The regulatory ancestral network of surgical meshes

12 Pages·2017·2.72 MB·English

RESEARCHARTICLE
The regulatory ancestral network of surgical
meshes
NasimZargar*,AndrewCarr
NuffieldDepartmentofOrthopaedics,RheumatologyandMusculoskeletalSciences(NDORMS),Botnar
ResearchCentre,UniversityofOxford,Headington,Oxford,UnitedKingdom
*[email protected]
a1111111111 Abstract
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Background
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AllsurgicalmeshesenteringtheU.S.markethavebeenclearedforclinicalusebythe510
(k)processoftheFoodandDrugAdministration(FDA),inwhichdevicessimplyrequire
proofof“substantialequivalence”topredicatedevices,withouttheneedforclinicaltrials.
However,recalledmeshesassociatedwithadverseeffectsmay,indirectly,continueto
OPENACCESS
serveaspredicatesfornewdevicesraisingconcernsoverthesafetyofthe510(k)route.
Citation:ZargarN,CarrA(2018)Theregulatory
ancestralnetworkofsurgicalmeshes.PLoSONE
Methodology
13(6):e0197883.https://doi.org/10.1371/journal.
pone.0197883
Hereweassessthepotentialmagnitudeofthisproblembydeterminingtheancestral
Editor:IratxePuebla,PublicLibraryofScience, networkofequivalenceclaimslinkingrecentlyclearedsurgicalmeshes.UsingtheFDA
UNITEDKINGDOM
websiteweidentifiedallsurgicalmeshesclearedbythe510(k)routebetweenJanuary2013
Received:May14,2017 andDecember2015alongwithalllistedpredicatesforthesedevices.Usinganetwork
Accepted:May6,2018 approach,wetracetheancestryofpredicatesacrossmultiplegenerationsofequivalence
claimsandidentifythosemeshesconnectedtodevicesthathavesincerecalledfromthe
Published:June19,2018
marketalongwiththereasonfortheirrecall.
Copyright:©2018Zargar,Carr.Thisisanopen
accessarticledistributedunderthetermsofthe
Conclusions
CreativeCommonsAttributionLicense,which
permitsunrestricteduse,distribution,and Wefindthatthe77surgicalmeshesclearedbetween2013and2015arebasedon771inter-
reproductioninanymedium,providedtheoriginal
connectedpredicateclaimsofequivalencefrom400otherdevices.Thevastmajorityof
authorandsourcearecredited.
thesedevices(97%)aredescendedfromonlysixsurgicalmeshesthatwerepresentonthe
DataAvailabilityStatement:Allrelevantdataare
marketpriorto1976.Oneoftheseancestralmeshesalone,providedthebasisof183sub-
withinthepaperanditsSupportingInformation
files. sequentdevices.Furthermore,weshowthat16%ofrecentlycleareddevicesareconnected
throughequivalenceclaimstothe3predicatemeshesthathavebeenrecalledfordesign
Funding:Theauthorsacknowledgefinancial
supportfromtheNationalInstituteforHealth andmaterialrelatedflawscausingseriousadverseevents.Takentogether,ourresults
Research(NIHR)OxfordBiomedicalResearch showthatsurgicalmeshesareconnectedthroughatangledwebofequivalencyclaimsand
Centre.Thefundingsourcehadnoroleinthe
manymeshesrecentlyclearedbytheFDAhaveconnectionsthroughchainsofequivalency
designandconductofthestudy,inthecollection,
todeviceswhichhavebeenrecalledfromthemarketduetoconcernsoverclinicalsafety.
analysisandinterpretationofthedata,orinthe
preparation,review,orapprovalofthemanuscript. Thesefindingsraiseconcernsovertheefficacyofthe510(k)routeinensuringpatient
safety.
Competinginterests:Theauthorshavedeclared
thatnocompetinginterestsexist.
