FDA细胞治疗临床试验监督

1、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):devicesf。

2、ortreatment,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:ty。

3、pesandusesofproductsthatwillberegulatedbytheserules;requirementsforregisteringandlistingproductsDonorEligibilityRequirementsfordonorscreeningandtestingfor“relevantcommunicablediseaseagentsanddiseases”CurrentGoodTissuePractice(CGTP)ManufacturingtoensurethatHCT/Psdonotcontaincommunicablediseaseagents;reporting;inspections521CFRPart1271Thesethreerulesformtheplatformforregulationofallhumancells,tissues,andcellularandtissue-basedproducts(HCT/Ps)ForcertainHCT/Ps(“361HCT/Ps”),theseregulationscomprise。

4、thesoleregulatoryrequirements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。

5、“onesizefitsall”conceptofproductdevelopmentandregulationRegulationssetframeworkofcriteriathatmustbefulfilled:safety,identity,purity,potency,andclinicalefficacyFlexibilityinhowtofulfillthecriteria8ExamplesofSafetyConcernsforStemCellsDefiningtheintendedmodeofactionCharacterizationoftheproduct,includingpotencyCelldifferentiationtoundesiredcelltypesCellmigration/traffickingtonontargetsite(s)PotentialuncontrolledcellproliferationortumorigenicityImmunogenicityGraft-vs-hosteffectsInteractions。

6、withdevices,othertissuesordrugsinvivoForgene-modifiedcellsPotentialuncontrolledbiologicalactivityofthetransgeneAlterationofexpressionofthenontransgenesInsertionalmutagenesis9ReviewDecisionCMCClinicalPharm/ToxProjectManagerStatisticsEpidemiologyComplianceREVIEWOFFICECBERFDAOUTSIDECONSULTANTProductQualityScientificExpertProductexpertClinicalspecialistMethodologyexpertPatientAdvocateScientificExpert(SGE)PolicyExpertOrphanproductsEthicistAnimalruleFDAReviewTeamBasicReviewTeamExtendedReviewTeamPo。

7、tentialConsultsorCollaboratorsAdvisoryCommitteePotentialConsults10ExamplesofCMCIssuesControlstopreventtransmissionofinfectionfromthedonororintroductionofinfectiousagentsduringcellprocessingDonorTestingandscreeningforrelevantcommunicablediseasesAutologousdonorsrecommendedbutnotrequiredAllogeneicdonorsmustcomplywith21CFR1271SubpartCHCT/Pdonorscreeningismedicalhistoryinterview,physicalassessmentandmedicalrecordreviewHCT/PdonorsaretestedusingFDAapprovedorcleareddonorscreeningtestsCellbanks-adv。

8、entitiousagenttesting&characterizationIfmousefeederlayersused-testforthepresenceofmurineviruses(andisaxenotransplantationproduct)Components,reagents,materialsqualification11ExamplesofCMCIssues-2AccountforandcontroldonortodonorvariabilityIntrinsicsafetyconcerns,basedoncellsourceorhistoryAdequatecharacterizationoftheproductIdentity,purity,potencyAdditionalcharacterizationSystemforproducttrackingandlabelingcriticalforpatientspecificproductsStabilityofproductandorcelllinenumberofpassages/。

9、doublingsovertimemaintaindesireddifferentiationpropertieskaryotypicalterationsProductcomparabilityformanufacturingchangesExamplesofPreclinicalIssuesScientificbasisforconductingclinicaltrialDatatorecommendinitialsafedose&doseescalationschemeinhumansProofofConceptStudiesinrelevantanimalmodelsToxicologyStudiesinrelevantanimalspeciesIdentify,characterize,quantifythepotentiallocalandsystemictoxicities13ExamplesofClinicalIssuesCollectionprocedureStandardmedicalpractice?Specialinstrumentorkit。

10、?OptimaldoseandadministrationStartingdoselevel/doseescalationschemeRouteofadministrationDosescheduleDefineappropriatepatientpopulationIfimmunosuppressionwillbeused:Isthedose-schedulejustified?Long-termvsshorttermSingledrugvsacombinationregimenSafetyMonitoringplansSafetyReportingrequirementsPediatricissues14AdministrationofStemCellProductsDeliveryofstemcellstocertainanatomiclocationsmayrequirenovelproceduresand/ornoveldeliverydevicesThisneedstobeconsideredearlyCellsdeliveredbycertai。