YannisJemiai,Ph.D.26September2017

ASABiopharmaceuticalSectionRegulatory-IndustryStatisticsWorkshop

SampleSizeRe-Estimation:ControllingtheType-1Error

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unblinded samplesizere-estimationisanessentialdesigntool

YJemiai– 26Sep2017

Addressesuncertaintyintrialdesignassumptions

Oneofthemostpopularadaptations,especiallywhenusingaPromisingZoneapproach

21st CenturyCuresAct,PDUFAVI,encouragetheuseofadaptivedesigns

RegulatoryguidancedocumentsexistfromEMA(2007),FDACDER/CBER(2010),andCDRH(2016)

Increasinglymanyexamplesofregulatoryacceptance

Regulatory-IndustryStatistics

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SowhataresomeoftheissuesconcerninguSSR designs?

YJemiai– 26Sep2017

Cantype-1errorbecontrolled?

Cansoundadaptivedecisionrulesbedeveloped?

Howdowegetapointestimateandconfidenceintervalsforthetreatmenteffect?

Howdoweavoidoperationalbiasduringtrialconduct?

Wefocushereontype-1errorcontrol

Regulatory-IndustryStatistics

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Whydoestype-1errorgetinflated?

YJemiai– 26Sep2017 Regulatory-IndustryStatistics

Consideratwo-stagedesignwithoutsamplesizeincrease

SupposenowthatweincreasethesamplesizeinstageIIfromn(2) ton*(2),butwedonotchangethecriticalvalue

Thiswillleadtotype-1errorinflation

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Howcanwecontroltype-1errorthen?

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Chronologyofdevelopment(partiallist)

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1.Useaweightedstatisticwithpre-specifiedweights

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Alsocalledthep-valuecombinationapproach

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2.UsetheConventionalWaldStatistic

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ExtendedCDLMethod

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Whydoesitwork?

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… andwhataretheconcerns?

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3.PreserveConditionaltype-1errorrate

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Preservingtheoveralltype-1errorrate

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Conditionaltype-1errorrate

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Conditionaltype-1errorrate

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Conditionaltype-1errorrate

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Conditionaltype-1errorrate

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Conditionaltype-1errorrate

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Pointstoconsider

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Handlingsurvivalendpoints

Usableinformationatinterimanalysis

Non-inferiority&equivalencesettings

Independentincrements

Smallsamples

Regulatory-IndustryStatistics

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Recap:challengesinunblinded SSRtrials

YJemiai– 26Sep2017

Type-1errorcontrolisnotanobstacle.Methodsexisttoensurestrongcontrol

Inferenceremainsachallenge,butmakingsomeprogress

Decision-makingalgorithmcanbeoptimizedusingsimulationsandlatestresearch

Operationalbiascanbeaddressed/minimizedbyusingiDMCs,puttinginplaceproperprocesses,andmakinguseoftechnology

Regulatory-IndustryStatistics

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“Byfailingtoprepare,youarepreparingtofail.”

- BenjaminFranklin

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Thankyou

YJemiai– 26Sep2017 Regulatory-IndustryStatistics