[Federal Register Volume 68, Number 25 (Thursday, February 6, 2003)]
[Rules and Regulations]
[Pages 6062-6081]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-2969]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 00N-1463]
RIN 0910-AB78


Labeling Requirements for Systemic Antibacterial Drug Products 
Intended for Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations to require that the labeling for all systemic antibacterial 
drug products (i.e., antibiotics and their synthetic counterparts) 
intended for human use include certain statements about using 
antibiotics in a way that will reduce the development of drug-resistant 
bacterial strains. The final rule reflects a growing concern in FDA and 
the medical community that unnecessary use of systemic antibacterials 
has contributed to a dramatic increase in recent years in the 
prevalence of drug-resistant bacterial infections. The final rule is 
intended to encourage physicians to prescribe systemic antibacterial 
drugs only when clinically necessary. The final rule is also intended 
to encourage physicians to counsel their patients about the proper use 
of such drugs and the importance of taking them exactly as directed.

DATES: This rule is effective February 6, 2004.

FOR FURTHER INFORMATION CONTACT: Christine F. Rogers, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
II. Highlights of the Final Rule
III. Comments on the Proposed Rule
    A. Statements of Support
    B. Sources and Frequency of Antibiotic Resistance
    C. Influence of Labeling
    D. Alternatives and General Comments
    E. Scope and Implementation
    F. Location of Statements
    G. Statements Under the Product Name and in the ``Precautions'' 
Section
    H. Culture and Susceptibility Tests
    I. Local Epidemiology and Susceptibility Patterns
    J. Practice of Medicine
    K. Information for Patients
IV. Environmental Impact
V. Analysis of Impacts
    A. Objective of the Final Rule
    B. Costs of Regulation
    C. Benefits
    D. Impacts on Small Entities
VI. Paperwork Reduction Act of 1995
VII. Federalism
VIII. References

I. Background

    In the Federal Register of September 19, 2000 (65 FR 56511), FDA 
proposed to amend its regulations to require that the labeling for all 
systemic antibacterial drug products (i.e., antibiotics and their 
synthetic counterparts) intended for human use include certain 
statements about using antibiotics in a way that will reduce the 
development of drug-resistant bacterial strains. The new labeling is 
intended to help educate physicians and the public about the resistance 
problem and to encourage physicians to prescribe systemic antibacterial 
drugs only when clinically necessary. FDA personnel involved in 
drafting the statements included practicing physicians who are in a 
position to evaluate the effect of the labeling on physicians. The 
statements were also reviewed by other practicing physicians in the 
agency.
    Antibacterial resistance among disease-causing bacteria represents 
a serious and growing public health problem in the United States and 
worldwide. Many bacterial species, including the species that cause 
pneumonia and other respiratory tract infections, meningitis, and 
sexually transmitted diseases, are becoming increasingly resistant to 
the antibacterial drugs used to treat them. Several bacterial species 
have developed strains that are resistant to every approved antibiotic, 
thus severely limiting the therapeutic options available for adequate 
treatment. The incidence of resistance in both hospital- and community-
acquired infections has increased dramatically in the past several 
years, making many common illnesses more difficult to treat than they 
were only 5 or 10 years ago.
    According to the Centers for Disease Control and Prevention (CDC), 
half of the 100 million antibiotic prescriptions a year written by 
office-based physicians in the United States are unnecessary because 
they are prescribed for the common cold and other viral infections, 
against which antibiotics are not effective (Ref. 1). Unnecessary use 
of antibiotics in hospitals is common as well. The more an antibiotic 
is used, the more likely it is that bacteria will develop resistance to 
it. Thus, using antibiotics when they are not necessary contributes to 
the increasing prevalence of antibacterial resistance without providing 
any patient benefit.
    Educating physicians and the public about the resistance problem 
and discouraging unnecessary use of antibiotics are important steps to 
decrease the prevalence of antibacterial resistance and slow its future 
development and spread. FDA believes that professional labeling has an 
important role in that educational effort. Therefore, FDA is requiring 
that the labeling for systemic antibacterial drug products include 
certain statements about unnecessary use of antibiotics and the link 
between such use and the emergence of drug-resistant bacterial strains.
    Recent reports of a reduction in antibiotic prescribing raise the 
hope that the trend in overuse of antibiotics can be reversed and 
provide additional support for the need to include information in 
labeling to ensure the continued safety and efficacy of antibiotics 
(Refs. 2 and 3). The studies reported were conducted in children seen 
in outpatient practice and have not been confirmed in either adults or 
hospitalized patients. Nevertheless, as the authors of the two studies 
and the editorial (Ref. 4) that accompanied them note, efforts to 
promote the appropriate use of antibiotics have likely contributed to a 
decrease in antibiotic prescribing. These authors observe that it is 
important to continue such efforts if these gains are to be maintained. 
The authors cite the ongoing role of the U.S. Public Health Service 
Action Plan (Ref. 5) to combat antimicrobial resistance. FDA is one of 
the three lead agencies for this plan. The plan indicates that 
educational efforts should be one of the highest priorities and placing 
information on the labeling of systemic antimicrobial products is 
specifically cited in the plan.