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Ancestralnetworkofsurgicalmeshes
Introduction
Since2008andfollowinganescalationinadverseeventsreportedtotheManufacturersand
theUserFacilityDeviceExperience(MAUDE)database,theUSFoodandDrugAdministra-
tion(FDA)hasissuedanumberofnotificationsassociatedwiththelongtermandirreversible
effectsofusingsomeofthesurgicalmeshesavailableonthemarket[1,2,3].Allsurgicalmeshes
ontheUSmarketaredesignatedbytheFDAaspotentiallyposingamoderaterisktopatient
health(classII)andwereclearedthroughthe510(k)framework.Clearancethroughthe510(k)
routeisbasedondemonstratingthe“substantialequivalence”ofadevicetoanexistingand
previouslyclearedpredicatedevice.Independentclinicalevidenceforthesafetyandeffective-
nessofthenewdeviceisrarelyrequired[4,5,6,7,8].Theseriouscomplicationssufferedby
somepatientshaveresultedinanumberofclass-actionlawsuitsandcriticismthatthe510(k)
isnotprovidingsufficientprotectionforpatients[9,10,11,12].In2014,asaconsequenceof
significantincreasesinthenumberofreportedadverseeventsassociatedwiththeuseofsurgi-
calmeshforpelvicfloorrepair,theFDAissuedorderstoreclassifytwoofthe37groupsofsur-
gicalmeshes(syntheticandnon-syntheticmeshesforPelvicOrganProlapserepair)fromclass
IItoclassIII.Asaresultofthisactionmanufacturersofnewmeshesaswellasthosecurrently
onthemarketmustsubmitaPre-marketApprovalbeforethosedevicescanbeapprovedfor
marketing.
Oneofthekeyproblemspreviouslyidentifiedwiththe510(k)frameworkisthatdespitethe
legalrequirementthatthescientificevidencedemonstratingsubstantialequivalencetoapredi-
catedevicebemadepubliclyavailable,thisinformationisofteneitherlackingorinsufficient
[13].However,evenwhensubstantialequivalencetoapredicateisdemonstrated,thisdoes
notensurethesafetyofthedevice,if—asisexclusivelythecase—thepredicatesusedwerealso
clearedwithoutevidenceofsafetyandeffectiveness[13].Indeed,givenrepeatedclaimsofsub-
stantialequivalency,acrossmultiplegenerationsofdevices,theultimatepredicatesofanynew
surgicalmeshcaneventuallybetracedbacktodevicesthatweremarketedpriortothe1976
MedicalDeviceAmendmentAct.Priortothisact,regulationwaslimitedtoissuesofmis-
brandingandthehygieneofthemanufacturingprocessandtherewasnoadditionalrequire-
menttoprovethesafetyandefficacyofthesedevices[13].Furthermore,giventherequirement
forsubstantialequivalencebetweendevices,unrecognizeddesignflawspresentinapredicate
havethepotentialtobepassedontoanydescendantdevicesinheritingthesefeatures.Andyet,
becausethefullgenealogyofancestralrelationshipsconnectingdevicesclearedthroughthe
510(k)frameworkisnotreported(onlytheimmediatepredicatesofadevicearelisted),these
inheriteddesignflawsmayoftengoundetected.Asaresult,evenifadevicehasbeenrecalled
duetoseriousdesignflawsresultinginadversepatientoutcomes,itispossiblethatnumerous
descendentdevices,potentiallysharingthesecriticalflaws,maystillbeonthemarketand
inregularclinicaluse.Theinheriteddesignflawsthatgoundetectedinsuchcaseshavethe
potentialtocauseseriouscomplicationsinpatientsreceivingthesedevicesbuttheextentof
thisproblemremainsunclear.
