# Presentation: 067415

## 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 Relevanceof 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 in

*751 people sickened by Salmonella typhimurium in*
*domestic 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)

## Slide 27

## 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)

## EM of Viral Particles in Intestine of SARS Patients

- Small Intestine

- Colon

## 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

## Thanks very much

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