# Presentation: 012321

## RAID Training for Investigators: Product and Regulatory Overview 

**Eda T. Bloom, Ph.D.**
- Chief, Gene Transfer and Immunogenicity Branch
- Office of Cellular, Tissue, and Gene Therapies
- Division of Cellular and Gene Therapies
- Center for Biologics Evaluation and Research
- FDA

## Outline

- FDA organization
- Products regulated
- Critical path issues in the development of cell based products

## Organization 

- Office of the Commissioner
- 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 Therapy
- CDER (Center for Drug Evaluation and Research):  drugs, some biological products
- Office of Oncology Drug Products
- Office of Biotechnology 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
- Deborah Lavoie, J.D., Director RPM
**Division of Cellular and Gene Therapies**
- Raj Puri, Ph.D., M.D., Director
**Division of Human Tissues**
- Ruth Solomon, M.D., Director
**Division of Clinical Evaluation and Pharmacology/Toxicology**
- Ashok Batra, M.D.

## OCTGT Regulated Products

- Products with Cancer indications
- Cellular therapies
- Tumor vaccines
- Gene therapies
- Tissue and tissue based products
- Combination products
- Anti-idiotype antibodies
- Products generally not used for cancer
- Xenotransplantation products
- Devices used for cells/tissues

## Office of Oncology Drug Products

- Richard Pazdur, M.D., Director
- Karen Weiss, M.D., Deputy Director
- Glen Jones, Ph.D., Associate Director of Regulatory Affairs
**Division of Drug Oncology Products**
- Robert Justice, M.D., Director
**Division of Medical Imaging and Hematology Products**
- R. Dwaine Reeves, M.D., Acting Director
**Division of Biologic Oncology Products**
- Patricia Keegan, M.D., Director

## Office of Biotechnology Products

- Steven Kozlowski, M.D., Director
- Elizabeth Shores, Ph.D., Deputy Director

**Division of Monoclonal Antibodies**
- Kathleen Clouse, Ph.D., Director
**Division of Therapeutic Proteins**
- Amy Rosenberg, M.D., Director

## Therapeutic Biological Products Regulated by CDER

- Monoclonal antibodies for *in vivo* use.
- Proteins intended for therapeutic use
- Includes cytokines (e.g. interferons), growth factors, enzymes (e.g. thrombolytics), and other novel proteins, except for those that are specifically assigned to CBER (e.g., vaccines and blood products).
- Includes therapeutic proteins derived from plants, animals, or microorganisms, and recombinant versions of these products.
- Immunomodulators (non-vaccine and non-allergenic products intended to treat disease by inhibiting or modifying a pre-existing immune response).

## Examples of Collaboration Between CBER, CDER and CDRH for Oncology Products

- Inter-center reviews and discussions
- Monday morning meeting to discuss cross-FDA oncology related activities
- Monthly Executive Briefing on oncology activities
- Joint participation in FDA and NCI Inter-Agency oncology Task force (IOTF)
- Joint participation in policy development and critical path initiative to promote development of oncology products

## FDA Perspectives (CMC)

- Greater product knowledge (mechanism of action, characterization, etc) will aid in developing meaningful assays and/or novel approaches for product characterization and comparability
- Potency and identity testing should provide meaningful information about the product prior to its release
- Control of manufacturing process is key to producing consistent biological products
- A flexible approach and open communication is needed by both regulators and product developers

## Potential CMC Issues for Biological Products

- Some unique concerns for cell/gene therapy products
- Replication competent viruses
- Oncolytic** **viruses
- Cell/tissue source

- Some unique concerns for protein products
- Post-translational issues
- Isoforms
- Glycosylation
- Aggregates

- Examples of cross-cutting concerns
- Immunogenicity
- Animal components
- Formulation, delivery, stability
- Identity, purity, potency, comparability

## Key Points to Consider for Pharmacology/Toxicology Testing

- Preclinical testing paradigm is influenced by:
- Data from previous preclinical studies on all components and combination
- Data from previous clinical studies (pre- and post-marketing) on all components and combination
- Regulatory status of each component
- Provide safety and activity data for individual components and combination in appropriate animal models by intended clinical route of administration

## Potential PT Issues for Biological Products

- Some unique concerns for cell/gene therapy products
- Insertional mutagenesis
- Alteration of germline
- Long-term toxicity
- Migratory potential

- Some unique concerns for protein products
- Immune-mediated problems
- Immune complexes
- Obfuscation of toxicity
- Allergy
- Species specificity

- Examples of cross-cutting concerns
- Picking the relevant animal model
- Dosing, safety
- Biodistribution
- Toxicity, tumorigenicity
- Immunogenicity (rejection/elimination)

## 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

## OCTGT 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

## 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

## Developmental Stages

**Characterization**
- Gene expression profile, Antibodies, Enzymes,
*In vitro *differentiation

- Manufacturing Concerns

**Lot Release**
- Identity
- Potency
- Safety
- Viability

**Manufacturing**
- Cell Banks
- Cell Characterization
**Testing and Screening**
- Donors, Viruses, Genetic defects?

## Slide 18

## Contact Information

**Eda Bloom, Ph.D.**
- Branch Chief,
- Gene Transfer and Immunogenicity Branch
- DCGT/OCTGT/CBER/FDA
- 1401 Rockville Pike (HFM 725)
- Rockville, MD  20852-1448
- eda.bloom@fda.hhs.gov
- 301-827-0452