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u.s, Oepa,rtment of Health and Human Services

. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Translational Syiences :
Office of Biostatistics

STATISTICAL REVIEW AND

EVALUATION

CLINICAL STUDIES

ND AlSerial N lUn ber:

. Drug Name:
Indication(s):

sBLA STN 125118.045 .

ORENCIA (abatacept, BMS-188667)
For reducing sign~ and symptoms in pediatric and adolescentpatients with ..
moderately to sevetelyactivejuvenile idiopathic arthritis / juvenile rheumatoid
.. arthritis 'Yith polyarticular course
,
.

Applicant:
. Date(s):

Bristol-Myers Squibb Company

. Submitted: June 8; 2007
PDUFA: April 7, 2008

Review Priority: .

Standard

BiOllletricsDiyisio I):

Division ofBiometrics II

Statistical Reviewer:

Yongman Kim, Ph.D., .

Concurring R~viewers:

Dionne Price, Ph.D.

Medical Division:

Division of Anesthesia, Analgesia, and Rheuinatology Products

ClinicalTeam: .

Keith Hull, M.D.

Jeffrey Siegel, M.D~

ProjectManager:
.

. Sara Stradley

.. KeyWords: Clinical studies, endpoint analysis

\ .

Table of Contents

1.

EXECUTNE SUMMARX'
1.1
1.2
1.3

2.

CONCLUSIONS AND RECOMMENDATIONS

BRlEF OVERVIEW OF CLINICAL STUDIES
STATISTICAL ISSUES AND FINDINGS

;
I

INTRODUCTION
2,1
2.2

3.

OVERVIEW
DATA SOURCES

:
;

STATISTICAL EVALUATION
3.1
3.2

EVALUATION OF EFFICACY
EVALUATION OFSAFETY

4.

FINDINGS IN SPECIAL/SUBGROUP POPULATIONS

5.

SUMMARY ANDCONCLUSIONS
.
5.1
5.2
5.3

SIGNATURESIDISTRIBUTION LIST

12

12

STATISTICAL ISSUES AND COLLECTIVE EVIDENCE

CONCLUSIONS AND RECOMMENDATIONS
REVIEWdF CLINICAL STUDIES OF PROPOSED LABEL

APPENDIX

12

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12

13

13

18

23

.LIStOF''fABLES
Table! P4tientDisposition ;.. ,...., ;.., ; ,
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Table.2. Applicant's Pnmary Efficacy Anrtlysis: I1TPopulatioIl ;
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Table 3.' Applicilllt's Supportive Allalysis with Proportions pfPatients ExperienQing DiseaseFlill;e: IT!'
.
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.Table. 4. 'Reviewer's.Analyses for~econdaryEfficacyVariables:ITrPopulatiQllWith.]iOCF Imputation.:;.:., '11'
.' .' .Table s. P4tlent Delnographic and BaselineCharacteristics for StudyIMIOl 033(ITTpopida#onEhtered.
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DoubleB1ind'Period);....... ,
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J,figitre'Z 'l\CRPediatric(ESR) Response Rates .over Time.fol'periodB-Ab~taceptCoh()rL ;......,..,,; 15.
.' . Figitre3 ACRPediatric(ESR)Respons~Rites.oyetTinieforPeriod
B-Plac(lboCohort ..: ;...:;.,..;. ;: 16
Figure 4"l\CRPediatric(ESR)l,{esponseRafes overTime for PedodB-Abatacept Cohortwith' ACR .
:RespondersatB169
:.. ,...., ;::::.:;.~ ;.:: :;~: ; ;........................,;
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Figllre5l\CRPediatric(ESR)l{esponseRates.o"erTiirieforPeriodB-Plac(lboCohortvvithACR
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Figi.ife6Reviewet'sKaplan-Meier Curve Estimation: InSubgrbup ofPatients'Age Less Than13:.., ; 19

.. Figi.i.te7.R,eviewer's.Kaplan-MeierCurveEstimation:ITT.Subgrbup.ofPatientsAge .areaterThilIlorEqualto.

