Flexible Surrogate Marker Evaluation from Several

1、TECHNICALREPORT0661FLEXIBLESURROGATEMARKEREVALUATIONFROMSEVERALRANDOMIZEDCLINICALTRIALSWITHCONTINUOUSENDPOINTS,USINGRandSASTILAHUNA.,PRYSELEYA.,ALONSOA.,andG.MOLENBERGHS*IAPSTATISTICSNETWORKINTERUNIVERSITYATTRACTIONPOLEﬁrststudiedbyPrentice(1989),whopresentedadeﬁnitionofasurrogateaswellasasetofcriteria.Freedmanetal(2001)supple-mentedthesecriteriawiththeso-calledproportionexplainedafternotifyingsomedrawbacksinPrentice’sapproach.Buyseetal(2000)framedtheevaluationexercisewithinameta-analyticsettin。

2、g,therebyovercomingdiﬃcultiesthatnecessarilysurroundevaluationeﬀortsbasedonasingletrial.Inthispaper,webrieﬂyreviewthemeta-analyticapproachforcontinuousoutcomes.Advantagesandproblemsarehighlightedbymeansoftwocasestudies,oneinschizophreniaandoneinophthalmology,andasimulationstudy.Oneofthecriticalissuesforthebroadadoptionofmethodologyliketheonepresentedhereistheavailabilityofﬂexibleimplementationsinstandardstatisticalsoftware.WehavedevelopedgenericallyapplicableSASmacrosandRfunctions,atthereader’sd。

3、isposal.SomeKeyWords:Adjustedassociation;Hierarchicalmodel;Meta-analysis;Proportionex-plained;Random-eﬀectsmodel;Relativeeﬀect;Surrogateendpoint.1IntroductionSurrogateendpointscomeintoplayinanumberofcontextsinplaceoftheendpointofinterest,referredcommonlytoasthetrueormainendpoint.Theuseofsurrogateendpointsispotentiallybeneﬁcial,whentheseendpointscanbemeasuredearlier,leadingtoarapidapprovalofexperimentaldrugs,orcanbeadministeredconveniently,whichcanbeequatedtolessburdenonthesideofboththeexperiment。

4、erandthepatients(BuyseandMolenberghs1998).Theuseofsurrogateendpointsinclinicalpracticeisincreasing.Thereareseveralcasesinwhichthereisaneedforanacceleratedapprovalofanexperimentaldrugsothatitsbeneﬁtcanbewitnessedinashortertimespan.Thisisespeciallytrueinthecaseofchronicdiseaseswithhighsocietalcost.1Ideally,thereshouldbeguidelinestodeclareamarkerausefulsurrogateforaclinicalendpoint.Twopossibleviewsarepossiblewhenevaluatingamarker.Theﬁrstdealswiththeindividualpatientlevelandisconnectedwiththebiologi。

5、calpathwayfromthesurrogatetothetrueendpoint.This,however,doesnotnecessarilymeanamarkerisusefultocapturethetreatmenteﬀectinthesettingofaclinicaltrial.Therefore,asecondview,focusingonthetreatmenteﬀectisnecessaryandpossible(FlemingandDeMets1996).Precisely,thislevelquantiﬁestheassociationbetweenthetreatmenteﬀectsonthemarkerandtheclinicalendpoint.Buyseetal(2000)andBurzykowskyetal(2004),amongothers,havepresentedameta-analyticmodelingframework,withinwhichbothformsofvalidationcanbeundertaken.Akeystumbli。

6、ngblockforthepracticaluseistheavailabilityofﬂexibleimplementationswithinstandardandcommonlyusedsoftwarepackages.Thepurposeofthispaperistoreviewthevalidationframework,toexemplifythemethodologyintwoclinicaltrialsettings,andtopresentagenericRfunctionandSASmacro.Computationalissues,thatcanbesourcesofconcern,andofwhichthepractitionershouldbeatcurrent,arediscussedindetailandillustratedthroughasimulationstudy.Theseissuescenteraroundthechoiceofunitofanalysis,treatmentcodingschemesandproblemswithnon-posi。

7、tivedeﬁniteandill-conditionedmatrices.Therestofthispaperisorganizedasfollows.AnintroductiontothemotivatingstudiesisgiveninSection2.ThediﬀerentvalidationmethodsareoutlinedinSection3withthemethodsthatarebasedonthemeta-analyticapproachreviewedﬁrstfollowedbynumberofsimpliﬁedcomputationalstrategies.Computationalissues,arisingwhenusingthemeta-analyticapproach,arediscussedinSection4.Section5containstheresultsofthecasestudiesperformedonthedatasetsintroducedinSection2.2MotivatingCaseStudiesWewillpresenta。

8、casestudyinschizophrenia,followedbyoneinophthalmology.22.1AMeta-analysisofFiveclinicalTrialsinSchizopherniaThedatacomefromameta-analysisofﬁvedouble-blindrandomizedclinicaltrials,comparingtheeﬀectsofrisperidonetoconventionalantipsychoticagentsforthetreatmentofchronicschizophre-nia.ThetreatmentindicatorforrisperidoneversusconventionaltreatmentwillbedenotedbyZ.Schizophreniahaslongbeenrecognizedasaheterogeneousdisorderwithpatientssuﬀeringfromboth‘negative’and‘positive’symptoms.Negativesymptomsarecha。

9、racterizedbydeﬁcitsincogni-tive,aﬀectiveandsocialfunctionsforexamplepovertyofspeech,apathyandemotionalwithdrawal.Positivesymptomsentailmoreﬂoridsymptomssuchasdelusions,hallucinationsanddisorganizedthinking,whicharesuperimposedonmentalstatus(Kay,Fiszbein,andOpler1987).Severalmea-surescanbeconsideredtoassesapatient’sglobalcondition.Clinician’sGlobalimpression(CGI)isgenerallyacceptedasanadmittedlysubjectiveclinicalmeasureofchange.Here,thechangeofCGIfrombaselinewillbeconsideredasthetrueendpoint,deno。

10、tedbyT.Itisscoredona7-gradescaleusedbythetreatingphysiciantocharacterizehowwellasubjecthasimprovedsincebaseline.AnotherusefulandsuﬃcientlysensitiveassessmentscalesisthePositiveandNegativeSyndromeScale(PANSS)。