Facilitating Biologics Product Development to Address Threats to Food Security

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Facilitating Biologics Product Development to
Address Threats to Food Security

• Jesse L. Goodman, M.D., M.P.H. Director, Center
  for Biologics Evaluation Research (CBER) FDA

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CT CBER Roles and Products

• Roles
• Facilitate Product Development
• Assure Emergency Use/Regulatory Approval Based on
  Best Possible Safety and Effectiveness Assessment
• Facilitate Product Availability
• Help assure Product integrity
• Related supporting research and regulatory
  activity
• Relevant Products
• Vaccines, Ig, Blood and blood products, gene,
  cell and tissue therapies
• 133 active IND/IDE/MF/ 561 amendments
• 93 CT unmet needs research projects

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Approaches to Speed Countermeasures Product
Availability or Licensure

• Early and frequent consultation between sponsor,
  end user (if different) and FDA
• Availability for emergency use under IND
• Fast track and accelerated approval processes
• Priority review
• Approval under Animal Rule
• Careful attention to riskbenefit
• and risk management issues
• Incentives

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Animal Rule I

• Drugs biologicals that reduce or prevent
  serious or life threatening conditions caused by
  exposure to lethal or permanently disabling toxic
  chemical, biological, radiological, or nuclear
  substances
• Human efficacy trials not feasible or ethical
• Use of animal efficacy data scientifically
  appropriate

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Animal Rule II

• Still need human clinical data
• PK/immunogenicity data
• Safety in population(s) representative of use
• Civilian use often includes pregnancy, children
• Approval subject to post-marketing studies, any
  needed restrictions on use
• Potential limitations
• Where there is no valid animal model of disease
• How to predictably bridge animal data to humans
• Confidence may be an issue, even in valid models

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Availability Under IND

• Can allow rapid access to an unlicensed product
  if there is an emergency need
• Simplification, flexibility for CT/BT issues
• Work towards licensure, wherever feasible
• Rapid turnaround/active assistance from FDA
  streamlining, multiple media etc.
• recent examples in smallpox, anthrax, botulism

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FDA/CBER BT Research Focus on Critical Pathways
to Development

• Generally target unmet needs with regulatory
  implications to facilitate the development of
  products
• Make regulation more scientific, less defensive
• Benefit multiple sponsors
• Maintain staff cutting edge expertise needed
  for dealing with evolving biotechnologies
• Scientific expertise and confidence foster
  objectivity
• Reduces risks of reflexive over- or under-
  protectiveness

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Mission Relevanceof Research Programs

• gt 122 Biologics Licensing Applications and 342
  Investigational New Drug Applications supported
  by Research Programs
• 61 of the Research Programs have
  Counter-bioterrorism components or are CBT
  relevant

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Types of Research at CBER, I

• Product Safety 42
• Mechanisms of toxicity
• Toxicity Assay development and validation
• Adventitious Agents
• Product characterization 26
• Development of methods (assays), standards and
  use of novel technology in regulatory setting
• Mechanism of action
• Mechanisms of Immunity or Immunomodulation
• Biological Responses
• Disease Pathogenesis

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Types of Research at CBER, II

• Product Efficacy 20
• Surrogate measures of efficacy
• E.g., Immunological endpoints
• Clinical Development and Analysis
• Clinical Trial Design
• Statistical and Epidemiological Analysis
• Other 7
• Anticipated product needs, e.g., SARS

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CBER Research Program Productivity Leveraging

• 369 Publications reported in FY 2003
• 142 Journals
• Collaborate with multiple outside institutions in
  gt 100 collaborations
• Academia
• Other Government Agencies (CDC, NIH, NCI, DOD)

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Threat of a biological terrorist attack on the US
food supply the CDC perspective. Sobel et al.
Lancet, 2002

• A biological terror attack that targets a food
  distributed over a wide geographical area could
  challenge the assurance of adequate medical
  supplies and personnel in far-flung locations.

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Countermeasures Vaccines for Food Borne
Pathogens

• Useful for BT/CT applications
• May be multiple exposure routes for high threat
  pathogens global protective needs
• Also useful for Emerging Infectious Diseases and
  accidental outbreaks of food-borne-illness
  contaminants
• If widespread or continuing threats, or defined
  population(s) at risk effectiveness of
  prophylaxis with vaccines vs. treatment in
  emergency situation
• Potential utility in combat situations

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Food Borne Pathogens Prophylaxis With Vaccines

• Traditional agents of terrorism warfare
• Anthrax, botulism
• Agents seen in epidemic outbreaks with utility as
  agents of terrorism warfare
• Above, plus
• Salmonella, shigella, rotavirus, calicivirus,
  Listeria monocytogenes, Escherichia coli 0157H,
  Vibrio Cholerae O1, etc.
• Considering the unknown
• SARS

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751 people sickened by Salmonella typhimurium
in domestic salad bar contamination by terrorists
in 1984
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Shigella Vaccine

• CBER collaboration with governmental, academic
  and industry partners
• Developed candidate live Salmonella typhi
  Ty21a-vectored vaccines against all predominant
  serotypes of Shigella
• Bivalent Ty21a-S. sonnei form I polysaccharide
  vaccine candidate has been constructed
• Protects against virulent animal challenge
• Packaged and distributed without refrigeration
• Can be self-administered, ideal for mass
  immunization
• Xu et al., 2002, Infect. Immun. 704414-4423 and
  U.S. patent application

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Live Oral Vaccine for Protection Against Bacillus
anthracis

