Cost effectiveness in practice and its effect on clinical outcomes

ContentslistsavailableatScienceDirect

Journal

of

Cancer

Policy

j o u r n a l ho me p a g e :w ww . e l s e v i e r . c o m / l o c a t e / j c p o

Cost

effectiveness

in

practice

and

its

effect

on

clinical

outcomes

夽

Bengt

Jönsson

_,

_Scott

_Ramsey

_,

_Nils

_Wilking

b_{FredHutchinsonCancerResearchCenter,1100FairviewAvenueNorth,M3-B232,Seattle,WA98109-1024,UnitedStates} c_{KarolinskaInstitutet,Stockholm,Sweden}

d_{SkåneOncologyClinic,Lund,Malmö,Sweden}

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c

l

e

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f

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Availableonline26February2014 Keywords: Cost-effectiveness Reimbursement Access Outcome

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Thevalueofnewcancerdrugsismaximizedwhentheyareusedfortherightpatientintherightway inclinicalpractice.Clinicaltrialsconductedduringdrugdevelopmentarethemostimportantsource ofinformationtopredictvalueatthetimeadrugisintroducedinpractice.Regulatoryapprovalis anindicationofvalue,whichlatelyhasbeencomplementedwithanassessmentofclinicalvaluefor decisionsaboutreimbursement,usingthemethodologyofhealthtechnologyassessment(HTA).Formal cost-effectivenessstudiesareanimportantpartofthismethodology,aimingtoassistdecisionsabout valueformoneyinhealthcarespending.ThequestionisiftheadditionofacomplementaryHTAand cost-effectivenessstudyincreasesthevaluerealizedbythedruginpracticecomparedtohowitwould beusedwithouttheseassessments.

Wereviewtheissuesinvolvedinprovidingananswerbyusingtheintroductionofnewtargeted therapiesformetastaticrenalcellcancer(mRCC).Specifically,weexaminethelinkbetweenclinicaltrial dataandestimationsofcost-effectivenessatdruglaunch,reimbursementdecisions,uptakeandusein differentcountriesandevidenceaboutimpactonoutcomeinpatientpopulationsforwhichthenew drugsareindicated.

Weconcludethatthereisaweaklinkbetweentheassessmentsusedatdruglaunchandthevalue createdinclinicalpractice.Wesuggestmeasuresthatarenecessaryfortheachievementof evidence-basedandcost-effectivecancercareinclinicalpractice.

©2014TheAuthors.PublishedbyElsevierLtd.

Introduction

Costeffectiveness studiesareincreasinglyused fordecisions aboutreimbursementandappropriateuseofnewcancerdrugs. Thesestudiesthusaffectaccessforpatientsandcliniciansto treat-mentsthatmaybeofpotentialvalue,anddirecttheefficientand equitableuseofhealthcareresourcesforcancer.

Whilethegeneralmethodologyofsuchstudiesiswell devel-oped,andappliedinasimilarfashionindifferentjurisdictions,the interpretationanduseofthefindingsdiffer.Thisisnotsurprising, sincetherelativevalueofa newmedicine,reflected in willing-nessaswellasabilitytopayfornewtreatmentoptions,willdiffer betweencountries. Thisresultsin greatvariationsintheuseof newcancerdrugs,andmoststrikingistheimpactofthepercapita incomelevelontheuptakeofnewtherapies[1].

夽 ThispaperispartoftheSpecialIssue‘DeliveringAffordableCancerCareinHigh IncomeCountries:PapersfromaSpecialSessionofOncologyAtTheLimits,13th– 15thFebruary2014’.

∗ Correspondingauthor.Tel.:+46723985678. E-mailaddress:[email protected](B.Jönsson).

However,thevariationsinuseofnewcancertreatmentscannot beexplainedsolelybydifferencesinincomelevelsandhealthcare spending.Thereissubstantialvariabilityintheuseofnewcancer drugsbetweencountrieswithsimilarincomepercapita.These dif-ferencescantosomeextentbeexplainedbydifferencesincoverage decisions[2].

But decisions about coverage do not directly translate into uptakeanduseofnewcancerdrugs.Nationalinstituteforhealth andcareexcellence(NICE)intheUKhasmade151individual rec-ommendationsoncancerdrugsofwhich57%havebeenpositive[3]. Still,theactualuseofcancerdrugsinUKwithNICEendorsements isratherlow,suggestingadisconnectbetweenrecommendations andactualuse[4].Thedisconnectbetweencoveragedecisionsis alsopresentinSweden,wheredecisionsbyTLV,TheDentaland PharmaceuticalBenefitsAgency,isnotdirectlylinkedtospending indifferentcountycouncils,resultingingreatregionalvariations inuseofnewcancerdrugs[5].

Thispaperwillreviewthelinkbetweenclinicaltrialdata,the cost-effectivenessstudiesfornewcancerdrugs,coveragedecisions informedbysuchstudies,uptakeanduseofthedrugs,and evi-denceofimpactonoutcomeintherelevantpatientpopulation.The http://dx.doi.org/10.1016/j.jcpo.2014.02.001

2213-5383 ©2014TheAuthors.PublishedbyElsevierLtd.

Open access under CC BY-NC-ND license.

Fig.1.Frameworkfortheanalysis.

inclusionofimpactonoutcomeintheanalysisreflectstheshiftin focusfromefficacytorelativeeffectivenessinassessingthevalue ofnewmedicines[6].Valueforpatientsiscreatedwhenanticancer drugsarechosenthatprovidemaximumdifferenceinthechance ofbenefitandharm,theoverallobjectiveforpersonalizedcancer medicine[7].TheframeworkfortheanalysisisillustratedinFig.1. Datafromclinicaltrialsisthekeysourceforestimationof effec-tiveness in cost-effectiveness studies. Such studiesare usedto informdecisionsaboutreimbursement,whichaimatguidingthe useofthedruginclinicalpractice.Theuseinclinicalpracticewill determineoutcomeandthusthevalueofthedrug.Useinclinical practicemayrevealevidencegapsthatneednewclinicaltrialsto beanswered.

