St.

Jude Medical

AMPLATZERAtrialSeptalOccluder ExecutiveSummary

AdvisoryCommitteeBriefingMaterials:AvailableforPublicRelease

St.JudeMedical 24May2012

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 St.JudeMedicalAMPLATZERASOExecutiveSummary
1 INTRODUCTION................................................................................................................ 3 1.1 SURGICALCLOSUREVS.TRANSCATHETERCLOSURE ..........................................................................3 1.2 ATRIALSEPTALDEFECTOVERVIEW ...............................................................................................4 2 DEVICESUMMARY ........................................................................................................... 7 2.1 2.2 2.3 2.4 2.5 3 BENEFITSOFTRANSCATHETERCLOSURE .........................................................................................7 INTENDEDUSEANDPATIENTPOPULATION .....................................................................................7 DEVICEDESCRIPTION .................................................................................................................8 REGULATORYPATHWAYTOUSAPPROVAL ...................................................................................12 MARKETEXPERIENCE ...............................................................................................................12

CLINICALTRIALSSUMMARY ............................................................................................15 3.1 IDEPIVOTALTRIAL ..................................................................................................................15 3.1.1 ASOUSPivotalTrialOverview ..............................................................................15 3.1.2 ASOUSPivotalTrialResults ..................................................................................16 3.2 POSTAPPROVALSTUDY ...........................................................................................................17 3.2.1 PostApprovalStudyOverview..............................................................................17 3.2.2 PostApprovalStudyData(54monthinterimresults) ..........................................18

POSTCOMMERCIALIZATIONEXPERIENCE ........................................................................19 4.1 ADVERSEEVENTREPORTING .....................................................................................................19 4.1.1 Arrhythmia...........................................................................................................20 4.1.2 DeviceEmbolization.............................................................................................21 4.1.3 Erosion .................................................................................................................22 4.1.4 Explants................................................................................................................23 4.1.5 Fracture................................................................................................................23 4.1.6 Malfunction..........................................................................................................23 4.1.7 Malposition ..........................................................................................................23 4.1.8 Mortality(allcause).............................................................................................24 4.1.9 Stroke ...................................................................................................................24 4.1.10 ThrombusonDevice.............................................................................................24 4.1.11 PostCommercializationExperienceConclusion ...................................................24 4.2 CORRECTIVEACTIONS ..............................................................................................................25 4.2.1 Embolization .........................................................................................................25 4.2.2 Erosion ..................................................................................................................25

5 6 7

CONCLUSION ..................................................................................................................33 SUMMARYOFSAFETYANDEFFECTIVENESSDATA(SSED) ................................................34 INSTRUCTIONSFORUSE ..................................................................................................35

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1 1.1

INTRODUCTION Surgical Closure vs. Transcatheter Closure

AtrialSeptalDefect(ASD)isoneofthemostcommoncongenitalheartdefects requiringproceduralintervention.AnuntreatedsymptomaticASDleadsto significantmorbidityandreduceslifeexpectancy.ComplicationsofanuntreatedASD canincluderightventricularfailure,atrialarrhythmias,paradoxicalembolism, pulmonaryhypertensionandcyanosissecondarytoreversalofshuntfrompulmonary vasculardisease.MortalityratesforuntreatedASDsareashighas25% 1 .American HeartAssociation(AHA)guidelinesrecommendclosureofsecundumASDs,either surgicallyorpercutaneously,inpatientswithrightatrialheartvolumeoverload. SurgicalclosureofthesecundumASDhasbeenstandardofcarefornearlyfive decades.Despitegoodclinicaloutcomesfollowingsurgicalrepair,rightventricular enlargementandabnormalventricularseptalwallmotionmaypersist.Overthelast 25years,minimallyinvasivetranscatheterclosurehasevolved,becomingthe preferredtreatmentoptioninthemajorityofsecundumASDs.Transcatheterclosure ofsecundumASDshasbeendemonstratedtobesafeandeffectiveinbothchildren andadults,withsimilarsuccessandcomplicationratestosurgery,andthepotential fordecreasedhospitalstay 2 . InFebruary2012,Kuttyetalreportedtheresultsofaretrospectiveobservational outcomesstudypublishedintheAmericanJournalofCardiology,comparinglong termresultsoftranscatheterandsurgicalASDclosure.Thisstudyrepresentsthe longestreporteddurationoffollowupaftertranscatheterclosurewithamean followupof10years.Overallcomplicationratesobservedinbothgroupswerelow anddifferedbylessthan2% 3 .AllcausemortalityratesfollowingtranscatheterASD closurecomparefavorablytosurgicalclosure.Table1summarizesrecentlyreported allcausemortalityratessegmentedbytreatmentmodalitycomparedtothe AMPLATZERAtrialSeptalOcclusion(ASO)device. ThesecontemporaryresultsvalidatetranscathetersecundumASDclosureasasafe andeffectivetherapeuticoptionforpatientsinwhomtheneedfordefectclosureis clearlyindicated.

Kirklin/BarrattBoyesCardiacSurgeryvol.1(Kochoukas,Kirklin/BarrattBoyesCardiacSurgery(2vol.Set)) DuZD,HijaziZM,KleinmanCS,etal.fortheAMPLATZERInvestigators.Comparisonbetweentranscatheterandsurgical closureofsecundumatrialseptaldefectinchildrenandadult:resultsofmulticenternonrandomizedtrial.JAMColl Cardiology.2002;8:CR787791. 3 Kuttyetal.,LongTerm(5to20Year)OutcomesAfterTranscatheterorSurgicalTreatmentofHemodynamically SignificantIsolatedSecundumAtrialSeptalDefect,AmericanJournalofCardiology,Feb132012AheadofPrint

1 2

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Table 1.

AllCauseMortalitybyTreatmentModality

AllCauseMortality Reference SurgicalClosure TranscatheterClosure 0.60% 0.093% 0.009%* AMPLATZERASOTranscatheterClosure

Karamlou 4 0.88% DiBardino 5 0.13%

*0.009% is based on post commercial experience. Reference Section4.

1.2

Atrial Septal Defect Overview

Theheartisdividedintofourseparatechambers.Theupperchambers,oratria, aredividedbyawallcalledtheatrialseptum.Anatrialseptaldefect(ASD)isa congenitalabnormalityoftheatrialseptumcharacterizedbystructuraldeficiency, orahole,intheatrialseptuminoneormorelocations.ASDsareoneofthemost commonheartdefects,andarecausedbyincompletegrowthoftheseptalwall duringfetaldevelopment.TheASDcreatesintracardiacshuntingattheatrial level,withbloodflowingthroughthedefect,usuallyfromtheleftatriumtothe rightatrium.Thisunintendedbloodflowpatternincreasesthebloodvolumein therightatrium,whichcausesmorebloodtobepumpedtothelungs.Thisshort circuitofbloodflowisinefficientforprovidingcirculationtothebody. ManyphysiologicalchangesmayoccurduetothepresenceofanASD.These changesdependessentiallyuponthesizeofthedefectortheamountofblood flowthroughthedefect,thedurationoftheanomaly,andtheconditionofthe pulmonaryvascularbed.Inlargedefects,withsignificantlefttorightshunts,the rightatriumandrightventriclebecomevolumeoverloadedandtheaugmented volumeisejectedintoalowresistancepulmonaryvascularbed.Overtime, microscopicchangesoccurinthelungswhichcanleadtopulmonaryvascular diseaseandpulmonaryhypertension. TherearefourtypesofASDs.Eachtypeisdefinedbyitslocationintheheartas follows: Thefirsttypeisanostiumsecundumdefect.Thisisthemostcommon typeofASD,representingupto80%ofallASDs.Thisdefectoccursinthe areaofthefossaovalisandpresumablyresultsfromexcessive fenestrationorresorptionofseptumprimum,underdevelopmentof septumsecundum,orsomecombinationofthetwoconditions. Thesecondtypeisanostiumprimumdefect.OstiumprimumASD(15 20%ofallASDs)islocatedatthelevelofthetricuspidandmitralvalves

