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
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
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 risk:benefit
and risk management issues Incentives
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
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
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
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
Mission RelevanceMission Relevanceof Research Programsof Research Programs > 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
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
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
CBER Research Program: Productivity & Leveraging 369 Publications reported in FY
2003 142 Journals Collaborate with multiple outside
institutions in > 100 collaborations Academia Other Government Agencies (CDC,
NIH, NCI, DOD)
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.”
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
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
751 people sickened by Salmonella typhimurium in751 people sickened by Salmonella typhimurium indomestic salad bar contamination by terrorists in 1984domestic salad bar contamination by terrorists in 1984
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. 70:4414-4423 and U.S. patent
application
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
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
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)? Dose:response 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?
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
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.)
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
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
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
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
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)
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)
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