HereweusetheFDA510(k)databasetoinvestigatetheancestralpathwaythroughwhich
surgicalmesheshavecometomarket.Giventhelargenumberofdevicesinvolvedweemploy
anetworkapproachthatenablesustorapidlytracetheconnectionsbetweenanyselected
deviceandbothitspredicatesanddescendants.Usingthistechnique,weaddressthreekey
aims.First,wedeterminethenumberofpredicatesonwhicheachdeviceisbasedandhowthis
accumulatesovermultiplegenerationsofsubstantialequivalencyclaims.Second,wedeter-
minethenumberofmeshesthataredescendedfrompredicatesthathavesincebeenrecalled
fordesignrelatedflaws.Finally,weevaluatethepotentialriskofinheritingdesignrelatedflaws
byquantifyingthenumberoforiginalmeshesfromwhichallrecentlycleareddeviceshave
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Ancestralnetworkofsurgicalmeshes
descendedandthedegreeofinterrelatednessamongstthesemeshes.Forthosemeshesthat
haveresultedinthehighestnumberofdescendantswecriticallyexaminetheoriginalscientific
and/orclinicalevidencefortheirsafetyandeffectiveness.
Methods
Weidentifiedallnewdevicesundertheproductcode‘surgicalmesh’clearedthroughthe510
(k)frameworkbetweenthe1stofJanuary2013andthe31stofDecember2015(n=77)and
tracedtheirancestrythroughmultiplegenerationsofpredicates(S1Data).Foreachdevice,we
identifiedthepredicatesthatwereusedassubstantialequivalents,andthenrepeatedthispro-
cessbackwardsthroughtimeforasmanygenerationsaspossiblegiventheinformationavail-
ableontheFDAwebsite(https://www.fda.gov).Insomecases,theidentityofthepredicates
wasnotprovidedpreventingasearchintothedeeperancestryofthatdevice.
Tracingtheancestryofdevicesistimeconsuming,becausethisinformationhastobe
extractedfromtheindividual510(k)devicesummaries.ApreviousstudybyZuckermanetal
[13]examinedtheevidenceforsubstantialequivalenceclaims,acrossavarietyofimplantable
devicescategories(cardiovascular,dental,generalandplasticsurgery,neurologicalandortho-
pedic)butfocusedonreconstructingtheancestryoftwocleareddevicespercategoryperyear,
from2008to2012,thusincludingatotaloftensurgicalmeshes.Incontrast,hereweperforma
morein-depthanalysisofall77surgicalmeshesclearedbetween2013–15andtheirancestral
predicates.Intotal,weexamined771device-predicateconnectionsacross477uniquesurgical
meshes.
Werecordedtheyearsinwhicheachpredicatedevicewasclearedformarket,whetherthat
devicewasclearedpriortothe1976MedicalDeviceAmendmentActandwhetherthedevice
hadsubsequentlybeenrecalled.TheFDAusestheterm“recall”whenamanufacturertakesa
correctionorremovalactiontoaddressaproblemwithamedicaldevicethatviolateslaws
administeredbytheFDA.AccordingtotheFDAwebsite“Recallsoccurwhenamedicaldevice
isdefective,whenitcouldbearisktohealth,orwhenitisbothdefectiveandarisktohealth”.
Inmostcases,acompany(manufacturerordistributor)voluntarilyrecallsamedicaldevice
thatisinviolationoftheFDAlawsbynotifyingtheFDAofthepotentialproblemsandinitiat-
ingtherecallthroughcorrectionorremovalofthedevicefromthemarket.However,incases
wherethecompanyfailstorecallthedefectivedevice,theFDAhasthelegalrighttorecallthe
devicebasedontheevidenceofapotentialrisktopublichealth.TheFDAthenreviewsand
monitorstherecallstrategyoftherecallingfirm.Inthecaseofrecalledimplantabledevices,
suchasmeshes,whichhavethepotentialtofailunexpectedly,companiesoftenrequesttherel-
evantmedicalprofessionalstocontactthepatientsanddiscusstheriskofremovingthedevice
comparedtotheriskofleavingitinthebody.Examplesofthetypesofactionsthatmaybe
consideredforarecalleddeviceinclude:inspectingthedeviceforpotentialproblems,monitor-
ingpatientsforhealthissuesandinsomecasesremovingtheimplantfromthebody.Devices
mayberecalledfornumerousreasonsincludingthosenotdirectlyassociatedwiththedevice
inquestion(e.g.issueswithpackagingorsterilisation).Foreachrecalleddevicewetherefore
searchedforthecauseoftherecallfromtheFDAmedicalrecallsdatabase.Weidentifiedthose
devicesrecalleddueto‘designandmaterialrelatedflaws’(e.g.mechanicalproblemsleadingto
devicebreakageorfailure).
