FDA細胞治療臨床試驗監(jiān)督

1、1FDA Oversight of Cell Therapy Clinical TrialsCelia Witten, Ph.D., M.D.Office Director, Office of Cellular, Tissue, and Gene TherapiesCBER/FDAISSCR/CIRM/ISCT WorkshopJune 15, 2010San Francisco, California2FDA Organization oOffice of the CommissionernOffice of Combination ProductsoCBER (Center for Bi

2、ologics Evaluation and Research): vaccines, blood and blood products, human tissue/tissue products for transplantation, cell therapy, gene therapy, donor screening tests for blood and tissue safety, devicesoCDRH (Center for Devices and Radiological Health): devices for treatment, implants, diagnosti

3、c devicesoCDER (Center for Drug Evaluation and Research): drugs, monoclonal antibodies, therapeutic proteins)oCVMoCFSANoNCTR3OCTGT ProductsoCellular therapies oTumor vaccines and immunotherapyoGene therapiesoTissue and tissue based productsoXenotransplantation productsoCombination products oDevices

4、used for cells/tissuesoDonor screening tests (for use with cadaveric blood samples)4The “Tissue Rules”(21 CFR 1271, Effective May 25, 2005)Tissue RuleIssues AddressedEstablishment Registration and ListingApplicability: types and uses of products that will be regulated by these rules; requirements fo

5、r registering and listing productsDonor EligibilityRequirements for donor screening and testing for “relevant communicable disease agents and diseases”Current Good Tissue Practice (CGTP)Manufacturing to ensure that HCT/Ps do not contain communicable disease agents; reporting; inspections521 CFR Part

6、 1271oThese three rules form the platform for regulation of all human cells, tissues, and cellular and tissue-based products (HCT/Ps)oFor certain HCT/Ps (“361 HCT/Ps”), these regulations comprise the sole regulatory requirementsoFor HCT/Ps regulated as drugs, devices, and/or biological products, the

7、 new tissue regulations supplement other requirements (GMP, QSR) 6Stem Cell-Based ProductsoFit regulatory definitions of the following:nHuman cells, tissues, or cellular and tissue based products (HCT/P) (21 CFR 1271.3(d)nBiologics (PHS Act)nDrugs (FDC Act)nCell therapynGene therapy- when genetic ma

8、terial is transferred to cells ex vivo7Evolution of Stem Cell FieldoCell therapy and gene therapy products and therefore stem cell products- do not lend themselves to a “one size fits all” concept of product development and regulationoRegulations set framework of criteria that must be fulfilled: saf

9、ety, identity, purity, potency, and clinical efficacyoFlexibility in how to fulfill the criteria8 Examples of Safety Concerns for Stem CellsoDefining the intended mode of actionoCharacterization of the product, including potencyoCell differentiation to undesired cell typesoCell migration/trafficking

10、 to nontarget site(s)oPotential uncontrolled cell proliferation or tumorigenicityoImmunogenicityoGraft-vs-host effectsoInteractions with devices, other tissues or drugs in vivooFor gene-modified cellsnPotential uncontrolled biological activity of the transgenenAlteration of expression of the nontran

11、sgenesnInsertional mutagenesis9Review DecisionCMCClinicalPharm/ToxProject ManagerStatisticsEpidemiologyComplianceREVIEW OFFICECBERFDAOUTSIDE CONSULTANTProduct QualityScientific ExpertProduct expertClinical specialistMethodology expertPatient AdvocateScientific Expert (SGE)Policy ExpertOrphan product

12、sEthicistAnimal ruleFDA Review TeamBasic Review TeamExtended Review TeamPotential Consults or CollaboratorsAdvisory CommitteePotential Consults10Examples of CMC IssuesoControls to prevent transmission of infection from the donor or introduction of infectious agents during cell processing Donor Testi

13、ng and screening for relevant communicable diseasesnAutologous donors recommended but not requirednAllogeneic donors must comply with 21 CFR 1271 Subpart CpHCT/P donor screening is medical history interview, physical assessment and medical record reviewpHCT/P donors are tested using FDA approved or

14、cleared donor screening testsoCell banks- adventitious agent testing & characterizationoIf mouse feeder layers used- test for the presence of murine viruses (and is a xenotransplantation product)oComponents, reagents, materials qualification11Examples of CMC Issues- 2oAccount for and control don

15、or to donor variabilityoIntrinsic safety concerns, based on cell source or historyoAdequate characterization of the productnIdentity, purity, potencynAdditional characterizationoSystem for product tracking and labelingncritical for patient specific productsoStability of product and or cell linennumb

16、er of passages/ doublings over timenmaintain desired differentiation properties nkaryotypic alterationsoProduct comparability for manufacturing changesExamples of Preclinical IssuesoScientific basis for conducting clinical trialoData to recommend initial safe dose & dose escalation scheme in hum

17、ansoProof of Concept Studies in relevant animal models oToxicology Studies in relevant animal speciesnIdentify, characterize, quantify the potential local and systemic toxicities13Examples of Clinical IssuesoCollection procedurenStandard medical practice? Special instrument or kit?oOptimal dose and