Wewillusedatafromtheintroductionofnewertargeteddrugs totreat mRCC toillustratethe methodological issues and data needsforassessingcost-effectivenessandimpactonuseand out-come. The paperwill conclude witha discussion of thepolicy implicationsofthegreateremphasisonrelativeeffectivenessand cost-effectivenessinclinicalpracticeasakeygoalforhealthpolicy.

Renalcellcarcinomaandnewtargetedtherapies

Kidneycanceraccountsforabout2–3percentofallcancers,and theannualglobalincidenceisabout340,000cases.Theincidenceis highestintheUSandEurope,andlowinAfricaandAsia.Renalcell carcinomaaccountsforabout80%ofallkidneycancers.For local-izeddisease,whichcanbetreatedwithsurgery,theprognosisis good.Foradvancedormetastaticdiseasethe5yearsurvivalrate isonlyabout10%,andtheannualnumberofdeathsinkidney can-ceris143,000,ofwhich53,000isinEuropeand28,000intheUS. Incidenceandmortalityistwiceashighinmenasinwomen,and varieswithafactorthreebetweencountriesinEurope[8].

AnumberoftargetedtherapiesformRCChavebeenintroduced since2005(Table1).

Mostofthenewtreatmentstargettyrosinekinasepathwaysand blockangiogenesis,theformationofnewbloodvessels,necessary fortumourgrowth.Thearrivalofsorafinibandsunitinibin2005–6 followedbyothertargeteddrugsrepresentsamajorstepforward comparedtothepreviousstandardtreatmentofinterferon-alpha andinterleukin-2.ForpatientswithagoodKarnofskyperformance statusandintactorganfunction,high-doseinterleukin-2hasoften beenusedin firstlinebecauseitcaninducedurablelong-term remissionsinapproximately10percentofpatients.Thenewdrugs offeredbenefitsintermsofbothoraladministrationandimproved outcome,butalsopotentiallyincreasedcosts.Thecostoftreatment withthenewtargetedtherapiesareintherangeofUKP3–6000per

6weeks,morethanmostpatientscanaffordtopay.Decisionsabout theiruseinclinicalpracticewouldthusbenefitfrominformation aboutcost-effectiveness[11].

Pazopanibwasapproved2009intheUS,andgotconditional approvalbyEMAin2011forfirstlinetreatment.Inarecentdirect comparison,pazopanibwasshowntobenon-inferiortosunitinib [12].Axitinibisthelatestapprovalin2012forRCC,afterfailureof priorsystemictherapywithacytokineorsunitinib.

TheclinicaltrialsandthedecisionsbyFDAandEMAonmarket authorizationindicatesurvivalbenefitsfromtheuseofthenew, targetedtherapies.Butsincetheprimaryclinicalend-pointinmost ofthetrialshasbeenprogressionfreesurvival(PFS),andpatients whofailonthecomparatormedicine(orplacebo)crossovertothe evaluateddrug,directestimatesofthemagnitudeoftheoverall survival(OS)benefitoftheseagentsarelacking.

Cost-effectivenessstudiesofnewtherapiesformRCC

Thenew,targetedtherapiesinmRCCarealsointerestingfrom aneconomicperspectiveduetothechallengesofferedfromtheir pricing. The costs of therapy range from 5 to 10,000 USD per month,and100,000USDormoreoverlifetime,havebeena chal-lengefor reimbursementagenciesmakingrecommendationson coverage basedon valuefor money, supportedby estimatesof cost-effectiveness.Thischallengehasamethodologicalaspect,the estimationofcost-effectiveness,andanethicalaspect,the trade-offbetweenequityand efficiencyinmakingdecisionsbasedon value.

Assessmentofcost-effectivenessaimsatproducingestimates of thelikely costs and improvement in health from theuseof thedrugsfor definedpopulationsinclinicalpractice,compared tothe present standard of care.Results fromclinical trialscan beusedformodellingthelikely consequences,butsuch predic-tionswillincorporatealltheuncertaintiesintheclinicaldataas well as uncertainty due to assumptions made in extrapolating thesedata.Additionalissuesinvolvedinmodellingarethe defi-nitionoftherelevantpatientpopulationandtherelevantstandard of carefor comparison, taking intoaccount thatthe drugs will beused differently inclinical practicethan inthe clinicaltrial. Aneconomic evaluationalsodemands a translationof thegain in median PFSto gain inmean OS, adjusted for quality oflife, in order toprovidean estimateof thegain in quality-adjusted life years (QALY).The extrapolationfrom medianto mean sur-vival requires estimatingthe entire survival curve, rather than only theportionabove 50%.The tailof thecurve oftencannot beobserveddirectly,andsinceitcontainsobservationswithlong survivalandthusalargeimpactonthemean,estimatesofmean survivaltendtobeuncertain.Theadjustmentforqualityoflifehas twoeffects. Itincorporatesgainsinqualityof lifefrom increas-ingthetimetoprogression,butalsoreducesthevalueofgainsin survivalthatarespentinstateswithlessthanfullqualityoflife (Fig.2).

Economicevaluationsdrawupondatafromavarietyofsources: clinical,epidemiologic,andeconomic,andtheuncertaintyaround theestimatesofcost-effectivenessareoftenlarge. Itisthusnot surprising that there are controversies around both data and methodologyforsuchstudies.Sincedecisionshavetobemade,the issueisnotaboutthelevelofuncertaintyoftheresult,butrather ifdecisionscanbeimprovedwith,ratherthanwithout,economic evaluations.

