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Long-Term Follow-up of Subjects in Gene Transfer Studies

Long-Term Follow-up of Subjects in Gene Transfer Studies. Philippe Bishop, M.D. FDA/CBER/DCTDA/Oncology. Presentation Outline. Prior BRMAC discussions Areas of clinical concerns Epidemiologic database (Steven Rosenthal, MD). Prior BRMAC Discussions. CURRENT FDA LTFU GUIDANCE.

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Long-Term Follow-up of Subjects in Gene Transfer Studies

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  1. Long-Term Follow-up of Subjects in Gene Transfer Studies Philippe Bishop, M.D. FDA/CBER/DCTDA/Oncology BRMAC 10-24-01

  2. Presentation Outline • Prior BRMAC discussions • Areas of clinical concerns • Epidemiologic database (Steven Rosenthal, MD) BRMAC 10-24-01

  3. Prior BRMAC Discussions BRMAC 10-24-01

  4. CURRENT FDA LTFU GUIDANCE LTFU is limited to GT strategies involving retroviral vectors October 18, 2000 Guidance Document http://www.fda.gov/cber/guidelines.htm BRMAC 10-24-01

  5. BRMAC Meeting November 16-17, 2000 • Efforts to gather data pertaining to the long-term risks of exposure are necessary for all GT products. • Vector characteristics may correlate with long term risks to participants. BRMAC 10-24-01

  6. BRMAC MeetingApril 5-6, 2001 FDA proposed a three-tier system based on vector characteristics. BRMAC 10-24-01

  7. Tier Vector Characteristics 1 Ex vivo gene transfer with non-replicating vector into cells with demonstrated limited survival 2 All other gene transfer products that are not in tiers 1 or 3 3 Replicating or potential to replicate, (except poxvirus and adenovirus) High integration potential Altered receptor tropism Latency potential Proposed 3-Tier System BRMAC 10-24-01

  8. BRMAC Discussion“Where we left off…” It was generally felt that identifying and focusing on the most important data would improve compliance. BRMAC 10-24-01

  9. FDA Working Group • Define clinical concerns related to gene transfer studies. • Define the duration of clinical follow-up appropriate to the specific clinical concerns. BRMAC 10-24-01

  10. FDA Working GroupConsiderations • Vector characteristics • Duration of gene product expression • Mode of administration • Targeted tissue • Patient-specific factors BRMAC 10-24-01

  11. Name Area of Expertise/Role Philippe Bishop, MD Oncology Patricia Keegan, MD Oncology/Hematology Harvey Luksenburg, MD Hematology Anne Pilaro, Ph.D. Toxicology Cindy Rask, MD Neurology Steve Rosenthal, MD Vaccines/Epidemiology Stephanie Simek, Ph.D. FDA RAC Liaison Joseph Temenak, Ph.D. Vaccines/Molecular Biol. Mark Thornton, MD Immunology Carolyn Wilson, Ph.D. Virology FDA Working Group BRMAC 10-24-01

  12. FDA Working Group 4 areas of clinical concerns were identified: • Malignancy • Hematopoeitic dysfunction • Autoimmune disease • Neurologic disease BRMAC 10-24-01

  13. Malignancy BRMAC 10-24-01

  14. Malignancy DNA and RNA viruses are known to cause or to be associated with human cancers: • HTLV-I  adult T-cell leukemia • HPV  cervical cancer • HCV  hepatocellular carcinoma BRMAC 10-24-01

  15. Malignancy Mechanisms of viral oncogenesis have been described: • Transformation by trans-gene expression (HTLV-1 tax) • Insertional mutagenesis (c-myc) • Chronic inflammation (HCV) • “Hit and run” hypothesis (Ad5 E1A + E4orf6) BRMAC 10-24-01

  16. Malignancy GT related mutagenesis has previously been demonstrated in non-human primates (Donahue et al, 1992) BRMAC 10-24-01

  17. Malignancy Treatment induced cancer may take years before clinical presentation • Hodgkin’s lymphoma • Breast Cancer • Testicular Cancer BRMAC 10-24-01

  18. Hematopoeitic Disorders BRMAC 10-24-01

  19. Hematopoietic Disorders Virus induced hematologic syndromes are well known: • Parvovirus B19  anemia • HBV  aplastic anemia • HIV  isolated or combined cytopenia BRMAC 10-24-01

  20. Hematopoietic Disorders • Hematopoietic progenitor cells (HPC) are self-replicating and give rise to HPC decendents. • HPC decendents make up the differentiated cells of blood and BM essential to human life BRMAC 10-24-01

  21. Hematopoietic Disorders GT related hematologic disorders (cytopenias), pre-malignant (MDS) and malignant (Leukemia) conditions may occur months to years following initial exposure. BRMAC 10-24-01

  22. Neurologic Disorders BRMAC 10-24-01

  23. Neurologic Disorders • GT vectors and administration strategies may lead to neurologic disorders • Integrating vectors • Long latency • Prolonged transgene expression • Immunogenic reactions BRMAC 10-24-01

  24. Neurologic Disorders • CNS is a highly specialized organ that has redundancy in functional capacity. • Many known neurologic disorders require significant neurologic damage before being clinically evident. BRMAC 10-24-01

  25. Neurologic Disorders Neuronal injury may go on for years before being clinically detected. • HIV  dementia • Prion  CJD • Diabetes  neuropathy BRMAC 10-24-01

  26. Autoimmune Disorders BRMAC 10-24-01

  27. Autoimmune Disorders Environmental and other xenobiotic agents can cause autoimmunity (e.g., viruses and bacteria can induce antibody-mediated autoimmune disease via molecular mimicry): • Group A strep  rheumatic fever • Infectious mononucleosis  ITP BRMAC 10-24-01

  28. Autoimmune Disorders Mechanisms for autoimmune diseases have been described: • Unmasking of “AID genes” • Molecular mimicry • Humoral autoimmunity • T-cell mediated autoimmunity BRMAC 10-24-01

  29. Autoimmune Disorders • Immune responses to GT vectors or transgene product are possible. • Risk may relate to vector characteristics, duration of transgene expression, route of administration, and host specific factors. BRMAC 10-24-01

  30. Autoimmune Disorders Clinical manifestation of autoimmune disorders resulting from environmental insults may take months to years. • Minocycline  SLE BRMAC 10-24-01

  31. Summary BRMAC 10-24-01

  32. Summary LTFU of GT participants should focus on 4 clinical areas: • Malignancies • Neurologic disorders • Hematologic disorders; • Autoimmune disorders. Years to decades Months to years BRMAC 10-24-01

  33. Summary FDA has previously proposed a 3-tiered system to assess risks to subjects based on vector characteristics. BRMAC 10-24-01

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