Real-time Safety Evaluation of Lab Values
in Multiple Databases
Brian Postle, Data Manager, DF/Net Research
Background and Definitions
• Theevaluationofadverseeventsrelatedtobloodchemistriesisofcriticalimportanceformonitoringsafetyinclinicaltrials.
oDoestheinvestigationalproductbeingstudiedhaveaneffectonthekidneysorliver?§ Creatinine[Kidneyfunction]
§ ALT,AST,AlkalinePhosphatase,Bilirubin[Liverfunction]
oHowsignificantistheeffect?Howlongdoestheeffectlast?
§ Potentialpauseinadministrationoftheinvestigationalproduct.
Background and Definitions
• Referenceranges: thresholdvaluessetbyeachlocallaboratorytodescribewherethetestresultsofahighpercentageofhealthyindividualswouldfall.o “labnormals”o “normalranges”
LaboratoryReferenceRangeReport:Analyte testAgerangeMale/FemaleReferencerangeUnits
Background and Definitions
• Severitygrading: Ascalefordescribingthelevelofseverityofaclinicalevent.oGrade1:MildoGrade2:ModerateoGrade3:SevereoGrade4:Potentiallylife-threateningoGrade5:Death
Background and Definitions
• Gradingscaleshavebeendevelopedbymanyregulatoryorganizations.
It’scomplicated
Searching for a Unified Theory ofLab Normals Evaluation
à Couldtherebeasinglestrategydevelopedasalabnormals module
inDataFax?
The Lab Normals Initiative (LNI)
• Weconcludedthatthereisnotaone-size-fits-allsolution.
• Requiresanindividualizedsolutionthatiscreatedtorespondtoaspecificsetofcircumstances.
Constraints,Challenges, and Opportunities
• SponsorhadpreviouslyexportedlabdatafromDataFax forSASanalysisandreportgeneration[multi-stepprocess;reportingdelays].• Limitedprogrammingresources.• Limiteddevelopmenttime.
• MultiplestudiesinDataFax withsharedsitesandnormalranges[60researchsites].
• Currentlynomechanismwithin DataFax forcross-studycommunication.
• Limitedabilitytogather/managelocalreferenceranges[sponsor=middleman].
• Providereal-timefeedbacktoclinicalmonitorsviainteractivedashboard.
• Providereal-timefeedbacktoclinicalsitesaboutentereddata.
First generation - successes
• Weachievedreal-timeevaluationandresultsreportingwithinDataFax.• Editcheckswereeasilyreplicatedinsimilarstudies.• ProvidedimmediatefeedbacktoEDCusersviaDFask dialogueboxes.
First generation - successes
• WedevelopedaclinicaldashboardthatinteractswithDataFax.oDashboardwascreatedutilizingtheShinyPackageinR.
• DataFax editchecksdeterminedthecalculated analytegradesandcomparedthemtothesite-reported analytegrades.o Externalquerieswereplacedifclarification/correctionrequiredfromstudysites.o Internalquerieswereplacedonhiddenfieldsreservedforclinicalreporting.
• Datawasexportedtothedashboardon-demandwithDFsas;dashboardpostingswereinitiatedbymonitor-specifiedcriteria.oPTID-specificsafetyreportswerecreatedon-demandbyclinicalmonitors.
First generation - successes
Clinicaldashboardreportingfields
Calculatedgradereportingfields[addedforLNI]
Sitequeryonreportedgradefield
First generation - successes
Clinicaldashboard:summarypage
A
B
C
D
E
F
G
H
I
J
First generation - successes
Clinicaldashboard:detailpage
StudyB
First generation - successes
SafetyHistoryreport[PTID-specific]
StudyB
9-88-1234
First generation - challenges
• ProgrammingresidedwithineachindividualDataFax databaseo Largeeditchecks[“If theparticipantismale,andisatsite123,and isbetween30and45yearsold,and thespecimendrawdateisbeforeApril17,2015,andtheanalytevalueisgreaterthan80andlessthan102,then thereportedseveritygradeshouldberecordedas‘1’.If theparticipantisfemale…”].
o Editchecksoperatedslowly;achallengeforsiteswithpoorinternetconnectivity.o Standardizing,updating,andmaintainingeditcheckswascumbersome.