18、administrationnStarting dose level/dose escalation schemenRoute of administrationnDose schedule oDefine appropriate patient populationoIf immunosuppression will be used:nIs the dose-schedule justified? nLong-term vs short termnSingle drug vs a combination regimenoSafety Monitoring plansoSafety Repor

19、ting requirementsoPediatric issues14Administration of Stem Cell Products oDelivery of stem cells to certain anatomic locations may require novel procedures and/or novel delivery devices nThis needs to be considered earlyoCells delivered by certain devices (i.e. catheter) will be a Combination Produc

20、tnCells under Biologics/Drug regulations and Device under Device regulations (see 21 CFR 3.2(e)nEarly consultation with FDA, and Device manufacturer, about regulatory aspectsoCompatibility of cells with the deviceoPreclinical testing of cells and device oDelivery procedure used during clinical trial

21、 and beyondnTraining of clinical investigators15oStandardized reporting/publication of results oTechnology to enable validated assays for enhanced product characterization and testingoBiologically relevant animal species/models that will provide useful information about safety of the productoTechnol

22、ogy to assess biodistribution and fate of the product in patients oData regarding optimal timing and methods for stem cell delivery Outstanding Needs for the Field16Scientific Advice from the FDA PostMarketingBLAReview CLINICAL TRIALS Ph I Ph II Ph IIIINDReview PreclinicalDevelopmentPre-IND PhaseIND

23、 Review PhaseMarketing Application PhasePost Marketing PhasePre Pre IND Meeting(Informal)IND review - 30 DaysEnd of Ph 3 MeetingPre-BLA MeetingSafety MeetingsEnd of Ph 2 MeetingPost BLA MeetingPre IND Meeting17Scientific Advice from the FDA oProvide advice in response to specific queriesoIn person o

24、r by teleconferenceoWritten minutes for formal meetingsoNo fee18CBER Outreach to StakeholdersoAdvisory CommitteesoRegulationsoGuidance DocumentsoStandards ActivitiesoWorkshopsoLiaison MeetingsoInternational Harmonization19Public Discussions of the IssuesoNov 9 2009 NIH/JDRF/FDA Workshop: Next Genera

25、tion Beta-Cell TransplantationoOct 27 2009 FDA/NCI Workshop: Therapeutic Cancer Vaccines Considerations for Early Phase Clinical Trials Based on Lessons Learned from Phase IIIoMay 14 2009 CTGTAC: Animal Models for Porcine Xenotransplantation Products Intended to Treat Type 1 Diabetes or Acute Liver

26、FailureoMay 15 2009 CTGTAC: Products Intended to Repair or Replace Knee CartilageoMar 13 2009 FDA/NIH/CIBMTR/ASBMT Workshop: Clinical Trials Endpoints for Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell TransplantationoApril 10 2008 CTGTAC: Safety of Cell Therapies Derived f

27、rom Human Embryonic Stem CellsoTopics prior to 2008: nCellular Replacement Therapies for Neurological DisordersnPlacental/Umbilical Cord Blood For Hematopoietic ReconstitutionnAllogeneic Pancreatic Islets for Type 1 DiabetesnCellular Products for the Treatment of Cardiac DiseasenCellular Products fo

28、r Joint Surface Repair nIn Vitro Analyses of Cell/Scaffold ProductsnInsertional Mutagenesis by Retroviral Vectors20Use of Consensus Standards by Federal AgenciesoCodified in the National Technology Transfer and Advancement Act of 1995nImplementation defined by FDA PolicyoStandards may be referred to

29、 in FDA Guidance and Regulation21Potential Benefits of Standards UseoFacilitate the development and maintenance of guidance oAddress issues not covered by FDA GuidanceoFacilitate product designoImprove time to marketoLeverage industry effortsoMay lead to international harmonization22Standards Exampl

30、es:oASTM F2386 Standard Guide for the Preservation of Tissue Engineered Products oASTM F2383 Standard Guide for Assessment of Adventitious Agents in Tissue Engineered Products oASTM F2315 Standard Guide for Immobilization or Encapsulation of Living Cells or Tissue in Alginate Gels oATCC ASN-0002 Aut

31、hentication of Human Cell Lines: Standardization of STR Profiling* oAMII/ISO 13022 Tissue Safety* oISO 11238 Identification of Medicinal Products Structures and Controlled Vocabularies for Substances and Ingredients* 23International EngagementsoAs an emerging product area, cell and gene therapies ar

32、e prime area for prospective harmonization and convergence of regulatory approachesnInternational Conference on Harmonisation (ICH)nFDA-EMA ATMP “Cluster”nRegulatory exchanges24ICH Gene Therapy Discussion Group (GTDG)oMonitor emerging scientific issuesoProactively set out principles that may have a

33、beneficial impact on harmonizationoEnsure that the outcomes of the GTDG are well understood and widely disseminatednPublic ICH web page p/nPublic communications papersnPublic press statements from the ICH SC nPublic ICH workshops 25Published ICH Considerationso General Principles to Address the Risk of Inadvertent Germline Integration of Gene Therapy Vectors, 10/2006o Oncolytic Viruses, 11/2008o Viral/Vector Shedding, 6/200926FDA-EMA ATMP “Cluster”oFormal cooperation and confidentiality arrangement between FDA and European Medicines Agency (EMA) for pharmaceuticals initi