FreeStyle Libre Flash Glucose Self-Monitoring System: A ... · Diabetes is a metabolic disorder...

2017

A SINGLE-TECHNOLOGY ASSESSMENT

FreeStyle Libre Flash Glucose Self-Monitoring System

REPORT

1 Executive summary

Title FreeStyleLibreFlashGlucoseSelf‐MonitoringSystem:ASingle‐TechnologyAssessment

Norwegiantitle FreeStyleLibresystemetforegenmålingavblodsukker:enhurtigmetodevurdering

Institution NorwegianInstituteofPublicHealth,DivisionforHealthServices(Folkehelseinstituttet)

CamillaStoltenberg,DirectorAuthors Bidonde,Julia,Researcher(projectleader),

Fagerlund,BeateCharlotte,HealtheconomistFrønsdal,KatrineB,SeniorresearcherLund,UlrikkeHøjslev,Healtheconomist

Robberstad,Bjarne,Seniorhealtheconomist

ISBN 978‐82‐8082‐852‐1Typeofreport Single‐technologyassessment(Hurtigmetodevurdering)No.ofpages 88(includingappendices107)

Client TheCommissionerForumRHA(BestillerforumRHF)Subjectheading(MeSH) BloodGlucoseSelf‐Monitoring,DiabetesMellitus

Citation BidondeJ,FagerlundBC,FrønsdalKB,LundUH,RobberstadB.FreeStyleLibreflashglucoseself‐monitoringsystem:asingle‐technologyassessment.NorwegianInstituteofPublicHealth(Folkehelseinstitutttet).Oslo:NorwegianInstituteofPublicHealth,2017.NorwegianInstituteofPublicHealth(NIPH)Oslo,August2017

2 Executive summary

Executivesummary

Background

Diabetesmellitus(DM)hasbecomeoneofthemostcommonpublichealthproblems

world‐wide.Accordingtothe2014NorwegianPublicHealthreport,diabetesaffectsan

estimated4.3%oftheNorwegianpopulation.Diabetesisametabolicdisorderresulting

fromadefectininsulinproduction,secretion,action,orall.Type1and2arethetwo

maintypes,withtheprevalenceoftype2accountingforthemajority(>85%)ofdiabe‐

tes.ThisassessmentwillfocusonFreeStyleLibre,flashglucosemonitorforinsulin

treatedindividualswithtype1and2diabetes(“Type1and2DM”).

Toachieveproperqualityoflifeandreducelong‐termproblems,peopleareincreas‐

inglyencouragedtotakeanactiveroleinthemanagementoftheircondition.Adequate

treatmentmanagement,aimedattightcontrolofbloodglucose,reducestheriskofthe

long‐termcomplicationsofdiabetessuchasretinopathy,nephropathy,neuropathy,

coronaryheartdisease,ischaemicstrokeandperipheralvasculardisease.‘Manage‐

ment’ofthediseaseshouldbeunderstoodasapackageincludingtestingofbloodglu‐

cose,takinginsulin(i.e.,multipledailyinsulininjections,usinganinsulinpump),using

antihyperglycemicdrugs,oradoptinglifestyleinterventionssuchasdietandphysical

activity.

Inrecentyears,andavailableinEuropesince2014,theFreeStyleLibreSystem‐a

‘wireless’methodusingasensorformonitoringinterstitialfluidglucose‐wasintro‐

ducedtohelpindividualswithtype1and2DMachievebetterglucosecontrol.Thesys‐

tem,unlikeothers,doesnotrequirefingerprickcalibration,sincethatfunctionalityis

embeddedintothecoretechnology.Also,unlikeothersystems,theindividualhasto

takeactiveactiontogetaccesstotherealtimeglucosevalue,byleadingthereceiver

overthesensor.Similarlytoothercontinuousglucosemonitoringoptions,itrelieson

theindividualtotakeactionontheinformationretrieved.

Objective

3 Executive summary

Ourgoalwastoassesstheclinicaleffectiveness,costeffectivenessandsafetyofFree‐

StyleLibreforindividualswithtype1and2DM.

Methods

Weconductedasystematicreviewaccordingtostandardmethodstosummarisethe

evidence.ThestudypopulationswereinsulintreatedindividualswithType1or2DM,

theinterventionwasFreeStyleLibre,andtheoutcomeswereHbA1c,hypoandhyper‐

glycaemia,qualityoflife,patientsatisfaction,pain,andadverseevents.

Wesearcheddatabases,trialregistries,healthtechnologyassessmentagenciesweb‐

sitesandgreyliteraturefrominceptiontoJanuary2017withnolanguagerestrictions.

Tworeviewersindependentlyscreenedthetitlesandabstractsofallrecordsidentified

bysearches,discussedanydiscrepanciesandsolvedthembyconsensus.Weobtained

fulltextcopiesofallstudiesdeemedpotentiallyrelevantandthesametworeviewers

independentlyassessedtheseforinclusion;solvinganydisagreementsbyconsensus.

Onereviewerextracteddatarelatingtostudydetails,participants,intervention,and

comparator,usingapiloted,standarddataextractionform.Asecondreviewerchecked

dataextractionandanydisagreementsweresolvedbyconsensus.Theassessmentof

themethodologicalqualityofeachincludedstudywasbasedontheCochraneCollabo‐

rationriskofbiastool.Qualityassessmentofevidencewascarriedoutindependently

bytworeviewers.Wesolvedanydisagreementsbyconsensus.Meta‐analysiswascon‐

sideredasuitableanalysisforthedataidentified,despiteheterogeneity.Forsomeout‐

comesweemployedanarrativesynthesis.

Assessmentofcosteffectiveness

Weassessedthecost‐effectivenessestimatesprovidedbythesubmitterofFreeStyleLi‐

brecomparedtoself‐monitoringbloodglucose(SMBG)forindividualswithtype1and

2DM.Thesubmitterusedacommerciallyavailablecost‐effectivenessmodel,IMSCORE

diabetesmodel(IMSCDM)forthisassessment.Themodelisinternetbased,witha

Markovapplication,forindividuals>18years.Theinteractivesimulationpredictsthe

long‐termhealthoutcomesandcostsassociatedwiththemanagementoftype1and2

DM.Themodelconsistof17sub‐modelsdesignedtosimulatediabetesrelatedcompli‐

cations,nonspecificmortality,andcostsovertime.Asthemodelsimulatesindividual

patientsovertime,itupdatesriskfactorsandcomplicationstoaccountfordiseasepro‐

gression.However,thismodelreceivedfromthesubmitter,lackstransparency,and

madeitdifficulttogainafirmunderstandingofthefactorsthatdeterminehowpatients

4 Executive summary

progressthroughthemodel,assumptionsandparameterseffectoutcomesandtoas‐

sessthevalidityofthemodel.BecausetheNorwegianInstituteofPublicHealthdidnot

havecompleteaccesstothemodel,itwasnotpossibletoperformafullassessmentof

themodelortomodifyunderlyingassumptionsandparametersinordertoinde‐

pendentlyassesstheimpactonreportedresults.Furthermore,thedocumentation

packagedidnotincludeanysensitivityanalysis,whichisessentialforconsideringthe

validityandrobustnessofresultsfromeconomicevaluations.

Results

Weincludedtworandomizedcontrolledtrials(RCTs)inthereview.Thesestudiescom‐

paredFreeStyleLibretoSMBG.Also,wefoundseveralpublicationsinvestigatingthe

accuracyofthedevice,however,thestudydesignsofthesestudies(singlearm)didnot

meettheinclusioncriteriaofthisevaluationand,althoughwecompiledthemforinfor‐

mation,theywereexcludedfromthesynthesis.Theinformationderivedfromthese

singlearmstudiesarepotentiallyimportanttovalidatethesensitivityandspecificity

estimatesofFreeStyleLibre.Inaddition,wefoundotherEuropeanassessmentscon‐

ductedinthepast6to8months.TheincludedRCTsreporteddataonmiddleaged

adultsfromEuropeancountrieswithtype1and2DMat6monthspostintervention.

Weratedthestudies’riskofbiasasuncleartohighrisk.

MainfindingsfromthesetrialsarethatFreeStyleLibremayslightlyimprovetreatment

satisfaction,timespentwithglucoseinrange3.9to10mmol/L,numberofnocturnal

eventswithglucoselevels<3.1mmol/Lwithin7h,andtimespentwithglucoselevels

>13.0mmol/LincomparisontoSMBG.FreeStyleLibreleadtolittleornodifferencein

qualityoflifeandHbA1clevelincomparisontoSMBG.Theevidenceisuncertainabout

whetherFreeStyleLibreleadstoanimprovementintimeandeventswithglucose

<3.9mmol/Lwithin24h,timewithglucose<3.1mmol/Latnightwithin7hours,and

timewithglucose>10mmol/L.

Thesubmittedeconomicmodelrunsa40‐yeartimehorizon.Thesubmitter´sbasecase

suggestedthatthetechnologyisdominantforindividualswithtype1DM,i.e.thatFree‐

StyleLibreisacheaperandmoreeffectivetechnology.Accordingtosubmitter´sbase

case,individualswithtype2DMtheincrementalcost‐effectivenessratio(ICER)was

calculatedtobeNOK235,673perQALY(wholestudypopulation)andNOK243,434

perQALY(under65years).Asthemodelreceivedbythesubmitterwasneithersuffi‐

cientlytransparentnorsufficientlyflexibletoallowchanges,wehavenotbeenableto

producealternativeincrementalcost‐effectivenessratios(ICERs).Fromahealthcare

5 Executive summary

perspective,thesubmitterhascalculatedabudgetimpactfortype1DMtohaveatotal

addedcostthefifthyearafteradoptionofthetechnology.Further,thesubmittercalcu‐

latedabudgetimpactfortype1and2DMthatleadtoacostsavingonthefifthyearaf‐

teradoptionofthetechonology.Thesubmitterdidnotcalculateabudgetimpactfor

type2DMonly.

Weestimatedthat,fromahealthcareperspective,theannualcostsfiveyearsafterin‐

troductionwouldbeNOK186millionaddedcostandNOK91,7millionsavedcostfor

type1and2DMalone,respectively,andNOK94millionaddedcostfortype1and2

DMcombined.

Conclusions

Overall,theevidencefortheinterventionofinterestwaslimitedbutsuggeststhatFree‐

StyleLibreincreasestreatmentsatisfaction,reducessomehypo‐andhyperglycaemic

measures(increasestimewithglucoseinrange3.9to10mmol/L,reducestimeand

numberofeventswithglucose<3.9in24hours,numberofglucose<3.1nightevents

andtimewithglucose>13mmol/L)andhassimilarseriousadverseeventsthanSMBG,

withoutdifferencesinotheroutcomesincludingHbA1candqualityoflife.

Thequalityoftheincludedstudieswasgenerallylowandtherewereonlytwosmall

studiesincludingmiddleagedadults.

Severalinconsistenciesleadustoquestiontheresultofthesubmittedhealtheconomic

report.Specifically,thesubmittedmodelincludedseveralinputdatathatdidnotmatch

theinputdatadescribedinthesubmitteddocumentationpackage,andnordiditmatch

theinputdatafoundinotherliterature.

Themostchallengingissueisthatthemodelisnotsufficientlytransparentorflexible,

sincewedidnothaveaccesstothecompletemodel.Therefore,wewerenotabletoas‐

sesshowthepossibleadjustmentswouldaffecttheresultsprovidedbythesubmitters.

Suggestedresearchpriorities

IndependentresearchforFreeStyleLibrewillbeimportant

Diabetesaffectsthelifeofchildren,adolescentsandtheircaregiversinmany

ways,aswellaspregnantwomen.Independentresearchincludingthesegroups

iswarranted

6 Executive summary

TheclinicaleffectivenessofFreeStyleLibreneedstobeinvestigatedindifferent

conditions,forexample,amongindividualswithpoorself‐monitoring

adherence,newlydiagnosed,impairedawarenessofhypoglycaemia,andin

additiontotrainingandeducationcomponents

FreeStyleLibrecomparedtoothercontinuousmonitoringsystemsiswarranted

Painisamajordeterminantofdiabetestreatmentadherence,especiallyfor

children,anditshouldbeincludedasanindividualoutcomeinfuturetrials

Futuretrialsshouldincludelongertermfollowupandqualityoflifeoutcome

assessmentsatvariouspointstoinformimprovedclinicalandcost

effectivenessmodelling

7 Sammendrag (norsk)

Sammendrag(norsk)

Bakgrunn

På verdensbasis er diabetes mellitus (DM) i dag blant de mest vanlige helseproble-

mene. I følge Folkehelserapporten fra 2014 regner man med at 4.3%avNorgesbe‐

folkningenerrammet.DMerenmetabolsksykdomforårsaketentenavmanglendein‐

sulinproduksjonellermanglendeinsulinresponsellerenkombinasjonavdisse.DM

type2stårforflerpartenavtilfellene(>85%).Idennerapportenharvivurdertbrukav

FreeStyleLibre‐systemetformålingavblodsukker(glukose)hospersonermedtype1

og2DMsombehandlesmedinsulin.

Foråoppnåbedrelivskvalitetogforhindrekomplikasjonerovertiderdetenfordelat

pasiententarenmestmuligaktivrolleiåovervåkeogbehandleegensykdom.God

oppfølgingogkontrollavglukosenivåreduserernemligrisikoenpålangsiktforkom‐

plikasjonergrunnetdiabetes,somforeksempelretinopati,nefropati,nevropati,(syk‐

dom/skadeinetthinne,nyreogperiferenerver),samthjerte‐ogkarsykdommerog

hjerneslag.Behandlingenavdiabetesbestårien«pakke»avuliketiltak,sominnebærer

testingavglukosenivåiblod,inntakavinsulin(foreksempelvedåinjisereinsulinflere

gangerperdagellervedbrukavinsulinpumpe),brukavblodsukkersenkendemedika‐

menterogendringilivsstilmedhensyntildiettogfysiskaktivitet.

Idesisteparårene,ogsiden2014iEuropa,harFreeStyleLibre‐systemetværttilgjeng‐

eligpåmarkedet.Dettenyesystemeterenmetodesombenytterensensorforåmåle

glukosenivåetideninterstitiellevæsken,somlesesavtrådløst.Hensikteneråoppnå

bedrekontrollavblodsukkernivåethospersonermedtype1og2DM.Tilforskjellfra

andremålemetoderkreverikkedettesystemetfingerstikkforkalibrering,dadenne

funksjonenerintegrertiselveteknologien.Itillegg,ogsåuliktandremetoder,måbru‐

kerenselvføreavleserennærsensorenogskannedenneforåfåviteaktueltglukose‐

nivå.Metodeneraltsåavhengigavatbrukerenbidrarselv,ogisåmåteerdettesyste‐

mettilsvarendeandremetoderforkontinuerligglukosemonitorering.


Mål

Måletmeddennerapportenvaråvurderekliniskeffektogsikkerhet,samtkostnadsef‐

fektivitetavFreeStyleLibrehospersonermedtype1og2DM.

Metode

Viutførteensystematiskoversiktihenholdtilstandardmetodikkforåoppsummere

kunnskapsgrunnlaget.Viinkludertestudierhvorpopulasjonenehaddetype1ellertype

2DMoghvorintervensjoneninnebarbrukavFreeStyleLibre.Depredefinerteutfalls‐

målenevarHbA1c,hypo‐oghyperglykemi,livskvalitet,pasienttilfredshet,smerteog

uønskedehendelser.

Visøkteidatabaserogstudieregistere,menogsåpånettsidenetilandreorganisasjoner

somgjørmetodevurderinger,samtettergrålitteraturpublisertfremtiljanuar2017

utenbegrensningmedhensyntilspråk.Toforskeregikkuavhengigavhverandregjen‐

nomtitlerogabstrakterpåalletreffeneidentifisertvialitteratursøket.Uoverensstem‐

melserblediskutertinntilkonsensusvaroppnådd.Viinnhentetmuligrelevantepubli‐

kasjonerifulltekst.Etterattoforskerehaddelestgjennomdisseuavhengigavhver‐

andrebestemteviomviskulleinkluderestudienimetodevurderingen.Ogsåpådette

trinnetløsteviuenighetergjennomdiskusjon.Mensénmedarbeiderekstraherteinfor‐

masjonomstudiene,detvilsiomdeltakerne,intervensjonen,komparatoren,utfallog

effektestimatervedbrukavetvelutprøvdstandardekstraksjonsskjema,sjekketenan‐

nenmedarbeiderdeekstrahertedataene.Viløsteuoverensstemmelsersombeskrevet

fordetidligeretrinneneiprosessen.Vurderingavdenmetodologiskekvalitetenpå

hveravdeinkludertestudienebleutførtvedbrukverktøyet for å vurdere risiko for

systematiske skjevheter utvikletavCochraneCollaboration(RiskofBias).Bedømmel‐

senavkvalitetenavkunnskapsgrunnlagetblegjortavtoforskerehverforseg.Ogsåher

varuenighetløstsombeskrevettidligereiavsnittet.Vivurderteatdataeneegnetsegtil

åinngåimetaanalyser,tiltrossforheterogenitetmellomeffektestimatene.Fornoenut‐

fallsmålvarsyntesengjortnarrativt.

Evalueringavkostnadseffektivitet

VievaluertekostnadseffektivitetentilFreeStyleLibresammenlignetmedselvkontrol‐

lertblodsukkermåling(SMBG)forpersonermedtype1og2DM.Abbottbrukteen

kommersielttilgjengeligkostnadseffektivitetsmodell,IMSCOREdiabetesmodellen(IMS

CDM)forevalueringen.ModellenerinternettbasertogMarkov‐basert,forpersoner

over18år.Deninteraktivesimuleringenpredikererdelangsiktigehelsemessigeutfal‐

leneogkostnadeneknyttettiladministreringenavtype1og2DM.Modellenbestårav


17delmodellerdesignetforåsimulerediabetesrelatertekomplikasjoner,uspesifisert

dødelighetogkostnaderovertid.Sidenmodellensimulererindividuellepasienterover

tid,oppdatererdenrisikofaktorerogkomplikasjonerforåtahensyntilsykdomspro‐

gresjon.ModellenvimottokfraAbbotterikketransparent,ogderforvardetvanskelig

åfåensolidforståelseavfaktorenesombestemmerenkohortsfremganggjennommo‐

dellutviklingen,antagelseneogparametereffektresultateneogforåvurderemodellens

validitet.Folkehelseinstituttethaddeikketilgangtildenfullstendigemodellen,ogdet

varderforumuligåutføreenfullstendigevalueringavmodellenelleråendreunderlig‐

gendeforutsetningerogparametereforåkunnevurdereeffektenavrapporterteresul‐

tater.Videreinkluderteikkedokumentasjonspakkennoensensitivitetsanalyse.

Resultater

Idennehurtigmetodevurderingeninkludertevitorandomisertekontrollertestudier

(RCTer).DissestudieneharsammenlignetFreeStyleLibremedSMBG.Itilleggfantvi

flerepublikasjonersomomhandletutstyretsmålenøyaktighet,mengrunnetstudiede‐

signet(single‐arm)ograpportensformålbleikkedisseinkludert.Dogerkjennervibe‐

tydningenavdissesingle‐armstudienemedtankepåatdevisersensitivitetenogspesi‐

fisitetenavFreeStyleLibresommetodeforåmåleglukosekonsentrasjon.Deinkluderte

RCTenerapportertefunnpåmiddelaldrendevoksnefraulikeeuropeiskelandmedtype

1og2DMseksmånederetteratintervensjonenpåbegynte.Ettervårvurderinghadde

studienefra«uklar»til«høy»risikoforsystematiskeskjevheter(riskofbiases).

HovedfunnenefradeinkludertestudieneeratFreeStyleLibremuligensforbedrerbru‐

kerstilfredshet,tidtilbraktmedglukosenivåmellom3,9og10mmol/l,antallnattlige

hendelsermedglukosenivåer<3.1mmol/liløpetav7timerogtidmednivåer>13.0

mmol/lsammenlignetmedSMBG.ImidlertidmedførerFreeStyleLibrelitentilingen

forskjellmedhensyntillivskvalitetognivåavHbA1csammenlignetmedSMBG.Vier

usikrepåomFreeStyleLibreførertilforbedringavtidoghendelsermedglukosenivå

<3.9mmol/Liløpetavettdøgn,tidmednivåer<3.1mmol/Lmåltpånatten(7timer),

samttidtilbraktmedglukosenivå>10mmol/l.

Denøkonomiskemodellen,innsendtavAbbott,haddeen40årstidshorisont.Deninn‐

sendtemodellentyderpåatFreeStyleLibreerdominantforindividermedtype1DM,

detvilsikostnadseffektiv.IfølgeAbbott,forpersonermedtype2DMbledeninkre‐

mentellekostnadseffektivitetsratioen(ICER)beregnettil235673kronerperQALY

(helestudiepopulasjonen)og243434kronerperQALY(under65år).Sidenmodellen


levertavAbbottikkevartransparent,harviikkehattmulighettilåproduserealterna‐

tiveinkrementellekostnadseffektivitetsratioer(ICER).Medutgangspunktiethelsetje‐

nesteperspektiv,estimerteAbbottbudsjettkonsekvensfortype1DMtilågimerkostna‐

derfemteåretterteknologienblirinnført.VidereestimerteAbbottbudsjettkonsekvens

fortype1og2DMtilåværekostnadsbesparendefemteåretterteknologienblirinn‐

ført.Abbottestimerteikkebudsjettkonsekvensfortype2DMseparat.Fraethelsetje‐

nesteperspektivestimerteviimidlertidatdentotaleårligekostnadenfemåretterin‐

troduksjonavFreeStyleLibrehenholdsvisvilgi186millionerkronermerkostnaderfor

type1DMaleneog91,7millionerkronerspartekostnaderfortype2DMalene.Ved

kombinasjonavtype1ogtype2DMvilintroduksjonenavFreeStyleLibregiomkring

94millionerkronermerkostnaderfemåretterintroduksjonen.

Konklusjoner

Genereltsettvarkunnskapsgrunnlagetbegrenset,menresultatenekantydepåat

FreeStyleLibreøkerpasienttilfredsstillelseogatdetreduserernoevarighetoghyppig‐

hetavhypo‐oghyperglykemi‐episoder.FreeStyleLibreøkermuligenstidtilbragtmed

glukosenivåmellom3.9og10mmol/l,reduserertidogantallhendelsermedglukose‐

nivå<3.9mmol/loveretdøgn,hendelsermedglukosenivo<3.1mmol/l‐iløpetavnat‐

tenogtidtilbagtmednivåerglukose>13mmol/l.FreeStyleLibremedførertilsvarende

antalluønskedehendelsersomSMBG.Detersmåelleringenforskjellermedhensyntil

deandreutfallene,somHbA1coglivskvalitet.Kvalitetenpådetoinkludertestudiene

vargenereltsettlavoginkludertevoksnemiddelaldrendedeltakere.

Deterflereuoverensstemmelsermellomforutsetningenenevntidenskriftligedoku‐

mentasjonspakken,iannenliteraturogantakelsenesomfaktiskerbruktidenhelse‐

økonomiskemodellen.Itilleggerdeninnsendtehelseøkonomiskemodellenikketrans‐

parent.Vihaddeikkefullstendigtilgangtilhelemodellen,ogdetførtetilstorusikker‐

hetomkringmodellensstrukturogkvalitetenavinnholdet.Pågrunnavdetteerdet

ikkemuligåsehvordanvårejusteringerogkorreksjonerhaddepåvirketresultatet.

Forslagtilvidereforskning

DeterviktigatdetgjøresuavhengigforkningpåFreeStyleLibre

Diabetesrammerogsåbarnogungdomogdesomharomsorgfordem,og

gravidekvinner.Deterderforbehovforuavhengigforskning,sominkluderer

dissegruppene

EffektavFreeStyleLibremåundersøkesunderulikeaktuelleforhold,somfor

eksempelblantpersonersomikkefølgeroppsinsykdomellersomhar


vanskelighetermedutførelsenavsinblodsukkerkontroll,hosdemsomnyliger

blittdiagnostisertmeddiabetesoghospersonersomikkeerklaroverellerikke

følereventuellhypoglykemi.Forholdknyttettiltreningogopplæringerdet

ogsåviktigåfåmerkunnskapom.

FreeStyleLibremåsammenlignesmedandremetoderforkontinuerlig

blodsukkermonitoring

Smerteervesentligmedtankepåtilslutningtilethvertbehandlingsprogramfor

diabetes,spesielthosbarn,ogdettebørinkluderessometseparatutfallsmåli

fremtidigestudier

Viderebørstudienefølgeoppdeltakerneoverlengretid,samtmåle

livskvalitetsutfallveduliketidspunktforåbidratilbedremodelleringavklinisk

effektogkostnadseffektivitet.

