Division of Hematology Emergency Preparedness Action Initiatives

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Division of Hematology Emergency Preparedness
Action Initiatives

• Prepared by Mark Weinstein, Ph.D., Dorothy Scott
  M.D. and Basil Golding M.D.
• Division of HematologyFDA/CBER/OBRR

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Strategic Plans

• Form working groups within CBER liaison with
  CDC, NIH and DoD to address
• Category A
• Anthrax
• Smallpox
• Botulism
• Plague
• Hemorrhagic Fever Viruses
• Tularemia

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Potential Plasma-Derived Products

• Polyclonal antibodies from hyperimmune donors
  (IGIV products)
• Human vaccinees
• Animals immunized
• Human Plasma (high titer)
• Interim procedure safety concerns

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Production of Immune Globulins

• Donors of plasma for hyperimmune globulin
• Identification through OVRR, NIH and DoD of
  vaccinees to be recruited as potential donors
• Collection of plasma suitable for initial
  development and large-scale manufacturing
• Meets FDA requirements for recovered or source
  plasma

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Product Status

• Assessment of Currently Available Treatments
• How much product is currently available?
• What is known about product efficacy?
• Estimation of Need
• number of affected individuals anticipated
• dose by weight
• availability and preparedness of supportive care

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Product Development

• Assays for assigning potency research and
  development
• binding assays
• in vitro neutralization and in vivo protection
• Potency standards
• IND(s) from CDC, DoD, or industry
• identification of potential sponsors and/or
  manufacturers
• facilitate submission and expedite review
• funding

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Vaccinia Immune Globulin (VIG) Issues

• Used to treat smallpox vaccination complications
• Supplies for massive vaccination campaign are
  insufficient
• VIG effectiveness is based on uncontrolled studies

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Challenges in Development and Use of VIG
Intravenous (VIGIV)

• Determining optimal clinical study real
  treatment studies not possible
• Monitoring effects of treatment ascertaining
  efficacy, determining effective serum levels of
  antibodies for treatment
• Assuring adequate supplies for possible
  scenarios assuring delivery of VIGIV where
  needed

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Current Thinking Clinical Trials for Licensure
of VIGIV

• Licensure based upon PK equivalence and safety
  data. PK not inferior (gt 0.8) to VIG given I.M.
• Accelerated Approval designation desirable (21
  CFR 601.40 601.46)
• expedited availability of product
• Phase IV commitments to study human surrogate
  markers (e.g. influence of VIGIV on vaccine take,
  lesion size)

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Current Thinking Clinical Trials for Licensure
of VIGIV

• New product indications limited to treatment of
  life-threatening smallpox vaccinations
• Eczema vaccinatum
• Progressive vaccinia

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Vaccinia Immune Globulin Current DH Research

• Developing and Testing Potency assays for VIG
  Products
• SCID mouse model
• In vivo neutralization assay
• Immune deficient mice (systemic spread of virus)
• Comparison to in vitro plaque reduction
  neutralization assays
• Comparison to novel high-throughput in vitro
  vaccina virus replication assay (collaboration
  with OVRR)

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Vaccinia Immune Globulin Current DH Research

• Determining levels of anti-vaccinia antibodies in
  licensed IGIV products
• IGIV product testing suggests that some products
  may be useful in treatment
• Certain IGIV products may serve as a potential
  second-line agent if VIG/VIGIV products are not
  in sufficient supply

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Vaccinia Immune Globulin Planned DH Research

• Evaluating Potency Assays relevance to in vivo
  situation ease of use validation
• Establishment of VIG working standard
• Correlates of VIG product potency
• immune globulin structure and subclass
• manufacturing effects
• improvements for future products
• Studies of high-titer IGIVs in SCID mice
• Vacccinia protection
• Prophylaxis and treatment of disseminated
  infection

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Botulinum Immune Globulin (BIG)

• Assess current supplies
• Licensed product (equine)
• IND products (equine and human)
• Facilitate accessibility of supplies for
  civilians
• Discussions with CDC, DoD and NIH
• IND drafted and sponsored by CDC
• Olympic Games 1996, modified for 2002

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BIG Future Plans

• Discussions with CDC and DoD to make additional
  human product from vaccinees
• Facilitate potency testing by contract labs. and
  FDA
• Establish potency standards

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Anthrax Background

• Treatment/Prevention
• Antibiotics (5/11 patients with IA died)
• Vaccines (mainly against PA, low titers)
• Antibodies?
• Evidence for Antibody Role
• In vitro neutralization
• Animal challenge

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Anthrax Immune Globulin

• Identify vaccinees treated under IND (OVRR
  reviewers)
• Discussions with CDC, DoD and NIH
• IND drafted and sponsored by CDC with advice from
  FDA
• Research plan to provide basis for development of
  a sheep AIG

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Current Status Anthrax

• High titer FFP units available for
  life-threatening anthrax and for production of a
  pilot lot of AIG
• Plan to test animals with human high titer AIG
• Consensus of AIGWG to plasmapherese vaccinees
  for manufacture of an AIG product

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AIG DH Research Plan

• Study different vaccines/immunogens in animals
• Choose immunogen that elicits highest titer
• Identify manufacturer/sponsor to make product in
  animals
• Facilitate pre-clinical testing mice, rabbits
  and possibly monkeys
• Develop standards and assays
• Facilitate IND submission and product approval

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AIG Assays and Standards

• Develop and validate in-house standard and assays
  (OVRR)
• Alternatively work with other govt. agencies or
  contractors to ensure that standards and
  validated assays are available
• Correlate assay to in vivo effects in animals and
  humans

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AIG Assays - available or under development

• Binding assays ELISA (NIH, FDA)
• In vitro Toxin Neutralization Assay (CDC,
  USAMRIID, FDA)
• Rodent challenge (CDC, USAMRIID, FDA)
• Monkey challenge (USAMRIID)

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Unresolved Issues

• Funding
• Coordination and prioritization
• Control of product distribution