Overview: Division of Cellular and Gene Therapies, Office of Cellular, Tissue and Gene Therapies Raj K. Puri, M.D., Ph.D. Director, DCGT Office of Cellular, Tissue and Gene Therapies FDA, CBER Gene Transfer and Immunogenicity Branch Site Visit Report to CTGTAC November 29, 2012 Good morning! Before I begin, I like to thank the subcommittee and CTGT AC for their time and efforts in the evaluation of research program in DCGT

Division of Cellular and Gene Therapies (DCGT) Raj Puri, M.D., Ph.D., Division Director Kimberly Benton, Ph.D., Deputy Director Gene Therapies Branch Daniel Takefman, Ph.D., Chief Gene Transfer and Immunogenicity Branch Andrew Byrnes, Ph.D., Chief Cell Therapies Branch Keith Wonnacott, Ph.D., Chief Tumor Vaccines and Biotechnology Branch Raj Puri, M.D., Ph.D. Chief DCGT is organized in five branches. Cell and gene therapy branches are comprised of regulatory scientists who not only review reg files but also participate and develop policy and guidance documents, do outreach activities and collaborations. Staff in other three branches, in addition to reg review and policy development, perform FDA mission relevant research to support development of OCTGT products. Cellular and Tissue Therapy Branch Steven Bauer, Ph.D., Chief

DCGT Regulatory Activities Ensure the safety of cellular, gene therapy and other products through: Development and implementation of a comprehensive risk-based regulatory framework and review Evaluation of new technologies for product characterization and rapid assessment of product safety Development of FDA Policies and Guidances for the regulation of cellular and gene therapy, regenerative medicine, combination and other products

DCGT Regulatory Activities continued.. Inspections: of manufacturing facilities, regulatory site visits Consultation and Education: Provide scientific and technical advice to other CBER Offices, FDA Centers, and Government Agencies Information sharing and discussion with sponsors Counterterrorism: COOP Coordination and Laboratory Red Alert Plan Participation in FDA’s CT exercise/simulations DCGT staff participate in inspections…. We provide consultation and technical advice to colleagues in other CBER offices…. Perform counter terrorism activities including COOP.

DCGT Regulatory Activities continued.. Community Outreach: (seminars, panel discussions, round table, workshops) Cell Therapy including stem cell Tumor Vaccines and Immunotherapy Gene Therapy Regenerative Medicine Xenotransplantation Round Table (CIRM, JDRF, ARM and others) Interaction/collaboration with NIH CRM Patient advocacy groups We perform outreach activities to….. These are extremely important activities allowing our staff to interact with our stakeholders (sponsors and investigators) and work together addressing challenges for optimal development of these products.

DCGT Regulatory Activities continued.. Partnerships: Development of Retrovirus and Adenovirus reference material ASTM representation and STR profiling for cell line authentication Workshops in collaboration with NIH “Pluripotent Stem Cells in Translation: Early Decisions” (March 21-22, 2011 and 2012) MOU with NIH NINDS and NHLBI for sharing of information and expertise ERCC and Fluorescence standards for microarray and flow technologies Inter Agency Oncology Task Force between NCI and FDA for joint fellowship training program Partnerships: National Toxicology Program, CDC, NIST, MATES, TERMIS, ASTM Partnership with academia, government agencies and industry to help produce RV and ad vector reference standards - being distributed by ATCC. Collaborated with NIH and held workshop on stem cells in 2011 and 2012. Additional workshop is planned - 2013. MOU with NINDS and NHLBI provide opportunities for joint workshops and other educational activities for grantees to facilitate both grant review and IND review. Participation in ERCC consortium to develop internal and spike-in controls standards for microarray technology and developing fluorescence standard materials for flow cytometry technologies both being used for characterization of our products. DCGT staff co-chair FDA/NCI IOTF Subcommittee for joint training and fellowship program. Partnership with NTP, CDC, National Institute of Standards and Technology, Multi-Agency Tissue Engineering Science working group, Tissue Engineering and Regenerative Medicine International Society, ASTM (formerly American Society for Testing and Materials, a standards organization)

