interpretation of immunogenicity results and …...after aggregation of data, cumulative profile can...
TRANSCRIPT
V.Devanarayan,Ph.D.AbbVie,Inc.
EuropeanBioanalysisForum(EBF)9th OpenMeeting:ReachingUtopia-TheKaleidoscopeofBioanalysis,November16-18,2016Barcelona,Spain
InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations
2InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
RecommendationspresentedherewereinfluencedbyourcollaborationsontheseAAPSwhite-papers:
AssessmentandReportingoftheClinicalImmunogenicityofTherapeuticProteinsandPeptides- HarmonizedTerminologyandTacticalRecommendations,AAPSJournal,2014
Thequintessenceofimmunogenicityreportingforbiotherapeutics,NatureBiotechnology,2015
Authors:• GopiShankar,Ph.D.(JanssenR&D/Johnson&Johnson)• ArnoKromminga,Ph.D.(EuropeanImmunogenicityPlatform)• StevenArkin,MD(Pfizer)•MeenaSubramanyam,Ph.D.(Biogen-Idec)• Viswanath Devanarayan,Ph.D.(AbbVie)• LaurentCocea,MD,Ph.D.(HealthCanada,CERB/ClinicalEvaluationDivision)• DanielaVerthelyi,MD,Ph.D.(FDA,CDER/OfficeofTherapeuticProteins)• SusanKirshner,Ph.D.(FDA,CDER/OfficeofTherapeuticProteins)•MarkBorgini,MD(FDA,CBER/OfficeofCellularandGeneTherapies)• SarahYim,MD(FDA,DivisionofPulmonary,AllergyandRheumatologyProducts)• ChristianSchneider,MD(EMA,DanishNationalHealthandMedicinesAuthority)
3InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
ClinicalADAdataevaluation
DescribecharacteristicsoftheADAimmuneresponse:pre-existingantibodies,ADAIncidence,Titer,NAb,Kinetics,any
endogenouscross-reactivities
Descriptiveillustrations Descriptive/ExploratoryStatistics
DeterminationofclinicallyimpactfulADAthresholdofADAattributes
DetermineSubjectADAstatusbasedonsampleADAresults
DeterminesampleADAstatus
4InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
Terms&Definitions
Simpleterminologyrequiringclarification:• ADA,BindingADA,NeutralizingADA,Non-neutralizingADA,sustainingADA,
clearingADA,HAMA,HACA,HAHA,Titer,etc.
TermsusedtodescribeADAstatusofasample:• ADAPositiveSample: whenADAisdetectedinasample,thesampleisconsidered
positive
• ADANegativeSample: whenADAisnotdetectedinasample,thesampleisconsiderednegative
• ADAInconclusiveSample: whenADAisnotdetectedinasamplebutdrugispresentinthesamesampleatalevelthatcanproduceinterferenceintheADAdetectionmethod,thenthenegativeADAresultcannotbeincontrovertiblyconfirmedandthesampleclassificationforADAstatusshouldbeconsideredinconclusive.
• UnevaluableSample:whenasamplecouldnotbetestedforADAduesampleloss,mishandling,orerrorsinsamplecollection,processing,storage,etc.
5InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
Terms&Definitions(contd.)
BaselineADA(pre-existingantibodies): referstoantibodiesreactivewiththebiologicdrugmoleculebeforeinitiationoftreatment.
Treatment-inducedADA: ADAdevelopeddenovo(seroconversion)followingbiologicdrugadministrationinasubjectwithoutpre-existingADA).
Treatment-boostedADA:Pre-existingADAthatwereboostedtoahigherlevelfollowingbiologicdrugadministration(i.e.,anytimeaftertheinitialdrugadministrationtheADAtiterisgreaterthanthebaselinetiterbyascientificallyreasonablemargin.
TermsusedtodescribeADAstatusofaSubject:
• ADAPositiveSubject:Subjectwithatleast1treatment-inducedortreatment-boostedADApositivesampleatanytimeduringthetreatmentorfollow-upobservationperiod.
• BaselineADApositiveSubject: AnADApositivesubjectwithbaselinepositivesample(s),regardlessofboostingafterbiologicdrugadministration.
6InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
SamplingRecommendations
ADAshouldbeevaluatedinallstudypatientsandnotonlyinasymptom-drivenmanner
Always collectabaseline sample
Samplingfrequency duringtreatmentshouldbedesignedtomaximizetheopportunityofdetectingtreatment-inducedADAand,whenapplicable,tounderstandthekinetics.
