HST190:IntroductiontoBiostatistics

Lecture4:Clinicaltrials

Simplelinearregression

1 HST190:IntrotoBiostatistics

Clinicaltrials

• Throughoutthecontinuumofhealthcare,patientsandprovidershavetomakedecisions§ e.g.betweenonetreatmentchoiceoranother

• Asresearchers,weseektoestablishevidencetohelpthatdecision

• Thearemanywaysthatwecouldchoosetoachievethis

• Randomizedclinicaltrialsareviewedasgeneratingthestrongest,mostcompellingevidence§ atleastforindividualstudies

§ metaanalyses/systematicreviews

HST190:IntrotoBiostatistics2

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• Clinicaltrialscanandhavebeenusedtoinvestigateawidevarietyofpotentialdecisions:1) prevention

§ Mediterranean-styledietoncardiovascularoutcomes§ Estruch etal(AnnalsofInternalMedicine,2006)

2) screening/earlydetection§ breastcancerscreening§ Tabar etal(TheLancet,1985)

3) diagnostictesting§ ventilator-associatedpneumonia§ CanadianCriticalCareTrialsGroup(NEJM,2006)

4) therapeutics/treatment§ chemotherapy&radiationvs.radiationaloneforesophagealcancer§ Cooperetal(JAMA,1999)

5) qualityoflife§ family-supportinterventioninICUs§ Whiteetal(NEJM,2018)

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• Fortherapeutics,thereareusuallyfourphases:

• Randomizedtrialsarerequiredtoberegistered§ atwww.ClinicalTrials.gov intheUS

§ otherentitiessuchaswww.clinicaltrialsregister.eu inEurope

§ submitadetailedprotocolbefore thestudybegins

Components

• FundamentalsofClinicalTrials.Friedman,Furberg,DeMets.2010

• Scientificcomponents:§ studypopulation§ interventionsandhypotheses§ primary(andpossiblysecondary)endpoints

• Studyfeatures:§ typeofrandomization§ extentofblinding

• Analyses:§ choiceofstatisticalframework§ samplesize/powercalculations§ interimmonitoring

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Specifyingthestudypopulation

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• Basisfortheinterpretationofthestudyresults

• BreastcancerscreeningfromLecture1:§ generalpopulation

§ women<40yearsofage

§ womenwhohadundergonebreastaugmentation

§ womenwhoare“medicallyvulnerable”

• Key:thereisnosingle“correct”answer

• Choiceshouldbe:§ clinicallymeaningfulandrelevant

§ onefromwhichitwillbefeasibletorecruitandfollowparticipants

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• Choicemaybedetermined,inpart,by§ previouswork/studiesinthesamearea

§ likelihoodofadverseeventsorcompetingrisks

• Importanttorecognizethatinterventionslikelyhaveheterogeneouseffects

• Thebroaderthechoiceofstudypopulation,theresultswillbe:§ moreinclusivebutlessspecific

§ moreamenabletouseinpolicydecisionsbutlesssotopersonalizeddecisions

Hypotheses

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• InLecture3wewereintroducedtohypothesistesting:§ nullhypothesisisthe“statusquo”§ gatherandquantifyevidenceinfavorofsomealternativehypothesis

• Inthissense,thealternativetypicallyrepresentstheprimarygoalsofthestudy

• Usuallyframedinoneoftwoways:1. Superiority

§ treatmentAbetter thanB

2. Non-inferiority§ treatmentAnotworse thanB§ treatmentAmaybebetterthanBintermsof,say,cost orsafety§ requiresspecificationofanacceptablemargin

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• TheARISTOTLEstudy§ Grangeretal(NEJM,2011)

• Primaryobjective:non-inferiority§ upper95%confidencelimitofthehazardratio<1.38

• Secondaryobjective:superiority§ upper95%confidencelimitofthehazardratio<1.00

n engl j med 365;11 nejm.org september 15, 2011 981

The new england journal of medicineestablished in 1812 september 15, 2011 vol. 365 no. 11

