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

Filing 33

DECLARATION of Jennifer A. Sorenson in Support re: 19 MOTION for Summary Judgment.. 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, # 6 Exhibit F, # 7 Exhibit G, # 8 Exhibit H, # 9 Exhibit I, # 10 Exhibit J, # 11 Exhibit K, # 12 Exhibit L, # 13 Exhibit M, # 14 Exhibit N, # 15 Exhibit O, # 16 Exhibit P, # 17 Exhibit Q, # 18 Exhibit R, # 19 Exhibit S, # 20 Exhibit T, # 21 Exhibit U, # 22 Exhibit V, # 23 Exhibit W, # 24 Exhibit X, # 25 Exhibit Y, # 26 Exhibit Z, # 27 Exhibit AA, # 28 Exhibit BB, # 29 Exhibit CC, # 30 Exhibit DD)(Sorenson, Jennifer)

EXHIBIT Z
TO DECLARATION OF
JENNIFER A. SORENSON
Excerpt from Institute of Medicine, Microbial Threats to Human Health:
Emergence, Detection, and Response (2003)

Microbial Threats to Health: Emergence, Detection, and Response
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MICROBIAL THREATS TO HEALTH
EMERGENCE, DETECTION, AND RESPONSE

Mark S. Smolinski, Margaret A. Hamburg,
and Joshua Lederberg, Editors
Committee on Emerging Microbial Threats to Health
in the 21st Century
Board on Global Health

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MICROBIAL THREATS TO HEALTH

termined to be the appropriate drug in this situation, and an ample supply
was readily available. The same may not be true when the next influenza
pandemic eventually occurs, likely resulting in tens of thousands of deaths.
Although stockpiling of antiviral drugs for influenza is a component of the
pandemic plan developed by the United States and WHO (WHO, 1999e),
we have yet to begin stockpiling antivirals effective against influenza. The
time has come to move forward with this plan and determine which drugs
are needed; the quantity required; the costs of production, storage, and
distribution; and the authority under which the drugs will be used.
The U.S. Secretary of Health and Human Services and the U.S.
Secretary of Homeland Security should protect our national security by ensuring the stockpiling and distribution of antibiotics, antivirals (e.g., for influenza), and antitoxins for naturally occurring
or intentionally introduced microbial threats. The federal government should explore innovative mechanisms, such as cooperative
agreements between government and industry or consortia of government, industry, and academia, to accelerate these efforts.
INAPPROPRIATE USE OF ANTIMICROBIALS
For a variety of reasons previously discussed, the pharmaceutical industry is developing fewer new antimicrobials than in previous years. Whereas
it appeared at one time that an endless supply of effective new drugs to treat
resistant infections would exist, such is no longer the case. Therefore, immediate action must be taken to preserve the effectiveness of available
drugs.
Factors leading to the increasing problem of antimicrobial resistance
are well known and understood. Many genes for resistance occur on cassettes that can move between organisms, across species boundaries
(Leverstein-van Hall et al., 2002), and between chromosomes and plasmids. Resistance genes in bacteria are commonly grouped together on the
same mobile genetic elements, with the crucial practical consequence that
the use of any single drug may select for resistance to a wide group of drugs.
Thus, an antimicrobial employed in food and animal production that has
never before been used to treat infection in humans can select for resistance
to other drugs used to treat humans.
Resistant bacteria often persist in vivo even in the absence of continued
selection by antibiotics, although in some cases resistance gradually diminishes once antibiotic pressures have been reduced. One explanation for
continued resistance involves the lethal effect of the loss of certain plasmids
when bacteria divide. Some resistant microbes are less fit, but resistant
strains arising in a clinical context are generally virulent and can often