Areviewofthecost-effectivenessstudiesofsunitinibcan illus-tratethechallengesofundertakingcost-effectivenessstudies,and theconclusionsthathavebeenmade[13].Thereviewedstudies werepublishedduring2007–2011,includingfivefulltextarticles, 24researchabstractsandoneHTAreport.

Table1

NewtargeteddrugsformRCC.

Drug FDAapproval EMAapproval ImprovementinPSFa _Comments

Sorafinib 2005 2006 PFScomparedwithIFNa(5.7versus5.6months)

whenusedfirst-lineb_{Secondlineafterfailureof}

IFNamedianPFS(5.5versus.2.8months)

LivercancerOrphandrug

Sunitinib 2006 2006 PFSversusINF(11versus5months) AlsoGIST

Temsirolimus 2007 2007 PFSversusINF(3.8versus1.9months) Ivadm.AndlymphomaOrphandrug

Bevacizumab 2009(RCC) 2009(RCC) PFSversusINF(10.2versus5.4months) Ivadm.Severalotherindications

Pazopanib 2009 2009 PFSversusINF(9.2versus4.2months)

Everolimus 2009 2009 PFS(4.9versus1.9months) Alsobreastandpancreascancersecondline

Axitinib 2012 2012 PFSversussorafinib(6.7versus4.7months) SecondlineonlyinmRCC.InEUonlypost

sunitinib/orinterleukin a_[9].

b _[10].

NearlyallstudiesusedaMarkovmodelthatsimulateddisease progressionanddeterminedsurvivalandcostsforahypothetical cohortofmRCCpatients.Thecost-effectivenessmodelsincluded three or four mutually exclusive health states, among which patientstransition,during themodelledtimehorizon:firstline untilprogression,secondlinetreatment,bestsupportivecare(BSC) anddeath(duetocancerorothercauses).

Outof the20 congress abstractsconcerningfirst-line mRCC treatment,16werebasedonasamemodelorsimilarmodel struc-turepresentedinmoredetailinthefullarticles[14–16].

Allthearticles(n=5)wereeithersponsoredbypharmaceutical industryoratleastoneoftheauthorswasanemployeeofa phar-maceuticalcompany;thiswasalsothecaseinnearlyallabstracts (21outof24).

Incremental cost-effectiveness ratios for first-line sunitinib rangedfrom_D4786to109,416/QALYand_D33,807to 100,212/life-yeargained(LYG)whencomparedwithIFN-alpha.Animportant driverofcost-effectivenesswastheassumptionaboutwhichdrug wasusedinsecondlinetreatment.

Doesthereviewprovidepracticalguidancefordecisionsbased oncost-effectiveness?Theanswertothisquestionmustbe“no”. Because of uncertainty in the clinical data, the key questions abouthowsunitinibeffectscostsandoutcomeintermsof (qual-ityadjusted)lifeyearsgainedisnotansweredinanunequivocal way.Theconclusion,thatinmostofthereviewedstudiessunitinib givesareasonablecostperQALYisnotveryhelpful.Analternative conclusioncouldbethatthecost-effectivenessstudiesofsunitinib donotprovideclearguidancetohelpguideuse.Thuswecannot expectthatthosestudieshaveasignificantimpactonuptakeand use.GivenlackofdirectdataestimatingOSandqualityoflife,at

Fig.2.Presentstandardofcaregives6monthuntilprogressionand14mothsfrom progressiontodeath.Qualityoflifeis0.78untilprogressionand0.70after progres-sion.ThetotalQALYis0.78*6/12+0.70*14/12=0.39+0.83=1.22QALY.OSis20 months.Newtherapyextendthetimetoprogressionuntil18months,followedby 8monthinprogressionuntildeath.OSisincreasedto26months(0.5LYG).When thesurvivalgainisadjustedforQoLthegainis0.35.TothisshouldbeaddedtheQoL improvementfromalongertimebeforeprogression,12monthsatadifferenceof 0.08,gives0.08QALY.Totalgainis0.43QALY.ThetotalQALYwiththenewtreatment is18*0.78/12+8*0.70/12=1.17+0.47=1.64QALY.

thepriceasked,thecost-effectivenessisatbestquestionable,and thusconsistentwithbothpositiveandnegativedecisions.

Several economic studies were developed by/for the phar-maceuticalindustrybasedonthesamecost-effectivenessmodel forseveraljurisdictions.Often,theadaptationtodifferent coun-triessimplyredefinedtheresourceuseandunitcostinformation. Becausetheunderlyingstructureisthesameinallcases,andthe dataonfactorsmostinfluencingtheoutcome—thebenefitof suni-tinibonOSandQoL—islacking,thelargenumberofstudiesdoes notnecessarilyincreasethepowerofevidence.

Informationontheuseofhealthcareresourcesmaybeobtained withdifferentmethodsandfromvarioussources(e.g.,expert opin-ion,registers,localpatientsandliterature).Theestimatescanoften beveryimportantfortheresultofeconomicevaluations.For exam-ple,inanarticlebyRemáketal.,thecostofbestsupportivecare (BSC)wasoneofthemostsensitiveparametersintheanalysisand a20%reductioninitscostdoubledtheincrementalcostsperQALY gained[16].Lackofadequateinformationonresourceuseandcosts, limitedclinicalevidenceandshortfollow-uptimespresentmajor challengesforperformingtimelyeconomic evaluationsof novel cancertreatments.

