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LTFU Presentation BRMAC 10-24-01
Long-Term Follow-up of Subjects in
Gene Transfer Studies
Philippe Bishop, M.D.FDA/CBER/DCTDA/Oncology
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LTFU Presentation BRMAC 10-24-01
Presentation Outline
•Prior BRMAC discussions•Areas of clinical concerns•Epidemiologic database (Steven Rosenthal, MD)
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LTFU Presentation BRMAC 10-24-01
Prior BRMAC Discussions
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LTFU Presentation BRMAC 10-24-01
CURRENT FDA LTFU GUIDANCELTFU is limited to GT strategies involving retroviral vectors October 18, 2000 Guidance Document http://www.fda.gov/cber/guidelines.htm
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LTFU Presentation BRMAC 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.
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LTFU Presentation BRMAC 10-24-01
BRMAC MeetingApril 5-6, 2001
FDA proposed a three-tier system based on vector characteristics.
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LTFU Presentation BRMAC 10-24-01
Proposed 3-Tier System
Tier
Vector Characteristics
1Ex 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 potentialAltered receptor tropismLatency potential
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LTFU Presentation BRMAC 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.
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LTFU Presentation BRMAC 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.
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LTFU Presentation BRMAC 10-24-01
FDA Working GroupConsiderations
•Vector characteristics•Duration of gene product expression
•Mode of administration•Targeted tissue•Patient-specific factors
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LTFU Presentation BRMAC 10-24-01
FDA Working GroupName 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/EpidemiologyStephanie Simek,
Ph.D.FDA RAC Liaison
Joseph Temenak, Ph.D.
Vaccines/Molecular Biol.Mark Thornton, MD Immunology
Carolyn Wilson, Ph.D. Virology
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LTFU Presentation BRMAC 10-24-01
4 areas of clinical concerns were identified:
• Malignancy• Hematopoeitic
dysfunction• Autoimmune disease• Neurologic disease
FDA Working Group
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LTFU Presentation BRMAC 10-24-01
Malignancy
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LTFU Presentation BRMAC 10-24-01
MalignancyDNA 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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LTFU Presentation BRMAC 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
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LTFU Presentation BRMAC 10-24-01
MalignancyGT related mutagenesis has previously been demonstrated in non-human primates (Donahue et al, 1992)
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LTFU Presentation BRMAC 10-24-01
MalignancyTreatment induced cancer may take years before clinical presentation
•Hodgkin’s lymphoma•Breast Cancer•Testicular Cancer
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LTFU Presentation BRMAC 10-24-01
Hematopoeitic Disorders
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LTFU Presentation BRMAC 10-24-01
Virus induced hematologic syndromes are well known:
•Parvovirus B19 anemia •HBV aplastic anemia•HIV isolated or combined
cytopenia
Hematopoietic Disorders
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LTFU Presentation BRMAC 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
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LTFU Presentation BRMAC 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
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LTFU Presentation BRMAC 10-24-01
Neurologic Disorders
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LTFU Presentation BRMAC 10-24-01
•GT vectors and administration strategies may lead to neurologic disorders– Integrating vectors– Long latency– Prolonged transgene expression– Immunogenic reactions
Neurologic Disorders
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LTFU Presentation BRMAC 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.
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LTFU Presentation BRMAC 10-24-01
Neuronal injury may go on for years before being clinically detected.
•HIV dementia•Prion CJD•Diabetes neuropathy
Neurologic Disorders
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LTFU Presentation BRMAC 10-24-01
Autoimmune Disorders
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LTFU Presentation BRMAC 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
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LTFU Presentation BRMAC 10-24-01
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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LTFU Presentation BRMAC 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.
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LTFU Presentation BRMAC 10-24-01
Clinical manifestation of autoimmune disorders resulting from environmental insults may take months to years.• Minocycline SLE
Autoimmune Disorders
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LTFU Presentation BRMAC 10-24-01
Summary
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LTFU Presentation BRMAC 10-24-01
SummaryLTFU of GT participants should
focus on 4 clinical areas:• Malignancies• Neurologic disorders• Hematologic disorders;• Autoimmune disorders.
Years to decadesMonths to years
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LTFU Presentation BRMAC 10-24-01
FDA has previously proposed a 3-tiered system to assess risks to subjects based on vector characteristics.
Summary