BOSTONSCIENTIFICCORPORATION



UpholdLITEVaginalSupportSystem(P180018)and

XenformSoftTissueRepairSystem(P180021)













PreparedforObstetricsandGynecologyDevicesPaneloftheMedicalDevicesAdvisory Committee:TransvaginalMeshforAnteriorProlapseRepair



February12,2019

1 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  

SECTION1:EXECUTIVESUMMARY...... 4

A. DISEASEBACKGROUND...... 5 B. CURRENTTHERAPIESANDCLINICALNEED...... 5 C. BOSTONSCIENTIFIC’SDEVICESFORTRANSVAGINALREPAIROFPELVICORGANPROLAPSE(POP)...... 6 1. UpholdLITEVaginalSupportSystemwithCapioSLIM...... 6 2. XenformSoftTissueRepairMatrix...... 7 3. SurgicalProcedure...... 7 4. Labeling...... 7 5. Training...... 7 D. SUPPORTINGCLINICALEVIDENCEFORBSCDEVICESFORPOP...... 8 1. PublishedLiterature...... 9 2. 522ClinicalStudies...... 10 BENEFITͲRISKANALYSISANDCONCLUSIONS...... 14 1. BostonScientific’sDevicesareEffectiveinRestoringAnatomicalPositionandDemonstratingClinically MeaningfulImprovement...... 14 2. BostonScientific’sDevicesareSafe...... 15 3. TheBenefitsoftheBostonScientificTransvaginalMeshDevicesOutweightheRisks...... 15 SECTION2:PELVICORGANPROLAPSEBACKGROUNDANDCLINICALNEEDFORTREATMENTOPTIONS...... 17

A. PELVICORGANPROLAPSE(POP)...... 17 B. NONͲSURGICALTREATMENTOPTIONS...... 18 C. SURGICALTREATMENTOPTIONS...... 19 SECTION3:DEVICEDESCRIPTION...... 20

A. UPHOLDLITEVAGINALSUPPORTSYSTEMWITHCAPIOSLIM...... 20 Components...... 20 PrinciplesofOperation...... 22 B. XENFORMSOFTTISSUEREPAIRMATRIX...... 24 PrinciplesofOperation...... 25 C. PROCEDUREANDSURGICALTECHNIQUE...... 25 D. LABELING...... 26 E. TRAINING...... 26 SECTION4.RELEVANTREGULATORYHISTORY...... 27

A. INITIAL510(K)CLEARANCES...... 27 B. 2008/2011PUBLICHEALTHNOTIFICATION...... 28 C. 2011PANELMEETINGANDRECLASSIFICATIONOFTRANSVAGINALMESHDEVICESFORPOPREPAIR...... 28 D. 522POSTMARKETSTUDYCOMPLIANCE...... 29 E. PREͲSUBMISSIONCOLLABORATIONWITHTHEFDA...... 29 F. PMASUBMISSIONSUMMARY...... 29 SECTION5:PRECLINICALTESTING...... 30 SECTION6:LITERATUREREVIEW...... 30

A. 2011FDAPANELLITERATUREREVIEWDISCUSSION...... 30 B. UPHOLDLITEVAGINALSUPPORTSYSTEM...... 32 C. XENFORMSOFTTISSUEREPAIRMATRIX...... 35

2 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  D. LITERATURECONCLUSION...... 35 SECTION7:CLINICALEXPERIENCE...... 37

A. OVERVIEWOFBSC522POSTMARKETSTUDIES...... 37 1. Introduction...... 37 2. OverviewofStudies...... 38 3. StudyPopulations...... 40 a. AnalysisPopulations...... 43 b. SampleSizes...... 43 4. FollowͲupSchedules...... 43 5. StudyStatus...... 44 6. InterimDataAnalysis...... 44 7. SummaryofUpholdLITE12ͲMonthHypothesisTestingResults(fromP180018/A001)...... 44 8. SummaryofXenform12ͲMonthHypothesisTestingResults(fromP180021/A001)...... 58 B. DISCUSSIONOFCLINICALDATAANALYSIS...... 74 1. ClinicalEfficacyOutcomes...... 74 2. ClinicalSafetyOutcomes...... 75 C. ADDITIONALCLINICALSTUDIES...... 76 SECTION8.BENEFIT/RISKDISCUSSION...... 78

A.THEREARESIGNIFICANTBENEFITSREALIZEDBYPOPREPAIRWITHTVM...... 78 B.THERISKSPRESENTEDBYTHETVMDEVICESARECOMPARABLETOOTHERINVASIVETHERAPIESFORPOPREPAIR...... 79 C.THEBENEFITSOFTVMOUTWEIGHTHERISKS...... 81 D.ADDITIONALCONTROLSSUPPORTTHEPOSITIVEBENEFIT/RISKRATIO...... 83 SECTION9:CONCLUSION...... 84 SECTION10:REFERENCES...... 85 APPENDIX1...... 88 



3 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  SECTION1:EXECUTIVESUMMARY

BostonScientificCorporation(BSC)firmlybelievesthatthetotalityofclinicalevidencesupportsthe positivebenefit/riskprofileoftransvaginalmeshdevicestotreatpelvicorganprolapse(POP).In particular,assupportedbynewandcompellingdatacollectedthroughstudiesdesignedinconjunction withFDA,aswellasreportsinthescientificliterature,BSC’stwotransvaginalmeshdevicesusedfor repairofPOP–theUpholdLITEVaginalSupportSystem(UpholdLITE)andtheXenformSoftTissue RepairMatrix(Xenform)–presentdemonstrablebenefitsthatoutweightheirpotentialandobserved risks.

Theprospectivecontrolled522postmarketsurveillancestudiesandothercontrolledstudiesofUphold LITEandXenformavailableinthepublishedliteraturehavefoundhighratesofbothanatomicand subjectivesuccessresultingfromPOPrepairwiththesedevices,includingbetteranatomicsuccessover nativetissuerepair(NTR).ThishasbeensupplementedbylowratesofPOPrecurrencesignalinga durabletreatmenteffect,basedoncurrentlyavailabledata.

WhilemeshpresentsthepotentialforcertaindeviceͲspecificrisksthatarenotseenwithNTR,the522 studiesdemonstratethatat12months,thereisnogreaterincidenceofseriousadversedeviceͲrelated and/orseriousprocedureͲrelatedrisksassociatedwiththeseproductscomparedtoNTR,andfurther suggestnolatetermseriousadversedeviceͲrelatedrisk.WithregardtomeshͲspecificadverseevents suchasexposureanderosion,thesestudieshaveseenzeroerosionsandlowratesofmeshexposure.In conjunction,theratesofnonͲmeshͲspecificadverseeventsseenwithUpholdLITEandXenformare generallycomparabletothosereportedforNTR.

ThedatafromBSCsponsored522studies,inconjunctionwiththeliteratureonBSC’sspecificdevices, demonstrateimprovedefficacyandfewercomplicationscomparedtomuchoftheliteraturepresented duringthe2011FDApanelmeetingconvenedtodiscusstherisk/benefitprofileoftransvaginalmesh devicesforPOPrepair.BSCslowdensity(lightweight)meshproductsandcurrentclinicalpracticein termsofpatientselection,implantationtechniques,andphysiciantrainingweredesignedtoreduce riskspresentedbytheearlierfirstͲgenerationmeshproductsreportedonduringthe2011panel meeting.Asthisdocumentpresentsindetail,theevidencetoͲdateofthesafetyandeffectivenessof BSC’smeshdevicesdemonstratesafavorablebenefit/riskprofileforproperlychosenpatientsinthe handsofproperlytrainedsurgeons.

Medicaltreatmentoptionsarenot–andoughtnottobe–consideredoneͲsizeͲfitsͲall,andphysician selectionoftheoptimaltreatmentinaparticularcasemustalwaysconsiderlikelybenefitsandrisksin conjunctionwiththepatient’sindividualcharacteristicsandclinicalneeds.Itisgenerallydesirablethata numberofsafeandeffectivetreatmentoptionsbeavailablesothatpatientscanreceivepersonalized treatmentbasedontheirindividualclinicalcharacteristics.Atthesametime,thecompanyhasbeen andremainscommittedtomitigatingthepotentialformeshͲspecificcomplicationsthrougharobust QualitySystemthatidentifiescomplaintsandultimatelyresultsinproductimprovementsthroughthe CAPAprocess.ItsofferingsincludetargetedphysicianandnursetrainingthroughitsPelvicFloor Institutethathasbeenvettedwithkeyopinionleadersandalignswiththemostcontemporarysurgical techniquetrainingͲallwiththeintentofimprovingtheoutcomesoftransvaginalmeshsurgeryforPOP repair.Asexplainedfurtherbelow,theseefforts,inconjunctionwiththetotalityofrecentdatasupport

4 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  thatUpholdLiteandXenformmeritcontinuedavailabilityasatreatmentoptionforcliniciansto considerincaringfortheirpatients.

A. DiseaseBackground

ItisestimatedthatPOPimpactsapproximately50%ofwomenwhohavehadoffspring1,with womenfacinganincreasedriskofprolapseastheyage;andover300,000surgeriesforPOPare performedannuallyintheU.S.POPcanhaveaprofoundeffectonawoman’squalityoflifeand herphysicalandpsychologicalwellͲbeing.Specifically,POPhasbeenassociatedwithavarietyof urinary,bowelandsexualsymptomswhichmaysignificantlycompromisepatients’comfortand abilitytoperformdailyactivities.

BostonScientificCorporation(BSC)hasdevelopeditsUpholdLITEandXenformdevicesforthe treatmentofanteriorandapicalprolapse.Anteriorprolapseoccurswhenthetissues/muscles betweenthebladderandvagina,whichtypicallyholdthebladderupinsidethepelvis,weaken and/orstretch.Thiscausesthebladdertofallintothevagina(cystocele),producingalargebulge inthefront(anterior)vaginalwall.Apicalprolapseisthedescentoftheuterus,cervix,orvaginal vaultwhichmaymanifestasuterineprolapse,vaginalvaultprolapse,orenterocele.

B. CurrentTherapiesandClinicalNeed

TherapeuticinterventionsavailablefortreatmentofPOPincludebothnonͲsurgicalandsurgical alternatives.Theriskandbenefitofeachtreatmentapproachmustbespecificallyconsideredfor theindividualpatientbasedonseverityofdisease,impactonqualityoflife,andfailureofprior treatments,amongotherfactors.

ForasymptomaticormildlysymptomaticPOP,regularobservationbyaclinicianalongwithnonͲ surgicallifestylemodificationsmaysufficetoreducesymptoms.Pelvicfloormusclestrengthening exercisescanalsobehelpfultorestoresupportfortheimpactedorgans.Another,nonͲsurgical optionisuseofasupportorspaceͲoccupyingpessary–adeviceplacedinthevaginatorestorethe normalanatomicpositionofprolapsedorgans.However,pessariesprovideonlytemporary symptomreliefanddonotcorrecttheunderlyinganatomicdefectorassociatedsymptoms.

ForwomenwithprolapsethatismoresevereorhasnotrespondedtononͲsurgicalalternatives, surgicalinterventionmaybeappropriatetorestoreanatomicpositionofprolapsedorgansand providesupport,therebyrelievingsymptomsandimprovingorrestoringpelvicorganfunctionsand associatedqualityoflifemeasures.Surgicalapproachescanbetransabdominalortransvaginal, usingthepatient’sowntissuetosupporttheprolapsedorgansorreinforcingtherepairusing surgicalmesh.Surgicalrepairinvolvingplicationandsuspensionofnativeconnectivetissues, NativeTissueRepair(NTR),isaneffectiveapproachforalargepopulationofwomenbutconcerns withthisapproachincludelatetermrecurrentprolapseand/oranatomicfailures.Surgicalmesh hasbeenconsideredanalternativetoNTRtoimprovethestrengthandultimatelythedurabilityof therepairwhilealsorelievingsymptoms.Implantationofmeshthroughatransvaginalprocedure allowsforeasieraccesstoprolapsedorgans,reducedproceduretime,fasterrecovery,andbetter

 1OlsenAL,SmithVJ,BergstromJO,CollingJC,ClarkAL.Epidemiologyofsurgicallymanagedpelvicorganprolapseandurinary incontinence.ObstetGynecol.1997;89(4):501–6

5 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  cosmeticresults(i.e.,novisiblescar)ascomparedtosacrocolpopexythroughopenabdominaland minimallyͲinvasiveroboticprocedures.

C. BostonScientific’sDevicesforTransvaginalRepairofPelvicOrganProlapse(POP)

BSCmakestwodistinctmeshproducts–theUpholdLITEVaginalSupportSystem(“UpholdLITE”) andtheXenformSoftTissueRepairSystem(“Xenform”)–foruseinperformingtransvaginalrepair ofanteriorand/orapicalprolapse.ThedevicesaredesignedtobeimplantedtoreͲcreatethe hammockingsupportofthebladderandsuspensionofthevaginalapexthataresupposedtobe providedbythepubocervicalfasciaanduterosacralligament,respectively.Itiscriticaltorecognize thatUpholdLITE,asecondͲgenerationmeshproduct,improvesuponcharacteristicsoffirstͲ generationtransvaginalmeshproductsandcorrespondinglyhasamorefavorablebenefit/risk profile,withlowerratesofmeshͲspecificadverseeventsthandiscussedatthe2011panelmeeting. Chiefamongchangesthathaveimprovedtransvaginalmeshoutcomesarechangestothephysical characteristicsofthemeshtouselighterdensity(lightweight)andlowertotalvolumeofmesh material,abandonmentofthe“meshinlay”surgicaltechnique,andabandonmentoftheuseof trocarstoplacemeshmaterial.

EachofthedeviceswasoriginallyclearedbyFDAthroughthe510(k)pathway.Followingthe reclassificationoftransvaginalmeshdevicesforPOPrepairfromClassIItoclassIIIbyFDA,BSC submittedpremarketapprovalapplications(PMAs)forbothdevices:UpholdLITEVaginalSupport System(P180018)andXenformSoftTissueRepairMatrix(P180021).

1. UpholdLITEVaginalSupportSystemwithCapioSLIM

TheUpholdLITEVaginalSupportSystemconsistsofsyntheticSurgicalMeshwhichissupplied withtwopreͲattachedlegassemblies(oneachofthelateralsides)designedtofacilitate passageofthemeshthroughbodilytissuesforproperplacement.Itisalsosuppliedwitha dedicatedFDAͲcleareddeliverydevice,theCapioSLIMSutureCapturingDevice(K172060),into whichtheLegAssembliesarespecificallydesignedtobeplaced. TheUpholdLITESurgicalMeshisconstructedfromknitted,lowͲdensity(lightweight), polypropylenemonofilamentfiber,whichisdyedbluetoimprovevisibilityduringthe procedureandhasanundyed(natural)centerlinetofacilitateeaseofvisualorientationduring placement.Ofnote,thislighterdensity(lightweight)syntheticmeshislowerindensity comparedtooldermeshproductswhicharenolongerontheU.S.market,afactorunderstood toreduceassociatedadverseevents.Toaccommodatephysicianpreferencesandpatient anatomies,themeshisofferedinapreͲcutconfigurationthatmaybefurthertrimmedtofit thepatientasneededtoachievethedesiredrepair.

TheUpholdLITEmeshisplacedtransvaginallythroughananteriorincisioninthevaginalwall andsecuredtoprovideapicalsuspensionbywayofadjustablearmsthatfixateintothe sacrospinousligamentandbladdersupportbywayattachingtothepelvicsidewall.Following implantation,themeshisincorporatedintothesurroundingtissue,andcollagendepositionand capillarypenetrationthroughthemeshresultinatissue/meshconstructthatprovideslongͲ termsupporttosupporttheprolapsedorgan.

6 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  2. XenformSoftTissueRepairMatrix

TheXenformSoftTissueRepairMatrixisapermanentimplantcomprisedofanextracellular collagenmaterialmanufacturedfrombovineskinssourcedsolelyfromcattleobtainedin compliancewithUSregulatoryrequirements.Thedeviceisprovidedinsheetformtobe trimmedandsuturedbythesurgeontomeetindividualpatientanatomy.Specifically,Xenform isintendedtobecutintoatrapezoidalshapesothattheproximalportionorbaseiswide enoughtosuturetothesacrospinousligamentsandlongenoughtoreachthebladderneck,so astoprovidebothapicalsuspensionandproperbladder/pelvicsupport.

Trimmed,hydratedXenformisplacedthroughananteriorincisioninthevaginalwalland suturedinthepelvicfloor,whereitremainsincontactwiththepatient’ssofttissue.Following implantation,theXenformextracellularscaffoldservesasatemplateforregrowthofnative tissueforlongͲtermintegration;theresultingtissue/meshconstructprovideslongͲtermsupport totheprolapsedorgan.Thedeviceisonlyminimallyresorbed.2

3. SurgicalProcedure

ThesurgicalprocedureforimplantationofbothUpholdLITEandXenformfeaturesstandardized instructions,includingstepstopreparethesiteforimplantationtominimizetheriskofmesh extrusionandpromotedurabilityofrepair,ensuretensionͲfreeplacement,whichmayminimize therisksofdenovodyspareunia,promotedurabilityoftherepair,andreduceperiͲoperative complications.Importantly,bothproductsareimplantedwithouttrocars,reflectingthe evolutiontotransvaginalmeshsurgicaltechniqueswhichhasbeenattributedtolowerratesof adverseevents.

4. Labeling

LabelingprovidedwithboththeUpholdLITESystemandXenformSoftTissueRepairMatrix containsinformationregardingthedevice,detailedinstructionsdescribingthesurgical techniqueforpreparationofthesurgicalsiteandimplantationofthedevice,and contraindicationsandwarningstoaidinappropriatepatientselection.Consistentwiththe recommendationsfromthe2011panelmeeting,thelabelingalsoincludesalistingofpotential adverseeventsassociatedwithuseoftransvaginalmeshdevicesgenerally,regardlessof whetherthespecificadverseeventhasbeenobservedwiththeBSCdevice.Patientbrochures arealsoavailableandprovideinformationontreatmentoptionsandthebenefit/riskprofileof thespecificdevicetoassistpatientsinmakinginformedcaredecisions.

5. Training

BSChasdevelopedaphysiciantrainingprogramtohelpsurgeonsusingUpholdLITEand Xenformdevicesfullyunderstandtherequirementsforsafeandeffectiveuseofthesedevices. Thisprogramcomplementsresidencyandfellowshiptraining,andemphasizesanunderstanding

 2CornwellK,Zhang,LineaweaverW,(2016).Bovinefetalcollagenreinforcementinasmallanimalmodelofherniawith componentrepair.J.SurgicalResearch.201,416Ͳ424.

7 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  ofpatientselection,devicemechanismsofaction,andpropersurgicaltechnique.Toachieve thesegoals,acontinuumofproductͲspecifictrainingisemployed,including:

x Accesstoonlineeducationcoveringsuchtopicsasdiseasestate,productfeatures, relevantanatomy,surgicaltechnique,andmanagementofcomplications; x Proctorshipwithanexperiencedsurgeon,duringwhichsurgicaltechniquetipsforuse ofthespecificproductaresharedandpatientoutcomesandmanagementof complicationsarediscussed. x AttendanceatahandsͲoncoursethatincludesadidacticsessionfromafaculty physicianaswellastrainingandpracticeonpelvicandcadavermodels x Preceptorshipwithanexperiencedsurgeonoveranumberofcasestoincrease physiciancomfortwiththerelevantsurgicaltechnique.

Thesetrainingeffortsaredesignedtobolsterthesafetyandefficacyofthetransvaginalmesh implantationprocedure,withfocusoncriticalstepsspecifictotheindividualBSCproductsas wellasdemonstratedprinciplesinthefield.

D. SupportingClinicalEvidenceforBSCDevicesforPOP

ThetotalityofclinicalevidencesupportsthesafetyandefficacyoftheBSCdevicesforrepairof POP.RecentliteraturespecifictoBostonScientific’sUpholdLITEandXenformdevicesreports lowratesofcomplicationsthatarecomparabletothoseseenwithNTR,withpositiveclinical outcomesreflectedbyrestoredanatomicalpositionandsubjective/symptomaticclinical benefit.Thisliteraturedemonstratesabenefit/riskratiofortheBSCtransvaginalmeshdevices thatiscomparabletoothertreatmentoptionsavailabletopatients,namelyNTR.Importantly, therecentliteratureshowsimprovedbenefitsandlowercomplicationratescomparedtothe datapresentedbyFDAduringtheprevious2011panelmeetingtodiscusstransvaginalmesh products.ThepreviouslysummarizedliteratureaddressedintheFDAExecutiveSummaryfor the2011panelmeetingtoassesstheadverseeventratesassociatedwiththesedevicesrelied onseveralsystematicmetaͲanalyseswhichreflectedoldermeshproducts.Mostnotably, retrospectiveanalysesbyAbedetal.3(incorporatingpublicationsfrom1950–2007)and Diwadkaretal.4(incorporatingdatapublishedfrom1985–2008)servedasprimaryreferences toassesscomplicationsfortransvaginalmeshcomparedtosacrocolpopexyandNTR.The transvaginalmeshkitsrepresentedinthesepublicationsincludefirstͲgenerationproductsthat arenolongeronthemarketandshareanumberofcharacteristicswhichhavebeen engineeredoutofthesecondͲgenerationmeshkits.Theseincludehigherdensitymesh materials(45Ͳ50gm/m2),selfͲfixingarmsthatmustbesuccessfullynegotiatedacrossmultiple tissueplanesandrequiringuseofatrocarforplacement.Incontrast,theUpholdLITEmeshis farlighterat25gm/m2,isplaceddirectlyviaasingleincisionwithouttrocars,hasasmaller surfaceareaandoverallmeshfootprint,andisdirectlyfixatedusingtheCapioSLIMsuturing

 3Abedetal.IncidenceandManagementofGraftErosion,WoundGranulation,andDyspareuniaFollowingVaginalProlapse RepairWithGraftMaterials:aSystematicReview.Int.UrogynecolJ.201122:789Ͳ798 4DiwadkarGB,etal.Complicationandreoperationratesafterapicalvaginalprolapsesurgicalrepair:asystematicreview. ObstetGynecol.2009;113(2Pt1):367Ͳ73.

8 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  devicewithadjustablemesharmsthatallowforsupportinboththeanteriorandapical compartments.

BSChasreviewedandsummarizedcontemporaryreportswhichprovidemorecurrent assessmentsofBSC’sowndevicesintreatmentofanterior/apicalPOP(discussedbelowin Section6).BSChasalsoconductedprospectiveclinicalstudiesforeachoftheUpholdLITEand XenformdevicesinresponsetoFDA’s522orders,asdiscussedfurtherinthefollowingsections.

1. PublishedLiterature

UpholdLITE

RecentpublicationsindicatesuccessoftheUpholdLITEintermsofrestorationof anatomicalposition,improvementtoqualityoflifemetrics,andlowratesofserious complicationsandmeshͲrelatedeventssuchasextrusion,erosionandexposure.Theresults asawholesuggestthatthebenefitsfromtheUpholdLITESystemaredurable,comparable to(orhigherthan)NTR,andachievedwithlowcomplicationrates.

Specifically,numerousstudiesfoundanatomicalsuccess(definedasachievingPOPͲQч1) ratesthatwereatleastashigh,andinsomecasesnotablyhigherthan,thosethathave beenreportedwithNTR.Forinstance,Altman,etal.(2011),astudyofnearly400subjects, reportedan82.3%rateofsuccessinanatomicalcorrectionofanteriorprolapseusing UpholdLITE,ascomparedtoonly47.5%withNTR,andthisdifferencewasfoundtobe statisticallysignificant.Successonthestudy’sprimarycompositeendpoint(comprisingthis anatomicelementplustheabsenceofvaginalbulgesymptoms)was68.0%fortheUphold LITEgroupascomparedto34.5%fortheNTRgroup,withthisdifferenceacrossgroupsalso foundtobestatisticallysignificant.NumeroussingleͲarmstudiesalsofoundhighanatomic cureratesforanteriorandapicalPOPwiththeBSCmesh.Lo,etal.(2018)reporteda97.7% anteriorsuccessand98.9%apicalsuccessat12months.Moreover,theavailablelongͲterm dataonefficacyoutcomeswiththisspecificmesh,albeitsomewhatlimited,supportthatthe POPrepairachievedisdurable.Ofnote,RahkolaͲSoisaloetal.(2017),thelongestͲduration prospectivestudyofUpholdLITEtoͲdate,reportednotonlya93.5%apicalanatomicsuccess achievedat1year,butalsonostatisticallysignificantdeclineinanatomicsuccessat5years (atwhichpointitwas83.3%).

Intermsofsubjectivesuccess,highratesofsymptomaticcureandqualityoflife improvementasassessedusingvalidatedmetricswerereportedinsubjectsreceiving UpholdLITE.Forinstance,Altman,etal.(2011)reported75.4%successonthesecondary endpointforabsenceofbulgesymptomsintheUpholdLITEgroupascomparedto62.1%in thatstudy’sNTRgroup.Patientsatisfactionwiththeoutcomesoftransvaginalmeshrepair wasveryhigh(>90%)inmostofthestudiesevaluatingUpholdLITE,andhighratesof improvementinqualityoflifewerealsoreported.Forinstance,RahkolaͲSoisaloetal. reportedimprovedqualityoflifeasassessedperthePFDIͲ20in78.8%ofmeshsubjects, withasignificantdecreaseofbotherthathadnotchangedsignificantlyfromthe1Ͳyear postͲoperativevisit–againsupportingthatthemeshachievesdurablerepairofPOP.In addition,thisstudyfoundthatpainlevels(VASscale)decreasedaftersurgeryandcontinued lesseninginpainbetweentheoneͲandfiveͲyearfollowͲupvisits.Gutman,etal.founda

9 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  95%satisfactionrate(inbothmeshandNTRgroups)perthePGIͲIscale,furtherconfirming thatsubjectivesuccessiscomparablewiththisdeviceandNTR.

ThesestudieshighlightthattheefficacyprofileofUpholdLITEisachievedinconjunction withanacceptablesafetyprofile,andmuchloweradverseeventratesthangenerally reportedinthetransvaginalmeshstudiesreviewedatthe2011panelmeeting.While surgicalmeshdoesposetheriskofcertainadverseeventswhichcannotoccurwithNTR– mostnotablymesherosion/exposure/extrusion–theratesforthesemeshͲspecificAEsin thestudiesassessingUpholdLITEspecificallyhavebeenlow,andtheoverallAErateswere generallycomparabletothoseobservedwithnativetissuerepair.Specifically,ratesofmesh erosionorexposure(almostalwaysexposure)wereverylow,includingsomestudieswith zeroexposures,andwereonly1.4%inthelarge,longͲtermRahkolaͲSoisaloetal.study. Ratesofmeshexposurerangedfrom2.6%to8%,whichisstillnotablylowerthanthe>10% ratereportedinAbed,etal.(priorto2011andnotspecifictoUpholdLITE).Moreover,allof thestudies’reportedexposureswereprimarilyofmildormoderateseverity,inthatthe reportedratesofreͲsurgeryforexposure/erosionwere<5%andsomeofthesecasesdid notevenrequireacorrectiveofficeprocedure.Theseresultsaremuchlowerthanthe7.2% reͲsurgeryrateformeshspecificcomplicationsreportedintheDiwadkar,etal.assessment referencedinthe2011panelmeeting.

MostofthestudiesidentifiedaspartofourliteraturesearchwithUpholdLITEalsoreported relativelylowratesofotherAEs(nonͲmeshͲspecific)thatarecomparabletothoseseenwith NTR,consistentwiththeresultsseeninBSC’s522studies.

XenformSoftTissueRepairMatrix

LimitedpublishedliteratureaddressestheuseofbiologictissuegraftstotreatPOP,with onlyasinglepublication(Goldstein,etal.5)specificallyaddressingtheXenformdevice.This studyassessedsuccessbasedonrestorationofnormalanatomyinanycompartment, symptomrelief,QoL,andsexualfunction.Theresultsshowedsignificantimprovementsin bothobjectiveandsubjectiveoutcomesat12monthsinsubjectswhounderwentPOP repairusingXenform,includingan88%successrateontheprimaryefficacyendpointwith statisticalimprovementsinbothanteriorandapicalsupport.Inaddition,therewereno meshexposuresorerosionsandminimalothercomplications,reflectingapositivesafety profile.

2. 522ClinicalStudies

BSCconductedprospectiveclinicalstudiesforeachoftheUpholdLITEandXenformdevices inresponsetoFDA’s522orders.ThestudiesweredesignedwithextensiveFDAinputand theprotocolswereapprovedbyFDA.Thestudiesenrolledpatientswhowerediagnosed withanteriorand/orapicalPOPandwerecandidatesforsurgicalrepair,andwhomayor

 5GoldsteinHB,etal.Amulticenterprospectivetrailevaluatingfetalbovinedermalgraft(XenformMatrix)forpelvic reconstructivesurgery.BMCUrology(2010)10:21.

10 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  maynothaverequiredaconcomitantprocedure(suchashysterectomyorslingplacement forstressurinaryincontinence).,

Acompositeendpointwasdesignedtoevaluatethedevices,wheretheendpointswerethe sameacrossbothstudies,asfollows:

PrimaryEfficacyEndpoint

1. Objectivesuccessisachievedbythesubjecthavingananatomicoutcomedefinedas theleadingedgeofprolapseatorabovethehymenintheoperatedcompartment:

• Anteriorsegment:Leadingedgeofanteriorprolapseisatorabovethehymenor PelvicOrganProlapseQuantificationSystem(POPͲQ)pointBaч0.

• Apicalsegment:ThevaginalapexdoesnotdescendmorethanoneͲhalfintothe vaginalcanal(i.e.,POPͲQpointC<Ͳ1/2TVLformultiͲcompartmentprolapseor POPͲQpointCч0forsinglecompartmentapicalprolapse).

2. Subjectivesuccessisachievedifthepatientdeniessymptomsofvaginalbulgingper PelvicFloorDistressInventory(PFDIͲ20)question3,answering“no”or“yes”but“Not atall”bothersome(<2).

3. NoretreatmentforPOP:noadditionalsurgicaltreatmentforPOPintheanatomic segment(s)treatedattheindexsurgeryornopessaryusesinceindexsurgery(i.e., ‘treatedsegment’referstothetargetcompartment).

SecondaryEfficacyEndpoint

1.Objectivesuccessisachievedbythesubjecthavingananatomicoutcomedefinedas theleadingedgeofprolapseatorabovethehymenintheoperatedcompartment:

•Anteriorsegment:Leadingedgeofanteriorprolapseisatorabovethehymenor PelvicOrganProlapseQuantificationSystem(POPͲQ)pointBa<0.

•Apicalsegment:ThevaginalapexdoesnotdescendmorethanoneͲhalfintothe vaginalcanal(i.e.,POPͲQpointC<Ͳ1/2TVLformultiͲcompartmentprolapseorPOPͲ QpointC<0forsinglecompartmentapicalprolapse).

2.Subjectivesuccessisachievedifthepatientdeniessymptomsofvaginalbulgingper PelvicFloorDistressInventory(PFDIͲ20)question3,answering“no”or“yes”but“Not atall”bothersome(<2).

3.NoretreatmentforPOP:noadditionalsurgicaltreatmentforPOPintheanatomic segment(s)treatedattheindexsurgeryornopessaryusesinceindexsurgery(i.e., ‘treatedsegment’referstothetargetcompartment).

SafetyEndpoint

TheprimarysafetyendpointforbothstudiesisacomparisonofseriousdeviceͲand/or seriousprocedureͲrelatedAEsbetweenbaselineandthe36Ͳmonthtimepoint.The

11 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  secondarysafetyendpointsincludeanalysisofoveralldeviceͲandprocedureͲrelatedAEs, mesherosionandexposure,anddenovodyspareunia.

EnrollmentandFollowͲupschedule

IntheUpholdLITEstudy,atotalof225patientsreceivedthetreatmentdeviceacross27 centersand482underwentnativetissuerepair.FortheXenformstudy,atotalof228 patientsreceivedthetreatmentdeviceacross25centersand482underwentnativetissue repair.ControlgrouppatientswereenrolledatdedicatedNTRspecialtycentersorfromthe AUGSPFDregistry.

