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

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

3. LTFU PresentationBRMAC 10-24-01 Prior BRMAC Discussions

4. LTFU PresentationBRMAC 10-24-01 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

5. LTFU PresentationBRMAC 10-24-01 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.

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

7. LTFU PresentationBRMAC 10-24-01 Proposed 3-Tier System TierVector Characteristics 1 Ex vivo gene transfer with non- replicating vector into cells with demonstrated limited survival 2All 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

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

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

10. LTFU PresentationBRMAC 10-24-01 FDA Working Group Considerations Vector characteristics Duration of gene product expression Mode of administration Targeted tissue Patient-specific factors

11. LTFU PresentationBRMAC 10-24-01 FDA Working Group NameArea of Expertise/Role Philippe Bishop, MDOncology Patricia Keegan, MDOncology/Hematology Harvey Luksenburg, MDHematology Anne Pilaro, Ph.D.Toxicology Cindy Rask, MDNeurology Steve Rosenthal, MDVaccines/Epidemiology Stephanie Simek, Ph.D.FDA RAC Liaison Joseph Temenak, Ph.D.Vaccines/Molecular Biol. Mark Thornton, MDImmunology Carolyn Wilson, Ph.D.Virology

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

13. LTFU PresentationBRMAC 10-24-01 Malignancy

14. LTFU PresentationBRMAC 10-24-01 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

15. LTFU PresentationBRMAC 10-24-01 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) Malignancy

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

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

18. LTFU PresentationBRMAC 10-24-01 Hematopoeitic Disorders

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

20. LTFU PresentationBRMAC 10-24-01 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

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

22. LTFU PresentationBRMAC 10-24-01 Neurologic Disorders

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

24. LTFU PresentationBRMAC 10-24-01 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.

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

26. LTFU PresentationBRMAC 10-24-01 Autoimmune Disorders

27. LTFU PresentationBRMAC 10-24-01 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

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

29. LTFU PresentationBRMAC 10-24-01 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.

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

31. LTFU PresentationBRMAC 10-24-01 Summary

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

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