Apixaban versus Warfarin in Patients with Atrial Fibrillation

Christopher B. Granger, M.D., John H. Alexander, M.D., M.H.S., John J.V. McMurray, M.D., Renato D. Lopes, M.D., Ph.D., Elaine M. Hylek, M.D., M.P.H., Michael Hanna, M.D., Hussein R. Al-Khalidi, Ph.D., Jack Ansell, M.D., Dan Atar, M.D.,

Alvaro Avezum, M.D., Ph.D., M. Cecilia Bahit, M.D., Rafael Diaz, M.D., J. Donald Easton, M.D., Justin A. Ezekowitz, M.B., B.Ch., Greg Flaker, M.D., David Garcia, M.D., Margarida Geraldes, Ph.D.,

Bernard J. Gersh, M.D., Sergey Golitsyn, M.D., Ph.D., Shinya Goto, M.D., Antonio G. Hermosillo, M.D., Stefan H. Hohnloser, M.D., John Horowitz, M.D., Puneet Mohan, M.D., Ph.D., Petr Jansky, M.D., Basil S. Lewis, M.D.,

Jose Luis Lopez-Sendon, M.D., Prem Pais, M.D., Alexander Parkhomenko, M.D., Freek W.A. Verheugt, M.D., Ph.D., Jun Zhu, M.D., and Lars Wallentin, M.D., Ph.D., for the ARISTOTLE Committees and Investigators*

A bs tr ac t

The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Granger at the Duke Clinical Research Institute, Duke University Medical Cen-ter, DUMC Box 3850, Durham, NC 27715, or at christopher.granger@duke.edu.

*The members of the steering commit-tee, as well as other committee members and investi gators in the Apixaban for Reduction in Stroke and Other Throm-boembolic Events in Atrial Fibrillation (ARISTOTLE) study, are listed in the Supplementary Appendix, available at NEJM.org.

This article (10.1056/NEJMoa1107039) was published on August 28, 2011, and up-dated on August 30, 2011, at NEJM.org.

N Engl J Med 2011;365:981-92.Copyright © 2011 Massachusetts Medical Society.

BackgroundVitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin.MethodsIn this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic em-bolism. The trial was designed to test for noninferiority, with key secondary objec-tives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause.ResultsThe median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the war-farin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P

Choiceofcontrolgroup

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• Suppose“TreatmentA”isthekeyinterventionthatweareinterestedin§ e.g.onedevelopedbyyourresearchgroup

• Howdowechoosethecomparisonorcontrolintervention,“TreatmentB”?§ choicehasimplicationsforboththeinterpretationandnumericalvalueoftheeffectthatisultimatelyestimated

• Ideally,thechoiceshouldreflectthechoicethatpatientsactuallyhave§ premiseisthatweareconductingthetrialtogatherevidencethatwillinformsomesuchdecision

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• Ifthereisnoestablishedstandardofcare,thenonemaysetthecontroltobeaplacebo§ i.e.interventionwithoutany(biological)therapeuticeffect

• Ifthereisanestablishedstandardofcarethenoneshould,arguably,useit§ unethicaltotreatpatientsinawaythathasthepotentialtobelesseffectivethanaknowncourseoftreatment

§ wouldnotgiveaplacebotoapatientwithmalaria!

Choiceofendpoints

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• IntheARISTOLEtrial,theprimaryendpoint wasincidenceofischemicorhemorrhagicstrokeorsystemicembolism§ duringupto30monthsoffollow-up

• Theyalsoreportontwosecondaryendpoints§ bleedingandmortality

• Usualparadigmrequirespre-specificationofprimaryendpoint:§ basisforpower/samplesize

§ dependingonthedisease,FDAmaymandatespecificendpoints

§ typicallyrequiredtoreporttheresultsfortheprimaryoutcome,regardlessofwhetherthehypothesesareconfirmed

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• Mayuseco-primaryendpoints,suchasfunctionalandcognitiveendpointsforAlzheimer’sdisease,oracompositeendpoint,suchasdisease-freesurvival

• Secondaryendpointsalsotypicallypre-specified§ typicallylessstringencywithregardtoerrorrates

§ consideraccommodatingpowerforsecondaryendpoints

Iteration

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• Studyisconceivedthroughdiscussionaboutquestionsofinterest§ arepopulationsavailabletoaddressquestions?

