Supplementary Online Content
Lakdawalla DN, Chou JW, Linthicum MT, MacEwan JP, Zhang J,
Goldman DP. Evaluating expected costs and benefits of granting access to new
treatments on the basis of progression-free survival in non–small-cell lung
cancer. JAMA Oncol. Published online March 19, 2015.
doi:10.1001/jamaoncol.2015.0203
eAppendix. Supplementary Materials—Data, Parameters, and
Calculations
eTable 1. Net PFS and OS Means by Trial
eTable 2. Expected Values by PFS Net Benefit Threshold
eTable 3. Incremental Treatment Costs
eTable 4. Incremental Social Value by PFS Net Benefit Threshold
eTable 5. Indifference Points for Payers When Choosing Between OS and
PFS Policies
eTable 6. Expected Net Benefit for Median PFS and OS
eTable 7. Expected and Incremental Social Value for Median PFS and OS
Analysis
eTable 8. Indifference Points for Median PFS and OS Analysis
eTable 9. Incremental Social Value by PFS Benefit Threshold and Value
of a Statistical Life Year
eTable 10. Incremental Social Value by PFS Benefit Threshold and
Incremental Lifetime Treatment Cost
eTable 11. NSCLC Trials With Separate PFS and OS Publications, 20092014
eTable 12. Incremental Social Value by PFS Benefit Threshold and
Publication Delay
eTable 13. Parameter Values Used for Sensitivity Analyses
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eTable 14. Sensitivity Analysis Scenarios Results
eTable 15. Net PFS Benefits for Clinical Uncertainty Sensitivity Analysis
eTable 16. Clinical Uncertainty and Publication Bias Sensitivity Analysis
Results
eReferences
This supplementary material has been provided by the authors to give
readers additional information about their work.
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eAppendix.SupplementaryMaterials—Data,Parameters,andCalculations
Frameworkforestimatingvalueofalternativepolicies
Wefirstdevelopaframeworkforcalculatingtheexpectedsocialvalue(or
cost)ofpoliciesthatgrantearlyaccesstodrugsonthebasisofPFSdataalone,
comparedtopoliciesthatwaitforOSdatabeforegrantingaccess.Webuildthis
frameworkbyconsideringtherangeofpossibledecisionsandoutcomes.
First,considerthecasewhereaccessisgrantedbasedonPFSdatabefore
dataonOSoutcomesareavailable.Inthiscase,accesswouldnotbegrantedfor
drugswithPFSbenefitbelowsomechosenthresholdof months(e.g.,zeromonths
ofPFSbenefit,1monthofPFSbenefit,andsoon).Thesocialvalueofearlyaccess
basedonPFSdata(NBPFS)dependson:theprobabilityofsuccess;the
complementaryprobabilityoferror;thebenefitsofsuccess,whichwedefinebelow;
thecostoffailure,alsodefinedbelow;themonthsofdelayinwaitingfordataonOS
outcomes(tOS–tPFS);thenumberofpatientsthatwouldbetreatedeachmonth
;
thelifespanofthedrug(T);thelifetimeincrementalcostoftreatment(c),andthe
valueofastatisticallifemonth(v).
WhenthepayerchoosestograntaccessbasedonPFS,therearefourtrue
statesoftheworldunderlyingherdecision:
1. PositivePFSoutcomesandpositiveOSoutcomes;
2. PositivePFSoutcomesandnegativeOSoutcomes;
3. NegativePFSoutcomesandpositiveOSoutcomes;and
4. NegativePFSoutcomesandnegativeOSoutcomes.
Inthefirsttwocases,payerscouldgrantaccessbasedonthePFSdataand
patientswouldhaveaccessforTmonths,butinthesecondscenariotheywould
revokeaccessaftertheOSdatabecameavailable,andthedrugwouldonlybe
availablefortheperiodoftimebetweenthePFSandOSoutcomesbeingrevealed
(tOS–tPFS).Inthethirdcase,payerswouldonlyapproveaftertheOSdatabecame
available,andpatientswouldhaveaccessfor(T–tOS)months.Inthelastscenario,
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payerswouldnevergrantaccess.Thus,theexpectednetbenefitofproceedingwith
PFSdataequalstheexpectedbenefitfromproceedingwhenPFSexceedsthecritical
threshold andOSbenefitispositivelesstheexpectedcostofproceedingwithPFS
whenPFSexceeds andOShasnegativeoutcomes:
EB
Pr
0,
∗
∗ E B |B
∗
0, B
0,
Pr
∗
c ∗
∗
∗ E B |B
∗
(1.1)
0, B
c
.
Similarly,theexpectedbenefitofwaitingforOSdataequals:
EB
Pr
∗
∗
(1.2)
0 ∗
∗ E B |B
.
