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Consultation‐ProposalfortheregulationofIVDcompaniondiagnostics

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THERAPEUTICGOODSADMINISTRATION


SUBMISSION

November2018

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Contents

OurCredo 3

SubmissionInformation&CompanyOverview 4

Commentsonconsultation‐ProposalfortheregulationofIVDcompaniondiagnostics 5

OverallComment5

ProposedTGAdefinitionofan‘IVDCompanionDiagnostic’5

Themeaningof‘essentialforthesafeandeffectiveuse’ 7

AmendmenttoclarifytheclassificationofIVDCDx7

AmendmentstoallowforcompulsoryauditsofARTGinclusionapplicationsforIVDCDx 8

AmendmentstoallowfortheidentificationofindividualIVDCDxintheARTGorotherdatabase 9

AssessmentfeesforinitialapplicationsandchangestoexistingentriesontheARTG 9

TransitionarrangementsforIVDCDxalreadyincludedontheARTG 10

Timeframefortransition 11

IVDCDxthatarein‐houseIVDs 11

CoordinatedPremarketAssessmentofanIVDCDxanditsCorrespondingMedicine/Biological 12

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OurCredo

Webelieveourfirstresponsibilityistothedoctors,nursesandpatients,tomothersandfathersandallotherswhouseourproductsandservices.Inmeetingtheirneedseverythingwedomustbeofhighquality.Wemustconstantlystrivetoreduceourcostsinordertomaintainreasonable

prices.Customers’ordersmustbeservicedpromptlyandaccurately.Oursuppliersanddistributorsmusthaveanopportunitytomakeafairprofit.

Weareresponsibletoouremployees,themenandwomenwhoworkwithusthroughouttheworld.Everyonemustbeconsideredasanindividual.Wemustrespecttheirdignityand

recognisetheirmerit.Theymusthaveasenseofsecurityintheirjobs.Compensationmustbefairandadequate,andworkingconditionsclean,orderlyandsafe.Wemustbemindfulofwaystohelpouremployeesfulfiltheirfamilyresponsibilities.Employeesmustfeelfreetomakesuggestionsandcomplaints.Theremustbeequalopportunityforemployment,developmentandadvancementforthosequalified.Wemustprovidecompetentmanagement,andtheir

actionsmustbejustandethical.

Weareresponsibletothecommunitiesinwhichweliveandworkandtotheworldcommunityaswell.Wemustbegoodcitizens‐supportgoodworksandcharitiesandbearourfairshareof

taxes.Wemustencouragecivicimprovementsandbetterhealthandeducation.Wemustmaintainingoodorderthepropertyweareprivilegedtouse,protectingtheenvironmentand

naturalresources.

Ourfinalresponsibilityistoourstockholders.Businessmustmakeasoundprofit.Wemustexperimentwithnewideas.Researchmustbecarriedon,innovativeprogramsdevelopedandmistakespaidfor.Newequipmentmustbepurchased,newfacilitiesprovidedandnewproductslaunched.Reservesmustbecreatedtoprovideforadversetimes.Whenweoperateaccordingto

theseprinciples,thestockholdersshouldrealiseafairreturn.

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SubmissionInformation&CompanyOverviewOrganisation: Johnson&JohnsonPtyLtd

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Johnson&JohnsonPtyLtdisasubsidiaryofJohnson&Johnson,theworld’smostcomprehensiveandbroadlybasedhealthcarecompany.InAustraliaweprovideproductsandservicesincludingmedicaldevices,diagnostics,pharmaceuticalsandconsumerhealthcareproducts.

TheJohnson&JohnsonFamilyofCompaniesinAustraliaconsistsof:• Johnson&JohnsonPacificPtyLimited–consumerhealthbrands;• Johnson&JohnsonMedicalPtyLimited–medicaldevicesandrelatedtechnology;and• Janssen‐CilagPtyLimited–pharmaceuticals.

Weemployapproximately1,500Australianswhobringinnovativeideas,productsandservicestoadvancethehealthandwell‐beingofthepatientsweserve.Werecognisetheimpactofseriousconditions on people's lives, and we aim to empower people through disease awareness,education and access to quality care. Our research and development focuses on identifyingmedicalneedsandharnessingthebestscience,whetherfromourownlaboratoriesorthroughstrategicrelationshipsandcollaborations.

Johnson& JohnsonPacific is a provider of consumerhealth andwellbeingproducts, offeringfamiliesmorethan650trustedsolutionsfortheirmostcommonhealthandwellbeingneeds.Manyofourbrandshaveearnedconsumers’trustovergenerations.

Johnson&JohnsonMedicalproducesarangeofinnovativeproductsandsolutionsusedprimarilybyhealthcareprofessionalsinthefieldsoforthopaedics,neurologicaldisease,visioncare,diabetes,infectionprevention,diagnostics,cardiovasculardisease,andaesthetics.WearethelargestmedicaltechnologyproviderinAustraliaworkingacrosspublicandprivatesectors.

Janssenisdedicatedtoaddressingunmetmedicalneedsinoncology,immunology,neuroscience,infectiousdiseasesandvaccines,andcardiovascularandmetabolicdiseases.Janssenhasalong‐standinghistoryinmakingameaningfuldifferenceinglobalpublichealth,datingbacktoDrPaulJanssen’spioneeringworkinmentalhealthandpainmedications,aswellasthedevelopmentofmorethan80medicines.

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CommentsonConsultation‐ProposalfortheregulationofIVDcompaniondiagnostics

OVERALLCOMMENT

TheJohnson&JohnsonFamilyofCompanieswelcomesthereviewofthisconsultation.WealsoacknowledgetheTGA’scommitmenttointroducealegaldefinitionforaninvitrodiagnosticmedical device (IVD) companion diagnostic (CDx) and a regulatory approach that ensuresthese devices are subject to an appropriate level of premarket scrutiny prior to supply inAustralia,giventheirroleindeterminingappropriatetherapy.WealsoacknowledgetheTGAefforts to be consistent with the Expert Panel Review of Medicines and Medical DevicesRegulation(MMDR)recommendationsthattheAustralianmedicaldeviceregulatoryschemewill be further aligned where appropriate with European regulatory requirements andensuringgreateruseofinternationalregulators’assessments.WeappreciatetheinvitationforcommentonthisConsultationpaper.

ProposedTGAdefinitionofan‘IVDCompanionDiagnostic’

Questionsforconsideration–Proposal1

IstheproposeddefinitionofIVDCDxclearenough?

IstheproposeddefinitionappropriatelyalignedwiththeEUandUSFDAdefinitions?

Doyouhaveanyothercommentsorsuggestionsabouttheproposeddefinition?

Doyouhaveanyothercommentsorsuggestionsforalternativeoradditionalstrategies?

Johnson&JohnsonFamilyofCompaniescomments:

TheproposeddefinitionofIVDCDxisclearandalignsverywelltotheEUIVDRdefinitionandisappropriate.TGAshouldalsoprovideexplicitguidancethattheTGAwillseektoapplysimilarjudgementtothisdefinition,e.g.ifanIVDisnotdefinedasacompaniondiagnosticintheUSAandEU,itwillgenerallynotbedefinedasacompaniondiagnosticinAustralia.