§ areendpointsavailableandmeasurabletoaddressquestions?

§ isthisallfeasible(time,money,ethics,patientsupport,cliniciansupport)?

• Questionsmayneedtoberevisedaccordingly§ givenreality,whatrelatedquestionscanactuallybeaddressed?

§ arethesequestionsasimpactfulasthoseoriginallyposed?

• Endpointsmayalsoberevised§ givenreality,whatcanactuallybemeasured?

§ willtheseendpointsservetoaddressthequestionsofinterest?

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• Asanexample,considerpatientswhoarehospitalizedafterhavingexperiencedanacutestroke

• Question:§ Dopatientsonoxygenexhibitbetterfunctionaloutcomesat24hoursthanpatientsonroomair?

• Plantoconductarandomized,double-blind,clinicaltrialofoxygenvsair§ primaryoutcome:NationalInstitutesofHealthStrokeScale(NIHSS)

§ measureNIHSSat0hoursand24hours

• Problem:§ somepatientsdiewithin24hours

§ NIHSSat24hoursisnotwell-definedfortheseindividuals

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• Possiblewaysforward:1) changequestion:amongpatientswhosurviveto24hours,are

patientsonoxygenbetterwithrespecttoNIHSSthanpatientswithoutoxygen?

2) somehowconstructacompositeendpointthatfoldsindeathwithin24hours

3) changeeligibilitycriteriatofocusonpatientswhoareveryunlikelytodiewithin24hours

Randomization

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• Centraltothestrengthofevidencethatclinicaltrialsprovide§ intuitively,ruleoutallotherexplanationsfordifferencesbetweenthetwogroups

§ onaverageatleast(!)

• Supposetherandomizedtrialhastwoarms§ asintheARISTOTLEtrial

• Onewayofallocatingpatientstoagiveninterventionistoflipa(digital)coinforeachpatientastheyarerecruited§ simpleandeasytoimplement

§ drawbackisthatyoumightget“unlucky”andendupwithunevennumbersinthetwogroupsand/oroverrepresentationofimportantsubgroupsinonearmortheother

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• Blocking:§ aspatientsarerecruited,createblocksofsize2,4or6etc

§ randomlyallocatehalftoonearmandhalftotheother

§ guaranteesbalance(orveryclosetoit)inthesamplesizeswithineacharm

• Stratification:§ toachievebalanceintreatmentassignmentwithinimportantfactors

§ itwouldbedisappointingif,bychance,allofthetreatmentAwasallocatedtoasinglestudysite

§ otherfactorsmightinclude:gender,baselinediseaseseverity,pastexposure

• Adaptivedesigns§ basedonbaselineprognosticfactors

§ basedonresponses

Blinding

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• Thereisapotentialforbiastoariseifeitherpatientsorstudystaffknowwhichtreatmentisbeingadministered§ perhapsespeciallysoinplacebo-controlledtrials

• Blindingcorrespondstoanefforttohidewhichtreatmentisbeingadministered§ e.g.shape,colorandsizeoftabletisthesame

§ e.g.labellingofstudymaterialsisgeneric

• Canbechallenginginsomesettings§ e.g.surgicalinterventions

§ e.g.mechanicalinterventions

Analyticframework

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• Determinedby:1. thenatureoftheendpoint

2. thehypothesisbeingassessed

3. thestudydesign

• Natureoftheendpoint:§ continuous(e.g.,cholesterol)

§ binaryorcategorical(e.g.,response)

§ time-to-event(e.g.recurrentormortality)