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FigUre8"Reviewer'sKaplali-Mei~rCurveEstitnation:ITTSubgroupofMalePatients; ................;...........; 20
Figtire9"Review~r's .Kaplan-Meier Curve Estilliation:'I1'T Subgroup of FemalePatients
20' .
FigutelO':Reviewer's Kaplan-MeierCurve Estilllatiott ITTSubgroup of White Patients::....................... , 21
Figure 11 Reviewer's Kaplan~MeierCurveEstilllatioli:ITTSubgroupofNoil-White Patients .................... 21
Figi.ife12 SchematicofStudyDesign .................... ,...........; ;
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T.3StatisticalIss~esandFindings

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2.

INTRODUCTION

2.1 Overview
2.1.1 Regulatory history
Abatacept was approved for marketing by the US FDA on December 2005 for the
treatment of adult rheumatoid arthritis. The trade name for abatacept is Orencia.
The following is a history' of regulatory interaction described in the submission.
The topic. ofP<::diatric Study Deferral for abatacept was initially discussed at the
End-of"Phase 2 meetill~with the US Food and Drug A(.\mittistration (FDA) on
25-Mar-2002 (refer to the FDA meetillg Jllinutes dated 25-Mar-2002).
TheJRA/JIA study protocol (1M 101033) was proVided to the FDA on 09-0ct
2003 (IND: 9391, Serial No. 0 I (j7) prior to its initiation for review and
comments. OnJ3-Nov-2003, the agencyprovided agreement (via telephone
contact) that the final protocol was appropriately designed to provide the
necessary data for evaluation ofthe safety and efficacy of the product ill the
children and adolescent pOPlllation, and recomtnended few changes to the
protocol. A revised protocol (with Amendm.ent 01) was submitted to the agency
on 11-Dec-2003 (IND: 9391, Serial No. 0184).
The abatacept Biologics License Application (BLA for adultRA wasapproved
on 23-Dec~2005. Post-marketing commitment #l (due on 30-Nov-2006) was the
submission of study results from the JRAlJIA study (IM101033); ttys
commitment was fulfilled on 29Nov-06 by submission of a clinical study report
on Periods A and Bof the study to the original BLA (STN BL 125118).
Further, Bristol-MyersSql.libb (BMS) requested feedbackfrom the FDA on
questions related to the planned pediatric SupplementalBLA (sBLA)
submission on ll-Apr-2007(IND: 9391, Serial No. 0437); an e-mail response
from the FDA was received on II-Apr-2007.

2.1.2 Proposed Indication

The proposed indication for abatacept is toreduce signs and symptoms in pediatric and
adolescent patients with moderately to severely activejuvenile idiopathic arthritis (JIA) /
juveni1~rheumatoid arthritis (lRA) with polyartiCular course who have had an inadequate
response to lor more disease modifying anti-rheumatic drugs (DMARDs), suchas
methotrexate (MTX) or tumornecrosis factor (TNF)-antagonists. Abatacept may be used
as monotherapy or concomitantly with MTX.

2.2 Data Sources

5

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sBLASTN125118.04S.wassllbmittedonJtine8;2Q07anelhas.beertloadedintothe
. GSreyiewtooLTheelectroniCSASdatasetswerealsO.p~ovide<lin the GSreviewusing .
thefollowirigpath:
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\\cbsap58\M\eCTDSubmisslons\STN1251.18\125118.enX
.

..

STATISTICALEVALUATION
..

. .

3;1 EvablationofEfficacy
3.1.1StudYllesignandEndpoints

StildyTMIOI033 wasamulti-national, multi~ceriter;iandomized,withdl'awal.trialto .

. eValllatethe.safetyand.efficacyofabataceptirichildrenaridadolescents with active

polyarlicularjuvenile rheuinatoidarthPtis.
..
,.

Thestudystartedwitha4-month, opell;:;label,Jead-inphase(PeriodA); Subjectswhomet.

thepre~specified'definitionofresponseattheend.ofPeriodAenterediritothe6-month;

randomized,.withdtawal,doub1y-blind,. parallel.group,.placebo-controlled.treatmentphase
..(JleriodB) in whichthe subjectswererandoniizedto continuationofabatacept or switch,
.to.placeb().Response criteriaforentryillto .thedoubleblindphasewasdefinedas.~39% ,
improvementi~at.least3ofthe6JRA/JIAcoresetvariablesarid.2:30%.worstminginnot

more than 1 ()fthe 6JRA/JIAcoreset variables.