12 Table of contents

Tableofcontents

EXECUTIVESUMMARY 2

SAMMENDRAG(NORSK) 7

TABLEOFCONTENTS 12

ABBREVIATIONS 14

PREFACE 15 Whatisasingle‐technologyassessment? 15 Objective 15 Log 15 History 16 Projectteam,consultantsandstakeholders 16

BACKGROUND 18 Thetechnology 18 Regulatorystatus(CE‐marking)andmarketaccessofthetechnology 18 Descriptionanduseofthetechnology 18 Descriptionofthehealthcondition 21

CLINICALEFFECTIVENESSANDSAFETY 25 Issueaddressed 25 Objective 25 Methods 25 Results 32 Characteristicsofincludedtrials 34 Riskofbiasinincludedstudies 35 EffectofFreeStyleLibre 38

COST‐EFFECTIVENESSANALYSIS 51 Methods for evaluating submitted cost-effectiveness models 51 Publishedcost‐effectivenessevaluationsidentifiedbythesubmitter 52 Populationandcomparatorinthesubmittedreport 54 Typeofanalysisanddecisionmodelofthesubmittedreport 54 Generalcommentsonthesubmittedhealtheconomicanalysis 56 Clinicalandepidemiologicaldata 57 Efficacy 58

13 Table of contents

Costs 59 Healthrelatedqualityoflife(HRQL) 62 NIPHcommentsonsubmitterparametersandinputdata 63 Cost‐effectivenessresults 65 Budgetimpactanalysis 66

DISCUSSION 71 Clinicaleffectivenessandsafety:summaryofmainresults 71 Overall completeness and applicability of evidence 72 Quality of the evidence 73 Other European assessments 73 Implications for clinical practice 76 Cost-effectiveness 84 KeyConclusions 87

APPENDICES 89 References 89 Appendix1.Glossaryofterms 95 Appendix2.Searchstrategy 97 Appendix3.Completed(publishedandunpublished)singlearmstudies 101 Appendix4.FreeStyleLibreregistryrecords 102 Appendix5.Includedstudiesinclusionandexclusioncriteria 104 Appendix 6. Results from Meta-Analysis 105

14 Abbreviations

Abbreviations

Technicaltermsandabbreviationsareusedthroughoutthisreport.Themeaningisusuallyclearfromthecontext,butaglossary(seeAppendix1)isprovidedforthenon‐specialistreader.CI ConfidenceintervalCPI ConsumerpriceindexDM DiabetesmellitusDRGs Norwegiandiagnoses‐relatedgroupsGP GeneralpractitionerHELFO TheNorwegianHealthEconomicsAdministration.HRQL HealthrelatedqualityoflifeHTA HealthtechnologyassessmentICER IncrementalcosteffectivenessratioIMSCDM IMSCoreDiabetesModelMD MeandifferenceMmol MilimolesMol MolesSMBG SelfmonitoredbloodglucoseNIPH NorwegianInstituteofPublicHealthNOK NorwegianKronerQALY QualityadjustedlifeyearRCT RandomisedcontrolledtrialRR RiskratioSD Standarddeviation

15 Preface

Preface

Whatisasingle‐technologyassessment?

Asingle‐technologyassessmentisoneofaseriesofhealthtechnologyassessment(HTA)productsthatcanbemandatedin“TheNationalSystemforIntroductionofNewHealthTechnologies”withintheSpecialistHealthServiceinNorway(https://nyem‐etoder.no/).Withinthissystem,theCommissionerForumRHA(“BestillerforumRHF”),wherethefourRegionalHealthAuthoritiesarerepresented,evaluatessubmittedsuggestionsanddecidesonwhichtechnologiesshouldbeassessedandthetypeofassessmentneeded.Inasingle‐technologyassessment,thetechnology(apharmaceuticaloradevice)isas‐sessedbasedondocumentationsubmittedbythecompanyowningthetechnology,ortheirrepresentatives(“thesubmitter”).TheHTAunitoftheNorwegianInstituteofPublicHealth(NIPH)receivesandevaluatesthesubmitteddocumentation,butisnotthedecision‐makingauthority.Single‐technol‐ogyassessmentsconductedatNIPHarepublishedonourwebsite(www.fhi.no)andonhttps://nyemetoder.no/

Objective

Toassesstheclinicaleffectiveness,cost‐effectivenessandsafetyofFreeStyleLibre(in‐terstitialmeasurementofglucose)forinsulintreatedindividualswithdiabetestype1and2.

Log

WereceivedtheFreeStyleLibrecomission,ID2016_044,onDecember23,2016.TheCommissionForumrequestedtheNIPHHTAUnittoperformaclinicaleffectivenessandsafetyassessmentalongwithacost‐effectivenessanalysisofthissingle‐technologyforthemanagementofinsulindependentindividualswithdiabetestype1and2.Infor‐mationonthecommissioncanbeseenherehttps://nyemetoder.no/metoder/system‐freestyle‐libre‐for‐egenmaling‐av‐blodsukker

https://nyemetoder.no/


http://www.fhi.no/


16 Preface

Date Correspondence

September 23, 2016 Publication of horizon scanning report on this device

October 24, 2016 The commissioning forum commissioned a single technology assessment

Oct. 2016 – Dec 2016 Dialogue and meeting with technology manufacturer

December 23, 2016 Valid submission acknowledged

April 26 – 27, 2017 Clinical experts, and stakeholders draft reviewing

May 12, 2017 Norwegian Institute of Public Health external review process

May 25, 2017 Norwegian Institute of Public Health internal review process

June 2, 2017 End of 180 days evaluation period –Report Submitted

June 8, 2017 Report available at FHI website

July-Aug 2017 Amendments to report considered (i.e. health economic)

August 21th 2017 Amended report available at FHI website

History

Reportfirstsubmissiontocommissionerforum:June2nd,2017Amendedversion:August21th2017:themethodsusedinoriginalreportremainintact.Amendmentsweredoneasfollow:removalofinformationdeemedconfidentialbythesubmitter,furtherexplanationoftransparencyissuesencounteredwiththeIMSCoremodel,andelaborationofdiscrepanciesbetweenthecost‐effectivenessanalysisandbudgetimpactanalysis.Inclusionofin‐textevidencederivedfromsinglearmstudyde‐signs(previouslyinappendices),andupdatedinformationonEuropeancountriesHTAs.

Projectteam,consultantsandstakeholders

Norwegian Institute of Public Health team

Julia Bidonde (project leader), Researcher

Beate C. Fagerlund, Health Economist

Katrine B. Frønsdal, Senior Researcher

Ulrikke Højslev Lund, Health Economist

Bjarne Robberstad, Senior Health Economics

Ingrid Harboe, Information Specialist

Ingvil Sæterdal, Acting Head of Unit

Acknowledgements

Torunn Tjelle, Researcher

Elisabet Hafstad, Information Specialist

Doris Tove Kristoffersen, Statistician

Arna Desser, Senior Health Economist Nils Vӧlker, Health Economist fellow

Angieszka Anna Zachariassen, Legal services

17 Preface

In process consultants Åsne Bakke, Chief Physician, Stavanger University Hospital

Kristin Aakre Moberg, Department Chief Physician, Haukeland University Hospital

Torstein Baade Rø, Head of Department, St. Olavs Hospital/Associate Professor, NTNU

Henrik Underthun Irgens, Chief Physician, Haukeland University Hospital

External consultants Tore Julsrud Berg, Chief Physician, OUS/ Associate Professor, UiO.

Member of board of medical advisors for the Norwegian Diabetes Association

Sven Magnus Carlsen, Professor, NTNU.

Stakeholders who provided feedback on this assesment Norwegian Diabetes Association

Ragnhild and Andreas Jansson

SigneAgnesFlottorpDepartmentdirector

IngvilSæterdalActingHeadofUnit

JuliaBidondeProjectleader

18 Background

Background

Thetechnology

Nameofthetechnology:FreeStyleLibre,FlashGlucoseSensorMonitorSystem(“Free‐StyleLibre”)Manufacturerwhichsubmittedtheapplicationandprovidedthedocumentationpack‐age:AbbottNorgeAS(Leverandør),Postboks1,1360Fornebu,Norge(“submitter”).

Regulatorystatus(CE‐marking)andmarketaccessofthetechnology

FreeStyleLibrehasEuropeanConformity(ConformitéEuropéenne)orCE‐markingClassIIb,notificationbytheBritishStandardsInstitution(No597686),UnitedKing‐dom.ClarificationofCEMarkingofMedicalDevicescanbefoundathttp://www.ce‐marking.com/medical‐devices‐class‐IIb.htmlFreeStyleLibreisavailableinNorway,butisnotreimbursedbytheNorwegianhealthcaresystem(SpecialistHealthCare)orthroughtheNationalSocial(Security)Insurance(Folketrygden).

Descriptionanduseofthetechnology

FreeStyleLibre(informationbelowtakenfromthesubmitter’spackageandweb‐

site)

FreeStyleLibreflashglucosemonitorisasystemthatreliesonasubcutaneousglucosesensor,usuallyplacedontheupperarm,thatmeasuresandcontinuouslystoresglucosereadingsdayandnight(seeFigures1and2below).Glucoselevelsarecheckedby‘scanning’thesensorwithareaderobviatingtheneedforregularself‐monitorbloodglucose(SMBG)testing.Itreportscurrentglucoseconcentration,glucosetrendanddisplaystheprevious8hoursasatrend;FreeStyleLibreupdatesreadingseveryminuteandstoresdataevery15minutes.Ahand‐heldreaderisusedtoscanandretrieveinformationfromthesensor.Thereadercancapturedatafromthesensorwhenitiswithin1to4cmdistanceofthesensor.Variousreportsareavailablefromthereader: Logbook:individualglucosereadingsanduser‐enterednotes

http://www.ce-marking.com/medical-devices-class-IIb.html

http://www.ce-marking.com/medical-devices-class-IIb.html

19 Background

Dailygraph:dailyoverviewofglucosereadings,includinghowtheyfallwithinthetargetglucoserange

Averageglucose:averageglucosereadingsalongwithfour6‐hoursperiodsduringtheday

Dailypatterns:indicateswhenglucoselevelsareinthetargetrangeandthevariabilityofglucoselevels

Timeintarget:indicatesthepercentageoftimeglucosereadingsareinthetargetrangeandaboveorbelowthetargetrange

Lowglucoseevents:indicatesthenumberoflowglucoseeventsatfourdifferenttimesoftheday

Sensorusage:indicatesaveragenumberofscansperdayandwhatpercentageofglucosedatahasbeencapturedbythesescans

FreeStyleLibreisfactory‐calibrated,andthesensorscanbewornforupto14days.Thesensoriswaterresistantinupto1meterofwaterforamaximumof30minutes;itcanbewornwhilebathing,showering,swimmingandexercising.

Figure1.FreeStyleflashglucosesystem(imageusedwithsubmitter’spermission)

Figure2.FreeStyleapplicationandscanning(imageusedwithsubmitter’spermission)FreeStyleLibreinitialpackageincludesthefollowingcomponents:AreaderKit

1FreeStyleLibreReader 1USBcable 1Poweradapter 1QuickStartGuide UserManual

20 Background

ASensorKit

DisposableSensor:ithasathin,sterilefilament(0.4mmwide,insertedapproximately5mmunderskin)attachedtoasmalldisk(30mmx5mm)

Medicalgradeadhesiveisusedtokeepthesensorinplaceontopoftheskinonceapplied

1Sensorapplicator 1Alcoholwipe ProductLeaflet

OptionalsofwareSpeciallydesignedsoftware,givespeoplethepossibilitytodownloaddatatoacom‐puterandtocreateaseriesofreportsthatprovideafullglycemicpictureacrossvari‐oustimeframes.Reportsarepresentedingraphicalformatsthatareeasyforpeopletointerpret.Thereportsareasfollow:

Snapshot DailyPatterns GlucosePatternInsights MealtimePatterns MonthlySummary WeeklySummary DailyLog ReaderDetails

ContextforUse(fromthesubmitter’spackage)

FreeStyleLibreisindicatedformeasuringinterstitialfluidglucoselevelsinpeopleaged4andolderwithdiabetesmellitus.Theindicationforchildren(age4‐17)islimitedtothosewhoaresupervisedbyacaregiverwhoisatleast18yearsofage.FreeStyleLibreisdesignedtoreplaceSMBGofdiabeteswiththeexceptionslistedbelow.

Duringtimesofrapidilychangingglucoselevels,interstitialglucoselevels,asmeasuredbythesensorandreportedascurrent,maynotaccuratelyreflectbloodglucoselevels.Whenglucoselevelsarefallingrapidily,glucosereadingsfromthesensormaybehigherthanbloodglucoselevels.Conversely,whenglucoselevelsarerisingrapidly,glucosereadingsfromthesensormaybelowerthanbloodglucoselevels.

Inordertoconfirmhypoglycaemiaorimpendinghypoglycaemiaasreportedbythesensor.

IfsymptomsdonotmatchFreeStyleLibrereading.Donotignoresymptomsthatmaybecausedbylowbloodglucoseorhighbloodglucose.

AdvantagesanddisadvantagesofFreeStyleLibre

21 Background

TheadvantageoftheFreeStyleLibreisthecontinuousprovisionofinformationabout

interstitialglucoseconcentrationthatcanfacilitateadjustinginsulindosage.The

technologyisfactorycalibrated,whichmeanstheindividualdoesnothavetoperform

dailySMBGbyfingerprick,thesensorissmallandcaneasilybehiddenunderclothing,

anditiswaterresistantwhichcanbeseenasanadvantageforthosewhoenjoywater

activities.

DisadvantagesofFreeStyleLibrearepotentialskinirritation,andassociatedcosts

(sensorhastobereplacedevery14days);therecanbesomedelayinthe

measurement,whichmayimpedeoptimalmonitoring.Althoughahighbodymass

indexmaynotinfluencereadings,accordingtoclinicalexpertsopinion,averynarrow

subcutaneousspaceinunderweightindividualsmayperhapsputlimitationstothe

sensoruse.Unlikeotherrealtimemonitors,FreeStyleLibredoesnothaveanalarm,

anditdoesnotworkinsynchronisationwithaninsulinpump.

Descriptionofthehealthcondition

Diabetesmellitus(DM)isametabolicdisorderresultingfromadefectininsulinpro‐

duction,secretion,action,orall.ThenumberofpeoplewithDMishighandrisingin

everycountry‐withthenumberofadultswithDMhavingmorethandoubledover

nearlythreedecades(1).Thelatestestimatesshowaglobalprevalenceof382million

peoplewithDMin2013,anumberthatisexpectedtoriseto592millionby2035(2).

AcrossEuropethereareabout60millionpeoplewithDMandthenumberisexpected

toincreaseto71millionby2040(3).

InNorway(4):

Approximately200,000‐220,000people(4.3%percentoftheNorwegianpopulation)havebeendiagnosedwithdiabetes,

BasedoncalculationsfromtheNorwegianPrescriptionDatabase,inNorway,approximately28,000people(0.6%ofthepopulation)havetype1diabetes,

Approximately28%ofpeoplewithtype2diabetesaretreatedwithdietandexercise,

InternationalstudiesandunpublisheddatafromNorwaysuggestthatmanypeoplearelivingwithundiagnoseddiabetes,

Theprevalenceandincidenceoftype2increaseswithagetoapeakat80years, Norwayisamongthecountrieswithhighernewcasesoftype1DMinchildren

peryear.

22 Background

Theaetiologicalclassificationofdiabeteshasbeenacceptedworldwide;type1and

type2DMarethetwomaintypes,withtheprevalenceoftype2accountingforthema‐

jority(>85%)oftotaldiabetes.Type1isthemostcommonformofdiabetesamong

children,butitcanalsodevelopamongadults.Type1DMrequiresinsulin;peoplewith

type2DMcanbetreatedwithoralmedicationbutmayalsorequireinsulin.Oftenmod‐

ificationsindietandlifestylehelptomanagethediseaseforindividualswithtype2

DM.OthertypesofDMaremonogenic,secondaryandgestational.Monogenicdiabetes

occurswhenthereisachangeinasinglegene.Togethermonogenicdiabetesaccount

for1‐2%ofalldiabetescases,anddependentonthegeneinvolvedthetreatmentisei‐

therinsulinorsulfonylureatablets(5).Secondaryformsofdiabetes(secondarytopan‐

creaticdiseaseoradministrationorcertaindrugs)accountfor1to2%ofalldiabetes

(6).Gestationaldiabetes(5‐10%ofpregnancies)representsariskfactorforfuturede‐

velopmentofDM(7‐9).

Childrenandadolescent

Type1diabetesisthemostcommontypeseeninchildren,andismostcommonlyfirst

diagnosedintheteenageyears.Type2diabetesinchildrenandadolescentsisarela‐

tivelynoveldiseasefacingpaediatrichealthcareproviders(10).Type2isbecomingin‐

creasinglymoreprevalentinyoungerpeople,andmaybemoreinpeopleofSouth‐

Asian,AfricanCaribbeanorMiddleEasterndescent.Childrenwithadiagnosisofdiabe‐

tesoftenpresenttothehealthservicewithissuessuchashypoglycaemia,hyperglycae‐

mia,ordiabeticketoacidosis(11).Diabetesaffectschildren’slifeincludingschoollife,

dailyactivities,theiracademicachievementsandpersonalaspirations.Forexample,

theymaybeaffectedbylackoffulltimeschoolnurses,lackofteacherknowledgeofdi‐

abetes,lackofaccesstodiabetestools,lackoffreedomtoperformdiabetesself‐care,

lackofnutritionalinformationincafeterias,orlackofcommunicationbetweenparents

andschoolpersonnel(12).

Childrenwithtype1DMneedmultipledailymeasurementsoftheirbloodglucose.In

smallchildren,parentsorothercaregiversareresponsibleforthetreatmentandthe

monitoringoftheirdiabeteswhichcaninterferewithdailyactivitiesandwork.Fur‐

thermore,bloodglucosemaybemeasuredafterthechildhasgonetobed.Thiscanaf‐

fectthequalityofsleep,inparticularifthechildneedstoeatduetolowbloodglucose

level.

Timeofyouthisachallengingperiodoflife;adolescentswithdiabetesfaceuniqueage‐

specificdemands.Somedifficultiesarelearningaboutthenewdiseaseandmanaging

23 Background

diseaseknowledge,maintainingapositivehealthbehaviourandensuringtreatmentre‐

gimeadherence.Youngpeoplefacedifficultiesinthetransitionfromchildhoodto

adulthood,andproblemscopingwithachronicdiseasearecommon.Managingemo‐

tions,navigatingsocialrelationshipswithpeersincludingthedisclosureofthedisease

aresomeoftheirdifficulties(13).Aperiodofdiseaseneglectisoftenseen,resultingin

areducednumberofdailymeasurementsandpoordiabetescontrol.Thiswillleadto

severalyearswithelevatedbloodglucose,thusincreasingtheriskofdevelopingdiabe‐

tesrelatedcomplicationslaterinlife.

Managementofthecondition

Withoutproperdiseasemanagementtheindividualislikelytobecomeprogressivelyill

anddebilitated.Managementofbloodsugarlevels‐hypoglycaemiaandhyperglycae‐

mia‐isextremelyimportantindiabetescare.Ifbloodglucoseisuncontrolleditcan

leadtocomplicationssuchasretinopathy,nephropathy,neuropathy,orheartdisease,

strokeandperipheralvasculardisease.Hypoglycaemiaoccurswhenthelevelofblood

glucosefallsbelow3.5millimolesperlitre(mmol/L).Indicationsincludehunger,nerv‐

ousness,shakiness,perspiration,dizziness,sleepinessandconfusion,andifunattended

itmayleadtounconsciousness.Fearofrecurrenthypoglycaemiacandecreasequality

oflifeintheshortterm,butcanalsohinderadherencetotreatmentandtheachieve‐

mentofgoodglycaemiccontrol.Hyperglycaemiaoccurswhenthelevelofbloodglucose

ishigherthan11millimolesperlitre.Hyperglycemiatogetherwithinsulindepletion

canleadtoketoacidosis.Thisisafearedconditionthatuntreatedhasahighmortality.

Admissiontohospitalisnecessary,oftenatanintensivecareunit.Long‐termconse‐

quencesofchronichyperglycaemiamaybenervedamage,kidneydamageorfailure,

damagetothebloodvesselsoftheretinaandothereyecomplications.Prematuremor‐

bidity,mortality,reducedlifeexpectancyandfinancialandothercostsofdiabetesmake

itanimportantpublichealthcondition(14).

Glucoseisgenerallymeasuredinthreeways:

a)first,bloodglucosecanbetestedbyadropofbloodwithaglucosemeter(ca‐pillarybloodglucosetesting),alsoknownasself‐monitoringofbloodglucoseorSMBG;b)second,continuousglucosemonitors(CGM)providefrequentautomatedtest‐ingofinterstitialtissueglucose,calibratedtoreflectbloodplasmaglucose;andc)third,longertermcontrolismeasuredbyglycatedhaemoglobin(HbA1c)whichreflectstheaveragebloodglucoselevelsover2to3months.

24 Background

Psychosocialandculturalaspectsofthediseasearealsoimportantconsiderationsin

successfuldiabetesmanagement.Positivefactors,e.g.,goodcopingskills,familysup‐

port,effectiveweightcontrolprograms,etc.,canincreaseinterestindiseasemanage‐

mentandimproveadherencetomedication,resultinginbetterglycaemiccontroland

improvedqualityoflife.Individualslackingpositiveinfluencesmayfinddiseaseman‐

agementmoredifficult,resultinginpoorglycaemiccontrolandanincreasedlikelihood

forlong‐termcomplications(15;16).

Self‐monitoringofbloodglucoseisanessentialpartofdiabetesmanagementandis

usedtooptimiseglycaemiccontrol.Managementofdiabetesrequireslifelongintegra‐

tionofmanyfactorssuchas,lifecircumstances,dailyadherencetodietaryandexercise

plans,frequentbloodglucosemonitoringandadherencetomedications.Trainingfor

self‐managementimprovestheknowledgeofdiabetes,glucoselevelsandglycatedhae‐

moglobin.Itcanalsoleadtoimprovedsystolicbloodpressurelevels,bodyweightand

canreducetheneedforDMmedicationfortype2DM.Effectivecontrolofbloodglu‐

coselevelsallowsindividualswithDMtoadjusttherapy(insulindosage)appropriately.

Impairedawarenessofhypoglycaemia

Recognizingsymptomsofhypoglycaemia(being‘aware’)attheironsetisfundamental

fortimelyself‐managementofbloodsugarlevels.Impairedawarenessofhypoglycae‐

miameanstheindividual’sabilitytoperceivetheonsetofhypoglycaemia,ortorecog‐

nizewarningsymptoms,isdiminishedorabsent.Thecounterregulatoryhormonere‐

sponse(insulin)isdeficientorlackinginindividualswithimpairedawareness(17).Im‐

pairmentintheabilitytorecognizetheonsetofhypoglycaemiacanhaveseriousconse‐

quencesandconstitutesasignificantproblemcommonlyseeninindividualswithtype

1DM,andlessoftenseeninindividualswithtype2DM.CGMisausefulsystemthat

helpsindividualstodetectasymptomatichypoglycaemia,asitprovidesreal‐datatime

andalertsfortheindividual(18).Hypoglycaemiaisthemaincauseofindividualsget‐

tingacontinuousglucosemonitoringsysteminNorwaytoday.

Norwayimplementedanationaldiabetesstrategy(2006‐2010laterprolongedto

2012)whichaimedtoimprovetheprimarypreventionofdiabetes,improvethecoop‐

erationbetweentheprimaryandsecondaryhealthcareandincreasetheresourcesof

healthcareinthelocalmunicipalities.Norwaypublishedthelatestnationaldiabetes

clinicalguidelinein2016.Theclinicalguidelinehasitsmainfocusonsecondaryand

tertiarypreventionofdiabetes.Althoughbothdocumentsemphasiselifestyleandself‐

managementofthedisease,theuseofFreeStyleLibreisnotincluded(19).

25 Clinical effectiveness and safety

Clinicaleffectivenessandsafety

Issueaddressed

Accordingtothesubmitter,byusingFreeStyleLibre,peoplewithDMmayimproveglu‐

cosecontrolmanagementandconsequentlyreducethenumberofdiabetesrelated

complicationsandimprovetheirqualityoflife.Moreover,thetechnologycouldmakeit

easierforpeopletoadheretotreatment.FreeStyleLibremayhelpreducingtheinci‐

denceofsevereandnocturnalhypoglycaemiaanditsassociatedanxiety.FreeStyleLi‐

bremayofferbenefitsthroughcostandresourcesavingsbyreducingthenumberof

hospitaladmissionsandconsultationsfordiabetesrelatedcomplications,andby

achievingoptimalbloodglucoselevelsmorequickly.

Objective

Theobjectiveofthisdocumentwastoassesstheclinicaleffectiveness,cost‐effective‐

nessandsafetyofFreeStyleLibreforinsulintreatedindividualswithtype1and2DM

(“type1and2”).

Methods

Inclusion and exclusion criteria

Weusedthepopulation,intervention,comparison,outcome,anddesign(PICO–D)

frameworktoevaluatethesuitabilityofevidenceforinclusion(seeTable1).

WeselectedtheseoutcomesincollaborationwiththeclinicalexpertsandtheNorwe‐

gianDiabetesAssociationviacommunicationandconsultationmechanisms.


Table1.PICO–Dframework

Population Insulin dependent individuals (of any age) diagnosed with diabetes type 1 or 2

Intervention FreeStyle Libre flash glucose monitor

Comparator Any other glucose monitoring system or procedure including conventional self-monitoring of blood glucose plus multiple insulin injections, pen device use, insulin syringe, etc.

Outcomes Change in HbA1c (glycosylated haemoglobin),

Hypoglycemia or hyperglycemia – day, night time, and episodes

Quality of life

Patient / treatment satisfaction

Pain

Adverse events (related to the device or not, withdrawals, etc.)

Design Randomised control trials (RCTs)* or controlled studies (i.e., controlled before and after with at least two intervention and two control sites; or interrupted time series with at least three data points before and three after the time point of the intervention).