§ ordinal(e.g.,functionalscale)

§ longitudinal(e.g.weightchangeovertime)

§ multivariate(e.g.,genes,familymembers,voxels)

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• Translatethehypothesesintoastatisticaltestand/ormodel§ two-sampletest

§ e.g.two-samplet-testorWilcoxontest

§ e.g.two-samplelog-ranktest

§ regressionmodelo e.g.linearregression

o e.g.logisticregression

o e.g.Coxregression

• Additionalanalysisconsiderations§ accommodatingdesignfeaturessuchasblockingand/orstratification

§ interactionterms,suchagroupxtimeinteractions

§ “siteeffects”inmulti-sitestudies

Elementsofdesign

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• Question:Howbigshouldmysamplesizebe?§ clearlyimportantimplicationsforcostandfeasibility

• Typicalframingistoconsiderstatisticalpower forafixedtypeIerrorrate(i.e.alphalevel)§ Recallslide56inLecture3

§ P(RejectH0|H1 istrue)=1– typeIIerror

• Asoneincreasesthesamplesizeweareincreasinglylikelytorejectthenullhypothesisifitisinfactfalse

• Option#1: Pre-specifypower(e.g.80%or90%)andcalculatetherequiredsamplesize

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• Insomesettings,theremaybefinancialconstraintsonhowmanypatientscanberecruited§ budgettotalsimposedbythefundingagency

§ costoftreatment

§ costoffollow-up

• Option#2:Pre-specifythesamplesizeanddeterminehowmuchpowerthestudywillhave

• Interplaybetweensamplesizeandpowerwilldependonarangeoffactors(slide65ofLecture3),including:§ effectsize

§ variationintheoutcomeinthepopulation

§ missingdata(e.g.drop-outorcensoring)

Performtheanalysis

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• Queryandcleanthedata§ resolveissuessuchasimplausiblevalues

• Performatestand/orfitamodel

• Typicallyprescriptive(atleastinitially)§ planshouldhavebeenlaidoutintheprotocol

§ minimizesthepotentialfor“gaming”thedata(oratleasttheperceptionofit)

§ manyjournalswillrequiresubmissionoftheprotocolandholdyoutowhatyousaidyouwoulddo

• Summarizeandinterprettheresults§ frombothastatisticalandscientificperspective

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• Oftenthecasethatadditionalissuesarise§ difficultiesinrecruitment

§ imbalancebetweenstudyarms

§ non-compliancewiththestudyprotocol(seelater)

§ drop-out

§ lowerthananticipatedeventrate

• Eachofthesewilllikelyrequiresomemodificationtothestatisticalanalysisplan

• Dangerinthatitopensthedoortotheperceptionthattheresultsmaynotbe“objective”§ strongargumenttothinkaboutthesethingsup-front

§ sensitivityanalyseswilllikelybeimportant

Per-protocolvs.intent-to-treatanalyses

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• Akeycomponentoftheprotocolisadetailedspecificationofwhatthe“intervention”is§ timing(e.g.singlevsatmultipletimepoints)

§ dosage,byarmandovertime

§ modificationsthatmaybeclinicallynecessary,suchascontraindicationsoradverseevents

• Ideally,patientsandstudystafffollowthisprotocol

• Inreality,deviationscanoccur§ non-compliancewithdosingand/orschedule

§ treatmentswitching

§ concomitanttreatment

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• Impactofdeviationsfromtheprotocol?

