FDA细胞治疗临床试验监督

FDAOversightofCellTherapyClinicalTrialsCeliaWitten,Ph.D.,M.D.OfficeDirector,OfficeofCellular,Tissue,andGeneTherapiesCBER/FDAISSCR/CIRM/ISCTWorkshopJune15,2010SanFrancisco,California2FDAOrganizationOfficeoftheCommissionerOfficeofCombinationProductsCBER(CenterforBiologicsEvaluationandResearch):vaccines,bloodandbloodproducts,humantissue/tissueproductsfortransplantation,celltherapy,genetherapy,donorscreeningtestsforbloodandtissuesafety,devicesCDRH(CenterforDevicesandRadiologicalHealth):devicesfortreatment,implants,diagnosticdevicesCDER(CenterforDrugEvaluationandResearch):drugs,monoclonalantibodies,therapeuticproteins)CVMCFSANNCTR3OCTGTProductsCellulartherapiesTumorvaccinesandimmunotherapyGenetherapiesTissueandtissuebasedproductsXenotransplantationproductsCombinationproductsDevicesusedforcells/tissuesDonorscreeningtests(forusewithcadavericbloodsamples)4The“TissueRules”(21CFR1271,EffectiveMay25,2005)TissueRuleIssuesAddressedEstablishmentRegistrationandListingApplicability:typesandusesofproductsthatwillberegulatedbytheserules;requirementsforregisteringandlistingproductsDonorEligibilityRequirementsfordonorscreeningandtestingfor“relevantcommunicablediseaseagentsanddiseases”CurrentGoodTissuePractice(CGTP)ManufacturingtoensurethatHCT/Psdonotcontaincommunicablediseaseagents;reporting;inspections521CFRPart1271Thesethreerulesformtheplatformforregulationofallhumancells,tissues,andcellularandtissue-basedproducts(HCT/Ps)ForcertainHCT/Ps(“361HCT/Ps”),theseregulationscomprisethesoleregulatoryrequirementsForHCT/Psregulatedasdrugs,devices,and/orbiologicalproducts,thenewtissueregulationssupplementotherrequirements(GMP,QSR)6StemCell-BasedProductsFitregulatorydefinitionsofthefollowing:Humancells,tissues,orcellularandtissuebasedproducts(HCT/P)(21CFR1271.3(d))Biologics(PHSAct)Drugs(FDCAct)CelltherapyGenetherapy-whengeneticmaterialistransferredtocellsexvivo7EvolutionofStemCellFieldCelltherapyandgenetherapyproducts–andthereforestemcellproducts--donotlendthemselvestoa“onesizefitsall”conceptofproductdevelopmentandregulationRegulationssetframeworkofcriteriathatmustbefulfilled:safety,identity,purity,potency,andclinicalefficacyFlexibilityinhowtofulfillthecriteria8ExamplesofSafetyConcernsforStemCellsDefiningtheintendedmodeofactionCharacterizationoftheproduct,includingpotencyCelldifferentiationtoundesiredcelltypesCellmigration/traffickingtonontargetsite(s)PotentialuncontrolledcellproliferationortumorigenicityImmunogenicityGraft-vs-hosteffectsInteractionswithdevices,othertissuesordrugsinvivoForgene-modifiedcellsPotentialuncontrolledbiologicalactivityofthetransgeneAlterationofexpressionofthenontransgenesInsertionalmutagenesis9ReviewDecisionCMCClinicalPharm/ToxProjectManagerStatisticsEpidemiologyComplianceREVIEWOFFICECBERFDAOUTSIDECONSULTANTProductQualityScientificExpertProductexpertClinicalspecialistMethodologyexpertPatientAdvocateScientificExpert(SGE)PolicyExpertOrphanproductsEthicistAnimalruleFDAReviewTeamBasicReviewTeamExtendedReviewTeamPotentialConsultsorCollaboratorsAdvisoryCommitteePotentialConsults10ExamplesofCMCIssuesControlstopreventtransmissionofinfectionfromthedonororintroductionofinfectiousagentsduringcellprocessingDonorTestingandscreeningforrelevantcommunicablediseasesAutologousdonorsrecommendedbutnotrequiredAllogeneicdonorsmustcomplywith21CFR1271SubpartCHCT/Pdonorscreeningismedicalhistoryinterview,physicalassessmentandmedicalrecordreviewHCT/PdonorsaretestedusingFDAapprovedorcleareddonorscreeningtestsCellbanks-adventitiousagenttesting&characterizationIfmousefeederlayersused-testforthepresenceofmurineviruses(andisaxenotransplantationproduct)Components,reagents,materialsqualification11ExamplesofCMCIssues-2AccountforandcontroldonortodonorvariabilityIntrinsicsafetyconcerns,basedoncellsourceorhistoryAdequatecharacterizationoftheproductIdentity,purity,potencyAdditionalcharacterizationSystemforproducttrackingandlabelingcriticalforpatientspecificproductsStabilityofproductandorcelllinenumberofpassages/doublingsovertimemaintaindesireddifferentiationpropertieskaryotypicalterationsProductcomparabilityformanufacturingchangesExamplesofPreclinicalIssuesScientificbasisforconductingclinicaltrialDatatorecommendinitialsafedose&doseescalationschemeinhumansProofofConceptStudiesinrelevantanimalmodelsToxicologyStudiesinrelevantanimalspeciesIdentify,characterize,quantifythepotentiallocalandsystemictoxicities13ExamplesofClinicalIssuesCollectionprocedureStandardmedicalpractice?Specialinstrumentorkit?OptimaldoseandadministrationStartingdoselevel/doseescalationschemeRouteofadministrationDosescheduleDefineappropriatepatientpopulationIfimmunosuppressionwillbeused:Isthedose-schedulejustified?Long-termvsshorttermSingledrugvsacombinationregimenSafetyMonitoringplansSafetyReportingrequirementsPediatricissues14AdministrationofStemCellProductsDeliveryofstemcellstocertainanatomiclocationsmayrequirenovelproceduresand/ornoveldeliverydevicesThisneedstobeconsideredearlyCellsdeliveredbycertai