2.3and2.4)-hazardsassociatedwiththesurgeryandinherenthazardsassociatedwiththeclinicaluseofbreastimplants(see2.5).Inthefollowingtable,thehazardsandtherelatedguidelinesarelisted.Themanufacturermustevaluatetheriskassociatedwitheachhazardlistedbelow.Thesecondcolumnofthetablegivesthecorrespondingguidelinestobeconsidered.Theinformationisnotexhaustive.Thisinformationcanbeconsideredasoneofthebasisfortheriskanalysiswhichmustbeperformed.2.GUIDELINES2.1TableofhazardsassociatedwiththedesignandmanufactureofthedevicewiththerelatedGuidelines.HazardsGuidelinesMechanicalfailureResultsofmechanicaltestingaccordingtoprEN12180,7.1andadequatequalitycontrolattherelevantstepsofmanufacturemustbeavailable.Withregardtothetestofabrasion,themanufacturershouldaddresstheserelatedhazardsevenforimplantsfilledwithsiliconegelandestimatethecorrespondingrisk.HeshoulddescribethetestusedandjustifyitRuptureafterimplantationCapsularcontractionOtherlocalcomplicationsTobeaddressedintheclinicalevaluationTobeaddressedintheclinicalevaluationTobeaddressedintheclinicalevaluationLackofsterilityoftheproductTheproductmustbeprovidedsterile.TheEN550seriesofstandardscanbeusedwhereappropriate.Thesterilisationprocessmusthavebeenvalidatedadequatelyanddocumentedinthetechnicalfile.ThevalidationmustdemonstratethefulfilmentofEN556.-4–LackofbiocompatibilityBleedingBiologicalevaluationcanbeperformedaccordingtoprEN14630andprEN12180,6and7.1.7incombinationwithEN30993-1,ISO/DIS14538,andEN1441,annexB.Evaluationofbiocompatibilityshouldcovertheshell,thefillingmaterialandthebleedmaterialsaswellasallothermaterialswhichcouldbeincontactwiththetissuesincaseofruptureoftheenvelope,asidentifiedintheriskanalysis.Allidentifiedhazardsshouldbeaddressed.Inparticular,allthefollowinghazardsshouldbeobjectoftheappropriatein-vitrotestsoranimalsstudies,unlessajustificationisgivenfornotperformingthem.Invitrotestscouldalsobeusedtoassesspropensitytoinducethereleaseofpro-inflammatorycytokines.-Envelope:cytotoxicity,haemocompatibility(haemolysis,{activationofcomplement}),genotoxicity,carcinogenicity.-Fillingmaterial:cytotoxicity,systemictoxicity,intradermalirritation,sensitisation,genotoxicity,carcinogenocity,haemocompatibility(hemolysis,activationofcoagulation,plateletactivation,{activationofcomplement}),-Endproduct:cytotoxicity,systemictoxicity,intradermalirritation,sensitisation,genotoxicity,carcinogenocity.-ChronictoxicityisaddressedinEN30993-1-Immunotoxicity:thishazardshouldbespecificallyaddressedinthedossiertakingaccountoftheresultsoftheriskanalysisTheeffectsofbleedingonthebiologicaltissuesaswellasonthemechanicalcharacteristicsoftheenvelopearenotknown.Forthesereasons,itissuggestedthat,onthebasisoftheriskanalysis,themanufacturershouldprovidethejustificationforthetestsperformed;heshouldalsoprovidetheresultsofthetestsandthecriteriausedforacceptingtheestimatedrisk.Thein-vitrotestdescribedinannex1ofthepresentguidelinesisprovidedasanexample.Physical/chemicalincompatibilitiesDataaboutcompatibilitybetweenshellandfillermustbeavailableOsmoticchangesDataabouttheosmoticsituationmustbeavailable,ifapplicableInterferencewithmedicaldiagnosisandtreatmentInformationaboutpossibleinterferencewithsubsequentdiagnosisandtreatmentmustbeaddressedinthelabellingLackoftraceabilityprEN12180,11.6hastobeappliedLimitedlifetimeExpectedlifetimeofimplants(stabilityafterimplantation)mustbeaddressedanddocumentedusingtheinformationavailable(includingresultsofanimalstudies).Datashallbeavailabletojustifyexpectedlifetimeofallcomponents(durabilityandagerelatedchanges).ThemanufacturerhastoprovideadequateinformationintheinstructionsforuseinrelationtolimitationoflifetimeUnknownshelf-lifeTheuse-bydatebasedonstabilitydatahastobegivenandisaddressedinprEN1041andEN9802.2Useofanimalstudiesforestimatingrisks-5–Asageneralprinciple,invivoanimalstudiesmaybeconsideredaspartofpre-clinicalevaluationwhenthethreefollowingconditionsarefulfilled:-theriskanalysispointsoutalackofrelevantdata,-noalternateappropriatewaysforobtainingthemissingdataareavailable,-suchstudiesarelikelytoprovidethemissingdata.Inparticular,invivoanimalstudiesremaintheonlymeanstoevaluatechronictoxicityandimmuno-toxicityaswellasageing.Theyalsoconstitutetheonlymeanstoevaluatethebiologicaleffectsofbleeding.2.3ClinicalevaluationTheNotifiedBodyshall,duringtheconformityassessmentprocedure,reviewtheclinicalevaluationinthetechnicalfileincompliancewithMDD,AnnexI,Section1inconjunctionwithannexX.Clinicalevidencecoversallidentifiedhazards,nevertheless,themainobjectiveofthepre-marketclinicalevaluationistheestimationoftherisksassociatedwiththehazardsduetolocalcomplications,includingcapsularcontractureandruptureafterimplantation.Clinicaldatatobeprovidedbythemanufacturershouldoriginate:-eitherfromclinicalinvestigationsperformedwiththeconcernedprosthesisorwithasufficientlysimilarprosthesis,takingaccountoftheobjectivesoftheStudy,andfollowingaspecificclinicalinvestigationplan.Suchclinicalinvestigationsshouldbeperformedwhentheriskanalysispointsoutalackofrelevantclinicaldata.-orfromretrospectivedataobtainedfromprevioususeoftheconcernedprosthesisorofasufficientlysimilarprosthesis,takingintoaccounttheobjectivesofthestudyTheacceptabilitycriteriashouldbeclearlydocumentedandjustifiedwithaclearidentificationoftheexpectedbenefitstothepatients.-6–2.4Post-marketingsurveillanceThemanufacturermustinstituteandkeepuptodateasystematicactiveproceduredefinedinaccordancewiththeresultsoftheriskanalysis,inordertogainandreviewexperiencefromdevicesinthemarketingphaseincludingreviewsofriskanalysisandplansforanynecessarycorrectiveaction.Thissystematicprocedureshouldspecificallyincludethereviewofdatarelatingtolongtermeffects,inparticularthoseinrelationtochronictoxicity.DuringeachsurveillanceaudittheNotifiedBodyshallreviewtheexperiencegainedbythemanufacturerinthemarketingphaseandanysubsequentaction.2.5HazardsassociatedwiththesurgeryandinherenthazardsassociatedwiththeclinicaluseofbreastimplantsInformationabouttherisksassociatedwithsurgeryshallbeprovidedinthelabellingTheseshallinclude:1.clearindicationsfortheuseoftheimplant,2.clearcontraindications,3.knownadversereactions,4.astatementthatbreastimplantsaresingleusedevicesandmustnotberesterilizedand/orreused.Risksassociatedwithlackofexpertiseofthesurgeonandtheneedforfollow-upofthepatientshallbeaddressed.Therearecertainrisksparticularlyinherentintheuseofbreastimplantsorpostulatedfromtheiruse.Theseareaddressedspecificallyduringconsultationbetweenphysicianandpatientandsubjecttoinformedconsent.Apatient’scardisanappropriatewaytoprovidetheinvolvedpartieswithalltheinformationneededduringthelife-cycleofthebreastimplantsNote:TheinformativeannexesIA,IBandICattachedtothisdocumentgiveexamplesofsomeparticularpre-clinicaltests,aswellasanexampleofclinicalinvestigationplanandofcriteriaofacceptability.TheinformativeannexIIprovidesanexampleofinformationtobeprovidedtothepatientpriortoanimplantationaswellasanexampleofapatientquestionnaireandofapatientconsentform.ThesedocumentshavebeendevelopedandissuedbytheEuropeanCommitteeonQualityAssuranceandMedicalDevicesinPlasticSurgery(EQUAM).