USA EU AustraliaProposal

AnIVDcompaniondiagnosticdeviceisaninvitrodiagnostictest/devicethatprovidesinformationthatisessentialforthesafeandeffectiveuseofa

‘companiondiagnostic’meansadevicewhichisessentialforthesafeandeffectiveuseofacorrespondingmedicinalproductto:(a)identify,beforeand/orduring

“An‘IVDCompanionDiagnostic’isanIVDmedicaldevicewhichprovidesinformationthatisessentialforthesafeandeffectiveuseofacorrespondingmedicineorbiologicaltherapeuticgoodto:

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correspondingtherapeuticproduct.Acompaniondiagnosticmaybeusedto:

Identifypatientswhoaremostlikelytobenefitfromthetherapeuticproduct

Identifypatientslikelytobeatincreasedriskforseriousadversereactionsasaresultoftreatmentwiththetherapeuticproduct

Monitorresponsetotreatmentwiththetherapeuticproductforthepurposeofadjustingtreatment(e.g.,schedule,dose,discontinuation)toachieveimprovedsafetyoreffectiveness

Identifypatientsinthepopulationforwhomthetherapeuticproducthasbeenadequatelystudied,andfoundsafeandeffective,i.e.,thereisinsufficientinformationaboutthesafetyandeffectivenessofthetherapeuticproductinanyotherpopulation

Reference:FDAGuidanceInVitroCompanionDiagnosticDevicesAug2014

treatment,patientswhoaremostlikelytobenefitfromthecorrespondingmedicinalproduct;or(b)identify,beforeand/orduringtreatment,patientslikelytobeatincreasedriskofseriousadversereactionsasaresultoftreatmentwiththecorrespondingmedicinalproduct.Reference:EUIVDR2017

a.identify,beforeand/orduringtreatment,patientswhoaremostlikelytobenefitfromthecorrespondingtherapeuticgood;or

b.identify,beforeand/orduringtreatment,patientslikelytobeatincreasedriskofseriousadversereactionsasaresultoftreatmentwiththecorrespondingtherapeuticgood.Reference:TGAproposalv.1,Oct.2018

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Themeaningof‘essentialforthesafeandeffectiveuse’


Isthemeaningof“essentialforthesafeandeffectiveuse”asusedinthedefinitionofIVDCDxclearenough?

DoyouhaveanyothercommentsorsuggestionsabouttheproposaltoincludereferencestoapprovedIVDCDxinthePIandCMIofcorrespondingmedicinesandbiologicals?

DoyouhaveanyothercommentsorsuggestionsabouttheproposalfortheIFUofapprovedIVDCDxtoincludereferencestothecorrespondingmedicineorbiological?


In the Consultation proposal, there is a caveat that tests that are used in monitoring anddiagnosisofdiseasestatesshouldnotbeidentifiedasCompanionDiagnostics.Wesupporttheuseofthiscaveatandanyadditionalexamplesthathelpinclarifyingthedefinition.

WeagreewiththeinclusionofagenericreferenceinthePIandCMItoanapprovedCDxandthe corresponding reference in the CDx’s IFU to the approvedmedicine or biological. Thisallowsfollow‐onteststhatachieveacceptableperformancetobeincludedbyTGAontheARTGandtobeimmediatelyused,withoutrequiringadditionalchangestothePIandCMI.Wenotethat the FDA system includes in the PI explicit links to an FDAwebpagewhere approvedCompanion Diagnostics are identified, linked to themedicine or biological they have beenvalidatedfor,e.g.”InformationontheFDA‐approvedtestsforthedetectionofHER2proteinoverexpression and HER2 gene amplification is available at:http://www.fda.gov/CompanionDiagnostics.” This linkageallows for13approved tests forHerceptintobelisted,withoutrequiring13separateupdatestothePIorCMI.Thissystemalsoallows the linkageof one companiondiagnostic toover15medicines,which is likely tobeincreasinglyimportantwithmorecompaniondiagnosticsusingNGStechnologies.TGAshouldlookatthefeasibilityofimplementingthislinkagesystemasusedbyFDA.SincetheEMAdoesnotdirectlyapprovecompaniondiagnostics(theyareapprovedthroughnotifiedbodies),theEMA cannot provide detailed information about the companion diagnostic, and the FDAexampleismorehelpful.

AmendmenttoclarifytheclassificationofIVDCDx


DoyouhaveanycommentsorsuggestionsabouttheproposaltoclassifyallcompaniondiagnosticsasClass3IVDstoensureappropriateandconsistentregulationofIVDCDxinfuture?

IstheproposedamendmenttoRule1.3clearenough?

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Theclassificationofacompaniondiagnosticappearstobeinthesameriskcategoryastheothertypesoftestsdescribedintheregulation.Class3wouldbethereforeanappropriateclassification.IthasbeensuggestedintheUS,thatsomeCDxassayswillbedowngradedtoClassII(i.e.requiring510(k)versusPMA).Someflexibilitytoallowforpotentialfuture“down‐classification”isthereforedesirable.Incorporatingintothelegislationtheabilityto“down‐classify”wouldalsobealignedtotheMMDRrecommendationsofensuringalignmentwithoverseasregulations.

TGAshouldprovideguidancethattheintendedscopeofthecompaniondiagnosticsregulationsistoalignwithcompaniondiagnosticregimensintheUSAandEU,whichmayalsoallowforfuturechangesininterpretationtobeadoptedinAustralia.

TGAshouldalsoprovideguidanceonthesituationwherethemedicinehasapositivebenefit:riskratioinabroadpopulation,butadiagnosticidentifiesasubpopulationwhichmayhaveamorepositivebenefit:riskratio.IfTGAapprovesuseinabroadpopulation,thenwebelievethisdiagnosticwouldnotbeclassifiedasaCDx.TGAshouldalsoprovideguidanceonthesituationwhereregulatoryapprovalorreimbursementisonlyprovidedforthesubpopulation,andwhetherthiswouldturnthediagnosticintoaCDx.Scheerensetal2017highlightsomerelevantexamples1.

AmendmentstoallowforcompulsoryauditsofARTGinclusionapplicationsforIVDCDxQuestionsforconsideration–Proposal4

DoyouhaveanycommentsorsuggestionsabouttheproposaltorequireacompulsoryauditofallIVDCDxpriortoinclusionontheARTG?

IstheproposedamendmenttoRegulation5.3clearenough?


Theproposedamendmenttoregulation5.3isclear.TheapprovalhistoryoftheCDxinothercountriesshouldbetakenintoconsiderationduringtheauditoftheclinicalinformation.

IftheTGAdoesproceedtorequirecompulsoryauditofallIVDCDxpriortoinclusionontheARTG,werequestthattherebesettimelinesforTGAtoadheretowhenconductingtheseaudits.Otherwisetheavailabilityofnewmedicines,requiringthepresenceoftheCDxontheARTGfortheiruse,havethepotentialtobesignificantlydelayedtopatientswhomayneedthemforlife‐savingtreatmentofoncological/haematologicalconditions.

1 H Scheerens, A Malong, K Bassett, Z Boyd, V Gupta, J Harrin, C Mesick, S Simnett, H Stevens, H Gilbert, P Risser, R Kalamegham, J Jordan, J Engel, S Chen, L Essioux, JA Williams. Current Status of Companion and Complementary Diagnostics, Clin Tranl Sci (2017) 10, 84-92. DOI: 10.1111/cts.12455

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Amendments toallow for the identificationof individual IVDCDx in theARTGorotherdatabase


DoyouhaveanycommentsorsuggestionsabouttheproposaltoamendRegulation1.6torequireauniqueproductidentifierasacharacteristicforidentificationofallIVDcompaniondiagnosticsinapplicationsforinclusionontheARTG?

DoyouhaveanyothersuggestionsfortheeffectiveidentificationofIVDcompaniondiagnosticsthatareincludedontheARTG?

DoyouhaveanycommentsorsuggestionsregardingthepublishingofalistofapprovedIVDcompaniondiagnosticsontheTGAwebsite(similartotheUSFDAapproach)?


TheuseofuniqueidentifiersisbeingacceptedasastandardinmanycountriesandwewouldsupportUniqueDeviceIdentifier(UDI)forapplicationsforinclusionofCDxontheARTG.ThepublicationontheARTGwouldbewelcometoalloweasyaccesstocurrentinformationbythepublic.WeproposethattheUDIalignwiththeUSorEUstandardsforUDI.

TGAshouldinvestigatethefeasibilityofimplementingtheIVDidentificationandlinkagesystemcurrentlyusedbyFDAathttps://www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/ucm301431.htm.SincetheEMAdoesnotdirectlyapprovecompaniondiagnostics(theyareapprovedthroughnotifiedbodies),theEMAcannotprovidedetailedinformationaboutthecompaniondiagnostic,andtheFDAexampleismorehelpful.TheFDAsystemallowsonetomanyandmanytoonelinkagesbetweenCDxandthecorrespondingmedicine/s.SeetheresponsetoProposal2above.

TheARTGentryforaCDxshouldprobablyexplicitlyidentifytheproductasaCDxintheproducttype.

