Working with FDA: Biological Products and Clinical Development

Working with FDA: Biological Products and Clinical Development
by
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

OCTGT Regulated Products

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

Therapeutic Biological Products Regulated by CDER

* Monoclonal antibodies for in vivo use.
* Proteins intended for therapeutic use
o 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).
o 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).

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
o 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
o Replication competent viruses
o Oncolytic viruses
o Cell/tissue source

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

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

Key Points to Consider for Pharmacology/Toxicology Testing

* Preclinical testing paradigm is influenced by:
o Data from previous preclinical studies on all components and combination
o Data from previous clinical studies (pre- and post-marketing) on all components and combination
o 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
o Insertional mutagenesis
o Alteration of germline
o Long-term toxicity
o Migratory potential

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

* Examples of cross-cutting concerns
o Picking the relevant animal model
o Dosing, safety
o Biodistribution
o Toxicity, tumorigenicity
o 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
o Retroviruses, adeno, herpes, PERV
* Immunology
o Host-vector interactions, transplant rejection
* Cell biology
o Control of differentiation in animal models, stem cell biology
* Cancer biology
o Molecular biomarkers, animal models
* Biotechnology
o 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
Exogenous Influences
Cell-cell interaction
Growth factors
Lot Release
Identity
Potency
Safety
Viability
Manufacturing
Cell Banks
Cell Characterization
Testing and Screening
Donors, Viruses, Genetic defects?
Tumorigenesis
mutation
Apoptosis
Self renewal
Commitment
Differentiation

are covered in this presentation.