Samplesizedeterminationinclinical

trials
withmultiplecoprimaryendpoints
TakashiSozu,Ph.D.
KyotoUniversitySchoolofPublicHealth

TomoyukiSugimoto,Ph.D.
HirosakiUniversityGraduateSchoolofScienceandTechnology

ToshimitsuHamasaki,Ph.D.
OsakaUniversityGraduateSchoolofMedicine

December16,2011
JointMeetingofthe2011TaipeiInternationalStatisticalSymposium
and7thConferenceoftheAsianRegionalSectionoftheIASC

Outline
Backgroundandobjectives
Statisticalsettings
Derivationofpowerformula
Behaviorofsamplesizes
Conclusion

Background
Clinicaltrialsoftenemploytwoormoreprimary

endpoints.

Amajorconcerniswhetherornotclinicaltrials
shouldachievestatisticalsignificanceonallofthe
multipleprimaryendpoints (i.e.,coprimaryendpoints).

StatisticalPrinciplesforClinicalTrials

ICH(1998)

MultipleEndpointExpertTeam(PhRMA)listed20

diseaseswhereregulatoryagencieshaverequired
coprimaryendpoints.

Offenetal.(2007)
3

Common solutionsforthemultiplicity
Compositevariable ICH(1998)

Thisapproachaddressesthemultiplicityproblem
withoutrequiringadjustmenttomultiplicity.
Aclinicallymeaningfulandvalidatedvariableisnot
alwaysavailable.
Interpretationofthevariableisnoteasy.
Assumingtheindependencyamongendpointsand

increasingthepowerforeachendpoint
Thepowerissimplydefined. EatonandMuirhead(2006)
Thepowerwouldbeunderevaluated.
(Thesamplesizeisoversized.)
4

Existingapproaches forpowerand
samplesizedetermination
Continuous (Normal)
Xiongetal.(2005)
Sozuetal.(2006,2011)
Eaton,Muirhead(2006)
Sugimotoetal. (2011)

Binary
IBC2010
(2010.12.6)

Sozuetal.
(submitted)

Song(2009)
Sozuetal.(2010,2011)
Hamasakietal.
(submitted)

MCP2011(2011.8.31)
MCP2011(2011.8.31)
Hamasakietal.
(submitted)

Ordinal

Timetoevent
5

Objective
Wediscussthepowerandsamplesizedetermination
forsuperioritycomparativeclinicaltrialswithmultiple
coprimaryendpoints(forachievingstatistical
significanceforalloftheendpoints).

Continuous
(Normal)

Cont.and Binary

Binary
6

Commonstepsofourresearch
Definetheresponsevariablesandassociation

measures(correlations)amongthem
Calculatethecorrelationcoefficientsamongthe

teststatisticstoderiveapowerformula
Evaluatethebehaviorsofsamplesizes

Associationmeasuresamongendpoints
Scale

Distribution

Cont.
Multivariate
(Normal) Normal(MN)

Associationmeasure(s)
Correlationcoefficient(r)

Binary

Multivariate
Bernoulli(MB)

Cont.
and
Binary

(1)rofMBdist.(MB.
corr.)
(2)Oddratio(OR)
(3)rofalatentMNdist.
(Tetrachoriccorr.)

MN
(latentdistribution)

rofalatentMNdist.
(Biserialcorr.)
8

Relationshipsamongassociation
measuresforbinaryvariables
(1)
MB.corr.

Joint
Prob.
(2)
OR

Bahadur(1961)
leCessie(1994)
Dale(1986)
Emrich,
Piedmonte(1991)
Prentice(1988)

(3)
T.corr.

Ajointprobabilitycanbeestimated
iftheindividualdataofendpointsareavailable.

Biserialmodelformixedcont.andbinary
variables
X2

Latentbivariate
normaldistribution

1
Y2:observedas
abinaryvariable

cutoff
point

0 BinaryPrimaryVariable
X1
Y1:observedasanormalvariable
NormalPrimaryVariable

Associationmeasure
=corr(X1,X2)
Pearson(1909)
Tate(1955a,1955b)
10

Hypothesistesting

DifferenceinmeansforNormalPrimaryVariable
Differenceinsuccessprobabilitiesfor
BinaryPrimaryVariable
Parameterspace
meansanimprovement
fortwoendpoints

foratlestone

forall

11

Testingmethods
NormalPrimaryVariable
Xiongetal.(2005)
(1)Ztest:Knownvariance
(2)Ttest:Unknownvariance Sozuetal.(2006,2011)

BinaryPrimaryVariable

(1)(2)Chisquaretestwithout/withcc
(3)(4)Arcsinetransformationwithout/withcc
(cc:continuitycorrection)
(5)Fishersexacttest
(6)Testbasedonlogtransformedrelativerisks
(15)Sozuetal.(2010) (6)Hamasakietal.(submitted)
12

Powerformula:
Asymptoticnormaltest(exceptforTtest)
Overallpower=

:Teststatistic
:Criticalvalue(:Significancelevel)

Transformintothestandardizedstatistics.

diagonal=1,offdiagonalisgivenbyafunction
oftheassociationmeasureoftheresponsevariables.