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TheACRpediatriccomponellts (JRA/JIAcoreset variables)wereasfollo"Ys:

nU111berofactiyejoints
'.. nU111berofjoititswithlimitedrange ofmotion
physician.global.~ssessr11ent.ofdisea.se.severity
"

parentglobal assessmentofovetall wellbeing

childhood health assessment questionnaire CGHAQ)
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erythrocyte sedimentation rate (ESR).

AUsubJectswho.successfully completed Period 13,.subjectswho.f1aredduringPeriod B,
andsubjects who di4n6tmeetthepre~specifiedresponse. criteria at the end of Period A
were given.anoption.to. enter anopen-label.extensioriphase(PeriodC),Subjects who
discolltinueddue to. safetyreasons wererestrictedfrom entering PeriodC.
In the study PeriodB, 122 eligible patients wererandomi:z:ed toabatacept or placebo in a
1:1ratioat32 centers worldwide including theUS, ,the Eutope (Austriq;France,
Gennany, Italy, Portugal, Spain, and Switzerland), and South Arnerica(13rilzll, Mexico,
and Peru);
6

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A,schematic Qfthestudy is,presenteclin the appendix, (Figure.,12)~.'

The,primaryefficacy'variable.was,tne,time,toocGurrence,9fJRNJIAdiseaBe't1are in.the
double-blind phase (Period B), defined as the elapsed'nuiliberofd!lYsbetween ,the,first
double-blind.dose,and,the'studidaytha-t'diseaseflare,Was' co~fiirned;"Fla.re.~asdefilled.
as:

~'30o/tlw()rsenil1ginatleast3 ofthe6JRAlJIAcoresetvariables

' ~', 30%imptovementinnotnidrethanl ofthe6JRAlJIA coresetvariables

'~',2 Cni,(p~ssibleup,tolOcm}()fworsel1illgmustl1avebeel1present iftlle

PhY1)i~ianorPa,reI1tGlobalAssessmertt wasusecltod~fine)f1are"

'

()~joints,withlimitedrangeofmotiOIiwas.usedto'defil1e.tlare..

w0rsellingill~" '2jointsniusthavebeen,presentifthe nllmberofactive joints

The,secondary,efficacyvanables.ilicIudedthefollowing:
. .~ .

'., proportioh ofsUbjectsthat'demonstrateJRA/JIAdiease'flareby'DayB169

number ofactiveJointsuslngthedefinitionpiovicledbyAiriericall College of
Rheumatology. (ACR)Pediatric 30 (JRAlJIA'core setvariable)
'number ofjoilltswith limited range ofmotiOI1.(JRAiJIAcoresetvariable)
'. disease,aCtivityas.measured,byth.e,pl1ysician;sgl()bal,assessniellt'ofdiseas~
severity{JRNJIAcoresetvariable} '.
,~
. chang;eiIithesubject'soverallw~ll-being'as
measured by the parent'global
'assessll1ent'ofoverall,wellbeil'lg,(JRAlJIA.' coreset,variable)
,.
.' . '. change ilFphysicaLfunction asineasuredbythedis~bilityindex oftheChildho()d
Health Assessment Questi9nnaire ( GEfAQ} (JRA/JIAcoresetvariable) ,.
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cl1anges,in.thesurrogate,inarke~s,Erythrocyte,SedirhentationRate.(ESR)and.C~
reactiveprotein' (CRP}.{JRA/HA'coreset.variable).

, 3.1.2 Patiel1t])isposition and Demographics

Table 1,. sUlll111arizesthe patientdispositionduringthe,open~ labellead-in'period '(Period
A)and double blind period (PeriodB).
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Source:Tables5J and6JoftheC;linicalStudyReport(pages 59 anlj72).IITpopu]atlqn:inc]uded all .
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.' yarra ..esoraCe, se~;age,an . . we1g t . . .sq~t .ere were np noflcea .. lma allces.
hetweentl:eatriieriJgrdups.'Yithn~spectt()thebaselineefficacy vari~~lesofphysician' '.: .
.'...... ... . .' global assessnJ.~nt.parentglobalassessITleIit,c;4ildhoodh ealth assessirH~lltquestionpaite
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.:' . '.' ...'.. ... .....:.'. wereriufnericCillinbalanceshetweertgrOups.inthebaseIine active Joil1fsapdj oirltswith', .'

