**Testimony of Dr. Richard Carnevale**

**Vice President, Scientific, Regulatory and International Affairs**

**Animal Health Institute**

**Committee on Agriculture**

**Subcommittee on Livestock, Diary and Poultry**

**Advances in Animal Health in the Livestock Industry**

**September 25, 2008**

Mr. Chairman and Members of the Subcommittee:

Thank you for holding this hearing on recent developments in animal
health. I am Dr. Richard Carnevale. I am a veterinarian by training with
a degree from the University of Pennsylvania and I am here today on
behalf of the Animal Health Institute, a trade association that
represents companies that make medicines for animals. Prior to joining
AHI about 12 years ago, I served as Deputy Director for the Office of
New Animal Drug Evaluation at FDA's Center for Veterinary Medicine and
later as Assistant Deputy Administrator for the Office of Science at
USDA's Food Safety & Inspection Service. AHI companies work to provide
products to livestock and poultry producers that help keep their animals
healthy. By doing this, companies contribute to public health and food
safety. Research shows that the first link in the chain of producing
safe meat, milk and eggs is keeping animals free from disease.

Food safety starts on the farm, and our companies spend millions of
research and development dollars to find new and innovative products to
keep farm animals healthy. Some animal health products are used to treat
and prevent or control disease in animals. Others help increase animal
productivity, allowing producers to meet the growing world food demand
while minimizing the use of natural resources. More recently, products
are being developed that will contribute to food safety by reducing
bacteria that do not make animals sick but have the potential to make
people sick.

Animal health products are subject to stringent, science-based review
processes at two federal agencies: pharmaceutical products are reviewed
by the Food and Drug Administration under the Federal Food, Drug and
Cosmetic Act, and biologic products, or vaccines, are regulated by USDA
under the virus, Serum, Toxins and Analogous Products Act. All products
are reviewed for safety and efficacy: Efficacy, which protects producers
by ensuring the products deliver the benefits they promise; and safety,
to ensure the products are safe for the animal being administered the
drug or vaccine and to ensure the meat from the animal is safe for human
consumption and safe for the environment.

One class of products important to the health of food animals is
antibiotics. Antibiotics are used by livestock producers, poultry
producers and the veterinarians who work with them to prevent, control
and treat often fatal bacterial infections. There are many benefits to
animals, producers and consumers that come from the use of antibiotics
in animal agriculture:

1.  Animal welfare is improved as a result of veterinarians and
    producers having the tools to be able to maintain the animal's
    health.

2.  Producers are more efficient because they can produce more food from
    fewer animals. Without antibiotics to prevent and control diseases,
    more animals get sick and die with producers losing not only the
    animal but all the input costs, including feed, that have gone into
    the animal.

3.  There are ecologic benefits. Without antibiotics that improve weight
    gains and feed conversion, more land and feed are necessary to
    maintain the same herd and flock sizes. Moreover, some studies have
    shown that certain antimicrobials used in cattle feeds reduce levels
    of methane emissions important as greenhouse gases.

4.  Benefits to global food markets. With the concern over food costs
    and availability in today's economic climate, antimicrobials and
    other animal drugs that improve animal health and productivity are
    critical to American agriculture's ability to feed the world's
    growing population. The Food and Agriculture Organization (FAO) of
    the United Nations estimates that 75 million more people worldwide
    were below the hunger threshold in 2007 due to increasing food
    prices. They propose that one solution is to help producers to raise
    their output.

5.  Consumers benefit because healthy animals are needed to produce safe
    food. Over the past five years, published, peer-reviewed studies
    have indicated that carcasses from chickens without subclinical
    diseases are more likely to be free of human foodborne
    pathogens.^1,2,3,4^ Research shows this is due in part to more
    standardized carcass size, reducing the potential for intestinal
    breakage during mechanical evisceration.

Antibiotics are approved and labeled for four specific purposes.

1.  Disease treatment

2.  Disease prevention

3.  Disease control

4.  Growth promotion, as measured by the amount of feed needed to
    produce a pound of animal weight or increased rate of weight gain.

The first three uses -- disease treatment, prevention and control -- are
considered to be therapeutic uses by FDA, the American Veterinary
Medical Association (AVMA) and such international bodies as Codex
Alimentarius and the OIE. While critics of antibiotic use like to use
the term "nontherapeutic" to refer to disease prevention, disease
control and growth promotion, this term is not used nor recognized in
national or international regulation.

Many assume in-feed uses equate to growth promotion, but this confuses
the use with the route of administration. In fact, any of the four uses,
including therapeutic , can be administered via feed or water, as that
is under certain circumstances the only practical way to administer
medication to large flocks or herds. In most cases, a veterinarian is
involved in this process, recommending feed that is specifically
formulated for the health management system used for the flock or herd.

[How are antibiotics regulated?]{.underline}

Animal health companies rely on a rigorous, efficient, predictable and
science-based review process at the Food and Drug Administration's
Center for Veterinary Medicine (CVM) to provide these products. The
standard for the approval of antibiotics used in animals is the same as
that for antibiotics used in human medicine: They must be shown to be
safe and effective.

![](media/image1.png){width="3.7104166666666667in" height="4.425in"}

The rigorous review process and monitoring systems in place are at the
heart of a broad system of protections that ensure that all medicines,
including antibiotics, are safe for animals and humans. Antibiotics for
use in animals must meet all the same requirements as antibiotics used
in humans, with two additional requirements: first, sponsors must show
the meat, edible tissues, milk and or eggs from animals in which the
medicine is used is safe for human consumption. Second, beginning in
2003, CVM instituted Guidance for Industry (GFI) \# 152, which outlines
a qualitative risk assessment process that is applied to all antibiotics
approved for use in animals. This guidance process is designed to
measure the risk of antibiotic resistant bacteria being transferred from
animals to humans if the product is approved. Based on this risk, FDA
makes decisions to either deny or approve the drug with certain
restrictions to significantly reduce risk. Restrictions can include
requiring a veterinary prescription, prohibiting extra-label use in
certain species or restricting the antibiotic to individual animals. In
most cases antimicrobial resistance monitoring is required post
approval. The methodology is very conservative -- meaning it is very
difficult to get an antibiotic approved. Further, the guidance is
sufficiently broad so that if new, previously unidentified or
undescribed, resistant organisms or genes were to become of concern, the
Agency can act swiftly to take this information into account. The
existing guidance allows the Agency sufficient flexibility to allocate
resources appropriately to changing issues of safety related to
resistance emergence.

The GFI \# 152 process applies not only to new submissions, but to all
existing products as well. FDA has established a priority list for the
re-evaluation of all antibiotics currently approved and marketed. Most
of the drugs on the list are antibiotics administered in animal feed for
the prevention and control of animal diseases or to increased the weight
gains and improve feed efficiency. The re-review under Guidance 152 was
stimulated by new funding that FDA received and continues to receive via
annual appropriated money specifically earmarked for these reviews. Bear
in mind, though, the evaluation of these products did not begin with
Guidance 152. In response to concerns raised some 30 years ago, the
Bureau of Veterinary Medicine in FDA, in the 1970's, required sponsors
of these products to conduct tests to determine the potential for
resistance to be selected in the animals and to be transferred to
bacteria that could cause human disease. While the standards and science
may have changed over the years, the safety of these products has been
an ongoing exercise at FDA. Moreover, published quantitative risk
assessments performed by both the agency and individual product sponsors
have generally affirmed that the risks to human health from these
antibiotics in animal feed under approved conditions of use are quite
low.

We fully support efforts by the agency to continue to evaluate the
safety of these products using all available scientific data under a
sound risk assessment approach in order to determine the true risk to
public health and guide appropriate risk management interventions to
protect public health.

FDA/CVM has a great deal of authority to act when data or risk
assessments indicate a threat to public health. CVM can -- and has \--
successfully asked companies to withdraw products voluntarily or to
modify their conditions of use, including restricting extra label use.
The agency can also undertake a notice of proposed rulemaking against a
product, setting in motion a process to rigorously review the science
and determine if a product should continue to be marketed. This
authority has been used to remove antibiotics from the market. Finally,
if the agency determines there is an imminent hazard to public health,
it can immediately remove a product from the market.

In addition to the rigorous review process and the additional public and
private risk assessments that have been conducted, there are other
post-approval layers of protection to ensure the safe use of
antibiotics.

[Monitoring programs]{.underline}

USDA's Food Safety and Inspection Service monitor meat samples for the
presence of antibiotic residues as a check on the observance of the
withdrawal times set by FDA. It is very uncommon for FSIS to find an
unsafe residue, an indication that products are being used according to
label directions.

The National Antibiotic Resistance Monitoring System (NARMS) is a
multi-agency program coordinated by FDA to monitor antibiotic resistant
bacteria and allow for implementation of management and control measures
if needed. The three agencies involved are:

-   The USDA Agricultural Research Service (ARS), which analyzes
    Salmonella and Campylobacter isolates collected from carcasses and
    meat samples in the USDA FSIS HACCP/Pathogen Reduction Program for
    antibiotic resistance;

-   The FDA, which monitors for resistant bacteria in retail meats;

-   The Centers for Disease Control and Prevention (CDC), which collects
    isolates from public health laboratories to monitor for the
    emergence of antibiotic resistant enteric pathogens in humans.

To date, the program has produced seven years of data representing over
19, 000 *Salmonella* isolates from livestock and poultry carcasses and
meats and 12,000 human *Salmonella* isolates. Most bacterial species
isolated from humans and tested for resistance against drug classes
potentially related to animal usage have shown stable or declining
resistance to most antimicrobials. Most of the multiple-drug resistance
types, such as *Salmonella typhimurium* DT104 show stable or declining
prevalence in both food animals and humans since 1996, according to an
expert report issued in 2006 by the Institute of Food Technologists
entitled "Antibiotic Resistance: Implications for the Food System."

While AHI strongly supports continued funding of the NARMS program we
would point out that there are inherent weaknesses in the sampling
strategies that prevent the data from estimating a true national
prevalence of resistance and yearly trends. The FDA Science Board has
identified these weaknesses as well and has encouraged the agencies
involved in NARMS to work to improve the data.^5^

[Judicious Use Guidelines]{.underline}

Responsible, or judicious, use programs that are specific to different
livestock species give veterinarians and producers specific guidelines
to help them safely and properly use of antibiotics in their health
management systems. Generally, these guidelines have been prepared
collaboratively by FDA, CDC and veterinary groups. These guidelines help
ensure there is no unnecessary use of antibiotics in animal agriculture.
Others testifying today will provide additional detail on how these
principles are used by veterinarians and producers.

There are two additional layers of scrutiny that antibiotic use
receives.

First, at the international level, Codex Alimentarius is responsible for
protecting the health of consumers and ensuring fair practices in food
trade. Codex has established a committee on antibiotic resistance.
Chaired by Korea, this committee is currently working to establish an
internationally recognized process for risk analysis of antibiotics used
in animals. International standards are important, because bacteria know
no borders and actions taken here can be nullified if there is not
concerted international action. It is also important that the
international community establishes a sound scientific basis for
countries to assess the risk of antibiotic use. Otherwise, government
regulators are left open to outside pressure to take overly zealous
precautionary measures that may be unjustified and in the long term
harmful to animal health and food safety.

Second, several risk assessments have been conducted on antibiotic
compounds, and have uniformly found extremely low levels of risk. Some
of these have been conducted and published by the sponsors, some by
independent authorities, and some by FDA. In particular, the FDA risk
assessment on virginiamycin found there were significant differences
between the resistant enterococci bacteria found in animals and those
found in humans. Even after they assumed an association for purposes of
conducting the risk assessment, the levels of risk they estimated were
quite small.

We firmly believe that risk assessment is the proper tool for making
policy decisions about the use of antibiotics in animals. Without this
scientific basis for decision making, we run the very real risk of
making decisions that have unintended consequences that are damaging for
both human and animal health.

[Does the Use of Antibiotics in Animals Contribute to Human Antibiotic
Resistance?]{.underline}

There is no question that antibiotic resistance is a serious public
health threat. But resistance is not a single problem: it is a problem
comprised of several different bacteria-drug combinations. For instance,
some of the most widely recognized antibiotic resistance problems in
humans are in respiratory tract infections and venereal diseases like
gonorrhea. In neither of these cases is there any evidence that
antibiotics used in animals are associated with these problems. In fact,
in a survey published in 2000 a group of medical experts estimated the
animal contribution to the overall human resistance problem is less than
4 percent.^6^

![](media/image2.png){width="6.319444444444445in"
height="2.704861111111111in"}That small contribution was attributed to
the potential for antibiotics used in food animals to contribute to
resistance in certain bacteria which can be transferred from animal food
products to humans. However, there is a chain of events from the "farm
to the fork" that must be traversed by bacteria that develop resistance
in animals as outlined in the accompanying chart:

In order for this to happen, the antibiotic must be used in the animal,
resulting in the selection of resistant bacteria in the animal. Those
bacteria then must survive the slaughtering and processing of the
animal. Remember, we have successfully reduced the number of bacteria
\-- both resistant and not resistant -- that survive this process
through the implementation of controls like HACCP. The bacteria must
then survive the normal cooking process. If enough resistant bacteria
survive to this point and are ingested in a large enough quantity, they
can make an individual sick with a common foodborne illness. As you
know, most foodborne illnesses are self-limiting -- they resolve
themselves in most cases without antibiotics being necessary. In the
event that an antibiotic is necessary, the illness could be treated with
the antibiotic that the bacteria is resistant to, and the treatment
could fail, prolonging the illness.

While we know this can happen, the question is, how often does this
happen and how severe are the consequences? The answer to this
much-studied question is that it does not happen enough that we can find
it and measure it. So, scientifically, we cannot say it does not happen,
but we can say it is rare.

Finally, there are some recurring questions in the debate about
antibiotic use I would like to address.

[First, what is the quantity of antibiotics used in animal
agriculture?]{.underline} Critics have charged that we don't know how
big the problem is because we don't have reliable data about the use of
antibiotics in animal agriculture. However, levels of antibiotic
resistance are not correlated to the amount of use. Not all antibiotics
are alike. Nevertheless, each year AHI surveys its members for the
amount of antibiotics sold for use in animals. Attached to my testimony
are the 2006 results. Note that there are large groupings of products.
This grouping is done because of the small number of companies in the
market and the need to protect confidential business information. The
information is not species specific, because many of the compounds sold
are used in more than one species. While critics have demanded species
specific information, this would only be available if it comes from
producers, adding to their costs and paperwork burden. About 7 years ago
CVM began work on a rule to require data collection but dropped the
effort as a result of these difficulties. Congress recognized this just
this summer when antimicrobial sales and distribution data reporting
requirements were included in the Animal Drug User Fee Amendments of
2008. We are appreciative of the cooperation we received from Members
and staff in working with the Animal Health Industry to craft
appropriate legislative language for these reporting requirements.

Notably, Congress also acted on this issue in the Farm Bill that was
signed into law earlier this year. That legislation contained an
authorization for USDA's Agriculture Research Service to conduct
additional research to study the development of antibiotic resistant
bacteria in livestock on how judicious use principles can help producers
use these products to protect both human and animal health.

Also, note that we ask sponsors to estimate the amount of antibiotics
used for growth promotion. This estimate dropped to less than 5 percent
of the total in 2006.

[What happens if producers lose access to these products]{.underline}?
This question can be answered with data from the European experiment. In
the late 1990s, the European Union phased out one particular use \--the
use of antibiotics for growth promotion. Data from the Danish
government, which you see on the accompanying chart, shows that use of
antibiotics to treat disease has doubled since the ban.

![](media/image3.png){width="7.277083333333334in"
height="2.2909722222222224in"}

This data, along with the discussion in the Danish report, clearly
indicates the ban led to additional animal disease and death. The
important question is what impact did it have on public health? There is
some evidence to indicate resistance declined in animals and humans in
certain bacteria. However, there is no evidence that this has resulted
in reducing the public health burden of resistant bacterial infections
in humans. The list of references at the end of my testimony includes
published papers on the results of the ban.

In summary, Mr. Chairman, antibiotics are vitally important to the
health of our nation's livestock and poultry herds and flocks.
Antibiotics are highly and vigorously regulated and are used carefully
by veterinarians and livestock and poultry producers. The many
regulatory layers of protection that have been put in place allow us to
use antibiotics to protect both human and animal health and not add to
the burden of antibiotic resistant infections in humans. The FDA
regulatory process and risk assessment are the proper tools for making
decisions about the use of these products, and to make decisions without
these tools we place unwarranted risks on both human and animal health.

NOTES

^1^Russell SM. The effect of airsacculitis on bird weights, uniformity,
fecal contamination, processing errors and populations of
*Campylobacter* spp. And *Escherichia coli*. Poult. Sci 2003;
82:1326-31.

^2^Cox Jr LA. Potential human health benefits of antibiotics used in
food animals: a case study of virginiamycin. Environ Int 2005;31:549-63.

^3^Hurd HS, et al. Swine Health Impact on Carcass Contamination and
Human Foodborne Risk. Public Health Reports, May-June 2008; 123:
343-351.

^4^Berrang ME, et al. Subtherapeutic Tylosin Phosphate in Broiler Feed
Affects *Campylobacter* on Carcasses During Processing. Poult. Sci.
2007;86:1229-1233.

^5^http://www.fda.gov/cvm/Documents/NARMSExecSum03.pdf.

^6^Bywater, RJ and Casewell M. An assessment of the impact of antibiotic
resistance in different bacterial species and of the contribution of
animal sources to resistance in human infections. J Antimicrob Chemother
2000;46:643-635.

ADDITIONAL REFERENCES

Phillips I, Casewell M, Cox T, et al. Does the use of antibiotics in
food animals pose a risk to human health? A critical review of the
published data. J Antimicrob Chemother 2004;53:28-52.

Antibiotic Resistance: Implications for the Food System. An Expert
Report, Funded by the IFT Foundation. Comprehensive Reviews in Food
Science and Food Safety 5 (3) , 71--137
doi:10.1111/j.1541-4337.2006.00004.x

Hurd HS. Assessing Risks to Human health from Antibiotic Use in Food
Animals. Microbe 2006;1:115-119.

Hurd HS, S Doores, D Hayes, et al. The public health consequences of
macrolide use in food animals: a deterministic risk assessment. J Food
Protect 67:2369-2374.

Wassenaar, TM. Use of Antibiotic Agents in Veterinary Medicine and
Implications for Human Health. Critical Reviews in Microbiology;
31:1155-169, 2005.