Inessence,thereonlyexisttwostudiesofthecost-effectiveness ofsunitinib,thecompanystudyPenTAGandtheHTAstudyused fortheNICEtechnologyappraisal[11].EstimatesfromthePenTAG model suggestedthat noneof theinterventionswould be con-sideredcost-effectiveatawillingness-to-paythresholdof30,000 poundsperquality-adjustedlife-year(QALY).Estimatesofcostper QALYrangedfrom71,462poundsforsunitinibto171,301pounds forbevacizumabplusIFN.Althoughtherearemanysimilaritiesin themethodologyandstructuralassumptionsemployedbyPenTAG andthemanufacturersoftheinterventions,inallcasesthe cost-effectivenessestimatesfromthePenTAGmodelwerehigherthan thosepresentedinthemanufacturers’submissions.

CoveragedecisionsfornewtherapiesformRCC

Despitethemanyproblemsinvolvedinprovidingrelevant esti-matesofthecost-effectivenessofthenew,targetedtherapiesin mRCC,suchstudiesareusedasabasisfordecisionsaboutvaluefor moneyincoveragedecisions.Sincethereinmostcasesareno pub-lishedeconomicstudiestorelyonwhentheproductcomestothe market,decisionsarebasedonstudiesundertakenbythecompany orbythereimbursementagencyitself.

NICEhas well-developedmethods and processes for under-takingeconomicevaluationfordecisionsaboutuseofadrugby NHS(theNationalHealthService)inEnglandandWales.Sunitinib wasrecommended in 2009 as a first-linetreatment option for peoplewithadvancedand/ormetastaticrenalcellcarcinomawho aresuitableforimmunotherapyandhaveanEasternCooperative OncologyGroup(ECOG) performance statusof 0or 1 [17].The

recommendationincludestheconditionthat thecompany pro-videsthedrugforthefirstcyclefreeofcharge.Thisprovidedtwo benefitsinthelightoftheuncertaintyaboutcost-effectiveness:it isahedgeagainstthepossibilitythatthetruecost-effectiveness of sunitinibis less favourablethan estimatedand it providesa low-costmechanismtogetbetterinformationduringtheinitial phaseoftreatmentregardingwhowouldrespondandwhowould not respond (presumably those who don’t respondin the first monthwillnotreceivefurtherdoses).

Inadditiontoitsguidanceonsunitinibstatedabove,another NICEguidance in 2009recommended against the useof beva-cizumab,sorafenibandtemsirolimusasfirst-linetreatmentoptions forpeoplewithadvancedand/ormetastaticrenalcellcarcinoma [18]. Sorafenib and sunitinib are not recommended as second-linetreatmentoptionsforpeoplewithadvancedand/ormetastatic renalcellcarcinoma.

Pazopanibwasrecommended byNICEin2011asa first-line treatmentoptionforpeoplewithadvancedrenalcellcarcinoma whohavenotreceivedpriorcytokinetherapyandhaveanEastern CooperativeOncologyGroup(ECOG)performancestatusof0or1

andifthemanufacturerprovidespazopanibwitha12.5%discount onthelistprice,andprovidesapossiblefuturerebatelinkedto theoutcomeofthehead-to-headCOMPARZtrial(Pazopanibversus SunitinibinMetastaticRenal-CellCarcinoma),asagreedunderthe termsofthepatientaccessschemeandtobeconfirmedwhenthe COMPARZtrialdataaremadeavailable[19].

Since2003,mostCanadianprovinceshaveparticipatedinthe CommonDrugReview(CDR),whichassessestheclinicaland cost-effectivenessof oralagents accordingtostandardized methods. Since 2009, most provinceshave also participated in theJoint OncologyDrug Review (iJODR), since 2011 replaced by pCODR (www.pCODR.ca).TheassessmentofsorafinibbyCanadianExpert DrugAdvisoryCommittee(CEDAC)oftheCDR,illustratestheuse ofeconomicevaluationwhenthefirsttargetdrugformRCCcame tothemarket[20].

ThesubmissioninCanadaforsorafinibfromthedrug’s manu-facturerusedaMarkovmodel,withkeyparameterestimatesbased ontheTARGETtrial(TreatmentApproachesinRenalCancerGlobal EvaluationTrial),whichstudiedsorafinibsecondlineafterfailure ofINFalpha.Thismodelestimatetransitionprobabilitiesbasedon thedataobservedinthetrialfromPFStoprogressivediseaseor deathupuntilthepointofcross-over.Themodelestimateda dif-ferenceinoverallsurvival(overalifetime)of1.21yearsandan incrementalcostperlife-yeargainedof$36,046.Initsassessment oftheevidence,theCDR concludedthat,giventheearly termi-nationofthetrial,theoverallsurvivaladvantage,andhencethe truecost-effectivenessofsorafenib,wereuncertain.Ratherthan accepting the manufacturer’sprojections, it conducted its own analysis,whichassumedthatoncepatientsenteredthe progres-sivedisease state, beingtreated with sorafenib had no further impactonsurvival.TheCDRanalysisgeneratedanestimateof over-allsurvivalgainof4.5months,whichwasclosertothatactually observedin thetrialatthetime ofthemostrecent analysisof outcome.Usingthisrevisedestimateofsurvivalgain,the incre-mentalcost-effectivenessratioroseto$78,227,morethantwice themanufacturer’sestimate.Consequently,CEDACrecommended thatsorafenibnotbelisted.

In2012pCODRrecommendedaxitinibforusesecondlinefor patientsthatcouldnottolerateeverolimus.Sorafinibwasnolonger consideredarelevantalternativeduetolackofdataon effective-nessaftersunitinib.In2013pazopanibwasrecommendedforfirst lineusebasedonacomparisonwithsunitinib;similareffectiveness andlowerprice[21].