Toinvestigatethehistoricalpatternsofancestrybetweenrecentlycleareddeviceswegener-
atedanetworkdescribingtheancestor-descendentrelationshipsbetweenall477meshes.
Thisnetworkisakintoagenealogicaltree.Eachnoderepresentsauniquemeshwiththelinks
betweennodesindicatingwhenadevicewasusedasapredicateor‘parent’ofanotherdevice.
Theterminalnodesofthetreecorrespondtodevicesthathaveyettobeusedasapredicateof
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Ancestralnetworkofsurgicalmeshes
anotherdevice.Wefirstusedthisnetworktotakea‘bottom-up’approach(i.e.fromthepres-
enttothepast),quantifyingforeachmeshboththenumberoffirst-generationpredicateson
whichsubstantialequivalencywasbasedandthetotalnumberofpredicatesinthemeshes
ancestry,potentiallystretchingbackovermanygenerations.Wequantifiedthetotalnumber
ofpredicatedevicesclearedduringeachyearsince1976andthenumberofgenerationscon-
nectingeachdevicetoitsfounderdevice(i.e.theearliestdevicelistedonthe510(k)database).
Wecalculatedtheproportionofmesheswithadeviceintheirancestrythati)wasplacedon
themarketpriortothe1976MedicalDeviceRegulationActorii)hadbeenrecalledfor‘design
andmaterialrelatedflaws’.
Wethentooka‘top-down’approach,andforeachmeshinourdatasetcalculatedthenum-
berofdevicesdescendingfromthatmesh.Forthosemesheswithmorethan100descendants
weusedthedevicesummariestorecordwhetherclinicalorpre-clinicalevidencewasprovided
andifsothetypeofevidenceused.
AllanalyseswereconductedintheRstatisticalprogrammingenvironmentusingthe‘graph’
and‘igraph’libraries.
Results
Ofthe77surgicalmeshesclearedinthestudyperiod,74providedinformationontheidentity
ofthepredicatesonwhichsubstantialequivalencewasbased.Thenumberofpredicates
citedbyeachmeshvariedfromonetoseven,butonaverageonlyasinglepredicatewasused
(median=1,mean=2).However,becausethepredicatesofeachdevicewerethemselves
clearedthroughthe510(k)frameworkthetotalnumberofancestralpredicatesunderlyinga
deviceissubstantiallygreater(Fig1a).Themediantotalnumberofuniquepredicatesaccumu-
latedbyeachdevicewas33(mean=39),spreadacross,onaverage,sevengenerations.The
maximumnumberofancestralpredicatesforanymeshwas165(device510(k)number=
“K133223”)(Fig1a).Intotalweidentified771predicatedevicesfromwhichthe77devices
hadarisen.Thisisanunderestimateofthetruenumberofpredicatesbecausein128casesno
informationontheidentityofthepredicateswasavailable,eitherbecausethiswasnotlisted
inthesummarysheet(n=22)orbecausethesummarysheetwasnotprovided(n=106).Of
the771predicates,only400oftheserepresentuniquedevicesbecausemanydevicessharethe
samepredicates.
Ofthe74recentlyclearedmeshesforwhichinformationontheirancestrywasavailable,
thepredicatesof52meshes(70%)couldbetracedbacktosurgicalmeshesarisingpriortothe
1976MedicalDeviceAmendmentAct.Inallothercases,ancestralrelationshipsweretermi-
natedbydevicesforwhichnoinformationonpredicateswasprovided.Hadthisinformation
beenavailable,allsurgicalmeshesclearedbetween2013and2015wouldhaveultimatelyarisen
fromapre-amendmentdevice.Meshesclearedbetween2013and2015rarelydirectlycitepre-
amendmentdevices(n=1),butinmanycasesitwaspossibletotraceameshbacktoapre-
amendmentdevicewithinonlytwo(n=9,17%)orthree(n=19,37%)generations.Thus,
despitethefactthatpre-amendmentdeviceswerenotsubjecttosafetyandeffectivenessstan-
dards,theycontinuetoprovidethebasisofsubstantialequivalenceforsurgicalmeshescur-
rentlyenteringthemarket.