II. Highlights of the Final Rule

    The final rule amends FDA regulations to require that all systemic 
antibacterial drug products (i.e., antibiotics and their synthetic 
counterparts) intended for human use contain additional labeling 
information

[[Page 6063]]

about the emergence of drug-resistant bacterial strains.
    The final rule has been revised in response to comments received on 
the proposed rule. The comments and responses are discussed in section 
III of this document. In the final rule, the agency has significantly 
revised the statements required directly under the product name, in the 
``Indications and Usage'' section, and in the ``General'' subsection of 
the ``Precautions'' section. The agency made minor revisions to the 
statement proposed for the ``Information for Patients'' subsection of 
the ``Precautions'' section. The final rule omits the statement that 
was proposed for the ``Clinical Pharmacology'' section.
    The final rule requires that the labeling for all systemic drug 
products indicated to treat a bacterial infection, except a 
mycobacterial infection, include the following information.
    At the beginning of the label, under the product name, the labeling 
must state that to reduce the development of drug-resistant bacteria 
and maintain the effectiveness of the antibacterial drug product and 
other antibacterial drugs, the drug product should be used only to 
treat or prevent infections that are proven or strongly suspected to be 
caused by bacteria.
    In the ``Indications and Usage'' section, the labeling must state 
that to reduce the development of drug-resistant bacteria and maintain 
the effectiveness of the antibacterial drug product and other 
antibacterial drugs, the drug product should be used only to treat or 
prevent infections that are proven or strongly suspected to be caused 
by susceptible bacteria. The labeling must state that, when culture and 
susceptibility information are available, they should be considered in 
selecting or modifying antimicrobial therapy. The labeling must also 
state that in the absence of such data, local epidemiology and 
susceptibility patterns may contribute to the empiric selection of 
therapy.
    In the ``General'' subsection of the ``Precautions'' section, the 
labeling must state that prescribing the antibacterial drug product in 
the absence of a proven or strongly suspected bacterial infection of a 
prophylactic indication is unlikely to provide benefit to the patient 
and increases the risk of the development of drug-resistant bacteria.
    In the ``Information for patients'' subsection of the 
``Precautions'' section, the labeling must state that patients should 
be counseled that antibacterial drugs, including the antibacterial drug 
product prescribed, should only be used to treat bacterial infections 
and that they do not treat viral infections (e.g., the common cold). 
The labeling must state that when an antibacterial drug product is 
prescribed to treat a bacterial infection, patients should be told 
that, although it is common to feel better early in the course of 
therapy, the medication should be taken exactly as directed. The 
labeling must also advise physicians to counsel patients that skipping 
doses or not completing the full course of therapy may: (1) Decrease 
the effectiveness of the immediate treatment, and (2) increase the 
likelihood that bacteria will develop resistance and will not be 
treatable by the antibacterial drug product or other antibacterial 
drugs in the future.

III. Comments on the Proposed Rule

    FDA received 19 comments on the proposed rule. The comments were 
submitted by pharmaceutical companies, trade associations, individuals, 
and public and private health organizations.

A. Statements of Support

    (Comment 1) Many comments supported the proposed rule. One comment 
expressed the view that the proposal will be another step in building 
public awareness and improving antibiotic use before there is a public 
health emergency. Another comment stated that the proposed rule is an 
important first step in more appropriate use of antimicrobial agents by 
health care workers and that regulatory actions have the potential for 
positive impact on the problem of antibiotic resistance. Another 
supportive comment stated that for the label changes to have an impact, 
it will be important to ensure that all antimicrobial drug promotional 
and marketing activities, whether directed at clinicians, health care 
organizations, or the public, explicitly and thoroughly communicate the 
cautions expressed in the rule.
    (Response) FDA recognizes the importance of increasing awareness by 
health care providers and patients about the appropriate use of 
antibiotics and the cautions about antibiotic resistance. FDA will work 
with sponsors on ways that these important messages can best be 
communicated.

