FDA-干细胞相关规定

PreparinganINDApplication:PreclinicalConsiderationsforCellandGeneTherapyProductsPatrickAu,PhD,DABTFDA/CBER/OCTGT/DCEPT/[e-mail]ourseNovember15,2013CosponsoredbyFDA’sCDER,OfficeofMedicalPolicyandTheDukeUniversitySchoolofMedicine2Overview•RegulatoryReviewPrinciples•CBER/OCTGT-RegulatedProducts:SafetyConcerns•PreclinicalEvaluation–StudyDesignConsiderations•INDContent•PotentialPitfalls/RegulatoryIssues•WorkingwithFDA/CBER/OCTGT321CFR312.20SubpartB:INDApplicationFormFDA157121CFR312.23(a)(1)TableofContents21CFR312.23(a)(2)IntroductorystatementandgeneralinvestigationalplanInvestigator’sbrochure21CFR312.23(a)(5)Protocols21CFR312.23(a)(6)Chemistry,manufacturing,andcontroldataPharmacologyandtoxicologydata21CFR312.23(a)(8)Previoushumanexperience21CFR312.23(a)(9)Additionalinformation21CFR312.23(a)(10)21CFR312.23(a)(7)21CFR312.23(a)(3)4WhatRegulationsGovernPreclinicalTesting?Pharmacologic&ToxicologicStudies“…adequateinformationaboutthepharmacologicalandtoxicologicalstudies…onthebasisofwhichthesponsorhasconcludedthatitisreasonablysafetoconducttheproposedclinicalinvestigations.Thekind,duration,andscopeofanimalandothertestsrequiredvarieswiththedurationandnatureoftheproposedclinicalinvestigations.”INDRegulations[21CFR312.23(a)(8)-PharmacologyandToxicology]5“FDA’sprimaryobjectivesinreviewinganINDare,inallphasesoftheinvestigation,toassurethesafetyandrightsofsubjects,and,inPhase2and3,tohelpassurethatthequalityofthescientificevaluationofdrugsisadequatetopermitanevaluationofthedrug’seffectivenessandsafety…”INDRegulations[21CFR312.22(a)-GeneralPrinciplesoftheINDSubmission]SafetyisAlwaysPrimary…CBERReview:Product-BasedNo“onesizefitsall”regulatoryapproachDatanecessarytosupportdevelopmentdependsonthecharacteristicsoftheproductPreclinicalstudiesaredesignedtosupportuseofaspecificproductforaspecificclinicalindicationReviewapproachisbasedonbalancingriskandbenefit6PreclinicalRegulatoryTestingStrategyA‘standardset’ofpreclinicaltestsandtestingparametersuniformlyapplicabletoallproductsdoesnotexistThediversityandinherentbiologicalpropertiesofcellandgenetherapyproductsnecessitateacase-by-casetestingstrategyAnoverarchingsetofgeneralconsiderationstoguidepreclinicaltesting789PotentialSafetyConcernsforCell-BasedProducts•Risksofthedeliveryprocedure•Exvivomanipulation(e.g.,expansion,geneticmodification,encapsulation,scaffoldseeding)•Potentialinflammatory/immuneresponsetotheadministeredcellularproduct•Inappropriatecellproliferation(i.e.,tumorformation)•Inappropriatecelldifferentiation(i.e.,ectopictissueformation)•Cellmigrationtonon-targetareas/tissues•Interactionswithconcomitanttherapies10PotentialSafetyConcernsforGeneTherapyProducts•Risksofthedeliveryprocedure•Typeofvector/virus•Vector/virusbiodistributiontonon-targettissues•Levelofviralreplicationandpersistenceinnon-targettissues•Inappropriateimmuneactivation•Potentialforinsertionalmutagenesisand/oroncogenicity•Transgenerelatedconcerns•Geneticallymodifiedcells–seecelltherapyconcerns11PotentialSafetyConcernsforTherapeuticVaccines/Adjuvants•Systemictoxicity–Immunemediatedtoxicity-autoimmuneresponse,inductionofpro-inflammatoryresponse/cytokinerelease,organtoxicity–Hypersensitivity/anaphylaxis–Potential“off-target”toxicity–Adjuvantrelatedtoxicity•Localtoxicity–Injectionsitereaction12ExpectationsfromPreclinicalData•Tosupportarationaleforthefirst-in-humanclinicaltrial–Forcellandgenetherapyproductthetrialisconductedinthediseasepopulation,notinhealthyvolunteers•Tomakerecommendationsregardingclinicaltrialdesign–Initialsafestartingdose,dose-escalationscheme,dosingschedule,organtoxicity,eligibilitycriteria,clinicalmonitoring•Tomeetregulatoryrequirements–21CFR312.23(a)(8)–21CFR58(GLPcompliance)13PreclinicalExpectationsforEarlyPhaseClinicalTrials•Proof-of-concept[POC]–invitro/invivo–Potentialmechanismofaction[e.g.,neuroprotective,neoangiogenesis,toleranceinduction]–Establishpharmacologicallyeffectivedose(s)–Optimizerouteofadministration(ROA)/dosingregimen–Rationaleforspecies/modelselectionforfurthertesting•Safetyofconductingclinicaltrial–risk/benefit–Dosingscheme–Potentialtargettissue(s)oftoxicity/activity–Parameterstomonitorclinically–Eligiblepatientpopulation14PreclinicalStudyDesign(s)•Assesspharmacology/POC/vectordistribution/cellfateinrelevantanimalmodel(s)ofdisease/injury,asfeasible•Assesssafety/toxicology(T)/vectordistribution/cellfateinhealthyanimals•Hybridpharmacology-toxicologystudydesign–POC+T+productfate–incorporateactivityandsafetyendpointsinananimalmodelofdisease/injury–Localmicroenvironmentandpathophysiologystatusofthemodelmayimpactthesafety/bioactivityoftheproduct•Applythe3R’s–Reduce,Refine,Replace–inpreclinicalstudydesigns15ComparabilityoftheCellsAdministeredtotheIntendedClinicalProduct•Manufacturingprocessofthecellularproductusedinthepreclinicalstudiesshouldbeassimilartotheintendedclinicalproductaspossible–Tissue/sampleharvest,cellisolation,expansion,culturing,formulation/scaffoldseeding,encapsulationprocedure,storageconditions,etc.•Adequate