• Live Salmonella typhi Ty21a-vectored candidate
  vaccine against anthrax.
• Engineered to stimulate protection against
  anthrax (or other agents of bioterrorism)
• The anthrax protective antigen (PA) has been
  shown to trigger solid protection against anthrax
  and has been chosen as the first antigen for
  vaccine construction.
• The PA gene, cloned into a stable plasmid vector,
  has already been transferred to Ty21a.
• Preliminary animal studies show anti-PA antibody
  in mice with significant protection in mouse
  lethal toxin challenges

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Gastrointestinal Anthrax Public Health
Significance

• GI anthrax often due to eating raw or poorly
  cooked contaminated meat
• Case fatality 25-60
• Food is at risk for deliberate or environmentally
  mediated contamination
• Medical impact
• Enhanced by delays in diagnosis due to low index
  of suspicion
• Economic impact
• Loss of consumer confidence in U.S. food supply
  and suppliers

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Gastrointestinal Anthrax CBER Research to
Establish Animal Model

• Role of anthrax vaccine in protection against gut
  infection pre-exposure? post-exposure?
  parenterally? mucosally?
• No established animal model for GI anthrax CBER
  developing model to determine
• Susceptible mouse strain(s)?
• Doseresponse for oral B. anthracis?
• Spore challenge in liquid and food
• Vegetative organism challenge in liquid and food
• Systemic and gut immune responses in orally
  infected animals?
• Vaccine efficacy against oral challenge?

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Botulinum Research and Food Safety

• Food contamination is one of most likely
  terrorist uses of Botulinum toxins
• Exposure constitutes a medical emergency
  requiring immediate action to mitigate the risk,
  extent and duration of paralysis
• Available countermeasures are limited
• Supportive care ICU, ventilator highly limiting
  for mass exposures
• Limited current therapeutic options all being
  developed
• Toxoid Vaccination
• Equine, other animal or despeciated multivalent
  antitoxins
• Human derived antisera polyclonal, MAbs

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Botulism Vaccines Under Development Examples

• Recombinant Neurotoxin
• Neurotoxin fragments from yeast (Diosynth RTP,
  Inc., USAMRID)
• VEE recombinant vaccine carrying neurotoxin
  serotype A (USAMRID)
• DNA vaccination (UK, USAMRID) Portions of
  neurotoxin serotype A, B, F
• Inhaled vaccination with heavy chain neurotoxin
  (Jefferson Med. College)
• Microsphere-encapsulated vaccine with
  biodegradable polymer (Whalen Biomedical, Inc.)

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Botulinum Neurotoxin Research at CBER

• Pathogenesis studies on targets for inhibition of
  the neurotoxin's ability to paralyze nerves
• Interaction of Botulinum Neurotoxin with Neuronal
  Proteins
• Botulinum Neurotoxin Translocation into Neuronal
  Cells
• Interaction of Clostridium Neurotoxins with
  Glycoconjugate Receptors

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Rotavirus A potential threat to infant food
security

• A major etiologic agent of severe diarrhea in
  infants (3-35 mo) and young children worldwide
  (600,000 deaths / yr)
• There is no vaccine available to date for US
  infant population
• Licensed rhesus reassortant vaccine no longer
  distributed by manufacturer due to rare but
  serious AE (intussusception)
• Other candidate vaccines are under study
• With this background, rotavirus can be a
  potential threat to infant food security

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Rotavirus Research Program at CBER

• Rotavirus pathogenesis and associated vaccine
  adverse reactions are studied at the molecular
  level to help evaluate the safety and efficacy of
  rotavirus candidate vaccines
• Ongoing research includes molecular
  characterization of the rotaviral enterotoxin and
  several other important rotaviral genes from
  several strains and elucidating their role in the
  virus pathobiology and vaccine AE
• Research performed in collaboration w/ CDC
• Will assist in assessing new vaccines

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Other Vaccines in Development

• Cholera
• Live, attenuated V. Cholerae strain, intranasal
  or oral delivery
• Oral, killed vaccine
• Recombinant, plant derived, edible toxin
• Toxin conjugated to SIV VLPs, IN delivery
• Vibrio ghosts nonliving bacterial envelopes
  devoid of cytoplasmic contents

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Other Vaccines in Development

• Listeria monocytogenes
• DNA vaccination with hemolysin (listeriolysin O)
• Oral inoculation with live, attenuated bacteria
• Recombinant Listeria used as live vaccine vector
  (Leshmania, papillomavirus, HIV)

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Food-borne Transmission of SARS Food Security
Risk?

• SARS patient with diarrhea visited Amoy Gardens
  complex, in Hong Kong spread within 10 days to
  321 Amoy Gardens residents - ? gastrointestinal
  transmission?
• 66 with diarrhea
• Virus found in building sewage system
• Virus cultured from intestinal biopsies of some
  patients
• Viral RNA found in stool of some patients (up to
  10 weeks post infection)
• Virus found in animals (e.g., Roof Rat, dogs,
  cats all found to have virus in stool)

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EM of Viral Particles in Intestine of SARS
Patients
Small Intestine
Colon
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Summary Facilitating Vaccine and Other
Countermeasure Development for Food Borne Illness

• Food security is an important mission of the FDA,
  including CBER possible dual use vaccines
• Prophylaxis (i.e., vaccination) for serious
  food-borne infectious diseases is a valuable
  approach for military and civilian armamentarium
• Antisera current mainstay Rx for botulism
• Vaccines to protect against food-borne infections
  are utilizing novel technological approaches
• Scientific needs include a better understanding
  of intestinal immunity and protection, and
  efficacy of oral vaccine delivery

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Thanks very much

• CBER will continue to work closely with
  developers and end users of products meeting
  critical counter-terrorism and food security needs