B. Sources and Frequency of Antibiotic Resistance

    (Comment 2) The agency received many comments concerning the 
sources of antibiotic resistance. One comment contended that the 
proposed labeling statements imply that inappropriate use of 
antibiotics is the only reason for the development of resistance, a 
notion with which the comment disagreed. Another comment maintained 
that more likely causes of resistance than individual misuse of 
antibiotics are a breakdown in basic infection control practices and 
hygiene (e.g., hand washing, immunization, adequate personal care in 
daycare centers for children and adults). Another comment cited 
daycare, veterinary use, and improper hand washing as reasons for 
antibiotic resistance. This comment also stated that even if doctors 
prescribe appropriately, resistance to antibiotics will still occur 
because of selection of resistant strains arising from normal 
physiological spontaneous mutations.
    One comment stated that the emergence of resistance involves many 
factors including intrinsic properties of the drug, such as whether it 
has a static or cidal mechanism of action and the nature of its 
cellular target, and extrinsic considerations, such as the target 
organism, the health of the patient, the type and site of infection, 
and prior exposure of the patient to antibiotics. Another comment 
stated that the proposal ignores other factors involved in minimizing 
resistance and determining clinical outcome. These factors include 
pharmacodynamic data, including information on tissue or drug 
concentrations at the site of infection, and host factors, such as risk 
for resistant bacterial infections.
    (Response) FDA believes labeling concerning antibiotic resistance 
has the potential to make a significant contribution toward the goal of 
reducing resistance. The agency is aware, however, that many factors 
contribute to antibiotic resistance and that there need to be efforts 
on many fronts to combat the resistance problem. FDA's proposal does 
not imply that the wisest use of antibiotics by physicians would 
eliminate the resistance problem entirely. FDA agrees that, regardless 
of the measures adopted, some level of antibiotic resistance will be 
present because of the selection of resistant strains that arise during 
normal bacterial reproduction.
    This final rule is one of many ongoing efforts by FDA to combat 
antibiotic resistance. FDA has previously and will continue to organize 
and participate in numerous advisory committee meetings, open public 
meetings, and workshops with industry and academia to focus on 
strategies to encourage the development of new antimicrobials while 
preserving the usefulness of existing drug products. Past meetings have 
already led to changes in the collection of clinical data by 
stakeholders that will ultimately shorten the development time of 
future antimicrobial products. The agency has an ongoing partnership 
with other

[[Page 6064]]

government agencies and medical organizations to educate the public 
about the proper use of antimicrobials and the risks of inappropriate 
use. FDA has recently awarded a contract to a company to obtain 
antimicrobial resistance surveillance information in an effort to help 
the agency identify resistant organisms that pose a significant health 
threat to the public.
    (Comment 3) One comment agreed that any use of antibiotics may 
increase selective pressure, but stated that decreased effectiveness of 
antibiotics is a greater clinical concern in empiric therapy when 
microbiological data for a particular patient are not readily 
available.
    (Response) Existing antibiotics may become less effective because 
of antibiotic resistance. Thus, reducing the development of resistance 
and maintaining the effectiveness of existing antibiotics are 
intertwined goals. FDA's concern with these goals is indicated in the 
revised statement to appear under the product name, which advocates 
using antibiotics only for bacterial infections in order to reduce the 
development of drug-resistant bacteria and maintain the effectiveness 
of existing antibiotics.
    (Comment 4) One comment objected to the general nature of the 
proposed labeling statements because certain antibiotics, for example 
cephalosporins, are more likely to be associated with the development 
of resistance than others. Another comment stated that newer 
antibiotics are less likely to generate resistance. The comment also 
stated that the differences in in vitro frequency of resistance in 
different classes of antibiotics suggest that continued research can 
decrease the frequency of resistance by emphasizing, in drug 
development, factors such as area under the curve/minimum inhibitory 
concentration (MIC) and maximum concentration (Cmax)/MIC ratios. 
Another comment maintained that there should be greater emphasis on the 
use of pharmacokinetic (PK) and pharmacodynamic (PD) data to provide 
clinically relevant information to establish which antibiotics are 
likely to maximize efficacy and minimize the risk of developing 
resistance. The comment stated that this suggestion accords with the 
FDA Anti-Infectives Advisory Committee's recommendation that the PK/PD 
relationship for antibiotics be investigated during drug development.
    (Response) The final rule affects all systemic antibacterial 
products because all antibiotics develop resistance, even though the 
frequency of resistance can vary among different antibiotics. FDA 
supports efforts by pharmaceutical companies to investigate PK/PD 
relationships during drug development. However, it would not be 
appropriate at this time to require PK/PD information in the labeling 
of antibiotic drug products. A number of factors limit the usefulness 
of PK/PD relationships in clinical practice. First, it has not been 
established that population PK/PD relationships are predictive of 
outcomes in individual patients. Second, there are practical obstacles 
to the use of this information by physicians. To make use of a PK/PD 
relationship, the physician would have to have access to PK 
information, that is the level of antibiotic in the patient's blood, 
and PD information, the MIC for the specific strain of bacteria. 
Measuring antibiotic levels in patients' blood requires specialized 
testing that is not available on an outpatient basis and may not even 
be available in hospitals. As discussed in section III.H of this 
document, susceptibility testing is often not performed. Even if 
susceptibility data were available, the information may not be provided 
quantitatively so that it can be used in a PK/PD ratio.
    (Comment 5) One comment maintained that all antimicrobials have 
built-in obsolescence, and thus there will be a natural progression of 
selection for resistance regardless of how appropriately doctors 
prescribe antibiotics.
    (Response) Regardless of whether all antibiotics will eventually 
lead to resistant bacteria, there are great benefits to delaying that 
progression as long as possible. As stated previously, there is a 
strong correlation between the improper use of antibiotics and the 
incidence of antibiotic drug resistance. The CDC estimates that as much 
as 50 percent of antibiotic use is unnecessary, that is, prescribed for 
diseases like the common cold that do not respond to antibacterial 
drugs. Judicious physician prescribing of antimicrobial agents and 
proper antibiotic usage by patients play an important role in slowing 
down the natural progression of selection for resistance to 
antibiotics. For example, limiting the use of erythromycin in Finland 
decreased the rate of resistance to this drug in group A streptococci 
causing sore throats by approximately 50 percent.