0, B
c
TheexpectednetbenefitofgrantingaccessbasedonthePFSdataratherthan
waitingfortheOSdataisthedifferencebetween(1.1)and(1.2),whichsimplifiesto:
∗
ENB
∗ Pr
∗ E B |B
Pr
∗ E B |B
(1.3)
0 ∗
0, B
c
0 ∗
0, B
c Notethatthistermscalesproportionallywiththenumberofpatientsnewly
treatedpermonth, .Thus,inordertoavoidhavingtomakeassumptionsaboutthe
sizeofthepatientpopulationthatwillbetreated,wedividethistermby ,and
recovertheexpectednetbenefitpernewpatienttreatedeverymonth.Wecallthis
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the“incrementalsocialvalueofearlyaccessforanadditionalpatientpermonth,”or
“incrementalsocialvalue”forshort.Mathematically,incrementalsocialvalueis:
ISV
(1.4)
∗ Pr
0 ∗
∗ E B |B
0, B
c
Pr
0 ∗
∗ E B |B
0, B
c Weestimatetheincrementalsocialvalueofgrantingaccesstonovel
therapiesforNSCLCbyparameterizingequation1.4foralternativevaluesof .The
firsttermrepresentsthenumberofadditionalmonthspatientshavetowaitfor
accesswhenOSrequirementsdelayaccesstodrugs.Thesecondtermincurly
bracketsrepresentsthenetchangeinsurvivalperpatientthatresultsfromdelay.
Bothofthesearemultipliedbythevalueofsurvivalgains.Ifexpectednetbenefitis
greaterthanzero,thismeansthattheexpectedbenefitsofearlyaccessoutweighits
expectedcosts,andvice‐versa.Acompletederivationofthisvalueframeworkisalso
describedinStevensetal(2014).1
DataCollection
Thediscussionabovesuggeststhatthefollowingpiecesofinformationare
neededinordertoquantifyincrementalsocialvalue:
1. Thelifespanofanaveragecancerdrug
2. ThedelayduetouseofOS,insteadofPFS;
3. ThecorrelationbetweenPFSandOSwithinadisease‐area;thiscorrelationis
sufficienttoproducealltheprobabilityestimatesandconditional
expectationsofinterest(Pr
0 ;E B |B
0, B
0 ;
|
0,
.
4. Thevalueofastatisticallife‐month, ;
5. Theincrementallifetimecostoftreatment, .
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;Pr
Below,wedescribehoweachoftheseisestimated.
Druglifespan
AsystematicreviewofcancerdrugutilizationrelativetoyearsfromFDA
approval/druglaunchindicatesthatpeakutilizationtendstooccuraroundyear7or
8andbeginstodeclinebyyear9.2Assuch,weestimatedthedruglifespaninour
modeltobe108months.
Dataondelay,OS,andPFS
Dataonoverallsurvival(OS),progressionfreesurvival(PFS),anddelay
betweenavailabilityofPFSandOSresultswereextractedfromphase3clinicaltrials
fornon‐smallcelllungcancer(NSCLC)publishedbetween2009and2014.As
describedinthemanuscript,thefollowingthreeinclusioncriteriawereused:1)
inclusionofprogressionfreesurvival(PFS)oroverallsurvival(OS)outcomes;2)
comparisonoftwoormoretreatments;and3)inclusionofKaplan‐Meiertablesfor
thenumberofpatientsatriskforeachtimeinterval(seeAppendixTable1).A
secondarytargetedsearchwasconductedwithinthecollectedtrialsforinstancesof
separatepublicationsforPFSandOSresultsfromthesametrial.FromtheKaplan‐
Meiertablespublishedineacharticleweextractedtheprobabilitythatatrial
participantontheinterventionorcomparatordrugwouldhavesurvivedateach
timeintervalafterrandomization.Theseprobabilitieswereusedtocalculatethe
meanPFSandOSforeachtreatmentarmineverytrial;thesecalculationsare
discussedbelow.
ExpectedOSbenefitwhenPFSisaboveagiventhresholdistheproductof
twovariables:theaverageOSbenefitacrosstrialswithPFSbenefitsatorabovethe
threshold,andtheprobabilityofapositive(ornegative)OSbenefitfortrialswith
PFSabovethethreshold.Thesevariableswerecalculatedseparatelyforcaseswhere
netOSeffectispositiveandnegative.
AverageOSbenefitgivenPFSbenefit
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TheaverageOSbenefit,conditionalonaPFSthreshold,iscalculatedsimply
astheaverageOSbenefitacrosstrialsthatmeetorexceedthePFSthreshold.As
discussedinthemanuscript,weusedestimatedmeansurvivaldatainsteadof
mediansurvivaldataandconductedasensitivityanalysisbasedonthereported
mediansurvivaldata.
Clinicaltrialstypicallymeasureandreportmediansurvivalbecause
censoringandtheskewednatureofsurvivaldatacanmakemeansurvivaldifficult
toestimate,butpatientsmayfindthemeanorexpectedsurvivaltimemore
meaningful.3,4Therefore,weestimatedmeansurvivaltimebasedondataprovided
inpublishedtrialresults.Thesecalculationsaredescribedbelow.
