Symposium
"Legislation on drug and vaccine use"
A US perspective
on the current and future regulation of anticoccidial
drugs and vaccines
Paul Duquette, Phibro
Animal Health (paul.duquette@pahc.com)
65 Challenger Road, Third Floor
Ridgefield Park, New Jersey 07660 - USA
Abstract
The US broiler industry is currently thriving, with
more than 8.5 billion broilers produced per year.
This success is partly due to the availability of
multiple anticoccidial drugs, both chemicals and polyether
ionophores, and anticoccidial vaccines. In the US,
the Center for Veterinary Medicine (CVM), Food and
Drug Administration, is responsible for approval of
new anticoccidial drugs, while the United States Department
of Agriculture (USDA) is responsible for approval
of anticoccidial vaccines. The CVM anticoccidial drug
approval process is quite rigorous, requiring demonstration
of manufacturing capability, efficacy, target animal
safety, human food safety, and environmental safety.
The USDA approval process for anticoccidial vaccines,
which differs somewhat from the CVM approval process,
also requires demonstration of manufacturing capability,
efficacy and safety. Although many anticoccidial drugs
are currently available (and expected to remain available),
few, if any, new drugs are under development, due
to the high cost and length of the approval process.
Only a few anticoccidial vaccines are currently available,
but new vaccines are under development. The US and
worldwide broiler industry should continue to thrive
as long as currently used anticoccidial drugs are
used prudently, anticoccidial vaccines are used when
and where effective, and necrotic enteritis and other
diseases that exacerbate coccidiosis are controlled.
Introduction
The broiler industry in the US is currently a thriving
industry. US broiler producers currently produce more
than of 8.5 billion broilers per year. The industry
relies on various feed additives, including growth
promotants used to enhance productivity and maintain
the health status of the animals, therapeutic antibiotics
used for disease treatment, and anticoccidials. Without
these products, all of which are approved by FDA after
extensive testing to demonstrate efficacy and safety,
it would be impossible for the industry to maintain
the quality of its products and to survive in its
current form.
In order to understand the current and future of the
industry in general, and anticoccidials in particular,
it is important to have a historical perspective.
History
of the US broiler industry and anticoccidials
In his campaign for the presidency in 1928, Herbert
Hoover used a campaign slogan “a chicken in
every pot and a car in every garage”. Hoover’s
intent was to promise affluence to the US public.
However, his slogan gives an important perspective
regarding the broiler industry. In 1928, only the
affluent, or farmers who grew their own, could afford
to eat chicken, which was considered a “high
priced” protein source. Although numbers for
broiler production aren’t available for 1928,
they are available beginning in 1940. In 1940, 143
million broilers were raised for consumption in the
US. This number grew to 631 million in 1950, 1.8 billion
in 1960, 3 billion in 1970, 4 billion in 1980, 5.8
billion in 1990 and 8.3 billion in 2000, and reached
over 8.8 billion in 2004. During this time period,
average live weight of broilers increased from 3 pounds
to over 5 pounds, feed conversion decreased from 4
pounds of feed per pound of broiler to under 2 pounds,
mortality decreased from 10% to 5%, and market age
decreased from 12 to less than 7 weeks. [Note that
the production data listed above was obtained from
various United States Department of Agriculture (USDA)
publications. For more information on the US poultry
industry, see the USDA web site at http://www.ams.usda.gov.]
The tremendous improvements in the broiler industry
can be attributed to many factors. Intensive breeding
programs have resulted in highly improved genetics.
Management practices include knowledge of nutrient
requirements and improved feedstuffs. Antibiotic feed
additives, especially those that control necrotic
enteritis, allow for intensive rearing conditions
with reduced mortality, while growth promotants improve
feed efficiency and growth rate.
Of course, without anticoccidial drugs and vaccines,
the growth of the US broiler industry described above
would have been impossible, as coccidia are ubiquitous
and extremely deleterious to the growth and survival
of broilers. Fortunately, introduction of the sulfur/sulfonimide
drugs in the 1930s started an era of treating and
preventing coccidiosis. Since that time, the emphasis
has been on prevention, with the introduction of the
chemical anticoccidial drugs in the 1940s through
1970s, introduction of the first polyether ionophores
in the 1970s, and the more recent introduction of
anticoccidial vaccines (although vaccines have been
used in broiler breeders since the 1950s, formulations
for broiler production are relatively new). Growth
of the US broiler industry demonstrates a high correlation
with the discovery of new anticoccidials.