-7–3.REFERENCES3.1StandardsprEN12180Nonactivesurgicalimplants–Bodycontouringimplants–SpecificrequirementsformammaryimplantsprEN14630Nonactivesurgicalimplants–GeneralrequirementsEN550:1994Sterilizationofmedicaldevices–ValidationandroutinecontrolofethyleneoxidesterilizationEN552:1994Sterilizationofmedicaldevices-ValidationandroutinecontrolofsterilizationbyirradiationEN554:1994Sterilizationofmedicaldevices–ValidationandroutinecontrolofsterilizationbymoistheatEN556:1994Sterilizationofmedicaldevices–Requirementsfordevicestobelabelled“Sterile”EN30993-1:1993Biologicalevaluationofmedicaldevices-Part1:GuidanceonselectionoftestsISO/DIS14538:1996MethodsfortheestablishmentofallowablelimitsforresiduesinmedicaldevicesusinghealthbasedriskassessmentEN1441:1997Medicaldevices-RiskanalysisEN1041:1998Terminology,symbolsandinformationprovidedwithmedicaldevices;informationprovidedbythemanufacturerwithmedicaldevicesEN980:1996Graphicalsymbolsforuseinthelabellingofmedicaldevices(underreview)3.2Reports*“RecommendationsforevaluatingbreastimplantspriortoMarketingapproval”(June1997):Coordinators:Anne-ClaudeKoegerandFrédéricFleurette.Panelofexperts:DanielMarzin,MarcPallardy,GérardBallon,LiseBarreau-Pouhaer,NathalieBricout,MoniqueLê,Jean-MichelNguyen,ClaudeNicoletis,Jean-MarieServant,AnneTardivon,HenriTristant.Consultedspecialists:RosyEloy,Marie-FrançoiseHarmand,Jean-LucJannic,OlivierMeyer.*“Siliconeimplantsandconnectivetissuedisease:evaluationofevidenceforanassociationbetweentheimplantationofsiliconesandconnectivetissuedisease”.Datapublishedfromend1991tillJuly1994.D.M.GottandJ.B.Tinkler.PublishedMedicalDevicesAgency,London1994.-8–ANNEXIATOTHEGUIDELINESFORCONFORMITYASSESSMENTOFBREASTIMPLANTS(asmentionedinchapter2)InformativeannexrelatingtopreclinicalevaluationThisannexismainlyconstitutedbylargeextractstakenfromthereportoftheexpertsgroupmentionedinchapter3.Itprovidesexamplesofsomeelementsofpreclinicalstudieswhichcouldbeperformedinthecontextofconformityassessment.1.Abrasionresistanceandanalysisofabradedsurfaces.Thesiliconeelastomersoftheshellareinfactrelativelysoftandsusceptibletodeteriorationduetosurfaceabrasion.Whenplacedinthethoracicwallofawoman,theyaresubjectedtopermanentfrictionforcesexertedbythesoftpartsabovethem.2.Bleeding.Aninvitrobleedtest,identifyingandcharacterisingalltheconstituentsremainingintheshellandallthosethathavepassedintothesolventattheendofthetest.Infuture,itwouldbedesirabletocarryoutthetestintwosolvents,oneconsistingofanelectrolytesolutionandonecontaininglipoproteins.Infact,leakageisasecondaryeffect,currentlyunavoidable,forbreastimplants.Theproductofleakagemaybedispersedinthebodyintwoways:simplediffusionintheextra-cellularliquid,orphagocytosisbyperi-prostheticmacrophages.Afteralongperiodofleakage,whichistheoreticallyinfinite,andintheeventofruptureoftheimplant,theproductcontainedintheshellmaypresentadifferentconstitutionfromtheinitialfillingmaterial.Itisnecessarytoknowthecompositionoftheseproducts.Thisinvitrobleedtestiscomplementedbyaninvivobleedtest.Thecontentsoftheexplantedimplantisanalysed(compositionofthesilicones,cohesivityofthegel,etc.)aquantitativeandqualitativeanalysisofthebleedproductsintheperi-prosthetictissueandinthedrainageganglionsiscarriedout.3.Ageing.Comparisonofthemechanical,physicalandphysical-chemicalpropertiesofimplants(shell,fillingmaterialandcompleteimplant)beforeandafterageing,inordertodocumentanymodificationsofthesesamepropertiesasaresultofageingisperformed.11Theoriginalreportprovidesalistofteststobeperformed.Thesetestsaredescribedinpartsofthatreportwhichhavenotbeenreproducedinthepresentdocument.Thetestsperformedforthecomparisonshouldbethesameasthoseindicatedinsection2.1ofthemainpartofthepresentdocument.-9–4.Evaluationofthebiocompatibilityofbreastimplants4.1ForewordGenerally,itshouldbenoted,thattherehavebeentodatenotestscarriedoutinbleedingconditions,i.e.involvingthepassageofthecontentsthroughthewallofthesiliconeshell.Allthefollowingtestswerecarriedouteitheronaqueousextractsorinasolvent,orbydirectcontact(cf.tableinannex1).Inordertoestablishbleedingconditions,itisimportanttodefinetheextractionconditions,sinceitisonanextractthatthesetestsarecarriedout,andtheextractionconditionsmustreproducethebleedingconditions.Thefollowingpointsrelatetotheproductoftheextract:-surface/volumeratioofatleast6cm²/mlor4g/ml,-extractiondurationhigherthanthatenablingtheacquisitionofasignificantextract,-extractiontemperature:37°C,-conditionsofmechanicalagitationwherebytheimplantissubjectedtostressmaypermittheextractiondurationtobereduced.Finallyitisvitalthatanalysisofthecompositionoftheextractsiscarriedoutusingsensitiveandspecificmethods.4.2Evaluationofbiologicalrisks4.2.1Evaluationofcytotoxicity:inastandardisedmodel,cytotoxicityisevaluatedbydirectorindirectcontact(viatheagar)lasting24to72hourswiththematerialtobetestedand/orontheextracts.Thecellsusedareingeneralfibroblasticcelllines.Theculturerarelylastsbeyond72hours.Theappreciationcriteriarelatetomodificationstothemetabolism,thecellcycleorthecellularviability.4.2.2Systemictoxicity:thissystemictoxicitytestmaybecarriedouteitherintravenouslyorintraperitoneally.Bearinginmindthenatureoftheextractedmolecules,itispreferabletocarryouttoxicitytestingintraperitoneallyinmiceusing50ml/kgoftheextractorofableedingproductinjectedperitoneally.Survivalandsignsoftoxicityaretheanalyticalcriteria.Itisalsopossibletoendeavourtoinvestigateactivationsigns,particularlyofperitonealmacrophages(tissueplasminogenactivators,orinterleukinsactivation).Thismodelshouldbevalidatedforthesilicones.Thismodelmaybeextendedfrom72hours(timerequiredforstandards)to15days(byusingrepeatedinjections).-10–4.2.3Intradermalirritationtest:hereagain,thistestinvestigatesalocaleffectandthestandardtestmaybeapplied.Thequestionmaysimplyberaisedwhetheritisreallyrelevanttocarryoutatestwithonesingleintradermalinjectionoftheproduct,bearinginmindtheexposureconditionstoproductsofbleedinginthehuman.4.2.4Sensitisationtests:thesetestsaretreatedintheimmuno-toxicitystudies4.2.5Hemocompatibilitytests:thesetestsinvestigatetheexistenceofaninteractionbetweentheproductsofbleedingandthebloodcellsorthemajorbloodsystems:-coagulationactivation,-plateletsystemactivation,-fibrinolyticsystemactivationorinhibition,-complementsystemactivation,-haemolysisactivationThesetestsareinvitrotestscarriedoutinstaticconditionsusingacontrol,inthepresenceofhumanblood,seekingforeachofthesystemsexploredtheappearanceortheappearancekineticsofaspecificsystemmarker:-fibrinopeptideorcoagulationtimeofthecoagulationsystem,-plateletactivationmarkets:betathromboglobuline,-complementactivation:liberationofC3a,C5aorofthefractionoftheterminalcomplex,-hemolysis:measurementoftherateofhaemoglobinafteracontactperiodof1to3hours4.3Immunotoxicitytests4.3.1Introduction:certainpathologicalconditionsassociatedwiththeimplantationofbreastimplantsareofimmunologicalorigin.Byvirtueofthisfact,itisnecessarytoevaluatetheimpactofimplantationofthistypeofmaterialontheimmunesystem.Immuno-toxicitystudieswillbeincludedinthechronictoxicitytestingandwillbebasedessentiallyonahistologyofthelymphoidorgans.Thesetestsshouldbringtolightanyeffectofimplantsontheimmunesystemandthereforeindicateifitisnecessarytoproceedwithsupplementarytesting.Howeverthesetestsarenotabletocastlightonthepotentialofthematerialtestedtoinduceauto-immunediseases.Atthepresenttime,thereisnosatisfactoryapproachconcerningtheseaspects.ThesensitisationpotentialwillalsobeevaluatedaccordingtoaconventionalprotocolusingtherecommendationsofOECDguideline406.-11–4.3.2Immunotoxicitystudyduringtoxicitytestsbyrepeatedadministration4.3.2.1Methodandprotocol:theend-productistestedalongwiththefillersolution.Theselectedanimalforthestudyiftheminiaturepig(onlythefemaleofthespeciesisused).Thepracticaldetailsofthetestprotocol(doses,implantationsites,animalbatches)arecoveredbytheprotocolforstudiesofchronictoxicityandbytheOECDguideline409.Attheendofthestudyandeachtimeananimaliskilled,sampleswillbetakenofthefollowinglymphoidorgans:thymus,spleen,bonemarrow,ganglionsdrainingtheimplantationsite,mesenteryganglions.Forthethymus,acortical/medullaryzoneratioiscalculatedaswellasthehistopathologicalexamination.Fortheganglions,inadditiontothehistopathologicalexamination,weightandcellularitydatamustalsobesuppliedandthepresenceofgerminationcentresisofparticularinterest.Fortheimplantedanimals,ahistologicalanalysisiscarriedoutonthefibrousshellsurroundingtheimplant,involvinginvestigationoftheinfiltratinggranulocytes,monocytesandlymphocytes.4.3.2.2Analysisofresults:intheeventofhistologicalalterationoftheexaminedlymphoidtissueswhichshowsadiminishingormodificationofthecellularpopulations,itisnecessarytoproceedwithfurthertestingaimedatevaluatingapossibleimmuno-suppressiveeffect.Thetestingshouldtakeaccountofthelatestscientificadvancesatthetimethetestingtakesplace.Ifthereisanincreaseinthenumberofgerminationcentreswithrelationtothecontrolsintheganglionsorthespleen,itisnecessarytoproceedwithsupplementarytestingdesignedtocharacterisethisresponse.Thetestingshouldtakeaccountofthelatestscientificadvancesatthetimethetestingtakesplace.4.3.2.3.Sensitisationpowerstudy:thisstudyistobecarriedoutaccordingtotheOECD406directivesconcerningtheMagnussonandKligmanmaximisationtest.Thematerialstestedwillbethefillingmaterialandtheshellintradermally.Severalnon-irritantconcentrationswillbetestedinordertodeterminetheminimalirritantconcentrationbeforethistestisbegun.-12–4.4Genotoxicitystudy4.4.1General:thegenotoxicitystudiesmustenableevaluationofthegenotoxicityofthefillingmaterialwhichmayaccidentallybereleasedbyruptureorbyleakagewithintheorganismandthegenotoxicityoftheend-product.Intheeventofthefillingmaterialrepresentingtoogreatatoxicityforoneofthereactivesystems(e.g.bacteriostaticactivityinthecaseofbacterialtests),the