Atleastonesampleshouldbecollectedfollowinganappropriateperiodoftimeafterthelastdrugadministration.
Fortheregistration(BLA/MAA)ofchronictreatments,regulatoryauthoritiestypicallyexpectimmunogenicitydatathroughthefirstyear.Dependingonclinicalstudylength,collectsamplesfortestingat:2weeks(optional),1mo,2mo,3mo,6mo,9mo,12mo,18mo,24mo,andeveryyearthereafterduringtreatment,andatleastonemoresampleafterthelastdrugadministrationwhenoff-treatmentpersistenceofADAneedsevaluation.
7InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
Pre-existingAntibodies
ADAatbaseline(“prevalence”)mayhaveclinicalconsequences
Reportseparatelytoenableanalysisofassociationwithclinicaloutcomesafterfirstdose
Assesstreatment-boostingofthepre-existingantibodiestounderstandassociationwithclinicaloutcomesafterrepeatdosing
“boostedbyascientificallyreasonablemargin”• Basedonareasonabletiterincrease;notlog-fold…• Titration with2-3foldserialdilutionschemeisencouraged;greater
dilutionisnotagoodidea.• titerincreasesuchasa4-fold(for2xdilutionscheme)or9-fold(for3x
dilutionscheme)isareasonablemarginforchangeintiter• Optionally,butcertainlyforhigherriskbiologics,a2-foldincreaseis
consideredsignificant.
8InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
DataAnalysis&Presentation
Descriptiveillustrations Descriptive/ExploratoryStatistics
DeterminationofclinicallyimpactfulADAthreshold/cut-offofADAattributes
DescribecharacteristicsoftheADAimmuneresponse:pre-existingantibodies,ADAIncidence,Titer,NAb,Kinetics,any
endogenouscross-reactivities
9InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
DescriptivecharacteristicsofanADAimmuneresponse
ADAPrevalence (baseline/pre-existing):o BaselineADApositivesubjectsasapercentageofthetotalnumberofsubjects
whosebaselinesamplesweretestedforADA.o Titerrange(median,IQR)ofthebaselineADApositivesamples
ADAIncidence:o OverallADAincidence:combinedresultsoftreatment-boostedADApositive
subjectsandtreatment-inducedADApositivesubjects.Computeasapercentageofthetotalnumberofevaluablesubjects,excludingbaselinepositivesubjectswithoutanysamplesavailableafterdrugadministration.
o Treatment-inducedADAincidence:computedasapercentageofthetotalnumberofevaluablesubjectsthatwereADAnegativeatbaseline.Alsoreportpeakpositivetiterandrange(median,IQR)forthisgroupofsubjects.
o Treatment-boostedADAincidence:computedasapercentageofthetotalnumberofevaluablesubjectsthatwereADApositiveatbaseline.Alsocomputethefold-increaseintiter(ratioofpeakpost-administrationtitertobaselinetiter)andrangeoftiterincreases(median,IQR).
10InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
ADAKinetics:o Onset:thetimeperiodbetweentheinitialadministrationofthebiologicdrug(ina
study)andthefirstinstanceoftreatment-inducedADA.o Computethe“mediantimetoADAdevelopment”andtheinter-quartilevalues
Q1andQ3,whichcanenableanunderstandingofonsetofADAinhalf,25%,and75%ofthetreatedsubjects,respectively.
o Duration:referstothelongevityoftreatment-inducedADA.Criteriafor“Transient”vs.“Persistent”shouldbebasedonthenaturalclearanceofendogenoushumanIg.o IfADAarepredominantlyIgG1/2/4,ADAresponselasting>16weekscanbeconsidered
asPersistent.Thisisbecauset1/2is21-25days,So97%oftheIgGwouldhavebeeneliminatedafter5half-lives(16weeks).
o IfADAarepredominantlyIgM,IgAorIgG3,use5weeks.o Donotbasedthisonwhensamplingwasstopped(i.e.,“transient”becauseseronegativity
wasachievedduringstudyiswrong)
o “Transient”vs.“Persistent”describethelongevityoftheADA. Itdoesnotimplynegativeorpositiveassociationwithclinicalconsequences!
DescriptivecharacteristicsofanADAimmuneresponse
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TransientADA:– Treatment-inducedADAdetectedonlyatonesamplingtimepointduringthetreatmentorfollow-upobservationperiod(excludingthelastsamplingtimepoint,asaconservativemeasure)
or– Treatment-inducedADAdetectedat2ormoresamplingtimepointsduringthetreatment(includingfollow-upperiod,ifany),wherethefirstandlastADApositivesamples(irrespectiveofanynegativesamplesin-between)areseparatedbyaperiodlessthan16weeks,andthesubject’slastsamplingtimepointisADAnegative.