Acrossthe74surgicalmeshesrecentlycleared,theaveragedateatwhichtheirimmediate
predicatesenteredthemarketwas2009.Inotherwords,mostdevicestypicallycitepredicates
thatenteredthemarketonaverageonly4.5yearsearlier.Althougheachmeshnecessarilyhas
atleastoneimmediatepredicate,thetotalnumberofancestralpredicatedevicesdecreases
withtimebeforethepresentbecausemanydevicesareusedinmultipleequivalencyclaims
(Fig1b).Forinstance,allofthe74newdevicesstemfromonly23predicatesthatenteredthe
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Ancestralnetworkofsurgicalmeshes
Fig1. a)ThenumberofancestralpredicatesunderlyingsurgicalmeshesclearedbytheFDAbetween2013–2015.Each
surgicalmeshhasonaverage33ancestralpredicates,butthenumberofancestorsdifferswidelybetweenmeshesb)the
numberofdevicesinourdataset(n=477)clearedbytheFDAeachyearfrompriortothe1976MedicalDevice
AmendmentAct2015(i.e.<1976)to2015.
https://doi.org/10.1371/journal.pone.0197883.g001
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Ancestralnetworkofsurgicalmeshes
Fig2.Thetotalnumberofdescendentdevicesconnectedtoeachancestralpredicate(n=400)bychainsof
substantialequivalency.Ancestralpredicatesaregroupedaccordingtothetimeperiodinwhichtheyenteredthe
market(barcolor)tohighlightthattheskeweddistributioninthenumberofdescendentdevicesisnotanartefactof
thetimeavailableforancestralpredicatestoaccumulatedescendants.MersileneSurgicalMeshhadthelargestnumber
ofdescendentdevicesandishighlighted(seeFig3fortheancestralhistoryofthisdevice).
https://doi.org/10.1371/journal.pone.0197883.g002
marketpriorto1990andtheseinturnareultimatelyderivedfromonlysixpre-amendment
devices(Fig1b).Thispattern,wherebyalldevicesultimatelycoalesceintoasmallnumberof
ancestralpredicatesispartiallyexplainedbytheabsenceofinformationonthepredicatesfor
somedevices.However,thisisnotthemaindriverofthistrend,whichinsteadsimplyreflects
thefactthatfewerdeviceswereavailableonthemarketinthepast[14].
Wefoundthatthenumberofdescendentdevicesderivedfromeachpredicateishighly
skewed.Forinstance,whilesomedeviceshaveonlybeenusedasapredicateonce,weidenti-
fiedtwelvedevicesthathaveeachultimatelyledtoover100descendants(Fig2).Thisvariation
isnotsimplyanartifactofsomepredicatedevicesenteringthemarketearlierthanothersand
thushavinglongertoaccumulatedescendentdevices,becausethispatternisalsopresent
amongstdevicesofsimilarage(Fig2).Forinstance,thesixpre-amendmentdevicesinour
datasethavecollectivelyledto387descendentdevices,but303(78%)ofthesearederivedfrom
justtwopre-amendmentdevices,MersileneMesh,whichhas183descendants(Fig3),and
ProlenePolypropyleneMesh,whichhas120descendants.
