CDERNewDrugReview:

2012Update

JohnK.Jenkins,M.D.
Director,OfficeofNewDrugs CenterforDrugEvaluationandResearch

FDA/CMSSummit
December10,2012

Housekeeping
Dataandanalysespresentedtodayarethoughttobe accurate,butinordertoprovidethemostuptodate informationtheyhavenotundergonethesame thoroughqualitycontrolasisperformedforofficial FDAreports AnalysesofNME/originalBLAfilingsandapprovals willbeabbreviatedtoNME ManystaffinCDERprovideddata,analyses,and PowerPointexpertiseforthistalk
AspecialacknowledgementtoMichaelLanthier,Nelson Cheung,Chintan Shah,andSallyWorrellfortheiroutstanding helpinconceivingandconductingmanyoftheanalyses.Their behindthescenesworkmakesmelookgood.

Topicstobecovered
HowisCDERdoingwithregardtomeetingPDUFA goals? Whatarethetrendsinnewdrugapprovals?
INDactivity,NMEsubmissions,andNMEapprovals Useofexpeditedpathways Rarediseases Emergingsponsors

ImplementationofPDUFAV/FDASIA
Program forNMEreview EnhancedCommunicationDuringDrugDevelopment BreakthroughProducts

WhataboutPDUFAGoals?
FDAcontinuestotakePDUFAgoalsveryseriously
ThesearecommitmentsthatwemaketoCongressandthe Americanpublicforhowwewilldoourwork

FDAismeetingorexceedingnearlyallPDUFAgoalsfor applicationreview

CDERReviewPerformance forFY2011*
SubmissionType Number Filed 2011 Performance Goal Current Performance NewDrugApplications/BiologicLicenseApplications** Standard Priority NMEs/NewBLAs Standard Priority NDA/BLAResubmissions Class1 Class2 NDA/BLAEfficacySupplements Standard Priority NDA/BLAEfficacySupplementResubmissions Class1 Class2 NDA/BLAManufacturingSupplements RequiringPriorApproval CBE *DataasofSeptember30,2012
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74 22 18 14 9 49 95 23 11 21 578 1318

90%in10months 90%in6months 90%in10months 90%in6months 90%in2months 90%in6months 90%in10months 90%in6months 90%in2months 90%in6months 90%in4months 90%in6months

99% 95% 100% 93% 100% 100% 95% 96% 82% 95% 94% 97%

CDERReviewPerformance forFY2012*
SubmissionType Number Filed** 2012 Performance Goal PotentialPerformance %ofActionsWithin Goal*** 100% 96% 100% 94% 100% 100% 100% 100% NewDrugApplications/BiologicLicenseApplications*** Standard Priority NMEs/NewBLAs Standard Priority NDA/BLAResubmissions Class1 Class2 NDA/BLAEfficacySupplements Standard Priority Undetermined**** NDA/BLAEfficacySupplementResubmissions Class1 Class2 NDA/BLAManufacturingSupplements RequiringPriorApproval CBE 2 14 716 1055 90%in2months 90%in6months 90%in4months 90%in6months 100% 86% 94% 98% 7 32 97 34 4 90%in2months 90%in6months 90%in10months 90%in6months 96 26 27 16 90%in10months 90%in6months 90%in10months 90%in6months

*DataasofSeptember30,2012 **Submissionsthatarependingafilingdecisionarecountedasfiled. ***PotentialPerformance levelofperformancethatcouldpotentiallybeachievedifalltheactionscurrentlypendingarereviewedwithintheirrequired goal date. ****Undetermined applicationsthathavenothadtheir60dayfilingmeetingyetandmaynothavetheirreviewclassificationdetermined.

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CDERPDUFAApplication ReviewPerformance (NDAs,BLAs,EfficacySupplements)

*CDERdataasof11/30/2012.FiguresreflectaggregateperformanceforallNDAs,BLAs,and EfficacySupplementsbasedonthemonthofthePDUFAreviewgoal.
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CDERPendingApplications withOverduePDUFAGoals

*CDERdataasof11/30/2012.FiguresreflectthenumberofNDAs, BLAsandefficacysupplementsthatare pendingandoverdueontheirPDUFAgoaldate,evaluatedonthefirstdayofeachmonth.