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persist for extended periods of time once established. Therefore, it is imperative to actively pursue and address the problem; it will be too late to
effect useful change once most microbes have become resistant to the available drugs.
Antibiotic resistance resulting from the inappropriate overuse of antibiotics is not a new problem. A number of expert committees and professional organizations have studied the problem, issued reports, and made
recommendations (Alliance for the Prudent Use of Antibiotics, 2001; CDC,
2001o; FDA, 2000; GAO, 1999; Center for Science in the Public Interest,
1998; NRC, 1999). Unfortunately, little has been done to change the situation, especially in the United States. Resistance due to the inappropriate use
of antibiotics compromises the efficacy of many classic and highly effective
antibiotics, such as penicillin for pneumococci and vancomycin for enterococci, as well as that of some newer antibiotics, such as ciprofloxacin and
other types of fluorinated quinolones for gonococci, Salmonella, and
Campylobacter. The recent discovery of an enterococcal gene for vancomycin resistance in S. aureus was alarming even though it had been predicted
on the basis of the ability of the genes to transfer across species boundaries
during mixed culture (CDC, 2002d). In the case of enterococcal and staphylococcal infection, alternative therapies have been introduced, but resistance to these new drugs has already been documented (Tsiodras et al.,
2001; Herrero et al., 2002). The specter of untreatable infections—a regression to the pre-antibiotic era—is looming just around the corner.
Preventing the overuse of antimicrobials is not an easy task because of
the revolutionary effects the drugs have had on human and animal health.
Because antimicrobials are highly effective, there is an understandable tendency to use them in any situation in which they might be helpful. These
effective drugs are relatively inexpensive compared with other medical interventions. Patients demand the drugs when they have an illness they
imagine to be treatable with antibiotics. Doctors prescribe antibiotics for
that same reason, often in the absence of diagnostic tests to determine the
etiology of infection, and also because patients want and expect to be
treated with them. In many areas of the world where little money is available for health care, antimicrobials are readily available without a doctor’s
prescription, and as a result are often taken unnecessarily or inadequately.
Many problems associated with antimicrobial resistance have arisen in
poor and developing areas of the world, and have subsequently spread
globally.
In addition to avoiding the inappropriate use of antibiotics to treat viral
disease, prudence dictates use of the appropriate antimicrobial when an
etiologic diagnosis is made. For example, the rapid rise in drug-resistant
malaria has led to the development of newer, generally more expensive
therapies for the disease. This in turn has resulted in an increase in the

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prescribing of these newer drugs, even in areas where there is no demonstrated resistance to first-line therapies. The use of first-line therapies must
be continued in areas where resistance has not been documented, and newer
therapies should be used only when first-line therapies are ineffective or in
areas of resistance. To this end, it is essential to monitor resistance patterns
around the world.
Decreasing Inappropriate Use of Antimicrobials in Human Medicine
Decreasing the inappropriate use of antimicrobials in human medicine
is a complex task that requires a multipronged effort fueled by a sense of
urgency. The inappropriate use of antibiotics for treatment of viral diseases
can be averted by the increased use of available diagnostic tests and the
development of better point-of-care, inexpensive, rapid, sensitive, and specific diagnostic tests, which would enable the rational use of new antivirals
as they become available (see the earlier discussion of the development of
diagnostics). The decreased use of antibacterials for viral respiratory infections and other syndromes should lessen selective pressures for the emergence of resistant bacteria. FDA has recently included this message on label
inserts of antibiotics.
If this important objective is to be achieved, the general public and
health care providers must be better educated and informed about the
importance of administering antimicrobial therapy properly. The need is
urgent to both educate and monitor all categories of practitioners and drug
dispensers in developing countries where medicines are sold directly to the
public over the counter and dispensed by private practitioners in an ad hoc
manner. More attention needs to be given to improving practitioner education and compliance. Patient care would be improved by the development
and dissemination of better evidence-based treatment guidelines. More research is needed on methods for treating infections to minimize the emergence of resistance without a loss of efficacy. Infection control programs
must be supported in hospitals in an effort to decrease the transmission of
resistance both within the hospitals and in the community. Surveillance for
patterns of resistance in hospitals and in the community must be continued
and expanded; this will require a coordinated effort among public health
organizations, private medicine, and industry. Because resistant microbes
arise throughout the world and travel broadly to all regions, the needs and
problems of the economically and health care disadvantaged regions of the
world must be considered.
The world is facing an imminent crisis in the control of infectious
diseases as the result of a gradual but steady increase in the resistance of a
number of microbial agents to available therapeutic drugs. Although defining the precise public health risk of emergent antimicrobial resistance is not

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a simple task, there is no doubt that the problem is of global concern and is
creating dilemmas for the treatment of infections in both hospitals and
community health care settings.
CDC, FDA, professional health organizations, academia, health
care delivery systems, and industry should expand efforts to decrease the inappropriate use of antimicrobials in human medicine
through (1) expanded outreach and better education of health care
providers, drug dispensers, and the general public on the inherent
dangers associated with the inappropriate use of antimicrobials,
and (2) the increased use of diagnostic tests, as well as the development and use of rapid diagnostic tests, to determine the etiology of
infection and thereby ensure the more appropriate use of antimicrobials.
Decreasing Inappropriate Overuse of Antimicrobials
in Animal Husbandry and Agriculture
Clearly, a decrease in the inappropriate use of antimicrobials in human
medicine alone is not enough. Substantial efforts must be made to decrease
inappropriate overuse of antimicrobials in animals and agriculture as well.
Although estimates vary widely, the total amount of antimicrobials
used in Europe and the United States in animal husbandry and agriculture
far outweighs the total used in humans (McEwen and Fedorka-Cray, 2002).
The majority of this use is for growth promotion or preventive therapy in
healthy animals. Mounting evidence suggests a relationship between antimicrobial use in animal husbandry and an increase in bacterial resistance in
humans (Alliance for the Prudent Use of Antibiotics, 2002), a view supported by an IOM committee that reviewed the use of drugs in food animals (IOM, 1999b). The use of antimicrobials in food animals leads to
antibiotic resistance, which can then be transmitted to humans through the
food supply (Swartz, 2002; Fey et al., 2000; Smith et al., 2002; White et al.,
2001).
A study published in 2001 found that 20 percent of ground meat
samples obtained from supermarkets in the Washington, D.C., metropolitan area were contaminated with Salmonella. Of these bacteria, 84 percent
were resistant to at least one antibiotic and 53 percent to at least three
antibiotics (White et al., 2001). This study supports previous findings that
foods of animal origin are potential sources of ceftriaxone-resistant Salmonella infections in humans. Similarly, researchers found that between 17
and 87 percent of chickens obtained in supermarkets in four states contained strains of Enterococcus faecium that were resistant to quinupristin–