AssessmentfeesforinitialapplicationsandchangestoexistingentriesontheARTGQuestionsforconsideration–Proposal6

Asdiscussedunderproposal4,acompulsoryaudittoensurethesafetyandperformanceofallIVDCDxcouldbecomearequirement.ItisthereforeproposedthatanapplicationauditfeeshouldapplytoallIVDCDxtoensurefullcostrecoverybytheTGAfortheassessmentsrequired.DoyouhaveanycommentsorsuggestionsabouttheproposalthatanapplicationauditfeeshouldapplytoallIVDCDxapplicationsforinclusion(subjecttoanyfeereductionsthatmaybeapplicableforabridgedassessments)?

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DoyouhaveanyothercommentsorsuggestionsabouttheproposalthatanassessmentfeeshouldapplytoapplicationstovaryanARTGinclusionofanIVDCDxwhereanassessmentisrequiredforanewintendedpurposeforthedevice?.


EventhoughacompulsoryaudittoensuresafetyandperformanceofallIVDCDxcouldbecomearequirement,thefeeshouldbevariable,basedontheamountofinformationrequiredtobereviewed,forexamplefeereductionsifdatafromreviewofotheragenciesisreliedupon,orotherjurisdictionalapprovalshavealreadybeenobtained.

IntermsofanewintendedpurposeofadevicethatmayalreadybelistedinARTGbutisnowbeingconsideredforARTGinclusionasaCDx,sincetheanalyticalperformancecharacteristicshavealreadybeenreviewed/acceptedbyTGA,afeereductionshouldapply.Additionally,ifthedevicewaspreviouslyselectedforaudit,thenafeereductionshouldapply.

TransitionarrangementsforIVDCDxalreadyincludedontheARTG


DoyouhaveanycommentsontheproposalfortransitioningofIVDCDxunderexistingARTGentriestomeettheproposednewrequirementsasoutlinedinthispaper?

Inparticular,doyouhaveanycommentsonoptionsa,bandcfortheauditingofexistingIVDCDxtransitioningtothenewframework?


Theidentificationoftheadditionalrisksassociatedwithoptionsb) iftheIVDwaspreviouslysubjecttoanapplicationauditwhichincludedatechnicalfilereviewpriortoinclusionthenthenewapplicationauditcouldbeabridgedandtheauditfeereducedorc)iftheIVDCDXhasbeensuppliedintheAustralianmarketandtherehavebeennoconcernsregardingthesafetyandefficacyofthecorrespondingtherapeuticgoodorthe safetyandperformanceoftheCDxthen,regardlessofwhetheritwaspreviouslyauditedbytheTGAthenewapplicationauditcouldbeabridgedandtheauditfeereducedarenoted.

Inadditiontotheseriskswewouldliketounderstandhowfollow‐onCDxtestswillbereviewedinthelightofthepotentiallackoforiginalsamplesfromthedrugtrialbeingavailable.Thisscenarioshouldbeaddressed,asthemanufacturermaybenewtothemarketforanexistingdrug/testcombination.Someclinicalevidenceisnecessary,andcomparabilitytestingisacceptedinotherjurisdictions(likeUSFDA).Arepeatoftheoriginalfulldrugstudywiththefirstdiagnosticshouldnotberequiredforthe‘follow‐on’diagnostictest.

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Timeframefortransition


DoyouhaveanycommentsonthetransitiontimeframeproposedforexistingIVDCDxtomeettherequirementsofthenewframework?


ThetransitiontimeforIVDCDx’s,alreadyexistingontheARTG,tomeettherequirementsshouldalignwiththetransitionperiodproposedintheEU(namely5years).InAustralia,theCEcertificationisutilisedasasuitableformofmanufacturerevidenceandtheAustraliansponsorwillmorethanlikelyrelyonthecertificationandaccompanyingSTEDtechnicalfileforsubmissioninAustraliaforCDx.ThereforealignmenttothetransitiontimeframesintheEUcanensuretimelyaccesstoproductsinAustralia.Manufacturersshouldbeallowedtousetheresultsofthetest,asithasbeenusedinthepublicsetting,tosupporttheclinicalperformancesuchthattheburdenofanadditionalclinicaltrialisnotmandatory.Itisunclearhowalreadyadoptedtestscurrentlyinclinicalpracticewillbehandledintermsofphysicianreporting,andresultsalreadyprovidedtopatientsgiventhisproposal.

IVDCDxthatarein‐houseIVDs


Doyouhaveanycommentsorsuggestionsontheproposalthatin‐houseIVDCDxshouldcomplywiththeclinicalevidenceandanalyticalperformancerequirementsapplicabletoallIVDCDx?

Doyouhaveanyothercommentsorsuggestionsregardingthecomplianceofin‐houseIVDCDxwiththeproposalsoutlinedinthispaper?


Wesupporttheapplicationofthesamecriteriatoin‐housetestsasisappliedtomanufacturers.Forfollow‐onin‐housecompaniondiagnostictests,asdescribedabove,analyticalperformanceandclinicalevidenceshouldbeappropriatelyconducted,giventhattheassociationofthebiomarkertothedrughasalreadybeenestablished,(i.e.clinicalcomparabilitytestingshouldprovideadequateevidence,notnecessarilyrepeatingtheoriginalclinicaltrial).

Withrespecttodatatosupportin‐houseIVDCDx,theremaybesomedifferencesinstudies/informationtosupportthedossierexpected,sinceitisasinglesite,andlabellingisin‐house.

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Coordinated Premarket Assessment of an IVD CDx and its CorrespondingMedicine/Biological


Toprovideassuranceofthesafetyandefficacyoftargetedtherapies,anIVDCDxanditscorrespondingmedicineorbiologicalshouldideallybeevaluatedandapprovedconcurrently.Doyouhaveanycommentsorsuggestionsregardingthewaysinwhichconcurrentevaluationmaybefacilitated?

Whereconcurrentevaluationisnotpossible,provisionneedstobemadeforcoordinationandreviewofevaluationsofanIVDCDxanditscorrespondingmedicineorbiological.

Doyouhaveanycommentsontheproposalundera)abovethatachangeinintendedpurposeofanIVDCDxwouldrequireanapplicationtovarytheARTGentryandsubmissionofevidencewhichsupportsthenewintendedpurpose?

Doyouhaveanycommentsontheproposalunderb)abovethatanyIVDCDxthatwasnotusedintheclinicaltrialsofatargetedtherapymustdemonstrateequivalentperformancetothereferencetestinconcordancestudies?


Inthecaseofconcurrentevaluation,thetimelinesfordeviceandmedicineevaluationshouldbealignedsoasnottoimpactthetimelinefornewmedicineorlineextensiontobeapprovedandavailabletopatients.ThisismademorecomplicatedduetothefactthatthemedicineanddeviceareevaluatedbyseparatebranchesoftheTGA.Perhapsacopythesectionofthedevicedossierthatpertainstothesensitivityofthedevicetodetectthebiologicalmarkerissharedwiththemedicineclinicalevaluationbranchorthedevicesection’sevaluationreport.Co‐ordinatedTGAmilestonedatesneedtobesetbetweenthetwobranchestoensurebothdeviceandmedicineareevaluatedwithinthesametimeframes.

TheconcurrentevaluationofaCDxandmedicinewillbedifficulttoco‐ordinatewithdifferentsponsorsbeingresponsiblefortheCDxandthemedicineorbiological.TGAwillneedtoprovideflexibilityintheprocesstoallowforpossibleco‐ordinationtooccur(e.g.byallowingeithertheCDxorthemedicineorbiologicalregistrationtooccurfirst,and/orbyprovidingwindowperiodsof1‐2monthswhereactivitiescanbeconducted.TGAmayalsoneedtoconsiderhowcommercialconfidentialitycanbehandledthroughe.g.agreementswithsponsorsonwhatdatacanbedisclosedtoeachsponsorateachstageoftheprocess.ItislikelythatCDxandmedicinesponsorswillnothavealocalcommercialagreementinplacetodefinethelimitsofdisclosuretoeachsponsor,soexplicitTGAguidanceinthisareamighthelpprovideasharedunderstandingofwhatwillbedisclosedtoeachpartyandwhen.

Ifunderproposala)thatthesponsorofIVDCDxneedstosubmitnewdatatosupporttheintendednewpurposeoftheCDx,thentherecouldpotentiallybelogisticaldifficultiesforthe

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CDxsponsorandthenewmedicine/biologicalsponsor(whichinmostsituationsaredifferentcompanies)co‐ordinatingthegenerationoftherequireddata.

