Facilitating Biologics Product Development to Address Threats to Food Security

1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. Mission Relevanceof 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

9. 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

10. 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

11. 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)

12. 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.”

13. 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

14. 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

15. 751 people sickened by Salmonella typhimurium in domestic salad bar contamination by terrorists in 1984

16. 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

17. 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

18. 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

19. 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?

20. 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

21. 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.)

22. 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

23. 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

24. 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

25. 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

26. 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)

28. 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)

29. EM of Viral Particles in Intestine of SARS Patients Colon Small Intestine

30. 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

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