1. 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

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

3. 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

4. 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

5. 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

6. 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)

7. 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

8. Early Clinical Development

9. [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?

10. [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?

11. Developing a Cell-Based product
Source Controls
Manufacturing Process controls

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

13. 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

14. 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

15. 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

16. 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.)

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

18. 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

19. 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

20. Examples from Other Fields
Cardiology
Pancreatic Islets

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

22. 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

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

24. Outreach/Meetings/Policy Development

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

26. 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
(phone) (fax)

27. 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

28. Recent Advisory Committee Meetings
April :
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 :
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 : Isolagen Therapy for moderate to severe nasolabial fold wrinkles

29. 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

30. 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)

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. Contact Information
Celia Witten, PH.D., M.D.
Office Director, OCTGT
CBER/FDA
1401 Rockville Pike (HFM 70)
Rockville, MD