UsingtheKaplanMeiertablesreportedineachclinicaltrialforthenumberof
patientsremainingor‘at‐risk’ateachtimeinterval,weestimatedtheshareof
patientsineachtreatmentarmstillaliveateachtimeinterval.Thatis,theheightof
thesurvivalcurveor
,
Pr
wherenjdenotesthenumberofpatientsintreatmentarmk(intervention,I,or
comparator,C)survivinguntilperiodjandNkrepresentsthetotalnumberof
patientsinthetreatmentarm.Wethencalculatedthemeansurvivaltimeas
Pr
ThemeansurvivaltimeequalstheareaunderthesurvivalcurveattimeJ.
Thenetmeansurvivaltime,orusedasaninputinourpatientbenefitmodel
(describedbelow),equals
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WeestimateboththenetmeanPFSandOStimes,
and
AppendixTable1belowforthelistoftrialsandtheir
.Pleasesee
and
values.
Probabilityofpositive(ornegative)OSeffect
Next,wecalculatedtheshareoftrialswithbothpositiveOSandPFSabove
thethreshold,i.e.,Pr
0,
.This“probabilityofsuccess”equalsthe
shareoftrialswithpositiveOSandPFSoutcomes.Wealsocalculatedtheshareof
trialswherethepositivePFSoutcomeincorrectlypredictedtheOSoutcome,i.e.,
Pr
0,
.This“probabilityoferror”equalstheshareoftrialswith
positivePFSoutcomesthathadnegativeOSoutcomes.
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eTable1.NetPFSandOSMeansbyTrial
Paper
InterventionDrug
ComparatorDrug
BPFS
BOS
Wu(2013)5
erlotinib+gemcitabine
gemcitabine+
3.523933137
1.686489676
+cisplatin/carboplatin
cisplatin/carboplatin
pemetrexed
3.319199524
3.076679215
Zukin(2013)6 carboplatin+
pemetrexed
Quoix(2011)7
carboplatin+paclitaxel
vinorelbine/gemcitabine
3.073156342
3.784424779
Shaw(2013)8
crizotinib
pemetrexed/docetaxel
2.17909109
0.15829513
Mitsudomi
gefitinib
cisplatin+docetaxel
2.151162791
0.290697674
Herbst
erlotinib+
erlotinib
1.485141857
0.129881432
(2011)10
bevacizumab
Morabito
cisplatin+gemcitabine
gemcitabine
0.964285714
0.428571429
Paz‐Ares
sorafenib+
gemcitabine+cisplatin
0.906690481
‐0.194265519
(2012)12
gemcitabine+cisplatin
Rodrigues‐
pemetrexed+
docetaxel+carboplatin
0.868463612
1.135579515
Pereira
carboplatin
(2010)9
(2013)11
(2011)13
Wu(2012)14
gefitinib
carboplatin+paclitaxel
0.838575393
1.006475486
Mok(2009)15
Gefitinib
Carboplatin+paclitaxel
0.808443523
1.85233558
paclitaxel+carboplatin+
0.786148514
‐0.085104163
Patel(2013)16 pemetrexed+
carboplatin+
bevacizumab
bevacizumab
Herbst
vandetanib+docetaxel
docetaxel
0.688833163
0.480788393
Johnson
bevacizumab+
bevacizumab
0.673190349
0.306803855
(2013)18
erlotinib
Ridolfo
IL2+cisplatin+
cisplatin+gemcitabine
0.533605174
‐0.126546682
(2011)19
gemcitabine
Shi(2013)20
icotinib
gefitinib
0.479858308
‐0.326238082
(2010)17
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eTable1.NetPFSandOSMeansbyTrial,continued
Kim(2008)21
gefitinib
docetaxel
0.401632472
‐0.067364074
Reck(2014)22
nintedanib
docetaxel
0.368297121
0.920812242
Kubota
vinorelbine+
carboplatin+paclitaxel
0.35786802
‐0.034497048
(2008)23
gemcitabine+
docetaxel
Lee(2010)24
gefitinib
docetaxel
0.277477617
3.21781414
Scagliotti
sunitib+erlotinib
erlotinib
0.183333333
0.3
S1+carboplatin
paclitaxel+carboplatin
‐0.032258065
0.720430108
ifosfamide+
gemcitabine+
‐0.072483565
0.145223256
gemcitabine+
cisplatin/vinorelbine
pemetrexed
‐0.174746459
1.185128519
paclitaxel+carboplatin
‐0.300791557
‐0.221635884
paclitaxel+carboplatin
‐0.378309526
‐0.097380374
(2012)25
Okamoto
(2010)26
Boni(2012)27
vinorelbine/cisplatin
Kim(2013)28
cetuximab+
pemetrexed
Treat
gemcitabine+
(2010)29
carboplatin
Treat
gemcitabine+
(2010)29
paclitaxel
Bepler
gemcitabine+
(2013)30
carboplatin,docetaxel+
gemcitabine+carboplatin ‐1.441197434
0.351389879
vinorelbine+
cisplatin+gemcitabine
‐1.314132104
gemcitabine
(ifosfamide)
carboplatin,
gemcitabine+
docetaxel,docetaxel+
vinorelbine
Boni(2012)27
‐1.510752688
(ifosfamide)
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ExpectedOSeffect
Last,wecalculatedtheexpectednetbenefittoeachpatienttreatedfor
“successes”and“failures.”Theformervalue,
|
0,
,equalsthe
expectedgaininOStopatientsfromusingtheinterventiondrugratherthanthe
comparatorwhenthePFSdatacorrectlypredictsapositiveOSbenefit,orthe
benefitsofsuccess.Thisexpectedchangeinsurvivalrepresentsthegaininsurvival
fromcorrectlypredictingthepositiveOSbenefitwiththePFSdata.Thelattervalue,
|
0,
,equalstheexpectedchangeinOSpatientsgetfromusing
theinterventiondrugwhenthePFSdataincorrectlypredictsapositiveOSbenefit,
orthecostoferrors.Thisexpectedchangeinsurvivalrepresentsthecostofthe
errorofgrantingaccesstoatherapybasedonpositivePFSoutcomeswhentheOS
outcomesturnouttobenegative.PleaseseeAppendixTable2belowwithtotal
overallexpectedvaluesbyPFSnetbenefitthreshold.