The current status of anticoccidials and anticoccidial
regulation in the US
Anticoccidial drugs and vaccines are regulated by
two US agencies. The Center for Veterinary Medicine
(CVM), Food and Drug Administration (FDA), regulates
anticoccidial drugs, while the United States Department
of Agriculure (USDA) regulates anticoccidial vaccines.
As such, they will be discussed separately, below.
Anticoccidial drugs
The US Food, Drug and Cosmetic Act mandates that a
new animal drug may not be sold in interstate commerce
unless it is the subject of a New Animal Drug Application
(NADA). In order to obtain an NADA, a drug product
sponsor must demonstrate that the drug is safe and
effective, and can be manufactured in a manner that
preserves its identity, strength, purity and quality.
The Center for Veterinary Medicine (CVM), Food and
Drug Administration (FDA) is responsible for the review
and approval of NADAs. See U.S. Code: Title 21-Food
and Drugs Part 514 – New Animal Drug Applications
at http://www.access.gpo.gov/nara/cfr/waisidx_98/21cfr514_98.html
for more information on the NADA process.
Twenty anticoccidial drugs/drug combinations are currently
codified (approved) for use in broilers in the US.
Table 1 lists the approved US anticoccidial drugs,
their approved withdrawal time, and their tissue tolerances/safe
concentrations.
Table 1. Anticoccidial drugs approved for use in broilers
in the US.a

A Data from United States
Code of Federal regulations, 21 CFR Parts 556 (tolerances)
and 558 (approvals and withdrawal times), 2005. For
further information, see http://www.gpoaccess.gov/cfr/index.html.
b C = chemical; I = polyether ionophore.
c US FDA sets tissue tolerances and/or safe concentrations,
which may differ from European MRLs. Tolerance refers
to a concentration of a marker residue in the target
tissue selected to monitor for total residues of the
drug in the target animal, and safe concentrations
refers to the concentrations of total residues considered
safe in edible tissues. Tolerances are shown in normal
font, while safe concentrations are shown in italics.
In cases where no safe concentration is listed separately,
the tolerance is the safe concentration.
Although all
of the drugs listed in Table 1 are approved, many
of them are no longer marketed.
The US CVM approval process for animal health drugs
used in food animal species (including anticoccidial
drugs) is quite rigorous and comprehensive. Submissions
for approval can be phased (each “technical
section” submitted separately) or complete (all
“technical sections” submitted simultaneously).
For further information on phased submissions, see
Guidance for Industry (GFI) #132 located on the CVM
website at http://www.fda.gov/cvm/Documents/dguide132.doc];
for further information on complete submissions, see
GFI #41 http://www.fda.gov/cvm/Guidance/Guideline41.htm).
Whichever submission format is chosen, the following
technical sections are required:
· Chemistry, Manufacturing, and Controls
· Effectiveness
· Target Animal Safety
· Human Food Safety
· Environmental Impact
· Labeling
· Freedom of Information Summary
· “All other information”
Each of these sections will be discussed briefly.
The Chemistry,
Manufacturing, and Controls (CMC) section should contain
complete information regarding the manufacture of
the new animal drug active ingredient and the new
animal drug product. It should contain information
on personnel, facilities, components and composition,
manufacturing procedures, analytical specifications
and methods, control procedures, stability, containers
and closures, Good Manufacturing Practice (GMP) compliance,
and other aspects of the chemistry and manufacturing
processes. CVM has published multiple GFIs that describe
different aspects of the CMC section process, including
those listed in Table 2.
Table 2. CVM Guidance on Chemistry, Manufacturing
and Controls.a

a All CVM GFI
can be found on the CVM website at
http://www.fda.gov/cvm/guidance/published.htm.
The Effectiveness section
must contain full reports of all studies that show
whether or not the new animal drug is effective for
its intended use. CVM has published Guidance for Industry
(GFI) that specifically outlines the studies necessary
to demonstrate effectiveness of anticoccidial drugs.
Specific studies described in this GFI include battery
studies (with both single Eimeria species and mixed
cultures), floor pen challenge studies, and field
trials. For further information, see GFI #40, at:
http://www.fda.gov/cvm/Guidance/dguide40.pdf.