C. Influence of Labeling

    (Comment 6) Some comments suggested that doctors will probably not 
be influenced by the proposed labeling. One comment stated that since 
doctors treat infections empirically despite advice in current labeling 
to determine the causative agent, it is unlikely that the new labeling 
will influence doctors' behavior. One comment stated that FDA's 
Director of the Office of Postmarketing Drug Risk Assessment expressed 
the opinion that labeling changes do not alter doctors' prescribing 
practices. Another comment expressed the view that doctors are already 
aware of the information contained in the proposed labeling and 
therefore might be offended by the labeling or might not read the 
warnings. Another comment stated that it is questionable whether 
prescribers read package inserts thoroughly because of their length and 
small print. Another comment contended that before adopting the 
proposal, FDA should assess whether physicians understand the proposed 
labeling and change their behavior as a result. One comment stated that 
FDA should send periodic letters to prescribers giving updates on 
antibiotic resistance and prudent use of antibiotics because doctors 
may not read package inserts.
    (Response) Antibiotic resistance is a serious public health problem 
that needs to be addressed by a major educational effort. FDA believes 
that physician labeling can contribute to that effort by reminding 
physicians that their individual prescribing decisions have a 
collective impact on the resistance problem. The agency believes that 
physicians frequently consult selected portions of the package insert 
and thus will encounter one or more of the statements on antibiotic 
resistance that appear in multiple, significant locations in the 
package insert. The agency believes that the prominence of the 
statement under the product name will be particularly likely to have an 
effect on prescribing decisions. FDA believes it is important to 
institute labeling discussing antibiotic resistance as soon as possible 
because it will be an important step in addressing the resistance 
problem; therefore, the agency declines to adopt the suggestion to 
measure the effect of the labeling before adopting the rule. The agency 
also rejects the suggestion to send ``Dear Doctor'' letters; the 
package insert, rather than letters, is FDA's primary tool for 
communicating with physicians.

D. Alternatives and General Comments

    (Comment 7) Many comments stated that labeling is not the best way 
to accomplish the goal of reducing antibiotic resistance and suggested 
alternative mechanisms. Several comments suggested using educational 
and scientific forums to educate doctors. Organizations mentioned as 
appropriate to provide educational programs included pharmaceutical 
companies