* Hierarchies of evidence rank research according to its validity. RCTs are commonly viewed as providing the highest level of evidence. This type of design minimises the risk of confounding factors influencing the results and it has been the ‘gold stand-ard’, or optimal research design, for evaluating effectiveness. Weexcludedstudiesif:

Populationofinterest/focusofthepublicationwasotherthaninsulindependent

diabetestype1and2DM

Theglucosemonitoringsystemintheinterventionwasdonebyaninstrument

otherthanFreeStyleLibre

NoneoftheoutcomesinTable1wereassessed

Datafortype1and2DMwerenotpresented/availableindependently

Typeofstudywereclinicalpracticeguidelines,conferenceabstractsandproceed‐

ings,books,bookchapters,animalormodellingstudies

Literature search and selection of studies

Thesearchstrategywasdesigned,peerreviewedandexecutedbytwoexperiencedin‐

formationspecialists.Thesearchwasadaptedtoeachdatabaseandhadnolanguage

restrictions.Wesearchedsystematicallyinthefollowingdatabases:MEDLINEandEm‐

baseviatheOvidinterface,CochraneLibrary:CochraneDatabaseofSystematicRe‐

views,OtherReviews,CentralRegisterofControlledTrials,EconomicEvaluationsdata‐

base,CentreforReviewsandDissemination:DatabaseofAbstractsofReviewsofEf‐

fects,HealthTechnologyAssessmentdatabaseuptoJanuary18,2017.Wealso

searchedtheTheInternationalNetworkofAgenciesforHealthTechnologyAssessment

(INAHTA)members’websiteforotherFreeStyleLibreassessment.


WesupplementedthedatabasesearchbyconsultingothersourcessuchasGoogle

scholar,HTAagencies’homepages,ClinicalTrials.gov,andWHOInternationalClinical

TrialsRegistryPlatformandbyhand‐searchingreferencelistsofrelevantpapers.We

usedacombinationofsubjecttermsandtextwords(seeAppendix2fordetailedsearch

strategy).

Pairofauthors(JB,KF,TTorIS)independentlyscannedtitleandabstractofthere‐

trievedrecords.Weinvestigatedallpotentiallyrelevantarticlesasfulltextregarding

eligibilitycomplianceaspercriteriamentionedinTable1.Differencesinopinionwere

resolvedbyathirdreviewer.TheresultsofthisprocessarepresentedinaPRISMA

(preferredreportingitemsforsystematicreviewsandmeta‐analysis)flowchart(Fig‐

ure3intheresultssection).

Alldatawasextractedindependentlybyonereviewer(JB)intoastandardiseddataex‐

tractionform,whichwasthenbeencheckedforaccuracybyanotherreviewer(KFor

TT).Weextractedthefollowingdata(seeTable2):

Table2.Dataextracted

Data Details to be extracted (if available)

Publication Summary Author & year, title, publication type, inclusion/exclusion, country (use first author affiliation) of origin

Population Total sample size, age, gender, diagnosis, years since diagnosis, type of di-abetes

Intervention Length, follow up

Comparator Blood capillary glucose monitoring, other system (Navigator, MiniMed) etc.

Outcomes Same as in table 1

Weextracteddatafromincludedstudiesasfaraspossible.Wecontactedprimarystud‐

ies’authorstorequestdataprovidedingraphicalformfortwooftheoutcomes.Pri‐

maryauthorssentourrequesttothesubmitter;duetoadelayintheresponse,weesti‐

mateddatafromthegraphusingagraphicaldatasoftware(EngaugeDigitizer).We

eventuallyreceivedaresponsefromthesubmitter.

Risk of bias assessment in included studies

Tworeviewers(JBandKF)independentlyevaluatedtheriskofbiasusingtheCochrane

"Riskofbiastool”(20).Theriskofbiastooladdressesspecificdomainsrelatedtothe

study’sinternalvalidity:sequencegenerationandallocationconcealment(selection


bias),blindingofparticipants,studypersonnelorstaff(performancebias),blindingof

studyassessors(detectionbias),incompleteoutcomedata(attritionbias),selective

outcomereporting(reportingbias),andothersourcesofbias.Abriefdescriptionof

thesebiasesispresentedinTable3below.

Table3:AssessmentofRiskofBiasinincludedRCTs

Domain-Item Description

Sequence Generation Was the allocation sequence adequately generated?

The method used to generate the allocation se-

quence should be described in sufficient detail

to allow an assessment of whether it should

produce comparable groups.

Allocation Concealment Was allocation adequately concealed?

The method used to conceal the allocation se-

quence should be described in sufficient detail

to determine whether intervention allocations

could have been foreseen in advance or during

enrolment.

Blinding of participants, personnel and outcome asses-sors Was knowledge of the allocated intervention adequately prevented during the study? Assessments will be made for each main outcome (or class

of outcomes).

All measures used, if any, to blind study partici-

pants and personnel from knowledge of which

intervention a participant received, should be

described. Any information relating to whether

the intended blinding was effective should also

be reported.

Incomplete outcome data Was incomplete outcome data adequately addressed? Assessments will be made for each main outcome (or class

of outcomes).

The completeness of outcome data for each

main outcome should be described, including

attrition and exclusions from the analysis. The

authors should report any attrition and exclu-

sions, the numbers in each intervention group

(compared with total randomized participants),

and reasons for attrition/exclusions and any re-

inclusions in analyses.

Selective Reporting* Were results of some outcomes not reported because the results were not statistically significant Assessment will be made by comparing trial registry record

or published protocol to the study publication

The authors should not select and report out-

comes in full text publications based on their

results. All of the study’s prespecified out-

comes should be reported (by checking the trial

protocol if available)


*Betweenstudiesreportingbiases:duetoalackofsamplestudies(i.e.,morethan10)

wewerenotabletoproducedfunnelplots(20)toinvestigatepublicationreporting

bias.

Withinstudiesreportingbiases:whenapublishedstudyprotocolwasavailable,we

comparedoutcomesinthestudyprotocolwiththeoutcomesinthepublishedreport.

Wedocumentedthetrialnumberortheavailabilityofapublishedprotocol.

Eachcriterionwasratedasbeingatlow,high,orunclearriskofbiasaccordingtothe

informationprovidedinthestudies.Weclassifiedstudiesas'lowriskofbias'ifallkey

domainshadlowriskofbiasandnoseriousflaws.Thecriterion'unclearrisk'wasas‐

signedwhentheabsenceorambiguityoftheinformationhinderedtheassessors'abil‐

itytodeterminethepotentialforbias.Ifthecriterionwasnotfulfilledweclassifieditas

‘highrisk’.Disagreementswereresolvedthroughconsensusmeetingsbyconsultinga

thirdteammember.

Theresultsoftheriskofbiasassessmentswereusedfordescriptivepurposestopro‐

videanevaluationoftheoverallqualityoftheincludedstudiesandatransparent

methodofdevisingrecommendationsforthedesignoffuturestudies.

Data synthesis

Whentwoormorestudiesreportedthesameoutcome,wepooledthedata(meta‐anal‐

ysis)usingRevMan5.32014(21).Forcontinuousdata,weusedthegrouppost‐test

meansandstandarddeviationstocalculatetheeffectsize.Effectsizeswereexpressed

preferentiallyintheformofmeandifference(MD)and95%confidenceinterval(CI).

Dichotomousdatawasanalysedbycalculatingrelativerisk(RR)andthecorresponding

95%CI.Forgraphicaldata,standarderrorsweretransformedtostandarddeviations.

Weorganisedthedatabyoutcomeandreportedtheresultsfortheoutcomesofinter‐

estintextandtables.

Assessment of Heterogeneity

Statisticalheterogeneitywasassessedbyvisualinspectionoftheforestplottoassess

obviousdifferencesinresultsbetweenthestudies,andusingtheI²andchi²statistical

Other sources of bias Was the study apparently free of other problems that could put it at a high risk of bias?

Overall, the study should be free from any im-

portant concerns about bias (i.e. bias from

other sources not previously addressed by the

other items).


tests.AsrecommendedintheCochraneHandbookforSystematicReviewsofInterven‐

tions(22),wefollowedtheinterpretationofanI²valuefrom0%to40%as'mightnot

beimportant';from30%to60%asrepresenting'moderate’heterogeneity;from50%

to90%asrepresenting'substantial'heterogeneity;andfrom75%to100%asrepre‐

senting'considerable'heterogeneity.BecauseI²hasoverlappingcategories(i.e.,0%to

40%,30%to60%)or"ambiguous"zones,whenmoderatetosubstantialstatisticalhet‐

erogeneitywasfound(i.e.,I²between50%and60%)weexploreditthoroughly.Inad‐

dition,clinicalandmethodologicaldiversitywasassessedintermsofparticipants,out‐

comes,andstudycharacteristicstodeterminewhetherameta‐analysiswasappropri‐

ate.

Giventhatvaluesbetween50%and60%fallinan'ambiguous'zone,whentherewere

noapparentcausesofheterogeneity,wekeptthetrialintheanalysisanddocumented

ourdecision.Thechi²testwasinterpretedwithapvalue≤0.10indicatingevidenceof

statisticalheterogeneity.

Grading of the evidence

Onereviewer(JB)usedtheGRADEtool(GradingofRecommendationsAssessment,

DevelopmentandEvaluation)developedbytheGRADEworkinggroup(23)todeter‐

minethecertaintyoftheeffectsofinterventionsreportedintheincludedreviews,i.e.

towhatdegreewecouldtrusttheresults.Asecondreviewer(KF)independently

checkedtheassessment.Ifdisagreementswerefound,theyweresolvedbydiscussion.

Weconsideredthecompileddocumentationforeachofthemainoutcomesusing

GRADEandpreparedsummaryoffindingstablesfortheoutcomesofinterest.Intheta‐

blesweintegratedthecertaintyofevidenceandthemagnitudeofeffectoftheinterven‐

tion.WemadetheGRADEratingsseparatelyforeachoftheoutcomesofinterest.

WeusedthefiveGRADEconsiderationsfordowngrading(studylimitations,con‐

sistencyofeffect,imprecision,indirectnessandpublicationbias)toassessthecertainty

ofthebodyofevidenceashigh,moderate,loworverylow.Thetablebelow(seeTable

4)presentswhatGRADEmeansbyeachofthesefourcategories.

Evidencefromrandomisedcontrolledtrials(RCTs)startedashighqualityevidencebut

mayhavebeendowngradeddependingonthefivecriteriainGRADEthatareusedto

determinethecertaintyoftheevidence.


Table4.GRADE

QualityLevel Significance

High We are very confident that the true effect lies close to that of the estimate of the effect

Moderate We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different

Low Our confidence in the effect estimate is limited: The true effect may be substan-tially different from the estimate of the effect

Very low We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Presentation of results in relation to the submitter’s package

Someresults(i.e.,searchandriskofbias)fromthesubmitter’sandtheNIPHhavebeen

comparedintabularform.Inthediscussionchapter,weincorporatetheclinicaleffec‐

tivenessimplicationsoftheresultsandpresentagreementsordisagreementswiththe

submitter’sfile.

Stakeholder involvement

Asstatedintheliterature,thereisnotaconventionalmodeltoinvolvestakeholders’in

HTAs(24).Nevertheless,theNIPHfollowedaconsultationprocessaimingtoincorpo‐

ratetheexperienceandknowledgeofclinicalexperts,consumersorusersofthedevice,

andpatientorganizations.Clinicalandexternalreviewexpertsweredesignatedbythe

RegionalHealthAuthorities.

First,thePICOframeworkwasagreeduponincollaborationandwiththefeedback

fromclinicalexpertsandtheNorwegianDiabetesAssociaton.Second,weaskedclinical

expertstoprovidefeedbackduringtheassessmenttovalidateourunderstandingofthe

diseaseandinitialfindings.Third,allstakeholders(clinicalexperts,users’andpatients’

organization)wereinvitedtoprovidefeedbackonthefirstdraftoftheassessment.The

projectleadercontactedthemandprovidedinitialinformation.Followinganinvitation

totakepartintheassessment,everyoneagreedtotheconfidentialitytermsandcondi‐

tionsandsignedcorrepondingforms.Users’expertswereinvitedfollowingasnowball‐

ingtechnique,andtheNorwegianDiabetesAssociation,themainstakeholderinthisre‐

port,wassentanemailinvitation.TheNIPHrequestedclarificationwhenneededon

thekeyevidenceresponsessubmitted.Lastly,followingthefirstdraft,weincorporated

feedbackintothemanuscriptandprepareditforexternalcontentexperts.Then,meth‐

odologistsatNIPHandexternalcontentexpertspeer‐reviewedthesecondandfinal

draft.


Results

Literaturesearch

Thesearchidentified1665citations,whichincluded1622journalrecordsand43trial

registryrecords.Weexcluded1576recordsbasedonscreeningoftitlesandabstracts.

Weassessed89fulltextarticlesandtrialregistryrecordsforeligibility.Thisresultedin

thefinalinclusionof2RCTsandcorrespondingregistryrecords.SeeFigure3forde‐

tails.

Severalsingle‐armstudies,whichprovideevidenceofinitialexplorationsofFreeStyle

Libreaccuracy,comparedsensorreadingstobloodglucosecapillarymeasurementsor

venousandcapillary‐pairedmeasurements.Giventheavailabilityofrandomizedcon‐

troltrialsandlackofacomparisongrouponthistypeofdesign,theteamdecidedtofo‐

cusontheevidenceprovidedbytheRCTs.Asummaryofcompleted(publishedandun‐

published)single‐armstudies(e.g.,populationstudies,author&year,countryoforigin,

duration,andoutcomes)ispresentedinAppendix3.

FreeStyleLibreregistryrecords

WefoundseveralregistryrecordsforFreeStyleLibre.Amongthese,sevensinglearm

studieshavebeencompleted,threeareongoingRCTs,andsevenareongoingsingle

armstudies.Wereporteddetails(e.g.,registrynumber,studytitle,studystatus,coun‐

tryoforigin,outcomes,andstudyduration)ofongoingstudiesinAppendix4.

OtherEuropeanassessments

WefoundfivecompletedandoneongoingFreeStyleLibreassessments.Also,wefound

aGovernmentclaim,apeadiatricguidelineandaSwedishreportusingFreeStyleLibre

asanexample.Wepresenttheresultsofthesereportsinthediscussion.


Figure3.Aflowchartoftheliteratureselection

Table5(below)presentsthecomparisonbetweenthesearchstrategyofNIPHandthe

submitter:thenumberofdatabasessearcheddifferedgreately,andsowerethe

numberoffulltextretrievedandscreened,otherHTAEuropeanassessments,and

ongoingstudiesandrecordsincluded.

Table5.NIPHandsubmittersearchfindings

Norwegian Institute of Public Health Submitter

Database search: MEDLINE, Embase (Ovid), Cochrane Library, Technology Assessments, Economic Evaluations database, Centre for Reviews and Disseminations, Database of Abstracts of Reviews of Effects, Health Technology Assessment, and PubMed databases up to January 18, 2017.

Database search: (pg 11) www.ncbi.nlm.nih.gov/gov/pubmed www.cochranelibrary.com up to Nov 11, 2016

Full text records screened: 89

Full text records retrieved: 4

Records identified through systematic searching

(n = 1622)

Additional records identified through other sources

(n = 43)

Total records screened (n = 1665)

Excluded records (n = 1576)

Full text assessed for eligi‐bility

(n = 89)

Full text records excluded with reasons (n = 85)

Full text publications included n=2 (and 2 registry records)

http://www.ncbi.nlm.nih.gov/gov/pubmed

http://www.cochranelibrary.com/


Reports from other HTA agencies: 1 ongoing and 4 published

Reports from other HTA agencies: 1

Registry records: 18

Ongoing: “to be supplied”

Records included in the analysis: 2 RCTs and 2 registry records

Records included: 1 article and 1 abstract/poster

Characteristicsofincludedtrials

Included Studies

TwoRCTs(andcorrespondingregistryrecords–hereafter“protocols”)wereincluded

inthisappraisal.Thestudieswerepublishedin2016and2017,andwereconducted

across23(25)and26Europeandiabetescentres(26)(IMPACTandREPLACEstudies

respectively)insevencountries(France,Germany,UnitedKingdom,Sweden,Austria,

SpainandtheNetherlands).Inbothtrials,thelengthofthetreatmentwas6months,

thetrialsusedarandomisedclinicaltrialwithparallelgroupstudydesign,andthe

FreeStyleLibregroupwascomparedtoSMBG.Individuals’insulinadministration

methodwasprimarilymultipledailyinjections(25;26).

Participants

Thestudiesincludedatotalof463adults,ofreportedwhiteethnicity(177females,286

males).DetailsofinclusionandexclusioncriteriatothetrialscanbeseeninAppendix

5.Table6showssomeimportantbaselinecharacteristics.TheIMPACTstudyincluded

individualswithtype1DMwhoshowedgoodglycaemiccontrolatbaseline,whilethe

REPLACEstudyincludedindividualswithtype2DMwithbaddiabetescontrol,HbA1c

of8.74%.

Table6Baselinecharacteristicsofincludedstudies

Study (Diabetes type)

BMI (SD) Age (range) Baseline HbA1c % (SD)

Years since diagnosis

SMBG per day (SD)

Bolinder (25):

Type 1 DM

25 (4) 43 years

(33-57)

6.7 (0.6) 20 years

(range 12-31),

5.5 (2.2)

Haak (26):

Type 2 DM

33 (6) 59 years

(22-81)

8.74 (1.04) 17 years

(range 2-43)

3.8 (1.3)

BMI: body mass index; DM: diabetes mellitus; SMBG: self monitor blood glucose; SD: standard deviation;

FreeStyle Libre vs SMBG

SMBGincludesselfmonitoringandthefollowupuseofinsulinintheformofapende‐

vice,orcontinuoussubcutaneousinsulininfusion.Inbothstudiesparticipantswore


FreeStyleLibretechnologyintomaskedmodefor14daysbaselineperiod;measure‐

mentswereblindedforparticipantandinvestigatoratthistime.Participantssup‐

portedtheirglucosemanagementbySMBG.TheyusedthestripportbuiltintotheFree‐

StyleLibreandcompatibleteststripsmadebytheAbbott.Participantswereaskedto

keeprecordofcapillaryglucoseconcentrationsinaglucosediaryandtologother

eventsinaneventdiary.Thosethathadsensordatafor50%oftheblindedwearpe‐

riod,ormorethan650individualsensorreadings,werethencentrallyrandomisedinto

twogroups.

Afterrandomisation,thetechnologywasunblindedforparticipantsintheintervention

groupwhothencontinuouslyusedsensorglucosedataforself‐managementofglucose

levelsthroughoutthedurationofthestudy.Participantsintheinterventiongroupwere

givenaccesstothetechnologysoftware,whichtheycoulduseathometoreviewtheir

sensordataiftheywished.Notrainingwasprovidedtotheseparticipantsforinterpre‐

tationofglucosesensordatainneitherofthestudies.Participantsinthecontrolgroup

self‐monitoredglucoseconcentrationsusingtheFreeStyleLibremeterandteststrips.

Figure4.Studydesign(reprintedfromBolinder2016withsubmitter’spermission)

Riskofbiasinincludedstudies

Tworeviewersevaluatedthe‘riskofbias’usingtheCochraneHandbooktool(20)

basedontheprimaryarticleandcorrespondingprotocol.Resultsoftheriskofbiasfor

thetwoRCTsarepresentedbelowinFigures5and6.Someconcernsintheriskofbias

weretheunclearinformationaboutallocationconcealment–althoughtherewereno

obviousbaselineimbalancesnoinformationisprovidedonconcealmentallocation‐

andlackofblindingintheincludedstudies(participants,personnel,andstaff).Weun‐

derstandthatforparticipantsandpersonnelitisalmostimpossibletoperformatrial

withtrueblindingwiththistypeofintervention.However,thisdoesnotmeanthatpo‐

tentialbiasescanbeignored.Thefactthatparticipantsandpersonnelwerenotblinded


maybiastheresultsandoutcomeassessment.

Detectionbiasforsubjectiveoutcomes(i.e.,qualityoflife,treatmentsatisfaction)was

assessedashighrisk,asitispossiblethatthenon‐blindedassessor(theindividual)

overestimatedtheeffectoftheintervention.Detectionbiasforsomeobjectiveout‐

comes(i.e.adverseevent)weretheobserverjudgementwasinvolvedwasassessedas

highrisk;foroutcomeswerenojudgementwasinvolved(i.e.,bloodtest)weconsid‐

eredtheassessmentoftheoutcomewasnotlikelytobeinfluencedbythelackofblind‐

ing.Furthermore,weareunclearhowthedatawastransferredandanalysedfromthe

FreeStyleLibreforanalysis.Itisclear,however,thatallstudypersonnelwasunmasked

andthereforethenon‐blindedassessorcouldoverestimatetheeffectbeingassessed.

Selectiveoutcomereportingwasassessedasunclear,astherearedifferencesbetween

theprotocol,thejournalpublication,andthesubmitterpackage,whichwecouldnot

explain.Overall,ourassessmenthadahighernumberofhighriskandunclearrisksdo‐

mainsthanthesubmitter’sassessment.Table7belowcomparesresultsregardingrisk

ofbias:

Table7.NorwegianInstituteofPublicHealthandsubmitter’sriskofbias

Norwegian Institute of Public Health Submitter

Tool utilized: Cochrane Handbook Tool (20)

Selection bias (randomization): Low risk

Selection bias (allocation): Unclear risk

No information on how this was done

Performance bias (blinding of personnel and

participants): High risk – no blinding

Detection bias (subjective outcomes): High risk

– self reported

Detection bias (objective outcomes): low to high

risk – outcomes requiring judgement high risk,

outcomes not requiring judgement are low risk

Attrition bias: Low risk – data accounted for, ap-

propriate statistical methods

Tool utilized: no information provided

Selection bias (randomization & allocation): Low

risk

Central interactive web response WRS using the

biased coin minimisation method; study centre

and type of insulin administration were prognostic

factors

Performance bias: Unclear risk -

no blinding

Detection bias: Low risk

Detection of hypoglecemia was done by sensor

and not subject to human evaluation

Attrition bias: Low risk

Minimal missing data. Missing data is accounted

for


Reporting bias: Unclear risk

Other sources of bias: High risk -sponsor stud-

ies

Reporting bias: Low risk

All outcomes accounted for

Other sources of bias: not evaluated

Figure5.RiskofBias:BolinderandHaak

Figure6.RiskofBias:studiescombined


EffectofFreeStyleLibre

Theincludedstudiesprovideddataforhealthrelatedqualityoflife,treatmentsatisfac‐

tion,HbA1c,glycaemicmeasures,andadverseevents.Thestudiesdidnotassesspain

asaseparateoutcome,butrecordedpainaspartofadverseevents.TheRCTsspecified

theevaluationoftheself‐managementofDMwasinthehomesetting.Theresultsre‐

latedtotheeffectsoftheinterventionfromthemeta‐analysisarepresentedbelowcor‐

respondingtotheobjectivesoftheassessment.

Followingthefeedbackfromclinicalexperts,wepresenttheeffectestimatesofeach

groupi.e.type1DMandtype2DMfortheglycaemicmeasuresforeachofthetwo

studiesseparatelyintheforestplotsandinAppendix6.Theforestplotsarefollowed

bythe“summaryoffindings”table,whichisthekeyinformationconcerningthecer‐

tainty(quality)ofevidenceandthemagnitudeofeffectoftheintervention.

Outcomes

Alloutcomes,withtheexceptionofadverseevents,weremeasuredatbaseline

and6monthsendpoints.Adverseeventsweremeasuredatbaselineand6

monthsendpointfortheinterventiongroup,andbaselineand4weeks,divided

intwosetsof14daysat3monthsand6month,inthecontrolgroup.

Health Related Quality of Life

Thisoutcomewasmeasuredwithadiabetesspecificscale(self‐report,DiabetesDis‐

easeQuestionnaire);thescaleisa1‐5pointLikertscalewithhighscoresindicatingdis‐

satisfaction,frequentimpact,orfrequentworry.TheMDwas‐0.05(95%CI‐0.16to

0.05;I20%indicatingnoheterogeneity;p=0.36).


TheGRADEqualityofevidenceforthisoutcomewaslowwhichmeansFreeStyleLibre

mayleadtolittleornodifferenceinhealthrelatedqualityoflifeforindividualswith

type1or2DM.

Table8.Summaryoffindingstable‐healthrelatedqualityoflifeFreeStyle Libre compared to self-monitoring of blood glucose in insulin-treated diabetes individuals

Patient or population: individuals with diabetes type 1 and 2 insulin dependent Setting: home setting Intervention: FreeStyle Libre technology Comparison: SMBG Outcome: measured at 6 months (end of intervention)

Outcomes Anticipated absolute effects* (95% CI) Relative effect

(95% CI)

№ of parti-

cipants

(studies)

Quality of the

evidence

(GRADE)

Risk with SMBG Risk with FreeStyle Libre technology

Health Related Quality of Life DQoL Likert scale (self-reported) from 1 to 5, lower scores are best

The mean health related quality of life ranged across control group from 2 to 2.2 points

The mean health re-lated quality of life in the intervention group was 0.05 lower (0.16 lower to 0.05 higher)

- 465 (2 RCTs)

⨁⨁◯◯ LOW a

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RCT: randomised control trial:

a. Issues related to unclear or high risk of selection, performance and detection biases (subjective outcome) (downgraded twice) Patient Treatment Satisfaction

Thisoutcomewasmeasuredwiththe(self‐report)DiabetesTreatmentSatisfaction

Questionnaire;scoresrangefrom‐18to18withhigherscoresindicatinghighertreat‐

mentsatisfaction.TheMDwas5.10(95%CI2.95to7.26;I2=70%indicatingsubstan‐

tialheterogeneity;P=0.07alsoindicatingstatisticallysignificantheterogeneity).

Duetostatisticalheterogeneity(I2=70%),clinicalheterogeneitywasexplored.On

evaluation,dailylifeofindividualswithType1and2DMisverydifferent.Buteven

whendiabetesmanagementimposesconsiderabledemandsonindividuals,treatment

methodusedhasanimpactontreatmentsatisfaction.Despitehighheterogeneityboth

groupsconsiderablyimprovedtheirtreatmentsatisfactionattheendofintervention.


TheGRADEqualityofevidence(seetable9)forthisoutcomewaslow,whichindicates

thatFreeStyleLibremayimprovetreatmentsatisfactionforindividualswithtype1or

2DM.