Thelackofavailablescientificevidencetosupportclaimsofsubstantialequivalencehaspre-
viouslybeennotedbyZuckermanetal[13]whousedasimilarmethodologytoassembleinfor-
mationonthepredicatehistoryofimplantsfromtheFDAwebsite.Toexplorethisfurther,we
analysedthescientificandclinicaldatapubliclyavailableinthe510(k)summariesofthose
mesheswithmorethan100descendants(n=11).Ofthese11devices,twoarepre-amendment
devices(MersileneMeshandProlenePolypropyleneMesh)andthusnoinformationabout
theirsafetyandefficacyisavailableontheFDAwebsite.Despitethelegalrequirements,sum-
mariesforsixdevices(50%)areabsentfromtheFDAdatabase[15].Finally,ofthethree
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Ancestralnetworkofsurgicalmeshes
Fig3.TheancestraldevicenetworkofMersileneSurgicalMeshmanufacturedbyEthiconInc.MersileneMeshhasledto183descendentdevices.Devicesin
theancestralnetworkthathavesincebeenrecalledfor‘designandmaterialrelatedflaws’(n=2)arehighlightedinred.Devicesthataredescendedfromrecalled
devicesbysubstantialequivalencychains(n=12)arehighlightedinyellow(seeS2Datafordevices).
https://doi.org/10.1371/journal.pone.0197883.g003
remainingdevices,allclaimtohaveperformedsomebenchtestingbutnodetailsofthetests
orresultsareavailableand,inallcases,noclinicaldataispresented(Table1).
Toassessthepotentialrisksassociatedwiththenon-independentancestryofdeviceswe
calculatedthenumberofrecentlycleareddevicesthathavebeenderivedfrompredicatesthat
havesincebeenrecalled.Acrossourdatasetof400uniquepredicatedevices,weidentified
threedevicesthathadbeenrecalledduetodesignandmaterialrelatedflawsthatresultedin
seriouslongtermandirreversibleadverseevents(ComposixKugelMesh(K003323),PRO-
CEEDTrilaminateSurgicalMesh(K031925)andPROCEEDSurgicalMesh(K060713))(Fig
4).Theserecalledmeshesrepresentlessthan1%ofallthedevicesinourdataset.However,
becausetheserecalledmesheswereonthemarketforaperiodofupto5yearsbeforebeing
recalled(K003323,5years;K031925,3years;K060713,5years)theyservedaspredicatesfor
multipledescendentmeshes(K003323,24descendentdevices;K031925,13descendent
devices;K060713,10descendentdevices).Infact,wefoundthat12outofthe74(16%)devices
clearedbetween2013and2015havedescendedfromoneofthesethreerecalleddevices,with
fivesurgicalmeshescontainingallthreerecalleddevicesintheirancestraltree.Furthermore,
theserecalleddevicesareoftenverycloselyrelatedtothoserecentlyenteringthemarket:on
averageoneonlyhastotravelbackthreegenerationsinthepredicateancestrytoreachadevice
thathassincebeenrecalled.
Discussion
Surgicalmesheshavebeeninuseforoversixtyyearsforawidevarietyofsofttissuerepair
indications.Manypatientshavebenefitedfromtheimplantationofthesedevices.Tragically,a
significantnumberofpatientshavealsosufferedfromlongtermandirreversiblecomplica-
tionsrelatedtosurgicalmeshes.Allsurgicalmeshesthathaveenteredthemarkethavedoneso
throughthe510(k)process,inwhichnewdevicesareclearedsimplyiftheyprovideevidence
ofsubstantialequivalencetoatleastonepredicatedevicealreadyonthemarket.Althoughitis
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Table1. Publicavailabilityofclinicalandscientificevidenceforthemeshesthathaveledtoover100off-springdevices.
DeviceName Manufacturer 510K Date Summary Evidencementioned/Data Numberof
Number cleared Provided descendants
MersileneMesh EthiconINC - Pre1976 - None 183
SUPPLEPERI-GUARD BIO-VASCULAR,INC. K923657 12/21/ Nosummary None 167
1992 available
BARDMARLEXMESHDART C.R.Bard,INC K922916 08/24/ NoSummary None 162
1992 available
PROLENEPROPROPYLENEMESH ETHICON,INC. - Pre1976 - None 120
NONABSORBABLESYNTHETIC
SURGICALMESH
MODIFIEDPROLENE ETHICON,INC. K962530 08/09/ Summary •Noclinicalevidence 119
POLYPROPYLENEMESH 1996 available •Benchtesting:OnlyBurst
NONABSORBABLESYNTHETIC strengthtest
SURGICALMESH
DEXON’S’POLYGLYCOLICACID Davis&Geck,INC K830889 05/09/ NoSummary None 118
MESH 1983 available
PROLENESOFT(POLYPROPYLENE), ETHICON,INC. K001122 05/23/ Summary •Noclinicalevidence 115
NONABSORBABALESYNTHETIC 2000 available •Nonclinicallaboratorytesting
SURGICALMESH wasnotperformed
•Accordingtothemanufacturer
benchtestingwasperformed
butthedetailswerenot
provided
TISSUEPATCH,TISSUEGRAFT BIO-VASCULAR,INC. K921895 11/04/ Statement None 106
1992 available
TRELEXNATURAL(R)MESH MEADOXMEDICALS, K945377 12/08/ Nosummary None 104
DIV.BOSTON 1994 available
SCIENTIFICCORP.