Karamlouetal.,Therushtoatrialseptaldefectclosure:istheintroductionofpercutaneousclosuredriving utilization?,AnnThoracSurg.2008Nov;86(5):158490;discussion15901. 5 DiBardinoetal.,AnalysisoftheUSFoodandDrugAdministrationManufacturerandUserFacilityDeviceExperience databaseforadverseeventsinvolvingAmplatzerseptaloccluderdevicesandcomparisonwiththeSocietyofThoracic Surgerycongenitalcardiacsurgerydatabase,JThoracCardiovascSurg.2009Jun;137(6):133441.

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andpresumablyresultsfromfailureoftheendocardialcushionstoclose theostiumprimum.Becauseendocardialcushionsalsoformthemitral andtricuspidvalves,ostiumprimumdefectsaretypicallyassociatedwitha cleftintheanteriormitralvalveleaflet. Thethirdtypeisasinusvenosusdefect.ThisASDisfoundintheposterior aspectoftheseptumnearthesuperiorvenacava(whereitmaycoexist withpartialanomalouspulmonaryvenousconnectionoftherightupper pulmonaryvein)ortheinferiorvenacava(whereitmaycoexistwith partialanomalouspulmonaryvenousdefectoftherightlowerpulmonary vein).SinusvenosusASDsrepresent510%ofallASDs. Thefourthtypeisacoronarysinusseptaldefect.Thisleastcommontype ofASD(<1%ofASDs)iscalledanunroofedcoronarysinusorcoronary sinusseptaldefect.Aportionoftheroofofthecoronarysinusismissing; therefore,bloodcanbeshuntedfromtheleftatriumintothecoronary sinusandsubsequentlyintotherightatrium.Thistypeisoftenassociated withaleftsuperiorvenacava.

TranscatheterdeviceclosureissolelyindicatedforsecundumASDs.Coronary sinusdefects,sinusvenosusdefectsandostiumprimumASDsareinteratrial communicationsthatarenotamenabletocatheterbaseddeviceclosurebecause oftheanatomicnatureofthedefectsandtheirproximitytothesemajorcardiac structures.Theyarealsooftenassociatedwithothercardiacmalfunctions. 6 Figure1illustratestheanatomyofthesecundumatrialseptaldefect.

Hijazi et al., Transcatheter closure of ASDs and PFOs a comprehensive assessment. Cardiac Textbook 2010.

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AtrialSeptalDefect

Figure1. HeartwithAtrialSeptalDefectandCrossSectionalViewofAtrialSeptum

Theanatomicmargins(alsoreferredtoasrims)surroundingtheatrialseptum aredefinedbelowanddetailedinFigure1: Aorticrim:rimrelatedtotheaortathatabutstheanteriorsuperiorseptumof thedefect.Itmayalsobecalledtheanteriorsuperiorrim,retroaorticrim,or retroaorticmound. Superiorrim:therimthatabutsthesuperiorwalloftheatrium. AtrioventricularValve(AV)rim:rimthatabutstheatrioventricularvalvesorcrux oftheheart,alsocalledtheinferioranteriorrim. InferiorVenaCava(IVC)rim:rimthatabutstheinferiorvenacava,alsocalledthe inferiorposteriorrim. Posteriorrim:mostrightwardandposteriorrimoppositetheaorticrim,and anatomicallyrelatedtotherightupperpulmonaryvein. SuperiorVenaCava(SVC)rim:posteriorsuperiorrimwhichisborderedbythe superiorvenacavaandisneartheupperpulmonaryvein. ThesecundumASDcanvarygreatlyinsizeandshape,butdoesnotdirectly involvethemajorcardiacstructures(venacava,rightpulmonaryveins,coronary sinus,oratrioventricularvalves).Relationshipstothesestructures,however,are importantconsiderationsfortranscatheterclosure.Thedefecttissuerimsmust bepresentandsubstantialenoughtoanchorthedevice.

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 2 2.1 DEVICESUMMARY BenefitsofTranscatheterClosure

TheAMPLATZERASOdevicewasdevelopedwiththeintenttotreatostium secundumatrialseptaldefectsusingminimallyinvasivetechniquesasa reasonablealternativetosurgicalclosure(sutureorpatch).Resultswithan AMPLATZERASOdevicehavedemonstratedtobecomparabletosurgicalclosure, withtheaddedbenefitsof: Noexposuretocardiopulmonarybypass Nochestincisionrequired Decreasedneedforbloodorbloodproducttransfusion Reductioninhospitalstay Significantlyreducedconvalescencetime Rapidreturntonormalactivities Potentialhealthcareeconomicbenefits

TheAMPLATZERASOdevicewasdesignedforeaseofusewithsimplemechanics andnitinolconstruction,whichallowsthedevicetobeplacedandeasilyretrieved and/orrepositionedwithina68Fr.deliverysystem.Becausedeviceposition relativetothedefectanatomyisanimportantfactorintranscatheterclosure,the abilitytorepositionandretrievethedeviceallowstheimplantingphysician greaterflexibilityforoptimaldeviceplacement.Thedevicesdesignisself centeringanddurable,andisabletoeffectivelyclosemostASDsinpatientswho meettheindicationsforuse(Figure2).

2.2

IntendedUseandPatientPopulation

TheAMPLATZERASOisapercutaneous,transcatheter,ASDclosuredevice intendedfortheocclusionofASDsinthesecundumpositionandforpatientswho haveundergoneafenestratedFontanprocedureandrequireclosureofthe fenestration. PatientsindicatedforASDclosurehaveechocardiographicevidenceofostium secundumatrialseptaldefectandclinicalevidenceofrightventricularvolume overload(i.e.,1.5:1degreeoflefttorightshuntorrightventricleenlargement).