Table9.Summaryoffindings‐patienttreatmentsatisfactionFreeStyle Libre compared to self-monitoring of blood glucose in insulin-treated diabetes individuals


Outcomes Anticipated absolute effects* (95% CI) Rela-tive effect (95% CI)

№ of partici-pants

(studies)

Quality of the evidence (GRADE)

Risk with SMBG

Risk with FreeStyle Libre technology

Patient satisfaction Satisfaction score (self-reported), scale from: -18 to 18, high scores are best

The mean pa-tient satisfac-tion ranged across control groups from 7 to 9 points

The mean patient sat-isfaction in the inter-vention group was 5.1 higher (2.95 higher to 7.26 higher)

- 465 (2 RCTs)

⨁⨁◯◯ LOW a


Sponsored studies but not further downgraded a. Issues related to unclear or high risk of selection, performance and detection biases (subjective outcome) (downgraded twice)

Pain: Painwasrecordedamongadverseevents

HbA1c:

HbA1c:(targetlevelof7%orless,analysedbyICONLaboratories,Dublin,Ireland).The

hemoglobinA1cMDwas‐0.00(95%CI‐0.14to0.14;I2=0%indicatingnoheterogene‐

ity;P=0.81alsoindicatingnostatisticallysignificantheterogeneity).


TheGRADEqualityofevidence(seetable10)forthisoutcomewaslow,whichindicates

thatFreeStyleLibremayleadtolittleornodifferenceonHbA1cchangesforindividuals

withtype1or2DM.

Table10.Summaryoffindingstable‐HbA1c%FreeStyle Libre compared to self-monitoring of blood glucose in insulin-treated diabetes individuals


Outcomes Anticipated absolute effects* (95% CI) Relative effect (95% CI)


(studies)

Quality of the evidence (GRADE) Risk with SMBG Risk with FreeStyle

Libre technology

HbA1c Target level 7% or less

The mean HbA1c (%) ranged across control groups from 7 to 8%

The mean HbA1c (%), target level 7% or less in the inter-vention group was 0 (0.14 lower to 0.14 higher)

- 462 (2 RCTs)

⨁⨁◯◯ LOW b


b. Issues related to unclear or high risk of selection and performance biases (downgraded twice)

Glycaemic Measures (time in range, without hypoglycaemia and hyper-glycaemia)

Timeinrange‐glucose3.9‐10mmol/L

Thetime(inhours)spentwithglucoserange3.9‐10mmol/L,showsastatisticallysig‐

nificantresultinfavorofFreeStyleLibre.TheoverallMDwas1.00(95%CI0.32to

1.68;I2=6%indicatingnoheterogeneity;p=0.30).Resultsshowedstatisticallysignifi‐

canteffectfortype1DM(238participants,MD1.2095%CI0.46to1.94)andnotsta‐

tisticallysignificanteffectfordiabetestype2(224participants,MD0.40,95%CI‐0.93

to1.73).TheGRADEqualityofevidenceforthisoutcomewaslow(seeTable11)which

meansFreeStyleLibremayslightlyimprovetimewithglucoseinrange3.9‐10ml/Lfor

insulindependentindividualswithtype1and2DM.


Glucose<3.9mmol/Lwithin24h

Time/hours

Thetime(inhours)spentwithglucose<3.9mmol/Lwithin24hoursdecreasedinthe

FreeStyleLibregroup.ThetotalMDwas‐0.60(95%CI‐0.88to‐0.32;I2=84%indicat‐

ingconsiderableheterogeneity,p=0.01).Thehighheterogeneityinglycaemicmeasures

isnotsurprisingandcanbeexplainedbyconsideringthephysiopathologyofeachtype

ofdiabetes.TheGRADEqualityofevidenceforthisoutcomewasverylow(seeTable

11)whichmeansweareuncertainwhetherFreeStyleLibreleadstolesstimewithglu‐

cose<3.9mmol/Lwithin24hforindividualswithtype1or2DM

Events

Themeannumberofeventswithglucose<3.9mmol/Ldecreasedforparticipantsinthe

intervention.ThetotalMDwas‐0.23(95%CI‐035to‐0.10;I2=64%indicatingsub‐

stantialheterogeneity;p=0.09).TheGRADEqualityofevidenceforthisoutcomewas

verylow(seeTable11)whichmeansweareuncertainwhetherFreeStyleLibrede‐

creasesthenumberofeventswithglucose<3.9mmol/Lwithin24hforindividualswith

type1or2DM


Glucose<3.1mmol/Latnight(23:00‐06:00)within7hTime/hours

Thetimespentinhypoglycemiaduringthenightshowedanon‐statisticallysignificant

result.TheoverallMDwas‐0.22(95%CI‐0.46to0.03;I2=85%indicatingconsiderable

heterogeneity;p=0.010).Results,however,showedstatisticallysignificanteffectfor

type1DM(MD‐0.3595%CI‐0.51to‐0.19)andstatisticallysignificanteffect,however

smaller,fortype2DM(MD‐0.1095%CI‐0.20to0.00).TheGRADEqualityofevidence

forthisoutcomewasverylow(seeTable11)whichmeansweareuncertainwhether

FreeStyleLibredecreasesnocturnaltimewithglucose<3.1mmol/Lwithin7h

Events

Thenumberofhypoglycemicnighteventsshowedastatisticallysignificantdecreaseininfavouroftheintervention.TheMDwas‐0.09(95%CI‐0.13to‐0.04,I2=0%indicat‐ingnoheterogeneity;p=0.35).TheGRADEqualityofevidenceforthisoutcomewaslow(seeTable11)whichmeansFreeStyleLibremayslightlydecreasenocturnaleventswithglucose<3.1mmol/Lwithin7h


Glucose <3.1 mmol/L within 24h

Time/hours

Thetimespentwithglucose<3.1mmol/Lwithin24hwasnotstatisticallysignificant.

ThepooledMDwas‐0.49(95%CI‐0.35to0.16;I2=89%indicatingconsiderableheter‐

ogeneity,p=0.002).Resultshowever,showedstatisticallysignificanteffectfortype1

DM(MD‐0.8595%CI‐1.24to‐0‐46)andhoweversmallerresults,theyarealsostatis‐

ticallysignificantfordiabetestype2(MD‐01895%CI‐0.35to‐0.01).TheGRADEqual‐

ityofevidenceforthisoutcomewasverylow(seeTable11)whichmeansweareun‐

certainwhetherFreeStyleLibreleadstolesstimewithglucose<3.1mmol/Lwithin

7hours.

Events

Similarly,resultsofthemeta‐analysisshowednon‐statisticallysignificanteffectsizein

thenumberofeventsparticipantshadwithglucose<3.1mmol/L.TheMDwas‐0.22

(95%CI‐0.47to0.03;I2=86%indicatingsubstantialheterogeneity;p=0.007).

Likewise,resultsshowedastatisticallysignificanteffectfortype1DM(MD‐

0.3695%CI‐0.53to‐0.19)andasmallereffectfortype2DM(MD‐0.1095%CI

‐0.19to‐0.01).TheGRADEqualityofevidenceforthisoutcomewasverylow(seeTa‐

ble11)whichmeansweareuncertainwhetherFreeStyleLibreleadstofewerevents

withglucose<3.1mmol/Lwithin7hours.


TimewithGlucose>10.0mmol/L(h)

Onestudy(N=224)provideddataforthisoutcome.Therewasevidenceofnoeffecton

timespentwithglucose>10mmol/Linindividualswithtype2DM.TheMDwas0.00

(95%CI‐1.44to1.44)TheGRADEqualityofevidenceforthisoutcomewasverylow

(seeTable11)whichmeansweareuncertainwhetherFreeStyleLibreleadstoless

timewithglucose>10.0mmol/Lforindividualswithtype2DM.

TimewithGlucose>13.3mmol/L(h)

Timespentwithaglucoseconcentration>13.3mmol/Ldetectionfavouredtheinter‐

vention.TheoverallMDwas‐0.39(95%CI‐0.75to‐0.03;I20%indicatingnoheteroge‐

neity,p=0.03).Howeverresultsshowedstatisticallysignificanteffectonlyfortype1

DM(MD‐0.3995%CI‐0.77to‐0.01)butnotfordiabetestype2(MD‐0.4095%CI‐1.52

to0.72).TheGRADEqualityofevidenceforthisoutcomewaslow(seeTable11)which

meansFreeStyleLibremayslightlydecreasetimewithglucose>13.3mmol/Lforindi‐

vidualswithtype1and2DM.


Table11.Summaryoffindingstable‐glycaemicmeasuresFreeStyle Libre compared to self-monitoring of blood glucose in insulin-treated diabetes individuals




(studies)


Libre technology

Time in range (hours) 3.9-10 mmol/L

The mean time with glu-cose range 3.9-10 mmol/L across control groups was 15 to 13 hours

The mean time (hours) with glucose range 3.9-10 mmol/L in the intervention group was 1 higher (0.32 higher to 1.68 higher)

- 462 (2 RCTs)

⨁⨁◯◯ LOW b

Hypoglycaemia

Time (hours): glucose < 3.9 mmol/L within 24h

The mean time with glu-cose < 3.9 mmol/L within 24h ranged across con-trol groups from 3 to 1hours

The mean time (hours) with glucose < 3.9 mmol/L within a period of 24h in the intervention group was 0.6 lower (0.88 lower to 0.32 lower)

-

462 (2 RCTs)

⨁◯◯◯ VERY LOW

b,c

Events (number): glu-cose < 3.9 mmol/L within 24h

The mean of glucose < 3.9 mmol/L within a pe-riod of 24h ranged across control groups from 0.5 to 2 events

The mean events (number) of glucose < 3.9 mmol/L within a period of 24h in the intervention group was 0.23 lower (0.35 lower to 0.1 lower)

- 462 (2 RCTs)


b,d

Nocturnal Hypoglycae-mia Time (hours): glucose < 3.1 mmol/L during a pe-riod of 7h (23:00-06:00)

The mean nocturnal time with glucose < 3.1 mmol/L in the control groups range from 0.2 to 0.7 events

The mean nocturnal time with glucose < 3.1 mmol/L in the in-tervention group was 0.22 lower (0.46 lower to 0.03 higher)

- 462

(2 RCTs)

⨁◯◯◯

VERY LOW b,e


FreeStyle Libre compared to self-monitoring of blood glucose in insulin-treated diabetes individuals




(studies)


Libre technology

Nocturnal Hypoglycae-mia Events (number): glu-cose < 3.1 mmol/L dur-ing a period of 7h (23:00-06:00)

The mean glucose < 3.1 mmol/L in the control groups ranged from 0.1 to 0.3 events

The mean glucose < 3.1 mmol/L in the in-tervention group was 0.09 lower (0.13 lower to 0.04 higher)

- 462 (2 RCTs)

⨁⨁◯◯ LOW b

Hypoglycaemia

Time (hours): glucose < 3.1 mmol/L within a pe-riod of 24h

The mean glucose < 3.1 mmol/L within a period of 24h ranged from 0.37 to 1.65 hours

The mean events (number) of glucose < 3.1 mmol/L within a period of 24h in the intervention group was 0.49 lower (1.15 lower to 016 higher)

- 462

(2 RCTs)


b,f

Events (number) of glu-cose < 3.1 mmol/L within a period of 24h

The mean events (num-ber) of glucose < 3.1 mmol/L within a period of 24h ranged across con-trol groups from 0.24 to 0.92

The mean events (number) of glucose < 3.1 mmol/L within a period of 24h in the intervention group was 0.22 lower (0.47 lower to 0.03 higher)

462 (2 RCTs)


b,g

Hyperglycemia Time (hours): glucose > 10.0 mmol/L

The mean time (hours) with glucose > 10.0 mmol/L in the control groups was 10

The mean time (hours) with glucose > 10.0 mmol/L in the intervention group was 0 (1.44 lower to 1.44 higher)

- 224 (1 RCT)


b,h

Time (hours): glucose > 13.3 mmol/L

The mean time (hours) with glucose > 13.3 mmol/L ranged across control groups from 2 to 4

The mean time (hours) with glucose > 13.3 mmol/L in the intervention group was 0.39 lower (0.75 lower to 0.03 lower)

- 462 (2 RCTs)

⨁⨁◯◯ LOW b


b. Issues related to unclear or high risk of selection and performance biases (downgraded twice) c. <3.9 mmol/L within 24hours/h: substantial heterogeneity (I2 84%) d. <3.9 mmol within 24hours /event: substantial heterogeneity (I2 64%) e. Nocturnal <3.1mmol (h): substantial heterogeneity (I2 85%) f. <3.1 mmol within 24hours/h: substantial heterogeneity (I2 89%) g. <3.1 mmol within 24hours/event: substantial heterogeneity (I2 86%) h. Imprecision: single study with small sample size (number of participants bellow 300 rule of thumb)


Adverse Events

Non‐devicerelatedadverseeventsweremeasuredatbaselineand6months

endpointfortheinterventiongroup,andbaselineand4weeks(14daysat3

monthsandagainat6month)intheSMGBgroup.

Seriousadverseevents(non‐devicerelated)

Bothincludedstudiesprovideddataonseverenon‐devicerelatedadverseevents.Com‐

paredtoSMBG,FreeStyleLibrewasassociatedwithsimilarnumberofseriousadverse

events,RR0.74(95%CI0.19to2.85),I2=0%indicatingnoheterogeneity.

TheGRADEqualityofevidenceforthisoutcomewaslow(seeTable12)whichmeans

FreeStyleLibremayleadtolittleornodifferenceinseriousadverseeventsforindivid‐

ualswithType1and2DM.

Table12.Summaryoffindingstable‐adverseeventsFreeStyle Libre compared to self-monitoring of blood glucose in insulin-treated diabetes individuals


Outcomes Anticipated absolute effects* (95% CI)

Relative effect (95% CI)

№ of participants (studies)

Quality of the evi-dence

(GRADE)

Adverse Events Moderate to Severe

26 per 1000 19 per 1000 (5 to 73)

RR 0.74 (0.19 to 2.85

462 (2 RCTs)

⨁⨁◯◯ LOW b


b. Issues related to unclear or high risk of selection and performance biases (downgraded twice) Devicerelatedadverseevents

Bolinder2016:“13adverseevents,reportedby10participantsintheintervention

group,wererelatedtowearingthesensor…therewere248sensorinsertion‐sitesigns

andsymptomsexperiencedby65participantsacrossbothgroups(26%ofpartici‐

pants).Signscanbesubdividedintothoseexpectedduetosensorinsertion:pain(38),


bleeding(25),oedema(8),induration(5),andbruising(5),andthoseassociatedwith

sensorwear:erythema(85),itching(51),andrash(31).”page2260

Haak2017:“six(4.0%)interventionparticipantsreported9device‐relatedadverse

events(2severe,6moderate,and1mild).Theseweresensor‐adhesivereactions,pri‐

marilytreatedwithtopicalpreparations…therewere158anticipatedsensorinsertion

sitesymptomsobservedfor41(27.5%)interventionand9(12%)controlparticipants.

Thesesymptomswereprimarilyduetosensoradhesive(erythema,itching,andrash)

andresolvedwithoutmedicalinterventions.”

Sevencardiaceventswerereportedfor4(2.7%)interventionandthree(4.0%)control

participants(noneconsideredtoberelatedtostudyproceduresorthedevice).

Withdrawaldevicerelated

Bolinder2016:“Sevenparticipantswithdrewfromthestudyduetodevice‐related

eventsorrepetitiveoccurrencesofsensorinsertion‐relatedsymptoms”.

Haak2017:“Threeparticipants(1intervention,2controls)experiencedanadverse

eventleadingtowithdrawalsfromthestudy;nonewereassociatedwiththedevice”.

Inregardstoadverseevents,TheLancetpublishedcorrespondencebetweenBrahimi

(27)andBolinder(25)regardingconcernsaboutskinadverseeventswhichmightaf‐

fectindividualsusingtheFreeStyleLibredevice.Assomeinformationprovidedby

Bolinderwasnotaddressedinthesubmitter’spackageorthejournalpublications(i.e.,

useofadifferentbodysiteforthesensor,designchangesinthetechnology)weconsid‐

ereditimportanttopresentithere.

(Brahimi)“…theauthorsreported13cutaneousadverseeventsrelatedtotheuseof

FreeStyleLibre.Theseadverseeventsoccurredintenpatients,andwerecategorisedas

mild(threecases),moderate(fourcases),andsevere(sixcases).Twopatientswithse‐

vereskinadverseeventsweretreatedbydrugtherapyandtwowerediscontinued

fromthestudy.Allsevencaseswithmildormoderateskinadverseeventsrequired

drugtherapies,andthreeofthemwerediscontinuedfromthestudy.Itseemsreasona‐

blethatpatientswithskinadverseeventsmightdecidetocontinueordiscontinuetheir

participationinthetrial,butthemanagementoftheseadverseeventsduringthisstudy

remainsunclearandnotproportionaltotheseverityoftheadverseevents.Itwouldbe

helpfulforbothpractitionersandpatientsiftheauthorscandetermineclearlywhat


typeofdevice‐relatedskinadverseeventsrequiretreatmentordevicediscontinuation,

orboth.”

Bolinder’sreply:

…thenumberandtypeofeventsreportedforFreeStyleLibreintheIMPACTtrialwere

similartothoseforothersystemsinwhichadeviceiswornontheskinforaperiodof

timeusingamedical‐gradeadhesive….Skinsymptomscanoccurwithhighskintem‐

peratureandhumidity,alongwithlongdurationofexposure,allofwhichmightbecon‐

tributingfactorstoadverseevents.Sensor‐wear‐relatedsymptomswererecordedas

adverseeventsintheIMPACTtrialiftheeffectsweresevereandlastedformorethan7

days,orifthepatientrequiredprescriptionmedicationfortheeventtoresolve.Ad‐

verseeventseveritieswererecordedonthebasisofahealth‐careprofessional’sassess‐

mentofmild,moderate,orsevereevents.

Accordingtothestudyprotocol,individualswithknownsensitivitytomedical‐grade

adhesiveswereexcludedfromparticipation.However,wereasonablyexpectedthata

fewparticipantsmighthavebeenunawareoftheirsensitivity...Forparticipantswith

adverseeventsinvolvingskinsymptomsduringthistrial,symptoms(includingsevere)

wereresolvedbyuseofbarrierproducts(e.g.,Cavilonspray)ordrugtherapy(e.g.,zinc

ointment,Fenistilgel,orhydrocortisonecream)asprescribed,orsimplybyrelocating

thedevicetoanotherareaoftheskinsuchthattheeffectsweremaintainedatatolera‐

ble,backgroundlevel.Inothercases,althoughtheadverseeventsweregenerallymild

ormoderate,thelongevityofthesymptoms,despiteuseoftreatment,contributedto

theparticipant'sdecisiontowithdrawfromthetrial.Noneoftheparticipantswithdrew

becauseofhealth‐careprofessionaladvicetostopwearingthesensor.

SincecompletionoftheIMPACTtrial,minordesignchangeshavebeenmadetoFree‐

StyleLibre.Thesechangesareexpectedtoimprovebreathabilityoftheskinthatisin

contactwiththesensorandtofacilitatetheexclusionofmoisturebetweenthesensor–

skininterface.

51 Cost-effectiveness analysis

Cost‐effectivenessanalysis

Methods for evaluating submitted cost-effectiveness models

Cost-effectiveness analysis

Theprimaryobjectivesofhealtheconomicmodellingaretoevaluatetheincremental

cost‐effectivenessofthespecifiedhealthintervention(s)comparedtostandardtreat‐

ment,usingthebestavailableevidence,andtoassessthemostimportantsourcesof

uncertaintysurroundingtheresultsandtherobustnessoftheresults.Inordertomake

comparisonsacrossdifferenttypesoftreatmentsandmultiplehealthoutcomes,eco‐

nomicmodelstypicallymeasuretreatmentbenefitsintermsofquality‐adjustedlife

years(QALYs),ameasuredesignedtocapturetheutilityofbothlifeextensionand

healthimprovement.QALYs,bydefinition,takeonavalueof1forperfecthealthand0

atdeath(28).Theoutputofacost‐effectivenessmodelisexpressedasanincremental

cost‐effectivenessratio(ICER),whichcanbethoughtofastheextracostofobtainingan

extralife‐yearinperfecthealth.TheICERisdefinedas

Evaluating cost-effectiveness models

Thereisnosinglecorrectwaytobuildaneconomicmodeltoestimatethecost‐effec‐

tivenessofaspecifichealthinitiative.Modellingrequiresconsultingwithclinicalex‐

pertstogainanunderstandingofnormaldiseaseprogression,andtodetermine,based

ontheresearchquestion,therelevanttreatmentpopulation,relevantcomparator,and

importanthealthoutcomesandadverseeventsconnectedtotreatment.Thisinforms

thebasicmodelstructure,andalsodetermineswhichclinicaleffectdataismostim‐

portanttoretrieveinthesystematicliteraturesearch.Oncethemodelstructureisin

place,systematicsearchesandevidencegradingareusedtoprovidethemostreliable

riskinformationforthemodel,butmustalsotocollectalloftherelevantcostandqual‐

ityoflifedatathatisneededforcost‐effectivenesscalculations.


Amodelisrarelymeanttocaptureeverypotentialdetailofthetreatmentlandscape;

ratherthegoalistoincludeenoughdetailtoprovidearealisticviewofthemostsignifi‐

cantpathwaysindiseaseprogression,giventheresearchquestion(s)oneistryingto

answer.Evaluatinganygivenmodelisprimarilyaboutdeterminingwhetherthe

choicesmadebythesubmitterregardingmodelstructureandtreatmentcomparator

arereasonablegiventheresearchquestion;whetherbaselineepidemiologicaldatare‐

flectthepopulationinwhichtheanalysisisbeingperformed;whethertheclinicaleffect

datausedinthemodelareofadequatequality;whetherresourceuseandcostsreflect

theconditionsofthehealthcaresysteminquestion;whethertherehasbeensufficient

sensitivityandscenarioanalysistodeterminethedegreeandsourceofuncertaintyin

themodelresults;andwhetherthemodeldisplaysexternalandinternalvalidity.

Checklistsareavailabletohelpresearcherssystematicallyexaminetheseissues(28).

Weproceedbyfirstdescribingthehealtheconomicmodelusedinthesubmissionand

theresultsgeneratedbythemodel.Wethenprovideourevaluationofthemodel,fo‐

cusingonthefollowingissues:modelstructure,choiceofmodelparameters,useofap‐

propriatesensitivityand/orscenarioanalysistoexaminetheextentofuncertaintyin

modelresults,andrelevanceofthemodelfortheNorwegiancontext(28).

Publishedcost‐effectivenessevaluationsidentifiedbythesubmitter

Thesubmitteridentifiedandprovidedtwopublishedcost‐effectivenessevaluationsof

flashglucosemonitoringsystems.OneeconomicanalysisexaminedEuropeanand

Australianindividualsreceivingintensiveinsulintreatmentfortype1DM(29).The

secondeconomicanalysisfocusedonEuropeanindividualsreceivingintensiveinsulin

treatmentfortype2DM(30).Bothstudieswerefundedbythesubmitterandwere

usedtheIMSCoreDiabetesModel(Table13).TheNIPHsearchedforotherpublished

economicevaluationsofFreeStyleLibre,withouthfindinganyrelevantones.


Table13.FreeStyleLibrecost‐effectivenessevaluationsfortype1and2DM

CEA:Cost‐effectivenessanalysis,CDM:Corediabetesmodel,SEK:Swedishcrones,ICER:incrementalcosteffectivenessratio,QALY:qualityadjustedlifeyear,SMBG:self‐monitoringbloodglucose

Descriptionofthepublishedcost‐effectivenessevaluationsidentifiedbythe

submitter

Biliretal.(29)estimatedthecost‐effectivenessofFreeStyleLibrecomparedtoSMBG

throughtheIMSCoreDiabetesModel(IMSCDM)forintensiveinsulin‐treatedType1

DM.TheIMSCDMcombinesMarkovmodelstructureswithaMonteCarlosimulation.

HbA1cprogressionwasbasedondatafromtheDiabetesControlandComplications

Trialstudy(31),whileotherphysiologicalparametersprogressionweretakenfromthe

FraminghamHeartStudy(32).Swedenwasthecorecase,withadditionalresultsfor

Germany,Italy,France,theNetherlandsandAustralia.Forthecorecase,cost‐

effectivenesswasmodelledfromasocietalperspectivewitha50‐yeartimehorizon.

TheestimatedICERforFreeStyleLibrecomparedtobloodglucosemonitoringwas

240,826Swedishcrones(SEK)/QALY.

Study Bilir et al (29) Li et al (30)

Model Analysis CEA CEA

Population Individuals >18 years with well-controlled

Type 1 diabetes, HbA1c of ≤7.5% (58

mmol/mol) treated by multiple daily insulin

injections or continuous subcutaneous

insulin infusion for at least 6 months (25).

Glucose levels were self tested by

individuals at least 10 times per week.

Individual characteristics in the analyses

reflect the IMPACT trial population and

estimates from the published literature were

used for CDM inputs unavailable from the

IMPACT study.

Individuals >18 years with poorly controlled

Type 2 diabetes, HbA1c of ≥7.5% (58

mmol/mol) treated by multiple daily insulin

injections or continuous subcutaneous

insulin infusion for at least 6 months

(REPLACE trial). SMBG was done by

individuals at least 10 times per week.

Individuals’ characteristics in the analyses

reflect the REPLACE trial population and

estimates from the published literature were

used for inputs unavailable from the

REPLACE study.