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Behindthescenes: AGrowingMountainofTracked GoalsunderPDUFA

*FY2011andFY2012FiguresasofSeptember30,2012 Number of tracked goals will increase further under PDUFA V for NME Program, etc.
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Whataboutnewdrugapprovals?
ThecommercialINDpipelineofnewdrugsunder developmentremainsstrongandisgrowing ThroughNov30,inCY12CDERhasreceived34NME applications
Somearestillwithinthe60dayfilingwindow,subjecttoRTF AsurgeofsubmissionsoftenoccursinDecember NumberofNMEsfiledforreviewisamajorratelimitingstepto thenumberofNMEsapproved

TodateinCY12CDERhasapproved31NMEapplications
CY12totaltodateisonemorethanthetotalapprovedinCY11 andhighesttotalsince2004 SeveralNMEshavePDUFAgoaldatesbeforeendofDecember
Potential existsforhighestnumberofapprovalssincemid90sbut itsprematuretopredictthefinaltotal
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Whataboutnewdrugapprovals(cont)?
NMEapprovalsin2012includeanumberof breakthrough drugsthatprovidemuchneedednew treatmentoptionsforpatients Continuingtrendin2012NMEapprovalsforrare diseasesandapplicationssubmittedbyemerging sponsors AveragefirstcycleapprovalratesforNMEapplicationsin PDUFAIVareatthehighestlevelssincethestartof PDUFA;possiblereasonsinclude:
Fullimplementationof21st CenturyReviewModel GreaterexperiencewithuseofFDAAAtools(e.g.,REMS,PMRs) Targetedtherapywithlargeeffectsizeandincreasedfocuson rarediseases,whichimprovesbenefit/riskratio Fallinmetoo submissionsforchronicsymptomaticdiseases wherebenefit/riskratioisoftenlessfavorable
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CommercialINDswithActivity BasedonPDUFAWorkloadAdjusterData

*Datarepresents12monthperiodofJuly1st June30th
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CDERNewMolecularEntityand NewBiologicEntityFilingsandApprovals

*CDERdataasof11/30/2012. *Sinceapplicationsarereceivedandfiledthroughoutacalendar year,thefiledapplicationsinagivencalendaryeardonotnecessarily correspondtoanapprovalinthesamecalendaryear. *Certainfiledsubmissionsarewithintheir60dayfilingreviewperiodandmaynotbefileduponcompletionof thereview.

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CDERNME/NBEFirstAction ApprovalRate

*FY11hasonependingandFY12hastwentyfivependingapplications. *CDERDataasof11/30/2012 FY2011and2012percentagesexclude"Pending"fromthedenominator

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CDERFirstAction ApprovalRatesforPriority NMEs/NBEs

FY12hasfiveprioritypendingapplicationsawaitingfirstaction PotentialforFY2012andPDUFAIVPriorityFAARtobe81%and72%respectively NMEandNBEactionsdataasof11/30/2012.

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CDERFirstAction ApprovalRatesforStandard NMEs/NBEs

*FY 12hastwentystandardpendingapplicationsawaitingfirstaction. NMEandnewBLAactionsdataasof11/30/2012.

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CDEROverall NMEs/NBEs MedianTotalTimetoApproval

NMEandNBEdataasof11/30/2012.

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CDERPriority NMEs/NBEs MedianTotalTimetoApproval

NMEandNBEdataasof11/30/2012.

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CDERStandard NMEs/NBEs MedianTotalTimetoApproval

NMEandNBEdataasof11/30/2012.