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2.3

DeviceDescription

TheAMPLATZERASOisaselfexpandabledeviceconstructedfrom0.004 0.008braidednitinolwires.Thesebraidednitinolwiresaremanufacturedina tubularformandaresettoadesignatedlengthbyplacingandlaserwelding platinummarkerbandsonboththeproximalanddistalends.Additionally,a femalethreadedcomponent,orendscrew,islaserweldedovertheproximal platinummarkerbandforattachmenttothedeliverysystem.Thebraidednitinol tubewithweldedendsisformedintotheASOgeometryusingamoldandheat treatmentprocess.Followingheattreatmentandcooling,polyesterfabric patchesaresewnsecurelyintothedevicetoincreaseocclusionproperties.The finalASOdeviceconsistsofacontinuousbraidedstructurecomprisedoftwo retentiondisks:arightandleftatrialretentiondiskconnectedbyacentralwaist thatiseither3or4mminlength. Becauseoftheimportanceofdevicesizingrelativetothedefect,AMPLATZER ASOdevicesareconstructedinavarietyofsizesrangingfrom4mmto38mm. TherequiredsizeoftheAMPLATZERASOisdeterminedbythediameterofthe waist,whichshouldbeequaltoorslightlylargerthanthemeasuredsizeofthe ASD.Whenimplanted,theconnectingwaistfillsoroccludesthedefect,andthe twoopposingretentiondiscsholdthedevicesecurelyinplace. Theradialspanoftheretentiondiscswasminimizedasmuchaspossibleinthe devicedesigninordertolowertheriskofdiscencroachmentonadjacentcardiac structures.Theleftatrialretentiondiscisslightlylargerthantherightatrial retentiondisc,toaccountforthetypicallefttorighttransatrialpressure gradientandtofacilitatedeployment. KeyfeaturesoftheAMPLATZERASOdevicearesummarizedasfollows: ASDtreatmentsizerangeof3mmto38mm CentralpositioningofthedevicewithintheASD StablepositioningofthedevicewithintheASD DevicewaistfillstheASDforreliableocclusion Polyestermaterialsewnintoeachdeviceincreasestheocclusiveproperties andprovidesasubstratefortissueingrowth Retrievability;theAMPLATZERASOremainsattachedtothedeliverycable untilthephysicianreleasesthedevicebyunscrewingthedevicefromthe deliverycable.Correctdeviceplacementisfirstconfirmed,andthedevice canberetrievedifplacementisnotsatisfactory

Figure2providesanillustrationoftheASOdevicedesignelements.

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Figure2. EssentialComponentsoftheAMPLATZERAtrialSeptalOccluder

Configurations TheAMPLATZERASOdeviceisofferedintwentysixsizestoaccommodate variousdefectsizes.Aspreviouslydescribed,thedeviceconfigurationisacentral waistwithtwoopposingretentiondiscs.TheAMPLATZERASOdevicetreatsa rangeofASDsizesfrom3mmto38mm.

Table 2.

ASODeviceSizeRange

DeviceSizes 4mm20mm 22mm38mm DesignElements

SizeIncrements 1mm 2mm

TheAMPLATZERASOdevicewasdesignedtoaddresseachoftheprimaryclinical functionsnecessaryforsafeandeffectiveclosureoftheASD,includingvisibility underimaging,easeofdeployment,stabilitywithinthedefect,andreliable occlusion.Table3detailstheindividualdesignelementsthataddressthesekey propertiesandmechanics.

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Table 3. DesignElementsandAssociatedClinicalFunctions

DesignElement DistalMarkerBand

ClinicalFunction Fluoroscopicvisibility Devicepositioning Devicestability DefectOcclusion Tissueingrowth Fillthedefect Selfcenterthedevice Defectocclusion Tissueingrowth Devicepositioning Devicestability DefectOcclusion Tissueingrowth Fluoroscopicvisibility Attachmenttodelivery system DefectOcclusion Tissueingrowth

LeftAtrialRetentionDisc

Waist

RightAtrialRetentionDisc

ProximalEndScrew

PolyesterFabricPatches PrinciplesofOperation

Implantationofthedeviceoccursinacatheterizationlaboratorybyinterventional cardiologistsexperiencedwithtranscathetertechniques.Usingapercutaneous techniquewithfluoroscopicandechocardiographicimageguidance,astandard 0.035inchJtip,commerciallyavailableguidewire,isinsertedthroughthe defectintotheleftatrium.TheAMPLATZERSizingBalloonII(orsimilarly compliantballooncatheter)isadvancedovertheguidewireintothedefectto determinethediameterofthedefect.Thesizingballoonisusedtomeasurethe sizeofthedefectwithechocardiographyusingastopflowtechnique.Oncesizing iscomplete,thesizingballoonisremoved.

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Oncethedefectsdiameterhasbeenconfirmed,adevicesizeisselectedequalto, oriftheidenticalsizeisnotavailable,1sizelargerthanthedefect.Thedeviceis screwedontoadeliverycableandloadedintoadeliverysystem(AMPLATZER TorqVueDeliverySystemortheAMPLATZERDeliverySystem).TheAMPLATZER ASOdeviceistheninsertedthroughthedeliverysystemtothedistaltipofthe catheterusingadeliverycablethatisattachedtothedeviceendscrew.Utilizing fluoroscopicandechocardiographicassessmentofthedeviceplacement (visualizationofdevicemarkerbands),thedeliverysystemisadvancedintothe leftatrium.Thedistaldiscofthedeviceisthendeployedandpositionedup againsttheleftsideoftheatrialseptum.Next,thedeliverysystemisretracted acrosstheASDandispositionedintherightatriumwheretheproximaldiscis deployedwithintherightatrium.Thephysicianconfirmsthetwodiscsare positionedtogetheronopposingsidesoftheASDinthecorrectlocation.The devicecanberetractedandeitherrepositionedorreplacedpriortofinalrelease ofthedevicefromthedeliverycable. Figure3illustratestheplacementoftheAMPLATZERASOdevice.

Figure3. ASODevicePlacement

Oncereleasedinoptimalposition,theAMPLATZERASOdevicewaistwillbe centrallypositionedwithintheASDwithequaldistributionoftheretentiondiscs aroundtheASDforstability.Thiscircumferentialcontact,combinedwiththe 11 | P a g e

polyesterpatch(sewnsecurelyintoeachdisc)isintendedtopreventtheflowof bloodthroughthedefectandthedevice,therebypromotingtissueingrowth.The devicebecomesfullyendothelializedinamatterofmonths. 2.4 RegulatoryPathwaytoUSApproval

TheAMPLATZERASOdevicewasoriginallyevaluatedinaUSclinicaltrialunderan InvestigationalDeviceExemption(IDE).ThisUSclinicaltrial(pivotalstudy)wasa multicenter,nonrandomized,controlledstudywithatotalof442patients enrolledinthedevicearmand154patientsenrolledinthesurgicalarm. Additionally,aregistrygroupwasstudiedtoevaluatethedevicein48patients withaFenestratedFontan(FF). Uponsuccessfulcompletionofthepivotalstudyandtheregistry,apremarket approval(PMA)applicationwasfiledwiththeFDA.Anadvisorymeetingwasheld onSeptember10,2001,andtheCirculatorySystemDevicesPanelrecommended approvalwithconditionsthatrelatedtolabeling,training,anda5yearfollowup ofasubsetofthepivotaltrialcohort.Anadditionalpostapprovalstudy,witha2 yearfollowupofpatientsimplantedoutsidethepivotaltrialcohort,wasinitiated in2007toevaluatethelongtermsafetyandefficacyoftheASOdevice. AllapprovalconditionswereagreeduponandtheAMPLATZERASOdevicewas approvedintheUSonDecember5,2001. 2.5 MarketExperience

TheAMPLATZERASOdevicereceivedCEmarkintheEuropeanUniononFebruary 24,1998.Thedevicealsoreceivedapprovalinseveralothermajorforeign marketsincludingCanada(May17,2000),Japan(March25,2005),andAustralia (December20,2006). AsofJanuary2012,totalsalesoftheAMPLATZERASOdevicewere223,965 devices.Ofthese,72,566deviceswereshippedtocentersintheUSandthe remaining151,399deviceswereshippedinternationally.

