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