DCGT Regulatory Activities continued.. Participation in ICH (international conference on harmonization) – Regulators Forum on Cell Therapy and Regulator Forum on Gene Therapy WHO Liaison activities with professional societies (ISCT, ASGCT, SITC etc) Publication of invited and peer-reviewed manuscripts on regulatory topics OCTGT Learn webinar series on product manufacturing and testing, clinical, and preclinical topics. http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm

Regulatory Science Related Research DCGT Research-Regulators perform mission relevant research to facilitate development of safe and effective cutting edge medical products

Current DCGT Research Areas Virology Retroviruses, Lentivirus, adenovirus Immunology Immune responses to viral and plasmid vectors, autoimmunity and immune regulation Cell and developmental biology Control of differentiation in animal models: cell fate and survival, stem cell biology Cancer biology/Immunology Cancer vaccines, immunotherapy, animal models Molecular biomarkers, Biotechnology Genomics, flow cytometry, proteomics, transgenics Microbiology of tissue safety Pyrosequencing and whole genome sequencing

Identification and correlation of MSC attributes with in vivo and in vitro assays of safety and efficacy: DCGT MSC consortium

Researcher Reviewer Model Cellular, tissue engineering, and gene therapies evolve rapidly and continually present new regulatory challenges These novel products raise extraordinarily complex issues DCGT seeks to foster a cadre of Researcher Reviewer scientists who : perform regulatory review and identify regulatory science related research needs to enhance and promote product development and patient safety perform research in key areas to support the FDA mission and help sponsors solve product development problems to advance cellular, gene therapy and other products to the market place We are not trying to reproduce industry or NIH expertise here. However, we need scientists in key areas that can engage in constructive and informed evaluations of files and productively interact with industry and academia including their cutting edge scientists.

Types of Researcher Reviewers Principle investigators (PIs) – tenured or tenure track researcher reviewers Staff Scientists – tenured researcher reviewers supporting PIs program: do both review and research Technicians: do primarily research, lab management, some also do limited regulatory review work Staff Fellows: do both review and research work Postdoctoral fellows funded as ORISE: do primarily research Note: Resources are provided to PIs PIs tenured or tenure track scientists and located in 3 branch structure. Individual groups within these branches are headed by PIs, who are expected to build and lead FDA mission relevant research programs. Resources flow to lab activities and support through PIs.

Responsibilities of PIs Product review INDs, IDEs, PMA, 510k, HDEs, licenses, master files, inspections - regulatory mentoring by branch chiefs Policy development working groups, guidance development, advisory committees Outreach presubmittal advice, scientific and regulatory talks, refereeing and editing for journals, chairing sessions at scientific conferences, scientific collaborations relevant to the regulatory science Research lab management, training/mentoring/supervising, publishing papers, grant writing, leveraging/collaboration PIs responsibilities include product review of ….. however, their regulatory workload is approximately half of the reg scientists.

Research Assessment/Management Publications (including research articles, guidance documents, and regulatory articles) Regulatory workload and quality Success in securing internal and external funding National and International recognition of scientific expertise Site visit and CBER Advisory Committee recommendations Promotion and Conversion Evaluation (PCE) Committee review At the division level: Each year, OCTGT ADR collects information on PIs accomplishments Division uses this information for resource distribution to PIs. In addition, PIs write projects for special funding request. These proposals are generally reviewed internally before funding decisions are made from ADR’s office based on available funds. PIs research programs are reviewed by external site visit committee every 4 years and approved by CTGT advisory committee. Internally, PCE reviews for tenure, promotion and cyclical review – evaluates research and regulatory work

DCGT Research Regulatory PIs GTIB: Andrew Byrnes, Ph.D. Suzanne Epstein, Ph.D. Jacob Reiser, Ph.D. Cheng-Hong Wei, Ph.D. Carolyn Wilson, Ph.D. CTTB Steve Bauer, Ph.D. Deborah Hursh Brent McCright, Ph.D. Malcolm Moos, M.D., Ph.D. TVBB Michail Alterman, Ph.D. Shyh-Ching Lo, M.D., Ph.D. Raj K. Puri, M.D., Ph.D.

Thank you We appreciate your feedback and recommendations for research program in DCGT GTIB Once again, thank you for your time and efforts. We look forward to your feedback and recommendations for research projects in GTIB. I will take any questions that you may have.