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

33

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

44

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

55

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

66

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)

77

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

88

Update on Recent Guidances and Meetings

99

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

1010

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

1111

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

1212

Safety of Cell Therapies Derived from Human Embryonic Stem Cells

CTGT Advisory Committee April 10, 2008

Safety ConcernsProduct CharacterizationTrial Design

1313

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

1414

Guidances 2009

1515

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

1616

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

1717

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

1818

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

1919

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

2020

Current Activities/Future Opportunities

Tissue SafetyStem Cells Gene Therapy International EngagementsInternational Engagements

2121

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

2222

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

2323

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

2424

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

2525

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

2626

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

2727

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

2828

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

2929

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

3030

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

3131

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

3232

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

3333

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

3434

Contact InformationCelia Witten, Ph.D., M.D.Office Director, OCTGTCBER/FDA 1401 Rockville Pike (HFM-700)Rockville, MD 20852-1448301-827-5102Celia.witten@fda.hhs.gov