ThenewintendedpurposefortheexistingCDx,thatisrequiredforthenewmedicine/biological,mightnotalwaysbecommerciallyviablefortheexistingCDxsponsortoregister.Thus,theapplicabilityoforphandesignationandwaiveroffeesshouldbeavailableaspermedicines.Otherwisepatientswithveryrarediseases,forwhichtargetedtherapiesrequirethatCDx,maynothavetheabilitytoaccesstothesenewtherapies.

Theuseofconcordancewouldallownewteststoprovethattheclinicalandanalyticalequivalenceismaintained.Wesuggestthattheuseofacombinationofclinicalsamplesandcontrivedsamplesbeallowedinthesupportofperformanceconcordance.

GeneralCommentsConsiderationshouldalsobegiventohowthisproposednewTGAprocesswillalignwiththePBACandMSACevaluationsforreimbursement.OneoftheaimsoftheMMDRwasensurepatientscanhavetheopportunitytoaccessnewtherapiesasquicklyaspossible.PerhapsaspectsoftheproposedcoordinatedregulatoryevaluationoftheCDxandthenewmedicine/biologicalmightbeharnessedtoalsoacceleratethereimbursementprocesstoensurepatientshavetheopportunitytoaccessnewtherapiesinasimilartimelinetopatientsoverseas.

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Citation: Clin Transl Sci (2017) 10, 84–92; doi:10.1111/cts.12455C© 2017 ASCPT. All rights reserved

TUTORIAL

Current Status of Companion and ComplementaryDiagnosticsStrategic Considerations for Development and Launch

H Scheerens1, A Malong1, K Bassett1, Z Boyd1, V Gupta1, J Harris1, C Mesick1, S Simnett1, H Stevens2, H Gilbert1, P Risser1,R Kalamegham1, J Jordan2, J Engel2, S Chen2, L Essioux3 and JA Williams1

US Food and Drug Administration (FDA)-approved diagnostic assays play an increasingly common role in managing patientsto prolong lifespan while also enhancing quality of life. Diagnostic assays can be essential for the safe and effective useof therapeutics (companion diagnostic), or may inform on improving the benefit/risk ratio without restricting drug access(complementary diagnostic). This tutorial reviews strategic considerations for drug and assay development resulting in FDA-approved companion or complementary diagnostic status.Clin Transl Sci (2017) 10, 84–92; doi:10.1111/cts.12455; published online on 25 January 2017.

INTRODUCTIONScope and definition of conceptsThe key scope of this article focuses on companion andcomplementary diagnostic status as determined by the FDA.However, there are also specific references to testing statusin the European Union (EU) and other geographic regions.The following concepts are defined briefly below and in theGlossary of Terms (Table 1): Analytical validation: establish-ing that the performance characteristics of a test, tool, orinstrument are acceptable in terms of its sensitivity, speci-ficity, accuracy, precision, and other relevant performancecharacteristics using a specified technical protocol (whichmay include specimen collection, handling and storage pro-cedures). This is validation of the test’s, tool’s, or instrument’stechnical performance, but is not validation of the item’s use-fulness; Clinical validation : establishing that the test, tool,or instrument acceptably identifies, measures, or predictsthe concept of interest; Clinical utility: the conclusion that agiven use of a medical product will lead to a net improvementin health outcome or provide useful information about diag-nosis, treatment, management, or prevention of a disease.Clinical utility includes the range of possible benefits or risksto individuals and populations.1

OVERVIEW

Several considerations are relevant for optimizing personal-ized healthcare (PHC) and improving access to new thera-pies for patients via positive clinical studies and subsequentregulatory approvals. The term PHC refers to developing tar-geted therapeutics for specific patients or patient subgroups(i.e., genotypes/phenotypes/endotypes) or optimizing dos-ing for certain patient subgroups.2,3 The objective of PHC

1Genentech Inc., San Francisco, California, USA; 2Roche AG, Basel, Switzerland; 3Pharmaceutical Sciences, Roche Pharma Research and Early Development, RocheInnovation Center Basel, F. Hoffmann-La Roche, Ltd, Basel, Switzerland. Correspondence: JA Williams ([email protected])Received 19 December 2016; accepted 18 January 2017; published online on 25 January 2017. doi:10.1111/cts.12455

is to identify and help direct therapies to patients who aremost likely to experience a favorable benefit–risk outcomewith a selected therapy. This is best accomplished by iden-tifying patients who are most likely to experience enhancedbenefits and/or decreased risks associated with a therapy,and if not, also restricting access of the therapy to patientswho are most likely to experience a positive benefit–risk pro-file with the therapy. For example, it has been shown thatthe subgroup of women with breast cancer who overexpressthe human epidermal growth factor receptor 2 (HER2) proteinderive clinically meaningful responses to trastuzumab (HER-CEPTIN), an anti-HER2 monoclonal antibody.4 This led tothe development of companion diagnostic assays for HER2where a positive result confirming overexpression is requiredfor patients to receive trastuzumab (HERCEPTIN), and otherHER2-directed therapies such as pertuzumab (PERJETA)and ado-trastuzumab emtansine (KADCYLA).

Significant advances are being made in understandingthe complex biologies of disease, including those influ-enced by immune mechanisms such as cancer5 and asthma,which comprises specific clinical phenotypes and underly-ing molecular endotypes.3,6 Most approved drugs for thesediseases have limitations in that they are either only partlyeffective in all patients, also known as an all-comer pop-ulation, show increased benefits in a subset of patients,and/or that patients generally respond less robustly overtime. These observations are strongly suggestive of multi-ple molecular pathways driving the underlying pathophysi-ology in these different subgroups of patients, or possiblyof resistance mechanisms emerging to overcome drug effi-cacy, or both. The obvious implication of this is that differentpatients may need different therapeutics to treat their dis-ease, but how does one know which patient needs whichtreatment?

Options for Companion and Complementary DiagnosticsScheerens et al.

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Table 1 Glossary of Terms

Term Definition*

Analytical validation (1) Establishing that the performance characteristics of a test, tool, or instrument are acceptable in terms of itssensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specifiedtechnical protocol (which may include specimen collection, handling and storage procedures). Thisis validation of the test’s, tool’s, or instrument’s technical performance, but is not validation of the item’susefulness.

Clinical validation (1) Establishing that the test, tool, or instrument acceptably identifies, measures, or predicts the concept of interest;

Clinical utility (1) The conclusion that a given use of a medical product will lead to a net improvement in health outcome or provideuseful information about diagnosis, treatment, management, or prevention of a disease. Clinical utility includesthe range of possible benefits or risks to individuals and populations.

Companion Diagnostic A companion diagnostic is a medical device, often an in vitro device (IVD), which provides information that isessential for the safe and effective use of a corresponding drug or biological product.

Complementary Diagnostic** (Draftdefinition from FDA as presented atASCO – 5 June 2016)

A complementary diagnostic is a test that aids in the benefit–risk decision–making about the use of the therapeuticproduct, where the difference in benefit–risk is clinically meaningful. Complementary IVD information is includedin the therapeutic product labeling.

Enrichment Enrichment is the prospective use of any patient characteristic, including demographic, pathophysiologic,historical, genetic, and others, to select patients for a study or to analyze patient data to obtain a studypopulation in which detection of a drug effect is more likely than it would be in an unenriched population.

In Vitro Diagnostic (IVD) IVD products are those reagents, instruments, and systems intended for use in the diagnosis of disease or otherconditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease orits sequelae. Such products are intended for use in the collection, preparation, and examination of specimenstaken from the human body.

Premarket Approval (PMA) Premarket approval (PMA) is the FDA process of scientific and regulatory review to evaluate the safety andeffectiveness of Class III medical devices. Due to the level of risk associated with Class III devices, the FDA hasdetermined that general and special controls alone are insufficient to assure the safety and effectiveness of ClassIII devices. Therefore, these devices require a PMA application (submission via modules is an option) undersection 515 of the Food, Drug and Cosmetic Act to obtain marketing clearance.

*Source: FDA.**As of December 2016, no formal FDA definition exists for complementary diagnostics. ASCO, American Society of Clinical Oncology.