eTable2.ExpectedValuesbyPFSNetBenefitThreshold
PFSnetbenefitthreshold
OverallE(OS|PFS>x)
0
0.854363475
0.5
0.928740387
1
1.521077984
1.5
1.799317295
2
1.799317295
2.5
2.84919789
3
2.84919789
DelayBetweenAvailabilityofPFSandOSResults
Exactlyonepublicationpairwasidentifiedwithinourdefinedliterature
sample,withadelayof22monthsbetweenpublicationofthePFSandOSoutcomes
data.15,31Usingexpandedliteraturesearchcriteriathateliminatetherestrictionto
PhaseIIItrialsandtherestrictiontostudieswithKaplan‐Meiertables,wealso
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obtainfouradditionalpublicationpairs,withdelaysrangingfrom7monthsto46
months.Weuse7monthsasour“low”scenariofordelayand46monthsasour
“high”scenario.
ValueofaStatisticalLifeYear
Asdescribedinthemanuscript,weconsiderarangeofvaluesforlife
expectancy,from$40,000to$400,000;forourmediumpatientbenefitparameter
estimate,weusetheConsumerPriceIndextoinflateamid‐rangevalueof$150,000
in1997dollarsto$217,717in2013dollars.32,33Forthepurposesofthemodel,we
rounddowntheinflated2013dollarvalueto$200,000forVSLY.Giventhatthe
meanchangeinsurvivalforNSCLCpatientsinmeasuredinmonths,weuseavalue
of$16,667perlifemonth.Wealsoconsider“low”and“high”VSLYscenariosof
$100,000and$300,000,respectively,withcorrespondingper‐monthvalues.
IncrementalLifetimeCostofTreatment
Tocalculatetheincrementalcostperpatientfora“noveltreatment,”we
conductedatargetedliteraturereviewforcosteffectivenessanalysesthatusedUS
costsforNSCLCtreatments.Wefoundfourpublishedstudies,withincremental
treatmentcostsrangingfrom$2,000–62,000,dependingonthedrugandits
comparator(seeAppendixTable3below).34‐37Wecomputedthemediumscenario
byusingthemeanincrementalcostfromthesestudiesofapproximately$22,000
perpatient.Thelowandhighscenariovaluesaregivenby$2000and$62,000,the
minimumandmaximumvalues.Incrementaltreatmentcostisdefinedasthe
differencebetweenthetotallifetimecostoftreatmentforpatientsusingthe
interventiondrugandthetotallifetimecostoftreatmentforpatientsusingthe
comparatordrug.
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eTable3.IncrementalTreatmentCosts
Paper
Intervention
Comparator
Incremental
Dollar
Incremental
Cost
Year
costin2013
dollars
Klein
pemetrexed(non
(2010)36
squamous)
Klein
pemetrexed(non
(2010)36
squamous)
Klein
pemetrexed(non
(2010)36
squamous)
Klein
pemetrexed(all)
bestsupportivecare $31,944
2009
$34,687
erlotinib
$24,474
2009
$26,575
bevacizumab
‐$9,187
2009
‐$9,976
bestsupportivecare $28,253
2009
$30,679
pemetrexed(all)
erlotinib
$18,142
2009
$19,700
pemetrexed
docetaxel
$4,655
2007
$5,230
pemetrexed
erlotinib
$6,782
2007
$7,620
docetaxel
erlotinib
$2,127
2007
$2,390
paclitaxel+
$19,137
2009
$20,780
$39,083
2009
$42,439
$20,435
2009
$22,190
$37,335
2009
$40,541
$20,116
2013
$20,116
$62,745
2013
$62,745
(2010)36
Klein
(2010)36
Carlson
(2008)35
Carlson
(2008)35
Carlson
(2008)35
Shah(2013)37 pemetrexed+
platinum
Shah(2013)37 paclitaxel+
carboplatin+
carboplatin
paclitaxel+
carboplatin
bevacizumab
Shah(2013)37 pemetrexed+
platinum(chemo
paclitaxel+
carboplatin
only)
Shah(2013)37
paclitaxel+
paclitaxel+
carboplatin+
carboplatin
bevacizumab
(chemoonly)
erlotinib
Bajaj
(2014)34
bevacizumab+
paclitaxel+
carboplatin
Bajaj
erlotinib
(2014)34
paclitaxel+
carboplatin
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Bajaj
erlotinib
pemetrexed+
(2014)34
2013
$31,438
$20,359
2013
$20,359
$11,079
2013
$11,079
carboplatin
erlotinib
Bajaj
$31,438
bevacizumab+
(2014)34
pemetrexed+
carboplatin
Bajaj
bevacizumab+
pemetrexed+
(2014)34
pemetrexed+
carboplatin
carboplatin
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Estimatesofincrementalsocialvalue
PleaseseeAppendixTable4,below,fortheincrementalsocialvalue
calculationsthatresultfromparameterizingthequantitativeframeworkwiththe
datadescribedabove.Thetablereportsvaluesbasedonmediumscenario
parameters.