InSwedenTLVisassessingprescriptiondrugsforinclusionin the reimbursementscheme. Both sorafenib and sunitinib were acceptedfor reimbursement onthe clinicaland economic data

providedbythecompany.Inthedecisionaboutsunitinib,some membersoftheBoarddidnotagree,andaskedformore informa-tionaboutcost-effectiveness[22,23].ForeverolimusTLVaccepted reimbursement for second line treatment of mRCC [24]. TLV acceptedtheeconomicmodel providedbythecompany,which estimated a cost per QALY of 285,000 SEK (30,000 Euro) for everolimuscomparedwithsorafinib.Thisindirectcomparisonwas acceptedsincesorafinibwasthemostusedtherapyforthisgroup ofpatients,despitenoevidenceofitseffectivenessafterfailureof sunitinib.

In the US, cost-effectiveness analyses are not usedto make yes/nofundingdecisionsregardingparticularcancerdrugsasthey are in Europeand Canada.In fact, laws enacted nationally for Medicareenrolees(adultsages65andgreater)andinmoststates (affectingcommercialinsuranceplans)mandatecoverageof can-cer drugs listedas safeand effectiveaccording to at leastone nationally-recognizedcompendiaorclinicalpracticeguideline(for example,theNationalComprehensiveCancerNetwork).Whatcan vary,however,istheco-payamountthatisleviedonspecificdrugs. Theprocessfordeterminingco-payscanvarywidelyfrominsurer toinsurer.AtoneextremeisPremeraBlueCross,aregionalinsurer inthePacificNorthwestthatsetsco-paysforneworalcancerdrug basedontheestimatedcost-effectivenessofthetherapyrelativeto thebestavailablealternative.Intermediateare“valuebased formu-laries”thatusesomecombinationofclinicalandeconomicefficacy todetermineco-paylevels.Attheother,perhapsmorecommon, extremeareplansthatbaseco-payson(branded)drugpricealone. Thus,intheUSallFDA-approveddrugsaregenerallyavailable,and therearefewbarrierstoprescribingthem.Theveryhighcostof thesenewtargetedagents,however,meansthathighco-payments caneffectivelyexcludeaccesstothedrugfromlargesegmentsof thepopulation.Totheextentthatevenmodestco-payscanleadto substantialout-of-pocketcosts,severalstudiesnowsuggestthat financialdistressandbankruptcyareincreasinglycommon prob-lemsforcancerpatientsandtheirfamilies[25–27].

UptakeanduseofnewdrugsformRCC

Thefiguresbelowpresenttheuseofsorafenib,sunitiniband temsirolimusin selectedcountries2005–2009.Pleasenotethat sorafinibisalsoapprovedforprimarylivercellcancer(Fig.3).

ThemoststrikingresultistheverylowuptakeanduseintheUK andtheUS.Francehasthehighestuse,whileGermany,Italyand SpainareallratherclosetoawesternEUaverage.ForSwitzerland weseearapiduptake,andthenadecline,whichmaybe depen-dentonsubstitutionwithsunitiniborotherdrugs.Thelowuseof sorafenibintheUSmayberelatedtothefactthatsunitinibwas availablefirst,andthatphaseIIstudydataforsorafenibatlaunch didnotshowanincreaseinPFSwithsorafenibcomparedwithIFNa (5.7versus5.6months) whenusedfirst-line,makingitsrolein therapyofuntreatedpatientsunclear[10](Fig.4).

ForsunitinibweseethesamefastandhighuptakeinFrance,and thatGermanyhereisclosetoFrance.UseinSwitzerlandrelatively lowerthanforsorafenib.UKisinthelowerend,butthedifference toothercountriesissmall.ForUSweseearapiduptake,andthen aplateaufrom2007onwards.

Francestandsoutintermsofamorerapiduptakeandhigher use.WiththeexceptionofUSandItaly,theuseisverymarginal untilQ22009(Fig.5).

ThelowuseinUKissupportedbydatainthereportbyMike Richards[28].AccordingtotableA6 inthereporttheUKusage was19and54percentoftheaverageuseinthe5bigEuropean countriesforsorafinibandsunitinibrespectivlyfortheperiodApril 2008toMarch2009.FortemsirolimustheUKuseagewas17%.Fig.6

Fig.3.Useofsorafinibinmgper100,000population.

Fig.5.Useoftemsirolimusinmgper100,000population. 0 100 000 200 000 300 000 400 000 500 000 600 000 700 000 800 000 2006 2007 2008 2009 2010 2011 Everolimus Pazopanib Sorafenib Sunitinib Temsirolimus Health care region Sweden

SEK per Population (100 000)

Year

Molecule

SLL02_131107_Sales1998-2013p7_L01_L02AB_L04TalidOchLenali

0 500 1 000 1 500 2 000 2 500 3 000 3 500 4 000 2011 2011 2011 2011 2011 2011 2011 Northern health care region

South East health care region

Southern health care region

Stockholm-Gotland Sweden

Uppsala-Örebroregion Western health care region Temsirolimus Sunitinib Sorafenib Pazopanib Everolimus ATC-code4(Alla)

SEK per incident case of cancer 2010

Health care regionYear

Molecule

SLL02_130109_Sales1998-2012_L01_L02AB_L04TalidOchLenali

Fig.7.UseofdrugsformRCCinthesixhealthcareregionsofSweden2011.

showstheuseoffivetargeteddrugsusedfortreatmentofmRCCin Sweden.

Fig.7showsthevariationswithinSweden,indicatingsignificant variations,bothintheuseoftheindividualdrugsandtheuseofall drugscombined.Moredetaileddataonuseinfirstlineversus sec-ondline,andaboutpatientcharacteristicsarenecessaryinorderto understandthemagnitudeofpotentialunder-and overconsump-tionindifferentregions/patientpopulations.