Forbothstudies,eachsubjectwasinstructedtoreturnforfollowͲupvisitsat2and6months (±4weeks)andat12,18,24and36months(Ͳ4/+12weeks).Theprimaryendpointwas designedforevaluationat36months.However,basedonFDA’sreclassificationofsurgical meshdevicesforPOPrepairandthetimelineforsubmissionofPMAdata,FDAandBoston ScientificagreedthePMAapplicationswouldpresent12Ͳmonthdata,withthepresentation oftheavailablelongerͲtermdata.

Results

ResultsfromtheUpholdLITEandXenformstudy,presentedbelow,showthattreatment witheitherdeviceisatleastaseffectiveasNTRat12monthsforthecompositeprimary efficacyendpointaddressingobjectiveandsubjectivesurgicalsuccessandsurgical interventionforPOPrecurrence,withacomparablesafetyprofile.Forthesecondary efficacyendpoint,thecompositetreatmentsuccessrateishigherintheUpholdLitearm comparedtotheNTR(85.8%vs.78.4%,pͲvalue=0.005),whileitiscomparablebetweenthe XenformandNTRgroup(85.2%vs.78.3%,pͲvalue=0.120).PleasenotethesepͲvaluesare notadjustedformultiplecomparison.Whileonlylimiteddataisavailableoutto36months, thedatasuggestssustainedorincreasedbenefit,withouttheriskofincreasedlateͲterm seriousadverseevents.Additionally,whenlookingattheindividualprongsoftheendpoint, objectivesuccessishigherwithUpholdLITE,drivenbythetreatmentsuccessintheanterior compartment.Whiletheobjectivesuccessoverallandintheanteriorcompartmentfor Xenformat12monthsisnotstatisticallysignificant,itisnumericallyhigher.

Table1.SummaryofUpholdLITEandXenformPrimaryEfficacyResults

UpholdLITEstudy XenformStudy Xenform Variable UpholdLITE NTR NTR %(count/ %(count/ %(count/ %(count/ samplesize) samplesize) samplesize) samplesize) 12ͲMonthComposite 91.6%(185/202) 87.3%(379/434) 88.2%(172/195) 87.3%(379/434) Success ObjectiveSuccess 98.0%(198/202) 94.0%(409/435) 96.9%(189/195) 94.0%(409/435) AnteriorCompartment 98.5%(199/202) 93.5%(362/387) 96.9%(189/195) 93.5%(362/387) ApicalCompartment 98.0%(198/202) 98.0%(400/408) 98.4%(190/193) 98.0%(400/408)

12 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  UpholdLITEstudy XenformStudy Xenform Variable UpholdLITE NTR NTR %(count/ %(count/ %(count/ %(count/ samplesize) samplesize) samplesize) samplesize) SubjectiveSuccess 93.6%(190/203) 92.2%(402/436) 89.8%(176/196) 92.2%(402/436) NoRetreatmentforPOP 99.6%(224/225) 97.9%(472/482) 99.6%(227/228) 97.9%(472/482) 24ͲMonthComposite 91.7%(88/96) 83.7%(221/264) 82.4%(140/170) 83.7%(221/264) Success ObjectiveSuccess 96.9%(93/96) 93.5%(244/261) 95.9%(162/169) 93.5%(244/261) AnteriorCompartment 99.0%(95/96) 92.7%(216/233) 95.9%(162/169) 92.7%(216/233) ApicalCompartment 96.9%(93/96) 98.8%(239/242) 97.0%(162/167) 98.8%(239/242) SubjectiveSuccess 93.8%(90/96) 93.9%(246/262) 85.8%(145/169) 93.9%(246/262) NoRetreatmentforPOP 99.6%(224/225) 96.7%(466/482) 98.2%(224/228) 96.7%(466/482) 36ͲMonthComposite 83.3%(35/42) 73.8%(107/145) 81.9%(68/83) 73.8%(107/145) Success ObjectiveSuccess 95.2%(40/42) 88.1%(119/135) 95.0%(76/80) 88.1%(119/135) AnteriorCompartment 97.6%(41/42) 87.1%(108/124) 97.5%(78/80) 87.1%(108/124) ApicalCompartment 95.2%(40/42) 97.6%(121/124) 96.3%(77/80) 97.6%(121/124) SubjectiveSuccess 87.5%(35/40) 92.6%(126/136) 88.9%(72/81) 92.6%(126/136) NoRetreatmentforPOP 99.1%(223/225) 96.3%(464/482) 98.2%(224/228) 96.3%(464/482) 

ThereweremeasurableimprovementsinpatientͲreportedoutcomesforallstudygroupsin bothstudiesfollowingsurgery.SubjectsreceivingUpholdLITEandXenformdevicesshowed significantimprovementinPFIQͲ7andPFDIͲ20scoresat12monthsoverbaseline. Moreover,therewasstabilityinthesescoresoutto36monthsforsubjectswhohave reachedthistimepoint.Mostsubjectsinbothgroupsreportedtheyfelt“muchbetter”or “verymuchbetter”aftersurgeryperresponsestoPGIͲIquestionnaire.

LookingatseriousdeviceͲrelatedandprocedureͲrelatedadverseevents(SADE)forthecoͲ primarysafetyendpoint,treatmentwiththeUpholdLITEandXenformdemonstrated equivalentSADEratesat12monthsat2.7%intherespectivestudies’intenttotreat population.Theserateswerefurtherequivalenttothe2.7%seriouseventrateforNTR subjectsinbothofthestudies.Lookingatthetotalityofthedataoutto36months,all SADEsfortheUpholdLITEandXenformdevicesoccurredwithinthefirst6monthsfollowing theprocedureandalleventshavebeenfullyresolved.Incontrast,3/17SADEeventsfor NTRsubjects(oneinfection,oneUTI,andoneworseningconstipation)werelateͲterm complications.

ForUpholdLITE,therewerenostatisticallysignificantdifferencescomparedtoNTRsubjects intheratesofindividualAEsemphasizedbytheFDAatthe2011Panelmeeting:pelvicpain, infection,vaginalshortening,atypicalvaginaldischarge,neuromuscularproblems,vaginal scarring,denovovaginalbleeding,denovovoidingdysfunction,denovodyspareunia,and fistulaformation.ForXenform,theonlyeventthatshowedastatisticallysignificant

13 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  differencewasdenovovoidingdysfunction(14.5%vs.4.4%forNTR).Despitethis observationtherewerenostatisticallysignificantdifferencesinUDI6scorebetween Xenformsubjectswhodidanddidnotexperiencedenovovoidingdysfunction.

AsofMarch10,2018therewerenomesherosionsineitherstudy.Atotalof1.8%(4/225)of subjectsexperiencedmeshexposureeventsintheUpholdLITEstudyat12months, increasingto3.6%(8/225)by36months.TheKaplanMeierestimateforthemeshexposure rateis6.2%atthreeyears.At12monthsandthrough36monthsoffollowͲup,mesh exposurehasbeendocumentedin0.9%(2/228)ofXenformsubjects.Forthemajorityof theseinstances,resolutionwasachievedwitheithernoactiontakenorofficeͲonly procedures,with4ofthe10instancesrequiringsurgicalintervention.

Insummary,the12ͲmonthdatademonstratenonͲinferiorityofUpholdLITEandXenformto NTRforprimaryefficacy.Inaddition,thecompositeprimaryandsecondarysurgicalsuccess ratestrendinfavorofUpholdLITEwithnumericallyhighervaluesat24and36months basedonthelimitedavailabledata,andobjectiveanatomicsuccessrateisalsohigherfor UpholdLITEat12monthscomparedtoNTR.UpholdLITE,Xenform,andNTRsubjects experiencedcomparableratesofSADEsat12monthsthusdemonstratingthattherearenot significantadditionalriskspresentedbythemeshdevices.

BenefitͲRiskAnalysisandConclusions

1. BostonScientific’sDevicesareEffectiveinRestoringAnatomicalPositionandDemonstrating ClinicallyMeaningfulImprovement

ThebenefitsseenwithBostonScientific’sdevicesaredemonstrableandclinicallyrelevant. Basedonanalysisofthe12Ͳmonthdatafromtheprospective522studies,subjectsreceiving theUpholdLITEandXenformdeviceshadcomparableorimprovedanatomicoutcomes comparedtosubjectsundergoingNTRparticularlyintheanteriorcompartment.Subjectsin eachoftheBSCdevicetreatmentarmsfurtherexperienceddurableeffectsoftreatment, withnumericallylowerratesofrepeatsurgicalinterventionforrecurrentprolapse comparedtoNTRsubjects.Whilesubjectivesuccesswascomparableat12monthsor somewhatloweratlaterfollowupvisitsinthedevicegroupscomparedtotheNTRgroups, theseresultsaresomewhatinconsistent,andmeshsubjectsstillexperiencedclinically meaningfulimprovementsinseveralvalidatedqualityoflifemeasures.

Lookingatthesefactorsintotality,thepreͲdefinedcompositeefficacyendpointoftheBSC 522studiesdemonstratescomparableperformancetoNTRat12months.Moreover, comparedtoNTR,theavailable36ͲmonthdatafortheUpholdLITEappearstoshowatrend ofsustainedhigheranatomicsuccesscomparedtoNTR.Thesedataareconsistentwithdata reportedintheliteratureintheSUPeRstudyoutto48monthsandRahkolaͲSoisaloetal. (2017),thelongestͲdurationprospectivestudyofUpholdLITEtoͲdate,reportinghigh anatomicalsuccessatoneyearwithnostatisticallysignificantdeclineat5years(atwhich timepointitwas83.3%)forsubjectsreceivingtheUpholdLITE.



14 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  

2. BostonScientific’sDevicesareSafe

TheUpholdLITEandXenformdeviceshaveademonstratedlongͲtermsafetyprofile establishedthroughtheprospective522studiesandreportsintheliterature.

The522studiesdemonstratethatat12months,thereisnogreaterincidenceofserious adversedeviceͲrelatedorseriousprocedureͲrelatedrisksassociatedwiththeproducts comparedtoNTR.Further,thedatafromthesestudiesdonotshowanotherwiseincreased overallriskprofile.Therewasasomewhathigherrateofdenovovoidingissuesobserved withtheXenformdevicecomparedtotheNTRcontrol.Despitetheseobserveddifferences therewasnostaticallysignificantdifferenceinUDI6betweenXenformsubjectsregardless ofwhetherornottheydevelopeddenovovoidingdysfunction.Further,potentialrisks specifictomeshproductssuchaserosionandexposuresawonlylimitedrealizationinboth studies.The12incidentsofmeshexposuresacrossthetwoclinicalstudies(3.6%Uphold LITEsubjects(n=8,twosubjectshad2exposures),0.9%Xenform(n=2))requiredonly minimalinterventiontoachieveresolution,with2incidentsresolvedwithoutpatient surgicalinterventionand2eventsrequiringsurgicalinterventionandstillongoing.Finally, theavailabledataoutto18,24,and36monthsshowahigherrateofoveralldeviceand procedureͲrelatedAEswithNTRversusUpholdLITE,andcomparableratesforXenform versusNTR.

WhiletheliteraturecitedbyFDAinthe2011panelmeetingnotedhigherratesofadverse eventsformeshPOPrepair,BSC’sdevicesaredistinguishablecomparedtothefirstͲ generationmeshproductsthatwerethesubjectofmanyofthestudiescitedbyFDAto establishthecomplicationrate.Notably,theBSCUpholdLITEdeviceuseslowdensity(light weight)mesh,boththeUpholdLITEandXenformareimplantedwithouttheuseoftrocars, anddesignedforsecurementtothesacrospinousligamentstoprovidehammockingsupport tothebladder.Accordingly,theadverseeventratesreflectedinthecurrentliterature,the prospective522studiesaremoreindicativeofthetrueadverseeventrateforthesespecific devices.

3. TheBenefitsoftheBostonScientificTransvaginalMeshDevicesOutweightheRisks

TheUpholdLITEandXenformdevicespresentdemonstrablebenefitsthatoutweighthe potentialandobservedrisksspecifictothesemeshproducts.Thedevicesserveasa valuabletreatmentoptionforpatientspresentingwithanteriorandapicalprolapsewith highersuccessratedemonstratedat12monthsintheanatomicalcorrectionofprolapse andreductioninsurgicalreͲinterventionforrecurrentprolapsecomparedtoNTR. Subjectivesuccessratesandqualityoflifeimprovements–anareaemphasizedbythe2011 Panelintermsofensuringclinicallymeaningfuloutcomesoftransvaginalmeshrepairs–are alsoveryhighwiththesedevices.Therateofseriousadverseeventsisnohigherfor patientsreceivingthesedevicescomparedtoNTR,andthegeneralcomplicationrateis comparableat12monthsandintheavailablelongerͲtermdata.Thedevicesfurther presentlongerͲtermbenefitsthroughsustainedanatomicalcorrectionoftheprolapse

15 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  withoutadditionalsafetyrisksbasedonthepreliminary522studydataaswellasthe reportsintheliterature(e.g.,SUPeRstudy).

Theclinicaltechniquesforpatientselection,implantationandtreatmentofpatientswith transvaginalmeshproductsinPOPrepairhaveshiftedinthe8yearssincethelastadvisory committeemeetingconvenedonthistopicbyFDA.Physiciansarecurrentlyreceiving dedicatedandincreasedtrainingregardingtheproperimplantationtechniquesforusing suchdevices,withmoretrainingprovidedbyBostonScientificspecifictoitsUpholdLITEand XenformdevicesandcredentialingofferedbyAUGS.

BostonScientific’sUpholdLITEandXenformtransvaginalmeshdeviceshavedemonstrated clinicalsafetyandeffectiveness,comparabletonativetissuerepair,basedonthe prospective522clinicalstudiesandthedatapresentedintheliteraturespecifictothese devices.Thesedevicesthereforepresentanappropriateandestablishedtreatmentoption forclinicianstoconsiderfortheirpatientsintherepairofanteriorandapicalprolapse. Transvaginalmeshproductsthatdemonstratesafetyandeffectivenessprofilesthatare comparableorsuperiortonativetissuerepairandshouldcontinuetobeavailableasa treatmentoptiontoservewomenexperiencingPOP.

16 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  SECTION2:PELVICORGANPROLAPSEBACKGROUNDANDCLINICALNEEDFORTREATMENTOPTIONS

A. PelvicOrganProlapse(POP)

POPisaconditionthatoccursinwomen,wherethepelvicorganssuchastheuterus,bladder, and/orbowelprotrudeintothevaginaduetoweaknessinthetissuesthatnormallysupport them.Acomplexnetworkofmuscles,ligaments,andfasciasurroundandsupportthevagina andpelvicorgans,holdingtheminplace.POPoccurswhenthissupportnetworkweakens, allowingoneormoreofthepelvicorganstodescendfromitsnormalanatomicpositionand pushintoorupagainstthewallofthevagina.POPcanoccurintheanterior,apical,and/or posteriorcompartments.IntheongoingBSC522studiesofUpholdLITEVaginalSupport System(UpholdLITESystem)andtheXenformSoftTissueRepairMatrix(Xenform),POPrepairs wereconfinedtotheanteriorandapicalcompartments;consequently,theremarkshereinwill belargelyconfinedtoanterior/apicalPOP.

IntheUnitedStates,over300,000surgeriesareperformedforPOPonanannualbasis.Itis estimatedthat50%ofparouswomenwillexperiencePOPatsomepointintheirlifetime1and upto11%ofwomenintheUnitedStateswillundergoasinglesurgeryforPOP(including incontinence)byage80.Themostcommonformofprolapse,anteriorprolapse,istwotimes morecommonthanposteriorprolapseandthreetimesmorecommonthanapical prolapse.Error!Bookmarknotdefined.

Anteriorprolapseoccurswhenthepubocervicalfasciasupportingthebladdereithertearsor losesitslateraland/orapicalsupportattachments,whichcausesthebladdertofalldowninto thevagina,producingacystocele.Whenthebladderprolapses,itfallstowardsthevaginaand createsalargebulgeinthefront(anterior)vaginalwall.

Anteriorprolapsemaybecausedbystrainingthemusclesthatsupportthebladder,suchas duringvaginalchildbirthorthroughchronicactivities(e.g.,coughing,heavylifting).Prolapse maybedelayedinonset,typicallyoccurringinperimenopausalwomenwhentheovaries graduallybegintomakelessestrogen,whichcanaffectpelvicregionmuscletone.

AnteriorprolapsecanpresentinconjunctionwithotherPOP,suchasapicalprolapsewhich mayincludeuterineprolapse,vaginalvaultprolapse,orenterocele.Theuterusisheldinan anatomicallycorrectlocationatthevaginalapexbytheuterosacralandcardinalligaments.If thestructuresbecomeattenuatedorrupture,thentheuteruswilldropdown(prolapse)into thevaginalcavity,producingauterineprolapse.Thisconditionmaycausediscomfortand difficultywithevacuationoftheboweland/orbladder.Vaginalvaultprolapsecanoccurin womenwhohavepreviouslyhadahysterectomy,whenthevaginaitselffallsdowneven thoughtheuterusisnolongerpresent.ThismayalsobereferredtoasapostͲhysterectomy vaginalprolapse.Lastly,ifafascialdefectexistsattheapexbetweentheanteriorpubocervical fasciaandtheposteriorrectovaginalfascia,thenanenterocelecanresult.Thisisaherniation ofsmallintestinethroughtheapexintothevagina.

Posteriorprolapsecanoccurduetooneorbothoftheconditionsdescribedhereafter.Ifthe rectovaginalfasciaeithertearsand/orlosesitslateralorapicalattachments,therectumcan bulgeintothevagina,producingarectocele.Thisconditionmaycausediscomfort,stool

17 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  trapping,constipationorfecalincontinence.Ifthesmallboweldissectsdownintothespace betweenthevaginalfasciaandthepararectalfascia(therectovaginalseptum),aposterior protrusionoftheposteriorwall–referredtoasaslidingenterocele–canoccur.Thismayor maynotbeaccompaniedbyarectocele.

POPcanhaveaprofoundeffectonawoman’squalityoflifeandherphysicalandpsychological wellͲbeing.Specifically,POPhasbeenassociatedwithavarietyofurinary,bowelandsexual symptomswhichmaysignificantlycompromisethequalityoflifeofthepatients.Symptoms fromtheprolapsealoneincludevaginallump,effectondailyactivitiessuchaswalking, draggingdiscomfortinthelowerabdomen,ulceration,andvaginalbleeding.Urinarysymptoms includestressurinaryincontinence(SUI),urgeurinaryincontinence,urinaryfrequency,urinary urgency,incompletebladderemptying,voidingdifficulty,slowstreamandintermittentflow. Defecatory/bowelsymptomsincludestrainingtodefecate,manualreductiontoemptybowel, andfecalincontinence.Sexualdysfunctionsincludelesseningofsexualdesire,arousal,orgasm, andpainwhichcanaffecttherelationshipbetweenpartners.Inadditiontotheabove, hysterectomyalsocarrieswithitasignificantlynegativeimpactonbodyimageandqualityof life.6,7,8

B. NonͲSurgicalTreatmentOptions

PhysicianshaveseveralchoicesfortreatmentofPOP,includingnonͲsurgicalandsurgical options.AsymptomaticormildlysymptomaticwomenwithPOPcanbeobservedatregular intervalswithoutintervention.NonͲsurgicallifestylemodificationsthatmayreduceprolapse symptomsincludeweightcontrol,propernutritionwithanappropriateamountofdietaryfiber, smokingcessation,andavoidanceofstrenuousoccupationalandrecreationalactivities.Pelvic floormusclestrengtheningexercisescanalsobehelpful,particularlyformildercasesof prolapsetorestoresupportfortheimpactedorgans.

UseofapessaryprovidesanonͲsurgicaltreatmentoption.Apessaryisadeviceplacedinthe vaginatorestoreprolapsedorganstotheirnormalanatomicposition.Therearetwokindsof commonlyusedpessaries:supportpessariessuchasaringpessary,andthespaceͲoccupying shelfpessary.PessariesareusedforallstagesofPOPinwomenwithorwithouturinary incontinence.9However,theymaynotbesuitableforallpatients,andseveraltrialsmaybe neededinordertoensurethecorrectsizeisselected.Moreover,whilepessariesarehelpfulto providesupporttotheprolapsedorganandthusprovidesymptomrelief,theydonotcorrect theunderlyinganatomicdefect.Assoonasthepessaryisremoved,theprolapsereturnsalong withtheaccompanyingsymptoms.Further,theproperplacementofapessarytypically requiresinsertioninaphysician’soffice,makingpatientsdependentonregularvisitsto healthcareprovidersforinsertion,removal,andcleaningofthedevices.

 6JelovsekJE,BarberMD.Womenseekingtreatmentforadvancedpelvicorganprolapsehavedecreasedbodyimageandquality oflife.AmJObstetGynecol.2006;194(5):1455–1461. 7FrickAC,BarberMD,ParaisoMarieFidelaR,RidgewayB,JelovsekJE,WaltersMD.Attitudestowardhysterectomyinwomen undergoingevaluationforuterovaginalprolapse.FemalePelvicMedReconstrSurg.2013;19:103–9. 8KorblyNB,KassisNC,GoodMM,etal.Patientpreferencesforuterinepreservationandhysterectomyinwomenwithpelvic organprolapse.ŵ:KďƐƚĞƚ'LJŶĞĐŽů2013;209:470.e1Ͳ6. 9KuncharapuI,MajeroniB,andJohnsonD.PelvicOrganProlapse.ŵĞƌŝĐĂŶ&ĂŵŝůLJWŚLJƐŝĐŝĂŶ͘2010;81(9):1111Ͳ1117.

18 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  C. SurgicalTreatmentOptions

ForpatientswhohavefailedtoobtainadequatereliefwiththenonͲinvasiveandminimally invasivetherapies,surgicalinterventionmaybeexplored.Thegeneralgoalofpelvicfloor reconstructivesurgeryistorestoreanatomicsupportandrelieveprolapsesymptoms,while improvingorrestoringbladder,bowel,andsexualfunction.Thecurrentgoldstandardspecific tovaginalvaultapicalprolapseisabdominalsacrocolpopexy.Despitesuch,nodefinitive“gold standard”surgicalprocedureexistsforconjunctiveprolapserepairofboththeapicaland anteriorcompartments,andastheoptimalproceduredependsonthespecificdefectspresent aswellasindividualpatientconsiderations.

Anteriorvaginalwalldefectsarethepredominantcauseofpelvicfloordysfunction.Reviewing pelvicflooranatomyprovidesimportantinsightregardingfailureandrestorationofanterior vaginalwallsupport.Theanteriorvaginalwallresemblesatrapezoidalplane.Theventraland moremedialattachmentsarenearthepubicsymphysisandthedorsalandmorelateral attachmentsareneartheischialspine.Themostcommonsurgicalmanagementapproachfor anteriorvaginalwallprolapseisanteriorcolporrhaphy(transvaginal).Additionalsurgical managementproceduresincludeabdominalorvaginalsurgicalrepair,paravaginalrepairfor treatmentofparavaginalcystocele,sacrocolpopexy,vaginaluterosacralligamentsuspension, andsacrospinousligamentsuspension.10

SurgicalvaginalrepairforPOPinvolvingplicationandsuspensionofnativeconnectivetissuesis aneffectiveapproachforalargeproportionofwomenseekingsurgery.However,thereisarisk ofrecurrentprolapsefollowingtreatment.KeyconcernsassociatedwithnativeͲtissueplication arethat:(1)theuseofalreadyweakenedtissuemayprovideaweakrepair;and(2)thesurgeon mayattempttousestrongerlateraltissuesforrepairandsuspension,whichcanresultin undesirablesideeffectssuchasconstrictionorforeshorteningofthevagina.Thisinturnmay resultinpelvicpain,dyspareunia,andurinaryretention.11Whenevaluatedincomparisonto biologicandpolypropylenemesh,recurrentanteriorcompartmentprolapsefollowingnative tissuerepair(NTR)waspredictedtobebetween27%Ͳ55%basedon6and36monthsfollowͲ updata.12

Surgicalmeshhasbeenusedbothinsacrocolpopexyandatransvaginalsurgicalapproachfor POPrepairtobolsterandreinforcetissueinordertorestoreanatomicpositionandprovide supporttoprolapsedorgans,resultinginsymptomrelief.Meshisutilizedintheseprocedures toovercomesomeoftheissuesexperiencedwithNTR,namelytoimprovethestrengthand ultimatelythedurabilityoftherepair.Historically,sacrocolpopexywasperformedinanopen abdominalprocedure,withsignificantproceduretimes,lengthierrecoverytimesandhigher riskofinfections.Implantationofmeshthroughatransvaginalprocedureallowedfor

 10BrincatC,LarsonK,andFennerD.AnteriorVaginalWallProlapse:AssessmentandTreatment.ůŝŶŝĐĂůKďƐƚĞƚƌŝĐƐĂŶĚ 'LJŶĞĐŽůŽŐLJ͘2010;53(1):51Ͳ58. 11JakusS,ShapiroA,andHallC.BiologicandSyntheticGraftUseinPelvicSurgery:AReview.KďƐƚĞƚƌŝĐĂůĂŶĚ'LJŶĞĐŽůŽŐŝĐĂů ^ƵƌǀĞLJ͘2008;63(4):253Ͳ266. 12MaherC,FeinerB,BaesslerK,ChristmannͲSchmidC,HayaN,BrownJ.Surgeryforwomenwithanteriorcompartmentprolapse. CochraneDatabaseofSystematicReviews2016,Issue11.Pg.21. 

19 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  reductioninproceduretime,fasterrecovery,andcosmeticbenefitswithnovisiblescar.The increasinguseofroboticlaparoscopicsurgeryallowsforsacrocolpopexytobeperformedina minimallyinvasiveprocedure,thoughthisapproachlimitsaccesstoprolapsedorgansand accordinglyiscommonlyusedforrepairofvaginalvaultprolapse(apical),oftenfollowing hysterectomy.Adverseeventsformeshsacrocolpopexyincludeileus/smallbowelobstruction, dyspareunia,bleeding,mesh/suturecomplications,infectionandurinarytractinfection,bowel injury,urinarytractinfection.13

LiteraturepreviouslycitedintheSeptember2011FDAExecutiveSummaryfromtheSurgical MeshObstetrics&GynecologyAdvisoryCommitteeMeetingreportedsignificantsafety concernswithtransvaginalmeshdevices,notingahighreoperationrateandgenerallyhighrate ofadverseeventswithminimaltonobenefitcomparedtoNTR.However,morerecent literature(seediscussioninSection6),whichreflectsmoremodernimprovedmeshdevices andrefinedsurgicaltechniques,reportslowerratesofcomplicationsthataremorecomparable totheratesexperiencedwithNTR,withsuggestionofbetteranatomicaloutcomesandlower ratesofsurgicalinterventions.

 SECTION3:DEVICEDESCRIPTION

BSCispresentingthisinformationtoaddresstwodistinctmeshproductsthatareindicatedforuseinthe repairofanteriorand/orapicalprolapsethroughatransvaginalapproach.Asexplainedbelow,whilethe twomeshproductshavethesameindications,theyareconstructedfromdifferentmaterialsandare shapeddifferently.Accordingly,dependingonthespecificanatomicalandclinicalconsiderationsfora patient,aphysiciancanchoosetouseonedeviceoveranother.

A. UpholdLITEVaginalSupportSystemwithCapioSLIM

TheUpholdLITEVaginalSupportSystem(UpholdLITESystem)isasterile,singleusemesh devicefortransvaginalplacementforPOPrepair.ItconsistsofoneSurgicalMesh,whichisa permanentimplant,andtwoLegAssemblies,whichareusedtoplacethesurgicalmeshinthe desiredlocationandarethenremovedanddiscarded.Thesurgicalmeshisimplantedwitha dedicatedFDAͲcleareddeliverydevice,theCapioSLIMSutureCapturingDevice(K172060).

Components

SurgicalMesh

TheSurgicalMeshisaknitted,lowdensity(lightweight),syntheticmeshthatconsistsof polypropylenemonofilamentfiberthatisdyedbluetoimprovevisibilityduringthe procedureandhasanundyed(natural)centerlinetofacilitateeaseofvisualorientation duringplacement.ThesurgicalmeshisofferedinapreͲcutconfigurationasa conveniencetophysicians.Dependingonphysicianpreferenceforagivenprocedure,

 13NazemaY.SIDDIQUI,MD,MHSc,CaraL.GRIMES,MD,ElizabethR.Casiano,MD,HusamT.ABED,MD,PeterC.JEPPSON,MD, CedricK.OLIVERA,MD,TatianaV.SANSES,MD,AdamC.STEINBERG,DO,MaryM.SOUTH,MD,EthanM.BALK,MD,MPH,and VivianW.SUNG,MD,MeshSacrocolpopexyComparedWithNativeTissueVaginalRepair:ASystematicReviewGroup,Obstet Gynecol,2015January;125(1):44Ͳ55

20 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  thepreͲcutconfigurationmaybemodified(i.e.,cut)tofitthepatientasneededto achievethedesiredrepair.ThepreͲcutconfigurationisshowninFigure1.

Figure1:UpholdLITESurgicalMeshPreͲCutConfiguration

  TheSurgicalMeshisassembledwithtwointegratedLegAssemblies,asshowninFigure 2. Figure2:SurgicalMeshwithTwoIntegratedLegAssemblies

  1)SurgicalMesh,2)Centerline,3)LegAssembly(SeeDetailsAandBinFigures4and5,respectively)  LegAssembly

EachLegAssembly,whichispreͲattachedtothesurgicalmesh,includesadart/needle, lead,dilator,twoleaderloop(s),andaprotectivesleeve.Thedart/needleatthedistal endoftheLegAssemblyisdesignedtobeplacedintothecarrieratthedistalendofthe CapioSLIMdeliverydevice.TheLegAssemblyisdesignedtofacilitatethepassageand fixationoftheSurgicalMeshthroughthesacrospinousligament.EachLegAssemblyis usedonlyonce,toplacetheSurgicalMeshoneithertheleftorrightside,andis removedanddiscardeduponplacement.ThedistalandproximalendsoftheLeg AssembliesaredetailedinFigure3andFigure4,respectively. 

21 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  Figure3:DetailAͲDistalEndofLegAssembly

   Figure4:DetailBͲProximalEndofLegAssembly:(4)Dilator,(5)Lead&(6)Dart/Needle

  PrinciplesofOperation

TheUpholdLITEmeshisintendedprovidestructuralsupportthatrecreatesthe hammockeffectofthepubocervicalfasciaanteriorlyandsuspensionofthe uterosacral/cardinalligamentcomplexapically.Indoingso,themeshisdesignedto providesupportoftheanteriorandapicalvaginalcompartments.  TheSurgicalMeshisplacedtransvaginallythroughasingleanteriorincisioninthe vaginalwall.Thephysicianutilizespalpationtolocatethedesiredanatomicallandmarks andfixationpoints.Oncethedesiredanatomicallandmarksareidentified,thesurgical

22 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  meshisreadytobeplacedusingthetwoLegAssemblies.Thephysicianfollowsthe belowstepstoimplantthemesh:  1. LoadsoneLegAssemblyontotheCapioSLIMdeliverydeviceand,thenusesfinger palpationtoalignwiththesacrospinousligament. 2. DepressestheCapioSLIMplungertopassthedart/needle,leadanddilatorportion oftheLegAssemblythroughtheligament. 3. RemovestheCapioSLIMandrepeatstheprocessforthesecondLegAssemblyin thecontralateralsacrospinousligament. 4. AdjuststheSurgicalMeshbypullingoutwardsontheLegAssembliestoplacethe meshinitsfinaldesiredlocation. 5. RemovestheLegAssembliesanddiscardsthemperhospitalprotocol. 6. Closesthevaginalincisiontocompletetheprocedure.

Figure5:CapioSLIMFacilitatesPlacement

Figure6:UpholdLITESurgicalMeshPlacement

Uterus

Bladder

UpholdLITE

Rectum

SacrospinousLigament



Aswithallmeshproducts,theUpholdLITEimplantisincorporatedintosurrounding tissuefollowingimplantation.Thisprocessinvolvescollagendepositionandcapillary penetrationthroughthemeshconstructthat,onceconcluded,signalscompletionof

23 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  scarformationandhostinflammatoryresponsetotheimplant.Theresulting tissue/meshconstructprovideslongtermsupporttotheprolapsedorgan.

