Office of Biotechnology Products

1. Office of Biotechnology Products Site Visit Report Cellular, Tissue, and Gene Therapies Advisory Committee Meeting April 17, 2013 Steven Kozlowski, Director, OBP Edward Max, Assoc. Dir. Research, OBP

2. Office of Biotechnology Products (OBP) Steven Kozlowski, MD, Director Edward Max, MD,PhD, Assoc Dir Research Division of Monoclonal Antibodies (DMA) Division of Therapeutic Proteins (DTP) Amy Rosenberg, PhD, Director Gibbes Johnson PhD, Deputy Lab of Molecular and Developmental Immunology Lab of Immunology Lab of Chemistry Serge Beaucage, PhD, Chief Lab of Cell Biology Serge Beaucage, PhD Lab of Molecular Oncology Jacek Cieslak, PhD Gibbes Johnson PhD Kula Jha, PhD

3. Office of Biotechnology Products Steven Kozlowski, MD, Director Edward Max, MD, PhD, Assoc Dir for Research Division of Monoclonal Antibodies Kathleen Clouse, PhD, Director Division of Therapeutic Proteins Amy Rosenberg, MD, Director Monoclonal Antibodies Enzymes Fabrazyme Avonex Epo Botox Rituxan ReoPro Bexxar Enbrel mAb Fragments Fab, sFv, diabodies Cytokines mAb Conjugates Radionuclide, drug, toxin Growth Factors Fc-Fusion Proteins Toxins

4. OBP PRODUCTSHAVE MANY CLINICAL INDICATIONS

5. 10 Approvals/Year 8 Approvals/Yr 6 5 Year Running Avg. 4 Linear fit 2 0 Yervoy ipilimumab 1980 1985 1990 1995 2000 2005 2010 belatacept Nulojix OBP Product Approvals/Year

6. Challenges in OBP Product Review • Variety of Cell Substrates • microbiology (virus, prion), host cell molecules • Heterogeneity • glycosylation, oxidation, PEGylation • Higher order structure : structure/function • receptor interaction and signaling • Manufacturing Issues • scale-up, solubility, aggregation • Mechanism of Action: sometimes unclear • design of bioactivity/potency assays • Immunogenicity: • safety and efficacy Issues • Comparability: manufacturing changes • Counter Bioterrorism: Animal Rule, stockpiles

7. BIOSIMILARS Challenges in OBP Product Review • Variety of Cell Substrates • microbiology (virus, prion), host cell molecules • Heterogeneity • glycosylation, oxidation, PEGylation • Higher order structure : structure/function • receptor interaction and signaling • Manufacturing Issues • scale-up, solubility, aggregation • Mechanism of Action: sometimes unclear • design of bioactivity/potency assays • Immunogenicity: • safety and efficacy Issues • Comparability: manufacturing changes • Counter Bioterrorism: Animal Rule, stockpiles

8. RESEARCH REVIEW & REGULATION OBP Research • Protein structure/function • Biotechnology manufacturing science • Mechanism of action • Bioassays, Biomarkers, etc. • Immunogenicity • Adventitious Agents

9. Researcher/Reviewer Model Advantages for all reviewers • Scientific knowledge to evaluate: • Mechanisms of action • Potency assays • Adverse events • Drug-drug interactions • Hands-on technical experience • State-of-the-Art science • Product development • Analytical techniques • Manufacturing methods

10. Temporary Employee Permanent Employee “Converted” Principal Investigator = Senior Investigator Independent Investigator Tenure-track Principal Investigator Dependent Investigator Staff Scientist Staff Fellow Definitions of Research Personnel

12. Research Career Paths

13. Site-Visit Team: Evaluate individual PIs and Service Fellows in a Laboratory Unit • RESEARCH accomplishments since last review cycle • RESEARCH proposals for next four years • Novelty and originality • Mission Relevance • Independence of the candidate • Productivity relative to time for research and research support available • Administrative/Management comments welcome • Regulatory activities and regulatory work quality NOT assessed by Site Visit Team

14. Thank you! To the Site Visit reviewers for your time, expertise, and suggestions to improve OBP’s research programs Your input is critical to fulfilling our regulatory mission!