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dalfopristin, an approved antimicrobial for use in humans (McDonald et
al., 2001). The researchers believed that the use of virginiamycin, an antibiotic of the streptogramin group, in farm animals had created a reservoir of
streptogramin–resistant E. faecium in the food supply, which could contribute to foodborne dissemination of resistance as the clinical use of
quinupristin–dalfopristin increases.
Substantial evidence supports that certain types of resistant organisms,
such as vancomycin-resistant enterococci, emerged initially in animals because of the use of similar drugs for growth promotion or prophylaxis
(O’Brien, 2002). Consideration of this association led to a ban on the use of
avoparacin, a vancomycin analogue, in Europe (Wegener et al., 1999). The
decreased use of antimicrobials for growth promotion or prophylaxis in
many European countries has been associated with a subsequent stabilization in resistance or a gradually decreasing resistance in animal flora
(Aarestrup et al., 2001). WHO has called for all antimicrobials used for
disease control in food animals to be prescribed by veterinary health care
providers, and for termination or rapid phase-out of antimicrobials used
for growth promotion if they are used for human treatment (WHO, 2000f).
Various other groups have suggested that because of the increasing risk of
antimicrobial resistance, the subtherapeutic use of antibiotics for growth
promotion should be banned (some would include use for prophylaxis in
the ban as well) if they are also used in humans (Union of Concerned
Scientists, 2002; Alliance for the Prudent Use of Antimicrobials, 2002).
The main argument against a ban is the potential economic hardships
to livestock and poultry producers, which would result in higher costs for
consumers. According to the IOM Committee on the Use of Drugs in Food
Animals, such a ban would increase the price of meat by an estimated 0.013
to 0.06 cents per pound; this translates to $4.84 to $9.72 per person each
year, depending on the meat and the cut (IOM, 1999b). Yet, evidence
suggests that animals can be raised efficiently without the use of growthpromoting antimicrobials (Emborg et al., 2001; Wierup, 2001).
Critics of the ban also argue that it would result in poorer production
efficiency and an increased incidence of infectious disease in animals. However, it has been noted that subtherapeutic antibiotics are most effective in
animals under the stress of inadequate nutrition and suboptimal sanitary
conditions (Braude et al., 1953); therefore, improved hygiene and changes
in animal husbandry practices to control disease could potentially eliminate
the need for growth promoters (Emborg et al., 2001). In Denmark, the
elimination of antimicrobial growth promoters from broiler chicken feed
did not result in a change in death rates or a decrease in kilograms of
broilers produced per square meter. Danish scientists also reported that the
decreased use of virginiamycin and avilamycin in animals was followed by
decreases in resistance to these drugs (Aarestrup et al., 2001).

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FDA should ban the use of antimicrobials for growth promotion
in animals if those classes of antimicrobials are also used in humans.
The committee endorses the Public Health Action Plan to Combat
Antimicrobial Resistance developed by the Interagency Task Force on Antimicrobial Resistance and the recommendations of the WHO Global Strategy for the Containment of Antimicrobial Resistance (see Boxes 4-9 and 410). Although the broad scope of these recommendations defies easy
implementation, we must seize the opportunity immediately to do as much
as we can while organizing the resources and plans needed to carry out
other initiatives. To do nothing is, in effect, to allow the continued evolution of antimicrobial-resistant microbes, which poses serious near- and
long-term threats to global health. The total burden of human illness due to
resistant bacteria that have been transferred from animals to humans is
unknown, but the guiding principle should be that we must do what the
available evidence suggests will help stem the tide of increasing resistance
before it is too late. By endorsing these recommendations, we will join
belatedly much of the rest of the developed world, which already has made
similar recommendations and, in many cases, implemented them. These
changes should be accompanied by substantial outcomes research on the
effects on animal health, resistance prevalence in animals and humans, and
the economics of food production.
VECTOR-BORNE AND ZOONOTIC DISEASE CONTROL
The majority of emerging infectious diseases are zoonoses (i.e., diseases
transmitted from animals to humans under natural conditions). Vectorborne and rodent-borne diseases are especially notable in this regard, remaining major causes of morbidity and mortality in humans in the tropical
world and representing a large proportion of newly emerged diseases (see
the discussion in Chapter 3). Exacerbating the situation is the potential for
many of these agents to be weaponized and used by bioterrorists. Because
of their resurging public health importance and their exceptional ability to
cause epidemics, vector-borne and zoonotic diseases will undoubtedly continue to pose significant risks to human health in the future.
Unfortunately, the national and international capacity to address these
diseases is limited. The many reasons for this include (1) the lack of efficacious vaccines for many of these pathogens; (2) decreased support for and
deterioration of the public health surveillance and control infrastructure for
vector-borne and zoonotic diseases; (3) erosion in the numbers of scientists
trained in relevant fields, including medical entomology, vector ecology,
zoonoses, and tropical medicine; (4) the development of resistance to drugs