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SnapshotofCY2012 NMEApprovals*(1/2)

*Dataasof11/30/12

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SnapshotofCY2012 NMEApprovals*(2/2)

*Dataasof11/30/12
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InCY2012,CDERcontinuedto ensuretheefficiencyoffirstcyclereview AllNMEsapprovedtodatein CY12mettheirPDUFAgoaldates

25outof31(81%)NMEs approvedtodateinCY12were approvedinthefirstreviewcycle

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CDERensuresthatnovel drugsreceiveexpeditedreview
11outof31(35%)NMEsapprovedto dateinCY12wereapprovedunder PriorityReview 10outof31(32%)NMEsapprovedto dateinCY12receivedFastTrack designation Kyprolis(Carfilzomib)and Synribo(OmacetaxineMepesuccinate) wereapprovedundertheaccelerated approvalpathway

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2012wasastrongyear fordruginnovationintheU.S.
Nearlyonequarter(23%)ofNMEs approvedtodateinCY12arefor rarediseases Almosthalf(45%)of NMEsapprovedtodate inCY12arethefirstin theirclass Fouroutoffive(81%) NMEsapprovedtodate inCY12werefirst approvedintheU.S.
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NMEapprovalsforrarediseases CY20062012
NMEsandNewBiologics CY2012* CY2011 CY2010 CY2009 CY2008 CY2007 CY2006 31 30 21 26 24 18 22 Rare (%oftotalapprovals) 7(23%) 11(37%) 7(33%) 9(35%) 8(33%) 6(33%) 6(29%)

*DataasofNov.30,2012 SeveralNMEapplicationsforrarediseaseshavePDUFAgoaldatesbeforeDec31,2012.
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CDERNME/NBERareDisease DrugApprovalCY20112012
2011,n=11(12indications) Ipilimumab(melanoma) Vandetinib(med.thyroidCA) Belatacept(organrejec,kdnytx,EBV+) Brentuximab(Hodgkins) Brentuximab(anapl.lgecelllymphoma) Vemurafenib(melanomaBRAF+) Crizotinib(NSCLCALK+) Icatibant(HAE) Asparaginase(ALL) Deferiprone(transfus.Feoverloaddueto thalassemias) Clobazam(LennoxGastaut) Ruxolitinib(Myelofibrosis) 2012,n=7* Glucarpidase(MTXtoxicity) Ivacaftor(CysticFibrosis) Taliglucerase(Gaucher) Carfilzomib(MultipleMyeloma) Bosutinib (ChronicMyeloidLeukemia) OmacetaxineMepesuccinate (ChronicMyeloidLeukemia) Cabozantinib(med.thyroidCA)

*DataasofNov.30,2012
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Emergingroleofemergingsponsors
Thenewdrugresearchanddevelopmentparadigmis shiftingrapidlyfromtraditionalbigpharmatoventure capitalbackedsmallcompanies Goodnewsisthatmanysmallcompaniesaresuccessfully bringinginnovativenewproductstomarket

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EmergingSponsorAnalysis: AnalyticalApproach
Approvalscategorizedasthosefromemerging ornonemerging sponsors AnemergingsponsorisdefinedasthesponsorlistedontheFDAapproval letterwho,atthetimeofapproval,wasnotaholderofanapproved applicationintheOrangeBookorRMS/BLA Sponsorsarestillclassifiedasemerging eveniftheyhavepartnershipor parentrelationshipswithsponsorscurrentlywithanapprovedproduct Datasourcesinclude: NMEapprovaldatafromDARRTS NBEapprovaldatafromRMS/BLA ApprovedproductdatafromFDAOrangeBook ParentcompanydatafromDun&Bradstreet Partnershipdatafromsponsorwebsites

Note:ThisapproachinvolvedsomeimputationofsponsornamesincethesamesponsorcanappearinmultipleformsinFDAdata systems
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ComparisonofEmerging SponsorApprovals:CY20112012*
NME/NBEApprovalswithEmergingSponsors CY2011andCY2012*
Approvals byEmergingSponsors 35 30 30 25 NME/NBEApprovals 20 15 11 10 5 0 CY11 Source: FDADBAR,OrangeBook CY12* 13 31 Total Approvals 100% 90% 80% NME/NBEApprovals 70% 60% 50% 40% 30% 20% 10% 0% CY11 Source: FDADBAR,OrangeBook CY12* 37% 42% 63% 58%

NME/NBEApprovalswithEmergingSponsors CY2011andCY2012*
EmergingSponsors NonEmergingSponsors

