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

LTFU Presentation BRMAC 10-24-01

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 GUIDANCELTFU is limited to GT strategies involving retroviral vectors October 18, 2000 Guidance Document http://www.fda.gov/cber/guidelines.htm


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 MeetingApril 5-6, 2001

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


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


BRMAC Discussion“Where we left off…”

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


FDA Working Group

•Define clinical concerns related to gene transfer studies.

•Define the duration of clinical follow-up appropriate to the specific clinical concerns.


FDA Working GroupConsiderations

•Vector characteristics•Duration of gene product expression

•Mode of administration•Targeted tissue•Patient-specific factors


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


4 areas of clinical concerns were identified:

• Malignancy• Hematopoeitic

dysfunction• Autoimmune disease• Neurologic disease

FDA Working Group


Malignancy


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


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


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


MalignancyTreatment induced cancer may take years before clinical presentation

•Hodgkin’s lymphoma•Breast Cancer•Testicular Cancer


Hematopoeitic Disorders


Virus induced hematologic syndromes are well known:

•Parvovirus B19 anemia •HBV aplastic anemia•HIV isolated or combined

cytopenia

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


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



Neurologic Disorders


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




•CNS is a highly specialized organ that has redundancy in functional capacity.

•Many known neurologic disorders require significant neurologic damage before being clinically evident.


Neuronal injury may go on for years before being clinically detected.

•HIV dementia•Prion CJD•Diabetes neuropathy



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



Mechanisms for autoimmune diseases have been described:

•Unmasking of “AID genes”•Molecular mimicry•Humoral autoimmunity•T-cell mediated autoimmunity



•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.


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



Summary


SummaryLTFU of GT participants should

focus on 4 clinical areas:• Malignancies• Neurologic disorders• Hematologic disorders;• Autoimmune disorders.

Years to decadesMonths to years


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

Summary

Documents

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