 B. XenformSoftTissueRepairMatrix

TheXenformSoftTissueRepairMatrix(Xenform)isadevicecomprisedofanextracellular collagenmaterialmanufacturedfrombovinedermisthataresourcedsolelyfromcattle obtainedincompliancewithUSregulatoryrequirements.Thedeviceisapermanentimplant, withonlyminimalresorption2,andisprovidedinsheetforminavarietyofsizestobetrimmed andsuturedbythesurgeontomeettheindividualpatient’sneeds.EachXenformdeviceis suppliedsterileinasingleͲuse,doublepeelpackage.

Xenformiscuttosizeforthedesiredrepairprocedureandhydratedinroomtemperature0.9% sterilesaline.Xenformmaybecutpriortohydrationorhydratedpriortocutting,perthe physician’spreference,solongasthedeviceremainsimmersedin0.9%sterilesalineuntilready foruse.SeeFigure7andFigure8.

Trimmed,hydratedXenformisthensurgicallyplacedtransvaginallythroughananteriorincision inthevaginalwallandsuturedinthepelvicfloorofthepatientatthedesiredlocationusing standardsuturingtechniques.Xenformisapermanentimplantdevicethatremainsincontact withthepatient’spelvicfloorsofttissueoncesuturedintoitsdesiredlocationbyatrained physician.WhenXenformisinitsfinaldesiredlocation,thephysicianclosesthevaginalincision.

Figure7:ImageofXenformBeingTrimmed

 Figure8:ImageofXenformWhenHydrated

 

24 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  PrinciplesofOperation

Xenformismeantfordeploymentintheanteriorandapicalvaginalcompartmentsto recreatethehammockingsupportofthebladderandsuspensionofthevaginalapex providedanatomicallybythepubocervicalfasciaanduterosacralligament,respectively. ThephysicianmaytrimtheXenformsheetintoatrapezoidalshapedgraftthatfeatures aproximalportionorbasewideenoughtoachievesuturingtothesacrospinous ligamentsandlongenoughtoreachthebladderneckforapicalsuspension.The anteriorportionliesunderneaththebladderandissuturedcentrallytothecervixand laterallyanddistallytothepelvicsidewallandwhitelinefordirectsupportofthe bladder.

Aswithallmeshproducts,themeshimplantisincorporatedintosurroundingtissue followingimplantation.Theextracellularscaffoldservesasatemplateforregrowthof nativetissue,whichisaccomplishedthroughtheconstructiveremodelingprocessthat providesforlongͲtermintegrationintothesurroundingnativetissues.Theresulting tissue/meshconstructprovideslongtermsupporttosupporttheprolapsedorgan.

C. ProcedureandSurgicalTechnique

ThesurgicalprocedureforimplantationofbothUpholdLITEandXenformmeshfeatures standardizedinstructionsthatcanbegroupedintothefollowingmajorsteps:

x Graftpreparation:ThisstepisspecifictotheXenformprocedureandincludesgraft hydration,graftcuttingintoatrapezoidalshapebasedonthelengthofthevaginaandthe anteriorvaginalspaceandthedistancebetweensacrospinousligaments.

x Surgicalsitedissection

o Hydrodissection:Salinesolutionmixedwithlidocaineforlocalizedanesthesiaand epinephrineforbleedingcontrolisinjectedintothevaginalwallatfullthickness depth,toseparatetissuesalongnaturalseparationlinesandcreatespaceforthe meshimplanttolay.

o Fullthicknessincisiontoreachhydrodissectedplane:Fullthicknessdissectionis criticaltoensuringmaximumseparationbetweenthemeshimplantandvaginal lumentominimizeriskofextrusions.

o Expandingdissectionplane:thisstepinvolvesextendingdissectionintheanterior compartmenttothevaginalapextocreateadequatespaceforthemeshtolay, wrinkleͲandfoldͲfree,aswellastoensurethattheproximaledgeofthemeshisat thelevelofthecervixfordurableattachmenttotheapex,andthatmaximum vaginallengthcorrespondstothelineofmeshsupportalongtheproximalmesh arms.

o TunnelingtoparaͲrectalspacetoaccessandclearsacrospinousligament:Thisstep isintendedtopreparethesacrospinousligamentforfixation.Failuretoperform adequatedissectiontoexposeandcleartheligamentcouldleadtopoorpalpation

25 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  oftheligament,resultinginfixationatanunintendedsitethatcarriesriskofinjury tocriticalstructuresintheareaorpoorfixationintotheligamentthatcould compromisedurabilityofoverallrepair.

x Mesh/Graftfixationandadjustment

o UpholdLITE:TheCapioSLIMdeviceisusedtoloadandpassthemesharms throughthesacrospinousligamentat2cmmedialtotheischialspineandtoadjust thegrafttoensuretensionͲfreeplacement.TensionͲfreeplacementiscriticalto minimizingpotentialriskofdyspareunia.

o Xenform:Thegraftissuturedproximallyoratthebaseofthetrapezoidtothe sacrospinousligaments,centrallytothecervix,andlaterallyanddistallytothe pelvicsidewallandwhiteline,ensuringtherearenofoldsorbunchesinitfor implantation.

x Vaginalincisionclosureandfinalexam:Thevaginalincisionisclosedandcystoscopyand rectalexamareperformedtoruleoutinjurytothebladder,ureters,orrectum.

D. Labeling

LabelingprovidedwiththeUpholdLITESystemandXenformcontainsdetailedcontraindications andwarningstoaidinappropriatepatientselection.Thelabelinghasalsobeenupdatedto providealistingofpotentialadverseeventsassociatedwithuseoftransvaginalmeshdevices generally(evenifnotpreviouslyobservedwiththeparticularproduct),consistentwiththe recommendationsfromthe2011panelmeeting.

Thelabelingfurtherprovidesdetailedinstructionsdescribingthesurgicaltechniquefor preparationofthesurgicalsiteandimplantationofthedevices,asdescribedinSection3C. Patientbrochuresarealsoavailable,whichprovideinformationontreatmentoptionsandthe benefit/riskprofileofthespecificdevicetoassistpatientsinmakinginformedcaredecisions.

E. Training

BSChasdevelopedaphysiciantrainingprogramthatservesasanadjuncttoresidencyand fellowshiptrainingwithanemphasisonunderstandingpatientselection,eachdevice’s mechanismofaction,propersurgicaltechnique,andsurgicalmaneuvers.Toachievethese goals,BSC’sphysiciantrainingprogramemploysacontinuumofproductͲspecifictrainingthat includesthefollowing:

PreͲCourseOfferings

x Accesstoonlineeducationcoveringsuchtopicsasreviewofdiseasestate,productfeatures, relevantanatomy,surgicaltechnique,patientselectionandmanagementofcomplications. x Preceptorshipwithanexperiencedsurgeonontheobservationofproductandsurgical procedure,duringwhichsharingofspecificsurgicaltechniquetipsanddiscussionofpatient outcomesandmanagementofcomplicationstakeplace. x Productoverview/inͲservicewithasimulationtrainingmodelontheproductfeatureswitha TerritoryManager.

26 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  HandsͲOnCourse

x HandsͲoncadavertrainingcoursethatincludesadidacticsessionfromafacultyphysician, surgicalvideooverviewsandbreakdownofprocedures,trainingandpracticeona simulationpelvicmodelallowingthephysiciansto“implant”theproductintothetraining model,trainingonacadaverwitharetroͲperitonealdissectiontoshowrelevantanatomy, andahandsͲoncadaversessionforthephysiciantoseeandallowfullimplantofthe products,aswellasfocusonkeycriticalstepstobolstersafetyandefficacyofthe procedure.

PostͲCourseOfferings

x Proctorshipinthetrainee’soperatingroomwithanexperiencedsurgeononsurgical techniqueoveranumberofcases,oruntilthephysiciantraineeiscomfortablewiththe technique. x Useofthetrainingmodeltopracticestepsandtechnique. x Abilitytoreachouttofacultywithquestions/comments.

 SECTION4.RELEVANTREGULATORYHISTORY

UpholdLITEandXenformwereinitiallyregulatedasClassIImedicaldevicesandeachreceived 510(k)clearancepriortomarketing.Bothdevicesarecommerciallyavailable.OvertimeFDA receivedadverseeventinformationassociatedwithsurgicalmeshdevicesgenerallyusedfor repairofPOPandstressurinaryincontinence(SUI),whichpromptedapublichealthnotification (PHN)andsubsequentpanelmeeting.Ultimately,theFDAmandatedthatsurgicalmesh productsindicatedfortransvaginalrepairofPOPbereclassifiedfromClassIItoClassIIIand subjecttoPremarketApproval(PMA)requirements,aswellas522orderpostmarketstudies. BSChasengagedinextensivediscussionswiththeFDAregardingtheUpholdLITESystemand XenformMatrixastheregulatorylandscapefortheseproductshasevolvedovertheyears.

A. Initial510(k)Clearances

TheUpholdLITESystemwasfirstclearedper510(k)K103426onSeptember14,2011.Since K103426,asubsequent510(k)(K122459)wassubmitted,andclearedDecember13,2012. Nochangesweremadetothemeshimplantitselfaspartofthissubmission,butrather minormodificationstothenonͲimplantLegAssembly.

It’simportanttonotethattheUpholdLITESystemisaseparateanddistinctproductfrom theUpholdSystem.TheUpholdSystemwasclearedviaK081048anddiscontinuedon January31,201314.

XenformwasoriginallydevelopedandpatentedbyTEI(Boston,MA,USA),whoobtained initialFDAclearanceforthedeviceonJune10,2005perK051190,andasubsequent clearance,K060984,onMay17,2006.Nochangesweremadetothedeviceitself,butrather

 14TheUpholdSystemwasalargeporemonofilamentmeshandhadthesameshapeasUpholdLITEbutwasdenserthanUphold LITE(40g/m2).

27 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  includedchangingtheproductnametoXenformSoftTissueRepairMatrixandaddinganew rawmaterialsourcinggeography.Atthetimeofthesesubmissions,TEIwasthelegal manufacturerofthedeviceanddistributionwasperformedbyBSC.In2014,BSCacquired thedesignofthedevicefromTEIandhassinceassumedtherequirementsasthelegal manufacturer,whileTEIactsasthecontractmanufacturer.

TheFDA510(k)PremarketNotificationreviewprocessdidnotrequirethatclinicalstudiesbe conductedtosupportclearanceofsurgicalmeshindicatedfortreatmentofPOP.The 510(k)sforthesedeviceswereinsteadsupportedbypreͲclinicalandbenchstudiesthat showedeachproductwassubstantiallyequivalent,intermsofsafetyandeffectiveness,toa legallymarketedpredicatedevice.

B. 2008/2011PublicHealthNotification

OnOctober20,2008,theFDAissuedaPHNtoinformcliniciansandpatientsaboutserious complicationsassociatedwithtransvaginalplacementofsurgicalmeshtotreatPOPandSUI andtoproviderecommendationsformitigatingrisksandcounselingpatients.TheAgency monitoredadverseeventsthroughtheMAUDEdatabaseandliterature,updatingthePHN onJuly13,2011tokeepcliniciansandpatientsapprisedofthecomplicationsrelatedto transvaginalPOPrepairwithmeshandinformthemthattheFDAnolongerconsidered meshͲrelatedadverseeventstobe“rare”.Theupdatealsoannouncedtheagency’splanto conveneanadvisorypanelmeetingofoutsideexpertstodiscusstheFDA’sfindingsandthe typesofclinicalstudieswhichmaybenecessarytobetterassesstherisksandbenefitsof usingtransvaginalmeshtotreatPOPandSUI.

C. 2011PanelMeetingandReclassificationofTransvaginalMeshDevicesforPOPRepair

TheFDAconvenedanObstetrics&GynecologyDevicesAdvisoryCommitteemeetingon September8Ͳ9,2011todiscusstheuseofsurgicalmeshfortreatmentofPOPandSUI(2011 Panelmeeting)inlightofadverseeventinformationobtainedthroughMAUDEdatabase reportsfromboththeclinicalandcitizencommunities,aswellaspublishedliterature.

InrelationtoPOP,thePanelwasaskedtoprovideinputontherisksandbenefitsof surgicalmeshusedforrepair.ThePanelwasalsoaskedtoweighinontheFDA’s proposedpremarketandpostmarketregulatorystrategiesforsurgicalmeshindicatedfor POPrepair,includingtheappropriatenessofimplementingnewClassIISpecialControls versusreͲclassifyingthedevicetypeforthisintendeduseintoClassIII(PMA),and whetherpostmarketsurveillance(Section522)studieswererequiredforthosedevices alreadyonthemarket.

ThePanelconsensuswasthat:“thesafetyofsurgicalmeshfortransvaginalPOPrepairisnot wellestablishedandthat,dependingonthecompartment,vaginalplacementofsurgical meshforPOPrepairmaynotbemoreeffectivethantraditional“nativeͲtissue”repair withoutmesh.Assuch,thePanelconcludedthattherisk/benefitprofileofsurgicalmeshfor transvaginalPOPrepairisnotwellestablished.ThePanelconsensuswasthatgeneral controlsandspecialcontrolstogetherwouldnotbesufficienttoprovidereasonable assuranceofthesafetyandeffectivenessofsurgicalmeshindicatedfortransvaginalPOP

28 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  repair,andthatthesedevicesshouldbereclassifiedfromClassIItoClassIII.”15For transvaginalmeshesalreadyonthemarket,thePanelagreedthattheFDAshouldmandate Section522postmarketsurveillancestudiestoobtainfurtherclinicaldataregardingsafety andeffectiveness.ThePanelalsorecommendedthatadditionalworkbedonetoensure thatpatientlabelingwithappropriatebenefitͲriskinformationonavailabletreatmentsfor POP,includingsurgicalandnonsurgicaloptions.

ConsistentwiththePanel’srecommendation,FDAreclassifiedtransvaginalmeshdevicesfor POPrepairfromClassIItoClassIII.Indoingso,theFDAnotedthatsuchdevicespresented perioperativerisks,risksofmeshexposureandextrusionthatmayresultinclinicalsequelae (e.g.,pelvicpain,infection,denovodyspareunia,fistulaformation,correctivesurgeries), andoccurrenceofsuchsequelaewithoutthepresenceofmeshexposureorextrusion.

D. 522PostmarketStudyCompliance

TheFDAissuedSection522OrdersPS130044fortheUpholdLITESystemonJuly1,2013 andPS120081forXenformonJanuary3,2012.FollowingtheseSection522studyorders, BSCworkedincooperationwiththeFDAtodevelopextensivepostmarketsurveillance studiestocomparetransvaginalmeshrepairforeachdevicetoNTRinwomenundergoing surgicaltreatmentforanteriorand/orapicalPOP.TwoseparateBSCͲsponsoredstudies wereapprovedbytheFDAandareongoingtoevaluatetheUpholdLITEandXenform devicesinthiscontext.ThestudyprotocolsbothhavecoͲprimaryendpointstoevaluate efficacyofeachdevicecomparedtoNTRbyacompositeofobjectiveandsubjective measures,andsafetybycomparingratesofseriousdeviceͲand/orseriousprocedureͲ relatedcomplications,wherethecompositeprimaryendpointisdefinedat36monthspostͲ surgicalprocedure.SecondaryendpointsincludeQualityofLife(QOL)measuresand additionalpelvicͲrelatedandmeshͲspecificadverseevents.Seefurtherdiscussionofthese studiesinSection7.

E. PreͲsubmissionCollaborationwiththeFDA

AsaresultofthereclassificationofsurgicalmeshfortransvaginalPOPrepairintoClassIII, BSCandtheFDAhavehadextensivecommunicationsrelatingtotheUpholdLITESystem andtheXenformSoftTissueRepairMatrix.PerdirectionfromtheFDA,BSCrequesteda bundledPreͲSubmissionMeetingwiththeFDAtodiscusstheplannedPMAsubmissionsfor boththeUpholdLITE(Q170382)andXenform(Q172064)devices.Duringthemeeting,the FDAandBostonScientificagreedthatthePMAsubmissionswouldpresent12Ͳmonthdata, althoughtheprimaryendpointforthestudieswasdefinedat36months.

F. PMASubmissionSummary

TheUpholdLITEVaginalSupportSystemPMA(P180018)wassubmittedandformallyfiled bytheFDAonJune27,2018.

 15https://www.federalregister.gov/documents/2014/05/01/2014Ͳ09907/reclassificationͲofͲsurgicalͲmeshͲforͲ transvaginalͲpelvicͲorganͲprolapseͲrepairͲandͲsurgical 

29 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  TheXenformSoftTissueRepairMatrixPMA(P180021)wassubmittedandformallyfiledby theFDAonJune28,2018.

ThePMAsubmissionsforbothproductsmettheFDA’srequirementthatPMAapplications fortransvaginalmeshproductsonthemarketbefiledbyJuly5,2018.  SECTION5:PRECLINICALTESTING

TheUpholdLITESystemandXenformhaveundergoneextensivepreͲclinicaltestingtosupporttheir design.Testingincludedevaluationstoensuresufficientstrengthandcharacteristicsofthematerial, andbiocompatibilitytestresults.inaccordancewithFDAͲrecognizedstandardstoconfirmthedevices werebiocompatiblefortheirintendeduse.Bothmeshproductsareimplantabledevicesthatare terminallysterilizedperISO11135requirements.Thedevicesandtheirrespectivepackagingeachhave avalidatedshelfͲlifeofthreeyearsbasedontestingtoensurecontinuedperformanceandpackaging integrityinaccordancewiththeirspecifications.Completeinformationonthepreclinicaltestingwas providedintheoriginal510(k)PremarketNotificationsforthedevices,aswellasinthependingPMA Submissions.

SECTION6:LITERATUREREVIEW

A. 2011FDAPanelLiteratureReviewDiscussion

IntheFDAexecutivesummaryforthe2011Panelmeeting,aliteraturereviewwasincludedto assesstherateofmeshͲspecificadverseevents.Thereviewreliedonanumberofsystematic metaͲanalysesthatspannedseveralyears,andmuchoftheencompassedliteraturereflect oldersyntheticmeshdesignproductsandlimitedliteraturewasincorporatedrelatedto biologicmeshdevices.Thefocusofdevicessubjecttotheliteraturereviewdidnotfully representsyntheticandbiologicmeshproductscurrentlyonthemarket.

TheretrospectiveanalysisbyAbedetal.3wasusedasoneoftheprimaryreferencesto establishadverseeventratesandincludedpublicationsfrom1950to2007.Abedetal. reportedexposureratesof10.3%fornonͲabsorbablesyntheticmeshand10.1%forbiologic grafts,where56%ofthoseexperiencingerosionrequiredsurgicalexcision.Itisimportantto notethatthisretrospectivereviewincludedliteraturearticlesthatdescribedofflabeluseof surgicalmeshintendedforabdominalherniarepairandnotnecessarilyFDAcleared urogynecologicalmeshintendedforPOP.

Diwadkaretal.4,whichisbasedonareviewofdatapublishedbetween1985Ͳ2008,alsoserved asaprimaryreferenceinthe2011Panelmeetingandwasinstrumentalinwhatwas determinedtobecomplicationsrequiringreͲsurgeryratesfortransvaginalmeshcomparedto sacrocolpopexyandNTR.InthismetaͲanalysis,thereͲsurgeryratesforcomplicationswere 7.2%fortransvaginalmesh,4.8%forsacrocolpopexy,and1.9%fortraditionalvaginal (presumednativetissue)repair.ThetransvaginalmeshkitsrepresentedincludedApogee (AmericanMedicalSystems,Inc.),PosteriorGynecareProliftSystemandTotalGynecareProlift System(EthiconWomen’sHealthandUrology),andTotalVaginalMeshandPosterior IntravaginalSlingplasty(TycoHealthcare,UnitedStatesSurgical).

30 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  Otherstudiesalsocitedinthe2011PanelmeetingwereIglesiaetal.(2010)16,whereEthicon Proliftmeshwasevaluatedin32subjectscomparedto33NTRsubjects,andWithagenetal. (2011)17,evaluating93womentreatedwiththeEthiconProliftmeshdeliveredthrougha trocarͲguidedimplantationprocedureand97NTRsubjects.Thesepublicationswereusedto supportthattherewasnoevidencethatmeshrepairofapicalprolapseresultedinsignificant improvementinanatomicoutcome.

ManyoftheproceduresperformedduringthetimethattheAbedetal.andotherpublications werewrittenwerebasedona“meshinlaytechnique”,whichinvolvedfascialplicationwith placementofmeshontopofit.Theseproceduresrepresentanearlymeshplacement techniqueanddonotreflectcurrentstandardpracticeforuseoftransvaginalmeshingeneral, orthedesignoftheUpholdLITEdeviceinparticular.Attachingmeshtoplicatedfasciadoes notofferbetterresultsoverstandardrepairs.Thiscanbereasonablyexplainedbythefactthat sincemeshinlayswereonlyattachedtoplicatedfascia,itcanbeassusceptibletofail,aseither thesuturesholdingtheplicatedfasciatogetherorthesuturesholdingthemeshtotheplicated fascia.Forpatientswhosufferfromparavaginalfailuresorseparationofpubocervicalfascia frompelvicsidewall,attachingmeshtofasciathatisalreadyseparatedandispartofthefailure cannotbeexpectedtoofferanydurability.Formeshtoofferdurabilityorprovideany structuralsupport,itmustbeattachedlaterallytopelvicsidewalltoformahammocksimilarto theonecreatedanatomicallybythepubocervicalfasciaortothesacrumtosuspendthe vaginalapex,asisdonewithsacrocolpopexyandcurrenttechniquesfortheimplantationof transvaginalmeshdevices.

Incontrasttothesyntheticmeshproductsthatwerecommerciallyavailableintheearly2000s, themeshusedintheUpholdLITEVaginalSupportSystemisfarlighterat25gm/m2,itisalso placeddirectlyviaasingleincisionwithouttheuseoftrocars,externalincisions,orpasses throughmuscles.Inaddition,UpholdLITEisdirectlyfixatedusingtheCapioSLIMsuturing device,thusavoidingfixationarmsacrossmultipletissueplanes.UpholdLITEoffersbetter repairdurabilitythanstandardrepairsgivenitsimprovedcharacteristicsintermsoflighter density(lightweight),lowersurfacearea,andlargerporesize.Mostimportantly,italsooffers afundamentallydifferentstructuralsupportandmechanismofrepairthanmeshinlaysandthe surgicaltechniqueusedtoimplantthem.AlthoughXenformisnotasyntheticmesh,as describedinSection3,theprocedureandsurgicaltechnique,includingrouteofplacement (transvaginalapproach),surgicalsitedissection,andfixationandadjustmentproceduralsteps arebyandlargethesameasthoseforUpholdLITE.Bothofthesedevicesoffer(1)apical suspensionthatfixateintothesacrospinousligamentand(2)bladdersupportbywayof attachingthemeshtothepelvicsidewall(thevaginalapex),whichisconsideredthe cornerstoneofpelvicsupportarchitecture.Halfoftheobservedvariationinanterior compartmentsupportmaybeexplainedbyapicalsupportandlossofapicalsupportiscritical

 16IglesiaC.B.,etal,Vaginalmeshforprolapse:arandomizedcontrolledtrial.ObstetGynecol,2010.116(2Pt1):p.293Ͳ303. 17WithagenM.I.,etal,TrocarͲguidedmeshcomparedwithconventionalvaginalrepairinrecurrentprolapse:arandomized controlledtrial.ObstetGynecol.2011.117(2Pt1):p.242Ͳ50. 

31 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  todevelopmentofanteriorvaginalprolapse.18Furthermore,suspensionofthevaginalapexis associatedwithcorrectionofcystocelesin55%ofcasesandrectocelesin30%.19

TheliteraturepresentedhereinforUpholdLITE(Section6B)andXenform(Section6C)offera significantamountofevidencedemonstratingthatthesedevicesareeffectivetreatment optionsachievingbothanatomicandsubjectivesuccessaswellasimprovementstoQOL measures.

B. UpholdLITEVaginalSupportSystem

PublishedliteraturesupportsthebenefitoftheUpholdLITEdeviceintermsofrepairofprolapse inadditiontoclinicallymeaningfulmeasures,andfurtherthatthesebenefitscanbeachieved withlowcomplicationrates.RefertoAppendix1foradditionaldetailsregardingtheliterature searchstrategy.

ThefiveͲyearprospectivestudybyRahkolaͲSoisaloetal.20isparticularlyvaluableinthatitis relativelylarge(207subjects)andrepresentsthelongestprospectivefollowͲupofsubjects treatedwiththecontemporaryUpholdLITEprocedure.Strengthsofthestudyincludethe relativelylowlosstofollowͲup,exclusionofconcurrentproceduresthatmaybeacausefor misclassification,thestandardizedsurgicalmethodandpostoperativeprotocol,anduseof validatedinstrumentsforoutcomemeasures.Anatomicsuccesswasachievedin93.5%of subjectsatoneyearandtherewasnotastatisticallysignificantdeclineatfiveyears(p=0.2).All thedomainsofthePelvicFloorDistressInventory(PFDIͲ20)improvedfromthepreoperative visittothefiveͲyearfollowͲupvisit,andtherewerenosignificantdifferencesinthescores betweentheoneͲyearandfiveͲyearvisits.Afterfiveyears,thetotalscorepointsexceededthe baselinepointsin89.4%ofthewomen,whereasin78.8%ofthewomen,aminimalclinically importantdifference(>23points)wasreached.

BetweenoneͲandfiveͲyearfollowͲup,atotalof29(19.7%)ofthewomenhadundergone additionalpelvicsurgery.Themajorityofadditionalsurgeriesperformedwerenotrelatedto recurrentanterior/apicalprolapseandnotspecifictoadverseeventsrelatedtotheUpholdLITE device.ThemostcommonoftheseadditionalsurgicalproceduresweremidͲurethralslings, hysterectomy,andposteriorcolporrhaphy.SeventeenwereprolapseͲrelatedandincluded proceduressuchasposteriorcolporraphy,hysterectomy,andanteriorcolporrphia.

Threesubjectsunderwentmeshremovalduetopainandtherateofextrusionatfiveyearswas 1.4%;allofthesesubjectsweretreatedwithlocalestrogenandnonerequiredsurgical intervention.Thisrepresentsthelongestprospectivelyfollowedcohorttoreceivea contemporaryUpholdLITEprocedureandtheresultsofthisstudysuggestthatthebenefitseen fromtheUpholdLITESystemcanbedurableandachievedwithmodestcomplicationrates,with

 18DeLanceyetal.,TheRelationshipBetweenAnteriorandApicalCompartmentSupport.AmericanJournalofObstetrics& Gynecology(2006)194,1438Ͳ43 19Lowderetal.,TheRoleofApicalVaginalSupportintheAppearanceofAnteriorandPosteriorVaginalProlapse.Obstetrics& Gynecology2008;111(1):152Ͳ7) 20RahkolaͲSoisaloetal.PelvicOrganProlapseRepairUsingtheUpholdVaginalSupportSystem:5ͲYearFollowͲup.FemalePelvic MedicineandReconstructiveSurgery.

32 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  themostcommonbeingurinaryincontinence(7.2%),prolapserelatedproblems(6.5%),and chronicpain(2.6%).

TherehavebeenthreerecentshortandlongͲtermfollowͲupstudieswheremeaningfulnumbers ofpatientswereimplantedwithsecondͲgenerationmeshthatcaninformanopinionon whetherornotimprovementsinthephysicalpropertiesofthetransvaginalmeshanduseof contemporarysurgicaltechniquesforimplantationresultinimprovedoutcomesand,more importantly,anacceptableriskͲbenefitratio.Mostrecently,theSUPeRstudy(seediscussionin Section6.C)abstractwaspresentedatthe2018AmericanUrogynecologySociety(AUGS) Meeting.Nageretal.21wasthefirstlongͲterm,multicenter,prospective,randomizedtrial comparingUpholdLITEversushysterectomyandnativetissueureterosacralligament suspension.FollowͲupthrough48monthswasreportedon175randomizedsubjects.The compositeprimaryendpointwasabsenceofprolapsesymptoms,noobjectiveprolapsebeyond thehymen,andnoretreatmentforprolapse.Resultsdemonstratedgoodefficacyforboththe UpholdLITEandNTR.Therewasnodifferenceinefficacybetweenthetwogroupsasassessed bytheprimaryendpointandthemeshexposureratewas8%.

In2016,Altmanetal.22publishedresultsfromaprospective,multicenterstudyon207patients usingtheUpholdLITEVaginalSupportSysteminwomenwithPelvicOrganProlapse Quantification(POPͲQ)Stage2orgreaterapicalPOP,withorwithoutconcomitantanterior vaginalwallprolapse.AftertwomonthsoffollowͲup,91%(157/172)ofsubjectsachievedthe optimalanatomicaloutcomeofPOPͲQStageч1.AfteroneyearoffollowͲup,therateof objectivesuccessbythismetricincreasedto94%(154/164subjects).Assessedseparately,both anteriorandapicalcompartmentsshowedsignificantanatomicimprovement(p<0.001).In addition,subjectivesuccesswasachievedin91%(165/181)ofsubjects.Withregardtosafety,at oneͲyearfollowͲup,therateofseriouscomplicationswas4.3%(9/207subjects);thisincluded threesurgeriesduetomeshexposure(1.4%),twomeshremovalsbecauseofpain,three bladderperforations,andonecaseof>1000mLbleeding.

In2011,Altman,etal.23reportedonamultiͲcenter,parallelͲgroup,randomizedcontrolledtrial thatcomparedtheuseofpolypropylenemeshrepair(UpholdLITE)comparedtoNTR (colporrhaphy)inwomenwithcystocele.Thestudyenrolledpatientswithprimaryorrecurrent prolapseoftheanteriorvaginalwallofPOPͲQstageш2andsymptomsofvaginalbulgeorpelvic heaviness.TwohundredsubjectsweretreatedwithUpholdLITEand189withNTR.Theprimary outcomewasacompositeofobjectiveanatomicaloutcomeofstage0or1,asmeasuredby POPͲQ,andsubjectiveabsenceofvaginalbulgesymptomsat12months.

 21NagerCW,ZyczynskiH,RogersRG,BarberMD,RichterHE,ViscoAG,RardinCR,HarvieH,WallaceD,MeikleSF;PelvicFloor DisordersNetwork.TheDesignofaRandomizedTrialofVaginalSurgeryforUterovaginalProlapse:VaginalHysterectomyWith NativeTissueVaultSuspensionVersusMeshHysteropexySuspension(TheStudyofUterineProlapseProceduresRandomized Trial).FemalePelvicMedReconstrSurg.2016JulͲAug;22(4):182Ͳ9. 22AltmanD,MikkolaTS,BekKM,RahkolaͲSoisaloP,GunnarssonJ,EnghME,FalconerC;NordicTVMGroup.Pelvicorgan prolapserepairusingtheUphold™VaginalSupportSystem:a1Ͳyearmulticenterstudy.IntUrogynecolJ.2016Sep;27(9):1337Ͳ 45. 23AltmanD.,etal,AnteriorColporrhaphyversusTransvaginalMeshforPelvicͲOrganProlapse.NEnglJMed.,2011.364:p.1826Ͳ 36.

