How the Changing Landscape of Oncology Drug Development and … · 2019-01-24 · Oncology Office...
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HowtheChangingLandscapeofOncologyDrugDevelopmentandApprovalWillAffectAdvancedPractitioners
RichardPazdur,MDDirector
OncologyCenterofExcellenceUSFoodandDrugAdministration
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LearningObjectives
1. UnderstandFDAregulatoryprincipleswithrespecttotrialdesign,endpoints,randomization,andacceleratedapprovalprograms
2. Differentiateamongvariousendpointsusedinclinicaltrialdesignandunderstandtheirstrengthsandweaknesses
3. Discussemerginginitiativesinthequesttoexpeditethedrugdevelopmentprocess
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Disclosures
Ihavenoconflictsofinteresttodisclose.
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FDAMission
• FDAisresponsiblefor:– Assuranceofthesafety,efficacy,andsecurity of:
• Drugandbiological products• Medicaldevices• Food supply
• Radiation products
– Accountsfor25centsofeverydollarspentbyAmericans…
• FDAdoesnottakeintoaccountcostorpaymentissues• FDAdoesnot regulate“practiceofmedicine”
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KeyFDACenters
CenterforDrugEvaluationandResearch(CDER)•Drugsandantibodies
•Sixofficesacrosstherapeutic areas,including theOfficeofHematology andOncologyProducts
CenterforBiologicsEvaluationandResearch(CBER)•Cellular andgenetherapies, vaccines
CenterforDevicesandRadiologicHealth(CDRH)•Devices, invitrodiagnostics, diagnostic andtherapeutic
radiologics
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OfficeofHematologyandOncologyDisease-specificstructureakintocurrentacademicmodels
OncologyOffice
Div.ofOncologyProducts1
Div.ofOncologyProducts2
Div.ofHematologyProducts
Div.ofHematologyandOncologyToxicology
• Breastcancer• Gynecologic
cancer• GUmalignancies
• Thoracic,headandneck• Gastrointestinal• Melanoma-sarcoma• Pediatric-neuroendocrine-
Raretumors
• Benignheme• Lymphomas• Leukemias• Transplant
• Toxicologistssupportingeachclinical division
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FDAOncologyCenterofExcellenceOverallAims
• Evaluateproductsforprevention,screening,diagnosis,andtreatmentofcancer
• Supportdevelopmentofcompaniondiagnostictestsanduseofcombinationsofdrugs,biologics,anddevices
• Developandpromoteuseofmethodscreatedthroughthescienceofprecisionmedicine
• Facilitateincorporationofthepatientviewinregulatorydecisionmaking
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HowIsOncologyDifferentFromOtherTherapeuticAreas?
• Severeandlife-threateningdiseases• Largepublicinterest,needtoexpeditedrugs• Differentrisktoleranceforsideeffects• Activeadvocacygroups• Activeareaofbiomedicalresearch• 50%ofbreakthroughtherapies• Biomarker-definedpopulations
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Traditional(“Regular”)Approval
• Traditionalapprovalrequires– Substantialevidenceofsafetyandefficacy– Well-controlledclinicaltrials(usuallytwoormore)– Basedonprolongationoflife,abetterlife,oranestablishedsurrogateforeitheroftheabove
• Nocomparativeefficacyfortraditionalapproval– Assafeandeffectiveasexistingtherapies,allowingfornon-inferioritydesigns
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AcceleratedApproval• Canbebasedona“surrogateendpoint…reasonablylikely…topredictclinicalbenefit”
• “Providemeaningfultherapeuticbenefit…overexistingtherapies”
• Post-marketingclinicaltrialsmayberequired– Shouldusuallybeunderwayatthetimeofacceleratedapproval
– Applicantshouldcarryoutstudieswithduediligence
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WhatIsClinicalBenefit?
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StrengthofEfficacyEndpointResults
• What isbeingmeasured?(EndpointSelection)
• How accuratelyisitbeingmeasured?(MeasurementCharacteristics)
• Howmucheffectontheendpointisobserved?(MagnitudeofEffect)
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How IstheEndpointMeasured?
• Howmuchinterpretation isrequired?– Moreinterpretation=moreriskforbias/variability
• Howaccurateisthetiming oftheevent?
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DirectMeasuresofEfficacyOverallSurvival:GoldStandard
• Strengths– Directmeasureofbenefit– Leastpronetobias,nointerpretationoftheevent(deathyesorno)– Eventtiming(dateofdeath)typicallyknowntotheday– Includesinformationregardingsafety
• Deathsduetodrugtoxicityarepartoftheendpoint
• Limitations– Lasteventinadisease’snaturalhistory=longerandlargertrial– Requiresrandomizedcontrolledtrial
• Comparisonwithhistoricalcontrollimited(differingpopulations,differingstandardsofcare,etc.)