DescriptivecharacteristicsofanADAimmuneresponse
12InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
PersistentADA:• Treatment-inducedADAdetectedat2ormoresamplingtimepoints
duringthetreatment(includingfollow-upperiod,ifany),wherethefirstandlastADApositivesamples(irrespectiveofanynegativesamplesinbetween)areseparatedby>=16weeksor
• Treatment-inducedADAincidenceonlyinthelastsamplingtimepointofthetreatmentstudyperiod,oratasamplingtimepointwithlessthan16weeksbeforeanADAnegativelast sample.[Byconservativeinference]
• Althoughrare,whenapatientpopulationinastudyispredominantlyfoundtodevelopIgG3orIgA,a5weekperiodshouldbeappliedtomodifythedefinitionsoftransientandpersistentADA(insteadofthe16weeks).ThisisbecauseIgG3andIgAhaveshorterhalf-livesthanotherIgGs (IgG3,7days;IgM andIgA,5days).
DescriptivecharacteristicsofanADAimmuneresponse
13InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
NAb Incidenceandkinetics: whenstudyresultsindicatedistinctNAb-containingversusnon-Nabcontainingsubjectgroups,itisusefultolookatNAb incidenceandkineticsseparatelyforeachgroupinthesamemannerasdescribedaboveforADA.
Cross-reactivity: whenabiologicdrugmoleculeisidenticalornearlyidenticaltoanendogenousprotein(wholeorinpart),itisimportantthatthecross-reactivityoftheADAwiththeendogenousproteinbeevaluatedbecauseofthepotentialtocauseanautoimmune-likesyndrome.• Comparethekineticsandtitersofthecross-reactiveADAversusthe
whole-drugADA,andrelatethistotheworseningofdisease.
DescriptivecharacteristicsofanADAimmuneresponse
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Treatment-inducedADAincidence&kinetics
15InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
ThisplotincludesADApositivepatientsforwhomtheADAonsettimeisatleast120daysbeforethelastvisitORtheywereADAnegativebythelastvisit.Referencelinesrepresentthequartiles.
Treatment-inducedADAincidence&kinesticsIllustrationwithexampleclinicaldata
ADADu
ratio
n(days)
ADAonsettime(days)
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Cumulativetreatment-inducedADAincidence&kinetics
Afteraggregationofdata,cumulativeprofilecanbeshownasbelow:
17InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
DescriptiveillustrationofADATiterKinetics
18InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
DescriptiveillustrationofADATiterKineticsIllustrationwithexampleclinicaldata
84 168 196 225 280 364 532 6161
5/500(1%)
29/485(6%)
29/298(8.7%)
40/291(13.7%)
43/472(9.1%)
47/468(10%)
9/187(4.8%)
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DescriptivestatisticsforADAKineticsComments
ThisapproachobviatesdefinitionsforADAimmuneresponsekinetics– theonset(early/late)orduration(transient/persistent).
Theseevaluationsarehardtointerpretforverysmallsamplesizeand/orincidencerate.
Complexstudieswithmultiplearmsandsatellitestudiesmaynotallowforstatisticalassessments.
AppliesonlytoTreatment-InducedADA(treatment-boostedADAaredifferentmechanistically).
ADAOnset:reportthequartiles(Q2is“Mediantimetoantibodyformation”)• Interpretation:“WhenhalfoftheADA+subjectsseroconverted”OR“when75%
(majority)oftheADA+subjectsseroconverted”
ADADuration:reportthequartiles(Q2is“Mediantimeofantibodyduration”)• Interpretation:“TheADAslastedQ2monthsinhalfofthesubjects andQ3monthsin
75%ofthesubjects”
20InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
AssessmentofADAvs.clinicaloutcomes
Requiresanintegratedanalysis ofPK(serumconc.,clearancerate),PD(whenapplicable),Efficacy,andADRs(acuteandnon-acute),inrelationtotheintendeddosage(testedinpivotaltrials).
Fordeterminingaclinicallyrelevant“threshold”,• ROCandTree-basedanalysisoftheADAcharacteristicsvs.PK/PD,
changesindiseaseparameters(efficacy),andlevelsofADR,maybeused.§ Notfeasible/relevantforsmallsamplesizeand/orincidencerate.
21InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
InfluenceofADAonClinicalEfficacy%ofP
atientsw
ithdesire
defficacy
22InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
ADAvs.ClinicalEfficacyIllustrationwithexampleclinicaldata
25
50
75
100
300 600 900scheduledvisitday
median patient
ADA
nonADA
MedianlongitudinalefficacyprofilesforADApositive&negativepatientsareplottedseparately.Errorbarsrepresentstandarderrorofmedian(estimatedusingMAD).EfficacyisreducedinADApositivepatientsatseveraltimepoints.
Med
ianEfficacy
Scheduledvisitdayanalyticalissues
23InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
ADAvs.ClinicalEfficacyIllustrationwithexampleclinicaldata(Titer,Duration,Onset)
Relationshipbetweenthe52weekefficacy(%reductionindiseaseactivityscore)vs.maximumtiterduringthe52-weekperiod,ADAdurationandADAonsettimearesummarizedhere.EachpointinthegraphisauniqueADApositivepatient.PatientswithADAonsetlaterthan300dayswereexcluded.Trendisapproximatedusingsmoothingspline.EfficacytrendslowerwithlongerADAduration(p<0.05),andalsowithhighertiterwithabreakpointataround120.
%Efficacy
Log(MaxTiter)
%Efficacy
ADAduration
%Efficacy
ADAonsettime
24InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
StatisticalevaluationofADAvs.ClinicalendpointsSomeimportantconsiderations
Trendsareusuallynon-linear,oftenwithastep-wiseassociation.
Therefore,linear-basedmodelssuchasLogisticorLinearRegressionmaynotcapturetheassociationswell.
Needflexiblenonparametricand/ornonlinearmodelstoevaluatetheseassociations.
TheADAparameters(onset,titer,duration)aretypicallynotindependent.Needtomodeltheirinteractions.
Theymaycorrelateinacollectivemanner(multivariate).
Whatstatisticalapproachaddressestheseneeds?
25InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
StatisticalevaluationofADAvs.ClinicalendpointsSomeconsiderations(contd.)
ForanalyzingtheimpactofeachADAparameterindependentlyonClinicalendpoints(univariate),ROCanalysisorunivariateTreemodelisuseful.• Nonparametric&nonlinear• Readilyprovidesathresholdestimatethatoptimizesthe
association(e.g.,sensitivity/specificity).
“GeneralizedAdditiveModels”(GAM)maybeusefulforvisualizingandmodelingthecollectiveassociationofADAparametersonclinicaldata.
ForcharacterizingthecollectiveimpactofADAparametersonclinicalendpoints,MultivariateTree-basedmodelmaybeuseful.• AccountsforinteractionbetweenADAparameters,inaddition
tomodelingthenonlinearityandbeingnonparametric.• Output:“DecisionThresholdsonmultipleADAparameters”
26InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
EachADAparametervs.Clinical outcomeIllustrationofROCanalysis(univariate)
Titerthresholdat120provides~76%Specificity&~74%Sensitivity.
i.e.,74%ofpatientswithfavorableefficacyhaveTiter<120,and76%ofpatientswithpoorefficacyhaveTiter>120.
IncreasingtheTiterthresholdto240,resultsin~68%Specificityand~83%Sensitivity.
Thisanalysispermitstheassociationofonlyonefeatureatatime.NeedMultivariateTree-basedmodelforassessingjointeffectofmultipleADAparameters.
27InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
ADAvs.ClinicalSafety(AEincidence)Visualizing&Modeling(GeneralizedAdditiveModels)
12345
6MRP x 1E3123
456MDR x 1E3
00.20.40.60.81
Probability of Refractory
0123456
MRP x 1E3
01
23
45
6MDR x 1E3
ColorshadesdenoteprobabilityofclinicalAE.Probabilityincreasesasthecolorchangesfromdarktolightblue.
ClinicalAE
WhenADAdurationis<4months(16weeks)andTiter<15,thereisnoimpactonClinicalAE.NotethesharpcorrelationtoclinicalAEwiththesteepincreaseintheslope/surfacewhenADAduration>16weeks&Titer>15.
Maxlog2(Titer)
ADAdu
ratio
n(m
onths)
28InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
ADAvs.ClinicalSafety(AEincidence)Illustrationof Tree-basedModel(multivariate)
18%ofpatientshaveAE(n=16)
HigherAEincidence(30%)forpatientswithADAtiter>20andonsetwithin6months.
NoAEincidenceforpatientswithlowADAtiter(<20)
*Significanceofonset-timeisnotstrong.
29InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
ADAvs.ClinicalEfficacyIllustrationof Tree-basedModel
*LogWorth >1impliesp<0.01(aftermultiplicityadjustment),
69.4%efficacy(n=61patients)
Efficacydropsto37%forpatientswithADAduration>442days(~15months)
Efficacystronger(80%)forpatientswithADAduration<16weeks.
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NAb NegativeMean=86,n=19
NAb PositiveMean=71,n=12
ADA&NAb vs.ClinicalEfficacy (RoleofNAb?)Illustrationof Tree-basedModel(multivariate)
69.4%efficacy(n=61patients)
Efficacydropsto37%forpatientswithADAduration>442days(~15months)
Efficacystronger(80%)forpatientswithADAduration<16weeks.
Efficacydropsto71%forNAb +patients
31InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
LimitationswithROC/Tree-basedanalysis,andproposedimprovements
Notverystable.• SignificanceofADAparametersmayvarygreatlyduetominorchangesin
thedata.
ADAThresholdestimatesmaybehighlynoisy/variable,especiallyforsmallersamplesizeorincidence (typical).
Toobtainmorerobustthresholdestimatesandevaluatevariability(confidenceinterval),wenowproposemethodstoextendtheunivariateROCandmultivariateTreeanalysisviaaboostrap resamplingscheme.• (nexttwoslides)
32InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
Original Data
Tree/ROC 1
>= C1< C1
Tree/ROC 2
>= C2< C2 ……...
Tree/ROC B
>= CB< CB
Aggregate Thresholds (C1, C2, …., CB)
Robust Threshold = Median of this distributionSpread of this distribution reflects the variability.
Bootstrapping (sampling with replacement)
Data 1 Data 2 Data B… … ...
Threshold estimated from this approach is robust to small perturbations in data, outliers, etc.
ForincreasingrobustnessofunivariatethresholdsfromROCorTreeanalysis,weproposethisresamplingmethod:
BATTing:Bootstrapping&AggregatingThresholdsfromROC/Trees
Devanarayan,1999
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Formorerobustmultivariatethresholds(signature),weproposethis“sequentialresampling”extension.
Model Growing within the potential Sig+ group• Get the BATTing threshold for each unused ADA parameter.• The best predictor is selected to split the current sig+ group• This procedure continues in the new Sig+ group
Stopping Rule:• The new added predictor goes through the likelihood ratio test for
significance.
WholePopulation (Sig+)
Sig-
(Sig+) (Sig+) Sig+
Sig- Sig- Sig-
Titer>20 Duration>16wks Onset<4wks
Sig+:subgroupofpatientswithloweredefficacy/PKorAE
SequentialBATTing:Huang,Sun,…,Devanarayan,2015
34InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
AdditionalcommentsonthestatisticalevaluationsofADAparametersvs.ClinicalPK/Efficacy/Safety
Asevidentfromthemethodsandillustrations,thisanalysisshouldideallybeperformedbyexperiencedbiostatisticians.
InadequateanalysesmayresultinfalsenegativeandfalsepositiveclaimsonADAassociationtoclinicaloutcomes!
False-NegativeAssociations:• Duetoinherentnon-linearity,linear-basedmodelsareinadequate.Mayleadto
incorrectconclusionsonlackofornoassociation.• Needflexiblenonparametric&nonlinearmethodsthataccountforstepwise
nonlineartrends&interactionsbetweenADAfeatures(Tree,GAM,etc.).• Needresampling-basedmethodstorobustify results&evaluatevariability.
False-PositiveAssociations:• Bewareofover-fitting.Performanceclaimsshouldnotbebasedonthesamedata
thatwereusedtoderivetheassociations&thresholds.• Needrigorousinternalcross-validationtoreducebiasintheestimatesofmodel
accuracyandperformance.Follow-upwithexternalvalidation.
35InterpretationofImmunogenicityResultsandEvaluationofClinicalAssociations|EBF9th OpenMeeting,November16-18,2016|V.Devanarayan
Summary:ClinicalADAdataevaluation
DescribecharacteristicsoftheADAimmuneresponse:pre-existingantibodies,ADAIncidence,Titer,NAb,Kinetics,any
endogenouscross-reactivities
Descriptiveillustrations Descriptive/ExploratoryStatistics
DeterminationofclinicallyimpactfulADAthresholdofADAattributes
DetermineSubjectADAstatusbasedonsampleADAresults
DeterminesampleADAstatus