[[Page 6065]]

and pharmaceutical industry trade organizations, the American Medical 
Association (AMA), and the CDC in conjunction with FDA.
    (Response) The agency agrees that labeling alone will not be 
sufficient to reduce or prevent antibiotic resistance. This final rule 
is one of many ongoing efforts by FDA to combat antibiotic resistance. 
FDA has previously and will continue to organize and participate in 
numerous advisory committee meetings, open public meetings, and 
workshops with industry and academia to focus on strategies to 
encourage the development of new antimicrobials while preserving the 
usefulness of existing drug products. Past meetings have already led to 
changes in the collection of clinical data by stakeholders which will 
ultimately shorten the development time of future antimicrobial 
products. The agency has an ongoing partnership with other government 
agencies and medical organizations to educate the public about the 
proper use of antimicrobials and the risks of inappropriate use. FDA 
has recently awarded a contract to a company to obtain antimicrobial 
resistance surveillance information in an effort to help the agency 
identify resistant organisms that pose a significant health threat to 
the public.
    (Comment 8) One comment urged FDA to focus on the effective 
implementation of existing guidelines, such as the CDC guidelines for 
the treatment of acute otitis media in children and the Sinus and 
Allergy Health Partnership guidelines for the treatment of acute 
bacterial sinusitis, as a means of addressing antibiotic resistance. 
The comment added that these guidelines are both comprehensive and able 
to be updated as new information becomes available, whereas labeling 
cannot be updated quickly.
    (Response) Many responsible organizations issue guidelines for the 
treatment of various types of bacterial infections. FDA supports these 
efforts and has worked with many of the sponsoring organizations to 
develop guidelines for clinical studies and related matters. The agency 
disagrees that labeling cannot be updated as quickly as guidelines. 
Guidelines for the treatment of bacterial infections are not usually 
revised more often than every 2 years. If necessary, FDA's professional 
labeling can be revised in 2 years.
    (Comment 9) Another comment stated that peer review of 
antimicrobial use and prescribing practices is preferred over static 
treatment guidelines and restrictions, given the complexity of the 
decisionmaking process in evaluating patients.
    (Response) The labeling statements required by this final rule are 
not static treatment guidelines or restrictions. Furthermore, nothing 
in the final rule forecloses the use of peer review as a way of 
reducing antibiotic resistance. FDA recognizes that many different 
approaches can assist physicians in making good prescribing decisions.
    (Comment 10) One comment asserted that resistant infections are 
most often acquired in hospitals and then spread to the community and, 
therefore, FDA should work with public health agencies and state boards 
of health to establish more effective hospital infection-control 
programs, rather than addressing the resistance problem through 
labeling.
    (Response) FDA is working with the CDC and other public health 
agencies to establish more effective hospital infection-control 
programs and to develop means for educating physicians and 
communicating current information on the resistance problem. However, 
the agency believes that antibiotic resistance labeling is also needed 
as a part of a multifaceted attack on the resistance problem. FDA also 
notes that some resistant organisms, for example, penicillin-resistant 
Streptococcus pneumoniae, are acquired in the community, rather than in 
the hospital.
    (Comment 11) One comment endorsed the development and 
implementation of a coordinated plan for monitoring antimicrobial 
resistance at the local level using standardized tests. This comment 
stated that the use of universally accepted standard tests is critical 
to the consistent and meaningful interpretation of surveillance data 
throughout the United States and that these standards need to be in 
place before collecting and collating surveillance data. Without such 
standards, collated surveillance data would be difficult to interpret 
and of very limited value.
    (Response) FDA is working with the CDC and other agencies to 
develop tools and methods that will allow for a coordinated plan for 
monitoring antibiotic resistance. However, efforts to curb the 
development of antibiotic resistance should not be delayed pending the 
creation of such a monitoring plan.
    (Comment 12) Another comment suggested requiring a special 
prescription blank for antimicrobials, formatted to include FDA 
criteria for prescribing antibiotics, and placing the responsibility on 
pharmacists to ensure that the criteria are met.
    (Response) Such a restriction would be extraordinarily difficult to 
implement because of the large number of systemic antibacterial 
products. The agency believes that measures less restrictive of medical 
practice are more reasonable at this time.
    (Comment 13) One comment recommended that marketed antibiotics be 
evaluated and that older products with higher potential for inducing 
resistance (i.e., poor PKs and/or potency, single-step resistance 
development) be retired in favor of newer antibiotics with optimized 
PKs, potency, and multiple-step pathways. This comment contended that 
doctors need to be educated to prescribe improved antibiotics and 
asserted that the rule might hinder this goal.
    (Response) FDA does not agree that newer antibiotics are 
necessarily preferable to older ones. While some newer antibiotics may 
require more than one pathway to develop resistance, newer antibiotics 
tend to be broad-spectrum, which, in itself, can increase the 
development of resistance.
    (Comment 14) One comment stated that the antibiotic labeling 
proposal should be coordinated with other agency labeling initiatives.
    (Response) Rulemaking requires an opportunity for the public to 
comment and thus have input into proposed agency actions. To make it 
easy for the public to comment on only those issues that are of 
interest, FDA generally pursues separate rulemakings for labeling 
proposals concerning different subjects. FDA has proposed to revise the 
content and format of labeling for prescription drugs (physician 
labeling rule) (65 FR 81082, December 22, 2000). The agency has 
received comments on the proposal and is in the process of finalizing 
it. Whether the requirements of the physician labeling rule will apply 
to a systemic antibacterial drug product will depend on the approval 
date of that product. For those systemic antibacterial drug products 
that must comply with the physician labeling rule by using the new 
format, the final physician labeling rule will explain where in the new 
format the statements required by Sec.  201.24 should be placed and 
when implementation of the new format must be completed.

