eugm 2011 mehta - execution of adaptive trials operational considerations
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Part II: Operational Considerations
• Sta&s&calmethodologyforcontrollingtype‐1erroriswellestablished(Cui,HungandWang,1999,East‐SurvAdapt,2011)
• Logis&calandopera&onalissuesassociatedwithtrialexecu&onarelesswellestablished
• Wehaveimplementedawebsolu&onforhandlingthetwomainissuesofconcerntoregulatoryagencies:opera&onalbiasandtrustworthiness
2 CytelUGM,Paris.14Oct2011
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)
3 CytelUGM,Paris.14Oct2011
Operational Bias and Trustworthiness
• Opera&onalBias– Canknowledgethatthesamplesizewasincreased(ornotincreased)affecttheintegrityofthestudy?
• Trustworthiness– Whosawwhatdata,andwhen?– Cananon‐invasiveaudittrailoftheen&redatahandlingprocessbeimplemented?
4 CytelUGM,Paris.14Oct2011
ACES: Access Control Execution System
• Webbasedtechnologytocontrolflowofinforma&onandaccesstoconfiden&aldocuments
• Preventsopera&onalbiasbyincludingtheactualadap&vealgorithmonlyinDMCcharterandtrackingaccesstothisdocument
• Establishestrustworthinessthroughsecurepasswordprotectedaccesstodocuments,execu&onofalgorithms,andaudittrail
5 CytelUGM,Paris.14Oct2011
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
Execution Cycle
10
InterimAnalysisbegins… ResponsesGenerated… ReportsGenerated.
CytelUGM,Paris.14Oct2011
Review: What Problems did ACES Address?
• DMCPortal– securecentralizedstorageofdocuments– customizedaccessforDMC,ISCandSponsor
• ACESEngineGeneratesInterimReports– analysisprogramspre‐testedandloadedtoACES– blindeddatasetuploadedtoACES
• Non‐InvasiveAuditTrail– whoseeswhatandwhenis&mestamped– datasetandanalysisprogramavailableforreview
12 CytelUGM,Paris.14Oct2011
Concluding Remarks
• Adap&vedesignreducesriskoffailingtodetectasmallerclinicallymeaningfuleffect
• Pragma&capproach;waittoseedatabeforecommikngaddi&onalresources
• Sta&s&calmethodologywellunderstood• Opera&onalchallengesandtrustworthinessareregulatoryconcernsthatarehandledwellbytheACESsystem
13 CytelUGM,Paris.14Oct2011
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