The Target Animal Safety technical section must contain
full reports of all studies that show whether or not
the new animal drug is safe to the target species.
In addition, any target animal safety issues that
become apparent in efficacy studies must be reported
in this section. Target animal safety study design
for poultry anticoccidial drugs is specifically mentioned
in section IX of GFI # 33, located at:
http://www.fda.gov/cvm/Guidance/Guideline33.htm.
The Human Food Safety technical section is the most
comprehensive technical section, and must contain
information on residue toxicology, residue chemistry,
residue analytical methods, pharmacokinetics and bioavailability.
CVM has recently (June 2005) updated GFI #3, General
Principles for Evaluating the Safety of Compounds
Used in Food-Producing Animals, including references
to the following Guidelines: Guidance for Metabolism
Studies and for Selection of Residues for Toxicological
Testing; Guidance for Toxicological Testing; Guidance
for Establishing a Safe Concentration; Guidance for
Approval of a Method of Analysis for Residues; Guidance
for Establishing a Withdrawal Period; Guidance for
New Animal Drugs and Food Additives Derived from a
Fermentation; and Guidance for the Human Food Safety
Evaluation of Bound Residues Derived from Carcinogenic
New Animal Drugs. In addition, CVM has adopted various
guidelines (GL) developed by the International Cooperation
on Harmonisation of Technical Requirements for Registration
of Veterinary Medicinal Products (VICH) regarding
safety studies for residues, including those listed
in Table 3.
Table 3. VICH safety study guidelines adopted by CVM.a

a These guidelines are
available on the CVM
http://www.fda.gov/cvm/guidance/published.htm.
It should be noted that,
for anticoccidial compounds that have anti-infective
properties (such as the polyether ionophores), CVM
has recently begun requiring studies on microbiology,
including the effects of residues on human intestinal
microflora (GFI #159) and evaluation of the safety
with regard to their microbiological effects on bacteria
of human health concern antimicrobial resistance (GFI
#152). GFI #152, which describes a “qualitative”
approach to antibacterial resistance risk assessment,
may be superceded by a more “quantitative”
approach. Although no examples of a quantitative risk
assessment are available for the polyether ionophores,
CVM has published a draft risk assessment on virginiamycin,
a product used in poultry to control necrotic enteritis
and improve growth rate and feed efficiency. The CVM
document:
(http://www.fda.gov/cvm/Documents/SREF_RA_FinalDraft.pdf)
demonstrates the CVM approach to risk assessment (and
also demonstrates that the continued use of virginiamycin
poses no significant risk to human health).
The Environmental Impact section must, by regulation,
contain either an environmental assessment (EA), or
a request for categorical exclusion. A claim of categorical
exclusion must include a statement of compliance with
the categorical exclusion criteria and must state
that to the sponsor’s knowledge, no extraordinary
circumstances exist. “Environmental Impact Considerations”
and directions for preparing an EA can be found in
21 CFR Part 25. In addition, CVM has adopted 2 VICH
environmental guidelines, GL6 [CVM GFI #89 Guidance
for Industry - Environmental Impact Assessments (EIA's)
For Veterinary Medicinal Products (VMP's) - Phase
I, http://www.fda.gov/cvm/Guidance/guide89.doc] and
GL38 [GFI #166 Draft Guidance for Industry - Environmental
Impact Assessments (EIA's) for Veterinary Medicinal
Products (VMP's) - Phase II:
http://www.fda.gov/cvm/Guidance/dguide166.doc].
The Labeling section should include facsimile copies
of container labels, package inserts and any other
labeling that will be used with the products. For
medicated feeds, copies of representative labeling
for the Type B and Type C medicated feeds, referred
to as “Blue Bird” labeling, should also
be included. Facsimile labeling is nearly final labeling
that adequately reproduces the package size (actual
or to scale); graphics; pictures; type size, font,
and color of text; and the substance of the text to
demonstrate to the reviewing Division that the final
printed labeling will be in compliance with applicable
regulations. Labeling should address any user safety
concerns identified during the review process. CVM
has not published final guidance on labeling; however,
labeling requirements are codified in 21 CFR Part
201:
(http://www.access.gpo.gov/nara/cfr/waisidx_98/21cfr201_98.html).
