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USFDAExpeditedProgramsandExpandedAccess

KeLiu,MD,PhDChief,OncologyBranchDivisionofClinicalEvalua;on,PharmacologyandToxicologyOfficeofTissuesandAdvancedTherapiesCenterforBiologicsEvalua;onandResearchOp;misingthedevelopmentofATMPstomeetpa;entneedsLondon,UnitedKingdomDecember16,2016

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Disclosures

Ihavenofinancialrela;onshipstodisclose.Iwillnotdiscussoff-labeluseofproducts.

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Outline

•  USFDAExpeditedPrograms– PriorityReviewDesigna;on:1992– AcceleratedApproval:1992– FastTrackDesigna;on(FTD):1997– BreakthroughTherapyDesigna;on(BTD):2012

•  USFDAExpandedAccess

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FDAExpeditedPrograms:Goalsv Fordrugsthataddressanunmetmedicalneedinthe

treatmentofaseriousorlife-threateningcondi;onv Intendedtohelpensurethatdrugsforthesecondi;ons

areapproved&availabletopa;entsassoonasitcanbeconcludedthatthetherapies’benefitsjus;fytheirrisks

v Allowforearliera]en;ontodrugsthathavepromiseintrea;ngsuchcondi;ons§  Earlyconsulta;onwithFDA

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FDAExpeditedProgramsGuidance

v GuidanceforIndustry:ExpeditedProgramsforSeriousCondi;ons–DrugsandBiologics(2014)

§  Singleresourceforinforma;ononFDA’spolicies&proceduresforfourexpeditedprograms

§  Describesthresholdcriteriaapplicabletoconcludingthatadrugisacandidateforanexpediteddevelopmentandreviewprogram

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Non-Clinical

Early Clinical

Phase 3 Trial(s)

NDA/BLA Submission APPROVAL

IND Submission

FDA Review

Priority Review

Fast Track Accelerated Approval

Breakthrough Therapy

FDAExpeditedPrograms

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v Qualifyingcriteria

v Features

v Breakthroughvs.FastTrack

BreakthroughTherapyDesigna;on(BTD)

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BTD:QualifyingCriteria

v A drug that

§  Is intended to treat a serious condition AND

§  Preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints

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BTD:QualifyingCriteriav Serious Condition

§  “condition” : A disease or illness §  Including life-threatening conditions §  A clinical judgment, based on the condition’s

impact on factors, such as: o Survival o Day-to-day function, OR o The likelihood that the condition, if left untreated, will

progress from a less severe condition to a more serious one

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BTD:QualifyingCriteriav Intended to have an effect on a serious

condition or a serious aspect of a condition

§ A direct effect on a serious manifestation or symptom of a condition

§ Other intended effects, such as

o A product intended to improve or prevent a serious treatment-related side effect

o A product intended to prevent a serious condition or reduce the likelihood that the condition will progress to a more serious condition or a more advanced stage of disease

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BTDQualifyingCriteria

v Preliminaryclinicalevidenceofsubstan;alimprovementoveravailabletherapyononeormoreclinicallysignificantendpoints

§  IsapprovedorlicensedintheUnitedStatesforthesameindica;on,AND

§  IsrelevanttocurrentUSstandardofcare(SOC)fortheindica;on

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BTDQualifyingCriteria

v  Preliminaryclinicalevidence§  Notsufficient(qualityand/orquan;ty)toestablishsafetyand

effec;venessforpurposesofapproval§  GenerallyderivedfromPhase1or2trials§  Shouldinvolveasufficientnumberofsubjectstobeconsidered

credible§  Ideallyderivedfromastudycomparingthedrugtoanavailable

therapy(orplacebo,ifnoavailabletherapy),orfromastudycomparingthedrug+SOCtotheSOCalone

§  Single-armstudiescomparingthestudysubjects’clinicalcoursewithwell-documentedhistoricalexperience,ifthemagnitudeofdifferenceislarge

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BTDQualifyingCriteria

v  Substan;alimprovement§  Ama]erofjudgment§  Dependson:

o  Themagnitudeofthedrug’seffectonaclinicallysignificantendpoint(includingdura;onoftheeffect) AND

o  Theimportanceoftheobservedeffecttothetreatmentoftheseriouscondi;onorseriousaspectofthecondi;on

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BTDQualifyingCriteria

v Approachestodemonstratesubstan;alimprovement§  Directcomparisonofthedrugtoavailabletherapyshowsamuch

greaterresponse

§  Ifthereisnoavailabletherapy,thedrugshowsaclinicallymeaningfuleffectonanimportantoutcomewhencomparedtoplacebo

§  Thedrugplusavailabletherapyresultinamuchgreaterresponsecomparedtoavailabletherapyalone

§  Thedrugreversesorinhibitsdiseaseprogression,incontrasttoavailabletherapythatprovidesonlysymptoma;cimprovement

§  Thedrughasanimportantsafetyadvantagecomparedwithavailabletherapy,andhassimilarefficacy

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BTDQualifyingCriteriav  Clinicallysignificantendpoint

§  Anendpointthatmeasuresaneffectonirreversiblemorbidityormortality(IMM)oronsymptomsthatrepresentseriousconsequencesofthedisease.