GORE-TEXSOFTTISSUEPATCH, W.L.GORE& K930822 01/28/ Nosummary None 104
SURGICALMEMBRANE,MESH ASSOCIATES,INC 1994 available
SURGICALFABRICS BOSTONSCIENTIFIC K963226 11/15/ Summary •Noclinicalevidence 103
CORP. 1996 available •Accordingtothemanufacturer
benchtestingwasperformed
butdetailswerenotprovided
https://doi.org/10.1371/journal.pone.0197883.t001
importanttoacknowledgethatsomeofthecomplicationsexperiencedbypatientsmayhave
arisenfrompoorsurgicaltechniquesorthegeneralrisksassociatedwithsurgicalprocedures,
thesignificantnumberofadversecasesassociatedwithseriousdesignflawsandcomplications
relatedtothetypeofmaterialsusedinsurgicalmeshesremainsaconcern[9,12,13].
Thekeyunderlyingassumptionofthe510(k)frameworkisthatifanewmeshissufficiently
similartoapreviousdevice,thenitwillbeatleastassafeandeffectiveasthedevicescurrently
onthemarket.However,inthevastmajorityofcases,thedevicesusedaspredicatesinclaims
ofequivalencehaveneverbeenadequatelyassessedforsafetyandeffectiveness[13,16],raising
thepossibilitythatundetecteddesignrelatedflawspresentinadevicemayinadvertentlybe
passedontomultiplefurtherdevices.Becauseclaimsofsubstantialequivalenceareoften
looselydefined,thedegreewhichdesign-relatedflawsareinheritedfrompredicatetodescen-
dentdevicesmaybedifficulttoquantify.However,ouranalysisrevealsthepotentialextentof
thisproblem,byshowingthatthesubstantialequivalenceprincipleusedinthe510(k)route
hasresultedinanextremelyhighdegreeofconnectednessamongstsurgicalmeshes.Almost
allnewsurgicalmeshesareultimatelyderivedfromonlyahandfulofancestraldevicesthat
lackclinicaldataandsufficientscientificevidence.
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Fig4.TheancestraldevicenetworkoftherecalleddevicesComposixKugelMesh(K003323)andPROCEED
TrilaminateSurgicalMesh(K031925).+Showsdeviceswithmorethan2recalledpredicates.
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Acrosssurgicalmeshes,wefoundthatdirectclaimsofequivalencywereoftenbasedon
predicatesthathadbeenonthemarketforonlyafewyears.Thisshort‘generationtime’
betweenancestralanddescendentdevices,raisesthepossibilitythatbythetimeadevicehas
beenrecalledduetosafetyissues,manysubstantiallyequivalentdevicessharingtheseprob-
lemsmayhavesinceenteredthemarket.Ourresults,highlightthemagnitudeofthisriskby
demonstratingthateventhoughthenumberofrecalledsurgicalmeshesisrelativelysmall,a
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substantialproportionofmeshesrecentlyenteringtheUSmarketarecloselyconnectedto
theserecalledmeshesthroughclaimsofsubstantialequivalence.Weemphasizethatbyonly
focusingonrecalleddevicesouranalysisprovidesaconservativeestimateofthenumberof
devicespotentiallycausinghealthrelatedproblemsbecauseevenwhensuchdesignandmate-
rialrelatedflawshavebeenidentified,andtheuseofadevicehasbeendiscontinued,thisrarely
resultsinarecallbytheFDA.
