FDA Regulation of Cell Therapy Celia M.Witten, Ph.D., M.D. Director, Office of Cellular, Tissue, and Gene Therapies Third Annual HD Clinical Research Symposium November 21, 2009 Baltimore, Maryland

Outline OCTGT Early Clinical Development FDA Outreach/Policy Development FDA Critical Path Research

Organization Office of Cellular, Tissue, and Gene Therapies CBER (Center for Biologics Evaluation and Research): vaccines, blood and blood products, human tissue/tissue products for transplantation, cells, gene therapy Office of Cellular, Tissue, and Gene Therapies Office of Vaccines Research and Review Office of Blood Research and Review CDER (Center for Drug Evaluation and Research): drugs, some biological products CDRH (Center for Devices and Radiological Health): devices for treatment, implants, diagnostic devices CVM CFSAN NCTR

Office of Cellular, Tissue, and Gene Therapies Celia M.Witten, Ph.D, M.D. Stephanie Simek, Ph.D., Office Deputy Director Richard McFarland, Ph.D, M.D. Associate Director for Policy Suzanne Epstein, Ph.D., Associate Director for Research Patrick Riggins, Ph.D., Director RPM Division of Cellular and Gene Therapies Raj Puri, Ph.D., M.D., Director Division of Human Tissues Ellen Lazarus, M.D., Director Division of Clinical Evaluation and Pharmacology/Toxicology Vacant

Organization Cont’d Office of Cellular, Tissue, and Gene Therapies, Celia M.Witten, Ph.D, M.D. Stephanie Simek, Ph.D., Office Deputy Director Richard McFarland, Ph.D, M.D. Associate Director for Policy Suzanne Epstein, Ph.D., Associate Director for Research Patrick Riggins, Ph.D., Director RPM Division of Cellular and Gene Therapies Raj Puri, Ph.D., M.D., Director Division of Human Tissues Ellen Lazarus, M.D., Director Division of Clinical Evaluation and Pharmacology/Toxicology Vacant

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)

Cells: Examples of Indications/Sources Pancreatic islets for diabetes Stem and skeletal muscle progenitor cells for ischemic cardiac Hematopoietic reconstitution in treatment of malignancies Stem cells for metabolic storage diseases Stem cells for CNS indications (Parkinson’s disease) Expanded autologous cartilage for joint repair

Early Clinical Development

[Some] Questions that Should be Asked What cell type(s) will be used? What is the source of the cell(s)? How many cells are needed? Are the cells implanted alone?...with a scaffold? Are the cells modified?...now a ‘gene therapy’? What is the proposed therapeutic action? What is/are the biologically relevant animal species for your product ? Are there potentially relevant animals models of disease/injury that can be used?

[Some] More Questions… What is the optimal method/route to deliver the product? What is the optimal timing for product administration relative to the onset of disease/ injury? What happens to the cells in vivo following delivery? Will repeat administration be needed? What is the risk/benefit ratio for the intended patient population?

Developing a Cell-Based product Source Controls Manufacturing Process controls

Product Safety and Efficacy Safety Issues: Sterility (bacterial, fungal, mycoplasma) Purity Identity Segregation and tracking Efficacy Issues: Potency Stability

Cell Therapy Product Characterization Morphologic evaluation Unique biochemical markers Gene and protein expression analysis Cellular impurities profile Biologic activity/Potency Identity: HLA, other unique marker

Preclinical Expectations for Early Phase Clinical Trials Proof-of-concept [POC] Potential mechanism of action [neuroprotective, neoangiogenesis, tolerance induction, etc…] Establish pharmacologically effective dose(s) Optimize ROA/dosing regimen Rationale for species/model selection for further testing Safety of conducting clinical trial – risk/benefit Dosing scheme Potential target tissue(s) of toxicity/activity Parameters to monitor clinically Eligible patient population Clinically relevant product and study design

Preclinical Study Design(s) Biologically relevant animal species/model Appropriate controls and multiple dose levels of product Dosing regimen – mimic clinical ‘Standard’ toxicology endpoints Mortality, clinical observations, body weights, appetite Hematology and coagulation Serum chemistry Pathology – target & nontarget tissues Other endpoints Cell fate [trafficking, survival, differentiation, etc…] Functional outcome, PK/PD Product-dependent [carcinogenicity/tumorigenicity, immunogenicity, etc…] Disease-dependent [cardiac, neurological, etc…] Sufficient study duration Endpoints measured at multiple intervals

Investigational Studies Study must be reasonably safe Risk vs.benefits First-time-in-humans--most attention of all Consider other trials, indications, similar products, riskds of procedure; Assess drug exposure; duration of therapy; number of patients exposed; stopping rules and expected/acceptable toxicity; potential benefits; type of patients treated; minimization of risks to subjects; plans for later phases; supporting animal data, clinical data, in vitro data, manufacturing issues (e.g., product sterility, lot release data, etc.)