The completed Freedom of Information Summary (FOI)
Summary should include the specific language relevant
to a technical section that was agreed upon during
the review of the individual technical section (e.g.,
the tolerance and withdrawal time for a new animal
drug intended for use in food-producing animals) and
should be accepted by the Division responsible for
the evaluation of the target animal safety technical
section. For further information on FOI summaries,
see GFI # 16 (FOI Summary Guideline, http://www.fda.gov/cvm/Guidance/Guideline16.htm).
The All Other
Information section must include all other information,
not included in any of the other technical sections,
that is pertinent to an evaluation of the safety or
effectiveness of the new animal drug for which approval
is sought. All other information includes, but is
not limited to, any information derived from other
marketing (domestic or foreign) and favorable and
unfavorable reports in the scientific literature.
It should be noted that, in the US, anticoccidial
drugs cannot be used in combination with any other
drugs until the combination is approved by CVM (see
CVM Guidelines for Drug Combinations for Use in Animals,
GFI # 24, at http://www.fda.gov/cvm/Guidance/Guideline24.htm.
For further information on the animal drug approval
process in the US, visit the CVM website and associated
links at:
http://www.fda.gov/cvm/nadaappr.htm.
Anticoccidial
vaccines
The U.S. Department of Agriculture (USDA) is authorized,
under the 1913 Virus-Serum-Toxin Act (see http://www.aphis.usda.gov/vs/cvb/vsta.htm)
as amended by the 1985 Food Security Act, to ensure
that all veterinary biologics produced in, or imported
into, the United States are not worthless, contaminated,
dangerous, or harmful. Federal law prohibits the shipment
of veterinary biologics unless they are manufactured
in compliance with regulations contained in Title
9 of the Code of Federal Regulations, Parts 101 to
118. Veterinary biologics for commercial use must
be produced at a USDA-approved establishment, and
be demonstrated to be pure, safe, potent, and efficacious.
Three anticoccidial vaccines (Table 4) are currently
USDA approved for use in broilers in the US.
Table
4. Anticoccidial vaccines approved for use in broilers
in the US.a

Note in the above table
that all currently approved vaccines contain wild
type live oocysts, but vary in the Eimeria species
they contain and their delivery method.
The USDA vaccine approval process is outlined as follows
(see http://www.aphis.usda.gov/vs/cvb/lpd/lpdfaqs.htm):
In order to manufacture and sell veterinary biologics
in the US, domestic manufacturers are required to
possess a valid U.S. Veterinary Biologics Establishment
License and an individual U.S. Veterinary Biologics
Product License for each product produced for sale.
Foreign manufacturers of veterinary biologics may
export veterinary biologics to the United States,
provided that the manufacturer's legal representative
(permittee) residing in the United States possesses
a valid U.S. Veterinary Biological Product Permit
to import these products for general distribution
and sale.
The following documentation must be submitted to USDA
for a biologics establishment license:
· Application for United States Veterinary
Biologics Establishment License
· Articles
of Incorporation for applicant and any subsidiaries
if a corporation
· Water quality statement
· An application for at least one United States
Veterinary Biological Product License
· Personnel Qualifications Statement for supervisory
personnel
· Blueprints, plot plans, and legends
The following
documentation must be submitted to USDA for a biologics
product license:
· Application for a United States Veterinary
Biological Product License
· Outline of Production and, if applicable,
Special Outlines
· Master Seed data, including test results
for purity, safety, identity, and genetic characterization
· Master Cell Stock data, including test results
for purity and identity
· Product safety data from laboratory animal
and contained host animal studies
· Host animal immunogenicity/efficacy data
· Field safety data
· Labels for all containers, cartons, and enclosures
(circulars)
· Potency test validation data, including correlation
with host animal efficacy 3 consecutively produced
pre-license serials that have tested satisfactorily
for purity, safety, and potency
Guidelines (Veterinary
Services Memorandums) on preparation and submission
of the above information can be found at the USDA
website, http://www.aphis.usda.gov/vs/cvb/vsmemos.htm.
In addition to the approved vaccines listed in Table
2, vaccines may be produced and used without USDA
approval, provided that:
· The product was manufactured by veterinarians
and intended solely for use with their clients' animals
under a veterinarian-client-patient relationship.
· The product was manufactured by individuals
or companies for use only in their own animals.
· The product was manufactured in States with
USDA-approved veterinary biologics regulatory programs,
for sale only in those States.
