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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?
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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Chronologyofdevelopment(partiallist)
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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1.Useaweightedstatisticwithpre-specifiedweights
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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Alsocalledthep-valuecombinationapproach
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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2.UsetheConventionalWaldStatistic
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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ExtendedCDLMethod
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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Whydoesitwork?
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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… andwhataretheconcerns?
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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3.PreserveConditionaltype-1errorrate
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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Preservingtheoveralltype-1errorrate
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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Conditionaltype-1errorrate
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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Conditionaltype-1errorrate
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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Conditionaltype-1errorrate
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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Conditionaltype-1errorrate
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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Conditionaltype-1errorrate
YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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Pointstoconsider
YJemiai– 26Sep2017
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
22YJemiai– 26Sep2017 Regulatory-IndustryStatistics
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Thankyou
YJemiai– 26Sep2017 Regulatory-IndustryStatistics