As defined by BEST,1 predictive biomarkers are biomark-ers used to identify individuals who are more likely thansimilar individuals without the biomarker to experience afavorable or unfavorable effect from exposure to a medicalproduct or an environmental agent. So, predictive biomarkerscan be used to identify patient subgroups that best benefitfrom targeted therapies. Targeting those biomarker-definedsubgroups with novel therapeutics could result in enhancedefficacy compared with all-comer populations and reduceunnecessary exposure to subgroups not deriving optimalbenefit. Prognostic biomarkers are defined as biomark-ers used to identify likelihood of a clinical event, diseaserecurrence, or progression in patients who have the dis-ease or medical condition of interest.1 Predictive biomark-ers of treatment response could at the same time also beprognostic for clinical events or disease progression. How-ever, in the context of identifying patient subgroups withenhanced response and associated companion or com-plementary diagnostic development, these biomarkers arereferred to as predictive for treatment response. Subsequentanalytical and clinical validation of assays for these biomark-ers can lead to the marketing approval of companion diag-nostics or, more recently, complementary diagnostics viaFDA approval in the United States. Examples of analyticalplatforms for diagnostic assays are immunohistochemistry(IHC) and quantitative polymerase chain reaction (qPCR), andthese are likely to increase as the field evolves to include plat-forms such as next-generation sequencing (NGS),7 imaging,and possibly immunoassays.

Although two complementary diagnostics for programmeddeath-ligand 1 (PD-L1) IHC assays for cancer immune thera-

pies (as described in detail in later sections) have receivedFDA approval, formal guidance describing the term andproviding a framework for approval is pending. In contrastto companion diagnostics, complementary diagnostics donot restrict patients from receiving codeveloped therapiesbased on the outcome of the diagnostic test. This is becausetherapeutic benefit has been demonstrated in all patients forcomplementary diagnostics, regardless of biomarker status.Nevertheless, the biomarker can inform on enhanced ben-efits in subgroups of patients; for example, those express-ing higher protein levels of the immune checkpoint PD-L1.These early PD-L1 IHC assay precedents of complementarydiagnostics are currently limited to cancer immune therapies,namely, atezolizumab (TECENTRIQ for bladder and non-small cell lung cancer (NSCLC) indications) and nivolumab(OPDIVO for melanoma and NSCLC indications). However,it is likely that they will be joined by other assays with com-plementary diagnostic status more broadly across therapeu-tic areas that will include additional examples in oncology asdrug combinations become more commonly used.

Historical context and case studiesFigure 1 shows a timeline of key events for development ofdiagnostic assays partnered to therapeutics in the UnitedStates. The FDA approved the first companion diagnostic(HER2 assay for trastuzumab) in 1998,8 and the first com-plementary diagnostic (PD-L1 IHC assay for nivolumab) in2015. Although the term “complementary diagnostic” hasbeen used since the 1990s, the FDA regulatory status didnot apply until 2015. Prior to 2015, the term “complemen-tary diagnostic” referred to tests used to improve disease

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Figure 1 Historical timeline of the first Companion and first Com-plementary Diagnostic assays in the United States.

management, early diagnosis, patient risk stratification, anddrugmonitoring, but did not require a regulatory link to a spe-cific therapeutic.9

Trastuzumab (HERCEPTIN) has been shown to improveoverall survival in both adjuvant and metastatic HER2-positive (HER2 protein overexpression in tumor tissue) breastcancer in patients.4 Thus, the HER2 test became the firstcompanion diagnostic (Figure 1). Additional assays to mea-sure HER2 have since been approved and now make upnearly half of all companion diagnostics approved by theFDA (Table 2). Importantly, most of these HER2 assayswere not codeveloped with trastuzumab, but were insteadapproved after the initial drug approval as technologies andcommercial opportunities evolved. The focus of the cur-rent tutorial is on strategic codevelopment of the drug andassay.

An excellent example of a companion diagnostic approvalis the COBAS BRAF V600E test which received simulta-neous FDA marketing approval along with vemurafenib(ZELBORAF) for metastatic melanoma. Data showedan overall survival benefit for patients with the BRAFV600E mutation relative to the comparator treatment,dacarbazine.10 Additionally, studies showed paradoxicalactivation of the RAF pathway in cell lines with wildtype sta-tus suggests potential harm to patients without the V600Emutation receiving this therapy, as reflected in the productlabel. Clearly, V600E mutation status is essential for the safeand effective use of vemurafenib (ZELBORAF) in metastaticmelanoma. Recognizing this fact, the sponsors undertook aregulatory strategy that included parallel development of thedrug and its associated assay. The simultaneous approval ofthe two represents an important example of a codevelopeddrug and diagnostic assay.

The first two approvals for complementary diagnosticassays highlight the FDA’s determination that patientsshould not be excluded from receiving cancer immune ther-apies even though efficacy in response to therapy increasedwith higher levels of PD-L1 protein expression levels in theirtumors. Importantly, although the FDA drug approvals pro-mote access for all patients to receive therapy, both PD-L1

IHC assays identify patients whomay respond better to thesedrugs as the levels of PD-L1 protein expressed in tumorsincrease. In 2015 the FDA approved the first complemen-tary diagnostic using the PD-L1 IHC 28-8 PharmDx assay(http://www.agilent.com/en-us/products/pharmdx/pd-l1-ihc-28-8-pharmdx/pd-l1-ihc-28-8-pharmdx-for-autostainer-link-48-1) for the cancer immunotherapy nivolumab(OPDIVO) based on a phase III trial in second-line non-smallcell lung cancer (NSCLC).11 Separately, positive PD-L1 sta-tus as determined by PD-L1 IHC 28-8 PharmDx in melanomais correlated with the magnitude of the treatment effect onprogression-free survival (PFS) from nivolumab (OPDIVO).PD-L1 protein expression is defined as the percentage oftumor cells exhibiting positive membrane staining at anyintensity, which may be associated with enhanced survivalfrom nivolumab (OPDIVO) in nonsquamous NSCLC. In 2016the FDA approved complementary diagnostic status for theVENTANA PD-L1 (SP142) assay based on successful pivotaltrials with atezolizumab (TECENTRIQ) in NSCLC12 and blad-der cancer.5 The SP142 IHC assay is a qualitative immuno-histochemical assay intended for use in formalin-fixed,paraffin-embedded (FFPE) urothelial carcinoma and NSCLCtissue (http://www.ventana.com/product/1827?type=2357).Scoring and interpretation of PD-L1 status is indication-specific. Discernible PD-L1 staining of any intensity intumor-infiltrating immune cells covering �5% of tumorarea determined by the VENTANA PD-L1 (SP142) assayin urothelial carcinoma tissue is associated with increasedobjective response rate (ORR) in a nonrandomized study ofatezolizumab (TECENTRIQ). In NSCLC, discernible PD-L1membrane staining of any intensity in �50% of tumor cells ortumor infiltrating immune cells covering �10% of tumor areaoccupied by tumor cells as determined by the VENTANAPD-L1 (SP142) assay may be associated with enhancedoverall survival (OS) from atezolizumab (TECENTRIQ).