§  AnendpointthatsuggestsaneffectonIMMorserioussymptoms,including:o  Aneffectonanestablishedsurrogateendpointthattypicallywould

beusedtosupporttradi;onalapprovalo  Aneffectonasurrogateendpointorintermediateclinicalendpoint

consideredreasonablylikelytopredictaclinicalbenefit(i.e.,theacceleratedapprovalstandard)

o  Asignificantlyimprovedsafetyprofilecomparedwithavailabletherapy(e.g.,lessdose-limi;ngtoxicityforanoncologyagent),withevidenceofsimilarefficacy

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Benefits/FeaturesofGrantedBTD

v All benefits of Fast Track designation § FDA takes actions to expedite development and

review § Eligible for rolling review of NDA or BLA (submission

and review of portions of an application before submission of the complete application)

v Intensive guidance on efficient drug development during IND, beginning as early as Phase 1

v Organizational commitment involving FDA senior managers

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FTDvsBTD:Similari;es

v Natureofprograms:Designa;onv TimelineforFDAresponse:Within60calendardaysv  Intendtotreatseriouscondi;onv Benefits:FDA’sAc;onstoexpeditedevelopmentandreview

§  Frequentinterac;onswiththereviewteam§  Maybeeligibleforpriorityreviewifsupportedbyclinicaldataatthe

;meofBLA/NDAsubmission§  Mayqualifyforrollingreview

v Designa;onmayberescindedifnolongermee;ngthequalifyingcriteria

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FTDvsBTD:Differences

FTD BTD

RequirementsforDesigna>on

SourceofData

Non-clinical or clinical data

Preliminary clinical evidence

Strength

ofEvidence

The potential to address unmet medical need

Substantial improvement on a clinically significant endpoint(s)

over available therapy

DevelopmentPlan

Specify how this potential will be evaluated in the drug

development program (e.g., a description of the Phase 3

trials)

Not required

Benefits

FDA takes actions to

expedite development and review

•  All benefits of FTD •  Intensive guidance on an

efficient drug development program

•  Involvement of FDA senior managers

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BreakthroughDesigna>onExperience

inCBEROTAT

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BTRequestsinOCTGT(12/2012–06/2016)

v  TotalRequests:54§  47products§  7Repeatedrequests

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2

Requests Denied

Requests Granted

Requests withdrawn

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BTDsbyProductTypes

Products Requested BTDs

Granted BTDs

Gene 26 12

Cellular 16 1

Tumor Vaccine 4 1

Oncolytic Virus 1 1

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BTDsbyIndica;ons

Indications Requests Granted Oncology 33 9

Non-oncology 21 6 Hematology 4 3

Ophthalmology 3 1

Cardiology 3 1

Neurology 4 1 Transplantation 2 0

Nephrology, Peripheral Vascular,

Burn, Hepatology

1 in each specialty

0

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CommonReasonsforBTDDenial

v Evidenceistoopreliminary(quan;tyand/orquality)tobeconsideredreliable§  Smallsamplesize§  Lackofappropriatecontrol§  Post-hocanalysesoffailedstudiesthatiden;fyasubsetthatmaybenefit

v Improvementoveravailabletherapydoesnotappeartobe“substan;al”

v Modifica;onofproduct

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WhatOTATHasLearned

v BTDdecisionsarecomplex.§  Thereisnoone-size-fits-allcharacteriza;onofaBTproduct.

v Thereliabilityandpersuasivenessofclinicalevidenceiscri;caltomakingtheBTDdecision.§  Thereisnotadefini;vethresholdforsubstan;al

improvement.

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ExpandedAccesstoInves>ga>onalDrugs

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WhatisExpandedAccess?

