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Model-InformedDrugDevelopment:Past,Present,Future
IssamZineh,PharmD,MPHOfficeofClinicalPharmacology
OfficeofTranslationalSciences|CDER|USFDAHuntington’sDiseaseRegulatoryScienceConsortium(HD-RSC)
SilverSpring,MD,November6,2017
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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.
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Model-InformedDrugDevelopment• “Developmentandapplicationofpharmaco-statisticalmodelsofdrug
efficacyandsafetyfrompreclinicalandclinicaldatatoimprovedrugdevelopmentknowledgemanagementanddecision-making”(Lalonde)
• Pathwayforloweringdrugattritionanddealingwithregulatoryuncertainty3
Lalonde 2007[PMID17522597]|Milligan2013[PMID23588322]
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AdvancingRegulatoryScience
20062010
2011
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CriticalPathOpportunitiesList
N=76OpportunitiesN=17Model-related
TOPIC1:BETTEREVALUATIONTOOLSTOPIC2:STREAMLININGCLINICALTRIALSTOPIC3:HARNESSINGBIOINFORMATICSTOPIC4:MOVINGMANUFACTURINGINTOTHE21STCENTURYTOPIC5:DEVELOPINGPRODUCTSTOADDRESSURGENTPUBLIC
HEALTHNEEDSTOPIC6:SPECIFICAT-RISKPOPULATIONS—PEDIATRICS
ExperimentalModels● StatisticalModels● EmpiricalModels● MechanisticModels● Simulations
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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.
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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
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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)
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1990– 2000EarlyDaysIVIVC,PK-PDPOPPKPharmacometricsGroup
2000– 2010RapidGrowthPOPPK,D/R,E/RGuidanceCTSanddiseasemodelsEarlydaysofPBPKresearchandapplicationDivisionofPharmacometrics(DPM)
2010– NowApproachingMainstreamRoutineapplicationofpharmacometrics,PBPKforDDIsEarlyapplicationsofsemi-mechanisticandmechanisticmodelinginreviewandresearchOpportunisticstandardizationRegulatoryacceptanceofDDTsOrganizationalgrowth,assimilationandprioritization
2017– Beyond?
AdaptedfromR.Madabushi,OCP
EvolutionofMIDDinOCP
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IntegratedViewofModelinginDrugReview
CourtesyT.Colatsky
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MIDD:FromConcepttoApplication
PMIDs:21191381,26225246,24747236,26170255,24336137,28986934
PBPK CiPA
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MIDDEnablersandDisablers:TwoSidesoftheSameCoin
EnvironmentAcceptanceofMIDDapproachesResources/BudgetStructure/focus/awarenessEvolutionofregulatoryprocessesProcessandguidanceTechnicaladvancement
AcceptanceofMIDDapproachesEnvironmentResources/BudgetStructure/focus/awarenessEvolutionofregulatoryprocessesProcessandguidanceTechnicaladvancement
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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
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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/
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IncreasedFocusonAdvancingRegulatoryScience
ModifiedfromJ.Barton,OSP/CDER/FDA
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PDUFA6:RegulatoryDecisionTools
ComplexInnovativeTrialDesigns
Model-informedDrugDevelopment
BiomarkerQualification
RealWorldEvidence Benefit/RiskAssessment
PatientVoice
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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
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AC,scientificmeetings,workshops
INDsandNDA/BLAs
Academia,govt,
industry,FDA
ProblemIdentificationandResolutionApplicationReview
ScientificResearch
PublicInput
Guidanceand
Standards
AdaptedfromCriticalPathReport2004
ProblemIdentification
RecommendscientificsolutionsDeveloppublicstandards
Usewithinreviewprocess
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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
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Risk-InformedCredibilityFramework
CourtesyT.Morrison,CDRH|ASMEV&V40 Subcommittee
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Conclusion• MIDDhasexhibitedimpressivegrowthoverthepastseveraldecades
withnotableexpansionoverthelast5-10years
• GrowingappreciationforthetheoreticalandactualbenefitsofMIDDhascreatedanimportantmomenttoadvanceMIDD
• RecentlegislationandmaturingofMIDD-relatedprogramscansetthedirectionre:MIDDfortheforeseeablefuture
• EnablersanddisablersexistandmustbeappreciatedinstrategicplanningforMIDD
• Evidentiaryconsiderationsandstakeholderexpectationsmustbeaddressed,andcanbethroughmulti-disciplinarycollaboration
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