What is different outside the United States?In the United States, the FDA regulates the approval of com-panion and complementary in vitro diagnostic (IVD) tests viathe Center for Devices and Radiological Health (CDRH). Thepackage insert (product label) of a therapeutic usually states“as determined by an FDA-approved test,” when referring tothe biomarker assays used to identify a subgroup of patients.FDA approval ensures verification of both analytical and clin-ical validation of the IVD test. The package insert of thediagnostic assay will refer back to the therapeutic with whichthe test is intended to be used. In Europe, the summary ofproduct characteristics (SmPC) describes the therapeuticand refers to the diagnostic assay “as determined by anaccurate and validated assay.” The European MedicinesAgency’s Committee on Medical Products for Human Use(EMA CHMP) does not regulate or approve the diagnostictest; rather, marketing of test requires that the sponsor obtaina “CE” marking. CE marking (Conformité Européene) indi-cates that the product had been assessed and meets Euro-pean Union (EU) safety, health, and environmental protectionrequirements (http://ec.europa.eu/growth/single-market/ce-marking/). For example, the herceptin SmPC states “HER2testing must be performed in a specialized laboratory whichcan ensure adequate validation of the testing procedures”

Clinical and Translational Science

Companion diagnostics came to the market ,vith trastuzumab (HERCEPTIN®)

Approval of nivolumab (OPDIVO®) for NSC LC with Complementary diagnostics (PDL1 IHC 28-8 (Dako)

• ~ '"'

1

•

Com ple m entary diagnostics term first applied by CSK, Alizyme to help tailor medicines (no,i.regulaWry status)

e.g. TGF-P suggested as NSCLC d iagnosis Co mplementary diagnostics

Approva l of atezolizumab (TECBNTRIQ®) for bladder cancer with Complementary diagnostics (PD-L l IHC assay (SP142)


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Table 2 List of all approved companion and complementary diagnostic assays in the United States

Companion Diagnostic Assays (listed in alphabetic order of drug trade name)

Drug trade name (generic name) Device trade name Disease Platform

1 ERBITUX (cetuximab); VECTIBIX(panitumumab)

DAKO EGFR PharmDx Kit Colorectal cancer � IHC


The cobas KRAS Mutation Test Colorectal cancer � PCR


therascreen KRAS RGQ PCR Kit Colorectal cancer � PCR

4 EXJADE (deferasirox) Ferriscan Thalassemia � MRI

5 GILOTRIF (afatinib) therascreen EGFR RGQ PCR Kit Non-small cell lung cancer � PCR

6 GLEEVEC (imatinib mesylate) DAKO C-KIT PharmDx Gastrointestinal stromal tumor � IHC

7 GLEEVEC (imatinib mesylate) PDGFRB FISH for GleevecEligibility in MyelodysplasticSyndrome/MyeloproliferativeDisease (MDS/MPD)

Myelodysplastic Syn-drome/MyeloproliferativeDisease

� FISH

8 GLEEVEC (imatinib mesylate) KIT D816V Mutation Detection byPCR for Gleevec Eligibility inAggressive SystemicMastocytosis (ASM)

Aggressive systemicmastocytosis

� PCR

9 HERCEPTIN (trastuzumab) INFORM HER-2/NEU Breast cancer � FISH

10 HERCEPTIN (trastuzumab) INSITE HER-2/NEU KIT Breast cancer � IHC

11 HERCEPTIN (trastuzumab) Bond Oracle Her2 IHC System Breast cancer � IHC

12 HERCEPTIN (trastuzumab) PATHWAY ANTI-HER-2/NEU (4B5)Rabbit Monoclonal PrimaryAntibody

Breast cancer � IHC

13 HERCEPTIN (trastuzumab) SPOT-LIGHT HER2 CISH Kit Breast cancer � CISH

14 HERCEPTIN (trastuzumab) PATHVYSION HER-2 DNA ProbeKit

Breast cancer � FISH

15 HERCEPTIN (trastuzumab) INFORM HER2 DUAL ISH DNAProbe Cocktail

Breast cancer � ISH

16 HERCEPTIN (trastuzumab) Bond Oracle Her2 IHC System Breast cancer � IHC

17 HERCEPTIN (trastuzumab);PERJETA (pertuzumab);KADCYLA (ado-trastuzumabemtansine)

HERCEPTEST Breast cancer � IHC

18 HERCEPTIN (trastuzumab);PERJETA (pertuzumab);KADCYLA (ado-trastuzumabemtansine)

HER2 FISH PharmDx Kit Breast cancer � FISH

19 IRESSA(gefitinib) therascreen EGFR RGQ PCR Kit Non-small cell lung cancer � PCR

20 KEYTRUDA (pembrolizumab) PD-L1 IHC 22C3 PharmDx Non-small cell lung cancer � IHC

21 LYNPARZA (olaparib) BRACAnalysis CDx Ovarian cancer � PCR

22 MEKINIST (trametinib);TAFINLAR(dabrafenib)

THxID BRAF Kit Melanoma � PCR

23 RUBRACA (rucaparib) FoundationFocus CDxBRCA Test Ovarian cancer � NGS

24 TAGRISSO (osimertinib) cobas EGFR Mutation Test v2 Non-small cell lung cancer � PCR

25 TARCEVA (erlotinib) cobas EGFR Mutation Test Non-small cell lung cancer

� PCR

(Continued)

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Table 2 Continued

Companion Diagnostic Assays (listed in alphabetic order of drug trade name)

Drug trade name (generic name) Device trade name Disease Platform

26 VENCLEXTA (venetoclax) VYSIS CLL FISH Probe Kit Chronic lymphocytic leukemia � FISH

27 XALKORI (crizotinib) VENTANA ALK (D5F3) CDx Assay Non-small cell lung cancer � IHC

28 XALKORI (crizotinib) VYSIS ALK Break Apart FISHProbe Kit

Non-small cell lung cancer � FISH

29 XALKORI (crizotinib) VENTANA ALK (D5F3) CDx Assay Non-small cell lung cancer � IHC

30 ZELBORAF (vemurafenib) COBAS 4800 BRAF V600Mutation Test

Melanoma � PCR

Complementary Diagnostic Assays (listed in alphabetic order of drug trade name)

Drug trade name (generic name) Device trade name Disease Assay format

1 OPDIVO (nivolumab) PD-L1 IHC 28-8 MelanomaNon-small cell lung cancer

� IHC

2 TECENTRIQ (atezolizumab) VENTANA PD-L1 (SP142) Assay Bladder cancerNon-small cell lung cancer

� IHC

IHC, Immunohistochemistry; PCR, Real-time polymerase chain reaction; MRI, Magnetic resonance imaging; FISH, Fluorescence in situ hybridization; ISH, In situhybridization; CISH, Chromogenic in situ hybridization; NGS, Next-generation sequencing.

and “for any other method that may be used for the assess-ment of HER2 protein or gene expression, the analysesshould only be performed by laboratories that provide ade-quate state-of-the-art performance of validated methods.Such methods must clearly be precise and accurate enoughto demonstrate overexpression of HER2 and must be ableto distinguish between moderate (congruent with 2+) andstrong (congruent with 3+) overexpression of HER2.”

In the EU specifically, regulation of medical devices hasbeen separated from the regulation of pharmaceuticals.However, there is growing momentum towards release ofnew guidance documents that may integrate the two paths(diagnostic and therapeutic) as more are codeveloped andas the diagnostic assays increasingly become more techno-logically sophisticated.13 In the meantime, CE-marking foranalytical grade tests without associated clinical outcomedata can precede tests with predictive status when associ-ated clinical data are available. Therefore, an analytical assaycan be marketed with limited information about clinical utilitybefore it is marketed to inform on predicted response to atreatment. The nivolumab (OPDIVO) 28-8 and atezolizumabPD-L1 (TECENTRIQ) IHC tests are two examples, where eachassay has shown increasing efficacy with increasing levelsof PD-L1 expression. Additionally, analytical concordancestudies can enable cross-referencing of CEmarking betweenassays for the same therapy, such as for the Ventana SP263PD-L1 IHC assay (http://www.ventana.com/ventana-pd-l1-sp263-assay-2/) to nivolumab (OPDIVO) following a concor-dance study with the 28-8 IHC assay.

In addition to the difference in regulatory status of the diag-nostic test (FDA-approved vs. CE marking), the payer envi-ronment outside the United States is also vastly different. Asexplained in the section on reimbursement and commercialconsiderations, certain geographic regions may only reim-burse for subgroups of patients with enhanced clinical bene-fit, even in the case of an all-comer label with a complemen-

tary diagnostic where no patients are restricted from receiv-ing the drug.

Considerations for nononcology indicationsThe vast majority of companion diagnostics and all com-plementary diagnostics are currently in oncological indica-tions, perhaps because of the plethora of targeted thera-pies developed in this indication reflecting our increasinglysophisticated understanding of the genetic and immunologicpathways underlying various cancers. The diagnostic assaytypically measures expression of the therapeutic target inthe tumor tissue or mutations in the gene of the therapeu-tic target (Table 2), clearly linking the biomarker measuredby the diagnostic test to the mechanism of action of thetherapeutic. In nononcological indications, this is often eithernot clinically feasible, or with current technologies, impos-sible. For example, in many neurologic, respiratory, oph-thalmologic, or rheumatologic diseases, obtaining diseasedtissue for routine sampling is often not easy, making it diffi-cult to measure target levels in the relevant organ in currentclinical practice and leading to a greater reliance on distalblood-based biomarkers. No common somatic or germlinegenetic variations were identified so far as major factors driv-ing disease pathology in these diseases. For these reasons,identifying a subgroup of patients most likely to respond toa therapeutic by measuring the target in a biopsy speci-men from the diseased tissue is often less feasible than inother (but not all) oncologic diseases where tissue is routinelybiopsied.