ThepowercanbecalculatedfromtheCDFof
Sozuetal.(2010,2011)
13

Powerformula: Ttest
Overallpower=

:Teststatistic
:Criticalvalue

CalculatethepowerusingaMonteCarlo

integration

GenerateWishartrandomnumbersfor
variancecovariancematrix
Calculatetheconditionalpower
Repeattheabovestepsandcalculatethemean
oftheconditionalpower

Sozuetal.(2006,2011)
14

Powerformula:Fishersexacttest
Overallpower=

:onesidedpvalue

CalculatethepowerusingaMonteCarlo

integration.

Generaterandomnumbersfortheresponse
variablesfromtheassumeddistribution
Sozuetal.(2010,2011)
15

Behaviorofsamplesizesfor
NormalPrimaryVariables:Ztest
Decreaseinsamplesize=
Power=80%

samplesizeateachr
samplesizeatr=0.0
Power=90%

K=2
K=3
11%

8%
11%

16%
r:correlationcoefficient(compoundsymmetry)

16

Behaviorofsamplesizes
Sozuetal.(2006,2011)
forNormalPrimaryVariables
Thesamplesizethecorrelation

whentheeffectsizesareapproximatelyequalamong
endpoints

ThedecreaseinSSisdeterminedbythefollowing

fourdesignparameters:
(1)Significancelevelofalpha
(2)Targetpower
(3)Effectsizeratios ofendpoints
(4)Correlationsamongendpoints

Sugimotoetal.(2011)

Thesamplesize(SS)basedonTtest(unknownvariance) +1

theSSbasedonZtest(knownvariance).
17

Behaviorofsamplesizes
forotherPrimaryVariables
BinaryPrimaryVariables:

Sozuetal.(2010,2011)

Thefeaturesofthetestingmethodsaresimilarto
thecaseofsingleendpoint(K=1).
e.g.TheArcsinetransformationwithCCprovides
samplesizesapproximatelyequaltothose
obtainedbyFishersexacttest.

MixedNormalandBinaryVariables:

Thedecreaseinthesamplesizeisrelativelysmallas
comparedtothecaseofNormalPrimaryVariable.
18

Convenientformulaforsamplesize
SamplesizeformulaforNormalPrimaryVariables
Single
endpoints(K=1)

isthefunctionofthefourdesignparameters
AValuecanbeobtainedfromthenumericaltable.

:Thenumberofsubjectsofeachgroup

Arequiredsamplecanbecalculatedwithoutusing

astatisticalsoftware.

Sugimotoetal.(2011)
19

Annumericalexample:K=2

(Correlationbetweentwoendpoints)

Numerical
table

20

Exampleofnumericaltablefor

0.0 0.2 0.3 0.5 0.7 0.8 0.95

1.00 1.250 1.226 1.210 1.168 1.109 1.066 0.961
1.02 1.219 1.195 1.179 1.138 1.079 1.038 0.934
1.25 0.979 0.962 0.952 0.925 0.890 0.870 0.843
2.00 0.842 0.842 0.842 0.842 0.842 0.842 0.842
21

Curveof

22

Conclusions
Weintroducedthemethodofpowerandsample

sizecalculationsformultiplecoprimaryendpoints
forachievingstatisticalsignificanceforallofthe
endpoints.
Itisimportanttoconsiderassociationsamong
endpointsintosamplesizecalculationwhen

theendpointsare(positively)correlatedand
theeffectsizes(i.e.,thecorrespondingindividualpowers)
areapproximatelyequalamongtheendpoints.
23

Thankyouverymuchforyourattention
Search IBC2012

ThisresearchispartiallysupportedbytheMinistryofEducation,Culture,Sports,
ScienceandTechnology,GrantinAidforYoungScientists(B),No.22700290.

