Model-InformedDrugDevelopment:Past,Present,Future

IssamZineh,PharmD,MPHOfficeofClinicalPharmacology

OfficeofTranslationalSciences|CDER|USFDAHuntington’sDiseaseRegulatoryScienceConsortium(HD-RSC)

SilverSpring,MD,November6,2017

2

AcknowledgmentsOfficeofClinicalPharmacology• AtulBhattaram(Pharmacometrics)• ElizabethFord(RegulatoryAffairs)• KevinKrudys(Pharmacometrics)• RajnikanthMadabushi(GuidanceandPolicy)• KimberlyMaxfield(ExecutiveProgramandProjectManagement)• JoseRuizVicente(AppliedRegulatoryScience)• YaningWang(Pharmacometrics)• DavidStrauss(AppliedRegulatoryScience)

CenterforDevicesandRadiologicalHealth• TinaMorrison(ASMEV&V40 Subcommittee)

NB:MyviewswillbeCDER-centric.

3

Model-InformedDrugDevelopment• “Developmentandapplicationofpharmaco-statisticalmodelsofdrug

efficacyandsafetyfrompreclinicalandclinicaldatatoimprovedrugdevelopmentknowledgemanagementanddecision-making”(Lalonde)

• Pathwayforloweringdrugattritionanddealingwithregulatoryuncertainty3

Lalonde 2007[PMID17522597]|Milligan2013[PMID23588322]

4

AdvancingRegulatoryScience

20062010

2011

5

CriticalPathOpportunitiesList

N=76OpportunitiesN=17Model-related

TOPIC1:BETTEREVALUATIONTOOLSTOPIC2:STREAMLININGCLINICALTRIALSTOPIC3:HARNESSINGBIOINFORMATICSTOPIC4:MOVINGMANUFACTURINGINTOTHE21STCENTURYTOPIC5:DEVELOPINGPRODUCTSTOADDRESSURGENTPUBLIC

HEALTHNEEDSTOPIC6:SPECIFICAT-RISKPOPULATIONS—PEDIATRICS

ExperimentalModels● StatisticalModels● EmpiricalModels● MechanisticModels● Simulations

6

Regulatory ScienceScience of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products

VisionFDA will advance regulatory science to speed innovation, improve regulatory decision-making, and get products to people in need. 21st Century regulatory science will be a driving force as FDA works with diverse partners to protect and promote the health of our nation and the global community.

7

FDASciencePriorityAreas1. Modernize toxicology to enhance product safety

1. Developbettermodelsofhumanadverseresponse2. Identifyandevaluatebiomarkers&endpointsthatcanbeusedinnon-clinical+clinicalevaluations3. Useanddevelopcomputationalmethodsandinsilico modeling

2. Stimulate innovation in clinical evaluations and personalized medicine to improve product development and patient outcomes1. Developandrefineclinicaltrialdesigns,endpoints,andanalysismethods2. Leverageexistingandfutureclinicaltrialdata(includingfordiseaseprogressionmodeling)3. Identifyandqualifybiomarkersandstudyendpoints4. Developavirtualphysiologicpatient

3. Harness diverse data through information sciences to improve health outcomes1. Developandapplysimulationmodelsforproductlifecycles,riskassessment,&otherreg sci uses2. Analyzelargescaleclinicalandpreclinicaldatasets3. IncorporateknowledgefromFDAregulatoryfilesintoadatabaseintegratingabroadarrayofdatatypestofacilitate

developmentofpredictivetoxicologymodelsandmodelvalidation4. Developnewdatasourcesandinnovativeanalyticalmethodsandapproaches

4. Facilitate development of MCM to protect against threats to health1. Develop,characterize,andqualifyanimalmodelsforMCMdevelopment2. ModernizetoolstoevaluateMCMproductsafety,efficacy,andquality3. Developandqualifybiomarkersofdiseasesorconditions

8

MIDD:SamplingfromNeuroscienceDisease Objective Application

Parkinson'sDisease Developdiseaseprogressionanddropoutmodels

Informtrialdesign; novelendpoints

Alzheimer's Disease Developdiseaseprogressionanddropoutmodels Inform CAMDDDT

Huntington’sDisease Developdiseaseprogressionmodel

Informtrial design(enrichment)

PartialOnsetSeizures Compare E/Rbetweenadultandpediatricpatients

Waivepediatric efficacystudies(>4yo)foradult-

approvedproducts

Duchenne MuscularDystrophy Developdisease progressionmodel

Informtrial design(inclusioncriteria)

9

1990– 2000EarlyDaysIVIVC,PK-PDPOPPKPharmacometricsGroup

2000– 2010RapidGrowthPOPPK,D/R,E/RGuidanceCTSanddiseasemodelsEarlydaysofPBPKresearchandapplicationDivisionofPharmacometrics(DPM)

2010– NowApproachingMainstreamRoutineapplicationofpharmacometrics,PBPKforDDIsEarlyapplicationsofsemi-mechanisticandmechanisticmodelinginreviewandresearchOpportunisticstandardizationRegulatoryacceptanceofDDTsOrganizationalgrowth,assimilationandprioritization

2017– Beyond?