One approach that has been used to identify molec-ular endotypes within a disease is through observationalexperimental medicine studies whereby disease tissue sam-ples are profiled molecularly. For example, Woodruff et al.first described TH2-high and TH2-low subgroups of asthmapatients based on gene expression of bronchial epithe-lial brushings.14 Subsequently, bronchial epithelial gene



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expression was correlated with biomarkers that were eas-ily detected in peripheral blood, and based on this analysisserum periostin was selected as a candidate diagnostic usedto identify asthma patients with TH2-driven disease.15 McK-inney et al. eloquently demonstrated disease heterogene-ity based on peripheral blood T-cell exhaustion phenotypein autoimmune and infectious disease, while also suggest-ing that targeted intervention may lead to new therapeuticopportunities.16 Whether these indirect predictive biomarkercandidates can ultimately be clinically validated and devel-oped into robust IVDs which will be approved as codevel-oped diagnostics in nononcology indications remains to bedetermined.

Another challenge encountered with many nononcologicaldiseases is the timing of the clinical efficacy study. The ear-liest clinical efficacy of a therapeutic subgroup of patientstested is in phase II studies since the phase I studies in theseindications are often done in healthy volunteers. As such,there is very limited time after phase II to establish and clin-ically validate these subgroups of patients defined by assayresult prior to launch of the therapeutic without delaying theapproval and availability of the drug. A successful co-launchof the therapeutic and the diagnostic test depends on manyfactors, but one key factor is establishing clinical utility, wherethe test use results in improved treatment decision-makingand thereby improved clinical outcome for the patient.17 Thevalue the diagnostic brings to the overall clinical practiceshould be clear to the physicians and regulators. The currentpractice of two independent phase III studies (as required inmany therapeutic areas outside of oncology) using a noveldiagnostic test may not be sufficient to change clinical prac-tice. It is therefore beneficial to start considering the clinicalutility of a novel diagnostic test early in clinical developmentto allow time to generate additional data that can supportphysician education and health economic analyses on thepotential clinical utility of the test.

If patient subgroups can be reliably identified using estab-lished clinical features or existing diagnostics, then develop-ing a novel diagnostic test (either companion or complemen-tary) may not be required, although clinical utility will still needto be established. For example, peripheral blood eosinophilcounts were used to enrich for patients with eosinophilicasthma in the pivotal clinical studies with mepolizumab(NUCALA) and reslizumab (CINQAIR), both antiinterleukin-5 (IL-5) antibodies.18–22 Blood eosinophil counts are a rou-tine clinical assessment (complete blood count with differ-ential, or CBC-D) and are directly linked to levels of thegrowth and survival factor IL-5, which is the target of thesedrugs. No specific companion or complementary assaywas considered necessary, allowing physicians consider-able flexibility both in testing prospective patients and forclassifying patients as falling under an eosinophilic pheno-type. There’s additional flexibility in the test hardware, soft-ware, and threshold of eosinophil number to assign asthmaas being of eosinophilic status.

Despite the many challenges present for nononcologicalindications, it is widely recognized that many of these com-plex disorders are of heterogeneous pathogenesis and there-fore patients will greatly benefit frommore targeted therapiesand a personalized health care approach.

Strategic considerationsIn the context of personalized healthcare, in the past decadethe focus in the pharmaceutical industry has been on code-veloping companion diagnostics as a prerequisite for ther-apeutic approval if the therapy is targeted for a specificpopulation. With the recent addition of complementary diag-nostics as an alternative tool to develop successful ther-apies, the question arises as to what strategy to use forwhich therapeutic? Should potential options to restrict piv-otal drug trial enrollment to only patients selected basedon diagnostic testing be considered, if this approach maypreclude the ability to support a complementary diagnosticstrategy? What are the advantages and disadvantages of astrategy on one end of the spectrum, where only diagnos-tic assay-positive patients are selected for the trial, whichmay enable a companion diagnostic, vs. the other end of thespectrum, where an all-comer patient enrollment approachenables a complementary diagnostic option? This questionarises early in clinical development, as it may impact theoverall clinical development plan, including the clinical trialdesign and regulatory strategy. Furthermore, it will likely haveimplications for patient access, as well as the commercialstrategies for both the pharmaceutical and the diagnosticcompanies.

Clinical trial design considerationsAn all-comer patient enrollment strategy with or withoutbiomarker stratification and retrospective assessment of sta-tus relative to a specific assay could enable either companionor complementary diagnostic assay status upon FDA reviewof the submission new drug application (NDA)/biologicslicense application (BLA) and premarket approval (PMA)packages. Based on the nivolumab and atezolizumabapprovals for non-small cell lung cancer (NSCLC) as a life-threatening disease with a serious unmet medical need, theprimary consideration would likely be not restricting patientsto therapy use based on favorable benefit/risk ratio relative tochemotherapy standards of care, thus defaulting to comple-mentary diagnostic status of the assay if the trial succeeds.Thus, diagnostic test-negative patients would also benefitbased on submitted data relative to concurrently availabletherapies. However, for future approvals in any therapeuticarea, positive test results in a subgroup using this designmayresult in companion diagnostic approval if the patients testingnegative did not exhibit a favorable benefit/risk ratio relativeto standards of care and/or unmet medical need. Conversely,selection of test-positive patients in pivotal studies (i.e., onlyenrolling test-positive patients) might enable FDA designa-tion of companion diagnostic status if the trial was posi-tive, but would likely not allow for complementary diagnosticstatus.

Specimen types and platform considerationsThe currently approved complementary diagnostics arefocused on a single analyte (PD-L1) and on an IHC plat-form for NSCLC, bladder, or melanoma cancer patients.Similarly, the vast majority of approved companion diag-nostics are tests using tumor tissue as the sample type,with either IHC or qPCR as the platform, with the exceptionof the Ferriscan MRI imaging assay for EXJADE (Table 2).

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Figure 2 Impact of companion and complementary diagnostic status on (a) use of diagnostic test and (b) use of drug in advanced NSCLC.Data from Flatiron Health database 31 July 2016.

Since the risk/benefit ratio of testing is lower for samplingcirculating specimens than taking biopsies, this is an attrac-tive alternative for patients and their physicians for compan-ion and complementary diagnostics to be used for chronicdiseases to inform on the potential for greater benefit andenhance the overall treatment dialog between patient andphysician. There is significant appeal for using levels of circu-lating analytes or proteins, such as FDA-approved cell-freeDNA (cfDNA) tests for NSCLC patients receiving epidermalgrowth factor (EGFR) inhibitors such as erlotinib and germlineDNA to guide treatment decisions in other diseases such ascystic fibrosis (e.g., ivacaftor), as well as metabolic, cardio-vascular, and diseases with immune mechanisms to guidetreatment decisions.

The likelihood of a broad use of specific tests would beincreased if the tests could show utility across a drug classand if they measured more than one relevant biomarkerrather than a single molecular entity or analyte. This con-cept and accompanying FDA requirements may be nearingapproval, with both Foundation Medicine and Illumina aimingfor a “universal companion diagnostic” for next-generationsequencing (NGS) panels via FDA approval for oncologyindications in the near future. This would represent the firsttime a multiplex/multimarker test received IVD approval asa companion diagnostic for multiple therapies,23 albeit asfollow-on companion diagnostics rather than as codevel-oped tests. This would provide a basis with which to betterunderstand what criteria might be applied to these multiplexNGS-based tests with respect to analytical validation, clinicalvalidation, and clinical utility. The very recent approval of theFoundationFocus CDxBRCA test for rucaparib is an exam-ple of an NGS-based companion diagnostic for two geneson separate chromosomes. (BRCA1 on 17q and BRCA2 on13q). Global platform-installed base and global access tospecific testing technologies are also important considera-

tions for pharmaceutical and diagnostic companies code-veloping therapies and assays. IHC, for example, has veryhigh global availability, even in emerging markets, while NGSholds great promise for universal companion diagnostic test-ing, and adoption of the technology is growing and is cur-rently more centralized in many regions.