eTable4.IncrementalSocialValuebyPFSNetBenefitThreshold
PFSnetbenefitthreshold
Incrementalsocial value
0
‐$170,733.39
0.5
‐$143,461.86
1
$73,728.59
1.5
$175,749.67
2
$175,749.67
2.5
$560,705.89
3
$560,705.89
IndifferenceCurves
Finally,weidentifythevaluesofincrementallifetimetreatmentcostandof
statisticallife‐yearsatwhichpayersareindifferentbetweenPFSandOSpolicies.
Specifically,wecalculatethepairofvalues–fortreatmentcostandvalueoflife
years–thatgenerateanetbenefitofexactlyzero.Thisenabledustoproducecurves
atwhichpayersshouldbeindifferentbetweenanOSorPFSaccessdecision.Please
seeAppendixTable5belowfortheincrementallifetimetreatmentcostvaluesthat
generatepayerindifference,givenaVSLYandPFSnetbenefitthreshold.
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eTable5.IndifferencePointsforPayersWhenChoosingBetweenOSandPFS
Policies
IncrementalLifetimeTreatmentCost
ValueofaLife
PFSthreshold>0
PFSthreshold≥1
PFSthreshold≥2
PFSthreshold≥3
$40,000
$2,848
$ 5,070
$ 5,998
$9,497
$60,000
$4,272
$ 7,605
$ 8,997
$14,246
$80,000
$5,696
$ 10,141
$ 11,995
$18,995
$100,000
$7,120
$ 12,676
$ 14,994
$23,743
$120,000
$8,544
$ 15,211
$ 17,993
$28,492
$140,000
$9,968
$ 17,746
$ 20,992
$33,241
$160,000
$11,392
$ 20,281
$ 23,991
$37,989
$180,000
$12,815
$ 22,816
$ 26,990
$42,738
$200,000
$14,239
$ 25,351
$ 29,989
$47,487
$220,000
$15,663
$ 27,886
$ 32,987
$52,235
$240,000
$17,087
$ 30,422
$ 35,986
$56,984
$260,000
$18,511
$ 32,957
$ 38,985
$61,733
$280,000
$19,935
$ 35,492
$ 41,984
$66,481
$300,000
$21,359
$ 38,027
$ 44,983
$71,230
$320,000
$22,783
$ 40,562
$ 47,982
$75,979
$340,000
$24,207
$ 43,097
$ 50,981
$80,727
$360,000
$25,631
$ 45,632
$ 53,980
$85,476
$380,000
$27,055
$ 48,167
$ 56,978
$90,225
$400,000
$28,479
$ 50,703
$ 59,977
$94,973
Year
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SensitivityAnalyses
Calculatedmeanssensitivity
Asasensitivityanalysis,were‐calculatedtheprobabilitiesandvaluesforour
sampleusingthemedianPFSandOSinsteadofourcalculatedmeans.Appendix
Table6,below,displaysthenetbenefitsbasedonthemedianchangesinPFSandOS.
eTable6.ExpectedNetBenefitforMedianPFSandOS
Paper
InterventionDrug
ComparatorDrug
BPFS
BOS
Wu(2013)5
erlotinib+gemcitabine+
gemcitabine+
1.6
3.1
cisplatin/carboplatin
cisplatin/carboplatin
Zukin
carboplatin+
pemetrexed
3
4
(2013)6
pemetrexed
Quoix
carboplatin+paclitaxel
vinorelbine/gemcitabine
3.2
4.1
Shaw(2013)8
crizotinib
pemetrexed/docetaxel
4.7
0.1
Herbst
erlotinib+bevacizumab
erlotinib
1.7
0.1
cisplatin+gemcitabine
gemcitabine
1.6
2.9
Paz‐Ares
sorafenib+gemcitabine
gemcitabine+cisplatin
0.5
‐0.1
(2012)12
+cisplatin
Rodrigues‐
pemetrexed+
docetaxel+carboplatin
‐0.2
0.2
Pereira
carboplatin
(2011)7
(2011)10
Morabito
(2013)11
(2011)13
Wu(2012)14
gefitinib
carboplatin+paclitaxel
0
‐0.2
Mok(2009)15
Gefitinib
Carboplatin+paclitaxel
‐0.1
1.4
Patel
pemetrexed+
paclitaxel+carboplatin+
0.4
‐0.8
(2013)16
carboplatin+
bevacizumab
bevacizumab
Herbst
vandetanib+docetaxel
docetaxel
0.8
0.6
bevacizumab+erlotinib
bevacizumab
1.1
1.1
Ridolfo
IL2+cisplatin+
cisplatin+gemcitabine
‐0.3
‐1.5
(2011)19
gemcitabine
Shi(2013)20
icotinib
gefitinib
1.2
‐0.6
(2010)17
Johnson
(2013)18
©2015AmericanMedicalAssociation.Allrightsreserved.