PopulationevidenceofimpactofTKIsofoutcome

Wehaveidentified fivestudiesthat examinedtheeffectson survivalfromtheuseoftargetedtherapiesinadvancedRCCpatients outsideoftrialsettings.

Shahetal.analyzedtheSurveillance,Epidemiology,andEnd Results (SEER) 18 registry database to compare 1- and 3-year relative survival rates among advanced RCC patients during 2001–2009,2001–2004,and2006–2009,the1-yearrelative sur-vivalrateswere27.0±0.8%and27.1±0.9%,(pvalue=1.3)and,the 3-yearsurvival were10.1±0.6% and9.6±0.8%,(pvalue=1.42), during2001–2004and 2006–2009,respectively.Thus, this pop-ulation based study suggested that there was no significant improvementinrelativesurvival ratesamongmRCCpatientsin theeraoftargetedagents[29].

In another study from the US, Shek et al. analyzed data from28,252patientswithRCCintheCaliforniaCancerRegistry (CCR),apopulation-basedcancersurveillancesystem,diagnosed between 1998 and 2007 [30]. Inter-era differences in clinical variables—including yearof diagnosis,histologiccharacteristics, age,sex, race, stage,nephrectomy status, overall survival (OS), and cause-specific survival (CSS)—were assessed, and analyzed withunivariate and multivariateCox models.Crude 3-year OS (68.2% vs. 74.6%; 2P.001) and CSS (78.1% vs. 82.3%; 2P.001) were significantly higher in the post-cytokine era. The three strongestpredictorsforimprovedsurvivalwerelocalizeddisease, nephrectomyandhistologictype. Insufficientfollow-up time in

thepost-cytokine era and a higherproportion of localized dis-easeinthateraconfoundthepossibilityofbenefitderivedfrom targetedtherapies. Longer follow-upfor patientstreated inthe post-cytokineerais necessaryfora morerobustcomparison of long-termOS.

InathirdUSoverallsurvival(OS)analysis,theanalyticcohort includedallpatientsintheregistrydiagnosedbetweenJanuary1, 2007,toMay31,2011[31].Patientsweregroupedbyuptothree treatmentexposuresaccordingtoeachdrug’smechanismofaction: vascularendothelialgrowthfactortyrosinekinaseinhibitor(VEGFR TKI),mammaliantargetofrapamicininhibitor(mTOR),orno sys-temictreatment(NSTx,whichcouldincluderadiationorsurgery). OSbyexposuresequencewasevaluatedusingKaplan–Meier, pair-wise comparison, and Cox regression analyses.Median OS was 17.2months.OS (months)foroneexposurewas:mTOR5.4,TKI 18.2, NSTx 18.4; for two exposures: mTOR/TKI 9.3, TKI/mTOR 13.9,TKI/TKI35.2;andfor threeexposures:TKI/mTOR/TKI 20.9, TKI/TKI/mTOR33.1.InCoxregressionanalysis,comparedwiththe referent(TKI),TKI/TKI(hazardratio0.53)hadalowerriskofdeath, andmTOR(hazardratio2.16)hadahigherriskofdeath.Thestudy concludesthatmRCCsurvivaloutcomesaredifferentbypattern, withgeneralfindingsconsistentwithtrial-basedexpectationsin similarpatientpopulations.Real-worlddatacanprovidecontext aroundpatternsofcareandimpactwhenexperimentaltrialdata arelacking.

Swedishresearchersconductedaretrospectiveregisterstudy assessed overall survival (OS) and influential factors on OS in Swedish renal cell carcinoma (RCC) patients. They used three mergednationalhealthregisterstoassesstheimpactofcytokine (interferon-␣ and tyrosine kinase inhibitor (TKI; sunitinib or sorafenib) treatmenton OS in metastatic mRCC. From 2000to 2008,8009patientswerediagnosedwithRCCand2753withmRCC (2002–2008).MedianOSinRCCpatientsdiagnosedfrom2006to 2008comparedwith2000–2005wasnotreachedvs.47.9months (p<0.001), andin mRCCpatientsdiagnosedfrom 2006to2008 comparedwith2002–2005,was12.4vs.9.6monthsrespectively

(p=0.004). FactorsassociatedwithsignificantlyimprovedOS in RCCwerefemalegender,lowerage,andpreviousnephrectomy, and,inmRCCfemalegender,previousnephrectomy,andanyTKI prescription (Model 1: median-adjusted OS, 19.4 months (TKI patients)vs.9.7months(non-TKIpatients);hazardratio,0.621; p<0.001).Theresultssuggestthat increasednephrectomyrates andtheuseofTKIscontributedtotheimprovementseeninmRCC patients.However,itshouldbenotedthatonly12%ofthepatients receivedaTKIinfirstlinetreatment[32].

Soerensenetal.includedallDanishpatientswithmRCCstarting firstlinetreatmentwithimmunotherapy,TKIsormTOR-inhibitors, between2006and2010inanoutcomestudy.Baselineandoutcome datawerecollectedretro-spectively.Between2006and2010,a totalof1073patientswerereferred.Ofthese,759patientsreceived firstlinetreatmentand314receivednosystemictreatment.The proportionoftreatedpatientsincreasedfrom64%in2006to75% in2010(p=0.02).In2006,22%receivedtargetedtherapyandthis increasedto75%in2010(p<0.00001). In2006,21%offirstline patientsreceivedsecondlinetreatmentcomparedto41%in2010 (p=0.01).From2006to2010,weobservedanimprovedmedian OSfrom11.5to15.7months(p=0.03.Theuntreatedpopulationof 314patientshadamedianOSof3.1monthsfromdateofmetastatic diseasewithnosignificantchangefrom2006to2010[33].