E. Scope and Implementation

    (Comment 15) A number of comments addressed the scope of the 
proposal. One comment stated that resistance can also develop from 
using topical, veterinary, and antimycobacterial antibiotics, and that 
there should be education about all these sources. One comment stated 
that the proposed rule should also apply to prescription and over-the-
counter (OTC) otic, ophthalmic, and topical agents. One

[[Page 6066]]

comment suggested that FDA propose another rule that would cover 
antimycobacterials, topical antibiotics, and antiseptics. Another 
comment stated that the proposal should cover topical products because 
they are sometimes an alternative to systemic antibacterials. Another 
comment questioned the exclusion of drugs to treat tuberculosis. 
Another comment anticipated that statements concerning antibiotic 
resistance will eventually be included in the labels of antiparasitic, 
antiviral, antifungal, and antimycobacterial agents, topical 
antibacterials, and topical antiseptics. This comment recognized that 
labeling for these products involves unique challenges, but expressed 
the view that development of resistance to these types of agents is a 
real or potential problem that may be aggravated by inappropriate use.
    (Response) Prescription and OTC topical antibacterials, topical 
antiseptics, antimycobacterial drugs, and veterinary antibiotics raise 
different scientific and regulatory issues than do systemic 
antibacterials. The agency is considering how to address concerns about 
the development of antibiotic resistance from the use of these other 
types of products and will consider whether additional rulemaking would 
be appropriate.
    (Comment 16) A few comments requested clarification of the scope of 
the proposed rule. One comment asked if the rule would apply to oral 
antibiotics or intravenous (IV) antibiotics, or both. Another comment 
asked whether the proposal would apply to antibiotics such as 
clarithryomycin and rifampin that are used for mycobacterial infections 
as well as for regular bacterial infections.
    (Response) The final rule applies to both oral and IV antibiotics. 
The final rule applies to all systemic antibacterials that are 
indicated for the treatment of bacterial infections, even if, like 
clarithryomycin and rifampin, they are also indicated for the treatment 
of mycobacterial infections.
    (Comment 17) One comment stated that generic antibiotics should be 
held to the same standard as innovator products. Another comment 
asserted that labeling that has already been approved should be 
grandfathered, and the rule should not apply to it. Another comment 
stated that the rule's effective date should be contingent on complete 
implementation of the surveillance, prevention, and control goals 
identified in the joint CDC, FDA, and National Institutes of Health 
``Draft Public Health Action Plan to Combat Antimicrobial Resistance'' 
(65 FR 38832, June 22, 2000).
    (Response) The final rule applies to both generic and branded 
systemic antibacterial drug products. FDA declines to adopt the 
suggestion that the rule not apply to already-approved labeling because 
there is no scientific basis to distinguish between products approved 
before the effective date of the rule and products approved after the 
effective date in terms of causing antibiotic resistance. The agency 
believes it is important to implement the final rule as soon as 
possible and therefore rejects the notion that the effective date 
should be delayed to coordinate the rule with other items in the June 
22, 2000, Action Plan.