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'..limited ratigeof motion, althoughnot s.tatisticallytested.~TheIl1ediarisc.oreofati\fe.
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not~cbeal' unf..J:)alan6esbetwe.ed~tre~thIIlel1AtlgroUhPS withTespect~~tlieb lde~ObgrlaphiC

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inotionf6ith~abataceptpatientswas-14: (r~ged\O--'59Yaridt1J.e:rnediartseorefor the

.placebop~ti~I}t~.was9'(tanged2~6,5r"

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.' analy:led.usirig.alog-ratlk.tesi.ACoxproporliopal.hazardregression'model with' a.term
forfteatmeritwasusedtoestimatethehazardratio.an4its95%confidel1ceintervaL
Curvesofthedistributionofdiseaset1are9vertill1efotthetWQtreattrient.grOllPs.were.
... generate4.u~ingtheKaphin-Meiermethod .. Acontinuity.c6rrected.chi~square.test.was.
llsedtocompare.proporti()l1s.of~diseas~.flaie~.betweeIlt~etwo treatrtlent.groups-the
cOtitilluitycortecHonlscrfhmusedWhensatnple sizes are.small andisgel1erally
. cOIlservatiye; An' analysis of cQVanance.ll1odel.witlltenns fortteatmentand'ba~eline
. ,,~lue ascoyatiatewasusedforthe.analYsisofsecqndaryefficacyvanablessuth.as
. hUinber()factiv~joiIitsandnU111herOf jointswith.limitedrangeOfmotipn.
The primaty.a11alysis.wascolldllGtedonthe.iIitent..to.;treat.populationdefiuedasall

.rau~()1liizedsrihjects.tak:irigatleas(onedQseofstlldymedication
..Tntheprimaryamilysis,
.' .sl.ibjeCtsdiscontiriuil1gtreat111elitdue.toieason$otherthan.~disease.flare'.werecensored.
,
.aithe. titlle ofdiscoIltinulltion,Tri the.arialysesofsecoridaiY,eftlcacyvariables,missing
efficacy.datawere.imputedl1sin~the.lastobservationcarried.forwardmethod;
.

".

.~.

3~1.4Re!nlltsand.Conclusiolls
.

- . " "

"

'
"

"

'I'ables.2,~4present.the.statisticalanalysescoliduet~d.~ythe.a.pplicant.andtne,.I
confinned.the.applicant'sanalyses..The.followingaretheres1.llts.bftlie.analyses.
.ItlStridy'IMIOI033,.agreatertreatment.effect(asnle~sured.bytimeto.diseaseflare)was
achieved.hypatients.ieceiving.abataceptas.colllpared{o.thosereceiving.placebo..The..
primaryanalysis4emonstratedsuperiorityofabataceptto,placebohasedoilthelog..tank
test(Table2)..Thetabh::also providedthe hazardratio and its 95% confidenceinterval
. estimationbased on.the.Gox.pfoporfiolialhazardregression.modelwithterm.for
.' treattiient.theriskofdiseaseflareforpatientsin.theabatacept.grollpwas.a.$outonethird
oftheriskfor. patlentsinthe placebo group, .TheKaplan~Meiercllr\Tes,.show1iin.Fj~re
1,depicted,thesi~ificantdifferenceinthetimetodisease.f1aie .amongtreatmen.ts.13ased'
QntheKaplan,;Meiercurves,themediantimeindaysto disea~e.flarefor.theplaceho
. groupwas.1~9 dayswitli95%lmverc()l1fidencebound' of139 days. However, because
most'patielits'inthe abataceptgroup did not experience a flate,'the median tlmewas nbt
estltllable. .
.
.

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~

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were. ~()mparedbetwel1 the:.:.:'.

... abatacep1:a.ndplacebo groups; Patients thatdiscol1timiedpri{)tto hayihgadisease flare

",'

.were c()Irsideredasilothavillghadadi$ease;flare.Jhe
prop6rlionofpatierits.
... ...........