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 Inadditiontothesemarkets,theAMPLATZERASOisapprovedformarketingin thefollowingcountriesasofMarch2012:
Argentina Armenia Austria Belarus Belgium Brazil Bulgaria China Colombia CostaRica Croatia Cyprus CzechRepublic Denmark Ecuador Estonia Finland France Georgia Germany Greece Hungary Iceland India Indonesia Iraq Ireland Israel Italy Kazakhstan Korea Kyrgyzstan Latvia Libya Liechtenstein Lithuania Luxembourg Macedonia Malta Mexico Moldova Monaco Netherlands NewZealand Norway Panama Peru Philippines Poland Portugal Romania Russia SaudiArabia Serbia Singapore Slovakia Slovenia Spain SriLanka Sweden Switzerland Taiwan Tajikistan Thailand Tunisia Turkey Turkmenistan Ukraine UnitedKingdom Uruguay Uzbekistan Venezuela Vietnam

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3 3.1

CLINICALTRIALSSUMMARY IDEPivotalTrial

ThedatafromtheUSIDEpivotaltrialprovidedevidencesupportingthesafetyandefficacyof theAMPLATZERASOinsecundumASDs.Transcatheterclosureresultswerecomparableto surgicalclosure,withaddedbenefitsofashorterhospitalstay.Adverseeventrateswere withinthelimitsdefinedbytheprotocol,andsignificantlylowerthanthoseobservedinthe surgicalarm.

3.1.1 ASOUSPivotalTrialOverview

ThepivotaltrialwasdesignedtoevaluatetheclinicalperformanceoftheAMPLATZER ASOdeviceforASDclosurecomparedtotheASDsurgicalrepairprocedure.Thestudy wasamulticenter,nonrandomized,controlledstudywithatotalof442subjects enrolledinthedevicearmand154subjectsenrolledintheASDsurgicalarm.Enrolled subjectshadechocardiographicevidenceofostiumsecundumASDwithaminimumof 1.5:1lefttorightshunt,rightventricleenlargement,orhadclinicalsymptomssuchas paradoxicalembolismoratrialdysrhythmiainthepresenceofaminimalshunt. Additionaldemographicinformationaswellasaresultssummarycanbefoundin Table4below. DetailsofthepivotaltrialresultscanbefoundintheSummaryofSafetyand Effectiveness(SSED)submittedaspartoftheoriginalPMA(Section5)andthe InstructionforUse(IFU)(Section6). PMAApprovalwasgrantedonDecember5,2001.

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3.1.2 ASOUSPivotalTrialResults PrincipalEffectivenessandSafetyResultsandAdverseEventsOverview
PivotalStudyDevice 442

Table 4. Item (asperPivotalstudydesign) #Subjects

PivotalStudySurgery 154

Age(years) GenderMale GenderFemale Height(cm) Weight(kg)

18.1 32.4% 67.6% 134.6 42.3

5.9 39% 61% 105.5 20.6

TechnicalSuccess ProcedureSuccess Early(<30days)Composite Success 12moCompositeSuccess 24hrClosureSuccess 1moClosureSuccess 6moClosureSuccess 12moClosureSuccess

95.7%(423/442) 97.6%(413/423) 90.7%(401/442) 91.4%(331/362) 96.7%(404/418) N/A 97.2%(376/387) 98.5%(326/331)

100%(154/154) 100%(154/154) 96.1%(148/154) 94.8%(146/154) 100%(154/154) N/A 100%(154/154) 100%(149/149)

MajorAdverseEvents(12 mo) MinorAdverseEvents(12 mo) 12moCompositeSuccess (KM) Survivalat30days(KM) Survivalat180days(KM)

1.6%(7/442) 6.1%(27/442) 0.934 0.939 0.936

5.2%(8/154) 18.8%(29/154) 0.938 0.956 0.947

EffectivenessoftheAMPLATZERASOfortreatmentofASDswasdemonstratedby 98.5%successfulclosureat12monthfollowupwithouttheneedforadditional surgicalrepair(326outof331subjects).Theseresultsarestatisticallyequivalentto the100%ratereportedfortheASDSurgicalRepairControlgroupwithinthe95% confidenceinterval. SafetyoftheAMPLATZERASOwasdemonstratedbytheadverseeventratesat12 months,whichwerewithintheprotocoldefinedacceptablelimits.Theoverall AMPLATZERadverseeventrate(7.7%)wasstatisticallysignificantlylowerthanthat reportedforthesurgicalarm(24.0%)(p=<0.001).Themajoradverseeventratefor AMPLATZERASOsubjectswas1.6%comparedtotheprospectivelyassumedrateof 10%.Themortalityrateforthedevicecohortwas0%comparedtothe2% prospectivelyassumedrate. 16 | P a g e

 Inadditiontostrongsafetyandeffectivenessresults,themeanlengthofhospitalstay forAMPLATZERsubjects(1day)wasstatisticallysignificantlylowerthanthemeanof 3.4daysdocumentedfortheASDSurgicalRepaircontrolgroup(p<0.001). 3.2 PostApprovalStudy

3.2.1 PostApprovalStudyOverview

ThecomprehensivepostapprovalstudywasapprovedbyFDAonAugust16,2007and initiatedinMarch2008.Thepostapprovalstudyisaprospective,nonrandomized, multicenterevaluationof1000subjects.Aminimumof800subjectswillbefollowed totwoyears.Thesubjectpopulationincludesbothpediatricandadultsubjects. St.JudeMedicalsubmitsinterimstudyreportsonasixmonthbasis.Thecompany recentlysubmittedthe54monthinterimreporttotheFDA,datedFebruary15,2012. Datapresentedhereinisreflectiveofthisinterimreport(876patients).However,as ofMarch30,2012,greaterthan970subjectshavebeenenrolled.

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3.2.2

PostApprovalStudyData(54monthinterimresults)

Thisstudywasdevelopedtoreflectrealworlduse.RatesasseeninTable5are consistentwithIDEfindingsbutaremorereflectiveofrealworldexperience.
Table 5.

