_2 IND and NDA in US_Chen

InvestigationalandMarketingNewDrugApplicationsintheU.S.Chi-wanChen,Ph.D.Pfizer,Inc.AAPS/CPAWorkshop(CMC):Quality,RegulatoryandScientificRequirementsandStrategiesShanghai,ChinaJune28-29,20102OutlineHowisINDregulatedintheU.S.?HowisNDAregulatedintheU.S.?CMCdifferencesbetweenINDsandNDAsFDAmeetingswithINDsponsors/NDAapplicantsMinimalvsenhanced,quality-by-design(QbD)approachtodrugdevelopmentandsubmissionFDACMCPilotProgramonQbDComparabilityprotocolSummary3WhatisanInvestigationalNewDrug(IND)andHowisitRegulated?Law:FoodDrug&CosmeticAct505(i)exemptsadrugintendedsolelyforinvestigationalusebyqualifiedexpertsfromfilinganNDAorANDAApplicationforthisexemptioniscalledInvestigationalNewDrugApplication(IND)Unlikeotherdrugapplications,INDsareneitherapprovednordisapproved.Rather,theclinicalstudiesareeitherallowedtobeginorareplacedonclinicalholdforsafetyreasons.NewINDsarerequiredtohavea30-daysafetywaitingperiod.Inotherwords,FDAhas30daystomakeadecisiononsafety.4WhatisanINDandHowisitRegulated*?(cont.)Regulation:21CodeofFederalRegulations(CFR)312INDscategoriesCommercialIND(sponsoredbydrugcompanies)non-CommercialIND(sponsoredbyindividualinvestigators)MajorrevisiontoINDregulationin1987:ObjectivesweretoestablishanefficientprocessToencourageinnovationanddrugdevelopmentwhilecontinuingtoassuresafetyoftestsubjectsinPhase1ToensureefficientreviewofsubsequentNDATobenefitthepatient*(cont.)Numerousguidancestoindustry,including“ContentandFormatofINDsforPhase1StudiesofDrugs,IncludingWell-Characterized,Therapeutic,Biotechnology-DerivedProducts”(1995)“FormalMeetingswithSponsorsandApplicantsforPDUFA*Products”(2000)“MeetingsforHumanDrugsandBiologicsChemistry,Manufacturing,andControlsInformation”(2001)“INDsforPhase2andPhase3StudiesChemistry,Manufacturing,andControlsInformation”(2003)“CGMPforPhase1InvestigationalDrugs”(2008)ManyManualsofPoliciesandProcedures(MaPPs)forreviewstaff*PrescriptionDrugUserFeeAct6OriginalINDsReceivedbyCDER*Calendaryear#CommercialINDs#non-CommercialINDsTotal#INDs2000419974138420015099951404200241713381755200339197213632004**621121618372005**637129719362006**713115018632007**n/an/an/a***IncludesINDsfortherapeuticbiologicstransferredfromCBERtoCDER7INDPhasesPhase1:InitialintroductionofanewdrugintohumansCloselymonitored,typically20-80patientsornormalsubjectsMetabolismandpharmacologicalactionsofdruginhumansSideeffectsassociatedwithincreasingdosesEarlyevidenceofeffectivenessPhase2:Limited,controlledclinicalstudiesCloselymonitored,usuallyseveralhundredsubjectsToobtainpreliminarydataoneffectivenessofthedrugTodeterminecommonshort-termsideeffectsandrisksPhase3:Expanded,controlledanduncontrolledtrialsUsuallyseveralhundredtoseveralthousandsubjectsTogatheradditionaleffectivenessandsafetyinformationToprovideanadequatebasisforextrapolatingresultstogeneralpopulationandtransmittingthatinformationinthephysicianlabeling8INDReviewObjectivesInearlyphaseofINDSafetypredominatesStudyprotocolcanbemodifiedbasedonexperiencewithoutpriornotificationtoFDAAmountofCMCandtoxicityinformationdependsonnatureandextentofclinicalstudyFDA’sprimaryobjectivesinreviewinganINDare:ToassurethesafetyandrightsofsubjectsinallphaseofinvestigationTofocusonassessingthesafetyinPhase1TohelpassurethatqualityofclinicalprotocolsandrelatedinformationisadequatetopermitassessmentofsafetyandeffectivenessofthedruginPhase2and39INDContent–GeneralDescribedinRegulation(21CFR312.23)ManyguidancesandMaPPsINDsgenerallyarerequiredtocontainsufficientinformationinthefollowingthreecategoriestopermitanassessmentastowhethertheinvestigationaldrugissafefortestinginhumansfortheintendeduseClinicalprotocol(s)andlistofinvestigatorsPharmacologicalandtoxicologicalstudiesinanimalorinvitroChemistry,manufacturing,andcontrols(CMC)10INDContent–aPhasedApproachtoCMCFDArecognizesmodificationstomethodofpreparationofdrugsubstanceanddrugproductandchangesindosageformitselfarelikelyasINDprogressesGradedinformation,dependingonPhaseoftheinvestigationDurationofthestudyNoveltyofthedrugPhase1(RefertoPhase1Guidance)BriefdescriptionofCMCfordrugsubstanceandproduct,statingifCMCpresentsanysignalsofpotentialhumanriskPhase2/3(RefertoPhase2/3CMCGuidance)AdditionalCMCinformationrelatedtosafetyininformationamendmentsDosageform/routeofadministrationPatientpopulationKnownorsuspectedrisks11StabilityDataforINDs–ExampleofPhasedApproachtoCMCPhase1AdequatedatatosupporttheperiodofclinicalstudiesNoneedfordetaileddataorstabilityprotocolNoneedforvalidatedanalyticalproceduresPhase2DefinestabilityprogramforDSandDPDevelopstability-indicatinganalyticalproceduresPhase3PivotaltowardsestablishingshelflifeDevelopfinalstabilityprotocolwithvalidatedanalyticalprocedures12DrugDevelopmentandINDReviewTimeline4NDA/BLAPost-MarketingADVERSEREACTIONREPORTAPPROVALPOST-APPROVALCHANGESDevelopment/registrationSYNTHESPURIFICATIONANIMALTESTINGLongShortPhase123