Intervention FreeStyle Libre FreeStyle Libre

Comparison SMBG SMBG

Incremetal QALY 0.80

0.56

Incremental costs SEK192,973

SEK144,360

ICER/QALY SEK240,826/QALY

SEK258,108/QALY


Lietal.(30)estimatedthecost‐effectivenessofFreeStyleLibrecomparedtoSMBG

throughtheIMSCDMforintensiveinsulin‐treatedType2DMusingthesameIMSCDM

modelasBiliretal.TheyalsousedSwedenasthecorecase,withadditionalresultsfor

Germany,Italy,FranceandtheNetherlands.TheSwedishNationalDiabetesRegister

riskequationwasusedforHbA1cvalueprediction,whiletheCDMdefaultriskequation

(basedonUnitedKingdomProspectiveDiabetesStudy(33))wasusedforother

countries.Otherphysiologicalparametersprogresiondataweretakenfromthe

FraminghamHeartStudy(32).Thecorecase,cost‐effectivenesswasmodelledfroma

societalperspectivewitha40‐yeartimehorizon.TheICERforFreeStyleLibre

comparedtobloodglucosemonitoringwas258,108SEK/QALY.

Scenarioanalysesperformedfortheothercountries,inbothstudies,showedsmiliarresultsastheSwedishcorecase.

Populationandcomparatorinthesubmittedreport

Thecost‐effectivenessanalysispopulationareindividualswithtype1andtype2DM.

Themaincharacteristicsofindividualswithtype1DMareage≥18years,HbA1clower

than7.5%,andperformedSMBGatleast3timeseachdayonaverage(25).Themain

characteristicsofindividualswithtype2DMareage≥18years,HbA1cbetween7.5%

and12%,andSMBGperformedatleast10timesaweekonaverage(26)(Appendix5).

ThesubmitterpresentedtheanalysisofFreeStyleLibrecomparedtoSMBG.Thelatter

isthecurrentreferencetreatmentforinsulindependentindividualswithtype1and2

DMinNorway.

Typeofanalysisanddecisionmodelofthesubmittedreport

ThesubmittedreportusedtheIMSCDM,whichwasdesignedtoassesslifetimehealth

outcomesandeconomicconsequencesofvariousmeasuresforDM.Themodeldeter‐

minestheICERperQALY.Theanalysiswasconductedfromtheperspectivesofboth

thehealthcareservicesandsocietymorebroadly,anduseda40‐yeartimehorizon.

Costsandclinicaloutcomesareextrapolatedinthemodelbeyondthestudyfollow‐up

periodof6months.Thediscountrateintheanalysiswassetto4%forbothcostsand

QALYs.Themodelincludedtwoarms:theFreeStyleLibreandSMBGarm.Theanalysis

assumedthattheindividualswithdiabetesusedeitheronlySMBGorFreeStyleLibre

continuouslythroughoutthelifetime.ThemodelisMarkov‐basedwithannualcycles


meaningthatanindividual’shealthstatewithcostandeffectimplicationsisevaluated

atannualintervals.

Accordingtothesubmitterthemodelquantifiesthedevelopmentofcomplications,life

expectancy,quality‐adjustedlife‐yearsandtotalcostsforthecohortinthestudyover

the40‐yearprojectiontime.Baselinecharacteristicsforindividualswithtype1DMare

fromtheIMPACTstudyandreflectthemeanbaselinecharacteristicsofthestudy’s

treatmentandcontrolgroups:ageof44years,HbA1cof6.78%,andmeandiabetesdu‐

rationof22years(25).Similarly,baselinecharacteristicsfortype2DMcohortarefrom

theREPLACEstudy:ageof59,HbA1cof8.70%,andmeandurationofdiabetesof17.5

years(26)(seeTable6).

Themodelstructurecomprises17sub‐models,independentofeachother,thatsimu‐

latethecomplicationsofdiabetes(Figure7).Eachsub‐modelisaMarkovmodelusing

MonteCarlosimulationstopredictoutcomes.Transitionprobabilitiesrepresentedby

distributionspredictoccurrenceofcomplicationduringayear,anddependontimeand

thecurrenthealthstatus.Themodelusesdifferenttransitionprobabilitiesandproce‐

duresfortype1andtype2DM.Fortype1DMthemostimportantdatasourcesarethe

diabetescontrolandcomplicationstrialandtheFraminghamHeartStudystudies(31).

Fortype2DMthemostimportantdatasourceistheUnitedKingdomProspectiveDia‐

betesStudy(33).Becauseeightofthe17diabeticcomplicationsmayresultinafatal

outcome,themodelalsocalculatesbackgroundmortality.

AccordingtothesubmitterthemodelusestheC++(Microsoft®VisualStudio2005)

programtoformthebasisofthecalculationsrequiredtoruneachsimulation(31).


Figure 7. Flow diagram of the IMS Core Diabetes Model. PVD: peripheral vascular disease, MI: myocardial infarction,

CVD: cardiovascular disease, CHF: congestive heart failure, ARB: angiotensin receptor blocker, ACE: angiotensin-

converting enzyme (34).

Generalcommentsonthesubmittedhealtheconomicanalysis

Themodelutilisedbythesubmitterlackstransparency,thisshallbeunderstoodasthe

difficultyfortheNPIHtogainafirmunderstandingofthefactorsthatdeterminehowa

singlepatientprogressthroughthemodel,whichassumptionsaremadeandwhich

parametersaffectthemodel´soutcomes.Specifically:

wedidnothaveinformationaboutseveralkeyequationsandassumed

relationshipsinthemodel,

welackedaccesstoamicrosimulationmodulewhereitshouldbe

possibletorunsensitivityanalyses(35),

welackedaccesstotheassumeddistributionofvariables,whichiscrucial

fortheassessmentofaMonteCarloprobabilisticmodel.

Patientleveldataaremissingfromthemodelthatwehaveaccessto(35).


Theproblemwithlackoftransparencyisreinforcedbytheunexpectedbehaviorofthe

model.Themodelgeneratedresultsthatwerehardforustoexplaingiventhe

informationprovidedbythesubmitteraboutthemodel.Forexample,thesubmitter

statedinameetingthatHbA1cwasthemaindriverfortheanalysislinkedtotype1and

2DM.WefoundthatchangesinHbA1cmadelittlechangeintheICERs.

Itwasalsodifficulttoassesstheinternalvalidityofthemodel.Becauseofourlackof

fullaccesstothemodel,itwasimposibletoperformafullassessmentortomodify

underlyingassumptionsandparametersinordertoindependentlyassesstheimpact

onreportedresults.Ouraccesswaslimitedtoaweb‐basedmodel,whichonlyallowed

ustoexaminethemodel'sinputdata.

ThesubmitterarguesthattheIMSCoreDiabetesModelhasbeenusedinmanypeer

reviewedpublications,andhasalsobeenvalidatedinanarticlepublishedinahigh

qualityjournal(34;36).Forvalidationpurposes,McEwanetalusedthemodelto

predictclinicaloutcomesin112clinicaldiabetesstudiesbasedonbaseline

characteristicsfromthestudies,andthencomparedthemodel’sresultswiththe“gold

standard”clinicaltrialoutcomes.TheresultingR2valuesof0.90and0.88fortype1and

2DMrespectively,indicatethatthemodelwasabletoexplainalargeportionofthe

variationinresultsofthe112clinicalstudies.TheythereforeconcludethattheIMS

CoreDiabetesModelisacredibletoolforpredictingtheabsolutenumberofclinical

episodesinthepopulationsfromtheDiabetesControlandComplicationsTrialandthe

UnitedKingdomProspectiveDiabetesStudy(33).Ourclinicalexpertsfoundthe

assumedpatientpopulationofthesubmissiontobereasonableforNorwegian

conditions.

Althoughthesubmittedanalysisexaminedbothahealthcareperspectiveandasocietal

perspective,ourassessmentfocusedonthehealthcareperspective.Ahealthcare

perspectiveisappropriatewhendecision‐makingoccurswithafixedbudget,asisthe

casefortheNorwegianRegionalHealthAuthorities.

Clinicalandepidemiologicaldata

ThesubmittedIMSCoreDiabetesModelusesseparatetransitionprobabilitiesand

strategiesofmanagementfortype1andtype2DM.Modelparametersarebasedon

datafromseveralpublishedclinicalandepidemiologicalstudiesfromdifferent

countries.


Themodelisdescribedtocapturethenaturalcourseofdiabetes,associatedwiththe

relationshipbetweenriskfactorsandspecificevents,mortalityfromcomplicationsand

long‐termmortality.Themodelincludesincidencedataforthefollowingadverse

eventsamongpatientswithtype1andtype2DM:fatalcardiovascularevents(stroke,

myocardialinfarction,heartfailureandangina),non‐fatalcardiovascularevents,

microvascularcomplications,footulcerandamputation,depressionandothermildor

severeadverseevents(i.e.,hypoglycemia,ketoacidosis,lacticacidosis).

Inthedefaultscenariotheamountofinsulinconsumedorrequiredisnotintensified

overtime.Thisisbasedon30monthsofdosingdatafromBuseandcolleagues(37).

Efficacy

TheefficacydatainthesubmittedmodelistakendirectlyfromtheIMPACTandRE‐

PLACEclinicalstudies(bothevaluatedovera6‐monthperiod).Efficacydatabasedon

intention‐to‐treatanalysisfromtheclinicalstudiesareassumedtoreflecttheinterven‐

tioneffectinthemodel.Thiseffectisbelievedtopersistthroughoutthestudy’stime

horizon.

TheclinicaleffectivenessofFreeStyleLibreforindividualswithtype1DMwasmeas‐

uredasthedifferencebetweenthegroupsintimeperdayspentinhypoglycaemia(glu‐

cose<70mg/dL[3.9mmol/L]),andinthemodelappliedbyadjustingthebaselineval‐

ues.IntheIMPACTtrial,theprimaryendpointoftimespentinhypoglycaemiawassig‐

nificantlyreducedintheinterventionarmcomparedtothecontrolgroup.Atbaseline,

themeantimespentinhypoglycaemiawas3.38hoursperdayintheFreeStyleLibre

armand3.44hoursinthebloodglucosearm,representinga2%reduction.Afterad‐

justmentsforbaselinehypoglycaemia,theadjustedmeandifferencebetweenthe

groupswas−1.24hoursperday,correspondingtoa38%reductionoftimewithhypo‐

glycaemiawithFreeStyleLibrecomparedwithSMBG(25).

Forindividualswithtype1DMintheSMBGarm,therateformildhypoglycaemic

eventsis6,760per100person‐year(27%oftheseeventswerenocturnalhypoglyce‐

micevents).Forindividualswithtype1DMintheFreeStyleLibrearm,therateformild

hypoglycaemiceventswascalculatedbasedon25.5%and33.2%reductioninthefre‐

quencyofdailyandnocturnalhypoglycemicevents,respectively(glucose<70m/dL).

Therateofwhatturnedouttobe4,897per100person‐years,(25%oftheseevents

werenocturnalhypoglycemicevents)(25).


AccordingtotheUnitedKingdomHypoglycemiaStudyGroup(2007)(38)theratesfor

severehypoglycemiaarethesameinbotharms.Theanalysisisbasedonthis.

Individualswithtype1DMinboththeFreeStyleLibreandSMBGarm,hadthesame

meanchangeinHbA1c(0.12%)atbaseline.ThiswaspresentedintheIMSCoreDiabe‐

tesModel.

TheclinicaleffectivenessofFreeStyleLibreforindividualswithtype2DMwasmeas‐

uredasthedifferencebetweenthechangesinHbA1c.Thestudywaspoweredtodetect

adifferenceinthechangeinHbA1cat6monthsof0.35%.Theprimaryendpointofthe

REPLACEstudy,reductioninHbA1c,wassimilarforbotharms.Theadjustedmean

changeinHbA1cfrombaselinewas−0.29%inFreeStyleLibrecomparedto−0.31%in

theSMBGgroupwithnosignificantdifferencebetweengroups(26).

Informationaboutthenumberofmildhypoglycaemiceventsforindividualswithtype

2DMintheSMBGarmwerefoundinarecentlypublishedmeta‐analysisstudyfor

SMBG.Forindividualswithtype2DMusingFreeStyleLibre,thenumberofmildhypo‐

glycemiceventswerecalculatedbasedontherelativedifferencebetweenthetreat‐

mentarms.Therateofmildhypoglycemiceventswas27.7%lowerintheFreeStyleLi‐

brearmcomparedtotheSMBGarmpresentedintheonline‐basedmodelforindividu‐

alswithtype2DM(26).Further,nodifferencewasassumedinseverehypoglycemic

eventsbetweenthearms.Theseratesareassumedtobeconstantduringthe40‐year

timehorizon.

Thesubmitterhasalsoincorporatedanadditionalutilityrateof0.03intheIMSCore

DiabetesModelfortheuseofFreeStyleLibrecomparedwithSMBGinalltheirscenar‐

ios,toaccountfortheassumedimprovementinuser‐friendliness.Theutilityvalueof

0.03(andotherutilityvalues)forFreeStyleLibreisbasedonaTimeTradeOffstudy,

performedbyEvideraandsponsoredbyAbbottDiabetesCare.TheEQ‐5Dhaslimited

sensitivitytoutilitybenefitsassociatedwithglucosemonitoringdevices,andisthere‐

forenotincludedintheREPLACEorIMPACTstudies(25;26).

Costs

Thesubmitteridentifiedresourceuseandcostdatabysearchinginpublished

Norwegiancoststudiesandadministrativedatabases.Allcostsarefromtheyear2016

andmeasuredinNorwegiankroner(NOK)andtheconsumerpriceindex(CPI)isused


toadjustcostsfromdifferentyears(39).Thesubmitteddocumentationpackage

containsdirectcostsrelatedtothehealthcareperspective,andindirectcostsrelatedto

asocialperspective.

ThecostofFreeStyleLibreincludesthecostoftheintervention,thecostoftreatment

forcomplications,thecostrelatedtosideeffectsandothertreatmentcosts.

Cost of the intervention

ThesubmittercalculatedthetotalyearlycostsrelatedtoFreeStyleLibreandstandard

SMBGforindividualswithtype1and2DM(seeTable14).Thecalculatedcostof

FreeStyleLibreislistedintable14.

Table14:CalculatedcostofFreeStyleLibre

Item Cost (NOK) Unit Source (REF)

Insulin 0.34 IU/ml (40)

Metformin 0.38 500 mg x 3 per

day

(40)

FreeStyle Libre 599 (excl. VAT) Per sensor ((41), read June, 2017)

Test strips 4.82 Per strip (42)

Lancets 0.53 Per lancet (43)

Additional GP visit 284

(x 2 for FreeStyle Libre year one)

Per consultation

(44)

GP: general practitioner, mg: miligram; SLV: The norwegian medicines agency; IU/ml: international

units per milimiter; VAT: Valute-Added Tax

TheunitpriceoftheFreeStyleLibresensor(NOK599)istakenfromthewebsiteofFreeStyleLibre(41).Thepricestatedinthesubmissionwaslower,butclaimedbythesumbittertobeconfidential.

Diabetestype2<65yearsold:

Forresourceusecalculation,thefollowingassumptionsobservedintheREPLACE

study(26)wereused.General:anindividualwithtype2DMusesmetformininaddition

toinsulin.

FreeStyleLibre:Thesubmitterassumethattheindividualneeds109.5SMBGstripsper

year,85.2insulinunitsperdayand0.65lancetsperday.Further,thesubmitter

suggeststhattheindividualneedstwoGPconsultationsthefirstyearandone

consultationinsubsequentyears.ThecostforFreeStyleLibreuserswouldbeabout

NOK24,954thefirstyear,andNOK24,670thesecondyear.Accordingtothewebsiteof


FreeStyleLibreasensorworksuptofourteendays(41).Ourclinicalexperts

consideredthatanindividualneedsbetween26to29sensorsperyear.

SMGB:ThesubmitterassumesthattheindividualneedsthreeSMBGstripsperday,87.8

insulinunitsperdayand1.26lancetsperday.Further,thesubmittersuggeststhatthe

individualneedsoneGPconsultationperyear.TheannualcostforSMBGuserswould

beaboutNOK17,116.

Diabetestype1:

ThefollowingassumptionslaybehindthedataintheIMPACTstudy(25).

FreeStyleLibre:ContinuousglucosemonitoringsystemsinNorwayaremainlyusedby

thoseindividualswithimpairedawerenessofhypoglycaemia.

Thesubmitterassumesthattheindividualneeds182.5SMBGstripsperyear,45.8

insulinunitsperdayand267.4lancetsperyear(25).Accordingtothesubmitter’s

websiteFreeStyleLibresensorworksuptofourteendays(41).Ourclinicalexperts

consideredthatanindividualneedsbetween26to29sensorsperyear.

Further,thesubmittersuggeststhatoneindividualneedstwoGPconsultationsinthe

firstyearandoneconsultationinsubsequentyears.ThetotalcostforFreeStyleLibre

userswouldthenbeaboutNOK23,446inthefirstyearandNOK23,162inthesecond

andsubsequentyears.

SMBG: Thesubmitterassumesthatoneindividualneeds1,971SMBGstripsperyear,

34.8insulinunitsperdayand657.6lancetsperyear(25).Further,thesubmitter

suggeststhatoneindividualneedsoneGPconsultationeachyear.Theannualcostfor

SMBGuserswouldbeaboutNOK14,904.

Cost of complications

Thesubmitterobtainedcostsrelatedtomyocardialinfarction,angina,strokeand

peripheralvasculardiseasebasedonNorwegiandiagnoses‐relatedgroups(DRGs)(45).

Thefirstyearcostsrelatedtomyocardialinfarction(NOK53,311),angina(NOK

21,840),heartfailure(NOK47,299)andperipheralvasculardisease(NOK39,259)are

basedonDRGs(45).ThecostrelatedtostrokeinthefirstyearisaboutNOK91,266and

basedonseveralpublishedsources(45‐47).

ThesubmitteradoptedtheassumptionofthereimbursementreportforPradaxathat

thecostsrelatedtomyocardialinfarctionwilldeclineby69%fromthefirstyeartothe

secondyearandbeyond(45;48).AccordingtothereimbursementreportbyLevemir

(46)andadjustmentsbyCPIfrom2007to2016oncostdata(39),thecostrelatedto


strokeandperipheralvasculardiseasewillbothdeclinetoNOK9,320inyeartwoand

beyond.Deathduetostrokewithin30daysisgiventhesamecostinthefirstyear,but

regardlessofthecostsrelatedtorehabilitation.Thecostrelatedtoanginainyeartwo

andbeyondareNOK415(40;44;45).Thesubmitterdoesnotmentionanysourcefor

thecostsassignedtoheartfailureinyeartwoandbeyond(NOK2,443).

Thecostsofdialysisinyearone(NOK792,887)(49)andthecostofperitonealdialysis

inyearone(NOK629,085)arealsousedinyeartwoandbeyond,minusthecosts

relatedtotrainingofhealthprofessionals.DRG,immunosuppressivedrugsand

corticosteroids,accordingtotheindicationofthedrugmycophenolateareusedto

estimatethetransplantationcosts(NOK539,558)(40;45).

Cost of the side effects

Inthesubmittedmodel,mildhypoglycaemiceventsareassumedtohavenocost.

SeverehypoglycaemiceventsaregivenacostofNOK31,583becausethesubmitter

assumethatindividualshavingseverehypoglycaemianeedhelpfromathirdparty.

Helpfromathirdpartyalsoappliestoindividualsaffectedbyketoacidosis,whichthe

submitterconsiderstocostNOK48,022.EdemaisgivenacostofNOK3,787(45).

Other treatment costs

TheinputcostsrelatedtomedicationswerederivedfromtheNorwegianMedicines

Agency(40)andthecostsrelatedtoscreeningandcataractsurgerywereobtained

fromtheNorwegianMedicalAssociationandUnilabs(44;50).Thecostrelatedtolaser

treatment,treatmentforblindness,neuropathy,amputation(eventbased),healed

woundandinfectedwoundweretakenfromtheNorwegianDirectorateofHealth(45).

Thecostrelatedtogangrenetreatmentandamputationprosthesiswereobtainedfrom

thestudybyGhatnekaretal.(51).

Healthrelatedqualityoflife(HRQL)

HRQLutilityvalues,basedonscoresfromthegenericEuroQolinstrument(EQ‐5D),

wereavailableforallhealthstates.MostoftheutilityvaluesweretakenfromEuropean

studies.Thehealthstate“Diabetestype2,withnocomplications”wasgivenautility

valueof0.785(52)andthehealthstate“Diabetestype1,withnocomplications”was

givenautilityvalueof0.9.Inthesubmittedmodel,theHRQLchangeovertime,depend‐

ingondisabilitiesrelatedtocomplicationsoreventsthatmayoccurforanindividual

withdiabetes.AnindividualstartswiththesamebaselineHRQLutilityvalueinboth


studygroups(FreeStyleLibreandSMBG),andexperiencedisutilityassociatedwiththe

variousminorandmajordiabetesrelatedevents.

Theutilityvaluesformildhypoglycaemiaandthefrequencyofhypoglycaemiaare

basedoncalculationsfromLauridsenetal(53).Thefirstindividualexperiencewithhy‐

poglycaemiawillbeperceivedassevere.Thedisutilitypereventdecreaseastheindi‐

vidualexperienceshypoglycaemicepisodesmoreoftenandadapttothesituation.Simi‐

larly,theaveragedisutilitypereventdependsontherateofhypoglycaemia.Takingthis

intoaccount,thedisutilityperhypoglycaemiceventwasestimatedineachtreatment

arm.

NIPHcommentsonsubmitterparametersandinputdata

Thereisgreatuncertaintyconnectedtotheefficacydata.Inputdataforthemodelis

takenfromseveralstudies,fromdifferentcountrieswithvariousstudypopulations.

Thus,thestudypopulationsmaynotbecomparableandmaynotrepresentthecurrent

Norwegianpopulation.Accordingtoourclinicalexperts,whenusingolddataitshould

bepointedoutasapossiblesourceofbiasedresults.Historicdataoftenoverestimate

treatmenteffects.Alotofthedatausedforinputinthehealtheconomicmodelareold.

Usingdatafromthe50s,60s,70s’(32)andmostly80s’(33)would,forinstance,greatly

overestimatecardiovasculardiseaseinindividualswithDM,andhencethepotentialfor

savingsbydecreasingglucoselevels.Further,atthattimeprimarypreventionwith

lipidloweringdrugswasnotinventedandthebordersforinitiationofantihypertensive

treatmentwerehigher.

Thesubmittedclinicalstudiesextrapolatetheeffectof6monthsovera40‐yearperiod

(25;26).A6‐monthperiodwaschosen,becauseitislongenoughtodetectdifferences

indurationspentinhypoglicaemiathatmayresultfromparticipantsandhealthcare

professionalsrespondingtothemorecomprehensiveglucosedataprovidedby

FreeStyleLibre(25;26).Thelongtermeffectsoftreatmentofhypoglicaemia,andthe

longtermeffectsofhypoglicaemiaincidence,arelessknown,which

increasetheuncertaintyregardingtheefficacydatainthemodel.Patientfatiguein

wearingFreeStyleLibreisnottakenintoaccount.Neitheristhefactthatinitialstudies,

inparticularlythoseinvolvingdedicatedindividuals,tendtooverestimatetreatment

effectscomparedtowhenthetreatmentisusedinageneraldiseasepopulation(clinical

expert).


Theclinicalinputdatausedforcost‐effectivenesscalculationspresentedinthemodel

deviatesubstantiallyfromtheclinicalinputdatapresentedinthesubmitted

documentationfileforbothtype1andtype2DM.Forindividualswithdiabetestype1,

theonline‐basedmodelusedclinicalinputdatafromtheREPLACEstudy(thisstudy

includesindividualswithtype2DM,under65years)inonesimulation,andclinical

inputdatarelatedtoaSwedishdatacollectioninanothersimulation.Theseconstitute

considerabledeviationsregardingclinicalrisksandprobabilitydatafromtheclinical

inputsfoundinIMPACTandREPLACE.ThemodeldidnothaveanyHbA1cadjustments

relatedtotype1DMforthecontrolgroup,butonlyfortheinterventiongroup.Inthe

submittedmodel,thechangeinbaselineHbA1cweredifferentbetweenthe

interventiongroupandthecontrolgroup.Accordingtotheliterature,thechangein

baselinehbA1cshouldbethesame.

Althoughtheraterelatedtomildhypoglycemiceventsweresomewhatlowerin

FreeStyleLibrearmcomparedtotheSMBGarmpresentedintheonline‐basedmodel

forindividualswithtype2DM,theseverehypoglycemiceventsweresimilarineach

arm.Thecostrelatedtoseverehypoglycemiceventsweremuchhigherthanmild

hypoglycemicevents.Thesubmitterassumesthateveryseverehypoglycemicevent

needsathirdpartyintervention(involvingahospital/doctor)andthengeneratesa

cost.However,oneofourclinicalexpertsstatesthatseveralpatientsmayhave

episodesofseverehypoglycemiathattheyhandlethemselveswithoutintervention

fromathirdparty.Andwhenathirdpartyisneededthatwouldmostoftenberelatives

athome.

ThesubmitterconsideredadifferenceinchangeHbA1cbetweenFreeStyleLibreand

SMBG.However,thestudiesfromBolinderandHaak(25;26)shownostatisticaly

significantchangeinHbA1cbetweeninterventionandcontrol.Thelackofstatistical

significanceisnotanerrorperse,butintroducesuncertaintythatmeritsfurther

considerationinone‐waysensitivityanalysis.Thiswasnotperformedbythesubmitter

andwasnotpossibletoexplorebythereviewersbecauseoftherigidityoftheIMS

onlinemodel.

Regardingthecostandresourceuse,ourclinicalexpertsconsiderthattheinsulincon‐

sumptionshouldbethesameifFreestyleLibreisused,giventhatdiabetesiscorrectly

treated.Inchildrenandyouthunder18yearsoldtheconsumptionofstripswould,ac‐

cordingtoourclinicalexperts,behigherthan5.4perdaywhichwasassumedbythe

submitter.Intheiropinion,severalchildrenusemorethan10stripsaday.


Cost‐effectivenessresults

Thesubmitterprovidedseparatecost‐effectivenessresultsfortype1andtype2DM.