SummaryofSafetyandEffectivenessData
PostApprovalStudy 54moAnnualReport 876

Item (asperPostApprovalstudydesign) #Subjects

Age(years) GenderMale GenderFemale Height(cm) Weight(kg)

20.9 35% 65% 135.1 45.4

TechnicalSuccess 1moClosureSuccess

Rate 98.1% 97%

N 859/876 789/813 N 33 247 0 0 0 0 0 0 3 (2cardiacarrest, 1pneumonia)

MajorAdverseEvents MinorAdverseEvents Deaths DuetoErosion DuetoEmbolization DuetoFracture DuetoStroke DuetoThrombus DuetoArrhythmia DuetoOther

Rate 3.8% 28.2% 0% 0% 0% 0% 0% 0% 0.003% Rate 0% 0.3% 0.1% 0% 0.1% 0% 0% 1.6% 11.9%

Erosion EmbolizationSerious EmbolizationMinor Fracture Stroke ThrombusSerious ThrombusMinor ArrhythmiasSerious ArrhythmiasMinor

N 0 3 1 0 1 0 0 14 105

Note:Allpotentialerosioneventsobservedinthepostapprovalstudyunderthe definitionofhemodynamiccompromiseareevaluatedbyanindependentErosion BoardaccordingtotheuniformmethodsdescribedinSection4.2.2.Sincethe54 monthfollowupreportwassubmittedtoFDA,twohemodynamiccompromiseevents havebeenadjudicatedasconfirmederosionevents.Theseeventsarecapturedinthe totaladverseeventsreportedinSection4. 18 | P a g e

Interimresultsforthepostapprovalstudydemonstratethecontinuedsafetyand efficacyoftheAMPLATZERASOforpercutaneous,transcatheterclosureofatrial septaldefectsinsecundumposition. 4 4.1 POSTCOMMERCIALIZATIONEXPERIENCE AdverseEventReporting

St.JudeMedicalcontinuouslymonitorsproductincommercetodetermineifthedeviceis performingasexpected,andtakesactionintheeventthatthereareunexpectedoccurrences. St.JudeMedicalmeetspostmarketregulatoryrequirementsthroughtheuseofstandard operatingproceduresdesignedtoensurepostmarketproductperformance,safety,and distributionchanneltraceability.St.JudeMedicalbecomesawareoffieldevents,associated withtheAMPLATZERASO,inavarietyofwaysincludingphysicianorpatientconcernsor comments,publishedliterature,orcustomerreportedadverseclinicalevents.Adverseevent reportingisakeycomponentofmonitoringfieldevents.Perregulatoryrequirements,allfield eventsarereviewedand,asappropriate,arereportedtotheFDAundertheMedicalDevice Reportingregulation(21CFR803).Withadverseeventsreportedoutsideofacontrolled clinicalinvestigation,devicemanufacturersarereliantoninformationfromreportinghealth careprovidersandpublishedliterature,whichmaybeincompleteoranecdotalwhencompared tothetypeofdataobtainedthroughaclinicaltrial.St.JudeMedicalconductsroutinetrending ofeventsreportedinallcommerciallyreleasedproductsandattemptsaremadetogainas muchinformationaspossibleonthesefieldevents. Table6representsthemajoradverseeventcategories;otherlessfrequentand/orlesssevere adverseeventsarenotdiscussedinthisdocument.Eventnumbers(seeTable6)areas reportedthroughJanuary2012,withtheexceptionoferosionevents,wheretheevent numbersarereflectiveofthelatestErosionBoardadjudication;encompassingeventsthrough 15March2012.AlleventsdescribedhereinincludeMDRreportedmajoradverseeventsfor theonlabeluseoftheAMPLATZERASOdevice,inthespecifiedcategories,withassociated ratesbasedonworldwidereportedeventsandworldwidesalesof223,965devices.

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Table 6.

WorldWideSeriousAdverseEventOverviewThroughJanuary2012* TotalReported Events(onlabel, ASO,worldwide) 54 347 97 1 0 9 6 11 Rate(basedonsales, worldwide)** 0.024% 0.155% 0.043% 0.0004% 0.000% 0.004% 0.003% 0.005%

AdverseEvent

Arrhythmia Embolization Erosion Fracture Malfunction Malposition Stroke ThrombusonDevice

*Erosioneventsareasof15March2012

**Alladverseeventratesarecalculatedusingtotalworldwidesalesof223,965units. NOTE:Thesamepatientmaybecountedinmorethanoneoftheabovereportedadverseevents.

4.1.1 Arrhythmia

Arrhythmias,occurringbothduringtheprocedureandwithinseveralmonthsafter treatment,areanticipatedpotentialadverseeventsforanycardiacinterventionand areusuallytransientinnature 7 .Clinicallysignificantarrhythmiasincludethosethat resultinheartblockand/orrequiretheplacementofapermanentpacemaker,those requiringlongtermmedicationandthoserequiringinterventionduringthe catheterizationprocedure.Thereportedincidenceofseriousarrhythmiafollowing surgicalrepairofASDsisapproximately8%. 8,9,10 Thissurgicalrateissignificantly higherthanthatobservedwithtranscatheterclosureusingtheAMPLATZERASOas evidencedinthepivotaltrial,postapprovalstudyandthepostcommercializationASO experienceTheobservedrateofseriousarrhythmiasinthepivotalstudywas0.5%, andinthepostapprovalstudy(PAS)was1.6%.Theworldwideeventrateof0.024% remainslowerthantheseriousarrhythmiaeventratesseeninthepivotalstudyand thePAS.ThearrhythmiaeventsreportedinTable6includeatrialfibrillation,atrial flutter,bradycardia,palpitations,prematureventricularcontractions,STwave abnormality,tachycardia,ventricularfibrillation,andheartblock.
7
8

Hijazietal.,TranscatheterclosureofASDsandPFOsacomprehensiveassessment.CardiacTextbook2010. RoosHesselinketal.,Excellentsurvivalandlowincidenceofarrhythmias,strokeandheartfailurelongtermaftersurgicalASDclosureat youngage.Aprospectivefollowupstudyof2133years.EuropeanHeartJournal(2003)24,190197 9 Mascioetal.,Outcomesinadultcongenitalheartsurgery:AnalysisoftheSocietyofThoracicSurgeonsDatabase.TheJournalofThoracicand CardiovascularSurgery,Nov2011:10901097. 10 Bergeretal.,Arrhythmiasinpatientswithsurgicallytreatedatrialseptaldefects.SwissMedicalWeekly,2005;135:175178

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Figure4. ArrhythmiaAdverseEventComparisonChart

4.1.2 DeviceEmbolization

Deviceembolizationismovementormigrationofthedeviceoutsideoftheatrial septaldefectafterdevicereleasefromthedeliverycable.Movementintotheright ventricleandpulmonaryarteryismorecommoncomparedtotheleftventricle,which israre.Followingproperdeviceimplanttechniqueandsizingguidance,asdefined withintheIFU,iscriticaltopreventingdeviceembolizations.IntheAMPLATZERASO USpivotaltrialexperience,embolizationwasreportedintwocategories,seriousand minor;theeventratesobservedwere0.9%and0.2%,respectively(overallrateof 1.13%forthedevicearm).Withinthepostapprovalclinicalstudy,anadverseevent rateof0.3%forseriousand0.1%forminorembolizationwasobserved;withan overallrateof0.46%.AsshowninFigure5,theworldwideeventrates(0.155%) remainlowerthantheeventratesobservedinthepivotalstudyandthePAS.