33 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  Resultsshowedastatisticallysignificantdifferenceinprimarysuccessinsubjectswhowere treatedwithUpholdLITEversusNTR(68.0%vs.34.5%,p<0.001).Offurthernote,meshrepair remainedsuperiortoNTRwithrespecttotheprimaryoutcomeinasensitivityanalysisthat imputedoutcomesthatweredisadvantageousformeshrepair(adjustedoddsratio,2.1;95%CI: 1.4Ͳ3.3).Forsecondaryoutcomes,UpholdLITEwassuperiortoNTRintermsofanteriorvaginal wallsupportrestorationtoPOPͲQstage0or1(82.3%vs.47.5%,p<0.001);superiorityof UpholdLITEwasalsoshownforsubjectivesuccessinpatientreportingofsymptomsofbulge (75.4%vs.62.1%,p=0.008).Onqualityoflife,meanPelvicOrganProlapse/Urinary IncontinenceSexualQuestionnaire(PISQͲ12)scoresweremodestlyimprovedoverbaselineand weresimilarbetweenUpholdLITEandNTRarms.RatesofdenovoSUIaftersurgerywere 12.3%forUpholdLITEvs.6.3%forNTR(p=0.05),anddenovoSUIsymptomswerestatistically significantlymorebothersomeinsubjectstreatedwithUpholdLITEversusNTR(p=0.02); however,obstructivesymptomsweresignificantlylessbothersome(p=0.01).Bladder perforationrateswere3.5%forUpholdLITEvs.0.5%forNTR(p=0.07).Meshexposure requiringsurgicalinterventionoccurredin3.2%ofUpholdLITEsubjects.OnesubjectintheNTR groupexperiencedrecurrentprolapseforwhichasecondanteriorrepairwasperformed.These resultsdemonstratedthattheuseofUpholdLITEforprimaryrepairofPOPresultedinahigher successratethanNTRbasedoncompositeobjectiveandsubjectiveoutcomesandalowerrisk ofprolapserecurrence.WhileUpholdLITEalsodemonstratedhigherratesofsurgical complicationsandadverseevents.Theauthorsconcludedthebenefitsofthehighersuccess ratesofUpholdLITEshouldbebalancedagainsthighercomplicationandAErateswhen counselingpatientsregardingsurgicaltreatmentoptions. OthernoteworthypublicationsthatsupportboththesafetyandefficacyofUpholdLITEinclude Gutmanetal.24Intermsofefficacy,thisstudyreportedthatlaparoscopicsacralhysteropexy (LSHP)andvaginalmeshhysteropexy(VMHP)usingUphold14andUpholdLITEhadsimilarcure ratesandhighsatisfactionatoneͲyearpostprocedure.Afteradjustingforbaselinedifferences, therewasnodifferencein: x Compositecure(72%LSHPvs.74%VMHP;adjustedOR,0.58;95%CI,0.2Ͳ1.5;P=0.27); x Anatomiccure(77%LSHPvs.80%VMHP;adjustedOR,0.48;95%CI,0.2Ͳ1.5;P=0.20); x Symptomaticcure(90%LSHPvs.95%VMHP;adjustedOR,0.4;95%CI,0.7Ͳ1.8;P=0.22).

Thevaginalmeshhysteropexygrouphadshortersurgicaltimecomparedtothelaparoscopic group.Bothreportedsimilarimprovementinpelvicfloorsymptomsandsexualfunction. Satisfaction,asmeasuredbythePatientGlobalImpressionofImprovement(PGIͲI) questionnaire,was95%ineachgroup.Withrespecttosafety,overallcomplicationrateswere low,withthemostcommonlyreportedAEbeingurinarytractinfection.Mesherosions occurredin2.7%(2/74)oftheLSHPand6.6%(5/77)oftheVMHPgroups.Moreover,AE classificationusingtheClavienͲDindoscalewassimilarinbothgroups.

 24GutmanRE,RardinCR,SokolER,MatthewsC,ParkAJ,IglesiaCB,GeoffrionR,SokolAI,KarramM,CundiffGW,BlomquistJL, BarberMD.Vaginalandlaproscopicmeshhysteropexyforuterovaginalprolapse:aparallelcohortstudy.ŵ:KďƐƚĞƚ'LJŶĞĐŽů͘ 2017Jan;216(1):38.e1Ͳ38.e11. 

34 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  Loetal.25retrospectivelyreportedon12ͲmonthfollowͲupofwomenwhounderwentcorrection ofanterior–apicalprolapsewithUpholdLITEbetweenFebruary2015andJuly2016.Of89 subjectsthatmettheinclusioncriteria,theobjectiveanatomiccurerateswere97.7%anteriorly and98.9%attheapex.TherewerenomeshexposuresreportedandtheonlySAEreportedwas abladderinjury.

C. XenformSoftTissueRepairMatrix

PublishedliteraturesupportsthebenefitoftheXenformdeviceintermsofrepairofprolapsein additiontoclinicallymeaningfulmeasures,andfurtherthatthesebenefitscanbeachievedwith lowcomplicationrates.RefertoAppendix1foradditionaldetailsregardingtheliterature searchstrategy.

Onerelevantclinicaltrialstudypublicationmettheinclusioncriteria.Forthisstudy(Goldsteinet al.5),restorationofnormalanatomyinanycompartment,symptomrelief,QOL,andsexual functionoveraoneͲyearperiodwereevaluated.In43of45patientsthatcompleted12months offollowͲup,thesuccessratewas88%andtherewerestatisticallysignificantimprovementsin anterior,posterior,andapicalsupport.MeanPFDIͲ20scoreimprovementof72%indicated significantlyimprovedsymptomaticoutcomes.PISQͲ12scoresalsoshowedsignificant improvement,indicatingnodeclineinsexualfunction.Complicationswereminimal,andthere werenografterosionsandnopainlastingmorethan30days.Theseresultsdemonstrated significantimprovementinbothobjectiveandsubjectiveoutcomesat12monthsinsubjects whounderwentPOPrepairusingXenform,reflectingapositiverisk/benefitprofileforthe device.

D. LiteratureConclusion

Takentogether,theUpholdLITEandXenformliteraturedemonstratethatthesedevicesare effectivetreatmentoptionsachievingbothanatomicandsubjectivesuccessandimprovements toQOLmeasures.TheserecentstudiesfurthersuggestthatmeshexposureratesandreͲ operationratesformeshexposurefortheUpholdLITESystemareimprovedcomparedtowhat wasreportedinthecompilationofstudiesreferencedinthein2011Panelmeetingthatlargely reportedonfirstgenerationsyntheticmeshkits.Itshouldbenotedthatthecomplicationrates reportedfortheUpholdLITESystemintheliteratureareinlinewiththosereportedforother secondͲgenerationmeshsystems.Forinstance,Suetal.26comparedtheElevateAnterior& ApicalTransvaginalMeshSystemin100patientsto101patientswhounderwentNTR.Inthe 100Elevatepatients,atoneͲyearfollowͲup,therewasa3%mesherosionrateand1%rateof repeatsurgeryformesherosion.Theratesofmeshexposure/erosionreportedinthestudies discussedabovefortransvaginalPOPrepairalsocomparefavorablytothereportedratesof meshͲspecificcomplicationsaftersacrocolpopexy.27  25Loetal.AnteriorͲapicalsingleͲincisionmeshsurgery(uphold):1Ͳyearoutcomesonlowerurinarytractsymptoms,anatomyand ultrasonography.InternationalUrogynecologyJournalJune2018. 26T.H.Su,H.H.Lau,W.C.Huang,C.H.Hsieh,R.C.Chang,C.H.Su,SingleͲincisionmeshrepairversustraditionalnativetissuerepair forpelvicorganprolapse:resultsofacohortstudy,IntUrogynecolJ,25(2014),pp.901Ͳ908 27See,e.g.,NygaardIE,McCreeryR,BrubakerL,ConnollyA,CundiffG,WeberAM,ZyczynskiH(2004)Abdominalsacrocolpopexy: acomprehensivereview.ObstetGynecol2004Oct;104:805–23(reportinga3.4%mesherosionrate).

35 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting   TheseoutcomescomparefavorablytostudiesreportingontheefficacyandsafetyofNTR,as canbeseeninthecontrolledstudiesdiscussedabovewhichdirectlycomparedanUpholdLITE armtoacontrolarm,aswellasinotherstudiesdiscussingtheoutcomesofNTR.TheCochrane review12ofsurgicalmanagementofPOP,whichcoveredatotalof5,954womenundergoing surgeryforPOPrepairin56randomizedcontrolledtrials,includedassessmentof10studies comparingNTRwithsyntheticandbiologicmeshforrepairofanteriorPOP.Basedonthedata fromthosestudies,transvaginalmeshwasmoreeffectivethanNTRbothintermsof sustainableanatomicrepairandsymptomaticimprovement.Specifically,NTRwasassociated withmorerecurrentanteriorprolapsethanwhensupplementedwithmesh.Threestudies assessingvaginalprolapseinmultiplecompartmentsalsofoundalowerprolapserecurrence ratewithpolypropylenemeshascomparedtoNTR.  Theliteraturedatareportedabovedemonstratesaconsistentsafetyandeffectivenessprofile fortheBSCdevices,whereeffectivenessinboththeshortandlongtermiscomparabletoor betterthanNTR,andwithacomparativerateofseriousandnonͲseriouscomplications. 

 

36 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  SECTION7:CLINICALEXPERIENCE

Thissectionprovidesdatafromtheongoing522postmarketstudiesfortheUpholdLITESystemand Xenform(Section7A).Notethatpertheapprovedprotocols,thepurposeofthestudiesistoinvestigate thelongͲtermsafetyandeffectivenessofthedevicesoutto36months.ForpurposesofthePMA submissionsandthereͲclassificationoftransvaginalmeshforPOPrepair,onlythecomplete12Ͳmonth dataarecurrentlyavailable.Datafromadditionaltimepointshavealsobeenmadeavailablefor informationalpurposesonly;noconclusionscanbedrawnbasedonthatdataduetothelowamount availableatthetimeofdatabaselockanddataextraction,andtheresultingassessmentsarelikelyto evolveasthestudyprogresses.

ThissectionalsocontainsadiscussionofallBSCclinicaldataavailableforbothdevices(Section7B), informationforoneadditionalclinicalstudythatthathasbeencompletedforUpholdLITE(Section7C), andrealͲworldcomplaintdataandanalysisforbothdevices(Section7D).

ARiskBenefitDiscussion,whichoutlinestherisk/benefitprofileforbothdevicesandjustifies,through thedatapresentedinthissection,whyitisappropriatetocontinuemakingthesedevicesavailable basedonthetotalityofevidence,isprovidedinSection8.

A. OverviewofBSC522PostmarketStudies

1. Introduction

BSCiscurrentlyconductingtwo522postmarketsurveillancestudiesforPOP,oneforthe UpholdLITESystemandoneforXenform.Bothstudiesareprospective,nonͲrandomized, parallelcohort,multiͲcenterclinicalinvestigationsdesignedtocomparetransvaginalmesh repair(TMR)toNTRinwomensurgicallytreatedforanteriorand/orapicalPOP.Thestudies arebeingconductedinpartnershipwithAUGSunderthePelvicFloorDisorders(PFD) RegistryandinvestigatelongͲtermsafetyandeffectivenessofPOPrepairoutto36months.

ThestudiesweredevelopedincollaborationwiththeFDAandweredesignedinaccordance withrecommendationsfromthe2011Panelmeeting,withextensivecommunications betweenBSCandtheFDAregardingstudydesign,subjectpopulation,statisticalanalyses, etc.The522studiesweredesignedtoevaluatetwoprimaryendpoints:(1)clinically relevantmeasuresofeffectiveness,basedonacompositeofanatomicandsubjective successandabsenceofretreatment,and(2)assessmentofseriousdeviceͲandprocedureͲ relatedadverseevents(SAEs).TheFDArecommendedthatstudysubjectsshouldbe evaluatedatleastoutto12monthstosupportsafetyandeffectivenessofeachdeviceprior tosubmissionofamarketingapplication,withatleastanadditionaltwoyearsof postmarketfollowͲup.Duringtheconductofthestudies,BSChasremainedinclosecontact withtheFDAregardingupdatestothestudyprotocols,allofwhichhavebeenfully discussedwithandapprovedbytheFDA.

BSCinitiatedandexecutedthestudiesinaccordancewiththeFDAͲapprovedprotocolsand believesthattheyincludeappropriate,clinicallyrelevantsubjectpopulations,rigorousstudy designs,andclinicallymeaningfulefficacyandsafetyendpoints.BSCbelievesthatthese studiessatisfytherecommendationssetforthbythePanelmembersduringthe2011Panel meeting,aswellastheFDA’srecommendationsandrequirementsasincludedinthe

37 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  reclassificationorder,andremainalignedwiththeFDA’sthinkingovertimeonthetopicof transvaginalsurgicalmeshforuseinPOPrepair.

2. OverviewofStudies

TheUpholdLITEPostmarketSurveillanceStudy,titledAProspective,NonͲRandomized, ParallelCohort,MultiͲCenterStudyofUpholdLITEvs.NativeTissuefortheTreatmentof WomenwithAnterior/ApicalPelvicOrganProlapse,isregisteredatClinicalTrials.govunder numberNCT01917968.Subjectsenrolledinthisstudyreceivedeithertransvaginalmesh (UpholdLITE)orNTR(sacrospinousligamentfixationoruterosacralligamentsuspension and/orcolporrhaphy),withscheduledfollowͲupvisitsat2,6,12,18,24and36months.

TheXenformPostmarketSurveillanceStudy,titledAProspective,NonͲRandomized,Parallel Cohort,MultiͲCenterStudyofXenformvs.NativeTissuefortheTreatmentofWomenwith Anterior/ApicalPelvicOrganProlapse,isregisteredatClinicalTrials.govundernumber NCT01945580.Subjectsenrolledinthisstudyreceivedeithertransvaginalmesh(Xenform) orNTR(sacrospinousligamentfixationoruterosacralligamentsuspensionand/or colporrhaphy),withscheduledfollowͲupvisitsat2,6,12,18,24and36months.

ThestudiesutilizecoͲprimaryendpointswheretheprimaryefficacyendpointisacomposite ofobjective,subjective,andretreatmentmeasuresandisevaluatedinconjunctionwiththe primarysafetyendpoint.Forbothstudies,theprimaryefficacyandsafetyendpointsare scheduledtobeevaluatedfollowingcompletionofsubject36ͲmonthfollowͲupvisits.

a. EfficacyEndpoints

Bothstudiesevaluateefficacyasacompositeofobjective,subjective,andretreatment measurestoensurebothsurgicalsuccessandsubjectsatisfaction.Thecriteriafor efficacywerechosenwithextensiveinputfromtheFDA.TheFDAcommentedintheir 2011Panelmeetingpresentationthatthemostusedstudyefficacyendpointfor“ideal pelvicsupport”wasPOPͲQstage0Ͳ1,wherethemostdistalprolapseis>1cmabovethe hymen,andtheFDAdidnotbelievethiswasaclinicallymeaningfuloutcomemeasure; thePanelagreed.Thus,thetwocompositeefficacyendpointswereagreeduponto betteraccountforadditionalrelevantconsiderationsinevaluatingthetreatment’s success.Theabsenceofretreatmentportionoftheprimaryandsecondaryefficacy endpointsandinclusionoftheassessmentoftheTrialofMidͲUrethralSlings(TOMUS) painscaleallowthestudiestoaddressefficacyinlinewithconcernsexpressedbythe FDA,specificallyfortreatmentfailureandpain.

Bothclinicalstudiesutilizethefollowingprimaryefficacyendpoint:

1. Objectivesuccessisachievedbythesubjecthavingananatomicoutcomedefinedas theleadingedgeofprolapseatorabovethehymenintheoperatedcompartment:

• Anteriorsegment:Leadingedgeofanteriorprolapseisatorabovethehymenor PelvicOrganProlapseQuantificationSystem(POPͲQ)pointBaч0.

38 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  • Apicalsegment:ThevaginalapexdoesnotdescendmorethanoneͲhalfintothe vaginalcanal(i.e.,POPͲQpointC<Ͳ1/2TVLformultiͲcompartmentprolapseor POPͲQpointCч0forsinglecompartmentapicalprolapse).

2. Subjectivesuccessisachievedifthepatientdeniessymptomsofvaginalbulgingper PFDIͲ20question3,answering“no”or“yes”but“Notatall”bothersome(<2).

3. NoretreatmentforPOP:noadditionalsurgicaltreatmentforPOPintheanatomic segment(s)treatedattheindexsurgeryornopessaryusesinceindexsurgery(i.e., ‘treatedsegment’referstothetargetcompartment).

Thesecondaryefficacyendpointforbothstudiesalsoconsistofacompositeof objective,subjective,andretreatmentmeasures.Thesecondaryefficacyendpoint measuresareidenticaltotheprimaryefficacyendpointrequirementsintermsof subjectivesuccessandtherequirementfortheretobenoretreatmentforPOP; however,theanatomiccriteriaareslightlydifferent.Inthesecondaryendpoint, anatomicsuccessintheoperatedcompartmentisdefinedasfollows:

• Anteriorsegment:Noanteriorprolapseatorbeyondthehymen(POPͲQpoint Ba<0).

• Apicalsegment:ThevaginalapexdoesnotdescendmorethanoneͲhalfintothe vaginalcanal(i.e.,POPͲQpointC<1/2TVLformultiͲcompartmentprolapseor POPͲQpointCч0forsinglecompartmentapicalprolapse).

PatientreportedoutcomesforvariousQOLmeasurements,includingpelvicfloor symptomsperPFDIͲ20,QOLperthePelvicImpactQuestionnaire(PFIQͲ7),sexual functioningperPISQͲ12,painpertheTOMUSpainscale,andsubject’slevelof improvementperPGIͲIforProlapse,arealsoincorporatedassecondaryefficacy endpoints.

b. SafetyEndpoints

TheprimarysafetyendpointforbothstudiesisacomparisonofseriousdeviceͲand/or seriousprocedureͲrelatedadverseevents(AEs)betweenbaselineandthe36Ͳmonth timepoint.ThesecondarysafetyendpointsincludeanalysisofoveralldeviceͲand procedureͲrelatedAEs,mesherosionandexposure,anddenovodyspareunia.Inorder tobetterunderstandthepotentialforpelvicͲspecificAEsthatwerediscussedduringthe 2011Panelmeeting,assessmentsofpelvicpain,infection,vaginalshortening,atypical vaginaldischarge,neuromuscularproblems,vaginalscarring,denovovaginalbleeding, denovovoidingdysfunction,andfistulaformationwereperformed.Additionally,in ordertoaddresstheFDA’sconcernfromthe2011Panelmeetingregardingsurgical intervention,BSCanalyzedinterventionsforrecurrentprolapseandcomplicationspost indexprocedureasseparatesecondaryendpoints.Theseendpointsencompassallof theFDA’ssafetyͲrelatedconcernsassociatedwiththeuseoftransvaginalmeshforPOP repair.

39 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  3. StudyPopulations

BoththeUpholdLITEandXenformPostmarketSurveillanceStudiesenrolledadult,nonͲ pregnantwomenwhohadbeendiagnosedwithanteriorand/orapicalPOP(i.e.,POPͲQ scoresofBaш0foranteriorprolapse,orCш0forapicalprolapse,orCшͲ½TVLandBaш0 formultiͲcompartmentanteriorandapicalprolapse;andwithsubjectͲreportedbothersome bulgetheycouldseeorfeel),werescheduledtoundergosurgicalrepair,andwhomayor maynothaverequiredaconcomitantprocedure(suchasaposteriorrepair,hysterectomy, orslingplacementforSUI).TheenrollmentcriteriareflectedtheFDArecommendations fromthe2011Panelmeetingincludingthatapopulationreflectwomenage18yearsor olderwithdocumentedPOPandwhowerealreadyscheduledforsurgeryshouldbe evaluated,withfurtherconsiderationgiventothelevelofprolapse(i.e.,aboveorbelowthe hymenalring).Subjectswhohadapreviousprolapserepairwithmeshinthetarget compartment,wereplanningtoundergoaconcomitantrepairwiththeuseofmeshinthe nonͲtargetcompartmentandhadchronicsystemicorfocalpaininthepelvicareawere excludedfromparticipationinthestudy.Followingarethespecificenrollment (inclusion/exclusion)criteriaforeachofthestudies:

UpholdLITE

Subjectswhometallofthefollowingcriteriaweregivenconsiderationforinclusioninthe UpholdLITEstudy(providednoexclusioncriterionweremet):

x Subjectisfemale x Subjectisш18yearsofage x Subjecthaspelvicorganprolapsewiththeleadingedgeatorbeyondthehymen.At orbeyondthehymenisdefinedasPOPͲQscoresofBaш0(forprolapseofthe anteriorcompartmentalone)orCш0(forprolapseoftheApicalcompartment alone)orCшͲ1/2TVLandBaш0(formultiͲcompartmentprolapsethatincludesthe anteriorandapicalcompartments) x SubjectreportsofabothersomebulgetheycanseeorfeelperPFDIͲ20,question3 responseof2orhigher(i.e.responsesof“somewhat”,“moderately”,or“quiteabit) x Subjectorsubject’slegallyauthorizedrepresentativemustbewillingtoprovide writteninformedconsent x SubjectiswillingandabletocomplywiththefollowͲupregimen

SubjectswhometanyofthefollowingcriteriawereexcludedfromtheUpholdLITEstudy:

x Subjectispregnantorintendstobecomepregnantduringthestudy x Subjecthasanactiveorchronicsystemicinfectionincludinganygynecologic infection,untreatedurinarytractinfection(UTI)ortissuenecrosis x Subjecthashistoryofpelvicorgancancer(e.g.uterine,ovarian,bladder,coloͲrectal orcervical) x Subjecthashadpriororiscurrentlyundergoingradiation,lasertherapy,or chemotherapyinthepelvicarea

40 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  x Subjecthastakensystemicsteroids(withinthelastmonth),orimmunosuppressive orimmunomodulatorytreatment(withinthelast3weeks) x Subjecthassystemicconnectivetissuedisease(e.g.scleroderma,systemiclupus erythematosus(SLE),Marfanssyndrome,EhlersDanlos,collagenosis,polymyositis, polymyalgiarheumatica) x Subjecthasaknownneurologicormedicalconditionaffectingbladderfunction(e.g. multiplesclerosis,spinalcordinjury,orstrokewithresidualneurologicdeficit) x Subjectisseekingobliterativevaginalsurgeryastreatmentforpelvicorganprolapse (colpocleisis) x Subjecthasapreviousprolapserepairwithmeshinthetargetcompartment x SubjectisplanningtoundergoaconcomitantrepairwithuseofmeshinthenonͲ targetcompartment x Subjectisnotabletoconformtothemodifieddorsallithotomyposition x Subjecthaschronicsystemicpainthatinvolvesthepelvicareaorchronicfocalpain thatinvolvesthepelvispelvicpain) x Subjecthasuncontrolleddiabetesmellitus(DM) x Subjectiscurrentlyparticipatinginorplanstoparticipateinanotherdeviceordrug duringthisstudy x Subjecthasaknownhypersensitivitytopolypropylenemesh

Xenform

Subjectswhometallofthefollowingcriteriaweregivenconsiderationforinclusioninthe Xenformstudy(providednoexclusioncriterionweremet):

x Subjectisfemale x Subjectisш18yearsofage x Subjecthaspelvicorganprolapsewiththeleadingedgeatorbeyondthehymen.At orbeyondthehymenisdefinedasPOPͲQscoresofBaш0(forprolapseofthe anteriorcompartmentalone)orCш0(forprolapseoftheApicalcompartment alone)orCшͲ1/2TVLandBaш0(formultiͲcompartmentprolapsethatincludesthe anteriorandapicalcompartments) x SubjectreportsofabothersomebulgetheycanseeorfeelperPFDIͲ20,question3 responseof2orhigher(i.e.responsesof“somewhat”,“moderately”,or“quiteabit) x Subjectorsubject’slegallyauthorizedrepresentativemustbewillingtoprovide writteninformedconsent x SubjectiswillingandabletocomplywiththefollowͲupregimen SubjectswhometanyofthefollowingcriteriawereexcludedfromtheXenformstudy:

x Subjectispregnantorintendstobecomepregnantduringthestudy x Subjecthasanactiveorchronicsystemicinfectionincludinganygynecologic infection,untreatedurinarytractinfection(UTI)ortissuenecrosis

41 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  x Subjecthasahistoryofpelvicorgancancer(e.g.uterine,ovarian,bladder,coloͲ rectalorcervical) x Subjecthashadpriororiscurrentlyundergoingradiation,lasertherapy,or chemotherapyinthepelvicarea x Subjecthastakensystemicsteroids(withinthelastmonth),orimmunosuppressive orimmunomodulatorytreatment(withinthelast3months) x Subjecthasasystemicconnectivetissuedisease(e.g.scleroderma,systemiclupus erythematosus(SLE),MarfanSyndrome,EhlersDanlos,collagenosis,polymyositis, polymyalgiarheumatica) x Subjecthaschronicsystemicpainthatincludesthepelvicareaorchronicfocalpain thatinvolvesthepelvis x Subjecthasuncontrolleddiabetesmellitus(DM) x Subjecthasaknownneurologicormedicalconditionaffectingbladderfunction (e.g.,multiplesclerosis,spinalcordinjuryorstrokewithresidualneurologicdeficit) x Subjectisseekingobliterativevaginalsurgeryastreatmentforpelvicorganprolapse (colpocleisis) x Subjectisnotabletoconformtothemodifieddorsallithotomyposition x Subjectiscurrentlyparticipatinginorplanstoparticipateinanotherdeviceordrug studyduringthisstudy x SubjecthasaknownsensitivitytoanyXenformcomponent x Subjecthashadpreviousprolapserepairwithmeshinthetargetcompartment x Subjectisplanningtoundergoaconcomitantprolapserepairwithuseofmeshin thenonͲtargetcompartment Additionally,theFDArecommendedthatconsiderationbegiventoriskfactorssuchas primaryversusrecurrentprolapse,menopausalstatus,estrogenuse,age,lifestylefactors, obesity,modificationofmeshpriortoplacement,surgicaltechnique,etc.Whilethese factorsdidnotformthebasisofanyenrollmentcriteria,thestudyprotocolsspecifiedthat demographicinformationbecollectedforeachsubjecttounderstandwhetherornotthese factorswerebalancedbetweenthetreatmentandcontrolarms.

IntheUpholdLITEandXenformPostmarketSurveillanceStudies,aportionoftheNTR controlarmsubjectswereenrolledatthestudysitesandtheremainderofcontrolsubjects weresharedfromtheAUGSPFDRegistry.Thiswastheresultofacollectiveandjoint agreementwiththeFDAthattheAUGSPFDRegistrydatabasewouldbeutilizedforthe studyandpooledsubjectswouldbeusedfortheNTRarmforallindustrypartners.Subjects selectedfromtheAUGSPFDRegistryfortheNTRarmwererequiredtoconformwiththe inclusion/exclusioncriteriafortheUpholdLITEandXenformstudiesinordertobeincluded inthedataanalysis. 

42 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  a. AnalysisPopulations

Subjectswerescreenedagainstthestudyinclusion/exclusioncriteriaand,ifeligible, wereaskedtoprovidewrittenInformedConsent.InformedConsentwasadministered priortoanystudyprocedure;therefore,subjectswereconsideredenrolledintothe studyonceanincisionwasmadeinthevaginalwall.Allenrolledsubjectsare consideredpartoftheIntentͲtoͲTreat(ITT)populationforanalysis.Alleligiblesubjects enrolledwhounderwenttheassignedstudyprocedureandhadnoinclusion/exclusion criteriaviolationsareconsideredpartofthePerProtocolpopulation.TheAsTreated populationweredefinedaccordingtostudyproceduresthattheyactuallyreceived.

b. SampleSizes

FortheUpholdLITEPostmarketSurveillanceStudy,asuperiorityhypothesistestis specifiedfortheprimaryefficacyendpointat36months.ThecoͲprimarysafety endpointwillbeassessedasanonͲinferiorityobjective.Asamplesizeof414subjects wasplannedtopowertheprimaryefficacyandprimarysafetyobjectivesatapower levelof80%orabove.

FortheXenformPostmarketSurveillanceStudy,anonͲinferiorityhypothesistestis specifiedfortheprimaryefficacyendpointat36months.ThecoͲprimarysafety endpointwillbeassessedasanonͲinferiorityobjective.Asamplesizeof454subjects wasplannedtopowertheprimaryefficacyandprimarysafetyobjectivesatapower levelof80%orabove.

4. FollowͲupSchedules

Forbothstudies,eachsubjectwasinstructedtoreturnforfollowͲupvisitsat2and6months (±4weeks)andat12,18,24and36months(Ͳ4/+12weeks).ThefollowͲupvisitschedule beganfromthedaythesubjectwasdischargedpostͲprocedure.Allsubjectswhocompleted surgeryanddischargearebeingfollowedoutto36months.Allsubjectscompletingthe36Ͳ monthfollowͲupvisitwillbeconsideredtohavecompletedthestudies.Assessments completedatdesignatedfollowͲupvisitsinclude:

x Pelvicexamwithvaginallengthmeasurement x ProlapseGrading(POPͲQScoring) x Assessmentofpain(TOMUSpainscale)andanalgesicintake x Assessmentofpelvicfloorsymptoms(PFDIͲ20) x Assessmentofadverseevents(device,procedure,orpelvicfloorrelated) x Assessmentofriskfactors x PelvicFloorImpactQuestionnaire(PFIQͲ7)(Month6,12,18,24and36only) x PelvicOrganProlapse/UrinaryIncontinenceSexualQuestionnaire(PISQͲ12)(Month 6,12,18,24and36only) x PatientGlobalImpressionofImprovement(PGIͲI)forProlapse(Month6,12,18,24 and36only)

43 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  x SurgicalSatisfactionQuestionnaire(SSQͲ8)forsurgicalsatisfaction(Month6,12,24, and36only) x EQͲ5Dforhealthstatus(Month12,24,and36only)  5. StudyStatus

TwentyͲsevenclinicalsitesactivelyparticipatedinenrollingsubjectsintotheUpholdLITE PostmarketSurveillanceStudyandenrollmentwascompletedonDecember31,2016.A totalof289subjectswereenrolled,with225subjectsintheUpholdLITEtreatmentgroup and64subjectsintheNTRcontrolgroup.Inaddition,418subjectsfromtheAUGSPFD RegistryareincludedintheNTRpopulation,yieldingatotalof482NTRsubjectsand707 subjectsoverall.Thestudyiscurrentlyongoingandall12ͲmonthfollowͲupvisitshavebeen completed,withanestimateddateforcompletionofall36ͲmonthfollowͲupvisitsin December2019.

TwentyͲfiveclinicalsitesactivelyparticipatedinenrollingsubjectsintotheXenform PostmarketSurveillanceStudyandenrollmentwascompletedonDecember31,2016.A totalof374subjectswereenrolled,with228subjectsintheXenformtreatmentgroupand 146subjectsintheNTRcontrolgroup.Inaddition,336subjectsfromtheAUGSPFDRegistry areincludedintheNTRpopulation,yieldingatotalof482NTRsubjectsand710subjects overall.Thestudyiscurrentlyongoingandall12ͲmonthfollowͲupvisitshavebeen completed,withanestimateddateforcompletionofall36ͲmonthfollowͲupvisitsin December2019.

6. InterimDataAnalysis

AlthoughtheUpholdLITEandXenformstudydesignsspecificthatassessmentofthe primaryendpointswouldoccurat36months,pertherequestoftheFDABSCconducted interimdataanalysesat12monthsforbothstudies.TheFDAagreedwithnonͲinferiority hypothesistestsspecifiedforboththeprimaryefficacyandsafetyobjectivesat12months beforeBSCstartedtheinterimdataanalysesfortheUpholdandXenformstudies.

TheseanalysesconsistedofstatisticalhypothesistestingusingamutuallyͲagreedupon propensityscoremethodology,whichwasdescribedinthelatestrevisionsoftheFDAͲ approvedstudyprotocols.TheUpholdLITE12Ͳmonthhypothesistestingresultswere submittedwithinPMAAmendmentP180018/A001onJune29,2018,andtheXenform12Ͳ monthhypothesistestingresultsweresubmittedwithinPMAAmendmentP180021/A001 onJuly2,2018.Theresultsdemonstratethat,at12months,bothUpholdLITEandXenform areatleastaseffectiveandassafeasNTRforthetreatmentofanteriorand/orapicalPOP andarefurtherdiscussedbelow.

7. SummaryofUpholdLITE12ͲMonthHypothesisTestingResults(fromP180018/A001)

a. SubjectInformation

AsofMarch10,2018,all707subjectsinthePMAcohort(225subjectsintheUphold LITEtreatmentarmand482subjectsintheNTRcontrolarm)hadreachedthe12Ͳmonth

44 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  followupvisit,and179subjects(42UpholdLITEand137NTR)hadreachedthe36Ͳ monthfollowͲuptimepoint(i.e.,studycompletion)(seeTable3).Pleasenotethatthe PMAsubmissionisstillunderFDAreview;therefore,thedatasummarypresentedin thissummarysectionisbasedontheoriginalandamendedPMAsubmission.Error! Referencesourcenotfound.