Thesubmittersresultsfortype1DMwerebasedonanequalchangeinHbA1cinboth

arms(0.12%),howeverresultsaredrivenbytheassumptionthatindividualsinthe

FreeStyleLibrearmhadautilitygainof0.03.Thesubmitter’sresultconsequentlyshow

thattheuseofFreeStyleLibregivesahigherQALYandalowercost,resultingina

dominantICER.

Table15.Cost‐effectivenessresults(type1DM)ofFreeStyleLibreversusSMBGaccordingtosubmitter’smodel

Population Incremental Cost (NOK) Incremental Effect (QALYs)

ICER

Type 1 DM -1 ,225 ,067 1.17 dominant NOK:NorwegianKroner;QALYs:qualityadjustedlifeyear;ICER:incrementalcosteffectivenessratioThesubmitters’resultsfortype2DMweregivenintwoscenarios,oneforall

individualsintheREPLACEstudyandoneforindividualsagedunder65years(Table

16).Thesubmitterassumedutilitygainwas0.03forFreeStyleLibreuse.Accordingto

thesubmitter,theuseofFreeStyleLibregivesahigherQALYandhighercosts,which

resultsinanICERofNOK235,673perQALYgained.Accordingtothesubmitter,the

scenariowithindividualsunder65years,theresultingICERisNOK243,434.

Table16.Cost‐effectivenessresults(type2DM)ofFreeStyleLibreversusSMBGaccordingtosubmitter’smodel

Population Incremental Cost (NOK) Incremental Effect (QALYs)

ICER (NOK)

Type 2 DM 88731 0.38 235673

Type 2 DM < 65 years 103119 0.42 243434 NOK:NorwegianKroner;QALYs:qualityadjustedlifeyear;ICER:incrementalcosteffectivenessratio

NIPH comments in the results

Wewerenotabletomakeourownresultsoradjustsubmittersresults,i.e.wewerenot

abletomakeourownincrementalcost‐effectivenessratios(ICERs).Thiswasbecause

thesubmitter’smodelwasnotfullytransparentregardinginput,andwehavenotbeen

abletoevaluatetheinterventionusingalternativeassumptions.Alsotheoutputisnot

reportedinadequatedetail.Thesubmitterhasreportedincrementalcosts,incremental


effectsandICERs,whileabsolutelevelsofdirectcostsandutilitieswerenotreported,

whichisgoodpracticeincludingforvalidationpurposes.

Thesubmitterdidnotperformasensitivityanalysis,whichleadstolackofinformation

abouttheuncertaintyassociatedwiththedataincorporatedinthemodel.Thelackof

onewaysensitivityanalysesalsomakesitdifficulttoconsidertheinternalvalidityof

themodel.

The overall comments in the sections above regarding the low quality of the effec-

tiveness input data make the submiters model´s results very uncertain. The lack of

sensitivity analysis and the fact that we were not able to perform our own sensitivity

analysis due to de model constraints make the submitted results of cost effectiveness

(ICER) even less reliable.

Budgetimpactanalysis

Thesubmittercalculatedabudgetimpact,fromaNorwegianhealthcareperspective,

forintroducingFreeStyleLibreasasecond‐linetreatmentforindividualswithdiabetes

type1ortype2comparedtoSMBG.Thebudgetimpactwasestimatedasthenetcost

differencebetweenascenarioinwhichFreeStyleLibreisadoptedforafullcohortof

eligibleindividualsrelativetoascenarioinwhichthedeviceisnotadopted.Thebudget

impactwasestimatedastheyearlycostfiveyearsafteradoptionofthetechnology.

Thesubmittercreatedtwobudgetimpactscenarioanalyses,onescenarioanalysis

limitedtotype1DMonlyandanotherscenarioanalysiswhichincludedbothtype1DM

andtype2DM.Thesubmitterdidnotcreateabudgetimpactfortype2DMonly.

The submitted budget impact analysis

AccordingtodatafromtheNorwegianDiabetesAssociation2015(54),therewere

28,000individualswithtype1DMand8,220individualswithtype2DM,usinginsulin,

inNorway(54).Basedonthesenumbers,thesubmitterassumeda0.9%increasein

individualshavingdiabetestype1foreachyearanda3%increaseinindividuals

havingdiabetestype2eachyear.Table17belowshowsthepredictionofindividuals

withyear1asbeing2017asassumedbythesubmitter.Itstatestheannualnumberof

individualsusingFreeStyleLibreifthisnewtechnologywasadopted.Ifthenew

technologywasnotadopted,alloftheseindividualswouldreceiveSMBG(seeTable

17).Thesubmitterassumedthatanindividualwouldchangetheirsensorevery14th

day(41).


Table17.Annualandincreasednumberofindividualswithadoptedtechnologyaccord‐

ingtosubmitter’smodel

Number of individuals if the new technology is adopted

Year 1 Year 2 Year 3 Year 4 Year 5

Annual number of individuals with type 1 DM 28,506 28,763 29,022 29,283 29,546

Increased number of individuals (type 1 DM) 0.9% 0.9% 0.9% 0.9%

Annual number of individuals with type 2 DM 8,721 8,982 9,252

Increased number of individuals (type 2 DM) 3% 3% 3% 3%

Annual number of individuals (type1 + type 2 DM) 37,227 37,745 38,273

Increased number of individuals (type 1 + type 2 DM) 1.4% 1.4% 1.4% 1.4%

Thecostoftype1and2DMwasestimatedbythesubmittertobeNOK239,515,116in

2015(55).ThesubmitterassumedthatthecostrelatedtoSMBGisequallydistributed

betweenindividualswithtype1and2DM.Further,thesubmitterassumedthatthe

costofFreeStyleLibrealsoincludesanadditionalcostof9%ofthetotalcostsrelatedto

SMGB.Thesubmitterassumedthatanincreasednumberofindividualswithbothtype

1and2DMwouldswitchfromSMBGtoFreeStyleLibreduringthefivefirstyears.

Thesubmittedbudgetimpactanalysisalsoincludesadditionalresourceuserelatedto

emergencyreception,ambulanceandhospitalstays.Numberofannualeventsperper‐

sonweretakenfromthetwotrials,IMPACT(25)andREPLACE(26).Theserates

showedmoreevents,whichledtomoreresourceuse,byusingSMGBonlyinsteadof

FreeStyleLibre.

ThesubmitterestimatedthatthetotaladdedcostswouldbeaboutNOK748millionfor

thefirstfiveyearsafteradoptionofFreeStyleLibreforindividualswithtype1DMin

Norway.Thesubmittercalculated,however,apotentialcostsavingofNOK75million

forthefirstfiveyearsafteradoptionofFreeStyleLibreforindividualswithtype1and

type2DMinNorway.Thesubmitter’sconcernsforconfidentialitydidnotallow

presentationoftheseresultsdisaggregatedly.

NIPH comments on the budget impact analysis

Thesubmitter’sbudgetimpactanalysiswasbasedonanExcel‐basedmodel,whichis

differentfromtheIMS‐CDMmodelusedforcost‐effectivenessanalysis.Thebudget

impactmodelincludesstudydataonresourceutilisationthatwherenotusedinthe

model.Basedonexpertopinions,theacuteeventswithseverehypoglycaemiaand


ketacidosisappliesbothtoindividualswithtype1andtype2DMwhouseinsulin.

FreeStyleLibremayleadtomorestableglucoselevelsamongtheseindividualsbecause

ofmorefrequentbloodglucosemeasurement.Therefore,theseindividualsmay

decreasethenumberofemergencyreceptions,ambulanceandhospitalstays,andthen

reducetheresourceuserelatedtothesecomplications.

However,accordingtoourclinicalexperts,theadditionalcostrelatedtoSMBGwhile

usingFreeStyleLibremayhavebeenunderestimatedinthesubmittedcalculations.We

thereforerecalculatedthebudgetimpactanalysisbasedontheassumptionthat20%of

thetotalcostsrelatedtoSMBGismorereasonablethanthe9%appliedbythesubmit‐

ter.Webasedtherecalculationonthesubmitter’smodel,whichisExcelbasedandal‐

lowedustomodifyinputparameters.Further,ourexpertsassumedthat60%ofthein‐

dividualswithtype1DMandabout30%oftheindividualswithtype2DMinsulinus‐

erswouldstartusingtheFreeStyleLibreinsteadofSMBGonly.Ourclinicalexpertsas‐

sumedthatanindividualwouldlikelyhavetouse29sensorsperyear,asomewhat

highernumberthanfoundonthesubmitter’swebsite(41).Inouralternativeanalysis

wealsousedthepublicprice,NOK599(excl.VAT),foundonthesubmitter’sFreeStyle

LibrewebsiteJune,2017(41),sincethepricestatedinthesubmissionwasclaimedby

thesubmittertobeconfidential.

Basedonthesubmitters’modelandassumptionswecreatedthreebudgetimpact

scenarioanalyses,onescenarioanalysisrelatedtotype1DMonly,asecondscenario

analysisrelatedtotype2DMonly,andathirdscenarioanalysiswhichincludedboth

type1DMandtype2DMinsulinusers.Thesubmitterdidnotcreateabudgetimpact

fortype2DMonly.

Table18showsthebudgetimpactforindividualswithdiabetestype1.Thebudgetim‐

pactincludsthetwoscenarios:(1)costrelatedtoadoptionoftheFreeStyleLibreand

(2)costwithoutadoptionoftheFreeStyleLibre.Thecalculationsshowthedifference

betweenthetwoscenariosineachofthefiveyearsoftheanalysis.Thecomparisonsbe‐

tweenthetwoscenariosshowsanincreaseintotaladdedcostsforeachyear.Weesti‐

matedthatthetotaladdedcostswouldbeaboutNOK913,000,000forthefirstfive

yearsafteradoptionofFreeStyleLibreforindividualswithdiabetestype1inNorway,

oraboutNOK186millionperyearfiveyearsafterimplementation.


Table18.NIPH’sbudgetimpactestimatesfortype1DM

Annual budget Impact

Year 1 Year 2 Year 3 Year 4 Year 5

+ Cost if the

New technology

is adopted

(NOK)

358,457,802 361,683,922 364,939,077 368,223,529 371,537,540

- Cost without

adoption of the

new technology,

i.e. current

situation (NOK)

179,074,804 180,686,477 182,312,655 183,953,469 185,609,051

Total added cost (NOK)

179,382,998 180,997,445 182,626,422 184,270,059 185,928,490

* Based on number of individuals estimated in Table 17; NOK: Norwegian Kroner

Table19showsthebudgetimpactforindividualswithtype2DMinsulinusers.Thecal‐

culationsshowthedifferencebetweenthetwoscenariosineachofthefiveyearsofthe

analysis.ThecomparisonsshowadecreaseintotalcostsofaboutNOK433,000,000for

thefirstfiveyearsafteradoptionofFreeStyleLibreforindividualswithtype2DMinsu‐

linusersinNorway,oradecreaseofNOK91,7millionperyearfiveyearsafterimple‐

mentation.

Table19.NIPH’sbudgetimpactestimatesfortype2DM

Annual budget Impact Year 1 Year 2 Year 3 Year 4 Year 5

+ Cost if the New

technology is adopted

(NOK)

29,801,725 30,695,777 31,616,650 32,565,150 33,542,104

- Cost without adoption of

the new technology, i.e.

current situation (NOK)

111,308,554 114,647,811 118,087,245 121,629,862 125,278,758

Total cost (NOK) (81,506,829) (83,952,034) (86,470,595) (89,064,713) (91,736,654)

* Based on number of patients estimated in Table 17; NOK: Norwegian Kroner

Inourthirdbudgetimpactscenarioanalysis,weassessedthetotaladdedcostof

introducingFreeStyleLibretobothindividualswithtype1DMandtype2DM.Based

onourcalculations,thetotaladdedcostwouldbethedifferencebetweenthetotal

addedcostsforindividualswithtype1DM(NOK913,000,000)andthetotalcost

savingsforindividualswithtype2DMinsulineusers(NOK433,000,000).Thetotal


addedcostforintroducingFreeStyleLibretobothpopulationswouldbeaboutNOK

480million,oraboutNOK94millionperyearfiveyearsafterintroduction.

Asmentioned,thesubmitterappliedtwodifferentmodelsforthecost‐effectiveness

andbudgetimpactanalyses.Thesetwotoolsproducedsomeresultsthatare

counterintuitive,seenincombination.Mostimportantly,fortype2DM,thecost‐

effectivenessanalysisandtheIMS‐CDMproducedpositiveincrementalcostsfor

FreeStyleLibrecomparedtoSMBG(Table16),whilethebudgetimpactanalysisgave

theresultthatintroducingFreeStylelibreiscost‐savingforthesepatients.Inversely,

theIMS‐CDMproducednegativeincrementalcostsfortype1DM(Table15),whilethe

budgetimpactanalysisshowedsubstantialcostincreasesrelatedtointroductionof

FreeStyleLibre.Theseresultsinsumappearnon‐consistent.Whetherthisisduetothe

utilisationofdifferentdataindemodelandinthebudgetimpactcalculationsis

uncertain.

71 Discussion

Discussion

Wehaveperformedanindependentclinicalsystematicreviewandassessedthesub‐

mittedcost‐effectivenessinformationofFreeStyleLibreforindividualswithtype1and

2DM.WeconductedanindependentreviewoftheclinicalevidenceusingaPICO

framework;thePICOcomponentswereselectedincollaborationwiththeNorwegian

DiabetesAssociationandclinicalexperts.Ourmainoutcomesareclinicaloutcomes,

andwedidnotevaluatethesensitivityorspecificityofthedevice–i.e.,measuringhow

wellthedevicedoeswhatitissupposedtodo.

Clinicaleffectivenessandsafety:summaryofmainresults

Thesubmitter’sliteraturesearchidentifiedtworecords(oneRCTandoneposter).

ThesetworecordsreportedclinicaltrialsofFreeStyleLibreforindividualswithtype1

and2DMrespectively.Thesubmitterindicatedotherpublicationsprovidedusefulin‐

formationfortheaccuracyofthedevice(i.e.singlearmstudies).Thesubmitteralsoin‐

cludedanauthorityevaluationconductedinFrance(July2016)inthedocumentation

package(56).

WeconsideredthatonlytheRCTswererelevanttorespondtotheclinicaleffectiveness

andsafetyresearchquestion(25;26);theresultsofthesetrialswereusedinthemain

analysesinthisassessment.Weregardedthesubmitter’sinformationtobefairandthe

submitter’sinterpretationtobemostlyappropriate.Afterreviewingthe(smallamount

of)evidenceavailable,weconsideredthevalueplacedonthebenefitsofFreeStyleLi‐

brebypeoplewiththecondition,thosewhorepresentthem,andclinicalexperts.

Themeta‐analysisofFreeStyleLibreversusSMBGprovidedlowtoverylowqualityevi‐

denceonoutcomespostintervention.Therewerenodifferencesinseriousadverse

eventswithFreeStyleLibrecomparedwithSMBG.Therewerecleardifferencesinthe

effectsofFreeStyleLibreversusSMBGforindividualswithType1vstype2DMfor

someoutcomes.

72 Discussion

Traditionalmethodsofmeta‐analysissuggeststudiesarecombinedinoneanalysisif

theycomparesimilarpopulationsandsimilarinterventionsatsimilarfollowuptime

points,usingsimilaroutcomes.However,theanswertothefeasibilitytoconducta

meta‐analysisornotmayalsodependonthequestionbeingasked.

Themeta‐analysiswascarriedoutdespiteclinicaldifferencesinType1and2DM,as

webelievedthesynthesismatchedourresearchquestion.Ouranalysisaimedtoprove

thesubmitter’sclaim(“thetechnologyisindicatedformeasuringinterstitialfluidglu‐

coselevelsinpeople(age4andolder)withdiabetesmellitus”).AsGøtzche(57)points

outthereisadebatebetween“lumpig”and“splitting”resultsofclinicaltrialswhile

consideringmeta‐analyses.Clinicalexpertsandstakeholdersbelievedthecharacteris‐

ticsoftheindividualsdifferinawaytheydidnotrecommendtopoolthedatafromthe

studiesfound;inthiswaytheyadvocatedfor“splitting”.Afterfurtherconsultationwith

theNIPHteamstatisticianandexperts,wedecidedtocombinethedataaswebelieve

thisstatisticalapproachmatchestheresearchquestionbeingasked.Therationalwe

followedwhenwedecidedto“lump”theincludedRCTswasthatFreeStyleLibreshould

reflecttheobjectiveofthereport.Thisapproach,ofcourse,didnotpreventusfrom

lookingat,exploreandpresenttheresultsoranyresonsforheterogeneityinsub‐

groupswhennecessary.Nevertheless,thereadershouldbeawarethatthesynthesisis

basedontwosmallsubmitterinitiatedRCTs;thisinitselfbringsdifficultiesestimating

between‐studiesvariance,whichhasimplicationsformanyaspectsoftheanalysis.

Overall completeness and applicability of evidence

GiventhesmallnumberofRCTsincludedinthisassessment,webelieveitislikelythat

newtrialsmayaltertheestimatedeffectsofFreeStyleLibrefordiabetes.

RCTsincludedonlyadults,individualswithwellcontrolledtype1andpoorlycon‐

trolledtype2DM.Thus,ourconclusionsarelimitedtoadultswiththesecharacteristics

andfurthergeneralizationsarenotrecommended.

Weconsideredtheinformationregardingadverseevents(e.g.,safetyandharm)impre‐

ciseandofuncertainvalidity,primarilybecauseoftheincomparabletimesutilized,but

alsothesmallnumberofparticipantsinthesetrials.

Thenumberofstudiesisstillnotsufficientlylargetodrawfirmconclusionsontheclin‐

icaleffectivenessofFreeStyleLibre,noristheliteraturesufficientlyexplicitorlarge

73 Discussion

enoughtoanswerclinicalquestionsabouttheidealroutineorcombinationofFreeStyle

Librefor(all)individualswithDM.

WeacknowledgetheevidenceforFreeStyleLibreisincreasingandevolvingrapidily.

Weidentifiedanumberofongoingandcompleted(published/unpublished)studies.

Amongtheongoingstudiesthereare3RCTs:oneincludingyouth12to17years,an‐

otheradultswithtype2DM,andoneadultswithseverehypoglycaemia.Theresults

fromtheseongoingRCTswillaidourunderstandingoftheclinicaleffectivenessof

FreeStyleLibre,andwillprovidebetterinformationfordecisionmakersandthose

planningservicesforindividualswithdiabetes.

Quality of the evidence

Riskofbiasassessmentshighlightedconcernsregardinginsufficientinformationonal‐

locationconcealment,blindingofparticipantsandcareproviders,anddetectionbias

relatedtoselfreportedinstrumentsandoneobjectiveoutcome.

Otherissuestoconsiderwheninterpretingtheseresultsare:a)thestudiesassesseda

largenumberofoutcomes(morethanpresentedinthisreport),increasingtheproba‐

bilityoffindingstatisticallysignificantdifferencesforoutcomesbychance;andb)im‐

portantclinicalheterogeneitywaspresentamongthestudieswhichremainsamajor

challenge.

Theincludedstudiesweresponsoredbythesubmitter.Studieswereregisteredinthe

trialregistryforrandomizedcontroltrials,whichensuredpublicaccesstothefull

studyprotocol.Thesubmitters’roleandresponsibilitieswerefullydisclosedinthe

publishedstudies.However,financialrelationshipsamongindustry,scientificinvesti‐

gatorsandacademicinstitutionshavebeenseentoinfluenceresearchinimportant

ways(58).Industrysponsoredresearchisatopicofconcernthatiscontinuouslybeing

investigated.Theconcernrelatestoindustrysponsoredresearchbeingmorelikelyto

favourtheproductdevelopedbythecompanythanresearchfundedbyothersources

(59;60).Itwillbeimportantforfurtherassessmenttohaveindependentstudiesto

comparetheseresultswith.

Other European assessments

FreeStyleLibreassessmenthavebeenpublishedinotherEuropeancountries(seeTa‐

ble20).Oneoftheseassessmentswasincludedinthesubmitteddocumentationpack‐

74 Discussion

age(*)andtheotherswereretrievedbyoursearch.Overall,wefoundtheirresultssim‐

ilartoourassessment.Afterconsideringsimilaritiesinthemethodsandreporting,we

chosetocommentontheresultsofHauteAutoritédeSanté(HAS,France),andSESCS

(Spain).WethenbrieflycommentonTLVreportastheSwedishHTAassesementhas

notyetbeenpublished(e‐mailcorrespondence).

Table20.EuropeanHTAFreeStyleLibreassessments

Agency Title (date)

AQuAS – Agència de Qualitat i Avaluació Sani-

tàries de Catalunya, Spain (61).

Dispositiu Flash FreeStyle Libre® per al

monitoratge de la glucèmia (October 2016)

SESCS – Informes de Evaluacion de Technolo-

gias Sanitarias (62), Spain (translated document)

Efectividad, seguridad y coste-efectividad del

sistema flash de monitorizacion de glucosa en

liquido intersticial (FreeStyle Libre) para diabetes

mellitus tipo 1 y 2 (June 2016)

*HAS – Haute Autorité de Santé, France (56) Systeme FreeStyle Libre, Systeme flash d'auto-

surveillance du glucose (July 2016)

HTA-centrum Göteborg – Sweden (translated

document)

Kontinuerlig glukosmätning med FreeStyle Libre:

effekt på HbA1c hos typ 1 diabetiker (2015)

Agenas, Agenzia nazionale per i servizi sanitari

regionali, Italy Under appraisal

InadditiontotheaboveFreeStyleLibreassessments

ZIN–ZorginstituutNederland,TheNetherlands(63)Flash

glucosemonitoringsysteem(FreeStyleLibre)(February2016).Thisisan

individual’sclaimforfinancialcompensation.Theapplicantdidnotreceiveit

duetoFreeStylenotmeetingZIN’sscientificcriteria(translateddocument).

SwedishPaediatricSociety:Thedocumentdoesnotmention“FreeStyleLibre”,

butreferstoCGM.Itincludesasetofrecommendationsofuseofcontinuous

glucosemonitoringinchildrenandyouthwithtype1DM.(64).

TheDentalandPharmaceuticalBenefitsAgency(TLV)–Sweden(65)

TheFrenchnationalcommitteefortheevaluationofmedicaldevicesandhealthtech‐

nologiesreviewedFreeStyleLibreclinicaleffectivenessandaccuracyJuly2016.Intotal,

thereviewincludedtwonon‐RCTstudies(66‐68)fortheaccuracyandprecisionofthe

technology,andtwoRCTsnotpublishedattimeofevaluation(IMPACTandREPLACE

studies).HASrecommendedtheinclusionofthetechnologyasfollows:“Measurement

ofinterstitialglucoselevelsforthetreatmentofpatientswithtype1and2diabetes

http://www.inahta.org/members/aquas/

http://www.inahta.org/members/aquas/

http://aquas.gencat.cat/web/.content/minisite/aquas/publicacions/2016/documents/Flash_freeStyleLibre_glucemia_aquas2016.pdf

http://aquas.gencat.cat/web/.content/minisite/aquas/publicacions/2016/documents/Flash_freeStyleLibre_glucemia_aquas2016.pdf

http://www.has-sante.fr/portail/jcms/fc_1249588/fr/accueil

http://www.has-sante.fr/portail/upload/docs/evamed/CEPP-5113_FREESTYLE%20LIBRE_12_juillet_2016_(5113)_avis.pdf

http://www.has-sante.fr/portail/upload/docs/evamed/CEPP-5113_FREESTYLE%20LIBRE_12_juillet_2016_(5113)_avis.pdf

https://www2.sahlgrenska.se/upload/SU/HTA-centrum/Kort-HTA/Kort-HTA%20Blodsockerm%c3%a4tning%20Libre_2015-11-30_TS_JK_IT.pdf

https://www2.sahlgrenska.se/upload/SU/HTA-centrum/Kort-HTA/Kort-HTA%20Blodsockerm%c3%a4tning%20Libre_2015-11-30_TS_JK_IT.pdf

https://www.zorginstituutnederland.nl/binaries/zinl/documenten/standpunten/2016/02/15/flash-glucosemonitoringsysteem-freestyle-libre/Flash+glucosemonitoringsysteem+%28FreeStyle+Libre%29.pdf

https://www.zorginstituutnederland.nl/binaries/zinl/documenten/standpunten/2016/02/15/flash-glucosemonitoringsysteem-freestyle-libre/Flash+glucosemonitoringsysteem+%28FreeStyle+Libre%29.pdf

75 Discussion

(adultsandchildrenaged4years)undergoingintensifiedinsulintherapy(usingexter‐

nalinsulinpumpor>3injectionsperday)andperformingtheSMBGseveraltimesa

day(>3perday).FreeStyleLibreisespeciallydesignedforindividualswhohavere‐

ceivedtherapeuticeducationandspecifictrainingontheuseoftheflashinterstitialglu‐

cosemonitoringsystem.”ThereportindicatesthattheinitialprescriptionofFreeStyle

Libremustbeensuredbyadiabetologistorapaediatricdiabetologist;theyfurtherin‐

dicatethereneedstobeaprovisionofatrialperiodofaminimumofonemonthforeli‐

gibleindividualsandthosewhocontinueusingFreeStyleLibreshouldundergoa3

monthevaluationtoassesswhetherornottocontinueusingthesystem.Inaddition,

priortoprescription,individualsshouldreceivespecificeducationtoprovidethem

withtheskillsandknowledgetoapplythesensorandtointerpreterandusetheinfor‐

mationprovidedbythesystem.Renewalisensuredbyanydoctor.Thecommission

emphasisedthatindividualcomfortandimprovedqualityoflifeduetolowercapillary

bloodglucosebyfingerpricktestimprovedwithFreeStyleLibre.HAS’assessmentpro‐

videsaguidanceforthereimbursementdecision.Nocost‐effectivenessassessment

analysiswascarriedoutforthisproduct(e‐mailcorrespondence)asitistheMinistry

ofHealththattakesthedecision.InMay2017theFrenchHealthMinistrygrantedna‐

tionalreimbursementofthetechnologyforinsulindependentindividualswithType1

and2DM.

