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

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 This is an abbreviated organizational chart to illustrate the general structure of the Division and to show the relative positions of those being reviewed today within that structure. Dr. Bonvini is serving as the Acting Deputy Director of the Division and Dr. Patrick Swann is in charge of the full-time reviewers in the Regulatory Science & Policy Branch. The 3 research labs are here headed by Dr. Clouse, Dr. Bonvini, and Dr. Kozlowski. Dr. Markovic is a Staff Fellow in Dr. Clouse’s lab and Dr. Frucht and Dr. Feldman are Staff Scientists in the LCB and LIB, respectively. Serge Beaucage, PhD Lab of Molecular Oncology Jacek Cieslak, PhD Gibbes Johnson PhD Kula Jha, PhD 2

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

OBP PRODUCTS HAVE MANY CLINICAL INDICATIONS

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

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

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 BIOSIMILARS

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

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 Extra edge of knowledge that can be disseminated to the whole office

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

Research Career Paths

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

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!