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Kim(2008)21
gefitinib
docetaxel
‐0.5
‐0.4
Reck
nintedanib
docetaxel
0.7
1
Kubota
vinorelbine+
carboplatin+paclitaxel
‐0.3
‐0.5
(2008)23
gemcitabine+docetaxel
Lee(2010)24
gefitinib
docetaxel
‐0.1
1.9
Scagliotti
sunitib+erlotinib
erlotinib
1.6
0.5
S1+carboplatin
paclitaxel+carboplatin
‐0.7
1.9
ifosfamide+gemcitabine
gemcitabine+
0.1
‐0.1
+vinorelbine/cisplatin
cisplatin/vinorelbine
Kim(2013)28
cetuximab+pemetrexed
pemetrexed
0.1
‐0.9
Treat
gemcitabine+
paclitaxel+carboplatin
‐0.4
‐0.8
(2010)29
carboplatin
Treat
gemcitabine+paclitaxel
paclitaxel+carboplatin
‐0.2
‐0.2
Bepler
gemcitabine+
gemcitabine+carboplatin
‐0.8
‐0.3
(2013)30
carboplatin,docetaxel+
vinorelbine+
cisplatin+gemcitabine
‐1.5
‐1.6
gemcitabine(ifosfamide)
(ifosfamide)
(2014)22
(2012)25
Okamoto
(2010)26
Boni(2012)27
(2010)29
carboplatin,gemcitabine
+docetaxel,docetaxel+
vinorelbine
Boni(2012)27
©2015AmericanMedicalAssociation.Allrightsreserved.
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AppendixTable7,below,containstheresultsoftheexpectedand
incrementalsocialvaluecalculationsforthesensitivityanalysisusingmedianPFS
andOS.
eTable7.ExpectedandIncrementalSocialValueforMedianPFSandOS
Analysis
PFSnetbenefitthreshold
OverallE(OS|PFS>x)
Incrementalsocial
value
0
1
‐$117,333.33
0.5
1.536363636
$79,333.33
1
1.766666667
$163,777.78
1.5
2.114285714
$291,238.10
2
2.733333333
$518,222.22
2.5
2.733333333
$518,222.22
3
2.1
$286,000.00
Finally,wereplicatedthebreak‐even(indifferencecurve)analysisusingthe
calculationsfromthemedianPFSandOSanalysis.Thelifetimeincremental
treatmentcostvaluesatwhichadecisionmakerwouldbeindifferenttoproviding
accessatPFSdataavailabilityratherthanwaitingforOSdataforeachvalueofa
statisticallife‐yearcanbefoundinAppendixTable8,below.
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eTable8.IndifferencePointsforMedianPFSandOSAnalysis
IncrementalLifetimeTreatmentCost
ValueofaLife
PFSthreshold>0
PFSthreshold≥1
PFSthreshold≥2
PFSthreshold≥3
$40,000
$3,333
$ 5,889
$ 9,111
$7,000
$60,000
$5,000
$ 8,833
$ 13,667
$10,500
$80,000
$6,667
$ 11,778
$ 18,222
$14,000
$100,000
$8,333
$ 14,722
$ 22,778
$17,500
$120,000
$10,000
$ 17,667
$ 27,333
$21,000
$140,000
$11,667
$ 20,611
$ 31,889
$24,500
$160,000
$13,333
$ 23,556
$ 36,444
$28,000
$180,000
$15,000
$ 26,500
$ 41,000
$31,500
$200,000
$16,667
$ 29,444
$ 45,556
$35,000
$220,000
$18,333
$ 32,389
$ 50,111
$38,500
$240,000
$20,000
$ 35,333
$ 54,667
$42,000
$260,000
$21,667
$ 38,278
$ 59,222
$45,500
$280,000
$23,333
$ 41,222
$ 63,778
$49,000
$300,000
$25,000
$ 44,167
$ 68,333
$52,500
$320,000
$26,667
$ 47,111
$ 72,889
$56,000
$340,000
$28,333
$ 50,056
$ 77,444
$59,500
$360,000
$30,000
$ 53,000
$ 82,000
$63,000
$380,000
$31,667
$ 55,944
$ 86,556
$66,500
$400,000
$33,333
$ 58,889
$ 91,111
$70,000
Year
Inadditiontotestingthesensitivityofthemodeltotheuseofcalculatedmeansas
comparedtoreportedmedians,wealsosimulatedtheeffectofusingthelowand
highvaluesforthefollowingmodelparameters:valueofastatisticallifeyear,
treatmentcost,andpublicationdelay.Finally,toassessrobustnesstoclinical
uncertaintyaboutthecorrelationbetweenPFSandOS,wealsosimulatedtheeffect
ofpublicationbiasonourmodel,asdescribedinthemanuscript.