Duetotheobservationalstudydesign,apropensityscoremethodologywascarriedout toaccountforpotentialdifferencesinbaselinecharacteristicsbetweentreatmentand controlarms.Thepropensityscoreanalysiswasperformedafterenrollmentclosureby independentstatisticianswhowereblindedtoallclinicaloutcomedata.Thisanalysis includedallITTsubjectsenrolledintotheUpholdLITEandNTRarmsofthestudy,as wellasNTRsubjectssharedfromtheAUGSPFDRegistry.

Factorsthatmayaffectthestudyoutcomeswereidentifiedbasedonrecommendations oftheFDA.Thesefactorsincluded:levelofprolapserelativetothehymen(i.e.,POPͲQ C,POPͲQBa,andPOPͲQBpmeasurements),primaryorrecurrentprolapse,menopausal status,estrogenuse,age,smoking,diabetes,bodymassindex(BMI),prior hysterectomy,concomitantprocedureforSUI,andsurgeonexperiencewithprolapse repair.Inaddition,racewasincludedinordertoaccountforpossibleracialdifferences.

ThebaselinecharacteristicsandbalanceassessmentareshowninTable1.ThepͲvalues beforeandafterthepropensityscoreadjustmentarepresentedinordertofacilitatethe assessmentofbalancebetweentheUpholdLITEtreatmentarmandtheNTRcontrol arminthisstudy.

Table1:UpholdLITEBaselineCharacteristicsandBalanceAssessment

 Treatmenta pͲvalue Before After Variable UpholdLITE NTR Stratificationb Stratificationc 66.6±10.8(225) 62.5±10.6(482) Age,yrs <0.001 0.79 (32.5,67.6,88.2) (27.1,64.1,91.0) Racewhite 93.3%(210/225) 85.0%(407/479) 0.002 0.84 28.4±6.1(225) 28.1±5.4(482) BodyMassIndex 0.44 0.97 (15.1,27.5,57.8) (17.2,27.1,56.5) Smoking,current 8.0%(18/224) 7.9%(38/482) 0.94 0.68 Diabetes 14.2%(32/225) 13.1%(63/482) 0.68 0.91 PostͲmenopausal 92.9%(209/225) 83.4%(402/482) <0.001 0.76 Prolapserepair,prior 17.3%(39/225) 10.4%(50/482) 0.009 0.82 Hysterectomy,prior28 64.9%(146/225) 30.1%(145/482) <0.001 0.65 Estrogenuseatbaseline 35.6%(80/225) 32.4%(156/481) 0.41 1.00 Ͳ1.4±3.7(225) Ͳ0.8±3.8(482) POPͲQApical:C 0.07 0.94 (Ͳ8.0,Ͳ3.0,10.0) (Ͳ9.0,Ͳ1.0,12.0)  28Hysterectomyrequirementwasincludedininitialversionsoftheprotocolandremovedinasubsequentversion(releasedon 24OCT2014).83Upholdand60NTRsubjectsindicatedtheyhadaprevioushysterectomy.



45 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting   Treatmenta pͲvalue Before After Variable UpholdLITE NTR Stratificationb Stratificationc 2.5±1.4(225) 1.9±2.0(482) POPͲQAnterior:Ba <0.001 0.60 (Ͳ1.5,2.0,7.5) (Ͳ3.0,1.5,12.0) Ͳ0.7±1.6(225) Ͳ0.4±2.1(482 POPͲQPosterior:Bp 0.047 0.88 (Ͳ3.0,Ͳ1.0,5.0) (Ͳ3.0,Ͳ1.0,12.0) ConcomitantSUIrepair 56.4%(127/225) 48.1%(232/482) 0.039 0.97 Surgeonvolume>median 48.4%(109/225) 50.8%(245/482) 0.55 0.90 aNumberspresentedare%(#/n)ormean±SD,samplesize(N),(minimum,median,maximum) bChiͲsquaredtest(categoricalvariables)oroneͲwayAnovaFͲtest(continuousvariables) cMantelͲHaenszeltest(categoricalvariables)ortwoͲwayAnovaFͲtest(continuousvariables)adjustingforstratum

b. PrimaryEfficacyEndpoint

At12months,theuseofUpholdLITEtransvaginalmesh(TVM)forthetreatmentof anteriorand/orapicalvaginalprolapsewasfoundtobeatleastaseffectiveasNTRfor thecompositeprimaryefficacyendpoint,asshowninTable2,withtheobjective successcomponentdefinedastheleadingedge(s)ofthetreatedsegment(s)atorabove thehymen.ThecompositesuccessintheITTpopulationusingmultipleimputationto handlemissingdatais91.4%(206/225)forUpholdLITEversus87.1%(420/482)forNTR. Thepropensityscoreadjustedtreatmentdifferenceis3.8%(90%CI:Ͳ1.3%,9.0%),thus thenonͲinferiorityofUpholdLITEcomparedtoNTRforthecompositeprimaryefficacy endpointat12monthsisestablished.

Table2:UpholdLITEPrimaryEfficacyEndpoint–CompositeAnatomicandSymptomatic Successat12Months PropensityScoreAdjusted Unadjusted MissingData TreatmentDifference  UpholdLITE NTR Treatment HandlingMethod (TVMͲNTR) %(count/ %(count/ Difference andAnalysis PͲvalueof samplesize) samplesize) (TVMͲNTR) Estimate Population Superiority Estimate(90%CI) (90%CI) Test MultipleImputation 4.3% 3.8% IntentͲtoͲTreat 91.4%(206/225) 87.1%(420/482) 0.112 (0.2%,8.4%) (Ͳ1.3%,9.0%) 4.2% 3.4% PerProtocol 91.3%(199/218) 87.0%(415/477) 0.147 (Ͳ0.0%,8.5%) (Ͳ1.9%,8.8%) AvailableCaseAnalysis 4.3% 3.4% IntentͲtoͲTreat 91.6%(185/202) 87.3%(379/434) 0.146 (0.1%,8.4%) (Ͳ1.9%,8.8%) 4.1% 3.1% PerProtocol 91.3%(179/196) 87.2%(376/431) 0.179 (Ͳ0.1%,8.3%) (Ͳ2.4%,8.6%)  Table3presentsdescriptivestatisticsfortheprimaryefficacycompositeanatomicand symptomatictreatmentsuccessrates,aswellastheresultsoftheindividual

46 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  componentsofthecompositeendpoint,fortheITTpopulationatthe12,24and36Ͳ monthfollowͲupvisits.Thepropensityscoreadjusteddifferencesbetweentreatment andcontrolarmsareonlyprovidedforthe12ͲmonthfollowͲupvisit,asthenumbersof subjectswhocompleted24and36ͲmonthfollowͲupvisitsaretoolowforvalid statisticalanalysis.

Table3:UpholdLITEPrimaryEfficacyEndpointͲCompositeTreatmentSuccessIntentͲtoͲTreat Subjects

GroupDifference(95%CI) UpholdLITE NTR Variable %(count/ %(count/ NoPropensity WithPropensity samplesize) samplesize) Score Score Adjustment Adjustment 4.3% 3.4% 12ͲMonthCompositeSuccess 91.6%(185/202) 87.3%(379/434) (Ͳ0.7%,9.2%) (Ͳ3.0%,9.8%) 4.0% 4.0% ObjectiveSuccess 98.0%(198/202) 94.0%(409/435) (1.1%,6.9%) (1.1%,6.9%) 5.0% 4.6% AnteriorCompartment 98.5%(199/202) 93.5%(362/387) (2.0%,7.9%) (1.6%,7.6%) Ͳ0.0% 0.5% ApicalCompartment 98.0%(198/202) 98.0%(400/408) (Ͳ2.4%,2.3%) (Ͳ1.9%,3.0%) 1.4% 1.2% SubjectiveSuccess 93.6%(190/203) 92.2%(402/436) (Ͳ2.8%,5.6%) (Ͳ4.5%,6.9%) 1.6% 1.6% NoRetreatmentforPOP 99.6%(224/225) 97.9%(472/482) (0.1%,3.2%) (Ͳ0.5%,3.8%) 8.0% 24ͲMonthCompositeSuccess 91.7%(88/96) 83.7%(221/264) ͲͲ (0.9%,15.1%) 3.4% ObjectiveSuccess 96.9%(93/96) 93.5%(244/261) ͲͲ (Ͳ1.2%,8.0%) 6.3% AnteriorCompartment 99.0%(95/96) 92.7%(216/233) ͲͲ (2.3%,10.2%) Ͳ1.9% ApicalCompartment 96.9%(93/96) 98.8%(239/242) ͲͲ (Ͳ5.6%,1.9%) Ͳ0.1% SubjectiveSuccess 93.8%(90/96) 93.9%(246/262) ͲͲ (Ͳ5.8%,5.5%) 2.9% NoRetreatmentforPOP 99.6%(224/225) 96.7%(466/482) ͲͲ (1.1%,4.7%) 9.5% 36ͲMonthCompositeSuccess 83.3%(35/42) 73.8%(107/145) ͲͲ (Ͳ3.8%,22.9%) 7.1% ObjectiveSuccess 95.2%(40/42) 88.1%(119/135) ͲͲ (Ͳ1.3%,15.5%) 10.5% AnteriorCompartment 97.6%(41/42) 87.1%(108/124) ͲͲ (3.0%,18.0%) Ͳ2.3% ApicalCompartment 95.2%(40/42) 97.6%(121/124) ͲͲ (Ͳ9.3%,4.6%) Ͳ5.1% SubjectiveSuccess 87.5%(35/40) 92.6%(126/136) ͲͲ (Ͳ16.3%,6.0%) 2.8% NoRetreatmentforPOP 99.1%(223/225) 96.3%(464/482) ͲͲ (0.8%,4.9%) 

47 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  TheuseofbothUpholdLITEandNTRforthetreatmentofanteriorand/orapical prolapseproducedsimilarresultswithinthesubjectivesuccessandfreeofretreatment forPOPcomponentsoftheprimaryefficacyendpointatthe12ͲmonthfollowͲupperiod. TheproportionofsubjectswithobjectivesuccessishigherintheUpholdLITEarm, drivenbythetreatmentsuccessintheanteriorcompartment.Bothgroupsachieveda highrateofinitialobjectiveandsubjectivesuccessevidencedbythelowrateofreͲ treatmentat12months.

ThecompositetreatmentsuccessratesintheUpholdLITEarmwerenumericallyhigher thanNTRat24and36months,albeitbasedonincompletedata.Lookingattheanterior compartmentspecifically,comparedtotheNTRarm,ahigheranatomicalsuccessratein theUpholdLITEarmisshowninthe12Ͳmonthdata,continuingthrough36months.The preliminary36Ͳmonthdataindicatesomewhatlowersubjectivesuccessforpatientsin theUpholdLITEarm(assessedbyselfͲreportingoffeelingofbulgeorwhetherabulgeis bothersome);however,therewerehigherratesofreͲtreatmentforPOPforNTR subjects.Eachoftheseobservationsmustbecarefullyconsideredwhenoneconsiders theverylimitednumberofsubjectsthatcurrentlyhavecompletedfollowͲupoutto theseextendedtimepoints.

c. SecondaryEfficacyEndpoint

Theresultsusingthesecondarycompositeefficacyendpointsuccessrate,withthe objectivesuccesscomponentdefinedastheleadingedge(s)ofthetreatedsegment(s) abovethehymen,revealedthattheUpholdLITEtreatmentarmfaredbetterthanthe NTRcontrolarm(p=0.005,notadjustedformultiplicity),asshowninTable4.At12 months,85.8%(193/225)ofsubjectsintheUpholdLITEtreatmentarmand78.4% (378/482)ofsubjectsintheNTRcontrolarmreportedtreatmentsuccesswiththe multipleimputationmethodformissingdatahandling.Thepropensityscoreadjusted treatmentdifferenceis9.5%(90%CI;3.5%,15.5%).

Table4:UpholdLITESecondaryEfficacyEndpointͲCompositeAnatomicand SubjectiveSuccessat12Months PropensityScoreAdjusted Unadjusted MissingData TreatmentDifference UpholdLITE NTR Treatment HandlingMethod (TVMͲNTR) %(count/ %(count/ Difference andAnalysis samplesize) samplesize) (TVMͲNTR) Estimate Population PͲvaluea Estimate(90%CI) (90%CI) MultipleImputation 7.6% 9.5% IntentͲtoͲTreat 85.8(193/225) 78.4(378/482) 0.005 (2.6%,12.6%) (3.5%,15.5%) 7.2% 8.9% PerProtocol 85.3(186/218) 78.2(373/477) 0.008 (2.2%,12.3%) (2.8%,15.0%) AvailableCaseAnalysis 8.0% 10.0% IntentͲtoͲTreat 86.1%(174/202) 78.1%(339/434) 0.004 (2.9%,13.2%) (3.9%,16.1%)

48 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  PropensityScoreAdjusted Unadjusted MissingData TreatmentDifference UpholdLITE NTR Treatment HandlingMethod (TVMͲNTR) %(count/ %(count/ Difference andAnalysis samplesize) samplesize) (TVMͲNTR) Estimate Population PͲvaluea Estimate(90%CI) (90%CI) 7.8% 9.6% PerProtocol 85.7%(168/196) 78.0%(336/431) 0.006 (2.5%,13.0%) (3.3%,15.8%)

aPͲvaluesnotadjustedformultiplecomparisons.

Table5presentsdescriptivestatisticsforthesecondaryefficacycompositeanatomic andsymptomatictreatmentsuccessrates,aswellastheresultsoftheindividual componentsofthecompositeendpoint,fortheITTpopulationatthe12,24and36Ͳ monthfollowͲupvisits.Thepropensityscoreadjusteddifferencesbetweentreatment andcontrolarmsareonlyprovidedforthe12ͲmonthfollowͲupvisit,asthenumbersof subjectswhocompleted24and36ͲmonthfollowͲupvisitsaretoolowforvalid statisticalanalysis.

Table5:UpholdLITESecondaryEfficacyEndpointͲCompositeSurgicalSuccessIntentͲtoͲTreat Subjects

GroupDifference(95%CI) UpholdLITE NTR Variable %(count/ %(count/ NoPropensity WithPropensity samplesize) samplesize) Score Score Adjustment Adjustment 8.0% 10.0% 12ͲMonthCompositeSuccess 86.1%(174/202) 78.1%(339/434) (1.9%,14.2%) (2.7%,17.2%) 7.4% 10.1% ObjectiveSuccess 91.6%(185/202) 84.1%(366/435) (2.3%,12.6%) (4.9%,15.2%) 9.9% 11.6% AnteriorCompartment 92.6%(187/202) 82.7%(320/387) (4.7%,15.1%) (6.2%,17.1%) Ͳ1.3% Ͳ0.1% ApicalCompartment 96.5%(195/202) 97.8%(399/408) (Ͳ4.2%,1.6%) (Ͳ2.8%,2.5%) 1.4% 1.2% SubjectiveSuccess 93.6%(190/203) 92.2%(402/436) (Ͳ2.8%,5.6%) (Ͳ4.5%,6.9%) 1.6% 1.6% NoRetreatmentforPOP 99.6%(224/225) 97.9%(472/482) (0.1%,3.2%) (Ͳ0.5%,3.8%) 10.4% ͲͲ 24ͲMonthCompositeSuccess 85.4%(82/96) 75.0%(198/264) (1.6%,19.2%) 6.1% ͲͲ ObjectiveSuccess 89.6%(86/96) 83.5%(218/261) (Ͳ1.5%,13.6%) 9.7% ͲͲ AnteriorCompartment 91.7%(88/96) 82.0%(191/233) (2.3%,17.1%) Ͳ3.6% ͲͲ ApicalCompartment 94.8%(91/96) 98.3%(238/242) (Ͳ8.3%,1.2%) Ͳ0.1% ͲͲ SubjectiveSuccess 93.8%(90/96) 93.9%(246/262) (Ͳ5.8%,5.5%)

49 BostonScientific ObstetricsandGynecology February12,2019 DevicesPanelMeeting  GroupDifference(95%CI) UpholdLITE NTR Variable %(count/ %(count/ NoPropensity WithPropensity samplesize) samplesize) Score Score Adjustment Adjustment 2.9% ͲͲ NoRetreatmentforPOP 99.6%(224/225) 96.7%(466/482) (1.1%,4.7%) 13.4% ͲͲ 36ͲMonthCompositeSuccess 81.0%(34/42) 67.6%(98/145) (Ͳ0.7%,27.5%) 9.0% ͲͲ ObjectiveSuccess 90.5%(38/42) 81.5%(110/135) (Ͳ2.0%,20.0%) 13.0% ͲͲ AnteriorCompartment 92.9%(39/42) 79.8%(99/124) (2.5%,23.5%) Ͳ2.3% ͲͲ ApicalCompartment 95.2%(40/42) 97.6%(121/124) (Ͳ9.3%,4.6%) Ͳ5.1% ͲͲ SubjectiveSuccess 87.5%(35/40) 92.6%(126/136) (Ͳ16.3%,6.0%) 2.8% ͲͲ NoRetreatmentforPOP 99.1%(223/225) 96.3%(464/482) (0.8%,4.9%)

ThecompositetreatmentsuccessratestrendinfavorofUpholdLITEwithnumerically highervaluesthanNTRat24and36months;however,theseobservationsarelimitedat thesetimepointsduetothelimitednumberofsubjectsthathavecompletedfollowͲup outtotheseextendedtimepoints.

d. QualityofLifeResults

ThereweremeasurableimprovementsinpatientreportedoutcomesinbothUphold LITEandNTRsubjectsfollowingsurgery.BothUpholdLITEandNTRsubjectsshowed significantimprovementperthePFIQͲ7andPFDIͲ20scoresat12monthsoverbaseline, andstabilityinthesescoresoutto36monthswasdemonstratedinthosesubjectswho havereachedthatfollowͲup.Therewasmodestimprovementinsexualfunctioninboth groupsbythe12ͲmonthfollowͲupperPISQͲ12responses,andthatimprovementtends tobemaintainedat36monthspostindexprocedure.Mostsubjectsinbothgroups reportedtheyfelt“muchbetter”or“verymuchbetter”aftersurgeryperresponsesto thePGIͲIquestionnaire.BasedonTOMUSPainScaleresponses,veryfewsubjectsin eithergroupreportedpainoranalgesicuseatbaseline,andinthosepatientsforwhom longerͲtermdataisavailable,overallpainlevelsremainedthesameordecreasedoutto 36monthsoffollowͲup.TheresultsofthePFDIͲ20arerepresentativeoftheoverallQOL assessmentsandarepresentedinTable6.TheTOMUSPainScaleresultsarepresented inTable7.

50  

Table6:UpholdLITEPFDIͲ20ChangefromBaseline,IntentͲtoͲTreatSubjects

GroupDifference ofChangefrom UpholdLITE NTR Baselinewith Visit PropensityScore Adjustment Changefrom MeanChange Changefrom MeanChange Estimate Score a Score a Baseline a 95%CI Baseline a 95%CI (95%CI) 115.1±57.0(225) 109.7±56.1(482) Baseline ͲͲ ͲͲ ͲͲ ͲͲ  (8.3,108.3,268.8) (4.2,104.7,280.2) 35.7±37.8(214) Ͳ78.6±57.2(214) 31.3±36.9(440) Ͳ77.6±53.3(440) 0.6 6Months Ͳ86.3toͲ70.9 Ͳ82.6toͲ72.6 (0.0,25.0,221.9) (Ͳ268.8,Ͳ75.0,80.2) (0.0,18.8,249.0) (Ͳ255.2,Ͳ71.3,119.8) (Ͳ10.2,11.4) 36.8±43.7(203) Ͳ74.6±61.5(203) 32.0±39.0(436) Ͳ76.9±54.1(436) 6.1 12Months Ͳ83.1toͲ66.0 Ͳ82.0toͲ71.8 (0.0,25.0,272.9) (Ͳ268.8,Ͳ72.9,131.2) (0.0,16.7,244.8) (Ͳ256.3,Ͳ73.0,86.5) (Ͳ5.4,17.6) 38.0±47.3(129) Ͳ74.2±61.3(129) 32.3±35.9(329) Ͳ77.7±54.9(329) 18Months Ͳ84.9toͲ63.5 Ͳ83.6toͲ71.7ͲͲ (0.0,20.8,241.7) (Ͳ262.5,Ͳ70.8,112.5) (0.0,21.9,190.6) (Ͳ260.4,Ͳ72.9,65.6) 32.2±38.8(96) Ͳ81.8±54.6(96) 33.0±37.9(263) Ͳ77.6±55.1(263) 24Months Ͳ92.9toͲ70.8 Ͳ84.3toͲ70.9ͲͲ (0.0,15.6,168.8) (Ͳ268.8,Ͳ78.1,30.2) (0.0,22.9,199.0) (Ͳ256.3,Ͳ72.9,75.0) 49.5±53.8(40) Ͳ72.8±52.6(40) 33.6±44.1(136) Ͳ77.9±61.5(136) 36Months Ͳ89.6toͲ55.9 Ͳ88.4toͲ67.5ͲͲ (0.0,29.2,190.6) (Ͳ187.5,Ͳ62.0,8.3) (0.0,16.7,210.4) (Ͳ254.2,Ͳ70.8,110.4) aNumberspresentedaremean±SD(samplesize),(minimum,median,maximum)  

51  

Table7:UpholdLITETOMUSPainScoreChangefromBaseline,IntentͲtoͲTreatSubjects

GroupDifference onChangefrom UpholdLITE NTR Baselinewith Visit PropensityScore Adjustment Changefrom MeanChange Changefrom MeanChange Score a Score a Estimate(95%CI) Baseline a 95%CI Baseline a 95%CI 8.3±9.3(225) 7.7±9.4(482) Baseline ͲͲ ͲͲ ͲͲ ͲͲ  (0.0,5.0,46.0) (0.0,4.0,70.0) 4.3±6.7(214) Ͳ3.8±8.1(214) 4.1±7.0(440) Ͳ3.3±8.3(440) Ͳ0.4 6Months Ͳ4.9toͲ2.7 Ͳ4.0toͲ2.5 (0.0,0.0,44.0) (Ͳ31.0,Ͳ2.0,15.0) (0.0,0.0,51.0) (Ͳ70.0,Ͳ1.0,32.0) (Ͳ1.9,1.1) 4.3±7.0(203) Ͳ3.4±8.3(203) 3.6±6.2(436) Ͳ3.8±8.7(436) 0.6 12Months Ͳ4.5toͲ2.2 Ͳ4.6toͲ3.0 (0.0,0.0,34.0) (Ͳ32.0,Ͳ1.0,19.0) (0.0,0.0,42.0) (Ͳ70.0,Ͳ2.0,26.0) (Ͳ1.1,2.2) 5.6±9.0(129) Ͳ2.5±11.2(129) 3.4±6.1(329) Ͳ4.3±9.1(329) 18Months Ͳ4.5toͲ0.6 Ͳ5.3toͲ3.3 ͲͲ (0.0,1.0,46.0) (Ͳ32.0,Ͳ2.0,38.0) (0.0,0.0,46.0) (Ͳ70.0,Ͳ2.0,20.0) 4.8±7.2(96) Ͳ2.9±9.9(96) 3.4±5.8(263) Ͳ4.4±9.3(263) 24Months Ͳ4.9toͲ0.9 Ͳ5.5toͲ3.3ͲͲ (0.0,0.0,31.0) (Ͳ31.0,Ͳ1.0,28.0) (0.0,0.0,30.0) (Ͳ70.0,Ͳ1.0,16.0) 6.3±10.4(40) Ͳ2.8±11.8(40) 3.9±6.9(136) Ͳ3.6±8.3(136) 36Months Ͳ6.6to1.0 Ͳ5.0toͲ2.2ͲͲ (0.0,0.5,45.0) (Ͳ31.0,Ͳ0.5,30.0) (0.0,0.0,42.0) (Ͳ36.0,0.0,16.0) aNumberspresentedaremean±SD(samplesize),(minimum,median,maximum)

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e. InterventionforRecurrentProlapse

Recurrentprolapsewasreportedas‘Prolapse’or‘SensationofBulge’(reportedby eitherthepatientduetosensationorbythephysicianduringpelvicexamination),and wasrecordedasanadverseevent.At12months,4%(9/225)ofsubjectsintheUphold LITEarmexperienced‘Prolapse’and4%(9/225)experienced‘SensationofBulge’,while 9.3%(45/482)ofsubjectsexperienced‘Prolapse’and5.4%(26/482)experienced ‘SensationofBulge’intheNTRarm.Table8showstheresultsforbothofficeͲbasedand surgicalͲbasedinterventionsforrecurrentprolapsefollowingtheindexprocedureinthe ITTpopulationwithin12and36months.Theproportionofsubjectswhoreceived interventionforrecurrentprolapseweresimilarbetweentheUpholdLITEandNTR arms.

Table8:UpholdLITEInterventionforRecurrentProlapsePostIndexProcedure AdjustedTreatment UpholdLITE NTR Difference Intervention %(count/samplesize) %(count/samplesize) (TVMͲNTR) Estimate(95%CI) OfficeͲBasedInterventionforRecurrence Within12months 0.4%(1/225) 0.2%(1/482) 0.0%(Ͳ0.6%,0.6%) Within36months 0.4%(1/225) 0.4%(2/482)Ͳ0.2%(Ͳ0.9%,0.5%) SurgicalͲBasedInterventionforRecurrence Within12months 0.4%(1/225) 1.5%(7/482)Ͳ0.8%(Ͳ2.8%,1.1%) Within36months 0.9%(2/225) 2.7%(13/482)Ͳ1.9%(Ͳ4.3%,0.5%)  f. PrimarySafetyEndpoint

Table9showstheanalysisofdeviceͲrelatedorprocedureͲrelatedseriousadverseevents (SAEs).At12months,2.7%(6/225)ofsubjectsintheUpholdLITEtreatmentarmand 2.7%(13/482)ofsubjectsintheNTRcontrolarmreportedSAEs.Thepropensityscore adjustedtreatmentdifferenceisͲ0.4%(90%CI;Ͳ2.6%,1.8%),thusthenonͲinferiorityof UpholdLITEcomparedtoNTRfortheprimarysafetyendpointisestablished.

Table9:UpholdLITEPrimarySafetyEndpoint–SeriousDeviceͲand/orProcedureͲRelated AdverseEvents

PropensityScore UnadjustedTreatment UpholdLITE NTR AdjustedTreatment Analysis Difference %(count/ %(count/ Difference Populationa (TVM–NTR)  samplesize) samplesize) (TVMͲNTR) Estimate(90%CI) Estimate(90%CI) Ͳ0.0% Ͳ0.4% IntentͲtoͲTreat 2.7%(6/225) 2.7%(13/482) (Ͳ2.2%,2.1%) (Ͳ2.6%,1.8%) Ͳ0.4% Ͳ1.2% PerProtocol 2.3%(5/218) 2.7%(13/477) (Ͳ2.5%,1.6%) (Ͳ3.1%,0.6%) Ͳ0.0% Ͳ0.4% AsTreated 2.7%(6/225) 2.7%(13/482) (Ͳ2.2%,2.1%) (Ͳ2.6%,1.8%)

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aOnlyeventsthathappenedwithin12monthsoftheindexprocedureandrelatedtothetargetcompartmentare includedintheanalysis.

KaplanͲMeiercurvesforSAEͲfreesurvivalexhibitconsiderableoverlap,suggestingthat thereisnoclinicallymeaningfuldifferenceinseriouscomplicationratesbetweenthe twoarmsat12months(seeFigure9Error!Referencesourcenotfound.).

Figure9:KaplanͲMeierCurveofSAEFreeComparingUpholdLITEvs.NTR,IntentͲtoͲTreat Subjectsat12Months

 LookingatthetotalityofdataaccountingforpatientsreachinglaterstudyfollowͲup timepoints,asofMarch10,2018,therehavebeenatotalof24seriousdeviceͲand/or seriousprocedureͲrelatedadverseeventsthatimpacted20subjects,withsevenevents insixUpholdLITEsubjectsand17eventsin14NTRsubjects.FortheUpholdLITE subjects,alleventsoccurredwithinthefirstsixmonthsfollowingtheprocedure,and accordinglytherewerenolateͲtermevents.Allseveneventshavebeenfullyresolved. FortheNTRsubjects,14ofthe17eventsoccurredwithin180dayspostͲprocedure, whereasthreeevents(oneinfection,oneUTI,andoneconstipationworsening)were lateͲtermcomplications.Fifteenofthe17eventshavebeenfullyresolvedwhiletwo (onepelvicinfection/abscessandoneconstipationworsening)remainedongoingasof March10,2018.Table10Error!NotavalidbookmarkselfͲreference.providesa summaryoftheseriousdeviceͲand/orprocedureͲrelatedadverseeventsandtheir associatedinterventionsintheUpholdLITEtreatmentarmandtheNTRcontrolarm.

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Table10:SafetySummaryofSeriousDeviceͲand/orProcedureͲRelatedAdverseEvents,IntentͲtoͲTreatSubjects

 UpholdLITE(N=225) Intervention NTRArm(N=482) Intervention Proportionof Proportionof NonͲ HospitalͲ NonͲ HospitalͲ Description Events Subjectswith Surgicalb Events Subjectswith Surgicalb Surgical ization Surgical ization ш1Eventa ш1Eventa InfectionͲOther,specifytype 2 0.4%(1/225) 2 0 2 3 0.6%(3/482) 3 0 3 UreteralKink/Injury 1 0.4%(1/225) 0 1 0 2 0.4%(2/482) 1 2 1 MeshExposureinVagina 1 0.4%(1/225) 0 1 0 N/AͲͲͲͲ Bleeding 1 0.4%(1/225) 1 0 1 0ͲͲͲͲ BleedingRequiringBlood 1 0.4%(1/225) 1 0 0 0ͲͲͲͲ Transfusion Fever 1 0.4%(1/225) 1 0 1 0ͲͲͲͲ Ileus/BowelObstruction 0 ͲͲͲͲ2 0.4%(2/482) 1 2 2 PelvicInfection/Abscess 0 ͲͲͲͲ2 0.4%(2/482) 1 0 2 UrinaryTractInfection(UTI),Lower 0 ͲͲͲͲ2 0.4%(2/482) 2 0 2 CardiacEventͲNEW 0 ͲͲͲͲ1 0.2%(1/482) 1 0 1 ConstipationͲWorsening 0 ͲͲͲͲ1 0.2%(1/482) 1 0 0 HematomaͲRetropubic 0 ͲͲͲͲ1 0.2%(1/482) 1 0 1 Diarrhea 0 ͲͲͲͲ1 0.2%(1/482) 0 0 1 PulmonaryEvent,SpecifyͲ 0Ͳ Ͳ Ͳ Ͳ 1 0.2%(1/482) 1 0 0 Worsening ThromboticEvent 0 ͲͲͲͲ1 0.2%(1/482) 1 0 1 Total 7 2.7%(6/225) 5 2 4 17 2.9%(14/482) 13 4 14 aNumbersarepercentage(count/samplesize) bInpatientoroutpatientsurgicalintervention







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g. SecondarySafetyEndpoint

ThesecondarysafetyendpointincludedanalysisofoveralldeviceͲrelatedand procedureͲrelatedAEs.Additionally,inordertobetterunderstandthepotentialfor pelvicͲspecificAEsthatwerediscussedduringthe2011panelmeeting,BSCevaluateda groupofspecificAEsthatincludedpelvicpain,infection,vaginalshortening,atypical vaginaldischarge,neuromuscularproblems,vaginalscarring,denovovaginalbleeding, denovovoidingdysfunction,denovodyspareunia,andfistulaformation.Mesherosion andmeshexposureswerealsoseparatelyevaluated.