*2012dataasofDecember3, 2012
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ComparisonofEmergingSponsorApprovals: EmergingSponsorswithParent/PartnershipAffiliation
NME/NBEApprovalswithEmergingSponsors CY2011andCY2012*
EmergingSponsors +ParentCompany 14 12 10 8 6 4 2 0 CY11 Source:FDADBAR,OrangeBook CY12* 4 5 4 3 5 3 NME/NBEApprovals +Partnership 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% CY11 Source: FDADBAR,OrangeBook CY12* 36% 38% 36% 38%
27% 23%

NME/NBEApprovalswithEmergingSponsors CY2011andCY2012*
EmergingSponsors +ParentCompany +Partnership

*2012dataasofDecember3, 2012
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NME/NBEApprovals

EmergingSponsorsforCalendarYear2012*

*2012dataasofDecember3, 2012
Last Updated: December 5, 2012 CDER Office of Planning and Informatics (OPI) 33 33

SelectedPDUFAV/FDASIA ProgramsThatImpactDrug DevelopmentandReview

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ReviewProgram forNME NDAsandOriginalBLAs

Goal
Improvetheefficiencyandeffectivenessofthefirstcyclereviewprocess anddecreasethenumberofreviewcyclesnecessaryforapproval, ensuring thatpatientshavetimelyaccesstosafe,effective,andhighqualitynewdrugs andbiologics. (PDUFAVGoalsLetter) Betterplanningbeforeapplicationsubmission,submissionofcomplete applications,improvedcommunicationandtransparencybetweenapplicant andreviewteamduringreview,andadditionalreviewtimewillimprovethe efficiencyofthefirstreviewcycle,whichmaydecreasethenumberof additionalreviewcyclespriortoapproval.

Concept

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ReviewProgram forNME NDAsandOriginalBLAs

Components
Presubmissionmeetingstronglyencouraged Complete applicationattimeofsubmission;incompletesubjecttoRTF 60dayfilingreviewperiodofftheclock 74DayLetter
Plannedreviewtimeline,planneddateofinternalmidcyclemeeting,preliminaryplanson needforACmeeting,earlycommunicationofdeficiencies/informationrequests Within2weeksofinternalmidcyclemeeting Communicationofsignificantissuesidentifiedtodate/informationrequests,preliminary thinkingonriskmanagement/REMS,proposeddatesforlatecyclemeeting,updatesonAC plans Summarizepreliminaryfindings/deficienciesbydiscipline Focusoninformationsharing,planningforAC,andplanningfortheremainderofreview
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MidCycleCommunication

Disciplinereviewletters

Latecyclemeeting(LCM)

SampleProgram Review Timeline StandardApplication

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ReviewProgram Implementation
AppliestoalloriginalNMEapplicationsandresubmissions followingRTFreceivedfrom10/1/12 9/30/17 21st CenturyDeskReferenceGuide(DRG)updatedto includenewactivitiesandtimelinesfortheProgram Trainingforallstaffinvolvedinreviewofmarketing applicationscompleted Workongoingtodevelopexpectations,templates,ground rulesforLCM Independentexpertcontractorhiredtoassessthe programinrealtime
InterimreporttobepublishedforcommentbyMarch31,2015 FinalreporttobepublishedforcommentbyDecember31,2016
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PromotingInnovationThrough EnhancedCommunicationBetweenFDA andSponsorsDuringDrugDevelopment

Goal
Promotetimelyinteractivecommunicationwithsponsorsduringdrug developmenttohelpachievetheAgencysmissiontofacilitatethe conductofefficientandeffectivedrugdevelopmentprograms. (PDUFA VGoalsLetter)

Components
DedicatedliaisonstaffinONDtofacilitatecommunicationandtodevelop anddelivertrainingonbestpracticestoFDAstaffandsponsors Liaisonstaffserveaspointofcontactforgeneralquestions(e.g.,which divisiontosubmitINDto)andsecondarypointofcontactforsponsors encounteringcommunicationsdelays(e.g.,>30days)withreviewdivision ProvidetrainingonbestcommunicationpracticestoCDERstaffinvolved inINDreviewbyendofFY14 Publishdraftguidanceonbestcommunicationpracticesbyendof second quarterofFY15
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PromotingInnovationThrough EnhancedCommunicationBetweenFDAand SponsorsDuringDrugDevelopment(2)

Implementation Actingteamleaderinplace,worktoestablishandfill additionalpositionsongoing InformationpostedtoFDAwebsite
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm32 7281.htm

Contactinformationforliaisonteam:
ONDEnhancedComm@fda.hhs.gov or3017960319

Todate:
9requestsfromexternalsources Variedtopics
DivisionassignmentforIND,BLAreviewtimeline,breakthroughtherapy, INDexemptionprocess,statusofoverdueCMCsupplement,etc.

