Fu#leorNot?AnInterimAnalysisCaseStudy

IngridFranklin,VeramedLimitedRosalindWalley,UCBPharma

10thOctober2017

  Iן

  Iן

  Cן

  Pן

  Sן

Contents2

InterimAnalysisDefined3

RulesofThumb•  Mustbepre-specified•  Conductwhen≥40%subjectshavecompleted

InterimConcerns•  IncreasedtypeIerrorrate(interimforefficacy)•  IncreasedtypeIIerrorrate(interimforfuElity)

ICHE9–Astudyshouldonlybestoppedearlyfor:•  Ethicalreasons•  Unacceptablepower

InterimAnalysis:Analysisofthedataconductedbeforedatacollec3on hasbeencompleted,whichmayresultinastudyadjustment

CaseStudyIntroduc#on4

StudyOverview:Ø PhaseIIstudy.Raredisease.Ø PrimaryEndpoint:TreatmentdifferenceatWeek12(Endof

treatment)indiseaseacEvityscore-conEnuous.Ø Double-Blind,ParallelGroupDesign:

–  PlacebovsTreatment(1:1randomisaEon)

TreatmentDifferenceatWeek12

SD False+veRate

Power nperarm(TotalN)

3.8 5 5% 80% 29:29(58)

ClassicalFrequen#stSampleSizeCalcula#on:

Nullhypothesis:Thereisnodifferenceindiseaseac.vityscorebetweentheplaceboandthetreatmentgroupsatweek12.

InterimAnalysisOp#ons5

Ø  InterimforFu#lity

Ø  InterimforEfficacy

Ø  InterimforSampleSizeAdjustment

Ø NoInterimAnalysis

Ini#alDecision:Ø NOTtoincludeaninterim

IncreasedBudget

Norecruitmentconcerns

+

TeamRequestforInterimAnalysis6

Why:Ø SlowRecruitment:

– ConcernaboutwasEngresources– Seniormanagementrequestformalinterimtoassessforfu.lity

Sta#s#cian’sRole:Ø Workwithstudyteamto:

– Createappropriaterule– CalculateitsoperaEngcharacterisEcs

PLANNINGANINTERIMAFTERSTUDYSTART

7

Crea#ngaDecisionRule8

AimofRule:StopstudyearlyifdrugisinefficaciousØ  Basicopera#ngcharacteris#cs

Probabilityofstoppingabaddrugatinterim

Probabilityofstoppingagooddrugatinterim

Overallfalsenega#verate

Ø  FurtherdetailstoconsiderbeforefinalruleischosenProbabilityabaddrugwouldhavebeensuccessfulatstudy-end

Probabilityagooddrugwouldhavebeensuccessfulatstudy-end

Numberofsubjectssavedifstudyisstopped

9

Ø Rule:If95%CIupperlimit<2,studymaybestoppedforfu#lityØ  Toostringent

32

TreatmentDifference

-6 -3 0Placebothreshold

3.8TargetTreatment

Difference

95%CI,N=100%Endofstudy

Opera#ngcharacteris#csimproveasNincrease,butlessresourceswouldbesaved.

95%CI,N=40%Ruleofthumbminimum

95%CI,N=30%EarliestOpportunity

95%CI,N=~70%

Marksthe80%CI

Ø Rule:If80%CIupperlimit<2,studymaybestoppedforfu#lity–toostringent!

PossibleInterimDecisionRule9

10

Ø Rule:If80%CIupperlimit<3.8,studymaybestoppedforfu#lity

32

TreatmentDifference

-6 -3 0Placebothreshold

3.8TargetTreatment

Difference

80%CI,N=100%Endofstudy

Opera#ngcharacteris#csimproveasNincrease,butlessresourceswouldbesaved.