ValueofaStatisticalLifeYear
WeselectedtwoadditionalVSLYstosimulate:$100,000and$300,000.These
valuescapturetherangeofmostestimatesofVSLYasreportedinawidelycited
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reviewoftheliteratureonVSLY,afteradjustedto2014USdollars.33AppendixTable
9belowdisplaystheincrementalsocialvaluesat$100,000;$200,000;and$300,000
ateachhalf‐monthPFSbenefitthresholdfrom0to3+monthsholdingother
baselineparametersconstant.LoweringtheVSLYto$100,000changesthe
indifferencethresholdfrom1monthto2.5months,whereasraisingtheVSLYto
$300,000changestheindifferencethresholdfrom1monthto0.5months.
eTable9.IncrementalSocialValuebyPFSBenefitThresholdandValueofa
StatisticalLifeYear
PFSbenefit>x
VSLY$100K
VSLY$200K
VSLY$300K
0
‐$327,367
‐$170,733
‐$14,100
0.5
‐$313,731
‐$143,462
$26,807
1
‐$205,136
$73,729
$352,593
1.5
‐$154,125
$175,750
$505,625
2
‐$154,125
$175,750
$505,625
2.5
$38,353
$560,706
$1,083,059
3+
$38,353
$560,706
$1,083,059
TreatmentCost
Asnotedabove,thevaluesfromourliteraturereviewonincrementallifetime
treatmentcostrangefrom$2,000to$62,000.Wecalculatedincrementalsocial
valueateachhalf‐monthPFSthresholdusingourotherbaselineparameterswith
incrementallifetimetreatmentcostsof$2,000;$22,000;and$62,000,asshownin
AppendixTable10below.Treatmentcostisthemostsensitiveparameter.
Increasingtreatmentcostto$62,000alsoincreasesthePFSbenefitthresholdto
greaterthan3months.Loweringthetreatmentcostto$2,000lowersthePFS
benefitthresholdto0months.
©2015AmericanMedicalAssociation.Allrightsreserved.
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eTable10.IncrementalSocialValuebyPFSBenefitThresholdandIncremental
LifetimeTreatmentCost
PFSbenefit>x
$62KCost
$22KCost
$2KCost
0
‐$1,210,996
‐$170,733
$109,004
0.5
‐$1,218,537
‐$143,462
$101,463
1
‐$1,140,909
$73,729
$179,091
1.5
‐$1,100,100
$175,750
$219,900
2
‐$1,100,100
$175,750
$219,900
2.5
‐$946,118
$560,706
$373,882
3+
‐$946,118
$560,706
$373,882
PublicationDelay
TofindadditionalinstancesofasingleclinicaltrialwithseparatePFSandOS
publications,werelaxedtworestrictioncriteria:phase3trialsandpublicationwith
Kaplan‐Meiersurvivaltables.Insodoing,wewereabletoidentifyfouradditional
pairedpublicationsasshowinAppendixTable11belowwithpublicationdelay
rangingfrom7monthsto46months.
eTable11.NSCLCTrialsWithSeparatePFSandOSPublications,2009‐2014
PFSPublicationDate
OSPublicationDate
MonthsDelay
AVAPERL
Jul‐1338
Feb‐1439
7
PARAMOUNT
Mar‐1240
Aug‐1341
17
FASTACT
Oct‐0942
Jul‐135
46
NEJ002
Jun‐1043
Jan‐1344
32
UsingthebaselinemodelparametersforVSLYandtreatmentcost,wecalculated
incrementalsocialvalueusingasevenmonthpublicationdelayanda46month
delay.ThelengthoftimeforthedelaybetweenPFSandOSpublicationdoesnot
alterthePFSbenefitthresholds,butservesasamultiplierthatscalesincremental
socialvalueupordown,asshowninAppendixTable12below.
©2015AmericanMedicalAssociation.Allrightsreserved.