AdaptedfromR.Madabushi,OCP

EvolutionofMIDDinOCP

10

IntegratedViewofModelinginDrugReview

CourtesyT.Colatsky

11

MIDD:FromConcepttoApplication

PMIDs:21191381,26225246,24747236,26170255,24336137,28986934

PBPK CiPA

12

MIDDEnablersandDisablers:TwoSidesoftheSameCoin

EnvironmentAcceptanceofMIDDapproachesResources/BudgetStructure/focus/awarenessEvolutionofregulatoryprocessesProcessandguidanceTechnicaladvancement

AcceptanceofMIDDapproachesEnvironmentResources/BudgetStructure/focus/awarenessEvolutionofregulatoryprocessesProcessandguidanceTechnicaladvancement

13

EvolutionofMIDDatOCP

1990– 2000EarlyDaysIVIVC,PK-PD,POPPKPharmacometricsGroup

2000– 2010RapidGrowthPOPPK,D/R,E/R,GuidanceCTSanddiseasemodeling,EarlydaysofPBPKresearchandapplicationDivisionofPharmacometrics(DPM)

2010– NowApproachingMainstreamRoutineapplicationofPharmacometrics,PBPKforDDIsEarlyapplicationsofsemi-mechanisticandmechanisticmodelinginreviewandresearchOpportunisticstandardizationRegulatoryacceptanceofDDTOrganizationalgrowth,assimilationandprioritization

2017– BeyondAcceptedStandardDevelopmentofstandardsfordata,analyses,andprocessesPathwaysfordedicatedregulatoryengagementIntegrationofvariousM&SactivitiesthroughoutthedrugdevelopmentandorganizationManagementofinformationandknowledge– diseasemodeling,PBPK2.0Incorporationofnewerapproachesandtechnologies–QSP,Bayesian,etc.LeveragingRWD

AdaptedfromR.Madabushi,OCP

14

Commissioner’sBlogonInSilicoTools

• InnovationInitiative• Useofinsilicotoolsinclinicaltrialsfor

improvingdrugdevelopmentandmakingregulationmoreefficient

• M&Stopredictclinicaloutcomes,informclinicaltrialdesigns,supportevidenceofeffectiveness,optimizedosing,predictproductsafety,andevaluatepotentialadverseeventmechanisms

• Creationofnaturalhistorydatabasestosupportmodel-baseddrugdevelopment

https://blogs.fda.gov/fdavoice/index.php/tag/in-silico-tools/

15

IncreasedFocusonAdvancingRegulatoryScience

ModifiedfromJ.Barton,OSP/CDER/FDA

16

PDUFA6:RegulatoryDecisionTools

ComplexInnovativeTrialDesigns

Model-informedDrugDevelopment

BiomarkerQualification

RealWorldEvidence Benefit/RiskAssessment

PatientVoice

17

OpportunitiesforMIDDPDUFAVI– EnhancingRegulatoryDecisionToolsToSupportDrug

DevelopmentandReview• AdvancingModel-InformedDrugDevelopment

– FDAwilldevelopitsregulatoryscienceandreviewexpertiseandcapacityinMIDDapproaches

– FDAwillconveneaseriesofworkshopstoidentifybestpracticesforMIDD.TopicsincludePBPK,designanalysisandinferencesfromdose-exposure-response,diseaseprogressionmodeldevelopment,immunogenicity

– FDAwillconductapilotprogramforMIDDapproaches.Forsponsorsparticipatinginthepilotprogram,FDAwillgrantapairofmeetingsspecificallydesignedforthispilotprogram

– FDAwillpublishdraftguidance,orreviserelevantexistingguidance,onmodel-informeddrugdevelopment

– FDAwilldeveloporrevise,asappropriate,relevantMAPPsorSOPPs,and/orreviewtemplatesandtraining,toincorporateguidelinesfortheevaluationofMIDDapproaches.

https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM511438.pdf

18

AC,scientificmeetings,workshops

INDsandNDA/BLAs

Academia,govt,

industry,FDA

ProblemIdentificationandResolutionApplicationReview

ScientificResearch

PublicInput

Guidanceand

Standards

AdaptedfromCriticalPathReport2004

ProblemIdentification

RecommendscientificsolutionsDeveloppublicstandards

Usewithinreviewprocess

19

ImpactofCollaboration

12

10

7

3

2

2

1 10 100 1000

Impact

Updates onPediatricMedicationSafety

Support ofRegulatory Actions(Approvals,Recalls)

NewClinicalTrialDesigns

Drug DevelopmentToolQualification

Drug DevelopmentToolLetterofSupport

SupportofIndustry Guidances

White PaperPubMed Citations

PPPImpactNumber

≥1000

AdaptedfromK.Maxfield,OCP|Maxfield2017[PMID28776943]

MAPP4100.2CDERStaffParticipation

inPublicPrivatePartnerships(PPP)and

Consortia

20

Risk-InformedCredibilityFramework

CourtesyT.Morrison,CDRH|ASMEV&V40 Subcommittee

21

Conclusion• MIDDhasexhibitedimpressivegrowthoverthepastseveraldecades

withnotableexpansionoverthelast5-10years

• GrowingappreciationforthetheoreticalandactualbenefitsofMIDDhascreatedanimportantmomenttoadvanceMIDD

• RecentlegislationandmaturingofMIDD-relatedprogramscansetthedirectionre:MIDDfortheforeseeablefuture

• EnablersanddisablersexistandmustbeappreciatedinstrategicplanningforMIDD

• Evidentiaryconsiderationsandstakeholderexpectationsmustbeaddressed,andcanbethroughmulti-disciplinarycollaboration