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BreakthroughTherapies
FDASIASection902
Createdabreakthroughtherapy designationdesignedtoexpedite thedevelopmentandreviewofadrugwhenitisintendedtotreat aseriousorlifethreateningdiseaseorconditionandpreliminary clinicalevidenceindicatesthatthedrugmaydemonstrate substantialimprovementoverexistingtherapieson1ormore clinicallysignificantendpoints,suchassubstantialtreatment effectsobservedearlyinclinicaldevelopment. Adrugsponsormayrequestdesignationasabreakthrough therapyconcurrentlywith,oranytimeaftersubmissionofanIND. Within60calendardaysofreceivingsucharequest,FDAmust makeadeterminationastowhetherthedrugqualifiesasa breakthroughtherapy.

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BreakthroughTherapies(2)
FDASIASection902
Actionstoexpeditedevelopmentandreviewofabreakthrough therapyapplicationmayinclude:
holdingmeetingswiththesponsorandthereviewteamthroughout thedevelopmentofthedrug; providingtimelyadviceto,andinteractivecommunicationwiththe sponsorregardingthedevelopmentofthedrugtoensurethatthe developmentprogramtogatherthenonclinicalandclinicaldata necessaryforapprovalisasefficientaspracticable; involvingseniormanagersandexperiencedreviewstaff,as appropriate,inacollaborative,crossdisciplinaryreview; assigningacrossdisciplinaryprojectleadfortheFDAreviewteamto facilitateanefficientreviewofthedevelopmentprogramandto serve asascientificliaisonbetweenthereviewteamandthesponsor; and takingstepstoensurethatthedesignoftheclinicaltrialsis asefficient aspracticable,whenscientificallyappropriate,suchasbyminimizing thenumberofpatientsexposedtoapotentiallylessefficacious treatment.

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BreakthroughTherapies(3)
Implementation
FDAisdevelopingadraftguidanceonexpediteddrugdevelopment andreviewpathways
WillarticulatecurrentthinkingonFastTrack,Breakthrough,Priority Review,andAcceleratedApproval

InformationtoguideBTsubmissionsandONDcontactinformation postedonFDAwebsite
http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugand CosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm32949 1.htm

BTrequestsarereviewedbyCDERsMedicalPolicyCouncilto ensureconsistencyinapplicationofstandardsacrossdivisions CDERhasreceived7BTdesignationrequeststodate

Twohavebeengranted,onewasdenied,and4arependingwithin theirgoaldates

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CDERNewDrugReview: 2012Summary
CDERismeetingorexceedingnearlyallPDUFAapplication reviewgoals 31NMEapprovalsin2012ishighesttotalsince2004; severalmorehavePDUFAgoaldatesthisyear CDERhasapprovedmanyimportantnewdrugsthisyear thatwillpositivelyimpactpatientsandpublichealth
Approvalsreflectbroaduseofexistingmechanismstoexpeditedrug developmentandreview

NMEfirstcycleapprovalratesforPDUFAIVatalltimehigh
50%firstcycleapprovalrateforstandardapplicationstillleaves roomforimprovement Shifttowardrarediseasesandtargetedtherapywithfavorable benefit/riskbalancefavorshigherfirstcycleapprovalrate
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CDERNewDrugReview: 2012Summary(cont.)
U.S.continuestoleadtheworldinfirstapprovalofnew activesubstances;U.S.patientsbenefitfromearlyaccess Shiftfrombigpharma tosmallcompanyparadigm continuestochangethedynamicofdrugdevelopmentand review Weareopenforbusiness onnewPDUFAV/FDASIA programsdesignedtoexpeditedevelopmentof breakthroughtherapiesandenhancecommunicationand efficiencyduringdrugdevelopmentandapplicationreview

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Thankyou!