• Supposetherearedeviationsfromtheprotocol

• Onecouldproceedwithananalysisthatattemptstorecoverwhatwewouldhaveseenhadtherebeennodeviations§ per-protocol(PP)analysis

§ onlyincludeonfollow-upduringwhichtheprotocolwasadheredto

§ statisticaladjustmentstoaddresspotentialbiasthatmaybeintroduced

• Analternativewouldbetoignorethefactthatthedeviationsoccur§ intent-to-treat(ITT)analysis

§ maynotreflectthe“biologicaleffect”butis,arguably,betteralignedwitheffectsthatwewouldseeinthe“realworld”

Subgroupanalyses

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• Theresultsfromclinicaltrialsaretypicallyreportedintheformofasinglecontrast§ acrossallparticipants

§ intentionisthattheresultsbegeneralizabletothestudypopulation

• Itmaybeplausiblethattheeffectofaninterventiondiffersindifferentsub-populations§ treatmenteffectheterogeneity

§ e.g.bydiseaseseverityatpresentation

§ e.g.bysomesocio-demographicfactor,likeageorsex

§ e.g.bysomegenomicmarker

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• Salloway etal(NEJM,2014)§ Bapineuzumab asatreatmentforAlzheimer’sdisease

§ twodouble-blinded,randomized,placebo-controlledPhaseIIItrialso APOEε4 allele carriers

o APOEε4 allele noncarriers

§ co-primaryendpoints:o Alzheimer'sDiseaseAssessment

Scale(ADAS-cog11)

o DisabilityAssessmentfor

Dementia(DAD)

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• Subgroupanalysesshouldbepre-specified§ ideally,inthestudyprotocol

• Evenifnotpre-specified,maybeimportantasameanstogeneratepreliminarydataforfuturestudies

• Statisticalassessmentofheterogeneityacrosssubgroupsviaaninteractiontest

• Subgroupanalyses,however,aresusceptibilityto§ falsepositivesbecauseofmultipletestingacrosssubgroups

§ falsenegativesbecauseoflowsamplesizewithinsubgroups

• Myownapproach:§ reportallsubgroupanalyses(i.e.notjustthosethathavep<0.05)

§ donotreportintheAbstract(i.e.justintheResults)

Interimmonitoring

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• Insomeinstances,itmaybedesirabletostopatrialearly§ efficacy,safetyorfutility

• Toinformsuchadecisionatrialmightpre-specifyinterimanalyses§ performedatasetofpre-specifiedtimesduringthetrial

§ e.g.onthebasisofpatientaccrual

• Decisiontostopistypicallymadebyadatasafetyandmonitoringboard(DSMB)§ independentboardofclinicians,statisticians,patientadvocates,andethicists

§ alsoreviewstudyprogress(e.g.accrualandconduct),andadverseevents

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• Advantages:§ findeffectivetreatmentquickly

§ minimizeexposuretoanunsafetreatment

§ savemoneyandtimeonineffectivetreatment

• Disadvantages:§ mayloseopportunitytogaininformationonsecondaryendpoints

• Requiresadjustmentstotheanalysistoensuretheoverallalphalevel§ thereisanopportunitytomakea“mistake”ateachinterimanalysis

§ desirabletopreservetheoverallP(rejectH0|H0 istrue)

• Interimmonitoringparameters§ numberofinterimanalyses

§ stoppingrule

Evidencetriangle

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SimpleLinearRegression

• Sofarwehavefocusedonstudieswherethereareafixednumber(typicallytwo)groupsbeingcompared§ Lecture3:hypothesistesting

§ Lecture4:clinicaltrials

• Framedthroughaninvestigationoftheassociationbetweentreatmentchoiceandsomeclinicalendpoint

• Achievedbycomparingsomepopulationparameter,suchasthemeanormedian,ofY within“levels”of𝑋§ e.g.E Y X = 1 − 𝐸 𝑌 𝑋 = 0 = 𝜇, − 𝜇-

• Note,thiscomparisoncanbeviewedasasummaryofthejointdistributionof(𝑋,Y)

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• Considerthequestion:Whatistheassociationbetweengestationalageandbirthweight?§ dataonbirthstofirst-timemothersinNorthCarolinabetween2003and2004

• “Exposure”iscontinuous,andnotreallyamendabletothe“twogroup”paradigm

• Needtothinkofanalternativewayofsummarizingthejointdistributionofgestationalageandbirthweightsothatwecanlearnabouttheirassociation

Gestational age, weeks

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