– Maybeconfoundedbycrossover(dependingonmagnitudeofeffect)andsubsequenttherapiesifgivenunequallybetweenarms
*MeaningfulclinicalbenefitofasurvivaladvantageisstillbasedontoxicityofdrugandmagnitudeofOSresult
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SurrogateEndpointsRadiographicEvidenceofAnti-TumorEffect
• Response rate(RR)– Shrinkingatumor– Criticallyimportant:tumorlocation,numberofCRs,durationofresponse
• Timetoprogression (TTP),progression-free survival (PFS)– Timefromrandomizationtogrowthoftumorpastpredefinedthreshold– PFScountsdeathasaprogressioneventandispreferred
• Radiographic endpoints: Strengths– Earliereventsthansurvival=smaller,shortertrial– Radiographscanbecapturedandstoredtoverifytheevent– Notconfoundedbycrossoverorsubsequenttherapies(eventoccurspriortocrossover)
• Radiographic endpoints: Limitations– Uncertaintyregardingclinicalbenefit:Willagivenchangeinanasymptomaticradiographic
findingpredicttrueclinicalbenefit?– Missing,incomplete,infrequent,orunevenassessments– Difficulttomeasuredisease(ill-definedlesions),bonemetastases,peritoneal
carcinomatosis
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FDAHistoricalPerspectiveOncologyEfficacyEndpoints
• 1970s:Asettingoflimitedavailable therapies– Tumorshrinkage (response rate)wasaccepted asaprimaryefficacy
endpoint forregularapproval• 1980s:Achangeinthisinterpretation occurred:
– 10%to20%ofpatientswithasymptomaticradiographictumorshrinkagemaynottranslate intoanimprovement inoveralloutcome(particularlygiventhetoxicityoftheagentsbeingevaluated)
• Ideally,measurement shouldreflectdirectclinicalbenefit• Howone“feels,functions, orsurvives”• AmoveawayfromORRfortraditional approval andafocusonoverallsurvival
FDAGuidance forIndustry:Clinical TrialEndpointsfortheApprovalofCancerDrugsandBiologics.
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Andthenthisstartedtohappen…
Completehematologic response in53of54patientswithIFN-refractorychronicphaseCML…
“Ourresults…demonstrate thepotentialforthedevelopment ofanticancerdrugsbasedonthespecificmolecularabnormalitypresentinhumancancer.”
DrukerBJ,etal.NEnglJMed 2001;344(14):1031-7.
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UnprecedentedResponseRates• Enrichedpopulations• Strongbasicscience
Afatinib:LUX-LUNG-2YangJC,etal.LancetOncol2012;13:539-48.
EGFR-Mut+NSCLC:ORR61%ALK+NSCLC:ORR61%
Crizotinib:Phase1CamidgeDR,etal.LancetOncol2012;13:1011-9.
CD30+Hodgkin:ORR75%
BrentuximabVedotin:Phase2YounesA.etal.JClinOncol201;30:2183-9.
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LookingCloseratORR
Therearemultiplevariablesin“responserate”– Locationoftumor– Numberofcompleteresponses– Durationofresponses– Whatwasinitialtumorburden?– Howmanypatients’tumorsreduced,but<30%?
– NotcurrentlycapturedinRECISTORR– Thesepatientsmayderivebenefit ifactivity/stability oflongdurationdependingontoxicityofthetreatment
– Valueofthewaterfall plot
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Where AretheTumorsThatAreResponding?When“response rate”maybeconsidered directclinical benefit…
VismodegibResponse
VonHoffDD,etal.NEnglJMed2009;361:1164-72.
DepsipeptideResponse
PiekarzRL,etal. JClinOncol2009;27:5410-17.
•Nearcompleteresponsesofdisfiguringorfungatingskinlesionsareadifferentcontext•Traditional approval grantedbasedonclinical responserate(andduration),thecosmeticimprovement,andthehighlikelihoodoftumor-relatedsymptomaticrelief
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ClinicalEquipoiseWhenthereisgeneraluncertaintyintheexpertmedical
communityonwhetheratreatmentiseffective
• Importantforethical conductofrandomizedtrialsANDcanaffectfeasibility• WhatisORRimprovement overexisting therapieswhereequipoise islost?
FDAReview:OxaliplatininColorectalCancer• 9%ORR,allpartialresponseswithadded
toxicityoverthechemobackbone…
FDAReview:CrizotinibforNon–SmallCellLungCancer• 50%–61%ORR,mediandurationofover10monthswithdeep
responsesandfavorabletoxicitywhencomparedwithchemotherapydoublet…
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BarrierstoRandomizedControlledTrials
• Feasibilityinlowfrequencypopulations• CrossoverimpactsOSdifferenceassessment• Ethicalissueswheninterventionishighlyactiveorcomparatoristoxic/hasminimalefficacy– Equipoiselost?