Table11summarizestheoveralldeviceͲand/orprocedureͲrelatedAEsintheITT populationat6,12,18,24and36months.OverallAEsareverysimilarbetweenthe UpholdLITEandNTRarmswithin12months,witharateof28.9%(65/225)forUphold LITEsubjectsand34.9%(168/482)forNTRsubjects(Ͳ7.2%differencewithpropensity scoreadjustment;95%CI:Ͳ15.8,1.4%).Bythe36Ͳmonthtimepoint,thedifferencein overallAEsbetweenthetwogroups(32.0%forUpholdLITEsubjectsvs.40.0%forNTR subjects)hadincreasedtoͲ10.7%(withpropensityscoreadjustment;95%CI:Ͳ19.5%,Ͳ 2.0%).

Table11:UpholdLITESecondarySafetyEndpoint–OverallDeviceͲand/orProcedureͲRelated AdverseEvents,IntentͲtoͲTreatSubjects

UpholdLITE NTR GroupDifference(95%CI)  %(count/ %(count/ NoPropensity WithPropensity samplesize) samplesize) ScoreAdjustment ScoreAdjustment OverallAdverseEventsa Occurredwithin6 Ͳ4.2% Ͳ6.5% 24.9%(56/225) 29.0%(140/482) months (Ͳ11.1%,2.8%) (Ͳ14.6%,1.6%) Occurredwithin12 Ͳ6.0% Ͳ7.2% 28.9%(65/225) 34.9%(168/482) months (Ͳ13.3%,1.3%) (Ͳ15.8%,1.4%) Occurredwithin18 Ͳ7.3% Ͳ8.9% 30.2%(68/225) 37.6%(181/482) months (Ͳ14.7%,0.1%) (Ͳ17.6%,Ͳ0.2%) Occurredwithin24 Ͳ7.5% Ͳ9.4% 31.1%(70/225) 38.6%(186/482) months (Ͳ14.9%,Ͳ0.0%) (Ͳ18.1%,Ͳ0.7%) Occurredwithin36 Ͳ8.0% Ͳ10.7% 32.0%(72/225) 40.0%(193/482) months (Ͳ15.5%,Ͳ0.5%) (Ͳ19.5%,Ͳ2.0%) aOnlydeviceͲand/orprocedureͲrelatedadverseeventsrelatedtothetargetcompartmentareincludedintheanalysis. Table12Error!Referencesourcenotfound.presentsanalysisofdeviceand/or procedureͲrelatedAEsreportedasofMarch10,2018fortheITTpopulation.

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Table12:SummaryofDeviceͲand/orProcedureͲRelatedAdverseEvents,IntentͲtoͲTreatSubjects

UpholdLITE NTR (N=225) (N=482)  Proportionof KM Proportionof KM Events Subjectswith Estimateat Events Subjectswith Estimateat ш1Eventa 3Yearsb ш1Eventa 3Yearsb Atypicalvaginaldischarge 2 0.9%(2/225) 0.9% 3 0.6%(3/482) 0.6% Denovodyspareunia 2 0.9%(2/225) 1.5% 7 1.5%(7/482) 1.5% Denovovaginalbleeding 0 0.0%(0/225) 0.0% 7 1.5%(7/482) 1.5% Denovovoiding dysfunction(includingde 12 4.9%(11/225) 4.9% 24 4.4%(21/482) 4.8% novoincontinence) DifficultyEmptying 5 2.2%(5/225) 2.2% 16 3.3%(16/482) 3.4% BladderͲNEW StressIncontinence– 4 1.8%(4/225) 1.8% 4 0.8%(4/482) 1.1% NEW UrgeIncontinence– 3 1.3%(3/225) 1.3% 4 0.8%(4/482) 1.1% NEW Fistulaformation 0 0.0%(0/225) 0.0% 0 0.0%(0/482) 0.0% Infection 31 9.8%(22/225) 10.4% 98 13.5%(65/482) 14.9% Infection/ 0 0.0%(0/225) 0.0% 0 0.0%(0/482) 0.0% InflammationofBone InfectionͲOther, 5 0.9%(2/225) 0.9% 6 1.0%(5/482) 1.1% specifytype PelvicInfection/ 1 0.4%(1/225) 0.4% 4 0.8%(4/482) 0.9% Abscess SinusTract 0 0.0%(0/225) 0.0% 0 0.0%(0/482) 0.0% UrinaryTractInfection 23 8.0%(18/225) 8.6% 84 11.8%(57/482) 13.2% (UTI),Lower VaginalInfection 2 0.9%(2/225) 0.9% 4 0.8%(4/482) 1.2% MeshExposureinVagina 10 3.6%(8/225) 6.2% 0 0.0%(0/482) 0.0% MeshErosion 0 0%(0/225) 0% 0 0.0%(0/482) 0.0% Neuromuscularproblems (includinggroinandleg 9 4.0%(9/225) 4.0% 13 2.7%(13/482) 3.4% pain) PelvicPain 12 5.3%(12/225) 5.7% 27 5.6%(27/482) 6.8% PelvicPainͲNEW 12 5.3%(12/225) 5.7% 26 5.4%(26/482) 6.6% PelvicPainͲWorsening 0 0.0%(0/225) 0.0% 1 0.2%(1/482) 0.3% Vaginalscarring 0 0.0%(0/225) 0.0% 1 0.2%(1/482) 0.2% Vaginalshortening 1 0.4%(1/225) 0.5% 0 0.0%(0/482) 0.0% aNumbersarepercentage(count/samplesize) bEstimatedeventrateat3yearsusingKaplanMeier(KM)method

FortheITTpopulationsimilareventrateswereobservedbetweentheUpholdLITEand NTRarmsforpelvicpain,infection,vaginalshortening,atypicalvaginaldischarge,

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neuromuscularproblems,vaginalscarring,denovovaginalbleeding,denovovoiding dysfunction,denovodyspareunia,andfistulaformation.

AsofMarch10,2018,therehavebeennoreportedmesherosionsintheUpholdLITE studypopulation.Eightsubjectshadexperiencedameshexposure,withtwosubjects eachreportingtwomeshexposureevents,yieldingatotalof10events.TheKaplan Meierestimateforthemeshexposurerateis6.2%atthreeyears.Noneofthemesh exposureshavebeensevere29;twoeventswereofmoderateseverityandtheremainder ofmildseverity.Sixmeshexposureshavebeenfullyresolvedwitheithernoaction taken(twoevents),officeonlyprocedures(twoevents),orsurgicalintervention(two events).Oneeventwasrecoveringwithofficeinterventionandmedication.Three eventswerenotyetresolvedatthetimeofdatareview,amongwhichtworeceived outpatientsurgicalinterventionandonereceivednointervention.

8. SummaryofXenform12ͲMonthHypothesisTestingResults(fromP180021/A001)

a. SubjectInformation

AsofMarch10,2018,all710subjectsinthePMAcohort(228subjectsintheXenform treatmentarmand482subjectsintheNTRcontrolarm)hadreachedthe12Ͳmonth postͲprocedurevisit,and218subjects(81intheXenformgroupand137intheNTR group)hadreachedthe36ͲmonthfollowͲuptimepoint(i.e.,studycompletion).(see Table18).PleasenotethatthePMAsubmissionisstillunderFDAinteractivereview; therefore,thedatasummarypresentedinthissummarysectionisbasedontheoriginal andsubsequentamendmentstoPMAsubmission.Error!Referencesourcenotfound.

Duetotheobservationalstudydesign,apropensityscoremethodologywascarriedout toaccountfordifferencesinbaselinecharacteristicsbetweentreatmentandcontrol armsandtoassessthebalancebetweenXenformandNTRsubjectsonrelevantbaseline characteristics.Thepropensityscoreanalysiswasperformedafterenrollmentclosureby independentstatisticianswhowereblindedtoallclinicaloutcomedata.Thisanalysis includedallITTsubjectsenrolledintotheXenformandNTRarmsofthestudy,aswellas NTRsubjectsextractedfromtheAUGSPFDRegistry.

FactorsthatmayaffectthestudyoutcomeswereidentifiedbasedonFDA recommendationsandincluded:levelofprolapserelativetothehymen(i.e.,POPͲQC, POPͲQBa,andPOPͲQBpmeasurements),primaryorrecurrentprolapse,menopausal status,estrogenuse,age,smoking,diabetes,BMI,priorhysterectomy,concomitant procedureforSUI,andsurgeonexperiencewithprolapserepair.Inaddition,racewas includedinordertoaccountforpossibleracialdifferences.

 29Severityofeventswasclassifiedasfollows:MildͲAwarenessofsignsorsymptoms,buteasilytoleratedandareofminor irritanttypecausingnolossoftimefromnormalactivities.Symptomsdonotrequiretherapyoramedicalevaluation;signsand symptomsaretransient;ModerateͲEventsintroducealowlevelofinconvenienceorconcerntotheparticipantandmay interferewithdailyactivities,butareusuallyimprovedbysimpletherapeuticmeasures;moderateexperiencesmaycausesome interferencewithfunctioning;SevereͲEventsinterrupttheparticipant’snormaldailyactivitiesandgenerallyrequiresystemic drugtherapyorothertreatment;theyareusuallyincapacitating 

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ThebaselinecharacteristicsandbalanceassessmentareshowninTable13.ThepͲ valuesbeforeandafterthepropensityscoreadjustmentarepresentedinorderto facilitatetheassessmentofbalancebetweentheXenformtreatmentarmandtheNTR controlarm.

Table13:XenformBaselineCharacteristicsandBalanceAssessment

 Treatmenta pͲvalue Before After Variable Xenform NTR Stratificationb Stratificationc 58.7±12.7(228) 62.5±10.6(482) Age,yrs. <0.001 0.58 (29.2,60.4,83.1) (27.1,64.1,91.0) Racewhite 88.8%(198/223) 85.0%(407/479) 0.17 0.80 28.5±5.5(228) 28.1±5.4(482) BMI 0.30 0.91 (17.6,28.2,47.7) (17.2,27.1,56.5) Smoking,current 9.3%(21/226) 7.9%(38/482) 0.53 0.97 Diabetes 9.6%(22/228) 13.1%(63/482) 0.19 0.88 PostͲmenopausal 74.1%(169/228) 83.4%(402/482) 0.004 0.67 Prolapserepair,prior 11.0%(25/228) 10.4%(50/482) 0.81 0.95 Hysterectomy,prior 34.6%(79/228) 30.1%(145/482) 0.22 0.95 Estrogenuseatbaseline 34.2%(78/228) 32.4%(156/481) 0.64 0.88 Ͳ2.9±3.5(228) Ͳ0.8±3.8(482) POPͲQApical:C <0.001 0.59 (Ͳ10.0,Ͳ4.0,10.0) (Ͳ9.0,Ͳ1.0,12.0) 1.4±1.6(228) 1.9±2.0(482) POPͲQAnterior:Ba 0.001 0.90 (Ͳ2.0,1.0,10.0) (Ͳ3.0,1.5,12.0) Ͳ0.5±2.2(228) Ͳ0.4±2.1(482) POPͲQPosterior:Bp 0.49 0.98 (Ͳ3.0,Ͳ1.0,10.0) (Ͳ3.0,Ͳ1.0,12.0) ConcomitantSUIrepair 61.0%(139/228) 48.1%(232/482) 0.001 0.68 Surgeonvolume>126 58.8%(134/228) 39.6%(191/482) <0.001 0.67 aNumberspresentedare%(#/n)ormean±SD,samplesize(N),(minimum,median,maximum) bChiͲsquaredtest(categoricalvariables)oroneͲwayANOVAFͲtest(continuousvariables) cMantelͲHaenszeltest(categoricalvariables)ortwoͲwayANOVAFͲtest(continuousvariables)adjustingforstratum  b. PrimaryEfficacyEndpoint

At12months,theuseofXenformTVMforthetreatmentofanteriorand/orapical vaginalprolapsewasfoundtobenonͲinferiortoNTRforthecompositeprimaryefficacy endpoint,asshowninTable14,withtheobjectivesuccesscomponentdefinedasthe leadingedge(s)ofthetreatedsegment(s)atorabovethehymen.Thecomposite successintheITTpopulationusingmultipleimputationtohandlemissingdatais88.9% (203/228)forXenformversus87.0%(419/482)forNTR.Thepropensityscoreadjusted treatmentdifferenceis0.6%(90%CI:Ͳ4.5%,5.6%);thusthenonͲinferiorityofXenform comparedtoNTRforthecompositeprimaryefficacyendpointisestablished.

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Table14:XenformPrimaryEfficacyEndpoint–CompositeAnatomicandSymptomatic Successat12Months PropensityAdjusted Unadjusted MissingData TreatmentDifference Treatment HandlingMethod (TVMͲNTR) Xenform NTR Difference  andAnalysis PͲvalueof (TVMͲNTR) Estimate Population Superiority Estimate(90%CI) (90%CI) Test MultipleImputation 1.9% 0.6% IntentͲtoͲTreat 88.9%(203/228) 87.0%(419/482) 0.427 (Ͳ2.7%,6.6%) (Ͳ4.5%,5.6%) 1.0% Ͳ0.1% PerProtocol 88.0%(187/213) 87.0%(415/477) 0.515 (Ͳ3.5%,5.6%) (Ͳ5.1%,4.9%) AvailableCaseAnalysis 0.9% Ͳ0.5% IntentͲtoͲTreata 88.2%(172/195) 87.3%(379/434) 0.565 (Ͳ3.7%,5.5%) (Ͳ5.5%,4.5%) 0.2% Ͳ0.9% PerProtocol 87.4%(160/183) 87.2%(376/431) 0.613 (Ͳ4.6%,5.0%) (Ͳ6.1%,4.3%)  Table15presentsdescriptivestatisticsfortheprimaryefficacycompositeanatomicand symptomatictreatmentsuccessrates,aswellastheresultsoftheindividual componentsofthecompositeendpoint,fortheITTpopulationatthe12,24,and36Ͳ monthfollowͲupvisits.Thepropensityscoreadjusteddifferencesbetweenthe treatmentandcontrolarmsareonlyprovidedforthe12ͲmonthfollowͲupvisit,asthe numbersofsubjectswhocompleted24and36ͲmonthfollowͲupvisitsweretoolowfor validstatisticalanalysis.

Table15:XenformPrimaryEfficacyEndpointͲCompositeTreatmentSuccess, IntentͲtoͲTreatSubjects GroupDifference(95%CI) Variable Xenform NTR NoPropensity WithPropensity Score Score Adjustment Adjustment 0.9% Ͳ0.5% 12ͲMonthCompositeSuccess 88.2%(172/195) 87.3%(379/434) (Ͳ4.6%,6.4%) (Ͳ6.4%,5.4%) 2.9% 1.8% ObjectiveSuccess 96.9%(189/195) 94.0%(409/435) (Ͳ0.4%,6.2%) (Ͳ1.7%,5.3%) 3.4% 2.3% AnteriorCompartment 96.9%(189/195) 93.5%(362/387) (Ͳ0.1%,6.8%) (Ͳ1.2%,5.8%) 0.4% Ͳ0.2% ApicalCompartment 98.4%(190/193) 98.0%(400/408) (Ͳ1.8%,2.6%) (Ͳ2.7%,2.3%) Ͳ2.4% Ͳ2.4% SubjectiveSuccess 89.8%(176/196) 92.2%(402/436) (Ͳ7.3%,2.5%) (Ͳ7.3%,2.6%) 1.6% 0.9% NoRetreatmentforPOP 99.6%(227/228) 97.9%(472/482) (0.1%,3.2%) (Ͳ1.6%,3.4%)

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GroupDifference(95%CI) Variable Xenform NTR NoPropensity WithPropensity Score Score Adjustment Adjustment Ͳ1.4% 24ͲMonthCompositeSuccess 82.4%(140/170) 83.7%(221/264) ͲͲ (Ͳ8.6%,5.9%) 2.4% ObjectiveSuccess 95.9%(162/169) 93.5%(244/261) ͲͲ (Ͳ1.9%,6.6%) 3.2% AnteriorCompartment 95.9%(162/169) 92.7%(216/233) ͲͲ (Ͳ1.3%,7.6%) Ͳ1.8% ApicalCompartment 97.0%(162/167) 98.8%(239/242) ͲͲ (Ͳ4.7%,1.2%) Ͳ8.1% SubjectiveSuccess 85.8%(145/169) 93.9%(246/262) ͲͲ (Ͳ14.1%,Ͳ2.1%) 1.6% NoRetreatmentforPOP 98.2%(224/228) 96.7%(466/482) ͲͲ (Ͳ0.8%,3.9%) 8.1% 36ͲMonthCompositeSuccess 81.9%(68/83) 73.8%(107/145) ͲͲ (Ͳ2.8%,19.1%) 6.9% ObjectiveSuccess 95.0%(76/80) 88.1%(119/135) ͲͲ (Ͳ0.4%,14.1%) 10.4% AnteriorCompartment 97.5%(78/80) 87.1%(108/124) ͲͲ (3.6%,17.2%) Ͳ1.3% ApicalCompartment 96.3%(77/80) 97.6%(121/124) ͲͲ (Ͳ6.3%,3.6%) Ͳ3.8% SubjectiveSuccess 88.9%(72/81) 92.6%(126/136) ͲͲ (Ͳ11.9%,4.4%) 2.0% NoRetreatmentforPOP 98.2%(224/228) 96.3%(464/482) ͲͲ (Ͳ0.4%,4.4%)

At12months,theuseofbothXenformandNTRforthetreatmentofanteriorand/or apicalprolapseproducedsimilarresultswithineachcomponentoftheprimaryefficacy endpoint.BothXenformandNTRachievedahighrateofobjectiveandsubjective successandhadadurableprolapserepairevidencedbythelowrateofreͲtreatmentat 12months.Thecompositetreatmentsuccessrateat24monthswasslightlylowerfor XenformascomparedtoNTR,andat36monthstheratewasnumericallyhigherthan NTR,basedonincompletedata.

c. SecondaryEfficacyEndpoint

Theresultsusingthesecondarycompositeefficacyendpointsuccessrate,withthe objectivesuccesscomponentdefinedastheleadingedge(s)ofthetreatedsegment(s)at orbeyondthehymen,demonstratedsimilarresultsforXenformandNTRforthe compositesecondaryefficacyendpoint(p=0.120,notadjustedformultiplicity),as showninTable16.At12months,85.2%(194/228)ofsubjectsintheXenform treatmentarmand78.3%(377/482)ofsubjectsintheNTRcontrolarmreported treatmentsuccess.Thepropensityscoreadjustedtreatmentdifferenceis4.3%(90%CI; Ͳ1.7%,10.3%).

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 Table16:SecondaryEfficacyEndpoint–CompositeAnatomicandSymptomaticSuccessinIntentͲtoͲ TreatSubjectsat12Months Unadjusted PropensityScoreAdjusted Treatment TreatmentDifference MissingData Difference (TVMͲNTR) HandlingMethodand Xenform NTR (TVMͲNTR) AnalysisPopulation Estimate Estimate PͲvalue* (90%CI) (90%CI) MultipleImputation 6.9% 4.3% IntentͲtoͲTreat 85.2%(194/228) 78.3%(377/482) 0.120 (1.5%,12.4%) (Ͳ1.7%,10.3%) 5.9% 3.8% PerProtocol 83.8%(179/213) 77.9%(372/477) 0.138 (0.6%,11.3%) (Ͳ2.0%,9.6%) AvailableCaseAnalysis 6.0% 3.3% IntentͲtoͲTreat 84.1%(164/195) 78.1%(339/434) 0.178 (0.6%,11.4%) (Ͳ2.6%,9.2%) 5.1% 2.8% PerProtocol 83.1%(152/183) 78.0%(336/431) 0.223 (Ͳ0.5%,10.7%) (Ͳ3.3%,9.0%) *PͲvaluesnotadjustedformultiplecomparisons Table17presentsdescriptivestatisticsforthesecondaryefficacycompositeanatomic andsymptomatictreatmentsuccessrates,aswellastheresultsoftheindividual componentsofthecompositeendpoint,fortheITTpopulationatthe12,24and36Ͳ monthfollowͲupvisits.Thepropensityscoreadjusteddifferencesbetweentreatment armsareonlyprovidedforthe12ͲmonthfollowͲupvisit,asthenumbersofsubjectswho completed24and36ͲmonthfollowͲupvisitsaretoolowforvalidstatisticalanalysis.

Table17:XenformSecondaryEfficacyEndpointͲCompositeSurgicalSuccess, IntentͲtoͲTreatSubjects

GroupDifference(95%CI) Variable Xenform NTR NoPropensity WithPropensity Score Score Adjustment Adjustment 6.0% 3.3% 12ͲMonthCompositeSuccess 84.1%(164/195) 78.1%(339/434) (Ͳ0.4%,12.4%) (Ͳ3.7%,10.4%) 7.7% 5.6% ObjectiveSuccess 91.8%(179/195) 84.1%(366/435) (2.5%,12.8%) (Ͳ0.1%,11.2%) 9.6% 8.2% AnteriorCompartment 92.3%(180/195) 82.7%(320/387) (4.3%,14.9%) (3.0%,13.4%) 0.1% Ͳ1.3% ApicalCompartment 97.9%(189/193) 97.8%(399/408) (Ͳ2.3%,2.6%) (Ͳ4.9%,2.2%) Ͳ2.4% Ͳ2.4% SubjectiveSuccess 89.8%(176/196) 92.2%(402/436) (Ͳ7.3%,2.5%) (Ͳ7.3%,2.6%) 1.6% 0.9% NoRetreatmentforPOP 99.6%(227/228) 97.9%(472/482) (0.1%,3.2%) (Ͳ1.6%,3.4%)

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GroupDifference(95%CI) Variable Xenform NTR NoPropensity WithPropensity Score Score Adjustment Adjustment 2.1% 24ͲMonthCompositeSuccess 77.1%(131/170) 75.0%(198/264) ͲͲ (Ͳ6.1%,10.3%) 3.5% ObjectiveSuccess 87.0%(147/169) 83.5%(218/261) ͲͲ (Ͳ3.3%,10.2%) 5.6% AnteriorCompartment 87.6%(148/169) 82.0%(191/233) ͲͲ (Ͳ1.4%,12.6%) Ͳ3.1% ApicalCompartment 95.2%(159/167) 98.3%(238/242) ͲͲ (Ͳ6.8%,0.5%) Ͳ8.1% SubjectiveSuccess 85.8%(145/169) 93.9%(246/262) ͲͲ (Ͳ14.1%,Ͳ2.1%) 1.6% NoRetreatmentforPOP 98.2%(224/228) 96.7%(466/482) ͲͲ (Ͳ0.8%,3.9%) 7.1% 36ͲMonthCompositeSuccess 74.7%(62/83) 67.6%(98/145) ͲͲ (Ͳ5.0%,19.2%) 4.8% ObjectiveSuccess 86.3%(69/80) 81.5%(110/135) ͲͲ (Ͳ5.2%,14.8%) 8.9% AnteriorCompartment 88.8%(71/80) 79.8%(99/124) ͲͲ (Ͳ1.0%,18.8%) Ͳ3.8% ApicalCompartment 93.8%(75/80) 97.6%(121/124) ͲͲ (Ͳ9.8%,2.1%) Ͳ3.8% SubjectiveSuccess 88.9%(72/81) 92.6%(126/136) ͲͲ (Ͳ11.9%,4.4%) 2.0% NoRetreatmentforPOP 98.2%(224/228) 96.3%(464/482) ͲͲ (Ͳ0.4%,4.4%)

TheuseofXenformforthetreatmentofanteriorand/orapicalprolapseproduceda similarcompositetreatmentsuccessratecomparedtoNTR.Theseresultsareconsistent at24and36months;however,theseobservationsarelimitedatthesetimepointsdue tothelimitednumberofsubjectsthathavecompletedfollowͲupouttotheseextended timepoints.

d. QualityofLifeResults

ThereweremeasurableimprovementsinpatientreportedoutcomesinbothXenform andNTRsubjectsfollowingsurgery.BothXenformandNTRsubjectsshowedsignificant improvement,perthePFIQͲ7andPFDIͲ20scoresat12monthsoverbaseline,and stabilityinthesescoresoutto36monthsforsubjectswhohavereachedthistimepoint. Therewasmodestimprovementinsexualfunctioninbothgroupsbythe12Ͳmonth followͲup,perthePISQͲ12scores,andthatimprovementwasmaintainedat36months postindexprocedure.Mostsubjectsinbothgroupsreportedtheyfelt“muchbetter”or “verymuchbetter”aftersurgeryperresponsestothePGIͲIquestionnaires.Basedon TOMUSPainScaleresponses,veryfewsubjectsineithergroupreportedpainor

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analgesicuseatbaselineand,inthosesubjectsforwhomlongerͲtermdataare available,overallpainlevelsremainedthesameordecreasedoutto36monthsof followͲup.TheresultsofthePFDIͲ20arerepresentativeoftheoverallQOLassessments andarepresentedinTable18.TheTOMUSPainScaleresultsarepresentedinTable19.

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Table18:XenformPFDIͲ20ChangefromBaseline,IntentͲtoͲTreatSubjects

GroupDifference onChangefrom Xenform NTR Baselinewith Visit PropensityScore Adjustment Changefrom MeanChange Changefrom MeanChange Estimate Score Score Baseline 95%CI Baseline 95%CI (95%CI) 115.4±61.0(228) 109.7±56.1(482) Baseline ͲͲ ͲͲ ͲͲ ͲͲ ͲͲ (8.3,103.6,284.4) (4.2,104.7,280.2) 34.3±35.2(209) Ͳ79.7±56.8(209) 31.3±36.9(440) Ͳ77.6±53.3(440) 4.4 6Months Ͳ87.4toͲ72.0 Ͳ82.6toͲ72.6 (0.0,25.0,158.3) (Ͳ240.6,Ͳ77.1,104.2) (0.0,18.8,249.0) (Ͳ255.2,Ͳ71.3,119.8) (Ͳ5.6,14.4) 33.8±34.6(196) Ͳ77.5±54.7(196) 32.0±39.0(436) Ͳ76.9±54.1(436) 6.3 12Months Ͳ85.2toͲ69.7 Ͳ82.0toͲ71.8 (0.0,24.5,211.5) (Ͳ240.6,Ͳ75.0,82.3) (0.0,16.7,244.8) (Ͳ256.3,Ͳ73.0,86.5) (Ͳ2.7,15.2) 32.1±33.5(176) Ͳ80.1±59.6(176) 32.3±35.9(329) Ͳ77.7±54.9(329) 18Months Ͳ89.0toͲ71.2 Ͳ83.6toͲ71.7 ͲͲ (0.0,23.4,209.4) (Ͳ262.5,Ͳ76.0,40.2) (0.0,21.9,190.6) (Ͳ260.4,Ͳ72.9,65.6) 30.1±32.8(169) Ͳ83.5±56.0(169) 33.0±37.9(263) Ͳ77.6±55.1(263) 24Months Ͳ92.0toͲ75.0 Ͳ84.3toͲ70.9 ͲͲ (0.0,21.9,205.2) (Ͳ238.5,Ͳ81.3,39.6) (0.0,22.9,199.0) (Ͳ256.3,Ͳ72.9,75.0) 27.3±29.5(81) Ͳ84.2±51.8(81) 33.6±44.1(136) Ͳ77.9±61.5(136) 36Months Ͳ95.7toͲ72.8 Ͳ88.4toͲ67.5 ͲͲ (0.0,18.8,143.8) (Ͳ240.6,Ͳ83.3,12.5) (0.0,16.7,210.4) (Ͳ254.2,Ͳ70.8,110.4) aNumberspresentedaremean±SD(samplesize),(minimum,median,maximum)  

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Table19:XenformTOMUSPainScoreChangefromBaseline,IntentͲtoͲTreatSubjects

GroupDifference onChangefrom Xenform NTR Baselinewith Visit PropensityScore Adjustment Changefrom MeanChange Changefrom MeanChange Score Score Estimate(95%CI) Baseline 95%CI Baseline 95%CI 8.9±11.4(228) 7.7±9.4(482) Baseline ͲͲ ͲͲ ͲͲ ͲͲ ͲͲ (0.0,5.0,70.0) (0.0,4.0,70.0) 4.3±6.8(208) Ͳ4.4±10.2(208) 4.1±7.0(440) Ͳ3.3±8.3(440) Ͳ0.8 6Months Ͳ5.8toͲ3.0 Ͳ4.0toͲ2.5 (0.0,0.0,37.0) (Ͳ70.0,Ͳ2.0,28.0) (0.0,0.0,51.0) (Ͳ70.0,Ͳ1.0,32.0) (Ͳ2.4,0.9) 3.4±6.2(196) Ͳ4.6±9.4(196) 3.6±6.2(436) Ͳ3.8±8.7(436) Ͳ0.1 12Months Ͳ5.9toͲ3.3 Ͳ4.6toͲ3.0 (0.0,0.0,50.0) (Ͳ70.0,Ͳ2.0,18.0) (0.0,0.0,42.0) (Ͳ70.0,Ͳ2.0,26.0) (Ͳ1.6,1.5) 3.1±5.7(176) Ͳ5.0±9.7(176) 3.4±6.1(329) Ͳ4.3±9.1(329) 18Months Ͳ6.4toͲ3.5 Ͳ5.3toͲ3.3 ͲͲ (0.0,0.0,34.0) (Ͳ70.0,Ͳ2.0,24.0) (0.0,0.0,46.0) (Ͳ70.0,Ͳ2.0,20.0) 3.3±7.1(169) Ͳ4.4±9.5(169) 3.4±5.8(263) Ͳ4.4±9.3(263) 24Months Ͳ5.9toͲ3.0 Ͳ5.5toͲ3.3 ͲͲ (0.0,0.0,63.0) (Ͳ70.0,Ͳ2.0,36.0) (0.0,0.0,30.0) (Ͳ70.0,Ͳ1.0,16.0) 2.6±4.5(81) Ͳ4.6±9.6(81) 3.9±6.9(136) Ͳ3.6±8.3(136) 36Months Ͳ6.7toͲ2.5 Ͳ5.0toͲ2.2ͲͲ (0.0,0.0,23.0) (Ͳ70.0,Ͳ3.0,9.0) (0.0,0.0,42.0) (Ͳ36.0,0.0,16.0) aNumberspresentedaremean±SD(samplesize),(minimum,median,maximum)

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e. InterventionforRecurrentProlapse

Recurrentprolapsewasreportedas‘Prolapse’or‘SensationofBulge’(reportedby eitherthepatientduetosensationorbythephysicianduringpelvicexamination),and wasrecordedasanadverseevent.At12months,6.6%(15/228)ofsubjectsinthe Xenformarmexperienced‘Prolapse’and9.6%(22/228)experienced‘Sensationof Bulge’,while9.3%(45/482)ofsubjectsexperienced‘Prolapse’and5.4%(26/482) experienced‘SensationofBulge’intheNTRarm.Table20showstheresultsforboth officeͲbasedandsurgicalͲbasedinterventionforrecurrentprolapsefollowingtheindex procedureintheITTpopulationwithin12and36months.Theproportionofsubjects whoreceivedinterventionforrecurrentprolapseweresimilarbetweentheXenform andNTRarms.

Table20:XenformInterventionforRecurrentProlapsePostIndexProcedure

AdjustedTreatmentDifference TimePeriod Xenform NTR (TVMͲNTR) Estimate(95%CI)

OfficeͲbasedInterventionforRecurrence 0.4% Within12months 0.4%(1/228) 0.2%(1/482) (Ͳ0.8%,1.7%) 0.3% Within36months 0.4%(1/228) 0.4%(2/482) (Ͳ1.0%,1.6%) SurgicalͲbasedInterventionforRecurrence 0.3% Within12months 0.9%(2/228) 1.5%(7/482) (Ͳ2.3%,3.0%) Ͳ0.2% Within36months 1.8%(4/228) 2.7%(13/482) (Ͳ3.4%,2.9%)  f. PrimarySafetyEndpoint

Table21showstheanalysisofdeviceͲrelatedorprocedureͲrelatedSAEs.At12months, 2.6%(6/228)ofsubjectsintheXenformtreatmentarmand2.7%(13/482)ofsubjectsin theNTRcontrolarmreportedSAEs.Thepropensityscoreadjustedtreatmentdifference is0.1%(90%CI;Ͳ2.3%,2.6%),thusthenonͲinferiorityofXenformcomparedtoNTRfor theprimarysafetyendpointisestablished.