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eTable12.IncrementalSocialValuebyPFSBenefitThresholdandPublication
Delay
PFSbenefit>x
7months
22months
46months
0
‐$54,324
‐$170,733
‐$356,988
0.5
‐$45,647
‐$143,462
‐$299,966
1
$23,460
$73,729
$154,160
1.5
$55,920
$175,750
$367,477
2
$55,920
$175,750
$367,477
2.5
$178,406
$560,706
$1,172,385
3+
$178,406
$560,706
$1,172,385
ForVSLY,treatmentcost,andpublicationdelay,wealsosimulatedtheeffectonthe
PFSbenefitthresholdwhenallthreeparametersweremodeledsimultaneously
usingallpossiblecombinationsofthelow,medium,andhighparameterscenarios
forVSLY,treatmentcost,andpublicationdelayasdescribedinAppendixTable13
below.
eTable13.ParameterValuesUsedforSensitivityAnalyses
VSLY
TreatmentCost
MonthsDelay
LowPatientBenefit
$100,000
$62,000
7
MediumPatient
$200,000
$22,000
22
$300,000
$2,000
46
Benefit
HighPatientBenefit
Asindicatedinthesingleparametersensitivityanalyses,treatmentcosthasthe
greatestimpactonthePFSbenefitthreshold,whilethepublicationdelayhasno
impact.ThePFSbenefitthresholdsforeachcombinationofparameterscanbefound
belowinAppendixTable14.
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eTable14.SensitivityAnalysisScenariosResults
Scenario
Valueofa
Lifetime
Delaybetween
Indifference
StatisticalLife
Incremental
PFSandOS
Threshold(PFS>
Year
TreatmentCost
publication
X;months)
(months)
A
$100,000
$62,000
7
3
B
$100,000
$62,000
22
3
C
$100,000
$62,000
46
3
D
$100,000
$22,000
7
3
E
$100,000
$22,000
22
3
F
$100,000
$22,000
46
3
G
$100,000
$2,000
7
0
H
$100,000
$2,000
22
0
I
$100,000
$2,000
46
0
J
$200,000
$62,000
7
3
K
$200,000
$62,000
22
3
L
$200,000
$62,000
46
3
M
$200,000
$22,000
7
1
N
$200,000
$22,000
22
1
O
$200,000
$22,000
46
1
P
$200,000
$2,000
7
0
Q
$200,000
$2,000
22
0
R
$200,000
$2,000
46
0
S
$300,000
$62,000
7
3
T
$300,000
$62,000
22
3
U
$300,000
$62,000
46
3
V
$300,000
$22,000
7
1
W
$300,000
$22,000
22
1
X
$300,000
$22,000
46
1
Y
$300,000
$2,000
7
0
Z
$300,000
$2,000
22
0
ZA
$300,000
$2,000
46
0
©2015AmericanMedicalAssociation.Allrightsreserved.
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PublicationBiasandClinicalUncertainty
Wereturnedtotheliteraturetoidentifythreephase3publicationswithpublished
PFSmedianoutcomes,butnoOSoutcomes.Totesttheimpactofbothpublication
biasandclinicaluncertainty,weassumedthattheOSoutcomesforthesethreetrials
waslessthanorequaltozeroandcalculatedupdatedprobabilitiesandexpected
benefitswiththesethreeadditionaltrialsincluded.AsshowninAppendixTable15
below,twoofthetrialshadnetPFSbenefitsofgreaterthan3months.
eTable15.NetPFSBenefitsforClinicalUncertaintySensitivityAnalysis
Paper
InterventionDrug
ComparatorDrug
BPFS
Rosell
erlotinib
cisplatin+docetaxel+
4.5
(2012)45
gemcitabine
Chang
bevacizumab+
(2011)46
cisplatin
Chen
erlotinib
(2013)47
pemetrexed+cisplatin
1
gemcitabine+
9.1
carboplatin
AppendixTable16belowcontainsthecorrelationsbetweenPFSandOSand
expectedbenefitsaswellastheincrementalsocialvalueat$100K,$200K,and
$300KVSLYforeachhalf‐monthPFSbenefitthreshold.Increasingtheclinical
uncertaintyandaccountingforpublicationbiasinthiswaychangedthePFS
thresholdsforVSLYvaluesof$100Kand$200K,butnotfor$300K.
©2015AmericanMedicalAssociation.Allrightsreserved.
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eTable16.ClinicalUncertaintyandPublicationBiasSensitivityAnalysisResults
PFSbenefit>x
Pr(BOS>0|PFS>x)
Pr(BOS<=0|PFS>x)
E(BOS|BOS>0,P
E(BOS|BOS<0,P
Incremental
Incremental
Incremental
FS>x)
FS>x)
socialvalue
socialvalue
socialvalue
(VSLY100K)
(VSLY200K)
(VSLY300K)
0
0.63
0.38
1.25
‐0.10
$(347,175)
$(210,350)
$(73,525)
0.5
0.67
0.33
1.19
‐0.07
$(342,415)
$(200,829)
$(59,244)
1
0.75
0.25
1.52
0.00
$(274,852)
$(65,704)
$143,445
1.5
0.71
0.29
1.80
0.00
$(248,375)
$(12,750)
$222,875
2
0.71
0.29
1.80
0.00
$(248,375)
$(12,750)
$222,875
2.5
0.60
0.40
2.85
0.00
$(170,588)
$142,824
$456,235
3+
0.60
0.40
2.85
0.00
$(170,588)
$142,824
$456,235
©2015AmericanMedicalAssociation.Allrightsreserved.
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