..
/"
'.:
"experiencingdisease flar~bythe end ofPerjoclBcitithe abatllc~p(gfouP was statistically
. significahtlylowerthanthepropQr(:lml
inthe'placebogtbup(Table 3); . .
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Aiff~r~ilCesinIl1eanpercentchang~frotrithebliSeliriejotheetidofdouble-b!in4pel'ioq.: . ".
. < . (periodB)hetweeilthe ~hataceptand>plac~~()g:rOUpS.fbrtheri~lnberQfactiv~;joit1ts;the..

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.........
.:. ipp1ic,mfpr~sehtedtheIIlediiiitpei'CeiltchangescotesfroIllbaseHtieWitJ1"thefirstartd
.. "
..
thirdquarti:lesalthotightheypre-spedfiedtheuse'oftheniea~percentchangescoteswith
..
.' 95%corifidenceiI)t~tvaIsinthestatisticalarialysisplan;A1th9ugh l1otcompletelyclear...
....... .... frol1lth~report;irseemsJhattheiiobjectivewiththesecOhdiu')'vaPables\yascha.n'ged
'
...
..... : ....
.. fromaf6rnial~Oltiparisonofthe.,,$:iClbles,betweentl1eireatinentgioups.toaninforillal
'. .. . .
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descriptioiiofbbserVedtreriddUrii1gPerioq:B:rher~fore,IGOnduciedtheanaiysisof
. .
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.....:. :.cqvariaiic~(ANCOVi\j'asplaIllledfuthestatistl(;alallaIysisplan.Theapplicantinchide4
:...... ' .
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Theeval~ati()l1ofsafety wasconduct~dbYthe~linicalreviei~r,J<'~ith.aull;MJ).

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'.<. ," >o:."CRP":

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..",:.;;., '.' .

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. . ..:::::AsS~ssmentbiff.fr0lll~llicebo:(95~cn . . >1~6(-21i;~62)<.

caAQ..... . ,BaSelin6MeliIi(SD) ." , ..' <8(8)

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.....

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..... :

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, ".' ":'::': .".: ,wouldhave6Yetestimatedthetreatiri(m~etf.ect.lAthean:alysisofthesecondaryvariables, .....

... . .. . . .:&~~~:diM:e:"totfh%=~S:u:-:::b~J~~~~~:~;:aZ~:;Il~~Ol1 . . .

";""~-"""~~.~"\;;".- .

oftreattneI1teffectsacmsscenterstobetneaning(uLAlso,.itisWorthwhile tonoteJhat

"'.' .. ' '

'analyse$'forth~'sec6ndary-elldpoilltsweie'ilotadjustedfoillltiltJplidty:
',':
,
.'., ..
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.',

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" "",' 'StridYIM.r()io33\\!ascolldllct~diticl1ildien~Ildad61escetltswith~ctiv~polyarticular
"'
... :
":'.: .. ''."
", 'j~venilerheum~toiqarthtHisf6rthepediatricefficacysupplrrierifforabata2epLThe
.
" ," '. ',' '. ""'itudydemoQstratect"agreater effectofab~ta~eprc()mparedtopI~cebo\titreatingsigns ' '.. ~. .
..... . .
. andsytnp~otnsofjuvenilerb.ellmatoidatthritis(J]tA)ljuvenilejd1oPtlthiC arthritis (JIAj . .
'.
..... . ". 'TheeffeCtwasID.eastiredbytiine.t(),()cc~rreric~()fdiseaseflarebasedonACRPediatric.
J O(JIWlIAcoresetvadables). The\effectwas'e"ideritinbot4theapplicant'sanalyses .....
andtheadditiol1aF~~aIYsesconductedbyt1ie~"
.
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' Thefonowin~isth~porti~ri()ftheClimcarStud)'.s~ctionfrol11thepropc>sedlabe1 with...

the results ofpediatncstUdy4ata arialyses~. ".' .....