Discussion

This paper reviews the link between clinical trial data, the cost-effectivenessstudiesfornewcancerdrugs,coveragedecisions informedbysuchstudies,uptakeanduseofthedrugs,andevidence ofimpactonoutcomeintherelevantpatientpopulation.

Thereviewofeconomicandclinicalevaluationsfornew tar-getedtherapiesformRCCrevealsthattherearegreatuncertainties intheestimatesofcost-effectiveness,resultinginuncertain rele-vanceofthesestudiesfordecisionmakingfollowinglaunch.This uncertaintyispartlyrelatedtothemethodologicalchallenges mak-ingextrapolationfromclinicaltrialdatatoclinicalpractice,since allmodels usedfor estimating cost-effectiveness haveto make assumptionstopredictlongtermcostsandoutcome.

Thechoiceofextrapolationmethodologycanhaveanimportant impactoncomparativeefficacy,costs,andcost-effectiveness.This wasshownbyEkmanetal.intheillustrativeexampleusingdata fromapivotalphaseIIItrialofsunitinibvs.IFN-aasfirst-linemRCC intheUS.Costeffectivenessresultscouldvaryquitesubstantially dependingonassumptionsmade.Ashorttimehorizon(oneyear) resultedinanICERof$120,304comparedtoanICERof$52,571 forthelifetimehorizonassumption.Dependingonchoiceof sur-vivaldistribution,ICERsvariedbetween$50,000and150,000the pessimistic(stopanddrop)scenarioandtheoptimistic(continued benefit)assumptionresultedinlargedifferencesinICERs;$114,000 vs.$50,000,respectively[34].

Offeringpatientsinoncologytrialstheopportunitytocrossover toactivetreatmentatdiseaseprogressionisacommonlyused strat-egytoaddressethicalissuesassociatedwithuseofplacebocontrols, but maylead tostatistical challenges inthe analysisof overall survival(OS)andcost-effectivenessascross-overleadstolossof informationanddilutionofcomparativeclinicalefficacy.Thiswas illustratedbycomparingalternativemethodsforanalysingOSdata inthepresenceofcross-over;simplemethods(intent-to-treat anal-ysisand censoringdata at cross-over) and advanced statistical methods(theinverseprobabilityofcensoringweighting[IPCW] and therank-preservingstructuralfailure time [RPSFT]models, usingdatafromtwophaseIIIclinicaloncologytrialsofsunitinib. Thestudyshowsthatthemethodforcorrectionmaysignificantly affectthecost-effectivenessratio,whilethiswasnotthecasein NICEassessmentofsunitinibfor mRCC.Theretheselectionofa populationwithnosecondlinetreatmentwasmostimportantto

bringthecost-effectivenessratiobelowthe50,000GBPperQALY [35].

Statisticalmethodsmaytosomeextenthelptoovercomethe problem that clinical studies for market authorization are not designedtotakeintoaccounttherequirementforhealth technol-ogyassessment.Thisproblemmaybereducedwiththeincreasing useofHTAandparallelregulatory/HTAscientificadviceduringthe developmentprocess [36].Progressionfree survival (PSF)asan outcomemeasureisalsoincreasinglyquestioned,alsofroma reg-ulatorypointofview[37].However,PFSwillremainanimportant endpoint,whichcanbemoreusefulasaninputtoestimationsof cost-effectivenessifitalreadyatthestartofthestudyisworkout howthemeasureofPFSislinkedtoOSandqualityoflife,thetwo measuresusedforcalculationofthegaininQALY.Reducingtheuse ofcrossoverisanimportantfactorforimprovingthevalueofPFS asanoutcomemeasure[38].

Indirect comparisons play an important role in assessment ofcost-effectiveness.Theassessment ofrelativeeffectivenessof pazopanibbyEuronetHTAprovidednoevidenceondifferencesin effectivenessbetweenthedifferenttargetedtherapiesformRCC [39].Thisconclusionwassupportedbytheresultsofthedirect comparisonbetweenpazopanibandsunitinib[12].

Withthe exception of UKand Canada,there is noevidence thatcost-effectivenessestimateshasplayedakeyrolefor reim-bursementanduseofthenewtargetedtherapiesinmRCC.This conclusionissupportedfroma studycomparingthenumberof reimbursedindicationsindifferentcountriesforaselectionof can-cerdrugs[40].Mostindicationswerereimbursedinothercountries thanUK,Canada,AustraliaandNewZealand.

From one perspective, it is not surprising that formal cost-effectiveness estimate have a limited impact on decisions to reimburseornotreimburse,sincetheuncertaintysurroundingthe ICERsishigh.Ontheotherhand,decisionmakersmayusethedata andthemodelsinthesestudiestocallforrestrictionsinusewhile furtherdataaregatherede.g.,inthecontextofanobservational studyora pragmatictrial.Value ofinformation analysiscanbe usedtodeterminewhethertheinvestmentinfurtherstudywill yieldsufficientreductionsinuncertaintytowarrantthecostand delayinaccessentailedinanothertrial.Therearealsoexamples thatcost-effectivenessstudiesareusedasabasisformarketaccess agreementsincludingreductionsinthepriseofthedrugs.

Whileitispossibletonoticeanimpactofthecost-effectiveness ratioontheprobabilityofapositivereimbursementdecisions,itis seldompossibletoassesstherelativecontributioninanindividual decision.Onereasonforthisisthatevidenceonclinicalefficacy,the probablymostimportantfactorforreimbursement,iscorrelated toestimatesofeffectiveness,andthuscost-effectiveness.Itisalso easiertoseethatcost-effectivenesshasanimpactwhenthereisa choicebetweentwodrugswithsimilareffectiveness,suchasthe casewithsunitinibandpazopanibforfirstlinetreatmentofmRCC. Priceswillthenbethekeydeterminantofcost-effectiveness,and sincepricescaneasilybechanged,theimpactofcost-effectiveness shouldbeassessedbasedondataonuse,ratherthandecisionson reimbursement.