80%CI,N=40%Ruleofthumbminimum

80%CI,N=30%EarliestOpportunity

80%CI,N=~70%

Ø  Clinicallyrelevantrule-opera#ngcharacteris#cslookreasonablevisually

PossibleInterimDecisionRule10

Calcula#ngOpera#ngCharacteris#cs

1 • Simulateindividualsubjectprimaryendpointdatafor10,000studies

2 • Calculatemeanandvarianceofsubjectsperarmatstudy-end(N=100%)

3 • Calculatemeanandvarianceofsubjectsperarmatinterim(N<100%)

4 • CalculateCIsformeanforeachsimulatedstudy

5 • Definethresholdusedininterimanalysisrule

6 • Calculateoverallα,β,andopera#ngcharacteris#cs

7 • RepeatforinterimscenariosfordifferenttotalN

Ø  Checkrulehasgoodchanceoffindingfu#lityifdrugisinefficaciousØ  Aiddecisionofwhentoperforminterimanalysis(N=?)

11

Opera#ngCharacteris#csofPossibleRules12

Ø  Overallfalsenega#veprobabilityincreasesslightlyto22%Ø  Lowprobabilityofstoppingagooddrug,thereforenegligibleimpactonoverall

falsenega#veprobability

N% N CI Probabilityof stoppingabad

drug

Probabilityof stoppinga gooddrug

30% 18 95% 32% 3% 30% 18 80% 61% 10% 40% 24 95% 45% 3% 40% 24 80% 72% 10% ~70% 40 95% 66% 3% ~70% 40 80% 87% 10%

32% 16% 38% 24% 48%

12% <1% <1% <1% <1% <1%

<1%

Ø Rule:UpperCIlimit<3.8,indicatesfu#lityØ Rule:UpperCIlimit<2.0,indicatesfu#lity

FinalInterimRule13

N% N CI

Probabilityofstoppingatinterim:

Probabilityofsuccessatstudy-endifyoucon#nueat

interim,despiteruleindica#ngyoushouldstop:

Es#mateddatethiscouldbeapplied

No.ofsubjectssavedifwestopforfu#lityBaddrug Gooddrug Baddrug Gooddrug

40% 24 80% 72% 10% 0.3% 4.4% Jul-2017 ~17~50% 30 80% 78% 10% 0.3% 3.5% Sep-2017 ~11~70% 40 80% 87% 10% 0.3% 2.5% Dec-2017 ~2

Ø Rule:Ifupperendofthe80%CI<3.8,thisindicatesfu#lity DifferencetoplaceboatWeek12

Riskofignoringtherule

14

ImpactofInterimonOverallProbabilityofSuccess

0Placebothreshold

3.8TargetTreatment

DifferenceTreatmentDifference

80%CI

CIincludes3.8threshold

53

1.Atinterim 2.Atendofstudy

Ø ReachingStudySuccess:Withaninterim,gooddrugsmustpasstwohurdles

Ø  IfagooddrugfailseitherrulethestudyisnotconsideredsuccessfulØ  Extentofimpactdependsonstringencyofinterimrule

0Placebothreshold

3.8TargetTreatment

DifferenceTreatmentDifference

95%CI

CIabove0effect

53

IMPLEMENTINGTHEINTERIMANALYSIS

15

InterimRuleChosen…NextSteps16

Ini#alDocumenta#on

Ø  Protocolamendment

Ø  InterimanalysisSAP

Ø  Iden#fica#onofunblindedteam

CROPartnership

Ø  Timeframe

Ø  Budget

ResultsPresenta#on

Ø  Keyresultsslides

Summary17

InanIdealWorld…

Ø  Aninterimanalysiswouldbeplannedintheoriginalstudydesign

Ø  However,circumstancescanleadtorequestsforaninterimmid-study

InterimDesignProcess–Sta#s#cian’sRoleØ  Workwithstudyteamtoiden#fyreasonforinterim

Ø  Presentop#onsinasimplis#cmanner

Ø  Adviseappropriaterulebasedonopera#ngcharacteris#csØ  Iden#fyunblindedteamandpreparenecessarydocumenta#on

Ø  Ensuresmoothrunningofinterim

  Rן.forthisstudy

  :DisclaimerDisclaimer:ןPharmaemployeeandholdsstockandstockoptions.IngridFranklinisan.e

Acknowledgements18