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14

l.foundthafthe"esultsollthepriinaryanalysesfo!timetodiseaseflare&re.consistent
'.'
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. .....
: .. ".
.. . . . . ....
'.
'..
.
withtheteports ofthe'analysesofpeqiatricefficacy dat~i;
' . ' , .' . .., '. .
.the.claitrl.ofinairltenanceofeffectmea~uredin.theopenlabelextensionphase.(Penod
'.' ,C)isnolsllbstantiafedcoti~i4eri1igthanhestudy,as riotcbniplete artdonlyapartial
ain()unt.ofinforp:iationwas.l;ivaila~le.Alsothe.ptesentati9n
ofthe.availaple.dataisnot

mostdesira\)le.withrespectto.fheclarU1.'I'h~.f()l1owiIigfigureswere.presented.tosupport

thedahnbytheapplicartt. .

..

. .

."

.. . '.

Figure'2 ACR:Pediatric.(ESR)]{esp()use.Rates,oYf.'r'timeforPerio4:B-Abatacept
Cohort
'.'
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'.
.
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.
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.

C169

Aba(n)
.

58.'

'~Ii!llion:AJI Trea12dSW!j:ects in PeriodC:

:AlIswbjei:!s ~ivedi!lJced.dose ofab~iriPeriod Q;
Resp:lnse inmrmaliQn rorPeriQII C isde!ilted frtm o~d data,

ClassJli!:aIiOrl Qhesp:lilse.basedoo Yalue observed atOiIJ/l\1.

VisitNumberCD1 =Perlod'8DiIJ/' 1ell LOCE

.'

Souroe: Tabk!5.5.1
.

,Source.Figure7.2Aofthe8tiIdY Repo]:tlMlOI033~LT"CSRcADDENDOl(pages59al1d
60}.

15

Figure'3 .ACR.Pediatric.(ESR.) Response Rates'ovet.Timefor.Petiod.B':Placebo

"Coh()rt
. ,
.

.....

'."'

"1','

51
pqlul;itJpn;A1IT~~~PeiiodC, .
Ail5ubjecl$~aieddc"trd~iJlPmiOdC.

, ,',

" .~~in~for'~Cfs~frI!m~crata,
.' ~~af~~ on~ueQtiseived atOiiyA,1.

VlSltNU.C01=PeriDdSOaytl19LOCF.
SI:Ul:e: Tilble SJi.1
.

"

..

Source.
Figure
7.2AoftheStiJdyReport
IM161033~LT::CSR-ADDENDOl(pages59and
60}.

_ _
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.
,

Apiobleniwith.thegraphs.isthatap~tientcollldpeanACR.responderat'somevisitdays
andnofatthe.othervisit.days;and,it.isdifficult,todeten11ineifa patient.maintains.an

'effectmeasured by the ACR. response over a>clinicallymeaningfulperiodoftime.In '.

addition,'this.portion.ofthestudyis.ongoillg.Thus,.patientshavevariable.al1lountsof
data collectedoVertiille. Afteradiscllssion withtheclinicalnwiewer,Dr, Keith'Hull,l
'.. genElratedthe.fol1owing.graphsto.be~terdescribe.the.ma.inteflanceoftheeffect.My
.
.analyses.focus'.on.tracking.therespollsestatusofpatiellts.who'wererespondersatthe
ehtryoftheopelllahelpeiiodarideValuating.howmanyofthemmaintained the effect
overan extendedperiod,However,sincethestudy is ongoing, it is hard torelyonmy
graphsbecauseattritionofpatients.acrossdays couldbesimplYdue.to.thenatl,lreof
.ongoingstlldyratherthanduetodropoutornon-response.

16

..

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APPENDIX
.. .

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. .

Table5.PatientDemogr~phicalld:lJaselilJ.eCharaeteristicsfo r'StttdyIlVIlOl033'(ITT
Population<EnteredUoubleBlfudPeriod)

(N=60)
..

'

".

..

43 (7Z%)
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...

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Native:Hawaiilitilbther .'
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.. "1(2%)

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..... Median
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8{13%)

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1
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37.9

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. . CIIAQ])isabj.lltYIndex

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.' ....

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2~65

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.'. ..1.3
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O.O~2.6

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0.0~92.0.

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..

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.' PareiitGlobalAssessnumt

Median
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1.0~95.0

....
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PhYsiciaDGlobalA,ssessment

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18.0-99.0 '.
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1O.0~98.0

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.. Median
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505

..