Worldwide, economic evaluations appear to have had little impactonthediffusionoftargetedtherapiesintopractice.Dataon internationalvariationsinuseindicatethatotherfactors,mainly fromthesupplyside,accountformostofthevariation.Themost importantdemandsidefactoristheeconomicpowerofthe coun-try,measuredasincomeorhealthcareexpenditurespercapita. Sincepricesofnewdrugsvarylessthanpercapitaincome,itmay beinterpretedaslinkedtothecost-effectiveness,aswellasthe affordability,ofnewdrugsincountrieswithlowpercapitaincome. Dataalsoindicatethathowthedrugsarepaidforinthehealthcare systemisimportant.ThehighuseinFrancecanbeexplainedby thepracticeofmakingpricevolumeagreements;incombination

withreimbursingthehospitalsforthecostofnewdrugsoutside theDRGbasedhospitalfunding.

Ourreviewofavailablestudiesofimpactonsurvivalforpatients withmRCCindicatesthattheremaybeaneffect,butthemagnitude isuncertain.Theproblemstodetectaneffectinepidemiological datasuggestthattheeffectissmall,andadefinitiveconclusion ishamperedbypatientselectionissuesthat cannotberesolved withavailabledata.Furtherstudiesareneededtogiveinformation onhowthenewtargetedtherapies shouldbeoptimallyusedin practice.Questionsaboutoptimaluseofthedrugsinparallelor sequencecanbeansweredwithinformationfromdatainclinical practice.

Conclusionsandpolicyrecommendations

Thevalueof newcancertherapies is basedontheiruse. To achieveanoptimalusethereareseveralstepsfromtheinitial eco-nomicevaluationsbasedonclinicaltrialdata,thereimbursement (coverage)decisionsbasedonthesedata,andtheimplementation ofthesedecisionsinclinicalpractice.

Considerableresourceshavebeendevotedtothestudyof cost-effectivenessofnewcancerdrugsasabasisfordecisionsabout paymentanduse.Thoseresourcescouldbemuchbetterusedif industryandHTAagencieswithhighcompetencecollaboratedatan earlystage.Thatwouldincreaseboththequalityandthe credibil-ityofstudies,andmakethemmoreusefultoguidedecisionsabout reimbursement.Themethodology forstudieshasbeendebated, and there are opportunities for improvement. Most important fromageneralmethodologicalpointofviewisthatallcostsare accountedforandthatthebenefitmeasureincorporatesall ele-mentsof social value. While there is a discussionif the QALY includesall relevant elementsof value, there is an acceptance fromallstakeholdersthatestimationsofcostperQALYare rele-vantfordecisionsaboutcoverage.Sinceimprovementsinsurvival forcancerpatient,itisimportantthatcostperLYGalsois calcu-latedandpresentedinparalleltothecostperQALY.Thereisalso aneedfor improvementsindatausedfor calculatingtheQALY gains.

Amajorproblemiswhentheclinicaltrialdatadonotprovide clearevidenceonoutcome,forexampleduetotheuseofsurrogate end-pointsandcrossoverdesigninthestudy.Statisticalmethods forextrapolationmaytosomeextendhelptoovercomethis prob-lem,butitisimportantthatclinicalstudiesaredecidedtakinginto accounttherequirementforhealth technologyassessment. The traditionaltrialmethodologywithPSFandcrossoverhasserious shortcomings,whenthedatashouldbeusedforassessmentof cost-effectiveness,andthereisaneedforanewstandard.Guidelinesfor thisnewstandardshouldbedevelopedincollaborationbetween regulatoryandHTAauthorities.

Indirectcomparisonsareoftennecessaryforassessmentof cost-effectiveness.Itisnotpossibletoundertakeclinicaltrialsforall potentiallyrelevantalternativesinclinicalpractice.Alimitation ofall indirectcomparisonsis thattheyare basedontrialdata. Theoptionsforusingobservationalstudiesinclinicalpracticeto answerquestionsaboutalternativetreatmentstrategiesshouldbe assessedasearlyaspossible.Suchstudiesshouldbecombinedwith datacollectionforassessmentofrelativeefficacyandrisk-benefit, initiateddirectlyaftermarketingauthorization.

Acloserlinkbetweenstudies,decisionsaboutcoverageandthe actualallocationofresourcesfornewdrugsisalsoneeded.Thedata forstudiesoftheimplementationofreimbursementdecisionsare scarce,andavailableevidenceindicatesthatthereisagapbetween decisionsandimplementation,resultinginaninefficientuseofnew drugsandthusalossofvalue.Linkingeconomicincentives,suchas payforperformanceisonewaytoclosethisgap.

Economic evaluations and coverage decisions are based on uncertaindata,andthustheimpactonoutcomeinclinical prac-ticeisuncertain.Itisthereforenecessarytocollectdataonactual useintomakeitpossibletostudytheeffectsonoutcomeinclinical practice.Sinceoutcomedependsonanumberoffactors, individ-ualpatientdataareanecessaryrequirementforrevealingimpact onoutcome.Suchdatamayalsohelptoinformdecisionsin clini-calpracticewhicharenot,andoftencannot,beinformedbyclinical trialdata;forexamplethecostandoutcomeofuseofdrugsin com-binationand/orsequence.Thesedatamustincludenotonlydrug therapiesbutalsoallrelevantdiagnosticandtherapeutic interven-tions,whichareimportantforoptimizingandrevealingthevalue ofnewthedrugsinclinicalpractice.

Conflictofinterest

Wehavenoconflictofinteresttoreport.

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