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11
FDA Regulation of Cellular, Tissue, and
Gene TherapiesCelia M.Witten, Ph.D., M.D.
Director, Office of Cellular, Tissue, and Gene Therapies, FDA
Phacilitate Cell and Gene Therapy Forum 2010
Washington, D.C.
22
Outline
Overview of Office and RegulationsUpdate on Recent Guidances and
MeetingsCurrent Activities/Future Opportunities
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FDA Organization Office of the Commissioner
Office of Combination Products CBER (Center for Biologics 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, devices
CDRH (Center for Devices and Radiological Health): devices for treatment, implants, diagnostic devices
CDER (Center for Drug Evaluation and Research): drugs, monoclonal antibodies, therapeutic proteins)
CVM CFSAN NCTR
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CBER Organization
Immediate Office of Director Office of Blood Research and Review Office of Cellular, Tissue and Gene Therapies Office of Vaccines Research and Review Office of Compliance and Biological Quality Office of Biostatistics and Epidemiology Office of Communication, Training and
Manufacturers Assistance Office of Management
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Office of Cellular, Tissue, and Gene TherapiesCelia M.Witten, Ph.D, M.D., Director
Stephanie Simek, Ph.D., Office Deputy DirectorRichard McFarland, Ph.D, M.D. Associate Director for Policy
Suzanne Epstein, Ph.D., Associate Director for ResearchPatrick Riggins, Ph.D., Director RPM
Division of Cellular and Gene TherapiesRaj Puri, Ph.D., M.D., Director
Division of Human TissuesEllen Lazarus, M.D., Director
Division of Clinical Evaluation and Pharmacology/ToxicologyVacant
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OCTGT Products
Cellular therapies Tumor vaccines and immunotherapy Gene therapies Tissue and tissue based products Xenotransplantation products Combination products Devices used for cells/tissues Donor screening tests (for use with cadaveric
blood samples)
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Premarket Review Pathways
Biologics Regulations IND – Investigational New Drug BLA- Biologics License Application
Device Regulations IDE- Investigational Device Exemption PMA- Premarketing Application HDE- Humanitarian Device Exemption
Combination products Pathway determined: Primary mode of action- RFD process
(Office of Combination Products) Previous intercenter agreements and precedents
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Update on Recent Guidances and Meetings
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Workshops 2008-2009
FDA/NIAID Workshop: Animal Models for the Treatment of Acute Radiation Syndrome — September 27, 2008
FDA/NIH/CIBMTR/ASBMT Workshop: Clinical Trials Endpoints for Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation — March 13, 2009
FDA/NCI Workshop: Therapeutic Cancer VaccinesConsiderations for Early Phase Clinical Trials Based on Lessons Learned from Phase III — October 27, 2009
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Workshops 2008-2009, cont’d
NIH/JDRF/FDA Workshop: Next Generation Beta-Cell Transplantation— November 9, 2009
Public Workshop: Emerging Arborviruses: Evaluating the Threat to Transfusion and Transplantation Safety— December 14-15, 2009
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Recent Advisory Committee Meetings
April 10-11 2008: Cellular Therapies Derived from Human Embryonic Stem Cells Scientific
Considerations for Pre-Clinical Safety Testing Response to September 2005 Review of OCTGT Research Program FDA Somatic Cell Therapy Letter Update: OCTGT Guidance Development Program
May 14-15 2009: The potential for Chlamydia trachomatis and Neisseria gonorrhea
transmission by certain human cells, tissues, and cellular and tissue-based products (HCT/Ps)
Animal models for porcine xenotransplantation products intended to treat Type 1 diabetes or acute liver failure
Clinical issues related to the FDA draft guidance “Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage.”