Objectives of Phase 1 Studies for Traditional Drug Development Safety/tolerability Pharmacokinetics Dose selection (MTD)

Objectives of Early Phase Studies for Cell/Gene Therapies may also include information to inform: Product characterization Product delivery/dosing/safety Proof of concept/mechanism of action Patient selection (include biomarkers) Assessment parameters for toxicity Effectiveness parameters (early surrogates and modeling of relationships) Timing of assessments Duration of observation

Huntington’s Disease: Challenges for Cell Therapy Relatively small patient population Defining the therapeutic product/target Early evidence from animal models Delivery modalities Duration of observation/availability of early measures

Examples from Other Fields Cardiology Pancreatic Islets

Rosenzweig, A. Cardiac Cell Therapy-Mixed Results from Mixed Cells (Editorial). N Eng J Med 2006;355: 1274-1277.

Product Administration Site of Injection Method to Determine the Sites of Injection Method to Match the Actual and Planned Sites Method to Record the Location of Injection Product Concentration Volume Rate Administration # Injections (total and per wall) # Balloon Inflations, Duration Delivery Hand delivery Device

Pancreatic Islets Mechanism of action understood Can follow metabolic activity with clinical measures Technical issues identified

Outreach/Meetings/Policy Development

FDA and Meetings Product specific confidential inquiries during pre-IND (IDE), IND (IDE) process Scientific meetings Advisory Committee Discussions Workshops Liaison Meetings

Early FDA Interaction Informal: Pre-pre IND discussion (Generally CMC and Preclinical topics) PreIND/Type B: Formal meeting (Discuss product development activities prior to submission of an Investigational New Drug (IND) application Contact: Patrick S. Riggins, Ph.D., Branch Chief Regulatory Management Staff Office of Cellular Tissue and Gene Therapies Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville Maryland 20852 301-827-5366 (phone) 301-827-9796 (fax)

Recent Meetings/Workshops Sponsored or co-sponsored by FDA on scientific/regulatory topics: 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 Vaccines Considerations for Early Phase Clinical Trials Based on Lessons Learned from Phase III — October 27, 2009 NIH/JDRF/FDA Workshop: Next Generation Beta-Cell Transplantation — November 9, 2009

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

Safety of Cell Therapies Derived from Human Embryonic Stem Cells April 10, 2008 Safety Concerns Product Characterization Trial Design Contributions from Advisory Committee Meetings Reviewer Experience/Interactions with Stakeholders

Safety Concerns Stem cells and inappropriate differentiation Teratoma Ectopic tissue Currently concerns restrict direct use of hESC Persistence of Undifferentiated Cells Likely to be present in ESC-derived products Proliferation, migration Anatomic location and constraints Enclosed space (eg IC vs. IV administration)

Preclinical Studies Reflect the proposed clinical indication as closely as possible Detect site-dependent toxicities Provide evidence to support therapeutic rationale Considerations for choice of Animal Models Immunosuppressed/immunodeficient animals Site of administration Absolute number of cells, percentage in the final product Number of animals for statistically valid evaluation of potentially rare adverse events Duration of study Appropriate monitoring

Product Characterization Establish sensitive analytical methods to detect cells with undesired characteristics Minimize undifferentiated stem cells Identify characteristics capable of reliably predicting safety and anticipating clinical effectiveness in-process and lot release testing Ensure that products are as safe as possible current limitations in scientific knowledge

Clinical Trial Design Rationale Appropriate trial design Contrast established risk (teratoma) vs. intended clinical benefit (little experience) For first in man studies, justified by particularly strong preclinical proof-of concept Appropriate trial design Doses/dose escalation Patient monitoring Follow-up

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

2009 Guidance Documents Draft Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines 9/2009 Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products 9/2009 Draft Guidance for Industry: Somatic Cell Therapy for Cardiac Disease 3/2009 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 3/2009 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) 1/2009

Outreach/Collaborations Government organizations MATES NINDS NCI CDC NIST NHLBI Liaison meetings ISCT AATB Standards organizations ASTM AAMI ISO Research collaborations NCTR NIST NIH CDC Academic Institutions International activities WHO ICH EU

Science in Research and Review: Critical Path Initiative Bring scientific advances to medical product development process (simulation models, validated biomarkers, new clinical trial designs) Stimulate development of applicable research programs in critical path scientific areas, aim to develop techniques that address challenges encountered during product development Regulatory guidance/practice and standards to reflect best available science, integrate FDA involvement

Research Program Areas Virology Retroviruses, adeno, herpes, PERV Immunology Host-vector interactions, transplant rejection Cell biology Control of differentiation in animal models, stem cell biology Cancer biology Molecular biomarkers, animal models Biotechnology Microarray, flow cytometry Tissue safety

Contact Information Celia Witten, PH.D., M.D. Office Director, OCTGT CBER/FDA 1401 Rockville Pike (HFM 70) Rockville, MD 20852-1448 witten@cber.fda.gov 301-827-5102