§ Referencerangesburiedwithineacheditcheck.§ Achangeforasinglestudysitenecessitatedmakingchangesacrossmultipledatabases.
o Testingandvalidationwastimeconsumingandrepetitive.
Objectives of a new approach
• Keepwhatworkswell!oMaintainreal-timeassessmentandfeedbackforstudysitesandclinicalmonitors.
• Findastreamlinedsolutiontothecurrentdecentralizedapproach.• Provideeaseofmanagementofreferenceranges.• Adapttochangingspecificationsduringthelifecycleofastudy.
o Labreferencerangeso Severitygradingcriteriao Site-specificimplementationofprotocolrequirements
• Automatesystemerrorreportingandvalidation.
Second generation - methods
• Wecreatedacombinationcentralized/internal toolthatevaluatessite-reportedlabvaluesagainstreferencerangesandstudy-specificcriteria.
• Thecomponentsofthenewapproach:oPythonprogramminginitiatedbyDataFax editchecks(outsideofstudydatabase;residentonstudyserver)[centralized]
o Singlemasterspreadsheetcontainingallreferencerangesforallstudies(outsideofstudydatabase;residentonstudyserver)[centralized]
oDataFax editchecksreducedinsize;moreefficient[internal]oDashboardreporting[centralized]
Second generation - process
Second generation - results
• Maintenanceoftheprogrammingbecamemorestraightforwardandefficient.• Potentialforadministrationerrorswasreduced.• Validationoftheprocesswasautomatedandsimplified;lessreliantonmanualreview.o Inputexpectedgradingvaluesforeachcombinationoftestingparameters(e.g.,analyte,age,sex,effectivedate)andcomparewithresultsreportedbyPython/DataFax.Thisvalidatesbothmasterspreadsheetandprogramming.
• Internalreportingmechanismwasdeveloped.oMessagesindicatewheretheprocesshasfailedorsiteshaveenteredunexpecteddata.
Unanticipated challenges
• Two-pagelabforms:o ThegradingeditchecksonPagetwoaredependentonthespecimencollectiondateandprotocoldesignationthatresideonPageone.§ Pageonenotcompleted.§ Pagescompleted/validatedoutoforder.
oUnevaluatedlabdataisidentifiedinbatch;datamanagercanmanuallyfireeditchecks-- howeverthereal-timereportingprocessesarecircumvented.
oUnlessthepage-twoCRFismodifiedtoaddaspecimencollectiondate,thissituationwillcontinuetoexist.
Unanticipated challenges
• RequiredrecordsnotcompletedasexpectedoBaselinecreatininedraw“notdone”duetohemolyzedsample.
§ Samplefromalatervisitwillbecomebaseline;currentlynotaccommodatedbythegradingeditcheck.
oMissingdemographicsform.
• Sitechangeslabpermanentlymid-studywithananalytereportedinadifferentunit[baselinediffersfromfollow-up].• Siteusesback-uplabonaone-timebasis[differentreferenceranges].• Communicationbetweensite->sponsor,andsponsor->DF/Netcanbeinefficient,creatingdelays.
Looking forward…
• StudysitescouldenterandmaintainlocalreferencerangesdirectlyintoiDataFax.
oAdvantage:Removethemiddleman;avoidcommunicationlags.
oAdvantage: Allstakeholderswouldseethereferencerangesinplay:studysite,datamanagers,statisticians,monitors.
oDisadvantage: AdditionalEDCburdenforstudysites?
oConsiderations: Shouldlocalreferencerangesbestoredwithineachindividualstudy,orinaseparateshared“study”database?
• Displaylocalreferencerangesonlabreportingplates[usefulformonitoring].
Looking forward…
Looking forward…
• Astudymaynotrequireorbenefitfromreal-timereporting.
• Astudymaynotneedcomplexgrading--onlynecessarytoevaluatewhetheralabvalueisinoroutofrange.
• Needtoevaluatethespecificsofeachstudyinordertodeterminetheresourcesthatshouldbeallocated:
oPaper/hybrid/EDC
oNumberofparticipants,lengthofstudy,reportingrequirements.
Thank you!
• MarkWessel,DF/Net
• PeteMcDonnell,DF/Net
• SaloniParikh,DF/Net
• RaisbeckAviationHighSchoolinternsoMatthewArnold,EleanorPahl,RachelPhuong,JoshuaSherbrooke
• DF/NetDataAnalyticsDepartment
• DF/NetDataManagers