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FDAExpeditedPrograms
Non-Clinical
EarlyClinical
RegistrationTrial(s)
NDA/BLASubmission
APPROVAL
INDSubmission Dose
Exploration/PrelimActivity
SPAEfficacyandSafetyData
FDAReview
PriorityReview
BreakthroughTherapy
FastTrack
Ifconsidering accelerated approval,post-marketing clinicaltrialsshouldbeunderwayatthetimeofapproval.
AcceleratedApproval
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BreakthroughTherapyDesignation
USFoodandDrugAdministration.www.fda.gov.
• Signedintolawin2012• Forseriouslife-threateningdisease,adrug,basedonpreliminaryclinicalevidence,hassubstantialimprovementoveravailabletherapy• About50%ofbreakthroughtherapyrequestsacrossdrugcenterhavebeeninoncology‒ Aboutone-thirdhavebeengranted
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BreakthroughTherapyDesignation
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MoonshotInitiatives
• Seamlessdesign—expansioncohort• Largesimpletrials• Reevaluatingeligibility criteria• Patient-reportedadverseevents• Real-worlddata• Site-agnosticindications
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• Oncology drugdevelopmenthistorically involvedthreediscretephases:– Phase1:MTD,DLTs,preliminaryefficacy– Phase2:Efficacyassessment for“go/no-go” – Phase3:RCTsdesigned toprovideadequateefficacy/safety datato
supportdrugapproval
• Thesedistinctphaseshavebecomemoreseamless:– Earlybiomarker discovery/companion diagnosticdevelopmentà earlier
identificationofefficacyandlarger treatmenteffect sizes– Desire forgreaterefficiencyindrugdevelopment– Demandforaccess topromisinginvestigationalagents
DiscretePhasestoSeamlessTransition
MTD=maximumtolerateddose;DLT=dose-limiting toxicity;RCT=randomizedcontrolledtrial.
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• Almost40commercialINDsforlargeFIHtrials(100to>1,200patients)– Upto14expansioncohortswith10–180patients/cohorts– Morethanone-thirdareanti-PD-1/PD-L1agents
• Natureofexpansioncohortsinthesetrials– Dose/schedule refinement– Varietyoftumortypes– Varietyofmolecularlydefinedsubsets– Varietyofdrugcombinations
• Stated objectives,endpoints,eligibilitycriteria,andinformedconsentlanguagearemoreconsistentwithusualphase1
• However,samplesize,natureofdatacollected,andactualgoalsmoreconsistentwithusualphase3
OHOPExperience
ProwellTM,etal.NEnglJMed2016;374:2001-3.
OHOP=OfficeofHematologyandOncologyProducts;IND=investigationalnewdrug;FIH=firstinhuman.
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LargeSimpleTrials
Randomizedtrialsconductedincontextofroutinecancercareinpost-marketingsetting(phase4)– Ask/answerlimitednumberofclinicallyrelevantquestions
– Utilizefocused datacollectionfromEHRs– Are(ideally)notburdensometobusycliniciansorpatients
– Benefitfromalargesamplesize(i.e.,highlevelofpower)toreliablyestimatetherisk-benefitofadrug
– Assessclinicalbenefitendpoints,notsurrogates
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WhyModernizeEligibilityCriteria?
• Manypotentialparticipantsexcluded:– CNSinvolvement– Marginalperformancestatus– Organdysfunctionorlimitedmarrowreserve– HIVpositivity– Extremesofage– Priormalignancy
• Resultisslowaccrualtotrialsinpatientswhomaynotcharacterizethosewhowillreceivethedruginpost-marketingsetting
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ProsandConsofBroadeningEligibilityCriteria
• Argumentsinfavor– Makesresultsmoregeneralizable– Expeditesaccrual– Potentialfor“niche”indication/labelingclaim(e.g.,
“onlyTKIshowntoimproveOSinpatientswithxtumor&brainmets”)
• Argumentsagainst– Potentialtoconfoundinterpretationofefficacy/safety
andintroduceriskintodevelopment(minimizedifeligibilitycriteriaarethoughtfullyselectedandeffectsizeismorethanmodest)
USFoodandDrugAdministration.www.fda.govTKI=tyrosinekinaseinhibitor.
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ChallengesforPROUniquetoOncology
• Asymptomatic/minimallysymptomaticpopulations• Open-labeltrials• Single-armtrials• Missingdata
• MostpivotaltrialshaveincludedlargeHrQOLinstruments– FACT,QLQ-C30,EQ-5D– Staticquestions, cannotadapttodiffering trialcontexts– Infrequently assessed leadingtomissingdata
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StrikingaBalance
DATACERTAINTY
Regulatory BURDEN
“Toxicdeaths!
Delayedsafetyfindings!
FDAasleep atthewheel”
“Toocautious!
Stifling innovation!
Reduceregulatoryburden!”
Less
More
Flexible, Efficient, Interactive
Consistent, Thorough,Independent
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HowWillDynamicsAffectAdvancedPractitioners?
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Thanks
Thanks toDr.PaulKluetzandDr.TatianaProwellforslidesandKirstenGoldbergfor
technicalassistance.
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