October 9 2009: Isolagen Therapy for moderate to severe nasolabial fold wrinkles
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Safety of Cell Therapies Derived from Human Embryonic Stem Cells
CTGT Advisory Committee April 10, 2008
Safety ConcernsProduct CharacterizationTrial Design
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CTGTAC April 10, 2008 Major Considerations
Stronger than usual proof of concept evidence may be required
The dose of cells administered to humans should be below the minimum number of cells observed to form tumors in animal models
First in man clinical applications should be picked carefully due to inherent risks
Long term follow up recommended due to perceived risk
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Guidances 2009
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Cord Blood Guidance – Hot Off the Press
Final Guidance for Industry: Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications (HPC-C Licensure Guidance) - 10/20/09http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM187144.pdf
Draft Guidance for Industry and FDA Staff: IND Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications (Draft HPC-C IND Guidance) – 10/20/09http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM187146.pdf
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Phase-in period for IND and BLA requirements, and comment period
With publication of these HPC-C guidance documents, FDA is also announcing that the phase-in implementation period for IND and BLA requirements for these products will end in 2 years after date of publication (October 20, 2011)
Sponsors are encouraged to send in IND and BLA applications as soon as possible to allow sufficient time for review, comment, and resubmission as needed to complete all actions by the end of this 2 yr period
Submit your comments on the draft IND guidance within 90 days of publication, to ensure that we can consider your comments before beginning work on the final version
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What is the purpose of the HPC-C Licensure Guidance, and why is there companion Draft
HPC-C IND Guidance? The HPC-C Licensure Guidance provides
recommendations to manufacturers applying for licensure of minimally manipulated, unrelated allogeneic placental/umbilical cord blood, for specified indications
Stakeholder input received on the December 2006 draft guidance were considered; this HPC-C Licensure Guidance finalizes the draft guidance
Input included comments on importance of access to and availability of HPC-C products that do not meet standards for licensure and therefore cannot be licensed; agency recognizes importance of these products and published draft guidance addressing IND submissions for these products
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Tissue Guidance Documents Draft Guidance for Industry: Current Good
Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) January 2009
Draft Guidance for Industry: Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components for Transfusion and Human Cells, Tissues, and Cellular and Tissue-Based Products March 2009
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Product-Specific Guidances Draft Guidance for Industry: Somatic Cell Therapy
for Cardiac Disease — March 2009
Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products — September 2009
Draft Guidance for Industry: Clinical
Considerations for Therapeutic Cancer Vaccines— September 2009
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Current Activities/Future Opportunities
Tissue SafetyStem Cells Gene Therapy International EngagementsInternational Engagements
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Goals for Tissue Safety
Enhance processes for adverse reaction report investigation and evaluation
Increase collaboration with professional organizations and State public health authorities
Improve outreach to consumers and health care providersEncourage reporting, educate on tissue safety
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Relevant Communicable Disease Agents and Diseases
Workgroup
Define gaps in current knowledge about transmission of infectious diseases by tissue transplantation
Develop approaches for leveraging Federal agency and industry research resources for filling gaps
Develop policies for screening and testing HCT/P donors for emerging infectious diseases
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CBER Pilot Biovigilance Projects
To assess the value of large medical encounter databases for tissue utilization and safety:Evaluation of system characteristics of eight
potential databasesExamine infections after certain tissue transplants
and identify health information system gaps to enable automated data systems to efficiently monitor infections in recipients
Collaboration with Harvard PilgrimCollaboration with Centers for Medicare and Medicaid
Services
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Trends in Cell Therapy
Sources of adult stem cellsPlacental and amniotic membrane, adipose
hESC cells/iPS cellsCell Products designed to induce immune
toleranceXenotransplantationCells encapsulated in a biomaterialTissue engineering
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Trends in Gene Therapy
Chimeric Antigen Receptors: Autologous T-cells transduced with retroviral or lentiviral vectors expressing Chimeric Antigen Receptor (CAR) or antigen specific T cell receptor (TCR)
Oncolytic Viruses (OV): OV are intended to replicate selectively in tumor tissue, destroying the tumor without causing excessive damage to normal tissues.
Bacterial Products/vectors: Live bacterial therapeutics primarily used in cancer indications
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International Engagements
As an emerging product area, cell and gene therapies are prime area for prospective harmonization and convergence of regulatory approachesInternational Conference on Harmonisation
(ICH)FDA-EMEA ATMP “Cluster”Regulatory exchanges
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ICH Gene Therapy Discussion Group (GTDG)
Monitor emerging scientific issues Proactively set out principles that may have a
beneficial impact on harmonization Ensure that the outcomes of the GTDG are well
understood and widely disseminated Public ICH web page
http://www.ich.org/
Public communications papers Public press statements from the ICH SC Public ICH workshops
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ICH Workshops
Workshop on Viral / Vector Shedding, Rotterdam October 30, 2007
ICH Workshop on Oncolytic Viruses, Chicago, November 7, 2005
Presentations at ICH6 on Gene Therapy, Osaka, November 15, 2003
First Workshop on Gene Therapy, Washington, September 9, 2002
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ICH Considerations
Gene therapy is a rapidly evolving fieldDifficult to write ICH guidelines on gene
therapy topics due to flux of the fieldConsideration papers are a way to
proactively set out principles that may have a beneficial impact on harmonization
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Published ICH Considerations
General Principles to Address the Risk of Inadvertent Germline Integration of Gene Therapy Vectors, 10/2006 Oncolytic Viruses, 11/2008 Viral/Vector Shedding, 6/2009
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FDA-EMEA ATMP “Cluster” Formal cooperation and confidentiality
arrangement between FDA and European Medicines Agency (EMEA) for pharmaceuticals initiated 9/03; extended 9/05 to 9/2010
Over time, “clusters” of specific areas of interest were developed for more targeted information exchanges
With EMEA product scope enlargement to include tissue engineering with cell and gene therapies (“advanced therapeutic medicinal products” – ATMPs), ATMP “cluster” initiated 2008
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FDA-EMEA ATMP “Cluster”
Regular teleconferences to share thinking on regulatory approaches, both general and specific issues
Information sharing on draft documentsEngage reciprocally in workshops and
advisory committees, working parties
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Regulatory Exchanges
OCTGT has hosted on limited basis regulatory colleagues, Fall of 2009:EMEA ATMP expert Japan Pharmaceutical and Medical Device
Agency (PMDA) cell therapy expertOCTGT experts routinely respond to
foreign regulatory inquiries, calls for assistance, both through written communication, face-to-face exchanges, presentations at international fora
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Contact InformationCelia Witten, Ph.D., M.D.Office Director, OCTGTCBER/FDA 1401 Rockville Pike (HFM-700)Rockville, MD [email protected]