TheassessmentbytheCanaryGovernment,SpainconductedinJune2016focusedon

theeffectiveness,safetyandcost‐effectivenessofFreeStyleLibreforindividualswith

type1and2DM.TheassessmentincludedoneRCTforindividualswithType1DM

(IMPACTstudy),andalsomentionstheREPLACEstudy,whichwasnotpublishedatthe

timethereportwasconducted.Researcherswerenotabletoidentifypublishedeco‐

nomicevaluations;thusAbbottprovidedone.Theagencyconcludedthereislimited

scientificevidenceregardingthesafetyandeffectivenessofFreeStyleLibre;similarlyto

ourassessment,theystatedtheavailablestudiesareindustryfundedandtheoverall

GRADEqualityoftheevidencewaslow.However,timespentinhypoglycemiawas

gradedamoderate.Alsoinagreementwithourreport,theassessmentmentionedthe

lackofseriousadverseeventsandrecommendstheuseofFreeStyleLibreshouldbe

donewiththeindividual,providingtrainingandeducationregardingadverseevents,

benefitsandrisks.Similarlytoourexperience,theeconomicassessmentpresentuncer‐

taintiesandlimitationsassociatedwiththeuseofcertainparametersandpointsoutto

thelackofasensitivityanalysis.Theagencystatestheresultsshouldbeinterpreted

76 Discussion

withcaution.Insummary,theagencymakesaconditionalrecommendationforFree‐

StyleLibreuseforindividualswithtype1DMwithcontrolledHbA1clevels(<7.5%),

andwithagoodprioradhesionintheuseofself‐monitoringglucoseinblood.

TheDentalandPharmaceuticalBenefitsAgency(TLV)inSweden,hasrecentlypub‐

lishedareportentitled“Nationalassessmentofmedicaldevicesforincreaseequityin

healthcare”(65).Thisreportdescribesaprocesswhichisabouttobeestablishedfor

assessingmedicaldevicesbeforedecidingonintroducingintotheSwedishhealthcare.

FreeStyleLibreisusedasexampleonhowamedicaldevicehasbeenintroducedbefore

anyassessmentonclinicaleffectivenessandcost‐effectivenesshasbeencarriedout.

Accordingtothereport,thishascausedsignificantbudgetimpactandledtounequal

accesstoFreeStyleLibretoindividuals,whichvarysignificantlybetweentheSwedish

regionstoday.PrescriptionsofFreeStyleLibrehaskeptonincreasingsincespring2016

inallregionsofSwedendespitethehighcosts,anditisestimatedthatuseofcontinu‐

ousglucosemonitors(suchasFreeStyleLibre)willleadtoatotalcostof600.000.000

SEKperyear.Therefore,inMay2016,TLVwasaskedtoassessthecost‐effectivenessof

continunousglucosemonitoring.Inthemeantime,theNewTechnologiesCouncil(NT‐

Rådet)haschosentoputonholdtherecommendationonusingFreeStyleLibreforin‐

dividualswithtype2DMuntiltheassessmentiscompletedinMay2017.TheNT‐Coun‐

cilisexpectedtogivetheirrecommendationthe7thofJune(69).ThefullSwedishHTA

reporthasnotbeenpublishedattimeofoursubmission(e‐mailcorrespondence).

Implications for clinical practice

WehaveusedtheEPICOTapproachtodescribingimplicationsofthepresentedevi‐

dence(70)

Evidence

Diabetesisachronicdiseasewithadurationofdecadesthatrequireslong‐termtreat‐

ment.Currentevidence(derivedfromtwoRCTs)isinadequatetoevaluatethebenefit

andharmsofFreeStyleLibreincomparisonwithstandardtreatment(SMBG).

Nevertheless,theevidenceseemstosuggestthatFreeStyleLibremayimprovetreat‐

mentsatisfaction,andslightlyimprovetimeinrange,glucose<3.9mmol/Lwithin24

hoursandnumberofevents,nocturnaleventsandtimespentwithglucose

<13.0mmol/LwhencomparedtoSMBG,howeverthequalityofevidenceislow.Indi‐

vidualsintheinterventionhadsimilarnumberofseriousadverseeventsasthoseinthe

77 Discussion

comparisongroup.Therewerenootherstatisticaldifferencesinotheroutcomesin‐

cludingqualityoflifeorchangeinHbA1c.Noneofthestudies,althoughconductedin

Europe,includedindividualsfromNorway.

Manystudiesconductedtodate(someprovidedbythesubmitter,retrievedbyour

search,andrecommendedbytheNorwegianDiabetesAssociation)wereexcludedbe‐

causetheydidnotmeetourPICOcriteria(eg,lackofacomparatorgroup).However,

withtheaimofpresentingacompletelistingofallFreeStyleLibreevidence,weprovide

informationonsinglearmcompletedstudies(publishedandunpublished)inAppendix

3andtrialregistryrecords(ongoingstudiesrecruitingornotyetrecruiting)inAppen‐

dix4.WesummarizedFreeStyleLibrecompletedandongoingstudiesintable21.

Table21.SummaryofcompletedandongoingstudiesforFreeStyleLibre

Population Completed(C)orOngoing(O)

RCTs Single arm

Type 1 DM – Children

Type 1 DM - Adolescent

--

1 (O)

3 (C) – 1 (O)

--

Gestational diabetes -- 1 (C)

Type 1 - adults 1 (C) 4 (C) – 1 (O)

Type 2 - adults 1 (C) – 1 (O) 1 (O)

Type 2-≥ 75 yrs of age -- 1 (O)

Type 1 & 2 - adults -- 4 (C) – 2 (O)

Adults - insulin dependent -- 1 (C)

Adults with severe hypoglycaemia 1 (O) --

Children, adults, seniors -- 1 (O)

Somesinglearmstudiespresentevidenceforpopulationgroupsnotaddressedbythe

includedRCTs.Forexample,threesinglearmtudies(66;71;72)includedchildren0to

18yearsold,andonestudyfocusedonType1and2pregnantwomen(73).Inaddition,

fourstudieshavefocusedexclusivelyonadultswithtype1DM(74‐77)andanother

fourincludedadultswithbothType1and2DM(68;78‐80).IshShalom(79)focusedon

individualswithdiabetesdifficulttocontrol.Oneunpublishedtrialregistryrecord(81)

doesnotspecifytypeofdiabetes(insulindependentadults).

78 Discussion

Simlarly,amongthetrialregistryrecords(orongoingstudiesrecruitingornotyetre‐

cruiting)wefoundevidencethatwillserveupdatingthisassessment.Therearethree

RCTs:onefortype1DMadolescents(82),oneinvolvingindividualswithtype2DM

(83),andthelastoneforindividualswithseverehypolgycaemia(84).Wealsofound7

singlearmstudies:oneinvolvingchildren(85),oneinvolvingindividuals4yrs+(chil‐

dren,adultsandseniors)(86),oneinvolvingadultswithType1DM(87)twoinvolving

adutlswithtype2DM(88;89),andtwoinvolvingadutlswithbothtype1and2DM

(90;91).

Population

Theempiricalevidenceincludedinthisreportislimitedtotwostudieswithlessthan

500whitemiddle‐agedadultparticipantslivinginEurope.Ourclinicalexpertsstressed

theinterpretationoftheresultsmustbelinkedtothecharacteristicsofthestudies’par‐

ticipants(e.g.,IMPACTstudyindividuals’HbA1clevels,REPLACEstudyindividuals’age

ofdiagnosisof40years).Therefore,thegeneralizabilityoftheresultstotheNorwegian

population/contextissubjecttodiscussion.

Althoughsinglearmstudieshaveinvolvedchildrenandpregnantwomentheseim‐

portantgroupswerenotincludedintheincludedRCTs.Also,thereisalackofevidence

(dervicedfromRCTs)forindividualswhomayrequirethesupportofacaregiverorex‐

periencedteamtousethetechnology.

Itwillbeimportanttoobtaininformationonlongtermuseofthetechnologyinchil‐

dren.TheinformationwillbeimportantasNorwayhasahighnumberofnewcasesof

type1diabetesinchildrenperyear(4).Accordingtooneoftheclinicalexpertscon‐

sulted,childrenandadolescentswilllikelybenefithighlyfromusingFreeStyleLibre.

Futurestudiesfocusingonchildren,pre‐teenagersandteenagersareimportant,asthis

cohortbehavesinadifferentwaythanadultsandFreeStyleLibreisafterall,abehav‐

iouralmanagementintervention.

Intervention

Individualswithdiabetes(and/ortheircaregivers)mustobtain,process,andunder‐

standbasichealthanddiabetesspecificdiseasemanagementinformationtomakeap‐

propriatedecisions.ThesubmittersuggestthepointofusingFreeStyleLibreistoin‐

creasethepatient’sglycaemicinsightanddiabetesmanagement.Weagreewiththe

submitterthattheinterventionmaycreateanopportunitytoencourageandempower

moresuitablediabetesmanagement.Butevidencepresentedinthestudiesislimitedto

79 Discussion

clinicaloutcomesandaselectedgroupofindividualswhohavelivedwiththedisease

formanyyearsandwerehabituatedto(self)managethedisease.Weagreetothe

uniquepotentialthetechnologyhastomakeanimpact,butcannotassumebasedon

thisassessmentorsubmitters’package,thetechnologyisbarrierfreeandadherence

andproperselfmanagementareguaranteed.Beforetechnologycanaidebehavioral

managementandadherence,ongoingdiabeteseducation,healthanddiabetesliteracy,

andsupportsystemsmayneedtobeestablishedsothatprovidersandindividualscan

usethetechnologysuccessfully.

Interactionsbetweenindividualsandhealthcareproviderspresentwithconsiderable

differencesindifferentcountries,whichwillaffectindividual’sbehaviourandtherefore

theeffectivenessofthetechnologyofinterest.Thus,theresultsfromtheincludedstud‐

iesmaynotberepresentativefortheNorwegiancontext.

ThesubmitterarguesthatFreeStyleLibremaychangediabetestreatmentas“itisthe

patientthatmakesthedaytodaydecisionsconcerningtreatment.”Treatmentdeci‐

sionswerenotassessedinthisreport.Forexample,theamountofinsulinperdayor

otherlifestylechangeslikedietandexercisewerenotconsidered,andthereforeweare

uncertainwhetherFreeStyleLibrecontributestochangetheseorotheraspectsofdia‐

betestreatment.

Notrainingwasprovidedtotheseparticipantsforinterpretationofglucosesensor

data.Thisisanimportantissueasonewouldexpectgreatereffectiftheindividualsin

theREPLACEstudyhadreceivedsuchtraining.Intheassessmentofcost,extraconsul‐

tationsareincluded,thusgivingthepossibilityforcorrecteducation.

Trainingandeducationaltoolsmaybeneededtoteachusersandtheircaregivershow

tomanageglucoselevels.Datainterpretationandcompetencemanagingglucoselevels

caninvolvealotoftimeanddedication.

Last,compatibilityregardingtechnologysoftwareandtechnologicalsystemsathome

forpeoplewithdiabetesandforhealthcareprofessionalsinNorwaycouldbeapointof

issue.

80 Discussion

Comparison

Thereiscurrentlyalackofevidenceforcomparisonsotherthancapillarybloodtesting.

Itisveryimportanttobeawarethatnoneoftheincludedstudiesusedcontinuousglu‐

cosemonitoring(withorwithoutcontinuoussubcutaneousinsulininfusion)asacom‐

parator.

Outcomes

QualityofLifeandTreatmentSatisfaction

QualityoflifeismentionedasoneofthemainfeaturesperceivedbyusersofFreeStyle

Libre.Ourassessmentshowedaneffectsizecrossingthelineofnoeffect,whichistell‐

ingusweareuncertainthatoneinterventionisbetterthantheotherforthisoutcome.

Theresultsweresurprisingforsomemembersoftheteam,butwerenotforsomeof

ourclinicalexperts.

Onepossibleexplanationfortheresultsisthattheparticipantswerealreadydedicated

tousenewtechnologies,andthelengthoftimetheindividualshavelivedwiththedis‐

easehasinfluencedtheirviewsonqualityoflife.Thisinadditiontoaperhaps‘short’

interventionnotallowingtoperceivefurtherimprovementsintheirqualityoflife.Also,

somestudieshavefoundthatbetterglycaemiccontrolisassociatedwithbetterquality

oflife,butotherstudieshavefailedtoshowthisrelationship(92;93).Oneofourclini‐

calexpertsadded,participantsrealizationofchangesinbloodglucosewithFreeStyle

Libre,evenwhentheydowhattheyaretoldbyhealthpracticioners,mayaffecttheir

qualityoflifeastheymayfeelnotbeingthemasterofthesituation.

Anotherpossibleexplanationisthetoolusedbyresearchers.TheDiabetesQualityof

Lifescalewasdevelopedforuseinthediabetescontrolandcomplicationstrial(DCCT)

tocomparetwotreatmentregimensforchroniccomplicationsinpatientswithType1

diabetes.Asoneofourstakeholderspointedout,thescaledoesnotseemtocoverim‐

portantpsychologicalaspectssuchasmotivationandcoping.Oneexplanation,isthat

thetoolisnotsensitiveenoughtomeasurechangesinthistypeoftrial.

Nevertheless,wefeltitwasimportattoaddthecommentofoneofthestakeholders

consulted(ayoungmanlivingwithdiabetesType1)ontheimpactofFreeStyleLibreon

hisqualityoflife.Hetoldus:

81 Discussion

Thelifeofadiabetes1patientischaracterizedbyahighdegreeoflimitationsand

FreestyleLibretakesawaysomeoftheselimitations(e.g.,soccertraining,swim‐

ming,skiingandatschool).Whenyouhaveachronicdiseasethatyouwillhave

for70‐80years,evensmallimprovementsinqualityoflifehaveamajorimpactin

thelongrun!!!

Treatmentsatisfaction,however,hadachangeof5points(onascale‐18to18points)

which,accordingtoourclinicalexperts,isclinicallysignificantimprovement.Typeof

insulinregimen,thefrequencyofbloodglucoseself‐monitoringandperceivedfre‐

quencyofhyperglycaemiacanhaveasignificantassociationwithtreatmentsatisfac‐

tion.Onecanarguethattreatmentsatisfactionispartofqualityoflife,thusconfirming

thatFreeStyleLibreimprovesthelivesofindividualswithdiabetes.

HbA1c(%)

ThesubmittersuggestedtheREPLACEandIMPACTtrialsweredesignedtoreflectrou‐

tineclinicalpracticeandthattheendpointsusedinthetrialswererelevant,inparticu‐

larHbA1c.Wedisagreewiththesubmitter’sstatement,andasoneofourclinicalex‐

pertssuggested,thepopulationinthetrialsmayhavebeenselectedpurposefully

Inotherwords,intheIMPACTtrialpopulationcharachteristics(i.e.,wellcontrolled

HbA1c)itwaslikelyresearcherswouldfindchangesinhypoglycemia(mainendpoint

ofthestudy).Similarly,wefoundednoteworthymaingoaloftheREPLACEstudy

(changesinHbA1c)andtheparticipants’characteristics(i.e.,notwellcontrolled

HbA1c).

TherewasevidenceofalackofaneffectforHbA1c,however,thiswasnotasurprising

result.IndividualsintheIMPACTstudywerewellcontrolled,withameanlevelof6.7%

(25).Oneofourclinicalexpertarguedthattheindividual’sdiseasewasextremelywell

regulatedinthisstudy,anditwouldevennotberecommendedforthemtoreducetheir

HbA1c<6.5%.Participantsinthisstudywereratherdedicatedandmeasuredblood

sugarregularlyandoften.Itislikelythatiftheywerenotthatwellregulated,itwould

bemorelikelytoseeareductioninHbA1c.ForindividualswithHbA1cof7.5%itwould

benecessarytoreducetheirHbA1c.Thisscenariohardlyreflectsclinicalpractice.

IndividualswithType2DMweredifferent,andlesspronetohypoglycaemia.Thegroup

studiedwasnotwellregulatedwithanHbA1cof8.8%(Haak),indicatingthattheyeven

fromthebeginningofthestudywerenotdedicatedindividuals.

82 Discussion

Inaddition,thestudybyHaaketal.includedolderparticipants,meanage59years.

Participantsyoungerthan65yearsofagehadalargerfallinHbA1clevelintheinter‐

ventiongroupcomparedwiththecontrolgroup.FurthermorethemeanBMIwasvery

high,33.1,indicatingthatseveraloftheparticipantshadametabolicsyndromeeven

thoughthosewithinsulinconsumptionover1.75units/kg/daywereexcluded.Those

withpoordiabetescontrolandsignsofmetabolicsyndromeneedcombinedinterven‐

tionstoachievegooddiabetescontrol.Thesubmitterindicated“Afocusonprevention

ofhypoglycaemiainthisgroupmayexplainwhyHbA1clevelswerenotsignificantlyre‐

duced”butwehavenotindicationofwhatthismeans.

Thishighlightsthedifficultiesinidentifyingandincludingindividualsforthetrialsrele‐

vanttothetechnology.Basedonthis,weareunsurehowFreeStylewouldperformon

individualswithpoorlycontrolledHbA1c.Thesubmitteracknowledgeslimitationsof

thetechnologyforsituationsofrapidlychangingglucoselevels,confirmationofhypo‐

glycaemiaorimpendinghypoglycaemia,orwhensymptomsdonotmatchFreeStyleLi‐

brereading.Asoneofourclinicalexpertsmentioned,thesearesituationswhenindi‐

vidualsareingreatestneedofknowingexactlywhattheirpresentglucoselevelis.

Theselimitationshavetobetakenintoconsideration.

Pain

Wehavenotbeenabletoreportonthisoutcomeasitwasnotdirectlymeasuredinthe

studies.Individuals’adherencetoinsulintherapyisanongoingchallengeinclinical

care.Painisobviouslyaveryrelevantoutcome,inchildreninparticular,andareason

forchoosingonetreatment(ortypeoftechnology)overanother.Injection/needlere‐

lateddiscomfortcontinuestobearheavilyintheindividual,thecaregiverandsome‐

timesthehealthcareprovider.

Glycaemiccontrol

Wedonotagreewiththesubmitters’claimthattheusersofFreeStyleLibredecreased

mostaspectsofhypoglycemia.Resultsofouranalysisshowonlyhalfoftheoutcomes

werestatisticallysignificant.

Thereweresomeclear,andexpected,differencesinglycaemiccontroloutcomesfor

type1and2DM.Asaclinicalexpertpointedout,intype1DMamorerapidriseandfall

inbloodglucoseisobservedsincetheseindividualsdonotproduceanyinsulinand

thusdependcompletelyoninsulinsuppliedsubcutaneously.Itisthereforenotso

strangethat,whenlookingattheforestplots,theeffectofFreeStyleLibreisgreatestin

83 Discussion

thetype1DMgroup.Whilelookingatthepooledresults,ouranalysisshowednostatis‐

ticallysignificantresultsfortimeandeventswithglucose<3.1mmol/L,and<3.1

mmol/Latnight.Thiswasalsothecaseforhyperglycaemiatime>10mmol/L(type

2DM).Aclinicalexpertmentionedareductioninhypoglycaemia(especiallyinthelow

group<3.1mmol/L)isofclinicallysignificance,andtheimportanceofthisasitmayre‐

ducemorbidityandmortalityduetolossofconsciousnessandsecondarycardiovascu‐

larincidents.Further,ourresultsshowedonlyareductionofnumberofeventswith

glucose<3.9mmol/Lwithin24hours.

Adverseevents

Wedisagreewiththesubmitter’sfavourableinterpretationofadverseeventsrelatedto

thedeviceandwithdrawalscomparedwithSMBG.Adverseeventsweremeasuredat

uncomparabletimes(i.e.,baselineand6monthsendpointfortheinterventiongroup,

andbaselineand4weeks‐14daysat3monthsand14daysat6month‐inthecontrol

group)constitutingamajorthreatintheinterpretationoftheresults.Assuch,thecur‐

rentresultsmaybemisleadingandneedtobereadwithcaution.Inaddition,thelow

numberofparticipantsandtheshortlengthoftheinterventiondonotjustify,inour

opinion,suchoptimisticconclusions.

Issuesrelatedtothetechnology,likescaringorirritabilityoftheskinintheareas

wheresensoriswornmayneedtobetakenintoconsiderationasalternativeareasto

sensorwearingasitwasneededinatleastoneoftheseRCTs(25).Thetrialperiodis

notlongenoughtounderstandtheassociationsbetweenconsequencesinsubcutane‐

ousskinandintersticialreading.

Somesensorsfailandconsistentsupplyofsensorsisnecessary;thiscancausetheuser

tohavetouseothermethodsformanagementofthedisease.Asoneofourclinicalex‐

pertsmentioned,individualswillstillneedsomeSMBGtocheckiftheFreeStyleshow

correctvalues.

Non‐devicerelated,device‐relatedandwithdrawalsfromthestudywerenotedinboth

trials.Inagreementwithourclinicalexperts,weconcludedthatFreeStylehasatolera‐

bleshorttermadverseeventprofile,enphasazingthateventhatinformationhastobe

takenwithcaution.

84 Discussion

Oneofourclinicalexpertsmentionedthatindividual’sfatigueinwearingtheFreeStyle

Libreisnottakenintoaccount.Neitheristhefactthatinitialstudiesinparticularlyded‐

icatedpatientstendtooverestimatetreatmenteffectscomparedtowhenthetreatment

isusedinageneraldiseasepopulation.

Limitationsoftheassessment/technology

Themainuncertaintiesregardingclinicaleffectivenessarethegenerallackofdata

(includingchildren,youth,andspecialpopulations)andlowqualityofavailable

data.

Duetoinheritdifferenceindiseasecharacteristicsitwasdifficulttoevaluateand

interpretthedatainthisassessment.

Oneoftheclinicalexpertssuggestedthereisaveryclearrelationshipbetween

timespentinhypoglycaemiaandriskofseverehypoglycaemia.Thisis

especiallyimportantinindividualswithimpairedawarenessofhypoglycaemia.

Theseindividualswill/shouldoftenchoseatechnologywithanalarmthatwill

indicatetheglucoselevelisapproachinghypoglycaemia.FreeStyleLibreis

unabletoprovidesuchalarm,andthisisthereforealimitationofthe

technology.

TheFreeStyleLibreglucosesensorissituatedundertheskinandtherefore

measurestheglucoselevelsinthefluidbetweenbloodcapillariesandthe

body’scells(interstitialfluid)ratherthancapillarybloodglucoselevels.

Becauseglucosemovesfromthecapillariestotissues,thereisalagbetween

bloodandinterstitialglucoselevelsofatleast6‐7minutes,butontopofthis

comesadelayinthesensor(94).Thelagincreaseswhenglusoeisincreasing

anddecreaseswhenglucoseisdecreasing,andtheeffectislargerwhenthe

speedofchangeinglucoselevelsarelarger.Toknowthedelayandtheabso‐

lutedifferenceonemustdotestwiththeactualglucosesensor.Further,

confirmatorycapillarybloodglucosetestsmaythereforeberequiredtoconfirm

thevaluedisplayedbythecontinuousglucosemonitorbeforemakingany

adjustmentstodiabetestherapyordrivingavehicle.

Cost-effectiveness

Thesubmitterprovidedacost‐effectivenessanalysisoveratimehorizonof40‐years.

Thesubmittercalculatedanincrementalcost‐effectivenessratioforFreeStyleLibre

comparedwithSMBG.Thehealtheconomicevaluationwasconductedusingaweb‐

basedmodel,beingtheIMSCDM.ThemodelwasbuiltuponMarkovmodellingof17

sub‐modelsofcomplicationsassociatedwithType1and2DM.

85 Discussion

Wehavehighlightedsomeweaknessesinthemodelthatwethinkshouldbeaddressed.

First,themodelreceivedfromthesubmitterlackstransparency,makingitdifficultto

gainafirmunderstandingofthefactorsthatdetermineacohort’sprogressthroughthe

model,assumptionsandparameterseffectoutcomesandtoassessthevalidityofthe

model.Thismadeusunabletoevaluatethemodelstructure,andtrackwhat’sinflu‐

encedtheresults(internalvalidation).Themodelhasbeenconsideredforitsexternal

validity,latestperformedbyMcEwanetal.2014(34).AccordingtoMcEwanetal.2014

(34)areviewmethodusedinlongtermcost‐effectivenessmodelsofdiabetesinterven‐

tionsalsoconfirmedtheprominentrolethatthediabetescontrolandcomplications

trialandtheUnitedKingdomProspectiveDiabetesStud(31;33)playinprovidingdata

onefficacyanddiseaseprogression,particularlyfordefiningtherelationshipbetween

HbA1candcomplications.

However,someissuesarenotsufficientlycommentedbythesubmitter.First,the

modelandvalidationfocusonthedisease,diabetes,butnotparticuarlythetechnology

andprocedurerepresentedbyFreeStyleLibre.Inputisthusnotvalidated.Secondly,

thesubmittedmodelshowsanimprovementinHbA1cforuseofFreeStyleLibrecom‐

paredtobloodglucosemonitoring.Thisisnotthecasewithourefficacyfindingsinour

singletechnologyassessment,whichshowsthattherewereapproximatelynodiffer‐

enceinHbA1cfortheinterventionversusthecomparator.Thesubmitterhasbasedthe

resultson6monthsdata,whichisaveryshortperiodoftime,asHbA1cissomething

thatinfluencesdiabetesthroughalifetimeperiod.Evidenceforalongertimeperiodis

notpresent,whichleadstolargeuncertaintyabouttheresults.Third,thesubmitterdid

notprovidereferencestoseveralsourcesoftheinputdataandqualityoflifeimprove‐

ments.Forexample,theutilityvaluerelatedtotype1DM,withnocomplicationsof0.9.