Table21:XenformPrimarySafetyEndpoint–SeriousDeviceͲand/orProcedureͲRelated AdverseEventsat12Months

PropensityScore UnadjustedTreatment Analysis AdjustedTreatment Xenform NTR Difference(TVMͲNTR) Populationa Difference(TVMͲNTR) Estimate(90%CI) Estimate(90%CI) Ͳ0.1% 0.1% IntentͲtoͲTreat 2.6%(6/228) 2.7%(13/482) (Ͳ2.2%,2.1%) (Ͳ2.3%,2.6%)

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PropensityScore UnadjustedTreatment Analysis AdjustedTreatment Xenform NTR Difference(TVMͲNTR) Populationa Difference(TVMͲNTR) Estimate(90%CI) Estimate(90%CI) Ͳ0.4% Ͳ0.1% PerProtocol 2.3%(5/213) 2.7%(13/477) (Ͳ2.5%,1.7%) (Ͳ2.6%,2.5%) Ͳ0.0% 0.2% AsTreated 2.7%(6/226) 2.7%(13/484) (Ͳ2.2%,2.1%) (Ͳ2.3%,2.6%) aOnlyeventsthathappenedwithin12monthsoftheindexprocedureandrelatedtothetargetcompartmentare includedintheanalysis.  KaplanͲMeiercurvesforSAEͲfreesurvivalexhibitconsiderableoverlap,suggesting thatthereisnoclinicallymeaningfuldifferenceinseriouscomplicationrates betweenthetwoarms(seeError!Referencesourcenotfound.).  Figure10:KaplanͲMeierCurveofSAEFreeComparingXenformvs.NTR,IntentͲtoͲTreatSubjects

 LookingatthetotalityofdataaccountingforpatientsreachinglaterstudyfollowͲup timepoints,asofMarch10,2018,therewere23seriousdeviceͲand/orserious procedureͲrelatedadverseeventsthatimpacted20subjects,withsixeventsinsix Xenformsubjectsand17eventsin14NTRsubjects.ForXenformsubjects,allsix eventsoccurredwithin180daysoftheindexprocedure,withnolateͲterm complications.Twoevents(oneinfectionandonecardiacevent,worsening) remainedongoingasofMarch10,2018.FortheNTRsubjects,14ofthe17events occurredwithin180dayspostͲprocedure,whereasthreeevents(oneinfection,one UTI,andoneconstipationworsening)werelateͲtermcomplications.Fifteenofthe 17eventshavebeenfullyresolvedwhiletwo(onepelvicinfection/abscessandone

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constipationworsening)remainedongoingasofMarch10,2018.Table22provides asummaryoftheseriousdeviceͲand/orprocedureͲrelatedadverseeventsand theirassociatedinterventionsintheUpholdLITEtreatmentarmandtheNTRcontrol arm.

providesasummaryoftheseriousdeviceͲand/orprocedureͲrelatedadverse eventsandtheirassociatedinterventionsintheXenformtreatmentarmandNTR controlarm.

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Table22:SafetySummaryofSeriousDeviceͲand/orProcedureͲRelatedAdverse,IntentͲtoͲTreatSubjects

 Xenform(N=228) Intervention NTRArm(N=482) Intervention Proportionof Proportionof NonͲ HospitalͲ NonͲ HospitalͲ  Events Subjectswith Surgicalb Events Subjectswith Surgicalb Surgical ization Surgical ization ш1Eventa ш1Eventa InfectionͲOther,specifytype 2 0.9%(2/228) 1 0 2 3 0.6%(3/482) 3 0 3 UreteralKink/Injury 0ͲͲͲͲ2 0.4%(2/482) 1 2 1 CardiacEventsͲWorsening 1 0.4%(1/228) 1 0 1 N/AͲͲͲͲ DifficultyEmptyingBladderͲnew 1 0.4%(1/228) 0 1 0 0ͲͲͲͲ BleedingRequiringBlood 1 0.4%(1/228) 1 0 0 0ͲͲͲͲ Transfusion VisceralOrganInjury 1 0.4%(1/228) 1 0 1 0ͲͲͲͲ Ileus/BowelObstruction 0ͲͲͲͲ2 0.4%(2/482) 1 2 2 PelvicInfection/Abscess 0ͲͲͲͲ2 0.4%(2/482) 1 0 2 UrinaryTractInfection(UTI),Lower 0ͲͲͲͲ2 0.4%(2/482) 2 0 2 CardiacEventͲNEW 0ͲͲͲͲ1 0.2%(1/482) 1 0 1 ConstipationͲWorsening 0ͲͲͲͲ1 0.2%(1/482) 1 0 0 HematomaͲRetropubic 0ͲͲͲͲ1 0.2%(1/482) 1 0 1 Diarrhea 0ͲͲͲͲ1 0.2%(1/482) 0 0 1 PulmonaryEvent,SpecifyͲ 0ͲͲͲͲ1 0.2%(1/482) 1 0 0 Worsening ThromboticEvent 0ͲͲͲͲ1 0.2%(1/482) 1 0 1 Total 6 2.6%(6/228) 4 1 4 17 2.9%(14/482) 13 4 14 aNumbersarepercentage(count/samplesize) bInpatientoroutpatientsurgicalintervention

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g. SecondarySafetyEndpoint

ThesecondarysafetyendpointincludedanalysisofoveralldeviceͲrelatedand procedureͲrelatedAEs.Additionally,inordertobetterunderstandthepotentialfor pelvicͲspecificAEsthatwerediscussedduringthe2011Panelmeeting,BSCevaluateda groupofspecificAEsthatincludedpelvicpain,infection,vaginalshortening,atypical vaginaldischarge,neuromuscularproblems,vaginalscarring,denovovaginalbleeding, denovovoidingdysfunction,denovodyspareunia,andfistulaformation.Mesherosion andmeshexposureswerealsoevaluated.

Table23summarizestheoveralldeviceͲand/orprocedureͲrelatedAEsintheITT populationat6,12,18,24and36months.OveralldeviceͲand/orprocedureͲrelatedAEs areverysimilarbetweenXenformandNTRarmswithin12months,witharateof38.6% (88/228)forXenformsubjectsand34.9%(168/482)forNTRsubjects(7.7%difference withpropensityscoreadjustment;95%CI:Ͳ0.8,16.1%).Bythe36Ͳmonthtimepoint,the differenceinoverallAEsbetweenthetwogroups(42.5%forXenformsubjectsvs.40.0% forNTRsubjects)haddecreasedto5.9%(withpropensityscoreadjustment;95%CI:Ͳ 2.7%,14.4%).TheoverallAEratesarecomparablebetweenthetwostudyarms.



Table23:XenformSecondarySafetyEndpoint–OverallDeviceͲandProcedureͲRelatedAdverse Events,IntentͲtoͲTreatSubjects

Xenform NTR GroupDifference(95%CI)  %(count/ %(count/ NoPropensity WithPropensity samplesize) samplesize) ScoreAdjustment ScoreAdjustment OverallAdverseEventsa Occurredwithin6 4.3% 8.2% 33.3%(76/228) 29.0%(140/482) months (Ͳ3.1%,11.6%) (Ͳ0.0%,16.4%) Occurredwithin12 3.7% 7.7% 38.6%(88/228) 34.9%(168/482) months (Ͳ3.9%,11.4%) (Ͳ0.8%,16.1%) Occurredwithin18 2.4% 6.1% 39.9%(91/228) 37.6%(181/482) months (Ͳ5.3%,10.0%) (Ͳ2.4%,14.6%) Occurredwithin24 1.8% 5.1% 40.4%(92/228) 38.6%(186/482) months (Ͳ5.9%,9.5%) (Ͳ3.4%,13.6%) Occurredwithin36 2.5% 5.9% 42.5%(97/228) 40.0%(193/482) months (Ͳ5.3%,10.3%) (Ͳ2.7%,14.4%) aOnlydeviceͲand/orprocedureͲrelatedadverseeventsrelatedtothetargetcompartmentareincludedintheanalysis. Table24presentsanalysisofdeviceͲand/orprocedureͲrelatedAEsreportedasof March10,2018fortheITTpopulation.

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Table24:SummaryofDeviceͲand/orProcedureͲRelatedAdverseEvents,IntentͲtoͲTreatSubjects

Xenform NTR (N=228) (N=482)  Proportionof KM Proportionof KM Events Subjectswith Estimateat Events Subjectswith Estimateat ш1Eventa 3Yearsb ш1Eventa 3Yearsb Atypicalvaginaldischarge 1 0.4%(1/228) 0.4% 3 0.6%(3/482) 0.6% Denovodyspareunia 3 1.3%(3/228) 0.9% 7 1.5%(7/482) 1.5% Denovovaginalbleeding 4 1.8%(4/228) 1.8% 7 1.5%(7/482) 1.5% Denovovoiding 41 14.5%(33/228) 14.8% 24 4.4%(21/482) 4.8% dysfunction DifficultyEmptying 26 11.0%(25/228) 11.1% 16 3.3%(16/482) 3.4% BladderͲNEW StressIncontinenceͲ 7 3.1%(7/228) 3.2% 4 0.8%(4/482) 1.1% NEW UrgeIncontinenceͲNEW 8 3.5%(8/228) 3.8% 4 0.8%(4/482) 1.1% Fistulaformation 0 0.0%(0/228) 0.0% 0 0.0%(0/482) 0.0% Infection 33 9.6%(22/228) 9.9% 98 13.5%(65/482) 14.9% Infection/Inflammation 0 0.0%(0/228) 0.0% 0 0.0%(0/482) 0.0% ofBone InfectionͲOther,specify 4 1.8%(4/228) 1.8% 6 1.0%(5/482) 1.1% type PelvicInfection/Abscess 0 0.0%(0/228) 0.0% 4 0.8%(4/482) 0.9% SinusTract 0 0.0%(0/228) 0.0% 0 0.0%(0/482) 0.0% UrinaryTractInfection 23 6.1%(14/228) 6.3% 84 11.8%(57/482) 13.2% (UTI),Lower VaginalInfection 6 2.6%(6/228) 2.7% 4 0.8%(4/482) 1.2% Mesh Exposure in Vagina 2 0.9%(2/228) 0.9% 0 0.0%(0/482) 0.0% MeshErosion 0 0.0%(0/228) 0.0% 0 0.0%(0/482) 0.0% Neuromuscularproblems (includinggroinandleg 2 0.9%(2/228) 0.9% 13 2.7%(13/482) 3.4% pain) PelvicPain 15 6.6%(15/228) 6.8% 27 5.6%(27/482) 6.8% PelvicPainͲNEW 14 6.1%(14/228) 6.3% 26 5.4%(26/482) 6.6% PelvicPainͲWorsening 1 0.4%(1/228) 0.5% 1 0.2%(1/482) 0.3% Vaginalscarring 3 1.3%(3/228) 1.3% 1 0.2%(1/482) 0.2% Vaginalshortening 0 0.0%(0/228) 0.0% 0 0.0%(0/482) 0.0% aNumbersarepercentage(count/samplesize) bEstimatedeventrateat3yearsusingKaplanMeier(KM)method

FortheITTpopulation,similareventrateswereobservedbetweentheXenformand NTRarmsforpelvicpain,infection,vaginalshortening,atypicalvaginaldischarge, neuromuscularproblems,vaginalscarring,denovovaginalbleeding,fistulaformation, anddenovodyspareunia.

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SubjectsintheXenformarmexperiencedahigherrateofdenovovoidingdysfunction: 14.5%(33/228)comparedwith4.4%(21/482)intheNTRarm.Denovovoiding dysfunctionisacompositeofdifficultyemptyingthebladder,stress,andurgeurinary incontinence.Foreachofthesecategories,thepercentageofaffectedsubjectsis greaterintheXenformtreatmentgroupthantheNTRcontrolgroup.Specifically,11.0% (25/228)ofXenformsubjectsversus3.3%(16/482)ofNTRsubjectsexperienceddenovo difficultyemptyingofthebladder.3.1%(7/228)ofXenformsubjectsexperiencedstress incontinencewhile3.5%(8/228)experiencedurgeincontinence;thecorresponding numbersofNTRsubjectswere0.8%(4/482)and0.8%(4/482)forstressandurge incontinence,respectively.Whiletheobservedrateofdenovovoidingdysfunctionin theXenformgroupishigherthanthatobservedintheNTRgroup,onlythreeevents requiredsurgicalinterventionorhospitalization.Denovovoidingdysfunctiondidnot appeartoaffectQOLsincetherewasnotanappreciabledifferenceinUDIͲ6score betweenXenformsubjectswhodidanddidnotexperiencedenovovoidingdysfunction (seeTable25).

Table25.UDIͲ6ScoreforSubjectswithDeviceͲand/orProcedureͲRelatedDeNovoVoiding DysfunctionintheXenformArm

 SubjectswithDeNovoVoidingDysfunction?  Noa Yesa Variables PValueb (N=195) (N=33) 46.5±28.9 44.2±26.2 UDIͲ6atBaseline 0.769 (n=195,41.7,20.8Ͳ66.7) (n=33,45.8,25.0Ͳ66.7) 15.2±18.6 15.2±15.2 UDIͲ6at6Months 0.455 (n=178,8.3,0.0Ͳ25.0) (n=31,12.5,0.0Ͳ16.7) 14.5±17.8 15.7±16.8 UDIͲ6at12Months 0.395 (n=166,8.3,0.0Ͳ25.0) (n=30,8.3,4.2Ͳ20.8) 13.1±17.4 13.0±15.2 UDIͲ6at18Months 0.786 (n=150,8.3,0.0Ͳ20.8) (n=26,8.3,0.0Ͳ20.8) 12.2±16.9 12.0±15.5 UDIͲ6at24Months 0.664 (n=145,8.3,0.0Ͳ16.7) (n=24,8.3,0.0Ͳ16.7) 10.4±14.1 16.7±18.6 UDIͲ6at36Months 0.298 (n=70,2.1,0.0Ͳ16.7) (n=11,8.3,0.0Ͳ37.5)

aDatapresentedasMean±SD(n=,Median,Q1ͲQ3). bWilcoxconRankSumtest AsofMarch10,2018,therehavebeennoreportedmesherosionsintheXenformstudy population.At12monthsandthrough36monthsoffollowͲup,meshexposurehasbeen documentedin0.9%(2/228)ofXenformsubjects.Thesetwomeshexposureswereboth mildinseverity,didnotrequireanysurgicalintervention,andhavefullyresolved.

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B. DiscussionofClinicalDataAnalysis

1. ClinicalEfficacyOutcomes

ThedatafromtheUpholdLITEandXenformBSCPostmarketSurveillanceStudiesshow similarresultswithrespecttoclinicalefficacyoftransvaginalmeshcomparedtoNTR. Analysesoftheprimaryefficacyendpoint,acompositeofobjectiveandsubjectivesurgical success,demonstratethatbothUpholdLITEandXenformareatleastaseffectiveasNTRat 12months.

a. UpholdLITEPostmarketSurveillanceStudy

TheuseofUpholdLITEandNTRforthetreatmentofanteriorand/orapicalprolapse producedsimilarresultsthatarenonͲinferiorforthecompositeprimaryefficacy endpointatthe12ͲmonthfollowͲuppoint.BothPOPtreatmentapproachesachievea highrateofobjectiveandsubjectivesuccessandhavedurableprolapserepair, evidencedbylowratesofreͲtreatmentat12months.Lookingattheindividualprongs oftheprimarycompositeendpoint,theproportionofsubjectswithobjectivesuccessis higherintheUpholdLITEarm,drivenbythetreatmentsuccessintheanterior compartment.AhigheranatomicsuccessrateisshownintheUpholdLITEarminthe anteriorcompartmentcontinuingthrough36months,albeitbasedonlimitedavailable data.

Whentheobjectivesuccesscomponentofthecompositeprimaryendpointisdefinedas theleadingedgeofanteriorprolapseatorabovethehymen,UpholdLITEisfoundtobe similartoNTR,asnotedabove.Whentheobjectivesuccesscomponentofthe compositesecondaryefficacyendpointisdefinedasnoanteriorprolapseatorbeyond thehymen,UpholdLITEisfoundtobegreaterthanNTR.SubjectivesuccessofUphold LITEiscomparabletothatofNTR,asdemonstratedbythepatientreportedoutcomes onthevariousadministeredQOLquestionnaires,includingthePFDIͲ20,PFIQͲ7,PISQͲ12, TOMUSpainscale,andPGIͲI.TheratesofofficeͲbasedandsurgicalͲbasedinterventions forrecurrentprolapseandcomplicationsarecomparablewhetherasubjectreceivedan UpholdLITEmeshrepairorNTR.

Insummary,the12ͲmonthdatademonstratenonͲinferiorityofUpholdLITEtoNTRfor primaryefficacy,andthetreatmentsuccessrateishigherintheUpholdLITEarm comparedtotheNTRarmforsecondaryefficacy.Inaddition,thecompositeprimary andsecondarysurgicalsuccessratestrendinfavorofUpholdLITEwithnumerically highervaluesat24and36months;however,theseobservationsarebasedonalimited subsetofdata.

b. XenformPostmarketSurveillanceStudy

TheuseofXenformandNTRforthetreatmentofanteriorand/orapicalprolapse producedsimilarresultsthatarenonͲinferiorforthecompositeprimaryefficacy endpointatthe12ͲmonthfollowͲuppoint.BothPOPtreatmentapproachesachievea highrateofobjectiveandsubjectivesuccessandhavedurableprolapserepair, evidencedbylowratesofreͲtreatmentat12months.

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Whentheobjectivesuccesscomponentofthecompositeefficacyendpointisdefinedas theleadingedgeofanteriorprolapseatorabovethehymen(primaryanatomicsuccess criterion),ornoanteriorprolapseatorbeyondthehymen(secondaryanatomicsuccess criterion),XenformiscomparabletoNTR.ThesubjectivesuccessofXenformisalso comparabletothatofNTR.Theimpactonthepatients’qualityoflifeiscomparable betweenthetreatmentarms,asdemonstratedbythepatientreportedoutcomeson thevariousadministeredQOLquestionnaires,includingthePFDIͲ20,PFIQͲ7,PISQͲ12, TOMUSpainscale,andPGIͲI.TheratesofofficeͲbasedandsurgicalͲbasedinterventions forrecurrentprolapseandcomplicationsaregenerallynotdifferentbetweenthe groups.

Insummary,the12ͲmonthdatademonstratenonͲinferiorityofXenformtoNTRforthe primaryeffectivenessendpoint.Thesecondaryendpointoutcomesweresimilar betweentheXenformandNTRat12months.Similarresultswereshownforthe compositeprimaryandsecondarysuccessratesat24and36months;however,these observationsarebasedonalimitedsubsetofdata.

2. ClinicalSafetyOutcomes

ThedatafromtheUpholdLITEandXenformPostmarketSurveillanceStudiesshowsimilar resultswithrespecttothesafetyoftransvaginalmeshforanteriorand/orapicalPOPrepair. AnalysesofthecoͲprimarysafetyendpoint,seriousdeviceͲrelatedorseriousprocedureͲ relatedAEs,demonstratethatPOPrepairsusingUpholdLITEorXenformarenonͲinferiorto NTRat12months.Thecompilationofdatademonstratesthatpatientsoptingforeitherof thesetwosurgicalapproachestoPOPrepaircanexpectsimilarsafetyprofiles.

a. UpholdLITEPostmarketSurveillanceStudy

UpholdLITEandNTRsubjectsexperiencedthesamerateofSAEs,2.7%,at12months andthenonͲinferiorityofUpholdLITEcomparedtoNTRforsafetyisestablished.Kaplan MeiercurvesforSAEͲfreesurvivalexhibitconsiderableoverlap,suggestingthatthereis noclinicallymeaningfuldifferenceinseriouscomplicationratesbetweenthetwoarms. NolateͲtermSAEswereobservedintheUpholdLITEarm,whereasthreelateͲterm events(post180days)wereobservedintheNTRarm.

Analysisofthesecondarysafetyendpointsshowsimilarresultsforratesofoverall deviceͲand/orprocedureͲrelatedAEs(28.9%forUpholdLITEversus34.9%forNTR)at 12months.TherewerenodifferencesintheratesofindividualAEsthatwereof concerntotheFDAatthe2011Panelmeeting:pelvicpain,infection,vaginalshortening, atypicalvaginaldischarge,neuromuscularproblems,vaginalscarring,denovovaginal bleeding,denovovoidingdysfunction,denovodyspareunia,andfistulaformation.

TherehavebeennoreportsofmesherosionintheUpholdLITEPostmarketSurveillance Study.Eightsubjectsreportedatotalof10meshexposures:sixsubjectsreporteda singlemeshexposureandtwosubjectseachreportedtwomeshexposures.Noneofthe eventsweresevere:eightwereclassifiedasmildandtwowereclassifiedasmoderatein

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severity.Oneeventwasclassifiedasseriousbythestudyinvestigatorandresolvedwith outpatientsurgicalintervention.

b. XenformPostmarketSurveillanceStudy

XenformsubjectsandNTRsubjectsexperiencednearlyidenticalratesofSAEsat12 months,2.6%and2.7%,respectively,andthenonͲinferiorityofXenformcomparedto NTRforprimarysafetyendpointisestablished.KaplanMeiercurvesforSAEͲfreesurvival exhibitconsiderableoverlap,suggestingthatthereisnoclinicallymeaningfuldifference inseriousAEratesbetweenthetwoarmsat12months.NolatetermSAEswere observedintheXenformarm,whereasthreelatetermevents(post180days)were observedintheNTRarm.

Analysisofthesecondarysafetyendpointsat12monthsshowssimilarresultsforrates ofoveralldeviceͲand/orprocedureͲrelatedAEs(38.6%forXenformversus34.9%for NTR).TheonlyAEthatwasdifferentforXenformcomparedtoNTRwasdenovovoiding dysfunction(14.5%forXenformversus4.4%forNTR).andonlythreeeventsrequired surgicalinterventionorhospitalization,andthisdidnotimpactQOLscoresonpatientͲ reportedmeasures.Despitethisobservationtherewerenoappreciabledifferencesin UDIͲ6scoresbetweenXenformsubjectswhodidanddidnotexperiencedenovo voidingdysfunction.

TherehavebeennoreportsofmesherosionintheXenformPostmarketSurveillance Study.Twosubjectseachreportedasinglemeshexposure,wherebotheventswere mildinseverityandneithereventrequiredsurgicalintervention.Botheventswere classifiedasnonͲseriousbythestudyinvestigators.

C. AdditionalClinicalStudies

TheUpholdLITESystemisalsobeingevaluatedinapostmarketstudysponsoredbytheEunice KennedyShriverNationalInstituteofChildHealthandHumanDevelopment(NICHD),and subjectfollowͲupiscurrentlyongoing.TherearenoadditionalclinicalstudiesfortheXenform SoftTissueRepairMatrix.  TheStudyofUterineProlapseProceduresRandomizedTrial(SUPeR)(hereinafter“SUPeRStudy”) isarandomized,multiͲcenter,superioritytrialthatcompareslongͲtermsafetyandeffectiveness oftwotransvaginalapicalsuspensionsurgeriesforuterovaginalprolapse.Anabstractcontaining theresultsofthisstudywaspresentedatthe2018AmericanUrogynecologySocietyMeeting. ThisabstractisalsodescribedinSection6A.21Nineclinicalsitesparticipatedinthestudyand 175womenwererandomlyassignedandmaskedtoreceiveeithervaginalhysterectomywith nativetissueuterosacralligamentsuspension(hysterectomy)(n=87)orUpholdLITEmesh hysteropexy(hysteropexy)(n=88).

Thecompositeprimaryoutcomeofsuccesswasdefinedasnoprolapsesymptoms,noobjective prolapsebeyondthehymen,andnoretreatmentforprolapse.Thisprimaryoutcomewas evaluatedaminimumof36monthspostͲsurgerywithsurvivalmodelsusingapieceͲwise proportionalhazardmodel.Secondaryoutcomesweremeasuredatbaselineandevery6

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monthspostͲsurgery.TheseoutcomesincludedAEs,conditionͲspecificQOLassessments,body image,andsexualfunctionmeasures.Thesecondaryoutcomeswereevaluatedwith longitudinalmodelsorchiͲsquaretests,asappropriate.

Therewasnodifferenceinprimaryoutcomeinwomenundergoinghysterectomyversus hysteropexy(aHR0.63,95%CI:0.39,1.03). Operativetimewassignificantlylessinthe hysteropexygroup(111.5±4.2min)versusthehysterectomygroup(156.7±4.7min).PostͲ operativeanteriorwallsupport,POPͲQpointBa(mean,SD)wasborderlinestatistically significantlydifferentbetweenthehysteropexygroup(Ͳ1.2,1.4)andthehysterectomygroup(Ͳ 0.7,1.5)at36months(p=0.050).Hysteropexymeshexposureratewasreportedtobe8%,with onesinglepatientrequiredsurgicalintervention.Atthetimeoftheabstractpublication,no additionalinformationregardingtheseverity,complications,orresolutionoftheseeventswas madeavailable.After12weeks,granulationtissueandpermanentsutureexposurewasmore commoninthehysterectomygroup(11%vs1%,p<0.01and20%vs3%,p<0.001,respectively). Therewasnodifferenceinpatientreportedoutcomesincludingpain,sexualpain,andsexual function.

SimilartotheUpholdLITEPostmarketSurveillanceStudy,theSUPeRStudyevaluatedsurgical successbasedoncompositeprimaryoutcomesofanatomic,symptomatic,andretreatment measures,aswellasoverallAEsandsecondaryQOLpatientreportedoutcomesandpelvicͲ specificsafetymeasures.Whilesuperiorityofhysteropexyoverhysterectomywasnot establishedat36monthsbasedonthecompositeendpoint,thestudyhasbeenextendedto followsubjectsoutto60months.TheadverseeventprofileobservedintheSUPeRStudyis closelyalignedwiththatseenintheUpholdLITEPostmarketSurveillanceStudy.Resultsfrom bothstudiesincludedinstancesofmeshexposuresthatresolvedwithoutmedicalintervention andaccordinglywerenotconsideredseriousevents.

ThedatafromtheSUPeRStudyindicatethatsurgicalsuccess,QOL,andsafetyweresimilar betweenthehysteropexyandhysterectomygroupsat36months.Accordingly,women undergoingvaginalsurgeryforapicalanteriorprolapsecananticipateequalefficacyandsafety outcomesregardlessofwhichofthesetwosurgicaltechniquesischosen.Theseresultsare consistentwiththoseseenintheUpholdLITE522PostmarketSurveillanceStudythrough12 monthsoffollowͲup.



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D. MAUDEDataConsiderations IntheExecutiveSummaryfromthe2011Panelmeeting,alistingofadverseeventswas presentedshowingthenumberofMDRsandratesforeachasreportedintheMAUDEdatabase. BSCbelievesthattherearelimitationsinconsideringtheMAUDEdataaloneandbelievesour internalcomplaintsystemprovidesanaccuraterepresentationofadverseeventratesbasedon sales.WhiletheMAUDEdataprovidesadverseeventdataonmedicaldevicesandisanexcellent sourceofdataformanufacturerstouse,research,andassistinunderstandingpotentialadverse eventsthroughoutaproduct’slifecycle,therearelimitationsinthatthedatamaynotbe comprehensive,maycontainredundantinformation,andnodenominatordataisavailablein ordertoassessthesecomplaintsinpropercontext.Thus,BSCisuncertainthattheMAUDEdata aloneprovidesanythingotherthanasignalthatbearsinvestigationanddidnotperforma comprehensivereviewofthecontentwithintheMAUDEdata.

SECTION8.BENEFIT/RISKDISCUSSION

Inaddressingthepotentialforclinicalbenefit,severaltherapeuticelementsmustbeconsideredby physiciansonanindividualperͲpatientbasistoensurethatthebenefitsofanyinterventionwill outweighthepotentialrisks.Suchelementsinclude:

x thedegreetowhichthediseaseislifethreatening, x whetherornottherearealternativetherapiesthatpresentmoreorlessriskthanthetherapyin question, x specificclinicalcriteriathatrenderothertherapiesineffectiveorinappropriatecomparedtothe therapyinquestionforcertainpatients,and x qualityoflifeaspectsthatfavorthetherapyinquestionincomparisontocompetingtherapies.

Basedonthetotalityoftheevidencefromtheprospective522postmarketstudiesandareviewof themorerecentliterature,therearedemonstrablebenefitsforuseofUpholdLITEandXenform transvaginalmeshproductsfortherepairofPOPintheanteriorandapicalcompartments.Further, itisBSC’spositionthatthesebenefitsoutweightheriskspresentedbythedevices,whichare generallycomparabletothelevelofriskexperiencedbyalternativeinvasivetreatmentoptions, includingNTR.Therisksoftransvaginalmeshproductshavebeenmitigated,ascomparedtothe useofpreviousgenerationPOPsurgicalmeshdevices.Thishasbeenachievedthrough improvementsindevicedesign,refinedsurgicaltechnique,andtheavailabilityofstructured educationviafellowship,societyͲsponsoredcourses,andindustryͲsponsoredproductͲspecific education,allofwhichcontributetosignificantmitigationoftherisksassociatedwithcontemporary transvaginalmeshproducts.Forthesereasons,BSCbelievesthatitisimportant,intermsof women’shealth,fortransvaginalmeshtoremainatreatmentoptionthatappropriatelytrained physiciansmayselectwheresurgeryisdeemedappropriateforPOPrepair.

A.ThereareSignificantBenefitsRealizedbyPOPRepairwithTVM

TherearesignificantandprovenbenefitsforuseofUpholdLITEandXenformtransvaginalmesh productsfortherepairofPOPintheanteriorandapicalcompartments.

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Lookingatcompositesuccessratesthatencompassobjectivesuccess,subjectivesuccess,and reͲoperationratesforrecurrence,theresultsfromtheUpholdLITEandXenformPostmarket SurveillanceStudiesdemonstratethat,at12months,bothUpholdLITEandXenformareatleast aseffectiveasNTRforthetreatmentofanteriorand/orapicalPOP.Highratesofprimary objectivesuccess(definedastheleadingedgeofprolapseatorabovethehymeninthe operativecompartment)wereachievedat12monthsforbothUpholdLITE(91.6%)andXenform devices(88.2%),withgooddurabilityshownintheavailable36Ͳmonthdata.Moreover,Uphold LITEsubjectsdemonstratedbenefitcomparedtoNTRinimprovementofanatomicoutcomefor apicalprolapserepair,whichpersiststhrough36ͲmonthfollowͲupbasedonthelimiteddata availablebeyond12months.UpholdLITEalsoshowedimprovementoverNTRforthe secondarycompositeefficacyendpointat12months,andXenformwasfoundtobeatleastas effectiveasNTRforcompositesecondaryefficacy.  TheUpholdLITEandXenformPostmarketSurveillanceStudies’resultsregardinganatomic outcomesoftransvaginalmeshPOPrepairarefurthervalidatedbytheliteratureaddressingthe commerciallyavailableUpholdLITEdevice,suchasAltmanetal.(2016)reporting94%anatomic success(POPͲQч1)andRahkolaͲSoisaloetal.reporting93.5%anatomicsuccessintheapical compartmentatoneyear;whereRahkolaͲSoisalodemonstratedsustainedimprovementwith nostatisticallysignificantdeclineinanatomicsuccessatfiveyears.Theserecentstudiesdirectly addressperformancewithUpholdLITEandaremorerepresentativeofcontemporarysurgical proceduresandthesecondͲgenerationmeshproductswhencomparedtothecontrasting literaturereportscitedatthe2011panelmeeting,wheretrocarͲguidedimplantation proceduresfortheEthiconProliftmeshevaluatedbyIglesiaetal.(2010)andWithagenetal. (2011)concludedthattherewasnoevidencethatmeshrepairofapicalprolapseresultedin significantimprovementinanatomicoutcome.  Further,theseanatomicbenefitsexperiencedbypatientsarealsoclinicallysignificant. SustainedimprovementsinanatomicalsuccesswereshownintheUpholdLITEandXenform PostmarketSurveillanceStudiestoresultinnumericallylowerreͲoperationratesforPOP recurrencewhencomparedtotheNTRcontrolarm.PatientstreatedwithUpholdLITEand Xenformalsoexperiencedclinicallysignificantimprovementsinqualityoflifemeasuresas reflectedinpatientͲreportedoutcomemeasuresandpainmetrics.Thequalityoflifebenefits arecomparabletoNTRat12months,withapotentialincreasedbenefitinthelongterm,based onthelimiteddatacurrentlyavailableoutto36months.Thesebenefitsareconsistently reflectedacrossthepublishedliteraturefortheBSCdevices.Forexample,withRahkolaͲSoisalo etal.reporting89.4%ofsubjectshavinganimprovementatfiveyearsinPFDIͲ20scores,with 78.8%achievingminimalclinicallyimportantdifferenceandGutmanetal.reporting95%patient satisfactionfortreatmentofanteriorPOPш2.  B.TheRisksPresentedbytheTVMDevicesareComparabletoOtherInvasiveTherapiesforPOP Repair

Giventhattherearesubstantialnumbersofwomenforwhommeshmayrepresentthebest opportunityforbothcureandmaintenanceofbodyimage/QOL,itisimportanttoassessthe relativesafetyoftransvaginalmeshcomparedtoothertreatmentmodalities.

