Emerging Infectious Diseases
[Volume 5 No.4 / July - August 1999]


Special Issue

Vaccines, Pharmaceutical Products, and Bioterrorism: Challenges
for the U.S. Food and Drug Administration

Kathryn C. Zoon
U.S. Food and Drug Administration, Rockville, Maryland, USA

In regards to bioterrorism, the goal of the U.S. Food and Drug
Administration (FDA) is to foster the development of vaccines,
drugs and diagnostic products, safeguards of the food supply, and
other measures needed to respond to bioterrorist threats. Many
products (vaccines, therapeutic drug and biological products, food,
devices, and diagnostics) regulated by FDA could be affected by
bioterrorism. Pathogens or pathogen products adapted for
biological warfare include smallpox (variola), anthrax (Bacillus
anthracis), plague (Yersinia pestis), tularemia (Francisella
tularensis), brucellosis (Brucella abortus, B. melitensis, B. suis, B.
canis), Q fever (Coxiella burnettii), botulinum toxin (produced by
Clostridium botulinum) and staphylococcal enterotoxin B. New
products are needed to diagnose, prevent, and treat these public
health threats.

FDA is participating in an interagency group preparing for response
in a civilian emergency. This group includes representatives of the
Department of Defense; the Veterans Administration; and
components of the Department of Health and Human Services
(DHHS), such as the Centers for Disease Control and Prevention
(CDC), National Institutes of Health (NIH), and Office of
Emergency Preparedness. In addition, FDA will be proposing
standards for the use of animal efficacy data in approving new
products to counter chemical and biological agents. The agency is
also participating in setting a broad-based federal research agenda
to facilitate the government's preparedness against bioterrorism; is
identifying facilities and activities suitable for the production of
biological weapons; is involved in product development, review,
and testing; and is ensuring that appropriate product surveillance
and sponsor compliance are executed in accordance with
regulations.

FDA's regulation of medical products is based on science, law, and
public health considerations (Figure 1). Research conducted at FDA
(in particular at the Center for Biologics Evaluation and Research)
contributing to biological warfare defense and other
counterbioterrorism efforts is in the following areas: design of new
vaccines (e.g., pox viruses); pathogenesis and mechanism of
replication of biological warfare agents; new methods and standards
to expedite the review of new vaccines and immunoglobulins (e.g.,
mucosal protection against a pathogen); and stem cell protection
and chemokine/cytokine and angiogenic agent defense mechanisms.

The development framework of most biological and traditional drug
products is shown in Figure 2. The principal evaluation and
research and development phases before a drug is submitted to
FDA for approval can take 1 to 3 years. The clinical research and
development program (investigational phase), depending on the
agent and clinical indication, can take 2 to 10 years. The marketing
application review period generally is 2 months to 3 years (average
1 year). Once a product is approved, long-term postmarketing
surveillance, inspections, and product testing are performed to
ensure the quality, safety, and efficacy of the product, as well as
appropriate product labeling. Accelerating product development is
important in many situations, including bioterrorism. Mechanisms
for advancing medicines through the approval process have been
developed for severe and life-threatening illnesses. For drugs and
biologic products, these mechanisms include expedited review and
fast-track development, as well as accelerated approval and priority
review of marketing applications. For a priority product, complete
review of marketing applications is 6 months.

Many of the biological warfare defense products pose difficult
problems with regard to obtaining clinical efficacy data. For many
of these infectious agents or toxins, human efficacy trials cannot be
performed, as such studies would involve exposing healthy human
volunteers to a lethal or permanently disabling agent without
proven therapy and field trials. In most cases, such trials are not
feasible because pockets of natural exposure do not exist. To
address this dilemma, FDA will be proposing that the use of animal
efficacy data be allowed when appropriate (1). This proposed rule
would identify the types of data required. Safety, pharmacokinetic,
and immunogenicity data will still be necessary in humans. Product
safety will likely be evaluated in healthy human volunteers at doses
and routes of administration anticipated in field use.

Some scientific considerations for animal studies include the toxic
agent's pathophysiologic mechanism of toxicity and how the test
drug or biologic product prevents it and the validity of the animal
study endpoint in humans. In addition, data showing that drug
effectiveness in animals predicts efficacy in humans would be
needed. Finally, product recipients should be given follow-up after
treatment to affirm product safety and efficacy.

For licensure or other approval, a biological warfare defense
product must have an acceptable quality, safety, efficacy, and
potency profile. Likewise, the product must have acceptable
stability characteristics and be produced in compliance with current
good manufacturing practices.

A case study of anthrax vaccine can serve as an example of our
capability to respond to a bioterrorist threat. Only one licensed
anthrax vaccine (Bioport Corp.) is available. This vaccine consists
of a membrane-sterilized culture filtrate of B. anthracis
V770-NP1-R, an avirulent, nonencapsulated strain. The culture
filtrate is adsorbed to aluminum hydroxide and formulated with
benzethonium chloride (preservative) and formaldehyde (stabilizer).
The administration schedule consists of 0.5 ml injected
subcutaneously at 0, 2, and 4 weeks, 6, 12, and 18 months, and
then annually thereafter. The vaccine was licensed in 1970. The
efficacy data in support of the license consisted of a single-blind,
well-controlled field study (2). The vaccine efficacy was 92.5%
(lower 95% confidence limit of 65%). Of the 26 cases of anthrax in
this study, 21 were cutaneous and 5 (4 fatal) were inhalation (2 in
the placebo group, 0 in the vaccinated group, 3 in the unvaccinated
group).