Reimbursement and commercial considerationsFor pharmaceutical and diagnostic sponsors codevelop-ing therapies with their respective tests, the prospect ofdeveloping and launching a complementary diagnosticprovides the opportunity to increase access of the therapyto all patients and not restrict it to a specific biomarkersubgroup based on test results. In the complementarydiagnostics scenario, with a corresponding therapy that hasdemonstrated all-comer benefit, the path to establishingclinical utility of the test may be more complex than fora companion diagnostic test. As described in BEST,1 thewidely accepted definition of clinical utility for an assay isthe conclusion that a given use of a medical product willlead to a net improvement in health outcome or provideuseful information about diagnosis, treatment, management,or prevention of a disease. Clinical utility includes the rangeof possible benefits or risks to individuals and populations.In the context of medical community uptake or healtheconomics, the concept of clinical utility may often also beused to encompass effectiveness and/or economic implica-tions including uptake, coverage, and reimbursement. Thepreliminary evidence to date, based mainly on testing forpreviously treated NSCLC, suggests that physicians mayorder complementary diagnostics far less frequently thancompanion diagnostic tests on a per-patient basis. This isillustrated in Figure 2a via Flatiron data, based on a July 2016snapshot, which shows nivolumab (OPDIVO), an anti-PD-1antibody approved for all-comers with a complementary


a b 65 3000

60

• pembrolizumab (KEYTRUDA• ) diagnostic test

SS (PD•Ll IHC 220 pharmDx)

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June 2015 Augvi12015 OC1obtt2015 Ot«mbtr201S ~bfu1ry2016 ~12016 June 2016 nlvolumab pembrollzumab Month of Result (OPDIVO• ) (KEYTRUDA•)


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Figure 3 Potential commercial strategies of evolving Complementary Diagnostics.

diagnostic status. In terms of testing volume, it isapparent that the pembrolizumab (KEYTRUDA) diagnostictest (PD-L1 IHC 22C3 PharmDx) is used much more than thenivolumab (OPDIVO) diagnostic test (PD-L1 IHC 28-8) rela-tive to the total number of patients treated with each drug,due to the difference in “need-to-test” status for a compan-ion vs. the “no-need-to-test” complementary diagnostic.However the drug nivolumab (OPDIVO) was prescribed tomore patients then pembrolizumab (KEYTRUDA) (Figure 2b).Also, as of July 2016, this emerging data showed that thecomplementary diagnostic PD-L1 28-8 IHC assay code-veloped for nivolumab (OPDIVO) was used much morefrequently overall in NSCLC than the companion diagnostic22C3 PD-L1 IHC assay pembrolizumab (KEYTRUDA) (also ananti-PD-1 antibody), which is approved with a restricted labelfor patients with elevated expression of PD-L1 in their tumortissue (Figure 2b). Importantly and for relevant context, thisJuly 2016 snapshot of PD-L1 IHC testing reflects only thecomplementary vs. companion status in the United Statesonly, where neither nivolumab (OPDIVO) nor atezolizumab(TECENTRIQ, approved in October 2016) are restricted byeither payers or the FDA based on PD-L1 status in previouslytreated NSCLC. Testing practices for PD-L1 IHC in cancerpatients, particularly for NSCLC, are still evolving outside theUnited States.

Outside of the United States, examples are emerging ofpayers utilizing the results of complementary testing to limitpatient eligibility for reimbursement based on financial con-siderations. For example, in both the United Kingdom andSouth Korea, nivolumab (OPDIVO) is only reimbursed for highexpressors of PD-L1 protein via IHC testing, thus acting as ade facto companion diagnostic from a payer and access per-spective. This contrasts with its complementary diagnostic

status determined by the FDA in the United States, where nopatients are restricted from receiving this therapy. Similarly,stand-alone diagnostics (tests that provide information topatients on disease or physiological status that are not linkedto a specific drug) can also evolve to companion and poten-tially complementary use if subsequently linked to a thera-peutic. An excellent example of this is the Myriad BRACAnal-ysis CDx test, initially available as a stand-alone diagnostictest for assessment of risk for developing hereditary cancers.This test was subsequently used in clinical studies approvedby the FDA via the PMA route as an approved diagnosticdevice that detects and classifies mutations in the BRCA1and BRCA2 genes, using genomic DNA obtained from wholeblood samples from a patient, as an aid in identifying ovar-ian cancer patients with deleterious or suspected deleteriousgermline BRCA variants eligible for treatment with olaparib(LYNPARZA).

Only FDA-approved or FDA-cleared tests have the oppor-tunity to come tomarket with data already available regardingthe clinical utility of the test. Further assessment of clinicalutility of an assay in the community may require additionalcapture of real-world evidence, and challenges in achievingthis goal in the postapproval setting may vary among com-panion and complementary diagnostics.

As shown in Figure 3, commercial strategies mayevolve in the United States following initial determinationof complementary diagnostic status. For example, com-plementary diagnostic status in the United States mayevolve to companion diagnostic status in other geographicregions. Specifically, as now seen for nivolumab, in pre-viously treated NSCLC in the United Kingdom and SouthKorea a positive test status is required to ensure reim-bursement for treatment. Another scenario laid out in

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Time

Real World Data analysis

Additional studies

Additional Indications

Payer requirement

Ex-US Health Authority feedback

New diagnostic technologies

Possible Scenarios

Complementary becomes a stand-alone marker

Complementary remains •complementary• for rhe

drug

Complementary diagnoslic becomes a Companion

Diagnonic (CDx) in some cases•

Better resrs developed for marker and ir becomes a

predictive CDx marker

• This could include additional indic.u ions for 1ht same molecule where a COx is needed. for example in earlier-lint ust.. Payers may dt- factort quirt 1t s1ing 10 form the basis of coverage decisions for the drug. The tcsi could also be considered complementary in the US, but required in 01her geographies e.g., UK and South Korea

for PO-l 1 IHC for nivolumab in 2L lung. pr;or to prescrib;ng,


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Figure 3 is that following initial complementary diagnosticapproval, a follow-on diagnostic approval using an improvedplatform may occur. This is a likely future scenario for can-cer immune therapies, with the aspiration of future com-prehensive cancer immune panels at diagnosis that couldcapture key information on oncogene activation, mutationalload, and gene expression. Overall, these could replace thecurrent practice of separate tests and extensive tissuesources for PD-L1 IHC, EGFR testing, etc.

Recognizing that the experience with FDA complemen-tary diagnostics is still limited in the United States, manyquestions remain as to further evolution of this field, on top-ics ranging from clinical development to regulatory approval,commercial launch, and post-launch status. Since the cur-rent examples are limited to a single analyte and platform(PD-L1 IHC) and only two tests, the potential for expansionis significant. It is worth considering potential future additionsto this short list of approved complementary diagnostics,such as tests for immune status in the nononcology space.

SUMMARY

In conclusion, predictive biomarkers help in identifyingpatient subgroups that are most likely to derive clinicallymeaningful benefit while reducing the risk of unnecessaryexposure and cost to patients who would not benefit. Com-panion diagnostics can be codeveloped with therapeutics,and are used to identify and restrict treatment only to thoseresponder subgroups of patients. Complementary diagnos-tics are a relatively recent new tool that are not required forthe safe and effective use of a therapeutic but can further aidphysicians in the benefit–risk decision-making about the useof a therapeutic (for instance, by identifying patients whomaybe relatively more likely to derive benefit). Although to datethere are limited precedents for complementary diagnostics,these may be another useful tool to help guide medical prac-tice as it is likely that in the future more diagnostic-partnereddrugs will be launched.

Acknowledgment. The authors thank Lisa Wang and ThirupathiPattipaka for expert insights.

Author Contributions. All authors contributed equally to thisarticle.

Conflict of Interest. The authors declared no conflicts of interest.

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C© 2017 The Authors. Clinical and Translational Sciencepublished by Wiley Periodicals, Inc. on behalf of Ameri-can Society for Clinical Pharmacology and Therapeutics.This is an open access article under the terms of theCreative Commons Attribution-NonCommercial License,which permits use, distribution and reproduction in anymedium, provided the original work is properly cited andis not used for commercial purposes.


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