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InBSC’s522studies,bothUpholdLITEandXenformdemonstratednonͲinferiorityforthe primarysafetyendpoint,deviceͲrelated/procedureͲrelatedseriousadverseevents(SAE)rates, comparedtoNTR.At12monthsintherespectiveITTstudypopulations,therateswere2.7%for theUpholdLITEsubjectsand2.6%fortheXenformsubjects,whichdidnotdifferfromthe2.7% seriouseventrateforNTRsubjectsinbothstudies.Further,nolatetermSAEswereexperienced withtheUpholdLITEandXenformdevices.whereasthreesubjectsexperiencedlatetermSAEs intheNTRcontrolarm.Surgicalinterventionandhospitalizationwasrequiredahigher percentageofthetimetoaddressSAEsintheNTRarmcomparedtoeventsexperiencedwith theUpholdLITEorXenformdevices.

ThetotaldeviceͲrelatedandprocedureͲrelatedAErateswere28.9%forUpholdLITEsubjects and38.6%forXenformversus34.9%forNTRsubjects.Inbothstudies,therewerenolarge differencesinoverallAEratesbetweenthetwostudyarmsateachfollowͲuptimepoint.For UpholdLITE,therewerenolargedifferencesintheratesofindividualAEsemphasizedbythe FDAatthe2011Panelmeeting:pelvicpain,infection,vaginalshortening,atypicalvaginal discharge,neuromuscularproblems,vaginalscarring,denovovaginalbleeding,denovovoiding dysfunction,denovodyspareunia,andfistulaformation.ForXenform,theonlyoneoftheseAEs whereadifferencewasseenisdenovovoidingdysfunction(14.5%vs.4.4%forNTR),andthe majorityofcasesweretransientandresolvedwithminimalornomedicalinterventionanddid notimpactQOLscoresonpatientͲreportedmeasures.Despitethisobservationtherewereno largedifferencesinUDIͲ6ͲscoresbetweenXenformsubjectswhodidanddidnotexperiencede novovoidingdysfunction.

Regardingmesherosionandexposure,theFDAandthe2011Panelraisedconcernsregarding theseadverseeventsandtheirclinicalsequelae,giventheirpotentialtointroducerisksto patientsthatwouldnotoccurifundergoingNTR.Inthe2011Panelmeeting,theFDAindicated thateventsofmesherosionwerereportedthroughoutthefollowͲupperiodofsixmonthsto threeyearsandrangedfrom7.7%to19%.Importantly,thesecitedmesherosionratesarenot specifictoUpholdLITEorXenformdevicesbutarereportedfromavarietyofmeshdevicesthat arenolongermarketed,manyofthempreviousgenerationdevicesandtechniquesthathave sincebeenimprovedupon.Thesepreviouslyreporteddataareinconsistentwiththespecific dataforUpholdLITEandXenformdevices,wheretherehavebeennomesherosionsreportedin eithertheUpholdLITEorXenformPostmarketSurveillanceStudies,andmeshexposurerates werereportedat3.6%forUpholdLITEsubjectsand0.9%forXenformsubjects.Anevaluationof thesymptomspresentaccompanyingtheexposureandthemedicalinterventionnecessaryto achieveresolutionledtotheconclusionthatonlyoneoftheseexposureswarranted classificationasserious.Mostoftheseeventswereresolvedwithnoorminimal treatment/surgicalinterventionanddidnotresultinanynegativeimpacttothesubject’sbodily function/structure,physicalactivities,orqualityoflife.

TheratesformesherosionandexposureintheserecentstudieswheretheBSCUpholdLITEor XenformdeviceswereusedforPOPrepairaregenerallyconsistentwiththedatareportedinthe literature,andpresentlowerratesthanthosepreviouslypublishedintheliteraturepresented bytheFDAinthe2011Panelmeeting,whichreportedonheavierweightandhigherdensity meshimplantedwithmoreinvasivetechniquesusingtrocars.Specifically,inthemorerecent

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studiesspecifictoBSC’sdevicespresentingaminimumof12monthsoffollowͲup,withmany studiesshowinglongͲtermfollowͲupresultsof30monthsorgreater,therateofmesherosion rangesfrom1.4%to6.6%andtherateofmeshexposurerangesfrom2.6%to8%.Further, occurrencesoferosionandexposuredidnotnecessarilyresultinsurgicalinterventions.

TheriskspresentedbytheUpholdLITEandXenformdevicesareinlinewiththeriskspresented byothersurgicalrepairoptionsforNTR,withcomparableSAEandgeneralcomplicationrates equivalenttothosepresentedbyNTR.ThepotentialmeshͲrelatedcomplicationsdonotpresent additionalsignificantriskstopatients,astheseratesarecapturedintheSAEratesandoverall AErates,which,aspertheprospectivecontrolled522studies,arecomparablebetweentheBSC devicesandNTR.InametaͲanalysis,themeshexposurerateforsacrocolpopexyranged between1.4%and10%withameanof4.2%.Theseratesaresimilartothoseobservedinthe BSC522studies.Finally,BSCbelievestheavailabledataoutto18,24,and36monthsshowa higherrateofoveralldeviceandprocedureͲrelatedAEswithNTRversusUpholdLITE,and comparableratesforXenformversusNTR.

C.TheBenefitsofTVMOutweightheRisks

Insummary,BSCbelievesthattheimprovementsinmeshproductsandsurgicaltechniqueand correspondingreductionsincomplicationrates,theestablishedbenefitsandgenerally comparablerisksversusNTRbasedonBSC’s522studydatatoͲdate,andtherecentliterature supportthatthebenefitsofthesetreatmentsoutweightherisks.Further,therearenot additionalriskspresentedbytheuseofthesedevicescomparedtoothersurgicaloptionssuch asNTR.Thebroadstudypopulationtreatedinthe522studiesexperiencedcomparable,ifnot increased,benefitscomparedtoNTR,withoutincreasedseriousorotherriskspresentedbyuse ofthemeshdevices.Thebaselinecharacteristicsforthepatientsevaluatedinthesestudies reflectthegeneralpopulationseekingsurgicalrepair.Accordingly,theavailabilityoftheseTVM devicesappearstoprovideaviabletreatmentoptionforwomenwhochoosetopursuesurgical repairofPOPandlongerͲtermbenefitsthroughsustainedanatomicalcorrectionoftheprolapse withoutadditionalsafetyrisks.Thisisbasedonthepreliminary522studydataaswellasthe reportsintheliterature(e.g.,SUPeRstudy)

Further,therearedefinedpopulationsforwhomtransvaginalmeshmaybethebesttreatment optionavailablefortheirPOPrepair.InestablishingthebenefitͲriskratiofortransvaginalmesh forPOPrepair,itisalsorelevanttoexamineanyspecificpopulationsofwomenwhomight benefitfrommeshcomparedtoNTRandthusbeacceptingofanyincrementalrisk.Thereare severalsubpopulationsofwomensufferingfromPOP,wherethebenefit/riskprofileofTVMis potentiallymorefavorable.Specifically,theseinclude(ataminimum):(1)womenwhoseek uterinepreservation;(2)womenwhohavepreviouslyfailedNTR;(3)womenwithhighͲstage POP;and(4)womenwithconnectivetissuedisorders.Therefore,inthefaceofsimilarsafety profilesandwhereclinicallyindicated,itiscriticalfortransvaginalmeshtoremainanoptionfor cliniciansandpatientstoconsiderinelectingasurgicalrepairforanteriorand/orapicalPOP.

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Multiplerecentstudieshaveshownthat,giventheoption,36%Ͳ60%ofwomenwouldchoose uterinepreservationatthetimeofprolapserepair.30Moreover,preservationoftheuterusis associatedwithreducedratesofmeshexposure.31Therefore,thereisconsiderableinterestin hysteropexywithuterinepreservationasatreatmentforanteriorandapicalprolapse.Theuse ofUpholdLITEinconjunctionwithuterinepreservationwasspecificallyassessedinthe prospectiverandomizedSUPeRStudy,whichevaluatedtheeffectivenessandsafetyofmesh augmentedhysteropexyusingtheUpholdLITESystemcomparedtovaginalhysterectomyand uterosacralligamentsuspension(USLS).Importantly,therewasnodifferenceinprimary outcomeandfailureriskbetweentreatmentarmsforthecompositeprimaryefficacyoutcome at48months.Theestimatedcompositeendpointtreatmentsuccessratefromthesurvival modeltrendshigherforUpholdLITEat36months.Thesuccessratewas74%forUpholdLITE comparedto63%forHysterectomy&USLS.Intermsofsafety,thisstudyhadan8%mesh exposurerateintheUpholdLITEarmanda20%sutureexposurerateinthehysterectomyarm. Importantly,womenintheUpholdLITEarmwerenotonlyabletopreservetheiruterus,butalso sufferedlessvaginalshortening,hadshorteroperatingtime,lessbloodloss,andrequiredfewer bloodtransfusions.Inthefaceofsimilarsafetyprofilesandwhereclinicallyindicatedwomen oftenpreferuterinepreservationwhenelectingsurgicalrepairforPOP,transvaginalmesh hysteropexywouldbeapotentialandclinicallybeneficialtreatmentoption.

WomenwhohavefailedNTRrepresentanotherpopulationthatcouldbenefitfromtransvaginal meshoverrepeatedNTR.ThereareseveralriskfactorsthatpredictfailureofNTRincluding levatoraniavulsion,stageofPOP(3/4),parityandBMI.NTRhasbeenassociatedwithafailure rateof27%uptoasmuchas55%.ManyofthesewomenwillrequirereͲoperationtocorrect theirprolapseandwillnothaveorganictissueintegritythatsupportsasuccessfulrepair. Recognizingthatthispopulationwouldbeservedbyanalternativesurgicalapproach,certain guidelines,suchasthoserecentlyproposedbytheUKNationalInstituteforHealthandCare Excellence(NICE),recommendthattransvaginalmeshbeconsideredinwomenwhohavefailed previousNTR.Inthe522studies,treatmentsuccessontheprimarycompositeefficacyendpoint intheUpholdLITEarmat12monthsforwomenwithpreviousfailedNTRrepairis88.9%(32/36) andintheNTRarmis83.7%(36/43),whereasXenformsubjectsachievedcompositesuccessin 82.3%ofcases.

Relatedly,womenwithhighͲstage(3/4)POP–whichisoneofthekeyriskfactorsforfailureof NTR–presentanothersubpopulationforwhomthebenefitͲriskprofileofTVMmaybe favorable.Inthe522studies,treatmentsuccessontheprimarycompositeefficacyendpointin theUpholdLITEarmat12monthsforwomenwithanterior/apicalprolapsegradedasstage3 and4subjectsis91.4%(159/174)andintheNTRarmis87.8%(224/255),whereasXenform subjectsachievedcompositesuccessin86.7%(78/90)ofcases.

Finally,womenwithconnectivetissuedisorders(e.g.,MarfanSyndrome,EhlersͲDanlos syndrome,oraformefrusteofeither),maybegeneticallypredisposedtodevelopingPOPand maynothavethetissueintegritynecessaryforasuccessfulNTR.Thus,womenwithMarfan’sor  30Fricketal.FPM&ReconSurg19(2)pp.103Ͳ109March/April2013andKorblyetal.AmJObst&Gyn2013;209:470.e1Ͳ6.^ĞĞ ĂůƐŽJelovsekandBarber,AmJObstetGynecol.2006May;194(5):1455Ͳ61(findingthathysterectomyhasasignificantlynegative impactonbodyimageandqualityoflife). 31Meriwetheretal.AmJObstetGynecol.2018Aug;219(2):129Ͳ146.e2

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EhlersͲDanlossyndromesoraformefrusteofeither,whochoosesurgicalrepairofPOP,could benefitfromtheopportunitytobetreatedwithtransvaginalmesh.

D.AdditionalControlsSupportthePositiveBenefit/RiskRatio

ToensurethatphysiciansunderstandtheBSCdevices,theappropriatepatientpopulation,and implantationtechniques,thelabelingforthedeviceshasbeenupdatedtoprovidefurther guidance,asdescribedinSection3E.BSChasalsodevelopedpatientͲspecificlabeling,as recommendedbythe2011Panel,toprovideinformationregardingthebenefitsandrisksof TVMtohelppatientsmakeinformedhealthcaredecisionsinconjunctionwiththeirphysician.

BSCisfurthercommittedtophysicianeducationasatoolformitigatingpatientrisksassociated withproductuse.BSCprovidesdetailedphysicianeducationcomprisingacontinuumoftraining aimedatadvancingphysicianfamiliaritywiththeproductandprocedureandmaximizingpatient outcomes.Trainingavailableandprovidedincludesaccesstoonlineeducationalinformation andhandsͲonexperiencethroughdirectedtrainingcourses,surgicalmodels,proctorships, preceptorships.

Benefit/RiskConclusions

Insummary,BSCbelievesthatthebenefitsoutweightherisksforbothUpholdLITEandXenform forthefollowingreasons:

x Thebenefitsofrepairwithmeshareclearlydemonstratedwithstudiesevaluatingthe BSCdevicesshowingefficacyinrestoringanatomyandclinicallysignificantimprovement inpatientsymptomsat12months. x ObjectivesuccessrateswerenumericallyhigherfortheUpholdLITEdevicecomparedto NTRat12monthsoverallandintheapicalcompartment,whichappearstopersistand increaseouttothe36Ͳmonthendpointbasedontheavailabledata. x ReͲoperationratesforPOPrecurrencewerecomparableorlowercomparedtoNTR. x Improvementsinthephysicalcharacteristicsofpolypropylenemeshandinsurgical techniqueforimplantingithavecontributedtodecliningadverseeventrates. x AdverseeventsassociatedwithtransvaginalrepairofPOPwithBSC’sdeviceshave generallybeenminorandtemporary.Therateofseriousadverseeventsobservedin the522studieswascomparableforboththeUpholdLITEandXenformsubjectstothe correspondingratesforNTRsubjects. x BSChasanextensivephysicianeducationandtrainingprograminplacetoprovide supportforphysicianswhodesiresupplementaleducationonsurgicaltechnique, patientselection,andmanagementofcomplications. x TheprospectivecontrolleddataandliteratureconcerningtransvaginalmeshPOPrepair supportthat(1)meshshouldbeconsideredasanalternativetoNTRgenerally,and(2) certainsubpopulationswhomanynotbeappropriatecandidatesforNTRcouldbenefit fromTVMprocedures. 

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SECTION9:CONCLUSION

Insummary,theexistingdatapresentedintheliteratureandtheprospectivecontrolledstudies evaluatingtheUpholdLITEandXenformdevicesdemonstratesthatthereissufficientinformationto supportthesafetyandefficacyofsurgicalmeshfortransvaginalPOPrepair.Theavailabledataprovide conclusiveevidencethatthetransvaginalplacementofsurgicalmeshforPOPrepairprovidesatleast comparableresultsasNTR,withoutpresentationofsignificantadditionalandunwarrantedrisks.The reportedincidenceofmeshexposureanderosionandsubsequentrequiredsurgicalintervention presentedduringthe2011Panelmeetingisnotreflectiveofcurrentmeshdevicesusedintransvaginal meshrepairofPOP,oroftheimplantationtechniquesnowusedforthedevices.Morerecentliterature demonstratesashiftintheadverseeventrate,withacomparablerisk/benefitprofiletoNTR.Further, longertermdatasuggesttheremaybeincreasedbenefitsinatleastasubsetofwomensufferingfrom POP.

PreclinicalandclinicalinformationdemonstrateareasonableassuranceofsafetyandefficacyforTVMin treatinganterior/apicalPOP,andthesedevicesshouldremainonthemarketasatherapeuticoptionfor indicatedpatients.Thecontinuedavailabilityoftheseproducts,includingtheUpholdLITEandXenform devices,wouldensureimprovedpatienttreatmentallowingsafetyandeffectiveoptionsavailableto physiciansformakingtheappropriateclinicalcaredecisioninanindividualcase.TheindustryͲwide trainingprogramsalreadyinplace,coupledwiththedetailedsurgicalinstructionsforuseandavailable traininginformationandsurgicalimplantationtechnique,willfurtherensurethatTVMproceduresresult inminimalcomplications,consistentwiththemorerecentliteratureandthedatainBSC’sprospective 522studies,thusfurtherimprovingthebenefit/riskratioofthedevices.

BostonScientificCorporationfirmlybelievesthatthetotalityofclinicalevidencesupportsthepositive benefit/riskprofileofitsUpholdLITEandXenformtransvaginalmeshdevicestotreatpelvicorgan prolapse(POP).

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SECTION10:REFERENCES

1. OlsenAL,SmithVJ,BergstromJO,CollingJC,ClarkAL.Epidemiologyofsurgicallymanagedpelvic organprolapseandurinaryincontinence.ObstetGynecol.1997;89:501–506. 2. CornwellK,Zhang,LineaweaverW,(2016).Bovinefetalcollagenreinforcementinasmall animalmodelofherniawithcomponentrepair.J.SurgicalResearch.201,416Ͳ424. 3. Abedetal.IncidenceandManagementofGraftErosion,WoundGranulation,andDyspareunia FollowingVaginalProlapseRepairWithGraftMaterials:aSystematicReview.Int.UrogynecolJ. 201122:789Ͳ798 4. DiwadkarGB,etal.Complicationandreoperationratesafterapicalvaginalprolapsesurgical repair:asystematicreview.ObstetGynecol.2009;113(2Pt1):367Ͳ73. 5. GoldsteinHB,etal.Amulticenterprospectivetrailevaluatingfetalbovinedermalgraft(Xenform Matrix)forpelvicreconstructivesurgery.BMCUrology(2010)10:21. 6. JelovsekJE,BarberMD.Womenseekingtreatmentforadvancedpelvicorganprolapsehave decreasedbodyimageandqualityoflife.AmJObstetGynecol.2006;194(5):1455–1461. 7. FrickAC,BarberMD,ParaisoMarieFidelaR,RidgewayB,JelovsekJE,WaltersMD.Attitudes towardhysterectomyinwomenundergoingevaluationforuterovaginalprolapse.FemalePelvic MedReconstrSurg.2013;19:103–9. 8. KorblyNB,KassisNC,GoodMM,etal.Patientpreferencesforuterinepreservationand hysterectomyinwomenwithpelvicorganprolapse.AmJObstetGynecol2013;209:470.e1Ͳ6. 9. KuncharapuI,MajeroniB,andJohnsonD.PelvicOrganProlapse.AmericanFamilyPhysician. 2010;81(9):1111Ͳ1117. 10. BrincatC,LarsonK,andFennerD.AnteriorVaginalWallProlapse:AssessmentandTreatment. ClinicalObstetricsandGynecology.2010;53(1):51Ͳ58. 11. JakusS,ShapiroA,andHallC.BiologicandSyntheticGraftUseinPelvicSurgery:AReview. ObstetricalandGynecologicalSurvey.2008;63(4):253Ͳ266. 12. MaherC,FeinerB,BaesslerK,ChristmannͲSchmidC,HayaN,BrownJ.Surgeryforwomenwith anteriorcompartmentprolapse.CochraneDatabaseofSystematicReviews2016,Issue11.Pg. 21. 13. NazemaY.SIDDIQUI,MD,MHSc,CaraL.GRIMES,MD,ElizabethR.Casiano,MD,HusamT.ABED, MD,PeterC.JEPPSON,MD,CedricK.OLIVERA,MD,TatianaV.SANSES,MD,AdamC. STEINBERG,DO,MaryM.SOUTH,MD,EthanM.BALK,MD,MPH,andVivianW.SUNG,MD, MeshSacrocolpopexyComparedWithNativeTissueVaginalRepair:ASystematicReviewGroup, ObstetGynecol,2015January;125(1):44Ͳ55 14. TheUpholdSystemwasalargeporemonofilamentmeshandhadthesameshapeasUphold LITE,butwasdenserthanUpholdLITE(40g/m2).Sourcedocumentationonfile. 15. https://www.federalregister.gov/documents/2014/05/01/2014Ͳ09907/reclassificationͲofͲ surgicalͲmeshͲforͲtransvaginalͲpelvicͲorganͲprolapseͲrepairͲandͲsurgical 16. IglesiaC.B.,etal,Vaginalmeshforprolapse:arandomizedcontrolledtrial.ObstetGynecol, 2010.116(2Pt1):p.293Ͳ303. 17. WithagenM.I.,etal,TrocarͲguidedmeshcomparedwithconventionalvaginalrepairin recurrentprolapse:arandomizedcontrolledtrial.ObstetGynecol.2011.117(2Pt1):p.242Ͳ50.

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18. DeLanceyetal.,TheRelationshipBetweenAnteriorandApicalCompartmentSupport.American JournalofObstetrics&Gynecology(2006)194,1438Ͳ43 19. Lowderetal.,TheRoleofApicalVaginalSupportintheAppearanceofAnteriorandPosterior VaginalProlapse.Obstetrics&Gynecology2008;111(1):152Ͳ7) 20. RahkolaͲSoisaloetal.PelvicOrganProlapseRepairUsingtheUpholdVaginalSupportSystem:5Ͳ YearFollowͲup.FemalePelvicMedicineandReconstructiveSurgery. 21. NagerCW,ZyczynskiH,RogersRG,BarberMD,RichterHE,ViscoAG,RardinCR,HarvieH, WallaceD,MeikleSF;PelvicFloorDisordersNetwork.TheDesignofaRandomizedTrialof VaginalSurgeryforUterovaginalProlapse:VaginalHysterectomyWithNativeTissueVault SuspensionVersusMeshHysteropexySuspension(TheStudyofUterineProlapseProcedures RandomizedTrial).FemalePelvicMedReconstrSurg.2016JulͲAug;22(4):182Ͳ9. 22. AltmanD,MikkolaTS,BekKM,RahkolaͲSoisaloP,GunnarssonJ,EnghME,FalconerC;Nordic TVMGroup.PelvicorganprolapserepairusingtheUphold™VaginalSupportSystem:a1Ͳyear multicenterstudy.IntUrogynecolJ.2016Sep;27(9):1337Ͳ45. 23. AltmanD.,etal,AnteriorColporrhaphyversusTransvaginalMeshforPelvicͲOrganProlapse.N EnglJMed.,2011.364:p.1826Ͳ36. 24. GutmanRE,RardinCR,SokolER,MatthewsC,ParkAJ,IglesiaCB,GeoffrionR,SokolAI,Karram M,CundiffGW,BlomquistJL,BarberMD.Vaginalandlaproscopicmeshhysteropexyfor uterovaginalprolapse:aparallelcohortstudy.AmJObstetGynecol.2017Jan;216(1):38.e1Ͳ 38.e11. 25. Loetal.AnteriorͲapicalsingleͲincisionmeshsurgery(uphold):1Ͳyearoutcomesonlowerurinary tractsymptoms,anatomyandultrasonography.InternationalUrogynecologyJournalJune2018. 26. T.H.Su,H.H.Lau,W.C.Huang,C.H.Hsieh,R.C.Chang,C.H.Su,SingleͲincisionmeshrepairversus traditionalnativetissuerepairforpelvicorganprolapse:resultsofacohortstudy,Int UrogynecolJ,25(2014),pp.901Ͳ908 27. See,e.g.,NygaardIE,McCreeryR,BrubakerL,ConnollyA,CundiffG,WeberAM,ZyczynskiH (2004)Abdominalsacrocolpopexy:acomprehensivereview.ObstetGynecol2004Oct;104:805– 23(reportinga3.4%mesherosionrate). 28. Hysterectomyrequirementwasincludedininitialversionsoftheprotocolandremovedina subsequentversion(releasedon24OCT2014).83Upholdand60NTRsubjectsindicatedthey hadaprevioushysterectomy.Sourcedocumentationonfile. 29. Severityofeventswasclassifiedasfollows:MildͲAwarenessofsignsorsymptoms,buteasily toleratedandareofminorirritanttypecausingnolossoftimefromnormalactivities. Symptomsdonotrequiretherapyoramedicalevaluation;signsandsymptomsaretransient; ModerateͲEventsintroducealowlevelofinconvenienceorconcerntotheparticipantandmay interferewithdailyactivities,butareusuallyimprovedbysimpletherapeuticmeasures; moderateexperiencesmaycausesomeinterferencewithfunctioning;SevereͲEventsinterrupt theparticipant’snormaldailyactivitiesandgenerallyrequiresystemicdrugtherapyorother treatment;theyareusuallyincapacitating.Sourcedocumentationonfile. 30. Fricketal.FPM&ReconSurg19(2)pp.103Ͳ109March/April2013andKorblyetal.AmJObst& Gyn2013;209:470.e1Ͳ6.SeealsoJelovsekandBarber,AmJObstetGynecol.2006May;

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194(5):1455Ͳ61(findingthathysterectomyhasasignificantlynegativeimpactonbodyimage andqualityoflife).Sourcedocumentationonfile. 31. Meriwetheretal.AmJObstetGynecol.2018Aug;219(2):129Ͳ146.e2  

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APPENDIX1

LiteratureSearchStrategy  UpholdLITEVaginalSupportSystem Numerousliteraturesearcheshavebeenconducted,bothnationallyandinternationally,tofully assessandsupporttheclinicalandsafetyprofileofUpholdLITEVaginalSupportSystem.The searcheswereconductedintheonlinedatabaseMedline,EMBASE,andArticlesofInterest.The searchstrategyisdeterminedbytheSearchCriteriaandemployedwithinresearchdatabases usingBooleanlogicforinformationretrieval.Eachsearch“set”progressestheoverallsearch resultsfromgeneraltospecificfindings.Thesearchstrategyiscapturedtoillustratetheprecise searchapproachtakentoyieldsearchresults.

LiteratureSearch#1:BSCperiodicallyconductsliteraturesearchtosupportBSC’sinternalclinical documentationforcurrentlymarketeddevices.Searchcriterialistedbelowwereincludedinthe initialsearchforthetimeperiodofApril1,2014throughSeptember30,2016. LiteratureSearchInclusionCriteria x Topic:Surgicalmeshorgraftsusedforpelvicfloorprolapse.Devicesof particularinterestinclude:BSC’sUpholdandPinnacle,AstoraWomen’s Health(EndoIntl,formerlyAMS,AmericanMedicalSystems)’ElevateProlapse RepairSystemandPerigeeTransobturatorAnterior,ApogeeVaultProlapse RepairSystemsorGynecare’s(Ethicon/J&J)’sProliftPelvicFloorRepairsystem; x DocumentTypes:clinicalstudies,reviewarticles x Language:EnglishlanguagefullͲtext x TimePeriod:April1,2014throughSeptember30,2016  LiteratureSearch#2:TofurthersupportUpholdLITE’sPostMarketApprovalapplication, currentlyunderreview,anadditionalsearchwasconductedwiththeprevioussearchcriteriafor anextendedtimeperiod. LiteratureSearchInclusionCriteria x Topic:anymentionofBSC’sUpholdorUpholdLITE x DocumentTypes:ClinicalStudies(includingmetaͲanalysis),reviewarticles. x Language:EnglishlanguagefullͲtext x TimePeriod:Publicationyear2012toMay2018  LiteratureSearch#3:Additionally,BSCconductedathirdsearch,specifictoavailableconference meetingabstractsforthetimeperiodof2000toMarch2018. LiteratureSearchInclusionCriteria x Topic:UpholdLITE.Thefollowingconferenceswereofparticular interest:AAGL,ACOG,AUA,AUGS,ICS,IUGA,SGS,SUFU. x DocumentTypes:meetingabstracts. x Language:Englishlanguagefulltext. x TimePeriod:publicationyear2000toMarch2018.

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 ConferenceAbstractsnotavailablethroughacommercialdatabase(CD),where available(throughsubscriptionoropenaccess),journalabstractsupplementswere checkedforthefollowingconferencesandyears: 1) AAGL(AmericanAssociationofGynecologicLaparoscopists):CDincluded2010Ͳ 2017(2018notyetpublished);checkedjournalsupplements(JMinimallyInvas Gynecol)for2005to2009.Nothingavailablefor2000Ͳ2004. 2) ACOG(AmericanCollegeofObstretriciansandGynecologists):CDincluded 2014Ͳ2017(2018notyetavailable).Journalsupplementschecked(ObstetGyn) for2000Ͳ2013. 3) AUA(AmericanUrologicalAssociation):CDincluded2009Ͳ2017(2018notyet available).Journalsupplementschecked(JUrol)2000Ͳ2008. 4) AUGS(AmericanUrogynecologicSociety):CDincluded2011Ͳ2017(2018notyet available).Journalsupplementschecked(FemalePelvicMedReconstr.2010;J PelvicMedSurg2002Ͳ2005,2007Ͳ2009).Abstractswerenotfoundfor2000Ͳ 2001or2006. 5) ICS(InternationalContinenceSociety):CDincluded2009Ͳ2017(2018notyet available).JournalsupplementscheckedfromtheLibrary’sarticlecollection, previouslypurchasedcontent,becausethejournalisnotanactivesubscription (NeurourolUrodyn2004,2007,2008).Unabletoaccessfullabstractsfor2000Ͳ 2003,2005Ͳ2006. 6) IUGA(InternationalUrogynecologicalAssociation):CDincluded2010Ͳ2008. JournalsupplementscheckedfromtheLibrary’sarticlecollection,previously purchasedcontent,becausethejournalisnotanactivesubscription(Int UrogynecolJ2004and2007).Unabletoaccessthefullabstractsfor2000Ͳ2003, 2005Ͳ2006. 7) SGS(SocietyofGynecologicSurgeons):CDincluded2009Ͳ2013,2015Ͳ2018. Journalsupplementschecked(JMinnimallyInvasGyn2014,JPelvicMedSurg 2004Ͳ2006,2008).AccessedtheSGSwebsitetoretrievetheabstractprogram for2007.Unabletoaccessfullabstractsfor2000Ͳ2003. 8) SUFU(SocietyforUrodynamicsandFemaleUrology):CDincluded2014Ͳ2018. JournalsupplementscheckedfromtheLibrary’sarticlecollection,previously purchasedcontent,becausethejournalisnotanactivesubscription(Neurourol Urodyn2007Ͳ2013).Unabletoaccessthefullabstractsfor2000Ͳ2006.

Articleswereexcludediftheywere: x specifictoproductsotherthanUpholdLITE x Interimreports/duplicatereferences x Invitrostudiesandanimalstudies x Reportsandarticlesavailableonlyinforeignlanguage x Nonsystematicreviews,editorials,letters x Unsubstantiatedopinions x Unrelatedtosearchtopic  Theseweresupplementedwithanadditionalmanualsearchforpublishedliteraturespecificto UpholdLITEwhichincludedafullreviewofrelevantarticlesreferencedintheSeptember2011 FDAExecutiveSummaryfromtheSurgicalMeshObstetrics&GynecologyAdvisoryCommittee

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Meeting,suggestedarticlesbyKeyOpinionLeaders,aswellasarticlesfoundthroughreference mining.  XenformSoftTissueRepairMatrix BSCperformedaliteraturesearchoftheMEDLINE,EmbaseandGoogleScholardatabasesto identifypublicationsspecifictoXenformforuseinPOP.Thefollowingsearchandinclusion criteriawereused:

Documenttypes: Clinicalstudies(includingmetaͲanalyses),reviewarticles. Language: EnglishLanguagefullͲtext Timeperiod: April26,2008April26,2018 SearchTerms: Xenform 

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