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.