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Figure5. EmbolizationAdverseEventRateComparisonChart

4.1.3

Erosion

Erosionreferstotheabrasionoftissueoftheatrium,primarilyintheareaoftheroof oftheatriumneartheaorta.BetweenDecember2001andMarch15,2012,97world widecases(49USand48OUS)oferosionhavebeenidentifiedinassociationwiththe onlabeluseoftheASOdevice,representinganoverallriskoferosionof0.043%.This riskhasremainedrelativelyconstantovertime.Erosionisdiscussedindetailin Section4.2. AsillustratedinFigure6,erosioneventsarerareandwerenotobservedinthepivotal study.However,asinpostcommercializationexperience,erosioneventshavebeen observedinthepostapprovalstudy(2of970).

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Figure6. ErosionAdverseEventComparisonChart

4.1.4 Explants

Explants,percutaneousorsurgicalremovalofthedevice,mayberequireddueto patientfactorsand/ordeviceorprocedurerelatedcomplications.TheAMPLATZER ASOhasbeenonthemarketforovertenyearswith223,965devicessold.Forthe seriousadverseeventslistedinTable6,deviceshavebeenexplantedsurgically(298 events,representing0.133%)orpercutaneously(130events,representing0.058%). Themajorityofexplantswereassociatedwithembolizationevents;ofthese,89% wereexplantedpriortopatientdischargefromthehospital.

4.1.5 Fracture

TherewasonereportedfracturefortheAMPLATZERASOdevice.Theimplanting physicianreportedseveralbrokenwiresonapercutaneouslyretrieveddevice followingdeviceembolizationoccurringonthefirstpostimplantday.Thephysician statedthatthewirefracturemostlikelyoccurredduringthedeviceretrievalprocess. Therehavebeennootherreportsoffractures.

4.1.6 Malfunction

Therehavebeennoreportedseriouseventsformalfunctionspecifictothe AMPLATZERASOdevice.
4.1.7 Malposition

Malpositionoccurswhenthedeviceisnotimplantedintheintendedpositionafter releasefromthedeliverysystem.Therewere9casesreported;representingavery low,0.004%incidencerate. 23 | P a g e


4.1.8 Mortality(allcause)

SincemarketintroductionoftheAMPLATZERASOdevice,therehavebeen20reported deathsthroughJanuary2012foranallcausemortalityrateof0.009%.Deathsoccurred secondarytothefollowingevents:embolization(2),erosion(8),strokeandthrombus(1) cardiacarrest(1),perforation(2),tamponade(1),effusion(2),CNSbleed(1),CVA(1)and seizure(1).TheallcausemortalityrateassociatedwithASOimplantationissignificantly lowerthantherateforsurgicalclosureofASDscitedinthemostrecentpublished literatureforallcausemortalityinbothadultandpediatricpatients(0.13%to0.88%,as describedinSection1).Themortalityrateassociatedwitherosionhasbeencarefully assessedandisdetailedinSection4.3.2.

4.1.9 Stroke

StrokeisananticipatedadverseeventwithrepairofASDs(surgicalorpercutaneous). ThereportedincidenceofstrokefollowingsurgicalrepairofASDrangesfrom2%to 6.5%. 11,12,13 Thissurgicalrateishigherthanthatobservedwithtranscatheterclosure usingtheAMPLATZERASOasevidencedthroughthepivotaltrial(0.0%),postapproval study(0.1%)andthepostcommercializationstrokeadverseeventrate(0.003%).

4.1.10 ThrombusonDevice

Thrombushasbeendemonstratedtobearareadverseeventfortranscatheterclosure usingtheAMPLATZERASO.Thisisevidencedbytheobservedpostcommercialization adverseeventrateof0.005%.Inthepivotalstudy,onlyminorthrombuseventswere noted;however,thrombusremainsapotentialadverseeventbutatanextremelylow incidencerate.

4.1.11 PostCommercializationExperienceConclusion

Theadverseeventspresentedinthissectionrepresentpostcommercialization experienceacrosstherangeofpatientdemographicsandimplanterexperience.These dataconfirmthatthereportedadverseeventratesfortheAMPLATZERASOdeviceare consistentwith,andinsomecases,lowerthan,thosereportedinthepivotalandpost approvalstudies. St.JudeMedicalmaintainsaglobalcomplainthandlingprocesstoensurethat potentialnonconformancesandadverseeventsareanalyzed,investigatedandacted

KuttyS,HazeemAA,BrownK,DanfordCJ,WorleySE,DelaneyJW,DanfordDA,LatsonLA.LongTerm(5to20Year)OutcomesAfter TranscatheterorSurgicalTreatmentofHemodynamicallySignificantIsolatedSecundumAtrialSeptalDefect.AmJCardiol.2012Feb13.[Epub aheadofprint]PubMedPMID:22335856. 12 ShibataY,AbeT,KuribayashiR,SekineS,SekiK,YamagishiI,ChandaJ.Surgicaltreatmentofisolatedsecundumatrialseptaldefectinpatients morethan50yearsold.AnnThoracSurg.1996Oct;62(4):10969.PubMedPMID:8823095. 13 MurphyJG,GershBJ,McGoonMD,MairDD,PorterCJ,IlstrupDM,McGoonDC,PugaFJ,KirklinJW,DanielsonGK.Longtermoutcomeafter surgicalrepairofisolatedatrialseptaldefect.Followupat27to32years.NEnglJMed.1990Dec13;323(24):164550.PubMedPMID: 2233961.
11

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uponappropriately.Anycorrectiveactionsareverified,validated,andmonitoredfor effectiveness.AllformalCorrectiveandPreventativeAction(CAPA)stepsare documentedthroughtheSt.JudeMedicalqualitysystem. 4.2 CorrectiveActions

InmonitoringthesafetyandeffectivenessoftheAMPLATZERASO,therehavebeentwo adverseeventtypesuponwhichSt.JudeMedicalhasprovidedadditionalfocus:embolization anderosion.TheseeventswereanalyzedforbothworldwideandUSexperience.

4.2.1 Embolization

Followingproperdevicesizingguidanceandimplanttechniqueasdefinedwithin theIFUiscriticaltopreventingdeviceembolization.St.JudeMedicalrecently implementedretrainingofallimplantingphysiciansonimplanttechniqueand devicesizingtoensuretheASOdeviceisaccuratelysizedtothedefectbeing treated.St.JudeMedicalcontinuestoactivelymonitortheseeventsinaneffortto ensureratesremainatthelowestpossiblelevel.