In December 1985, the Federal Register (3) published the FDA's
advisory panel review of the efficacy of anthrax adsorbed. The
panel recommended that this product be placed in category I (safe,
effective, and not misbranded) and that the appropriate license be
continued because there was substantial evidence for this product.

Studies of new anthrax vaccine products are in progress. They
include protective antigenbased vaccines, e.g., purified protein
from B. anthracis culture or live-attenuated spore vaccine.
Production and product testing will differ for each of these
candidate vaccines. The immunogenicity of the product in humans
and animal models should be assessed. The cell-mediated immunity
elicited by the vaccine may also need to be evaluated. One of the
immune correlates of protection of anthrax vaccines is likely to be
the antibody response to protective antigen. However, the
quantitative relation of antiprotective antigen antibody to protection
has not been established in humans but is being investigated by the
Department of Defense. Animal challenge and protection models,
especially rabbit and nonhuman primate models, may be particularly
useful. Passive transfer of protection, also an indication of the
importance of antibodies for protection, has been observed in
animal models. Therefore, human challenge protection studies and
new field efficacy trials are not feasible in studying the efficacy of
new anthrax vaccines. Animal challenge and protection studies
against spores will be important for new vaccines based on
protective antigen. Comparisons of immune responses in human
cohorts receiving new or licensed vaccines should be performed.

Data should be obtained on various target populations, including
adults and children, to evaluate the safety of new anthrax vaccines.
Systemic and local adverse events are particularly important to
monitor. For live-attenuated and vector vaccine approaches, the
potential for transmission to others will be an important
consideration in clinical development and use. After these vaccines
are licensed and administered, the safety and adverse reactions of
these vaccines should be assessed.

In conclusion, FDA will be providing a critical link in access of new
medicines for biowarfare defense (Table). The expected outcomes
of these activities include safe and effective products to treat or
prevent toxicity of biological and chemical agents; methods to
rapidly detect, identify, and decontaminate hazardous organisms; a
greater ability to ensure the safety of the food supply; and a greater
ability to provide appropriate medical care and a public health
response.

--------------------------------------------------------

      Kathryn Zoon is Director of the Center for Biologics
Evaluation and Research (CBER) at the Food and Drug
Administration. As former Director of the Division of Cytokine
Biology in CBER, Dr. Zoon was actively involved with regulatory
issues related to cytokines, growth factors, studies on interferon
purification and characterization, and interferon receptors.

      Address for correspondence: Kathryn C. Zoon, Center for
Biologics Evaluation and Research, Food and Drug Administration,
Mailstop HFM-1, 1401 Rockville Pike, Rockville, MD 20852,
USA; fax: 301-827-0440; e-mail: zoon@cber.fda.gov.

References

  1. Federal Register Vol 63 #80, Monday, April 27, 1998, p. 1957.
  2. Brachman PS, Gold H, Plotkin SA, Fekety FR, Werrin M,
Ingraham NR. Field evaluation of a human anthrax vaccine. Am J
Public Health 1962;52:632-45.
  3. Federal Register. Vol 50 #240, Friday, Dec. 13, 1985, p. 
51002-17.

[fig]
Figure 1. Regulation of medical products.

[fig]

Figure 2. Development of biological and tradition drug products.

  Table. Proposed activities of the U.S. Food and Drug
Administration to counter bioterrorism

  -------------------------------------------------------
  1. Enhancing the expeditious development and licensure 
of new vaccines and biological therapeutics through research
and review activitiesanthrax vaccine and antisera to
botulinum toxin, for example.

  2. Enhancing the timeliness of application reviews of
new drugs and biological products and new uses of 
existing products.

  3. Participating in the planning and coordination of
public health and medical response to a terrorist
attack involving a biological or chemical agent(s).

  4. Participating in the development of rapid detection
and decontamination for agents of bioterrorism
such as Clostridium botulinum toxins, Yersinisa
pestis, Bacillus anthracis.

  5. Ensuring the safety of regulated foods, drugs,
medical devices, and biological products; arrange
for seizure and disposal of affected products.

  6. Developing techniques for detection of genetic
modifications of microorganisms to make them
more toxic or antibiotic-or vaccine-resistant.

  7. Rapidly determining a microbe's sensitivity to drug
therapy.

  8. Determining the mechanism of replication and
pathogenicity or virulence of identified organisms
including elements that can be transferred to other
organisms to circumvent detection, prevention, or
treatment 

  9. Enhancing adverse product reporting surveillance
capabilities.


Emerging Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA

URL: ftp://ftp.cdc.gov/pub/EID/vol5no4/ascii/zoon.txt

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