FDA Oversight of Gene Therapy

Transcription

1 FDA Oversight of Gene Therapy Celia M. Witten, Ph.D., M.D. Deputy Director, FDA CBER Rare Disease and Orphan Products Breakthrough Summit NORD October 17, 2016 Hyatt Regency Crystal City Crystal City, Virginia

2 FDA Organization CBER (Center for Biologics Evaluation and Research): vaccines, blood and blood products, human tissue/tissue products for transplantation, cells, gene therapy Office of Tissues and Advanced Therapies (formally Office of Cellular, Tissue and Gene Therapies) Office of Vaccines Research and Review Product Offices Office of Blood Research and Review CDER (Center for Drug Evaluation and Research):drugs, some biological products CDRH (Center for Devices and Radiological Health):devices for treatment, implants, diagnostic devices CVM (Center for Veterinary Medicine) CFSAN (Center for Food Safety and Applied Nutrition) NCTR (National Center for Toxicological Research) CTP (Center for Tobacco Products) ORA (Office of Regulatory Affairs) OC (Office of the Commissioner) 2

3 OCTGT Responsibilities Regulatory review Mission-relevant Research Regulatory policy and guidance development International Activities and Standards Outreach Advisory Committees Symposia, workshops Seminars, panel discussions, round table Publications 3

4 Examples of OCTGT Products Gene therapies Genetically modified cells Plasmids, viral vectors, bacterial vectors Stem cell and stem cell-derived products Hematopoietic, mesenchymal, cord blood, embryonic, ipsc, etc. Somatic cell therapies Pancreatic islets, chondrocytes, myoblasts, keratinocytes, hepatocytes Therapeutic vaccines and other antigen-specific active immunotherapies Cancer vaccines and immunotherapies, such as dendritic cells, lymphocytebased therapies, cancer cell-based therapies, peptides, proteins Non-infectious disease therapeutic vaccines, such as peptides, proteins, small molecules Devices and combination products Devices with a cellular component Selection devices for the manufacture or delivery of cells 4

5 Number of Submissions Yearly New Gene Therapy IND Submissions to OCTGT Year 5

6 Gene Therapy Products Viral vectors Bacterial Vectors (e.g. Listeria, Salmonella, etc.) Plasmid DNA Ex vivo genetically modified cells (e.g. CD34+ cells) Engineered nucleases for human gene editing (e.g. ZFN) ~ 530 Active Gene Therapy INDs ~ 6

7 Human Gene Therapy: Ex vivo and in vivo Administration ex vivo in vivo 2. Use vectors to genetically modify cells Introduce modified cells back to to patient 1. Extract cells (BM, PBMCs) Direct delivery to patient using viral or non-viral vector 7

8 Gene Therapy Requirements and Risks Requirements: Long lasting expression Depends on indication Targeted expression Efficient delivery On target gene modification Risks: Germ line transmission Immune response to vector or transgene Insertional mutagenesis Off target expression Off target editing ~Risk Benefit Analysis is Critical~ 8

9 Gene Therapy History 1989: Gene Marking study: retrovirus expressing neomycin into TILs (melanoma, S.Rosenberg) 1990: First FDA-approved gene therapy trial (ex vivo gene transfer for treatment of ADA- SCID) 9

10 Gene Therapy History (continued ) 1999: Death in a gene therapy study for treatment of Ornithine Transcarbamylase Deficiency (OTC) 2002: Patient developed leukemia in French X- SCID trial 10

11 Gene Therapy Advances Human genome sequenced; rapid sequencing tools developed New vectors for gene therapy CAR T cells Gene editing 11

12 Professional Societies/NIH ASGCT: major stakeholder society representing the field of gene therapy Co-sponsorship of workshops on product manufacturing and safety Liaison to clinical trials and regulatory affairs working group Drug development training sessions at ASGCT meetings NIH FDA serves as liaison on the RAC Investigations into safety events, safety symposia MOU with NHLBI, NINDS 12

13 International Regulatory Leadership FDA/EMA/HC/PMDA ATMP Cluster ICH Gene Therapy Discussion Group (predecessor of Regulators Forum, wrote 3 discussion papers) International Pharmaceutical Regulators Forum Gene Therapy Working Group Product manufacturing, characterization, and safety issues Biodistribution studies for gene therapy clinical investigations 13

14 OCTGT Virology Research 1:3 Adenovirus: A popular vector for gene therapy in the clinic--fda regulates a large number of adenovirus gene therapy INDs The potential Gene delivery to any organ or tumor The reality Poor pharmacokinetics Acute toxicity due to innate immune activation Ad in blood (% initial) Time (min) 14

15 OCTGT Virology Research 2:3 Adenoviruses have a defense mechanism that protects them from innate immune defenses This defense mechanism increases vector stability and activity in vivo Ad + FX = FX-coated Ad Ad specifically binds coagulation factor X. FX shields Ad from being attacked by complement and destroyed. Xu Z, Qiu Q, Tian J, Smith JS, Conenello GM, Morita T, Byrnes AP. Coagulation factor X shields adenovirus type 5 from attack by natural antibodies and complement. Nature Medicine 2013 Apr; 19(4):

16 OCTGT Virology Research 3:3 Engineer safer, more targeted vectors Preclinical models that better predict the behavior of adenovirus vectors 16

17 Other Activities Education/outreach Guidance documents OCTGT learn Patient Focused Drug Development meetings Joint with CDER htm Meetings with patient groups/presentations at patient meetings Research activities Sokolic R, Iyengar S, Scalchunes C et al. Quality of life (QOL) in patients with Wiskott-Aldrich syndrome (WAS). J.Clin Immunol 2016 Apr; 36(3): 237. Abstract. Xu Z, Qiu Q, Tian J, Smith JS, Conenello GM, Morita T, Byrnes AP. Coagulation factor X shields adenovirus type 5 from attack by natural antibodies and complement. Nature Medicine 2013 Apr; 19(4):

18 Contact Information Celia Witten, Ph.D., M.D. Deputy Director, FDA CBER New Hampshire Ave Silver Spring, MD

19 Public access to CBER CBER website: Phone: Consumer Affairs Branch (CAB) Manufacturers Assistance and Technical Training Branch (MATTB) Follow us on Twitter 19

20 Helpful Resources Office of Combination Products (OCP) General information for OCTGT and related regulatory references: plianceregulatoryinformation/otherrecommendationsfor Manufacturers/ucm htm 20

21 OCTGT contact information Regulatory Questions: Contact the Regulatory Management Staff in OCTGT at or References for the regulatory process for OCTGT mplianceregulatoryinformation/otherrecommendationsf ormanufacturers/ucm htm OCTGT Learn Webinar Series: m htm 21

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