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)

EM of Viral Particles in Intestine of SARS Patients

Small IntestineColon

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