F. Location of Statements

    (Comment 18) Many comments expressed the view that requiring 
statements in five locations in the labeling would be redundant. One 
such comment stated that the repetitiveness would clutter the label 
without adding value. Another comment contended that the redundancy of 
the warnings would cause doctors to view them as ``boilerplate noise.'' 
Another comment pointed out that the same statement appears under the 
product name and in the ``Precautions'' section. Another comment stated 
that the statements in the ``Clinical Pharmacology'' section and the 
``Indications and Usage'' section are redundant.
    (Response) In response to these comments, FDA has eliminated the 
statement proposed for the ``Clinical Pharmacology'' section. In 
addition, the same statement does not appear under the product name and 
in the ``Precautions'' section in the final rule; the statements for 
these locations have been revised. As discussed in the response to 
comment 6 in section III.C of this document, FDA recognizes that 
physicians are unlikely to read the package insert in its entirety 
whenever they prescribe an antibiotic. Instead, physicians consult 
selected portions of the package insert. The agency's intent in 
requiring warnings directly under the product name and in the 
``Indications and Usage'' and ``Precautions'' sections was to ensure 
that most physicians will encounter one of the statements on antibiotic 
resistance when they are considering whether to prescribe an 
antibiotic.
    In addition, the context and wording of each of the four statements 
is different. The statement under the product name emphasizes that the 
goal of reducing the development of drug-resistant bacteria and 
maintaining the effectiveness of antibacterial drugs can be 
accomplished by using antibacterials only to treat infections that are 
proven or strongly suspected to be caused by bacteria. The statement in 
the ``Precautions'' section warns that prescribing antibacterials other 
than to treat a proven or strongly suspected bacterial infection is 
unlikely to provide benefit to the patient. The ``Indications and 
Usage'' section is where the physician looks to see what the uses of 
the product are. It is the most frequently consulted portion of the 
labeling. The statement in this section advises physicians to consider 
culture and susceptibility information and local epidemiology and 
suspectibility patterns when prescribing antibacterial therapy. The 
context of the statement in the ``Information for Patients'' section is 
very different from the other statements because it is information for 
physicians to convey to their patients. Patients should be advised not 
to skip doses of antibacterial therapy and to complete the full course 
of therapy, even if they start to feel better. Patients should also be 
advised that antibacterials do not treat viral infections.
    (Comment 19) One comment asserted that standard statements about 
inappropriate use of antibacterial drugs do not merit the extraordinary 
prominence of appearing directly under the product name, thus giving 
the impression that these statements are the most important information 
about the product.
    (Response) FDA believes it is important that the pressing public 
health problem of antibiotic resistance be highlighted in a prominent 
location. Furthermore, there is precedent for the appearance of a 
statement in this location. Oral contraceptives contain a statement 
under the product name indicating that they do not protect against 
sexually transmitted diseases. The antibiotic resistance statement, 
like the statement in oral contraceptive labeling, provides an 
important context for product use.
    (Comment 20) Several comments stated that placement of a statement 
concerning antibiotic resistance under the product name would dilute 
the effectiveness of black boxed warnings, which are often placed 
there. One comment also claimed that the placement of a statement under 
the product name would conflict with FDA regulations at Sec.  201.57(e) 
(21 CFR 201.57(e)) that reserve the area under the product name for 
boxed warnings, which, in turn, are reserved for critical safety 
information on hazards that may lead to death or serious injury.
    (Response) FDA disagrees with the assertion that a statement under 
the

[[Page 6067]]

product name would detract from boxed warnings that appear at the 
beginning of labeling. Systemic antibacterial products rarely contain 
boxed warnings. Furthermore, physicians recognize that a box demarcates 
a critical warning; therefore, placement of a statement before the 
boxed warning would not detract from that warning.
    The agency disagrees with the claim that placing a statement under 
the product name conflicts with Sec.  201.57(e). That section does not 
state that the only information that can be placed directly under the 
product name is a boxed warning. Nor does the section state that boxed 
warnings must be placed directly under the product name. Section 
201.57(e) states: ``If a boxed warning is required, its location will 
be specified by the Food and Drug Administration.'' It should be noted 
that boxed warnings may appear anywhere in the package insert, not only 
under the product name.
    (Comment 21) One comment objected to placement of the statement 
under the product name because the same statement appears in the 
``Precautions'' section.
    (Response) In the final rule, the statements for both locations 
have been revised, and two different statements now appear in these two 
sections.
    (Comment 22) One comment opposed the proposal but stated that if 
the agency were to proceed with it, a statement concerning 
antimicrobial resistance should be in a new section entitled 
``General,'' which would appear before one of the existing sections of 
labeling that doctors are likely to read such as ``Microbiology,'' 
``Indications and Usage,'' or ``Dosage and Administration.'' Another 
comment stated that of the two locations proposed for a general 
statement on antibiotic resistance, the ``Precautions'' section is a 
more suitable place for such a statement than directly under the 
product name.
    (Response) FDA believes that the labeling statements required by 
this final rule are appropriately placed to be as visible as possible 
to readers; therefore, the agency declines to adopt the suggestion to 
create a new labeling section entitled ``General'' or to adopt the 
suggestion not to require a statement under the product name.
    (Comment 23) Three identical comments stated that all anti-
infective labeling should contain a new section entitled ``Clinical 
Microbiology'' because physicians and nurses are used to seeing 
clinical microbiology information under that heading rather than under 
``Clinical Pharmacology.'' The comments maintained that the statement 
proposed for the ``Clinical Pharmacology'' section appear instead in 
this new section because the statement is more correctly a ``Clinical 
Microbiology'' statement rather than a ``Clinical Pharmacology'' 
statement. The comments also stated that readers would recognize the 
statement more easily if it were in a separate section. Another comment 
stated that the language proposed for the ``Clinical Pharmacology'' 
section should appear in a ``Microbiology'' subsection of the 
``Clinical Pharmacology'' section, adding that this type of information 
does not belong in any other area of the ``Clinical Pharmacology'' 
section. Another comment stated that the ``Clinical Pharmacology'' 
section should also include a summary of the preclinical and clinical 
data regarding PK and PD parameters to predict clinical response and 
minimize development of resistance, but that if such data are lacking, 
that should be stated.
    (Response) The agency has decided that advice about obtaining 
cultures belongs in the ``Indications and Usage'' section rather than 
the ``Clinical Pharmacology'' section. Because the rule does not 
require microbiology information, there is no need for a separate 
microbiology section.
    (Comment 24) Two comments stated that the proposal contradicted 
approved labeling for prophylaxis indications. One comment stated that 
antibiotic use for prophylaxis is within the standard of care and is 
found in indications in several labels (i.e., mezlocillin, cefuroxime, 
and metronidazole). Another comment noted that antibiotic use for 
prophylaxis of bacterial infection in some settings is an FDA-approved 
and valuable clinical use of several antibacterial drugs. Another 
comment stated that the ``proposed statements deviate from the long-
standing practice of FDA to grant indications for each specific 
infection that was studied in adequate and well-controlled trials.''
    (Response) FDA recognizes that some antibacterial drug products are 
indicated for prophylactic use, for example, to prevent postoperative 
bacterial infection. The statements required by the final rule to 
appear under the product name and in the ``Indications and Usage'' 
section advise that antibacterial drug products ``should be used only 
to treat or prevent infections that are proven or strongly suspected to 
be caused by bacteria.'' The statement required in the ``Precautions'' 
section, under the ``General'' subsection, also recognizes that some 
antibacterial drug products are indicated for prophylaxis. The final 
rule has no impact on the approval of antibiotics for various 
indications.