26.0

LO~129.0

....

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.. '

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... 23.5

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CJ.Ul(mg/dL) ...

..Median
Range

....

1.2
....

0:9

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18

.
.

..

..4LO

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'

"0(0%)"

NmnberofJoii,lts withLOIVl.

Range

.
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9(14%) .

6'7-1'1

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. Median
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NuIriber ofActive Joints

Median

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Other .'

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4H13%)' .
17{i'7%)' ....

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~=62)

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'17(28%)
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'Plac~bo

Abatacept

Figure 6 Reviewer's Kaplan-Meier Curve Estimation: ITT Subgroup of Patients Age

Less Than 13
1.00

0.75

0.50

0.25

0.00

25

75

50

100

125

150

175

200

Qlys to R rst Rare

trt~

--trt~

000 Gnsoreel

--trt~

o 0 0 Gnsor eel t rt nare=A...JlCEB:

Note: V-axis denotes proportion of patients without disease flare.

Figure 7 Reviewer's Kaplan-Meier Curve Estimation: ITT Subgroup of Patients Age

Greater Than or Equal to 13
1.00

O. 75

0.50

0.25

0. 00'

50

25

75

100

125

l:Bys toR rst

STfil>.TA

- - trt~

- - t rt

150

175

200

225

A are

0 0 0 Cl3nsored trtnaro<=PBKPr
Q 0 0 Cl3nsored t rtnart<J>=Fl..l.'

Note: V-axis denotes proportion of patients without disease flare.

19

Figure 8 Reviewer's Kaplan-Meier Curve Estimation: ITT Subgroup of Male Patients

1.00

0.75

0.50

0.25

0.00

25

75

100

STR\.TA

--

175

150

125

Doys to Rrst

200

A a-e

0 0 0 Oonsored t r t ~
o 0 0 Clansor ed t rt ......-=t.J'CEE

trt~

- - t rt nart6FR..JOCEB:

Note: Y-axis denotes proportion of patients without disease flare.

Figure 9 Reviewer's Kaplan-Meier Curve Estimation: ITT Subgroup of Female

Patients
1.00

O. 75

0.50

0.25

0. 00

75

25

125

100
[Bys toR ,-st

STR\.TA

- - t rt

- - t r t name=R.PCEEO

150

175

200

225

A are

0 0 0 Clansored t rt ~
0 0 0 Clansored t rt nan<e=A..PCEB::

Note: Y-axis denotes proportion of patients without disease flare.

20

Figure 10 Reviewer's Kaplan-Meier Curve Estimation: ITT Subgroup of White

Patients
1.00

O. 75

0.50

0.25

0.00

25

75

50

125

100
OJys to A r51

SfRl\TA

- - t rt~
- - trt~

175

150

2DO

22S

A are

0 0 0 Gnsored t rt ~
0 0 0 Gnsored t r t ~

Note: Y-axis denotes proportion of patients without disease flare.

Figure 11 Reviewer's Kaplan-Meier Curve Estimation: ITT Subgroup of Non-White

Patients
1.00

O. 75

0.50

0.25

0.00

25

50

75

100

125

t:::llys to R rst

SfRl\TA

--trt~

--

trt~

150

175

2DO

Rare

OOOGnsoredtrt~

0 0 0 Gnsored

trt~

Note: Y-axis denotes proportion of patients without disease flare.

21

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SIGNATURES/DISTRIBUTION LIST

Primary Statistical Reviewer: Yongman Kim, Ph.D.

Mathematical Statistician

Date:
February 7, 2008
Concurring Reviewer:

~j)()

'~ef/~

Dionne Price, Ph.(J_

Team Leader
~

cc:

DAARP/Sara Stradley
DAARP/Keith Hull, M.D.
DAARP/Jeffrey Siegel, M.D.
DAARP/Rigoberto Roca, M.D.
HFD-715/YongmanKim, Ph.D.
HFD-715/Dionne Price, Ph.D.
HFD-715/Thomas Permutt, Ph.D.
HFD-700lEdward Nevius, Ph.D.
HFD-700/Lillian Patrician

23