24

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Backup

34

Whymultipleendpointsarerequired?
(1) Lackofaconsensusonasinglemostimportant
variablefromthemedicalperspective
(2) Noclearaetiologyofdiseases
(3)Adiseaseconditionischaracterizedinmulti
dimensionalways
Pocock(1997)
PongandSheinChung(1997)
Sankohetal.(2003)
ChuangSteinetal.(2007)
35

StatisticalPrinciplesforClinicalTrials
2.2.2PrimaryandSecondaryVariables

Thereshouldgenerallybeonlyoneprimaryvariable.

2.2.5MultiplePrimaryVariables

Itmaysometimesbedesirabletousemorethanone
primaryvariable,eachofwhich(orasubsetof
which)couldbesufficienttocovertherangeof
effectsofthetherapies.
ICH(1998)
36

Examplesofcoprimaryendpoints
MultipleEndpointExpertTeam(PhRMA)listed20

diseaseswhereregulatoryagencieshaverequiredco
primaryendpoints.
Frequency

Offenetal.(2007)

Thenumberofendpoints

37

Exampleofaclinicaltrial
Arandomized,paralleltreatment,placebo

controlled,doubleblindtrial
Acutemigraine
Fivecoprimaryendpointsareconsidered.
(1)painfreedom
(2)painrelief
(3)phonophobia
(4)photophobia
(5)nausea

Hoetal.(2008)
38

Exampleofguidance
IrritableBowelSyndrome
Primaryendpoint

FDA(2010)

(1)Abdominalpain (11points:0to10)
(2)IBSC(Constipation):stoolfrequency
(2)IBSD(Diarrhea):stoolconsistency
TheBristolstoolFormScale(sevenlevels)

http://www.e
chiken.com/shikkan/kabinsei.htm

39

Rsler etal.(1999;BMJ)

40

Threepossibleclinicalscenarios
Showingsignificancefor

Sankohetal.(2003)

(1)all primaryvariables
coprimaryendpoints
Offenetal.(2007)
reversemultiplicityproblem
(2)majority oftheprimaryvariables

(Theconstitutionofthemajorityisdefinedintheprotocol)

(3)oneormoreoftheprimaryvariables

alternativeprimaryendpoints

Offenetal.(2007)

41

Featureofthreeassociation
measures
Pros
Parameterofthe
B.corr
assumeddistribution
Norestrictedrange
from0toinfinity
OR
Adirectextensionto
aglobalcrossratio
L.corr

Norestrictedrange
from1to1

Cons

Restrictedrange

Ascaledepends
stronglyonresponse
probabilities

Iterativecalculations
arenecessarytospecify
thevaluefromavalue
ofothermeasure
42

Assumptionsforresponsevariables
Biserialmodel

NPV(X)isobservedasX(X=X)
BPV(Y)isobtainedbyadichotomizedofX(X>Y)

Pointbiserialmodel

Pearson(1903)

NPV(X)isdistributedasamixednormaldistribution
BPV(Y)isdistributedasaBernoullidistribution

43

Standardizedteststatistics

44

Correlationbetweenstandardized
teststatistics

45

Samplesizecalculation
Specifythevalueofparameters.

NPV:meanandvariance
BPV:successprobability

Specifythevalueof .

(Considerequalsamplesizes:)
Chooseastartingvalueofandcalculatethepower.
Repeattheabovestepsbygraduallyincreasing.

Endtheoperationwhenthecalculatedpowerexceeds
thedesired,andselectastheminimumvalue
ofsamplesize.
46

Behaviorofoverallpower(mixed)
onecontinuousandonebinaryvariable(K=2)

individualpower=0.8
47

Behaviorsofsamplesizes

48

Behaviorsofsamplesizes(cont.)

49

Summaryoftheresults
Thebehaviorsofsamplesizesareinagreement

withtheresultsinthecontinuouscase.

isnotcloseto1

AS= AN<<ASc= Fi= ANc

iscloseto1

AS<AN<<ASc= Fi<ANc

ThebehaviorsofachievedsamplesizesforK=3

aresimilartothoseforK=2.
Theempiricalpowerattainsaprespecifiedpower.

TheperformanceofAScandFiisbetter.
50

Anillustration:PREMIERstudy
Earlyaggressiverheumatoidarthritis
ACR50

ThepercentageofpatientsinwhomanACR50
responsewasachieved

mTSS

Themeanchangefrombaselineinthemodified
totalSharpscore.

Adalimumab+Methotrexatev.s.Methotrexate
Breedveld(2006)
51

Anillustration:PREMIERstudy
Samplesizespergroupwith

E1,E2:Samplesizeseparatelycalculatedfor
eachendpointsothattheindividualpowerisatleast0.8.
Breedveld(2006)
52

Jointdensityfunctionofteststatistics
Rejection
region

.
53