CTGTAC Meeting, February 10, 2006

1. CTGTAC Meeting, February 10, 2006 OCTGT Research Suzanne Epstein, Ph.D. Associate Director for Research, OCTGT

2. OCTGT Site visit, September 29, 2005 • Office-wide site visit convened to review • OCTGT research • CTGTAC members and invited experts • Critical Path needs, priorities • Management practices • Examples of accomplishments

3. Why OCTGT Research? • Cellular, tissue and gene therapy products use new regulatory paradigms, evolving rather than established. • Some scientific issues important for progress are not being adequately addressed by others, so CBER participation is needed. • Need to address entire product classes, rather than each sponsor having to revisit for each individual product. CBER research helps fill gaps of these kinds.

4. Research Management Communication Tools • Within OCTGT: Work-in-progress presentations, abstracts, annual reports • Beyond OCTGT: • FDA: Briefings of Center and Agency leadership, CBER Grand Rounds • Information exchanges with stakeholders: Publications, talks in scientific conferences, workshops, meetings of advisory committees like this one Tracking tools

5. OCTGT Research Strategies Anticipate needs, as well as addressing current problems: • Stay ahead of the curve as products and technologies change • Perform studies relevant to entire product classes • Make results public and thus accessible to all sponsors, to advance the entire field • Some OCTGT research uses current product systems, some of it addresses underlying issues we must understand to move products forward.

6. How OCTGT Identifies Research Priorities • Receive input about new products on the horizon from pre-submission inquiries, conferences, literature • Identify anticipated areas of major product activity, related Critical Path issues • Monitor for gaps and weaknesses in expertise or redundancies, and address them • Example: A few years ago, we identified the need for adenovirus expertise and recruited an adenovirus research expert to fill the gap.

7. OCTGT Future Research Priorities Identified Expertise identified as needed for future product review: • Tissue engineering: partnering/leveraging, adapting by existing staff • Cancer biology models for surrogate endpoints: Build on existing programs. New capability, Xenogen In Vivo Imaging System (IVIS 50) • Bioinformatics: enhance/leverage FDA capabilities, collaborate outside FDA • Proteomics: recruitment successful, new investigator coming in April.

8. LTR gag pol env LTR Critical Path Challenges in Gene Therapy Major issues: vector safety and characteristics, patient immune responses. • Strategies to address them - Projects: • Adenoviral vector safety and biodistribution. • Retroviral vector safety and detection. • Herpesvirus vector safety and characterization. • Host immune responses induced by viral and plasmid vectors.

9. Adenovirus Vector Gene Therapy Public health issue: • Unexpected toxicity in clinical trial, lack of an animal model. Outcomes: • Insight into how adenovirus vectors cause toxicity • Animal model for gene therapy in the context of pre-existing liver disease – influence on clinical trial design • Model can be used for safety testing of new vectors

10. National Toxicology Program Recognized need for pharm-tox models for cell and gene therapy. Discussed in morning session. Leveraging: • NTP is administered by NIEHS, federally funded. • Preclinical model for assessing risk of retroviral vector-mediated insertional tumorigenesis, will permit comparing modifications, new vectors. • Quantitative method assessment of plasmid vector biodistribution, persistence, expression. Will permit bridging to new vectors, formulations.

11. Critical Path Challenges in Cell Therapy Major issues: controlling growth and differentiation of cells, product characterization, immune rejection • Strategies to address them: • Key signaling pathways determining cell fate, cell death, and development of anatomic structures • Immune cell activation and immune responses to cellular therapy products Outcomes: • Identification of markers for product characterization and process control

12. Critical Path Challenges in Tissue Engineering Major issues: Interactions yielding proper tissue structure and function. Strategies to address them - Projects: • Tissue anatomy and factors controlling joint development • Molecular signals determining liver development Outcomes: • Identification of novel factors contributing to successful joint formation

13. Critical Path Challenges in Xenotransplantation Major issues: Organ supply Transmission of infectious agents between species, immune rejection. • Strategies to address them - Projects: • Porcine endogenous retrovirus (PERV) detection and species tropism • Transplantation immunology - approaches to avoiding rejection Outcomes: • Assay for PERV, approach to avoiding xeno rejection

14. Critical Path Challenges in Tumor Vaccines MAJOR ISSUES: Product characterization, including tests for identity, purity, potency • Strategies to address them - Projects: • Animal models of targeted intervention. • Markers of tumor growth for monitoring. • Immune response assays (used for potency tests) Outcomes: Marker of identity for tumor vaccines, serum biomarker for monitoring

15. New Technologies Uses of gene expression microarray and flow cytometry High throughput screening provides detailed information. Can be used for characterization of: • Cellular products • Cell substrates • Patient samples

16. Fluorescence Technology for the 21st Century • Flow Cytometry and Microarrays Need Standards • Federal Standardization Initiative: NIST – FDA – CDC • Standard Fluorescein Solution Developed • Standard Microbeads Developed NIST Microbead Standard

17. LTR gag pol env LTR Reference Materials: Needed to Assure Sensitivity and Comparability of Test Methods Retroviral reference material Adenovirus reference material • Available from ATCC. • Used to show RCR assay sensitivity, reduce testing without compromising product safety. External RNA spike-in controls for microarray and RT-PCR ERCC • Available from ATCC. • Allows precise titers: • Viral particle • Infectious titer Outcome: Sensitive, consistent testing facilitates progress, provides savings

18. Summary: Research Prioritizationas an Ongoing Process • New product classes present novel scientific and regulatory challenges and opportunities • We identify scientific questions of regulatory importance and address them. • Solutions to key problems facilitate product development, inform regulatory decisions and policy. We welcome questions and comments from the Committee.