4.2.2 Erosion

Background Erosionisdefinedasabrasionoftissueoftheatrium,primarilyintheareaofthe roofoftheatriumneartheaorta.Althoughrareinoccurrence,erosioncan potentiallyresultinserioushealthconsequencesforthepatient.St.JudeMedical recognizesthepotentialseverityofthisevent,andhasthusensured(1) adjudicationofallpotentialerosioneventsbytheErosionBoard,(2)completionof arigorousrootcauseanalysis,and(3)implementationofsubstantialcorrective actions. Followingthefirstreportofanerosionfieldeventin2002,AGAMedical,nowaSt. JudeMedicalcompany,establishedanindependentpanelofexpertphysicians(the ErosionBoard)toassistinthemonitoringandanalysisoftheseevents.TheErosion Boardisactivelyinvolvedintheadjudicationofallpotentialerosionevents, monitoringofincidencetrends,andprovidingrecommendationstothecompany onpotentialcontributingfactorstoerosion.TheErosionBoardalsoassistsinthe developmentofappropriateclinicalguidancethroughupdatesoftheIFU,technical notes,andpublicationsinordertominimizethepotentialforanyfutureerosion events.InadditiontotheinternalanalysisconductedbySt.JudeMedical,the ErosionBoardalsoconductsanindependentreviewofallpotentialerosionevents onbehalfofSt.JudeMedical. 25 | P a g e

Themethodsofidentifyingandinvestigatingeventsareuniformlyappliedtoeach potentialeventidentifiedthroughfield/complainteventreporting,postapproval clinicalstudyandmonitoringofMAUDEandpublishedliterature.Potentialerosion eventsreportedunderaprespecifiedsetofeventtermsarereviewedand adjudicatedbytheErosionBoard.TheErosionBoardconfirmsevidenceoferosion anddifferentiates,whenpossible,thecausalitybetweentheevent,defect anatomy,implantprocedureand/orimplantdevice.Thisprocessservesto continuallymonitortheincidenceoferosionandguidethecompanytowards necessarymodificationstolabeling,implanttechniqueandphysicianmaterialsfor thepurposeofreducingtheincidenceoferosionandfurthermitigatingpatientrisk. AsummaryoftheactionstakenbyAGAMedical/St.JudeMedicalsincethefirst reportederosioneventaresummarizedbelow: 1999 2001 2002 AMPLATZERASOCEMarkApproval AMPLATZERASOPMAApproval Firstreportederosioncase(US)

IndependentErosionBoardformedbyAGAMedicalwith establishedadjudicationprocessforallreportedpotential erosionstodetermineclinicalcontributorsandrootcause. TheErosionBoarddeterminedthatdeviceoversizingwas asignificantcontributingfactor IFUupdatedwithdevicesizingrecommendationto mitigatetheriskofdeviceoversizing ErosionBoardpublishedresultsandrecommendationsto mitigateriskofdeviceoversizing AGAMedical/FDAdiscussiontoreviewincidenceof erosioneventsandmitigationsimplemented PhysicianTechNotepublished,patientIDcardandpatient guideverbiageupdatedforguidance IFUupdatedwithadditionalwarningstatements(balloon sizingandstopflowtechnique) St.JudeMedical/FDAdiscussionregardingincidenceand

2004

2005

2006

2009

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mitigatingactions FDAapprovesadditionalIFUmodificationstofurther mitigateagainstpotentialerosionevents;St.JudeMedical publishesmodificationstoIFUandPatientGuidein January2012;St.JudeMedicalproposesphysicianletter

Asevidencedbytheactionssummarizedabove,thecompanyhasconsistentlyand progressivelyimplementedcorrectiveactionstohelpmitigateanddecreasethe potentialincidenceoferosionwhenadditionalknowledgeislearned.Theactions previouslytakenwerebaseduponinternalanalysis,recommendationsfromthe ErosionBoard,andrecommendationsfromtheFDA. InNovember2010,St.JudeMedicalacquiredAGAMedical.Inearly2011,St.Jude Medicalcompletedathoroughrootcauseanalysissupplementingtheprevious analysisconductedbyAGAMedical.Thiscomprehensiveanalysisresultedina recentupdatetotheIFUandthePatientGuide,andfocusedtrainingandre trainingforallphysiciansspecifictoatrialseptalanatomyanddeviceimplant technique.Additionally,thecompanydevelopedaproposedphysicianletterwith asummaryofinvestigationfindingsandspecificmitigationguidance.Thesemost recentactionsrepresentthecompanysongoingdiligenceandcommitment towardsmonitoringandmitigationofthisrarebutseriousevent. PrevalenceandProbability Erosioneventsrecordedannuallysince2002(Figure7)indicateastabletrendover time.

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ErosionTrendbyEventYear
20 18 16 14 12 10 8 6 0.06% 4 2 0 2002 2003 2004 2005 ErosionEvent 2006 2007 Rate/Sales 2008 2009 2010 2011 Trendline 0.05% 0.06% 0.04% 0.02% 0.05% 0.04% 0.03% 0.05% 0.06% 0.05% 0.10% 0.15% 0.25% 0.30%

0.20%

0.00%

Figure7.

ErosionRate(bydevicesales)

Inanefforttofullyunderstandtheprevalenceandprobabilityoferosionevents occurringinimplantedpatients,atimetoeventanalysiswasconducted.Aconsistent trendemergedasnotedinFigure8,below;87.6%oferosionincidentsoccurredwithin1 yearofimplant. UtilizingconfirmederosiondatafromtheErosionBoardsanalysis,St.JudeMedical employedaWeibulldistributiontoestablishthepredictiveprobabilityoflateoccurring erosionevents.Basedonthispredictionmodelandthestrongassociationtotheactual data,theprobabilityforexperiencinganerosioneventat5,10or15yearsdecreases significantlyovertimeforcurrentlyimplantedpatients,andcontinuestodecreasein probabilitytoanalmostnegligibledegree(Figure8below).

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Figure8. PredictiveProbabilityofLateEvent

Mortality Themortalityrateassociatedwiththisrareeventhasbeencarefullyassessed.The overallincidenceofmortalityis0.004%(8eventsoutof223,965devices).Notall erosionshaveresultedindeath,astherearerecognizedclinicalsymptomsforerosion eventsthatfacilitateidentificationandintervention.Importantly,nodeathsassociated witherosionoccurredinpatientsyoungerthan15yearsofage,andallreporteddeaths occurredwithin16monthsofimplant.Eacheventwasadjudicatedwiththeconfirmed presenceofdeviceoversizing,deficientrim,orboth. ThemortalityrateassociatedwitherosionfollowingASOimplantation(0.004%) comparesfavorablytotheallcausemortalityrateforsurgicalclosureofASDscitedin themostrecentpublishedliteratureforallcausemortalityinbothadultandpediatric patientsaspreviouslydescribedinSection1.1,Table1(0.13%0.88%)aswellasthe 0.07%mortalityratederivedfromtheSTSpediatricdatabase(January2006to December2009). 29 | P a g e