•  Useofaninves;ga;onaldrugtotreatapa;entwithaseriousdiseasewhohasnoothersa;sfactoryop;ons

•  IntentisTREATMENT;alsocalled“CompassionateUse”

•  Contrastwithusinganinves;ga;onaldruginaclinicaltrial,wheretheprimaryintentisRESEARCH

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TypesofExpandedAccessPrograms(EAPs)

TherearethreetypesofEAPsdefinedinthecodeoffederalregula;ons:

Individual Intermediate Treatment

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RequirementsforallEAPs21CFR312.305

•  Seriousorimmediatelylife-threateningillnessorcondi;on

•  Nocomparableorsa;sfactoryalterna;vetherapy

•  Poten;albenefitjus;fiesthepoten;alrisksofthetreatment(risksarenotunreasonableinthecontextofthedisease/condi;onbeingtreated)

•  Providingdrugwillnotcompromiseproductdevelopment

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HumanSubjectProtec>onsApplytoAllEAPs

DrugsinEAPsareinves*ga*onaldrugs,andtheyaresubjecttothefollowingrequirementsfrom21CFR:

–  Part50-Protec;onofHumanSubjects(informedconsent)–  Part56-Ins;tu;onalReviewBoard

–  Part312-includingClinicalHoldsbasedonsafetyandrepor;ngrequirements(adverseeventreports,annualreports)

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IndividualPa>entEAPs21CFR312.310

•  Physicianmustdetermineprobableriskfromdrugdoesnotexceedthatfromdisease

•  FDAmustdeterminethatthepa;entcannotobtainaccessunderanothertypeofIND

•  Proceduresforemergencyuse(whenthereisnot;metomakeawri]enINDsubmission)–  FDAmayauthorizeaccesswithoutsubmission,withveryquickturn-around(F/Uwri]ensubmissionrequiredwithin15workingdaysofauthoriza;on)

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ObtainingaSinglePa>entIND

PhysicianandPa>ent/FamilyDiscussRisks&

Benefits

ApprovalFromIRB

AgreementFromDrugCompany

SubmitForm3926toFDA,forapproval

TreatPa>ent

To provide drug, and for FDA to reference

commercial IND

30-45 minutes!! Turn around time generally < 48h,

99.4% approval rate

•  Form 3926 is 2 pages and includes: o  Brief medical history and rationale for trying drug o  Proposed treatment plan with safety /efficacy monitoring

•  Also submit: o  Letter of authorization from sponsor o  Investigator qualification statement / form 1571

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IntermediateSizePopula>on21CFR312.315

•  Intended for situations where multiple patients with the same condition might benefit from a particular investigational product

•  No set numerical parameters – meant to be practical – more than a few, and less than a lot

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TreatmentIND21CFR321.320

•  Drugisbeinginves;gatedinclinicaltrialdesignedtosupportmarke;ng,ortrialsarecomplete

•  Companyisac;velypursuingapproval•  Sufficientevidenceofsafety&effec;veness

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Cau>onsforEAPUse•  Riskhasnotbeenestablishedforinves;ga;onaldrug

–  Confidenceinsafetymoreimportantthanconsidera;onofefficacy

–  Forachildwithanimmediatelife-threateningcondi;on,evidenceburdenislow

•  Poten;albenefitisomenoveres;mated–  DruggivenunderEAPwithinten;ontoprovidebenefit–  Anecdotalevidenceofevenoverwhelmingefficacymay

holduponlyinaverysmallsubsetofpa;ents,buthavetoxici;esthatincreasesufferingand/orhastendeathineveryoneelse

•  Poten;alfornega;veimpactonclinicaldevelopmentplan

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BenefitsandBarriersBENEFITS:•  Provideaccessandhopetopa;entswithno

alterna;ves,willingtoacceptpoten;allygreaterrisk

•  Mayprovidepa;entswithameasureofautonomyovertheirownhealthcaredecisions

•  Can be a foothold into marketplace for sponsors

BARRIERS: •  Paperwork/time (New! Form 3926) •  Manufacturing (drug availability) •  Fear that adverse events may disrupt clinical product

development

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CBEROTATDCEPTOncologyBranchMembers

KeLiu,MD,PhD(BC)

LaronnaColbert,MD

SadhanaKaul,MD

PeterBross,MD(TL) Ching-Hsien(Jessica)Lee,MD,PhD

LydiaMartynec,MD

AdnanJaigirdarMD

Open

Posi;on(M.O.)

ChaohongFan,MD,PhD

Open

Posi;on(M.O.)

Open

Posi;on(TL)

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OTATContactInforma>on

RegulatoryQues;ons:•  ContacttheRegulatoryManagementStaffinOTAT:atCBEROCTGTRMS@fda.hhs.govorLori.Tull@fda.hhs.govorbycalling(301)827-6536

•  OCTGTLearnWebinarSeries:

h]p://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm