Natural Resources Defense Council, Inc. et al v. United States Food and Drug Administration et al

Filing 59

DECLARATION of Mitchell S. Bernard in Support re: 56 MOTION for Summary Judgment on Plaintiffs Third Claim for Relief.. Document filed by Center For Science In The Public Interest, Food Animal Concerns Trust, Natural Resources Defense Council, Inc., Public Citizen, Inc., Union Of Concerned Scientists, Inc.. (Attachments: # 1 Exhibit A, # 2 Exhibit B, # 3 Exhibit C, # 4 Exhibit D, # 5 Exhibit E)(Bernard, Mitchell)

EXHIBIT C
TO THE DECLARATION OF MITCHELL S. BERNARD

Richard A. Carnevale, VMD
Vice President, Regulatory, Scientific & International Affairs

August 27, 2010

Division of Dockets Management Branch (HFA-305)
Food and Drug Administration
5630 Fishers Lane, rm. 1061
Rockville, MD 20852
Re: Docket No. FDA–2010–D–0094; Draft Guidance: The Judicious Use of
Medically Important Antimicrobial Drugs in Food-Producing Animals; Availability
The Animal Health Institute (AHI) submits these comments to draft Guidance #209
published June 28, 2010 on FDA’s current thinking with regard to the use of medically important
antimicrobial drugs in food producing animals. AHI is the national trade association
representing manufacturers of animal health products – the pharmaceuticals, vaccines and feed
additives used in modern food production, and the medicines that keep livestock and pets
healthy.
General Comments:
AHI companies have developed and marketed antimicrobials for use in livestock and
poultry for many years. These products have become a critical part of maintaining animal health
and productivity leading to safe, abundant, and affordable animal protein. We understand the
concerns which prompted FDA to publish this guidance setting forth the agency’s intention to
limit antimicrobials to assuring animal health and to expand veterinary oversight over the use of
those products currently used in feed. AHI strongly supports the use of antibiotics in feed for
therapeutic claims. The use of antimicrobials in feed must be maintained for the assurance of
animal health. AHI further believes any changes to the current situation must be made with
sufficient involvement of all stakeholders so as to minimize any disruptions in animal
agriculture.
AHI appreciates that “FDA is committed to working with animal drug sponsors, the
veterinary and public health communities, the animal agriculture community, and all other
interested stakeholders in developing a strategy to address antimicrobial resistance concerns in
a manner that is protective of both human and animal health.”
 AHI is also committed to working with the agency to address the concerns outlined in the
guidance with the intention of assuring the availability of these products to prevent, control and
treat animal disease.
AHI notes FDA/CVM in the proposed guidance does not claim existing uses are unsafe,
but rather not judicious. This suggests current science cannot implicate existing indications for

Animal Health Institute Comments to Docket No. FDA–2010–D–0094
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growth promotion as unsafe uses of antibiotics, but certain opinion leaders believe the use is
inappropriate.
AHI believes use of antimicrobials can benefit animal health when approved labels are
followed. There are almost assuredly judicious disease control and prevention effects that occur
with antibiotic growth promotants. While FDA has articulated a regulatory policy on production
claims, the agency has not identified in this guidance specific safety issues with approved
antimicrobials used in animal feed.
Certainly, there has been a misunderstanding with the public and a negative perception of
the value of low dose uses of antibiotics for growth promotion. These claims were established
many years ago when antibiotics were first being used in animal production. There has not been
a new growth promotion indication approved in more than 20 years for any antimicrobial
considered medically important for human medicine. While the so-called growth promotion
indications imply these uses simply “fatten” the animal, in fact, what many veterinarians and
researchers believe is their use functions in maintaining gut health by suppressing bacteria
causing subclinical disease. Current scientific technologies may allow proof subclinical disease
is safely and effectively controlled or prevented by medicated feeds. Subclinical infections may
not be readily apparent but can affect the animals’ ability to efficiently utilize nutrients and
resources to reach its optimal production potential. It’s important to remember the best measures
of a healthy animal are rate of weight gain and feed efficiency. This was most evident in
Denmark when withdrawal of antibiotic growth promoters from pig production resulted in the
outbreak of intestinal disease in weaners, leading to increased incidence of scouring with
attendant increase in mortalities.
Specific comments:
III. Key Scientific Reports on the Issue
This is a very controversial issue which has been studied for over 4 decades. There is an
abundance of scientific reviews and opinions rendered both favorable and unfavorable on the
significance of animal antibiotic use to human health. The referenced reports discussed in the
guidance represent only some of the information available and are only those that have emanated
from governmental or international organization studies. There is another side to the story not
presented in the guidance that comes to a different conclusion as to the actual impact of animal
antimicrobial use on human health. The following is a partial listing of key publications that do
not support the contention that animal use of antibiotics necessarily represents a significant risk
to human health:
 Antimicrobial Resistance: Implications for the Food System, Comprehensive
Reviews in Food Science and Food Safety, Vol. 5, 2006.
This report was conducted under the auspices to Institute of Food Technologists and the
IFT foundation. The panelists found the extent to which antibiotic use in food animals
produces clinically important antibiotic resistant infections in humans is unknown. They
further concluded regulatory targeting of specific antibiotic-resistant foodborne

Animal Health Institute Comments to Docket No. FDA–2010–D–0094
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pathogens may not be the most successful or cost effective means to reduce overall
foodborne illness. Thus, applying interventions to control foodborne pathogens in
general, rather than focusing on antibiotic-resistant strains specifically, would have the
greatest impact in reducing foodborne illness.


Ian Phillips, Mark Casewell, Tony Cox, Brad De Groot, Christian Friis, Ron Jones,
Charles Nightingale, Rodney Preston and John Waddell, Does the use of antibiotics
in food animals pose a risk to human health? A critical review of published data,
Journal of Antimicrobial Chemotherapy (2004) 53, 28–52.
This is a critical peer reviewed article by a group of independent experts who examined
over 250 published studies to draw distinctions among events that do happen, may
happen, might happen, or do not happen relative to the potential for transfer from animal
derived food to humans of various bacterial species. They found little data to suggest
resistant bacteria transferred from animals have had a significant adverse impact on
human and animal health.
Wassenaar, T. Use of Antimicrobial Agents in Veterinary Medicine and Implications
for Human Health. Critical Reviews in Microbiology, 2005; Number 3 / JulySeptember (31):155-169.
This review discusses why veterinary usage of antimicrobial agents is wrongly accused of
causing a substantial part of the problem of resistant human pathogens. Although
resistant organisms in animals are selected by veterinary antimicrobials, the author
concludes these are not a major human health risk either because the role of veterinary
usage in selection or propagation is insignificant, or because resistant populations
selected by veterinary usage do not pose a substantial risk to human health. Indeed,
resistant bacterial infections in humans causing serious quantitative and qualitative health
consequences are rarely food-borne and are not the same as those selected by veterinary
usage of antimicrobial agents.



Bywater R. and Casewell M. Assessment of the impact of antimicrobial resistance in
different bacterial species and of the contribution of animal sources to resistance in
human infection. Journal of Antimicrobial Chemotherapy 2000; 6: 643-645.
Individual bacterial species vary in prevalence and the extent of multiple antibiotic
resistances. This paper attempted to quantify this variation, or to assess the
contribution from animal sources to the overall antibiotic resistance problem in humans.
The publication presents the results of a questionnaire directed to recognized experts in
the UK and elsewhere chosen on the basis of their experience and wide knowledge of
clinical microbiology, and not on prior knowledge of their attitudes to the topics in
question. The perceived contribution of animal sources to the overall impact of resistance
was estimated to be very low. Overall, the mean scores indicate animal sources might
account for 3.88% of the human antibiotic resistance problem.

Animal Health Institute Comments to Docket No. FDA–2010–D–0094
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

Phillips, I. Withdrawal of growth-promoting antibiotics in Europe and its effects in
relation to human health (review). Int. J. Antimicrob. Agents 2007; 30:101-107.
Several growth promoters were withdrawn in the European Union between 1995 and
1999 on the basis of the Precautionary Principle. Analyses suggest the added risk to
human health from resistance among enterococci and campylobacters selected by growth
promoter use is small, whilst the benefit to human health from their use, hitherto largely
ignored, might more than counterbalance this.



Louis Anthony (Tony) Cox Jr*. and Douglas A. Popken, Assessing Potential Human
Health Hazards and Benefits from Subtherapeutic Antibiotics in the United States:
Tetracyclines as a Case Study, Risk Analysis, Volume 30 Issue 3, Pages 432 – 457.
Published Online: 2 Feb 2010.
As a case study, examining specific tetracycline uses and resistance patterns suggests
there is no significant human health hazard from continued use of all tetracyclines in food
animals regardless of route of administration. Simple hypothetical calculations suggest an
unobservably small risk (between 0 and 1.75E-11 excess lifetime risk of a tetracyclineresistant infection), based on the long history of tetracycline use in the United States
without resistance-related treatment failures.



Louis Anthony (Tony) Cox, Jr. , Douglas A. Popken , and Jeremy J. Mathers,
Human Health Risk Assessment of Penicillin/Aminopenicillin Resistance in
Enterococci Due to Penicillin Use in Food Animals, Risk Analysis, Volume 29 Issue
6, Pages 796 – 805. Published Online: 26 Mar 2009.
This article considers the possibility such uses might increase the incidence of
ampicillin-resistant Enterococcus faecium (AREF) of animal origin in human
infections, leading to increased hospitalization and mortality due to reduced
response to ampicillin or penicillin. Multiplying the total at-risk population of
intensive care unit (ICU) patients by a series of estimated factors suggests that not more
than 0.04 excess mortalities per year (under conservative assumptions) to 0.14 excess
mortalities per year (under very conservative assumptions) might be prevented in the
whole U.S. population if current use of all penicillin drugs (regardless of route of
administration) in food animals were discontinued and if this successfully reduced the
prevalence of AREF infections among ICU patients. These calculations suggest current
penicillin usage in food animals in the United States presents very low (possibly zero)
human health risks.

Animal Health Institute Comments to Docket No. FDA–2010–D–0094
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

Risk Assessment of Streptogramin Resistance in Enterococcus faecium Attributable
to the Use of Streptogramins in Animals “Virginiamycin Risk Assessment”, FDA
Center
for
Veterinary
Medicine,
November
23,
2004.
http://www.fda.gov/downloads/AnimalVeterinary/NewsEvents/CVMUpdates/UCM0547
22.pdf.
The FDA CVM’s own draft risk assessment for this drug found it difficult to assess the
extent of transfer of streptogramin resistance from virginiamycin-exposed E. faecium to
E. faecium found in human infections based on the available data. Literature reports
demonstrate there are differences in the characteristics of resistant E. faecium
isolated from animal and human sources, with respect to minimum inhibitory
concentration (MIC) distributions and the presence of known resistance genes. These two
findings, along with the current incomplete knowledge of the genetic basis of
streptogramin resistance, prevents the risk assessment from making firm conclusions as
to whether, and, if so, how much, the use of streptogramins in food animals contributes to
the occurrence of streptogramin-resistant E. faecium infections in humans via a
foodborne pathway.



Cox L.A. Potential Human Health Impacts of Banning Antimicrobials Used in Food
Animals: A Case Study of Virginiamycin. Environ Int. 2005; 31(4):549-63.
This paper presents a quantitative human health risk and benefits assessment for
virginiamycin (VM), a streptogramin antibiotic recommended for withdrawal from use in
food animals in several countries. Increased human health risks from more
pathogens reaching consumers if VM use is terminated (6660 estimated excess
campylobacteriosis cases per year in the base case) are predicted to far outweigh benefits
from reduced streptogramin-resistant vancomycin-resistant Enterococcus faecium
(VREF) infections in human patients (0.27 estimated excess cases per year in the base
case).



Hurd, H. S.; S. Doores; D. Hayes; A. Mathew; J. Maurer; P. Silley; R. Singer; RN
Jones. Public Health Consequences of Macrolide use in Food Animals: A Semiquantitative Risk Assessment. J. Food Protection 2004; 67:980-992.
Using the CVM Guidance for Industry # 152 this paper presents a deterministic model to
assess the risk from two macrolide antibiotics, tylosin and tilmicosin. The scope of
modeling included all label claim uses of both macrolides in poultry, swine, and beef
cattle. Risk was defined as the probability of this hazard combined with the consequence
of treatment failure due to resistant Campylobacter spp. or Enterococcus faecium. The
risk assessment demonstrated that use of tylosin and tilmicosin in food animals presents a
very low risk of human treatment failure, with an approximate annual probability of
less than 1 in 10 million Campylobacter-derived and approximately 1 in 3 billion
E.
faecium-derived risk.

Animal Health Institute Comments to Docket No. FDA–2010–D–0094
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VI. Status of FDA’s Current Activities
Medically Important Antimicrobial Drugs
 AHI recommends the principles articulated in draft GFI #209 be restricted in application to only
those antimicrobials drugs identified in Appendix A of GFI #152 as critically important, highly
important, or important.
The guidance defines medically important antimicrobial drugs, “…as those that are
important for therapeutic use in humans.” There are some antimicrobials used in animals that
are not used for therapeutic purposes in humans, and would logically be exempted from the
guidance. Many human infections have no origin in animal hosts, thus are unlikely to be
affected by the use of antimicrobials in animals, even if the same or similar antimicrobial is used
to treat those human infections. The elimination of claims or restriction of marketing status for
these antimicrobials would also seem to be unnecessary.
The agency has already considered the issue of what drugs constitute medically important
antimicrobials during the development of Guidance for Industry # 152. That guidance includes
Appendix A, “Ranking of antimicrobial drugs according to their importance in human
medicine.” That listing includes criteria to classify antimicrobials as either critically important,
highly important, or important based on their use in foodborne illness and use as the sole therapy
for an important non-foodborne human infection. The development of this list was accomplished
as a cooperative effort between the Center for Veterinary Medicine and the Center for Drug
Evaluation and Research utilizing the advice and counsel of the FDA Advisory Committee on
Anti-infective drugs. As a stakeholder in the process AHI presented information in support of
that classification. Until that guidance is updated we believe it should be the operative listing for
defining what is medically important for the purposes of this guidance.
We agree with FDA there are significant differences in applying GFI # 152 to products
presented for approval as opposed to applying the guidance to products that have been approved
and safely marketed for many years. Conditions of use for marketed products were approved by
the agency based on the data submitted to the NADA’s establishing dose rates, duration of
therapy and extent of use. GFI #152 is based on certain assumptions as to risk and has built in
risk management limitations on conditions of use for products presented to FDA for approval.
Simple application of the criteria in that guidance to approved products could cause
inappropriate actions to propose to withdraw products that are not a risk to public health.
We would also like to correct the record with regard to the impression suggested in the
guidance that currently approved antimicrobial products for production or growth promotion
purposes were never subject to a safety assessment for antimicrobial resistance since their
original approvals. The discussion fails to discuss the specific requirements which were imposed
on all sponsors of feed use antimicrobials in 1975 under 21 CFR 558.15 – “Antibiotic,
nitrofuran, and sulfonamide drugs in the feed of animals”. Specific studies were required to
determine effects of antimicrobials in the feed to both the Salmonella reservoir as well as
antimicrobial resistance selection pressure on E. coli gut flora. The regulation stated these
evaluations were necessary for continued approval and were conducted and submitted to CVM

Animal Health Institute Comments to Docket No. FDA–2010–D–0094
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for review. While the scientific approach for assessing resistance may have changed since that
time, considerable effort was expended to satisfy the agency that human health was not being
jeopardized
VII. Recommended Principles Regarding Judicious Use in Animals
Principle: The use of medically important antimicrobial drugs in food-producing animals should
be limited to those uses that are considered necessary for assuring animal health.
 AHI recommends FDA remove this factor from the final guidance or clarify that it is not a
regulatory requirement that will be enforced by the agency.
As previously stated, AHI believes use of antimicrobials can benefit animal health when
approved labels are followed. There are almost assuredly judicious disease control and
prevention effects that occur with antibiotic growth promotants. AHI strongly agrees with FDA
that the continued availability of effective antimicrobial drugs is critically important for
combating infectious disease in both humans and animals. We appreciate that FDA
acknowledges antimicrobials are necessary for use in animal feed, as this may be the most
effective means of administering medications to large groups of animals and birds in preventing
or controlling disease.
We generally support the criteria suggested in the guidance on page 16 for justifying
preventive use of antimicrobials and agree veterinary involvement is important in assuring these
uses are judicious. However, we do take issue with the final criteria (5) evidence that no
reasonable alternatives for intervention exist. While a veterinarian may consider a range of
options which could be used to prevent bacterial disease, including the use of an antimicrobial,
we believe this is not a factor that FDA has authority to apply in the course of deciding on the
safety and efficacy of label indications. There is no statutory requirement in 512 of the Act or in
21 CFR 514 of the regulations for sponsors to demonstrate an approved product or one submitted
for approval is the only intervention available for preventing a particular disease. While we
understand the guidance is not binding, this factor could be used to prevent or block an
indication from being approved or used to request approved indications be withdrawn when this
document becomes finalized and is applied.
Principle: The use of medically important antimicrobial drugs in food-producing animals should
be limited to those uses that include veterinary oversight or consultation.
 AHI recommends the agency consider all options to achieving the goal of increasing veterinary
oversight, including application of the Veterinary Feed Directive. We encourage FDA to work
with the AVMA and veterinary specialty groups to seek out alternative solutions.
From a practical standpoint antimicrobials and other animal drugs were historically
approved for use as over the counter products due to the nature of animal agriculture and the
difficulty of obtaining veterinary services in rural areas of the country. The FD&C Act
recognized the difference between animal and human medicine and the need for producers to be
able to maintain their animals’ health when a veterinarian was not readily available. The Act

Animal Health Institute Comments to Docket No. FDA–2010–D–0094
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requires adequate directions for use be written for a drug to be properly labeled. It was assumed
that producers could read and follow label directions for production and preventive uses of
medicated feed and regulatory controls are in place to assure feed mills were properly mixing
antimicrobials into the feed according to label conditions of use. Although veterinarians have
been frequently involved with decisions on the use of antimicrobials in food animals, until 1996
there was no specific legislative requirement for veterinary feed directive labeling and there was
no regulatory provision for product labels to restrict use by or on the order of a licensed
veterinarian. The Animal Drug Availability Act provided for Veterinary Feed Directive labeling
which allowed for the agency to consider all new antimicrobials added to feed to be used under
the supervision of a veterinarian.
AHI recognizes the intention to increase veterinary oversight but points out the logistical
difficulties if the agency intends to require products that contain antimicrobials considered
medically important to only be labeled as VFD drugs. AHI is commenting separately on the
Advance Notice of Proposed Rulemaking for Veterinary Feed Directive. Conversion of
currently approved OTC product labels to VFD labels is a complex task and would likely require
a lengthy phase-in time for veterinarians, feed mills, and producers to successfully implement.
In conclusion AHI appreciates the FDA’s willingness to work with sponsors and the
veterinary and agriculture community to achieve the stated goals in this guidance.

Sincerely,

Richard A. Carnevale, VMD