放眼世界向FDA注册药品

SuccessfulINDFilingtoFDA:CurrentExperienceswithChinesePharmaceuticalCompaniesforNewDrugDevelopmentProgramsEnteringClinicalDevelopmentintheU.S.DerekZhang,Ph.D.FrontageLaboratories,Inc.FDAInteractionsandDrugDevelopmentDrugDevelopmentandRegulatoryReview/ApprovalareintegratedprocessestosuccessfulproductmarketlaunchGoodunderstandingindrugdevelopmentandregulatoryreview/approvalprocessescanmakesignificantcontributionstoyourdrugdevelopmentprograms:TonavigatethroughtheregulatoryreviewandapprovalprocessmoresmoothlyToadvanceyourdrugcandidatesfrompre-clinicalresearchtoclinicaldevelopmentmoreefficientlyNewDrugDevelopmentandRegulatoryReviewLifeCycleManagementPreclinicalDevelopmentClinicalDevelopmentP1FDAFiling/ApprovalP2P3Pre-INDMeetingInitialINDSubmissionEOP2A/2MeetingPre-NDAorPre-BLAMeetingNDAorBLASubmissionINDReviewNDA/BLAReviewEOP1MeetingSupplementsRegulationofDrugInvestigation-Implementationofthe1962AmendmentsEstablishedbythe1962AmendmentsanddevelopedinsubsequentregulationsClinicalinvestigationofanewdrugintheU.S.mustbecarriedoutunderanIND(investigationalnewdrugapplication)FDAevaluationofanINDfocusesonsafety1962amendmentsrequired“substantialevidence”ofeffectiveness,derivedfromadequateandwell-controlledstudiesINDFilingSponsor'sprimarygoal:Todetermineiftheproductisreasonablysafeforinitialuseinhumans,ifthecompoundexhibitspharmacologicalactivitythatjustifiescommercialdevelopmentFDArequirespre-clinicaldataadequatetoestablishthattheproductwillnotexposehumanstounreasonableriskswhenusedinlimited,early-stageclinicalstudiesINDContent:AnOverviewAnimalPharmacologyandToxicologyStudiesPreclinicaldatatopermitanassessmentastowhethertheproductisreasonablysafeforinitialtestinginhumansManufacturingInformationInformationpertainingtothecomposition,manufacturer,stability,andcontrolsusedformanufacturingthedrugsubstanceandthedrugproduct.ThisinformationisassessedtoensurethatthecompanycanadequatelyproduceandsupplyconsistentbatchesofthedrugClinicalProtocolsandInvestigatorInformationProtocolsforproposedclinicalstudiestoassesswhethertheinitial-phasetrialswillexposesubjectstounnecessaryrisksInformationonthequalificationsofclinicalinvestigatorsInformedconsentfromtheresearchsubjectsReviewofthestudybyanInstitutionalReviewBoard(IRB)AnyPreviousExperiencewiththeDruginHumansINDCMCContentDrugSubstanceDrugProductSponsor’sgoal:toprovidesufficientinformationtoensuredrugproductsafetywithoutunnecessaryrestrictionThesamesortsofCMCinformationarerequiredacrossdifferentphasesofdevelopmentThedepthanddetailincreaseacrossphasesPharmacologyandToxicologyRequirementforFirstInHumans(FIH)MammalianToxicology(GLP)Acute(singledoseinmiceorrats)Rodent(2-4weeks:dependsonclinicaltrial,andusuallyrat)Nonrodent(2-4weeks,dog,cynomolgusmonkey)SafetyPharmacology(GLP)Cardiovascular(nonrodent)Irwintest(CNS,behavioral)RespiratoryGenotoxicity(GLP)Amesassay,Chromosomeaberrationassay(CHOcellsorhumanlymphocytes)andMicronucleustest(invivo)PharmacologyandToxicologyToxicityStudies(rodentandnon-rodent)Singledose(acute),repeated-doseForselectedproducts(i.e.,biotechnologyproducts)singlespeciesmaysufficeSafetyPharmacology(invitro;invivo)CNS,cardiovascular,respiratoryGenotoxicityInvitro(Ames,invitromicronucleus,chromosomalaberration)andinvivo(micronucleus)ReproductiveandDevelopmentalFertility,teratology,peri-/post-natalCarcinogenicityOtherRequirementsforFirst-in-HumanStudyCMCandFormulationsPharm/ToxStudiesNoObservableAdverseEffectLevel(NOAEL)HumanEquivalenceDose(HED)MaximumRecommendedStartingDose(MRSD)StudyDesignInvestigator’sBrochure(IB)Acompilationofnon-clinicalandclinicaldatathatarerelevanttoitsstudyinhumansItissubmittedtoinvestigators,IRBs/ECs,andregulatoryauthoritiesIBmustbereviewedannuallyIRB=InvestigationalReviewer’sBoardEC=EthicsCommitteesInvestigationalPlanDescriptionofclinicalstudiesplannedfortheexperimentaldrugMinimum1yearScaleofstudyRationaleforthedrugorresearchstudyIndicationstobestudiedTypesoftrialstobeinitiatedNumberofstudysubjectsRisksFirst-in-HumanStudyPrimaryobjectives:SafetyandTolerabilitySecondaryobjectives:Drugconcentrationtimeprofile(PK)Pharmacodynamicresponse(PD)ClinicalStudyProtocolsEndpointsi.e.,Primary,SecondaryTrialtype/designi.e.,Double-blinded,Placebo-controlled,CrossoverMeasurestominimizebiasi.e.,Randomization,BlindingTypesofComparisoni.e.,Superiority,EquivalenceorNon-inferiorityInclusionandExclusionCriteriaStoppingRulesFDAreviewsprotocolsto:EnsuresubjectsnotexposedtoanyunnecessaryrisksEnsureclinicalstudydesignisappropriatetoprovidethetypeandamountofinformationthatisadequatetoallowthesafeconductofeachphaseofdrugdevelopmentInitialIND–FDA30-DayReviewCollectiveDisciplineReviewsMedical,Pharm/Tox,ClinPharm,CMC,StatsClinicalDivisionReviewMeetingAmeetingforallinitialINDsActionsaredecidedduringthesafetymeeting:•Noissues:safetoproceed(phonecallandletterfromFDA)•Clinicalhold(phonecallandletterfromFDA)ClinicalPharmacologyStudiesTobetterunderstanddrugcharacteristics:Anintegratedpartofclinicaldevelopmentfromfirst-in-humantolife-cyclemanagementTo