 RootCauseAnalysis AsconcludedbytheErosionBoardfrom2002to2010,themostfrequentlyobserved causalrelationshiptoerosionwasdeviceoversizing;notedin40%ofcases(31% pediatricand46%ofadultcases).In2011,St.JudeMedical,incoordinationwiththe ErosionBoard,completedanadditionalrootcauseanalysisforallerosionevents reportedbetweenDecember1998andNovember2011(97worldwideerosioncases; 49USand48OUS).Allavailableechocardiographicimageswerereviewed,coupled withsourcemedicalrecords.Erosioneventswereexaminedacrossmultiplefactors, includingbutnotlimitedto:age(pediatricvs.adult),sufficiencyofatrialseptaldefect rims(specificallyanteriorsuperiorrim),gender,devicesize(oversizing),eventoutcome andtimetoevent. Fromthisanalysis,St.JudeMedicalconcludedthaterosioniscausedby(1)adevice implantedwithinadefectwithinsufficientrimdistance(anteriorsuperiorrim),or(2)by anoversizeddevice,thusresultingindeviceedgecontactwithadjacentstructures.In pointoffact,reviewofallavailableechocardiographicimagesconfirmedthepresence ofdeficientrimand/oroversizingofthedeviceineacherosionevent. Morespecifically,anteriorsuperiorrimdeficiencywasnotedin90%ofallcases.From thedataavailable,100%ofpediatricerosioncasesand84%ofadulterosioncases demonstrateddeficientanteriorsuperiorrims.Asufficientrimwasdefinedasthe presenceofatleast5mmriminmultipleANDsequentialshortaxisviewsconfirmedby ICEorTEE. CorrectiveActions Priorto2011,correctiveactionswerefocusedondeviceoversizingsincethiswas determinedtobetheleadingcausalrelationshiptoerosion.Incidenceofdeviceover sizinghasdecreasedovertimeduetomitigatingactionstaken(priorIFUupdates, physiciantechnicalnotes,etc.)andoverallincreasedexperienceandawareness. Thecomprehensiveanalysis,conductedin2011,revealedthatalthoughdeviceover sizingremainsanimportantcontributortoerosion,asecondcausalrelationshipis evident,i.e.,adeviceimplantedwithinadefectwithinsufficientrimdistance(anterior superiorrim).Basedupontheseincrementalfindings,St.JudeMedicalimplemented thefollowingmitigatingactionsin2012:

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 Updatedlabeling(IFU)includinganadditionalcontraindications,modified warning,andspecificechocardiographicimagingguidance Additionofnewphysiciantrainingmodulesaddressingerosionmitigationand retrainingofphysiciansonimplanttechnique;specifictrainingoftheIFUhas beeninitiatedatbothimplantingphysicianandinstitutionallevels UpdatedPatientGuidetoprovideadditionalawarenessandguidancetopatients Thesemitigatingactionsprovideimplantingphysicianswithadditionalclearand actionableguidanceforavoidanceoferosionevents. ThenewcontraindicationsaddedtotheIFUwereanintentionallyconservativemeasure aimedateliminatingthepotentialforerosionsbyavoidingdeviceedgecontactbetween thedeviceandadjacentcardiacstructures.Theadditionofthislanguagealigned contraindicationsacrosstheindustry(i.e.,allcurrentlymarketedASOtranscatheter closuredevicesarecontraindicatedforcontactwithadjacentnonseptalintracardiac structures). Themodificationtoanexistingwarningandthenewechocardiographicimaging guidance,withintheIFU,wasspecificallyaddedtoaddressrimsufficiency;advisingthe physiciantoconductafullassessmentofdefectrimanatomypriortodevice implantation.Particularly,rimsmustbeobservedinmultipleandsequentialviewsto thoroughlyevaluatedevicecontactwithanyadjacentcardiacstructure. ThespecificIFUupdates,implementedinJanuary2012,aredetailedasfollows: Additionalcontraindications: Anypatientinwhomthedevicewouldinterferewithorcontactother intracardiacorintravascularstructures(e.g.atrialroof,cardiacvalves, pulmonaryveins,coronarysinus,oraorta). Anypatientwithechocardiographicevidenceofabsentordeficient anteriorsuperiorrim(sufficientrimisdefinedasthepresenceofat least5mmofriminmultipleANDsequentialshortaxisviewsconfirmed byICEorTEE).

Updatedwarning: DonotreleasetheAMPLATZERSeptalOccluderfromthedeliverycableif thedevicedoesnotconformtoitsoriginalconfiguration,orifthedevice positionisunstableand/orincontactwithanyadjacentcardiacstructure. 31 | P a g e

Recapturethedeviceandredeploy.Ifstillunsatisfactory,recapturethe deviceandreplacewithanewdeviceorreferthepatientforalternative treatment. Additionalechocardiographyguidance: Toallowforcomprehensiveassessmentofanteriorsuperiorrim adequacy,therimmustbeevaluatedinmultipleandsequentialshort axisviews(e.g.20,30,40,50,60or70degrees)confirmedbyICEorTEE. Rimadequacyisdefinedassufficienttissue(atleast5mm)surrounding thedefecttoensurethedevicedoesnotcomeincontactwithadjacent cardiacstructures. UpdatedPatientGuide: ThePatientGuideisprovidedtopatientsattimeoftheprocedureandis alsoavailableontheSt.JudeMedicalwebsite.ThePatientGuidewas updatedtoensurepatientsareawareoferosionrelatedsymptomsand theneedtoseekimmediatemedicalassistanceintheeventofthese symptoms. Lastly,St.JudeMedicalproposedaphysiciancommunication(technicalnote)toinclude asummaryoftherootcauseanalysisfindingsandtoprovidespecificmitigation guidancetoavoidthepotentialoferosioneventsandtoultimatelymitigateriskto patients.St.JudeMedicalhasproposedatechnicalnoteaswell;thiscommunication waspreviouslyprovidedtotheFDAwiththeintentoffinalizingsubsequenttothepanel discussion.

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 5 CONCLUSION

Minimallyinvasivetranscatheterclosurehasbecomethepreferredtreatmentforsymptomatic ostiumsecundumASDsoversurgery.TheAMPLATZERASOdeviceisdesignedtoachieve stabilitywithinthedefectandreliableocclusion,addressingtheprimarymechanismsnecessary forsafeandeffectivetranscatheterclosureoftheASD.TheAMPLATZERASOdevicehasa strongrecordofreliableandeffectiveperformance.Thedevicehasbeenstudiedinmorethan 1,200subjectsbetweentheoriginalUSIDEpivotalandpostapprovalstudies,andhasbeenon themarketformorethan10yearswith223,965devicessoldworldwide. WhiletheAMPLATZERASOdevicecontinuestobeasafeandeffectivemeansfortranscatheter ASDclosure,St.JudeMedicalrecognizesthepotentialseverityassociatedwiththerareadverse eventoferosion.Thecompanysdiligentpostmarketsurveillanceprocessemploysarigorous anduniformmethodtoinvestigateallpotentialerosionevents.Throughthisvigilantpost marketsurveillanceprocess,andthesubsequentanalysisdescribedinprevioussections,two causalrelationshipshavebeenclearlyidentifiedwiththeoccurrenceoferosionevents:device oversizing,andadeviceimplantedwithinadefectwithinsufficientrimdistance.The substantialandintentionallyconservativecorrectiveactionsimplementedbySt.JudeMedical areintendedtosignificantlydecreasethepotentialforerosionevents,thusmitigatingand reducingpatientrisk. Resultsfromthepivotalandpostapprovalstudies,pairedwiththedevicespost commercializationdata,confirmthattheAMPLATZERASOisasafeandeffectivetreatmentfor closureofASDsandcontinuestodemonstrateoverallcomplicationratescomparableor favorabletosurgicalclosure.Furthermore,thesafetyprofileoftheAMPLATZERASOremains withintheanticipatedrangespredictedattimeofPMAapproval(2001).Insummation,the totalityofthebenefitstothepatientcontinuetofaroutweightherisksassociatedwithonlabel useoftheASOinlightofthecontextofthediseaseandexistingtreatmentoptions.

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 6 SUMMARYOFSAFETYANDEFFECTIVENESSDATA(SSED)

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 7 INSTRUCTIONSFORUSE

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