1. Cellular Products for Cardiac Diseases Dwaine Rieves, MD Center for Biologics Evaluation and Research FDA Perspective on:

2. Cellular Products Overview Topics Purpose Regulatory background Questions

3. Cellular Products Purpose A scientific discussion of – Manufacturing – Preclinical testing – Pilot clinical studies

4. Cellular Products Purpose Cellular Products – Blood or bone marrow-derived cells – Skeletal muscle-derived cells – Predominantly autologous

5. Cellular Products Purpose Early Stage of Evolving Field – Little precedent – Limited data – Hypothetical considerations

6. Cellular Products Purpose A Scientific Focus – All insights tentative – No definitive assessment of data – No specific product assessment

7. Cellular Products Regulatory A Scientific Focus ResearchRegulatory Cellular Products

8. Cellular Products Regulatory Regulatory Mission Promote & Protect Public Health by: – Pre-marketing product development – Post-marketing product monitoring

9. Cellular Products Regulatory Cellular Products for Cardiac Diseases Biologic/drug/device regulations IND Early clinical development: – Safety and bioactivity

10. Cellular Products Regulatory Safety Concerns Manufacturing Sufficient preclinical testing Sufficient clinical study design

11. Cellular Products Regulatory Manufacturing--Product Safety Cell source & reagents Procedures – aseptic collection, processing, cell selection, storage, tracking & labeling Testing – sterility, endotoxin, viability, enumeration

12. Cellular Products Regulatory Manufacturing—Product Characterization Identification of cell populations Purity (non-cellular) Potency

13. Cellular Products Regulatory Pre-clinical Testing Evolving paradigm Generally c/w biological products Catheters – novel use of marketed – non-marketed

14. Cellular Products Regulatory Pre-clinical Testing Relevant species Disease model Administration (catheter)

15. Cellular Products Regulatory Clinical Study Design Adverse event detection – evaluation plan duration, frequency, extent – safety monitoring sequential enrollment, stopping rules

16. Cellular Products Regulatory Clinical Study Design Adverse event analysis— --Txt-related vs natural history – randomization – controls (placebo vs other) – masking – other?

17. Cellular Products Summary Topics Purpose Regulatory background Questions

18. Cellular Products Questions Questions Manufacturing – extent of testing & characterization Pre-clinical and catheter – extent and nature of testing Clinical study – adverse event detection & analysis

19. Cellular Products Regulatory References (www.FDA.gov/cber) Draft Guidance for CMC Reviewers: Human Somatic Cell Therapy Investigational New Drug Applications ICH Guideline: Preclinical Safety Evaluation of Biotechnology-derived pharmaceuticals (S6) ICH Guideline: Good Clinical Practice (E6)