Inaddition,thesubmitterusedifferentvaluesintheefficacypartandinthemodel.Re‐

gardingthecosts,thepriceofFreeStyleLibrewerebasedonthepricefoundontheoffi‐

cialweb‐siderelatedtothedevice(41),whichisanotherpricethanusedbythesubmit‐

ter.Thepriceandtheothercostsdidnotincludevalueaddedtax(VAT).VATshould

havebeenincludedinthisanalysissinceitappliestheperspectiveofthehealthcare

provider.

Basedoninputgivenbytheclinicalexpertsandthoroughreview,webelievethatthe

healtheconomicmodelcapturedtheoutcomesthatareclinicallyrelevantforthede‐

finedpopulationandintervention.Accordingtoourclinicalexperts,thestudypopula‐

tioninIMPACTandREPLACEweresaidtobecomparabletotheNorwegianpopulation.

86 Discussion

Ontheotherhand,variousinputdatainthemodelistakenfromstudieswithdifferent

inclusioncriteria(forexampleaboutthestudypopulationanddiabetestype),which

leadstoagreatuncertaintyabouthowwellthedatafittotheuseofFreeStyleLibrein

Norway.Theclinicalinputdatarelatedtoindividualswithtype1DMwerebasedon

differentreferences.InonesimulationtheirclinicalinputswerebasedontheREPLACE

trial,whichincludespatientswithtype2DM,under65years.Inanothersimulation

theincludedclinicalinputdatawerebasedonSwedishfindings.Severaloftheclinical

inputdataincorporatedinthesubmittedmodel,didnotcorrespondtotheclinical

inputdatalistedupinthesubmitteddocument.Further,itisuncertainhowcompara‐

bletheinputdataaretoeachother,sincemostofthecomplicationsarefromseparate

studies.ThetimehorizonintheIMPACTandREPLACEtrialswasonly6months,andin

themodeltheoutcomesareextrapolatedover40yearsassumingcontinuousbenefits.

Thecalculatedincrementalcost‐effectivenessratio(ICER)basedonthesubmittedeco‐

nomicmodelovera40‐yeartimehorizonwasdominantforpatientswithtype1diabe‐

tes,meaningthatFreeStyleLibreaccordingtothemanufacturerisbothcostsavingand

moreeffective.Forpatientswithtype2diabetestheICERwascalculatedtobeNOK

235,673perQALY(wholestudypopulation)andNOK243,434perQALY(under65

years).Asthesubmittedmodelwasnottransparentandnotsufficientlyflexible,we

werenotabletorunamodelwithadjustedinputdata.

ThesubmitterestimatedthatFreeStyleLibrewouldbepotentiallycostsavingthefirst

fiveyearsafteritsadoptionforpatientswithdiabetestype1anddiabetestype2insu‐

lineusersinNorway.However,weadjustedsomeofthecalculationsrelatedtothe

budgetimpactanalyses,basedoninputdatafromourclinicalexperts.Ourresultsindi‐

catedthatthetotaladdedcostswouldbeaboutNOK913millionthefirstfiveyearsaf‐

teradoptionofFreeStyleLibreforonlypatientswithdiabetestype1,andaboutNOK

480milliontotaladdedcoststhefirstfiveyearsafteradoptionofFreeStyleLibrefor

patientswithdiabetestype1anddiabetestype2insulineusers.Theannualcostsfive

yearsafterintroductionwouldbeNOK186millionaddedcostandNOK91,7million

savedcostfortype1and2DMalone,respectively,andNOK94millionaddedcostfor

type1and2DMcombined.

Wefounditstrangethatthesubmitter’scost‐effectivenessresultsandbudgetimpact

resultsdeviatesfromeachother,i.e.adominantedICERandahightotaladdedcostin

thebudgetimpact.

87 Discussion

Nosensitivityanalyseswereprovidedbythesubmitter,whichisacrucialpartofan

economicevaluation,anditwasthereforenotpossibletoassesshowrobusttheresults

aretovariationinuncertainsingleparameters.Wecanthusnotseehowpricesand

otheraspectsmightinfluencetheresults.Onewaysensitiveityanalysesareinaddition

importantforconsideringtheinternalvalidityofthemodel.Thesubmitterhasonly

doneonescenarioanalysiswithasmallpricedifference.

KeyConclusions

Alloftheexistingdiabetestechnologieshaveadvantagesanddisadvantages,andperse

noneenableeveryonewithdiabetestoachievetargetHbA1clevels.FreeStyleLibre

maybeusedtoinformindividualsregardingtheirinterstitialglucoseleveltoallowde‐

cisionmakingregardingtreatmentandtogivethepersoninformationontheimpactof

changesinlifestyle,dietandphysicalactivity,whichcouldinfluencethelong‐termcon‐

troloftheirdisease.

Efficacy

ThereislimitedandlowqualityscientificevidenceontheclinicalefficacyofFreeStyle

Libre;thisbringslimitationstothegeneralizationoftheresults.Thetwotrialswehave

evaluatedindicatethatFreeStyleLibremayimprovetreatmentsatisfaction,timespent

inhypoglycaemiaandnumberofhypoglycaemicevents,butthestudiesweretoofew

andsmalltosupporttheclinicalefficacyofFreeStyleLibretothebroadercommunity

ofindividualswithdiabetes.Inaddition,thestudiesincludedrepresentonlyapartof

thepopulationofpeoplewithdiabetesinNorway,anditisthereforedifficulttomake

generalizationstotheNorwegiancontext.

FreeStyleLibremayslightlyimprovetreatmentsatisfaction,timeinrange,numberof

nocturnalevents<3.1mmol/Lwithin7h,andtimewithglucose>13.0mmol/Lincom‐

parisontoSMBG;FreeStyleLibreleadtolittleornodifferenceinqualityoflifeand

HbA1cincomparisontoSMBG.WeareuncertainwhetherFreeStyleLibreleadstoan

improvementintimeandeventswithglucose<3.9mmol/Lwithin24h,timewithglu‐

cose<3.1mmol/Latnightwithin7hours,andtimewithglucose>10mmol/L.Thisap‐

pliesonlytoindividuals18yearsorolder,andindividualsunder65yearswithtype2

DM,aswellasindividuals18yearsorolderwithtype1DM

OursearchfoundseveralFreeStyleLibreregistryrecordsofongoingstudies(seeAp‐

pendix4).Amongtheseongoingtrials,threehavearandomizedcontrolleddesignand

88 Discussion

canfurtherourknowledgeontheclinicaleffectivenessofFreeStyleLibre.Theresultsof

thisassessmentwilllikelychangewhennewevidencebecomesavailable.

Cost‐effectiveness

Theresultsofsubmitters’analysisshowedthatFreeStyleLibreisacost‐effectivealter‐

nativetoSMBG.However,wewerenotabletocontrolthesubmittedresultsandto

makeourowncost‐effectivnessresults(ICERs).Thereareseveralproblemswiththe

modelthatleadustoquestionthesubmittedresult.Themostchallengingissueisthat

themodelisnottransparent.Otherchallengingissuesaretheshorttermdatausedin

themodel,whichshouldcapturethedifferenceinefficacybetweentheFreeStyleLibre

usersandindividualswhoareusingSMBGonly.Also,thesubmittedmodelincluded

severalinputdatathatneithermatchedtheinputdatadescribedinthesubmitteddocu‐

mentationpackagenormatchedtheinputdatafoundinotherliterature.

Becausewedidnothaveaccesstothecompletemodelwewerenotabletoassessthe

validityofthesubmitters’estimates,norhowadjustmentofthemodelwithalternative

assumptionswouldaffecttheresultsprovidedbythesubmitters.Takinginaccountthe

commentsabovetheNIPHfindstheICERestimatesunreliable.TheNIPHistherefore

notabletoconsiderwhetherornotFreeStylelibreiscost‐effectivebasedonthesub‐

mitteddocumentation.

AccordingtothebudgetimpactanalysisperformedbyNIPHtheannualcostsfiveyears

afterintroductionwouldbeNOK186millionaddedcostandNOK91,7millionsaved

costfortype1and2DMalone,respectively,andNOK94millionaddedcostfortype1

and2DMcombined.

OverallFreeStyleLibredoesnotseemtoprovideahigherefficacyorfeweradverse

eventsorincreasedqualityoflifemeasuresforinsulintreatedpatiensthanotherSMBG

devices,thusitmakesdifficulttosupportthelowercostsassociatedwithFreeStyleLi‐

bre.

89

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Appendix1.Glossaryofterms

Cost‐effectivenessanalysis:aneconomicanalysisthatconvertseffectsintohealthtermsanddescribesthecostsforadditionalhealthgain.

HbA1c:thetermHbA1creferstoglycatedhaemoglobin.TheHbA1ctestmeasuresdia‐betesmanagementovertwotothreemonths.

HELFO:TheNorwegianHealthEconomicsAdministration.HELFOisresponsiblefordi‐rectpaymentstovarioushealthserviceproviders,individualreimbursementforcer‐tainmedicines,dentalservicesandhealthservicesabroad.

Health‐relatedqualityoflife:isanindividual'soragroup'sperceivedphysicalandmentalhealthovertime.

Hypocalcaemia:thisisatermthatreferstolowbloodcalciumlevel.HyperglycaemicandhypoglycaemicAUC:theareaunderthecurveistheproductofthemagnitudeanddurationofthesensormeasuredglucoselevelaboveorbelowaspecifiedcutofflevel.Highervaluesforthiscalculationindicatemorenumerous,se‐vere,orprotractedglycemicevents.

Impairedawarenessofhypoglycaemia:atermusedtodescribeasituationwherepeoplewithdiabetes,usuallytype1diabetes,arefrequentlyunabletonoticewhentheyhavelowbloodsugar.Incrementalcost‐effectivenessratio(ICER):thedifferenceinthemeancostsoftwointerventionsinthepopulationofinterestdividedbythedifferenceinthemeanout‐comesinthepopulationofinterest.Millimole:afigurethatisapartoftheInternationalSystemofUnitsandequalto1/1,000ofamole(SI).Amoleisaunitofmeasurementcommonlyusedinchemistrytodenoteamountsofatomsandmolecules.

Nephropathy:thisisatermthatreferstodamagetoordiseaseofakidney.Neuropathy:thisisatermthatreferstodiseaseordysfunctionofoneormoreperiph‐eralnerves,typicallycausingnumbnessorweakness.Retinopathy:Diabeticretinopathyisacommoncomplicationofdiabetes.Itoccurswhenhighbloodsugarlevelsdamagethecellsatthebackoftheeye(knownastheret‐ina).Ifitisn'ttreated,itcancauseblindness.

96

Type1diabetes:Diabeteswherethebodydoesnotproduceinsulin.Type2diabetes:thebodyusuallystillproducessomeinsulin,butthisisnotenoughtomeetdemandandthebody'scellsdonotproperlyrespondtotheinsulin.

97

Appendix2.Searchstrategy

Literaturesearch–FreeStyleLibreDateRun: 2017.01.18Databases: OvidMEDLINE,Embase(Ovid),CochraneLibrary;CochraneDatabaseof

SystematicReviews,OtherReviews;CentralRegisterofControlledTri‐als);TechnologyAssessments;EconomicEvaluationsDatabase,CentreforReviewsandDissemination;DatabaseofAbstractsofReviewsofEf‐fects;HealthTechnologyAssessments,PubMed.

Othersources:Googlescholar,HTAagencies,ClinicalTrials.gov,WHOInternationalClinicalTrialsRegistryPlatform.

Allresults: 1662recordsofwhich40ongoingtrials(2197includingduplicates)Searchedby: IngridHarboe,peerreviewedbyIngvildKirkeheiSearchstrategiesDatabase: CochraneLibraryAllResults: CochraneReviews(2);OtherReviews(8);Trials(175);TechnologyAs‐

sessments(11)

ID Search Hits

#1 MeSH descriptor: [Diabetes Mellitus] explode all trees 19557

#2 diabet*:ti,ab,kw

in Cochrane Reviews (Reviews and Protocols)

418

#3 diabet*

in Other Reviews, Trials, Technology Assessments and Economic Evaluations

48765

#4 #1 or #2 or #3 49246

#5 MeSH descriptor: [Blood Glucose Self-Monitoring] this term only 599

#6 ((glucose) and (monitor* or scan*)):ti,ab,kw


31

#7 ((glucose) and (monitor* or scan*))


4937

#8 #5 or #6 or #7 4968

#9 (flash* or interstitial* or real-time or realtime):ti,ab,kw


56

#10 (flash* or interstitial* or real-time or realtime)


7494

#11 #9 or #10 7550

98

#12 #4 and #8 and #11 196

#13 (freestyle and (flash* or libre)):ti,ab,kw i

n Cochrane Reviews (Reviews and Protocols)

0

#14 (freestyle and (flash* or libre))


6

#15 ((guardian and (real-time or realtime)) and diabet*):ti,ab,kw


0

#16 ((guardian and (real-time or realtime)) and diabet*):ti,ab,kw


9

#17 #13 or #14 or #15 or #16 15

#18 #12 or #17 196

99

Database:Embase<1974to2017January17>,EpubAheadofPrint,In‐Process&OtherNon‐IndexedCitations,OvidMEDLINE(R)DailyandOvidMEDLINE(R)<1946toPresent>

SearchStrategy:# Searches Results

1 exp Diabetes mellitus/ 1212267

2 diabet*.tw. 1292593

3 or/1-2 1524496

4 Blood Glucose Self-Monitoring/ 20461

5 blood glucose monitoring/ 21246

6 (glucose and (monitor* or scan*)).tw. 74233

7 or/4-6 90759

8 (flash* or interstitial* or real-time or realtime).tw. 727888

9 3 and 7 and 8 2547

10 (freestyle and (flash* or libre)).tw. 38

11 (guardian and (real-time or realtime) and diabet*).tw. 112

12 or/10-11 150

13 9 or 12 2551

14 remove duplicates from 13 1747

15 14 use oemezd [Embase] 1573

16 14 use ppez [MEDLINE] 174

Database:CentreforReviewsandDissemination:DARE(DatabaseforReviews

andDissemination)andHTA(HealthTechnologyAssessmentDa‐tabase)

Results: 22records Line Search Hits

1 MeSH DESCRIPTOR Diabetes Mellitus EXPLODE ALL TREES 2427

2 (diabet*) 4453

3 #1 OR #2 4459

100

4 MeSH DESCRIPTOR Blood Glucose Self-Monitoring EXPLODE ALL TREES 110

5 ((glucose and (monitor* or scan*))) 371

6 #4 OR #5 371

7 ((flash* or interstitial* or real-time or realtime)) 411

8 #3 AND #6 AND #7 22

9 ((freestyle and (flash* or libre))) 0

10 ((guardian and (real-time or realtime) and diabet*)) 1

11 #9 OR #10 1

12 #8 OR #11 22

Source:ClinicalTrials.gov

WHOICTRP(InternationalClinicalTrialsRegistryPlatform)Results:40recordsSearch:"GlucoseMonitoringSystem"ANDflash;DiabetesANDflash;freestylelibreHTAagencies(orsimilar):AHRQ(AgencyforHealthcareResearchandQuality),AHTA(AdelaideHealthTechnologyAssessment),(CADTH,QueenslandHealth,DIMDI(GermanInstituteofMedicalDocumentationandInformation)ECRI,IHE(InstituteofHealthEconomics),NICE(NationalInstituteforHealthandCareExcellence),McGillTechnologyAssessmentUnit,SBU(SwedishAgencyforHealthTechnologyAssessmentandAssessmentofSocialSer‐vices).Results:7recordsSearch:"GlucoseMonitoringSystem"ANDflash;DiabetesANDflash;freestylelibreGooglescholar:Results:2recordsSearch:Search:"GlucoseMonitoringSystem"ANDflash;DiabetesANDflash;freestylelibre

101

Appendix3.Completed(publishedandunpublished)singlearmstudies

Population Author Study Design (country)

Duration Outcomes

Type 1- Children 4 to 17yr

Edge 2017 BEAGLE NCT02388815 (66;95)

Single arm (UK)

14 days Accuracy, safety and acceptability


Rai 2016 (72)

Single arm (India)

14 days Feasibility and accepta-bility


NCT02821117 (completed) SELFY (71)

Single arm (Germany, Ireland, UK)

10 weeks Change in time in range, time in range

Type 1 or 2 Pregnant women,

NCT02665455 (completed) FLIPS (73)

Single arm (Austria, UK)

14 days Accuracy

Type 1 - adults Olafsottir 2017 NCT02677454 (77;96)

Single arm (Sweden)

10-14 days Accuracy and treatment experience

Type 1 - adults Aberer 2017 NCT02614768 (74;97)

Single arm (Austria)

12 hours 3 systems performance

Type 1 – adults Bonora 2016 (75) Ethics approval prot no 74889

Single arm (Italy)

14 days FreeStyle Libre and CGM Dexcom G4 Plati-num performance

Type 1- adults Dover 2016 (76)

Single arm (UK)

16 week Impact of FreeStyle to patients attending dia-betes clinic in a univer-sity teaching hospital

Type 1 & 2 adults Ji 2016 (80)

Single arm (China)

14 days Performance in Chinese patients

Type 1 & 2 adults Ish Shalom 2016 (79) Single arm (Israel)

12 weeks Experiences in difficult to control diabetes

Type 1 & 2 adults Fokket et al (TC5348) (78;98)

Single arm (The Netherlands)

14 days Performance

Type 1 & 2 adults Bailey 2015 NCT02073058 (68;99)

Single arm (US)

14 days Performance and usa-bility

Adults on insulin treatment

UMIN000018692 (completed) (81)

Single arm (Japan)

14 days WHO-5 questionnaire, DTSQ, safety

102

Appendix4.FreeStyleLibreregistryrecords

Population Registry number-(country)-Title Duration Outcomes

Randomized controlled trials

Type 1 Adolescents 12- 17yr

NCT02776007 (82) – (Israel) - Patients Perceptions of Using the "Libre" System Compared With Conventional SMBG in Adolescents With Type 1 Dia-betes The Libre Sat Trial Recruiting

12 weeks Treatment satisfaction, HbA1c change, average fasting blood glu-cose, sensor readings at week 12 and 24 hours, number of measure-ments on intervention and each arm, percentage of readings with 70 to 180 mg/dl, below 60mg/dl, above 240mg/dl

Type 2

Adults

NCT02809365 (83) – (Israel) - FreeStyle Libre-effect on QOL in Type 2 diabetes patients Not yet recruiting

10 weeks QoL, treatment satisfaction, HbA1c change, percentage to reach HbA1c as per physician prescrip-tion, reduction in hypoglycemic events

Adults with se-vere hy-poglycaemia

ACTRN12616001695493 (84) – (Aus-tralia)- Assessment of the utility of the Flash Libre subcutaneous glucose moni-toring system to prevent recurrent severe hypoglycaemia in patients with diabetes

Recruiting

24 weeks Recurrence or occurrence of se-vere/non-severe hypoglycaemia, time to first recurrence or occur-rence severe/non-severe hypogly-caemia, time between recruitment and first occurrence/recurrence of severe and non-severe hypogly-caemia

Single Arm/Non Randomized

Type 1

Children 4 to 18 yr

NCT02824549 (85) – (Belgium) An Evaluation of the FreeStyle Flash Glucose Monitoring System

Recruiting

24 weeks?

“0.5 yr”

Usability, skin reactions to sensor, accuracy

Type unspeci-fied

children, adults, seniors

NCT02898714 (86) – (Belgium) Flash Glucose Monitoring Study for Dia-betes (FUTURE)

Recruiting

3 years Quality of life, change in HbA1c

Type 1 -Adults

Recruiting

NCT02734745 (87) – (Italy) Accuracy of FreeStyle Libre

Recruiting

14 days Accuracy

Type 2 – ≥ 75 yrs of age

NCT03020264 (89) – (France) Frequency of hypoglycemia inpatients with type 2 diabetes under insulin ther-apy older than 75 years in real life (HY-POAGE)

4 weeks Number of confirmed or severe hy-poglycemia, events/patient/month of severe hypoglycemia, number of hospitalizations due to hypoglyce-mia, death, falls, transition to ER,

103

hypoglycemia in subroups, fear of hypoglycemia, pseudo hypoglyce-mia and unconfirmed hypoglyce-mia, nocturnal hypoglycemia, threshold blood glucose <0.54g/L, number of elderly admitted to EHPAD

Type 2 -adults UMIN000023593 (88) – (Japan) Use of FreeStyle Libre Flash Glucose Monitoring System and the Effect on Hy-poglycaemia in People with Type 2 Dia-betes in Japan Pre-initiation

12 weeks Change from baseline in time in hypoglycaemia (<3.9 mmol/L [70 mg/dL]), time in range, hyper/hypo glygaemic episodes, accuracy, var-iability measures, glucose rate change, TDD of insulyne, body weight, blood pressure, treatment satisfaction, hypoglycemia patient questionnaire, number of scans performed, user questionnaire, HCP questionnaire

Type 1 and 2 - adults

ISRCTN12543702 (90) – ( UK) Masked performance check of the Abbott FreeStyle Libre Flash glucose monitoring system. Recruiting

14 days Accuracy, precision within sensor lot

Type 1 and 2 - adults

ISRCTN87654534 (91) – (UK) Performance check of the Abbott Free-Style liver flash glucose monitoring sys-tem Recruiting

14 days Accuracy, precision within sensor lot, relationship between HbA1c levels and glycaemic variability

104

Appendix5.Includedstudiesinclusionandexclusioncriteria

InclusionCriteriaBolinder 2016

Adults 18 years or older diagnosed with type 1 DM for 5 yrs or

longer, on their current insulin regimen for at

least 3 months before study entry,

had a screening HbA1c concentration of 58mmol/mol (7.5%) or lower,

reported self monitoring of blood glucose levels on regular basis (equivalent to > 3 times/day) for 2 months or more before study entry,

considered technically capable of using the flash sensor base glucose monitoring system

Haak 2017 adults 18 years or older individuals with type 2 DM treated with

insulin for at least 6 months, on thier current regime (prandial only or

prandial and basal intensive insulin therapy or CSII therapy) for 3 months or more,

had a screening HbA1c concentration level 58-108mmol/mol (7.5-12%)

reported self monitoring regular blood glucose testing (more 10/week for at least 2 months prior to study entry)

were considered by the investigator to

be technically capable of using the flash sensor based glucose monitoring system.

Exclusioncriteria Bolinder 2016

currently diagnosed with hypoglycemia unawareness;

diabetes ketoacidosis or myocardial infraction in the preceding 6 months;

known allergy to medical grade adhesives,

used continuous glucose monitoring within the preceding 4 months,

currently using sensor augmented pump therapy,

pregnant or were planning pregnancy, or receiving oral steroid therapy for any

disorder

Haak 2017

if they had any other insulin regime to that described in inclusion;

ketoacidosis or hypersmolar-hypoglycemia state in the preciding 6 months,

if the had a total insulin >1.75 units/kg on study entry;

known allergy to medical grade adhesives

had severe hypoblycemia (requirieng third party assistance),

were pregnant or planning pregnancy, used continuous glucose monitoring

within the previous 4 months, were receiving steroid therapy for any

condition considered by the investigator

unsuitable to participate

105

Appendix 6. Results from Meta-Analysis

Outcome Type 1 DM MD[95%CI]1

Type 2 DM MD[95%CI]1

Overall MD[95%CI]1

Health Related Quality of life2 -0.10 [-0.25, 0.05] 0.00 [-0.16, 0.16] -0.05 [-0.16, 0.05]

Treatment Satisfaction3 6.20 [4.54, 7.86] 4.00 [2.32, 5.68] 5.10 [2.95, 7.26]

Pain n/a n/a

HbA1c -0.01 [-0.18, 0.16] 0.03 [-0.26, 0.32] -0.00 [-0.14, 0.14]

Glycemic Measures

Time in Range 3.9-10mmol/L3 1.20 [0.46, 1.94] 0.40 [-0.93, 1.73] 1.00 [0.32, 1.68]

<3.9mmol/L within 24 hours2 -1.24 [-1.82, -0.66] -0.40 [-0.72, -0.08] -0.60 [-0.88, -0.32]

<3.9mmol/L within 24 hours-events2 -0.37 [-0.58, -0.16] -0.15 [-0.30, 0.00] -0.23 [-0.35, -0.10]

<3.1mmol/L at night within 7 hours2 -0.35 [-0.51, -0.19] -0.10 [-0.20, -0.00] -0.22 [-0.46, 0.03]

<3.1mmol/L night within 7hr/events2 -0.11 [-0.18, -0.04] -0.07 [-0.12, -0.02] -0.09 [-0.13, -0.04]

<3.1mmol/L within 24 hours2 -0.85 [-1.24, -0.46] -0.18 [-0.35, -0.01] -0.49 [-1.15, 0.16]

<3.1mmol/L within 24 hours/events2 -0.36 [-0.53, -0.19] -0.10 [-0.19, -0.01] -0.22 [-0.47, 0.03]

>10mmol/L – time2 n/a 0.00 [-1.44, 1.44]

>13mmol/L – time2 -0.39 [-0.77, -0.01] -0.40 [-1.52, 0.72] -0.39 [-0.75, -0.03]

Moderate to severe adverse events 0.50 [0.09, 2.68]4 1.51 [0.16, 14.27]4 0.74 [0.19, 2.85]4 1MD: mean difference; [95% CI: confidence interval]; 2 lower scores are best, 3 higher scores are best; 4RR: risk ration; n/a: not assessed.

Norwegian Institute of Public Health August 2017P.O. Box 4404 NydalenNO-0403 OsloPhone: +47 21 07 70 00

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