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

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

• Philippe Bishop, M.D.
• FDA/CBER/DCTDA/Oncology

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Presentation Outline

• Prior BRMAC discussions
• Areas of clinical concerns
• Epidemiologic database (Steven Rosenthal, MD)

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Prior BRMAC Discussions
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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

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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.

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BRMAC MeetingApril 5-6, 2001

• FDA proposed a three-tier system based on vector
  characteristics.

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Proposed 3-Tier System
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BRMAC DiscussionWhere we left off

• It was generally felt that identifying and
  focusing on the most important data would improve
  compliance.

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FDA Working Group

• Define clinical concerns related to gene transfer
  studies.
• Define the duration of clinical follow-up
  appropriate to the specific clinical concerns.

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FDA Working GroupConsiderations

• Vector characteristics
• Duration of gene product expression
• Mode of administration
• Targeted tissue
• Patient-specific factors

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FDA Working Group
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FDA Working Group

• 4 areas of clinical concerns were identified
• Malignancy
• Hematopoeitic dysfunction
• Autoimmune disease
• Neurologic disease

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Malignancy
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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

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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)

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Malignancy

• GT related mutagenesis has previously been
  demonstrated in non-human primates (Donahue et
  al, 1992)

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Malignancy

• Treatment induced cancer may take years before
  clinical presentation
• Hodgkins lymphoma
• Breast Cancer
• Testicular Cancer

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Hematopoeitic Disorders
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Hematopoietic Disorders

• Virus induced hematologic syndromes are well
  known
• Parvovirus B19 ? anemia
• HBV ? aplastic anemia
• HIV ? isolated or combined cytopenia

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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

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Hematopoietic Disorders

• GT related hematologic disorders (cytopenias),
  pre-malignant (MDS) and malignant (Leukemia)
  conditions may occur months to years following
  initial exposure.

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Neurologic Disorders
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Neurologic Disorders

• GT vectors and administration strategies may lead
  to neurologic disorders
• Integrating vectors
• Long latency
• Prolonged transgene expression
• Immunogenic reactions

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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.

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Neurologic Disorders

• Neuronal injury may go on for years before being
  clinically detected.
• HIV ? dementia
• Prion ? CJD
• Diabetes ? neuropathy

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Autoimmune Disorders
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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

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Autoimmune Disorders

• Mechanisms for autoimmune diseases have been
  described
• Unmasking of AID genes
• Molecular mimicry
• Humoral autoimmunity
• T-cell mediated autoimmunity

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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.

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Autoimmune Disorders

• Clinical manifestation of autoimmune disorders
  resulting from environmental insults may take
  months to years.
• Minocycline ? SLE

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Summary
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Summary

• LTFU of GT participants should focus on 4
  clinical areas
• Malignancies
• Neurologic disorders
• Hematologic disorders
• Autoimmune disorders.

Years to decades
Months to years
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Summary

• FDA has previously proposed a 3-tiered system to
  assess risks to subjects based on vector
  characteristics.