Execu&onofAdap&veTrials:Opera&onalConsidera&ons

CytelUserGroupMee&ng

Paris,14October,2011

Part II: Operational Considerations

•  Sta&s&calmethodologyforcontrollingtype‐1erroriswellestablished(Cui,HungandWang,1999,East‐SurvAdapt,2011)

•  Logis&calandopera&onalissuesassociatedwithtrialexecu&onarelesswellestablished

•  Wehaveimplementedawebsolu&onforhandlingthetwomainissuesofconcerntoregulatoryagencies:opera&onalbiasandtrustworthiness

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What is Required?

"A well‐trusted firewall established for trialconduct beyond those established forconven&onal group sequen&al trials can helpprovide assurance that sta&s&cal andopera&onalbiaseshavenotbeenintroduced."

FDAGuidanceonAdap/veDesign(2010)

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Operational Bias and Trustworthiness

•  Opera&onalBias– Canknowledgethatthesamplesizewasincreased(ornotincreased)affecttheintegrityofthestudy?

•  Trustworthiness– Whosawwhatdata,andwhen?– Cananon‐invasiveaudittrailoftheen&redatahandlingprocessbeimplemented?

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ACES: Access Control Execution System

•  Webbasedtechnologytocontrolflowofinforma&onandaccesstoconfiden&aldocuments

•  Preventsopera&onalbiasbyincludingtheactualadap&vealgorithmonlyinDMCcharterandtrackingaccesstothisdocument

•  Establishestrustworthinessthroughsecurepasswordprotectedaccesstodocuments,execu&onofalgorithms,andaudittrail

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Traditional Process

6

CreateDocuments(Protocol,SAP,DMCCharter)

Store/ArchiveDocuments

EnrollSubjects&CollectResponses

SendResponseDatatoISC

PerformAnalysisand

CreateReports

SendAnalysistoDMC

Spon

sor

ISC

DMC Make

Recommenda&on

SendRecommenda&on

toSponsor/Steering

Commibee

MakeDecisionAboutTrial

Steerin

gCo

mmibee

Acerdecision…1.DMCno&fied2.DrugSupplyno&fied3.IVRSno&fied

CreateandTestAnalysisPrograms

CytelUGM,Paris.14Oct2011

ACES Process

7

CreateDocuments

(Protocol,SAP,DMCCharter)

Store/ArchiveDocuments

EnrollSubjects&Collect

Responses

SendResponseDatatoISC

PerformAnalysisand

CreateReports

SendAnalysistoDMC

Spon

sor

ISC

DMC Make

Recommenda&on

SendRecommenda&ontoSponsor/Steering

Commibee

MakeDecisionaboutTrial

Steerin

gCo

mmibee

inACES

Acerdecision…1.DMCno&fied2.DrugSupplyno&fied3.IVRSno&fied

inACES inACES

CreateandTest

AnalysisPrograms

LoadFinalAnalysisPrograms

intoACES

CytelUGM,Paris.14Oct2011

Sign In

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Document Dashboard

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Execution Cycle

10

InterimAnalysisbegins… ResponsesGenerated… ReportsGenerated.

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Audit Trial: Document Access Log Summary

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Review: What Problems did ACES Address?

•  DMCPortal– securecentralizedstorageofdocuments– customizedaccessforDMC,ISCandSponsor

•  ACESEngineGeneratesInterimReports– analysisprogramspre‐testedandloadedtoACES– blindeddatasetuploadedtoACES

•  Non‐InvasiveAuditTrail– whoseeswhatandwhenis&mestamped– datasetandanalysisprogramavailableforreview

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Concluding Remarks

•  Adap&vedesignreducesriskoffailingtodetectasmallerclinicallymeaningfuleffect

•  Pragma&capproach;waittoseedatabeforecommikngaddi&onalresources

•  Sta&s&calmethodologywellunderstood•  Opera&onalchallengesandtrustworthinessareregulatoryconcernsthatarehandledwellbytheACESsystem

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