The
future of anticoccidials and anticoccidial regulation
in the US
The Animal Health Institute (AHI) has recently published
a news release entitled “Antibiotic Use in Animals
Rises in 2004” (see http://www.ahi.org/mediaCenter/documents/Antibioticuse2004.pdf)
that shows that ionophore/arsenical (grouped to abide
by disclosure agreements) sales in the US increased
from 8,644,638 pounds in 2003 to 9,444,107 pounds
in 2004. At first glance, this appears to be good
news for the animal health industry; however, these
data demonstrate increased reliance on existing compounds,
as no new compounds have been approved in the past
few years. In fact, the last new anticoccidial drug
approval in the US occurred in 1999, when diclazuril
was approved. Prior to diclazuril, semduramicin was
approved in 1994. The approval of new anticoccidial
drugs has come to a standstill due to the high cost
and length of time it takes for approval with the
current approval requirements: estimates are that
it currently costs more than $25 million and at least
10 years to obtain CVM approval of a new anticoccidial
drug (information based on AHI sponsor input). Industry
information suggests that no new anticoccidial drugs
are under development. The good news is that currently
marketed anticoccidial drugs will remain on the market,
as there is no indication that CVM has any concerns
with these compounds.
If no new anticoccidial drugs will become available,
what will happen to the US and worldwide broiler industry?
It appears that new anticoccidial vaccine technology
may fill some of the void. Dalloul and Lillehoj (2005)
have recently published a paper describing functional
genomic technology and recent advances in live and
recombinant vaccine development that may result in
broiler vaccination strategies that work better than
current vaccines. Bedrnik (2004) reviews information
on multiple anticoccidial vaccines that have been
or are being developed worldwide. MacDougald et al.
(2005) have recently patented vaccine for coccidiosis
in chickens prepared from four attenuated Eimeria
species: E. acervulina, E. maxima, E. mitis and E.
tenella (see http://www.uspto.gov/ patent number 6,908,620).
Industry sources suggest that at least 4 new anticoccidial
vaccines are currently under development for the US
market.
However, anticoccidial vaccines are not the complete
answer as they are not always effective and do nothing
to control necrotic enteritis, and anticoccidial drugs
must continue to be used. The broiler industry must
use these products prudently to avoid over use and
possible resistance issues. Shuttle programs must
be adopted to “rest” popular anticoccidial
drugs. Both chemical and polyether ionophore anticoccidial
drugs should be used as seasonal conditions and coccidial
challenge allow. Efforts should be made to control
necrotic enteritis and other disease conditions that
may exacerbate coccidiosis.
The US and worldwide broiler industry should continue
to thrive as long as currently used anticoccidial
drugs are used prudently, anticoccidial vaccines are
used when and where effective, and necrotic enteritis
and other diseases that exacerbate coccidiosis are
controlled. The anticoccidial drugs are amongst the
most important tools that allow the broiler producer
to produce healthy birds, because they are the safest
and most effective method to control coccidiosis.
In turn, the consumer benefits through low-priced,
high-quality animal protein produced using drugs that
have been proven safe and effective in rigorous scientific
studies.
References
[Note: much of the information presented in this paper
was gathered from official US government websites,
which have been referenced throughout this document.
Key websites used, and referenced publications, are
listed below.]
Websites
United States Department of Agriculture, Agriculture
Marketing Service at http://www.ams.usda.gov
United States
Code of Federal regulations, 21 CFR Parts 556 (tolerances)
and 558 (approvals and withdrawal times), 2005 at:
http://www.gpoaccess.gov/cfr/index.html
United States
Food and Drug Administration, Center for Veterinary
Medicine guidance documents at http://www.fda.gov/cvm/guidance/published.htm
United States
Department of Agriculture, Center for Veterinary Biologics,
Veterinary Services Memorandums (guidance documents)
at:
http://www.aphis.usda.gov/vs/cvb/vsmemos.htm
United States
Patent and Trademark Office at http://www.uspto.gov/
Animal Health
Institute at http://www.ahi.org/
Publications
Bedrnik, P., 2004. Control
of Poultry Coccidiosis in the 21st Century. Praxis
veterinaria 52 (1-2):49 – 54.
Dalloul,
R.A. and H.S. Lillehoj, 2005. Recent Advances in Immunemodulation
and Vaccination Strategies Against Coccidiosis. Avian
Diseases 49:1-8.