Furthermore,althoughmostdevicesciteonlyoneortwopredicates,thetotalnumberof
predicatesunderlyingadeviceissubstantiallygreaterthanthisandmostdevicesaretheprod-
uctofalongchainofsubstantialequivalenceclaimsstretchingbackdecades.Thisprocesscan
resultinnewdevicesenteringthemarketthataresubstantiallydissimilartotheirpredicates,a
phenomenonknownas‘predicatecreep’[17].Anexampleofthisproblemwastheclearance
ofmetalonmetalhipimplantsandtheReGenMenaflexcollagenscaffoldwheresmalldiffer-
encesbetweenadeviceanditspredicateweremagnifiedovertimeandamongtheoffspring
predicatedevices[17,18,19,20].Thisgeneralissuehasbeenidentifiedpreviously[13],butour
in-depthanalysisofallsurgicalmeshesclearedfrom2013–2015,furtherhighlightsthelack
ofpubliclyavailablescientificevidencetosupportclaimsofsubstantialequivalence,safety,or
effectivenessinthisgroupofsurgicalimplants.Theseresultsidentifyconcernswiththe510(k)
frameworkandwethereforesuggestthattheclearanceofcertaingroupsofclassIIdevices,
suchassurgicalmeshesthathavethepotentialtocauseirreversiblecomplications,shouldbe
supportedbyclinicaldataandrigorouspre-clinicalevaluations,ratherthansimplyclaimsof
equivalencetopre-existingdevices.In2014,asaconsequenceofmajorcomplicationsreported
inthemedicalliteratureandaseriesoflegalclaimsforcompensationbypatientsharmedby
certaintypesofpelvicfloorrepairmeshes,theFDAissuedorderstoreclassifytwoofthe37
groupsofsurgicalmeshes(syntheticandnon-syntheticmeshesforPelvicOrganProlapse
repair)fromclassIItoclassIII.Thischangerequiredmanufacturerstosubmitapre-market
approval(PMA)application.However,todate,nomanufacturerhaschosentodothis,and
thuseffectivelyallsurgicalmeshescurrentlyontheUSmarketcontinuetobeclearedthrough
the510(k)route.
Thefirststeptowardsachievingasuitableregulatorysystemwouldbetodefineappropriate
clinicaltrialdesignsforfirst-in-manstudiesandastandardizedreportingsystemtouniformly
assessthesafetyandeffectivenessofdevicesbasedontheirpotentialrisktothehumanbody.
Anotherimportantparallelimprovementistodevelopauniformsetofrequirementsbased
oninternationalstandardsforreportingthescientificdataandpre-clinicaltestsperformedby
manufacturersandtoensurethattheinformationisavailableforpublicscrutiny.Finally,the
FDAcurrentlyonlyprovidesinformationontheimmediatepredicatesusedbyadeviceand
thusuncoveringthedeeperancestralrelationshipbetweendevicesisextremelytimeconsum-
ing.IftheFDAweretopublishthefullgenealogicalrelationshipsbetweendevicesontheir
websitethiswouldenableresearcherstorapidlycheckwhetheranyofthedevicestheyhave
usedaspredicateshavedescendentfromotherdevicesforwhichflawshavesincebeenidenti-
fied.Wearguethatthiswouldrepresentasimplebuthighlyeffectivewayofminimizingthe
riskthatdesignormaterialrelatedflawscausingadversepatientoutcomesarepropagated
amongstdevices.
Conclusion
Theframeworkforthecurrentregulatorysystemforapprovalandclearanceofmedicaldevices
wascreated40yearsagoinaneraofmuchsimplermedicaltechnologiesandasmallernumber
ofdevices.Recentcomplicationswithanumberofsurgicalmeshesandothermedicaldevices
haveraisedquestionsregardingtheextenttowhichthecurrent510(k)processiscapableof
PLOSONE|https://doi.org/10.1371/journal.pone.0197883 June19,2018 10/12