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BOX 4-9
WHO Global Strategy for Antimicrobial Resistance
In response to the growing problem of antibiotic resistance, WHO has worked
with many partners, including the American Society for Microbiology and the Alliance for the Prudent Use of Antibiotic (APUA), to develop the WHO Global Strategy for Containment for Antimicrobial Resistance. The seven key recommendations emanating from the 25 expert reports used to formulate the strategy are
summarized below.
Increase Awareness of the
Antibiotic Resistance Problem
International organizations:
Obtain worldwide commitments to
establish prudent antibiotic use
policies
National and municipal organizations:
Publicize the outcomes of programs
from other countries
Educate the general public
Promote communication
Evaluate the curricula of universities
Health care institutions:
Use effective teaching methods for
education prescribers
Health care workers:
Educate the general public
Improve Surveillance of Antibiotic
Resistance
National and municipal organizations:
Coordinate local surveillance
networks
Recruit leaders for surveillance
networks
Support a reference laboratory
Share results of surveillance with
international organizations
Monitor resistance in food animals
Monitor sentinel human populations
Health care institutions:
Develop local surveillance network
Maintain a laboratory with adequate
quality assurance and trained
technicians

Health care workers:
Initiate a local surveillance network
Pharmaceutical companies:
Undertake postmarking surveillance
to detect the emergence of
resistance to new antibiotics
Support surveillance networks
Improve Antibiotic Use in People
National and municipal organizations:
Enforce the prudent use of
antibiotics
Create national and regional
guidelines
Update guidelines based on
surveillance data
Eliminate financial incentives that
promote the misuse of antibiotics
Monitor advertising
Consider the impact of new drugs
on resistance during the drug
approval process
Limit general access to new drugs
Establish postmarking surveillance
accords
Health care institutions:
Establish an Infection Control
Committee
Establish a Drugs and Therapeutics
Committee
Establish guidelines for appropriate
antibiotic use
Appoint an antimicrobial resistance
monitor
Reduce the spread of infection
Create pharmacy reports

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Establish and disseminate list of
essential drugs
Educate employees
Maintain a laboratory
Health care workers:
Prescribe antibiotics prudently
Improve hygiene
Improve Antibiotic Use in Animals
National and municipal organizations:
Increase awareness of the antibiotic
resistance problem
Regulate antibiotic prescriptions for
animals
Restrict growth promoter use in
animals
Regulate antibiotic use in animals
Set a risk standard for resistance
Consider human and nonhuman
uses simultaneously
Monitor advertising
Veterinarians:
Promote a prudent use of
antibiotics in animals
Develop local guidelines for
antibiotic use
Food animal producers:
Improve farm hygiene
Reduce the use of antibiotics as
growth promoters
Improve animal husbandry
Researchers:
Perform risk–benefit analysis of
growth promoter use
Assess environmental impact
Examine food processing and
distribution methods

Encourage New Product
Development
National and municipal organizations:
Provide incentives to industry
Protect intellectual property rights
Facilitate networking
Pharmaceutical companies:
Increase research and development
in several areas
Increase Resources to Curb
Antibiotic Resistance in the
Developing World
International organizations:
Share results of surveillance
internationally
Secure technical and financial
support for developing countries
Invest in a worldwide vaccine
strategy to reduce antibiotics
Ensure the availability of vaccines
and quality drugs
Facilitate communication among the
countries of the world
Safeguard privacy and human
rights
Promote appropriate international
laws
National and municipal organizations:
Decrease the risk of infectious
disease
Ensure antibiotic availability
Share resources with other
countries
Increase Funding for Surveillance,
Research, and Education
National and municipal organizations:
Increase funding for a surveillance
network
Increase funding for research
Increase funding for education

SOURCE: World Health Organization, 2001i.

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