G. Statements Under the Product Name and in the ``Precautions'' Section

    The proposed rule would have required that the following statement 
appear directly under the product name and also in the ``Precautions'' 
section:
    Inappropriate use of (insert name of antibacterial drug product) 
may increase the prevalence of drug resistant microorganisms and may 
decrease the effectiveness of (insert name of antibacterial drug 
product) and related antimicrobial agents.
    Use (insert name of antibacterial drug product) only to treat 
infections that are proven or strongly suspected to be caused by 
susceptible microorganisms. See Indications and Usage section.
    This statement used the term ``inappropriate use'' of antibacterial 
drug products.
    (Comment 25) Several comments objected to the term ``inappropriate 
use'' as vague and subject to varying interpretations. One comment 
asked that inappropriate use be defined. Another comment maintained 
that the rule should focus on appropriate, rather than inappropriate, 
prescribing and should include a clear definition of appropriate 
prescribing. This comment asserted that it is important to distinguish 
between unnecessary use, such as prescribing an antibiotic for a viral 
infection, and inappropriate use, such as prescribing antibiotics at 
the wrong dose or for the wrong duration, or prescribing the wrong 
antibiotic to treat a particular bacterial infection. The comment also 
maintained that it is entirely appropriate to prescribe antibiotics 
whenever a bacterial infection is suspected, even in patients who 
initially have influenza-like symptoms.
    The comment also stated that a definition of appropriate 
prescribing should include the following points: (1) There must be a 
known or suspected bacterial infection, and (2) the choice of 
antibiotic should effect a rapid inhibition of bacterial growth, 
ideally by bacterial kill, and minimize the development of resistance 
and drug-related toxicity. This comment also stated that failure to use 
antibiotics may lead to serious bacterial infections that progress, and 
that the proposed rule's focus on inappropriate use might have the 
unwanted result of making doctors hesitate to prescribe antibiotics 
when they are truly necessary to treat a bacterial infection. One 
comment expressed the opinion that when a doctor uses his judgment 
about prescribing, that is not inappropriate use. Another comment 
stated that appropriate use of antibiotics may also

[[Page 6068]]

increase resistance if patients do not comply with the full course of 
therapy or otherwise alter the prescribed dosing regimen.
    (Response) In response to the comments, the agency has decided not 
to use the words ``appropriate'' or ``inappropriate'' because it 
recognizes that determining appropriate use, and therefore what is not 
appropriate, involves many factors and requires the exercise of the 
physician's judgment in using available information to select an 
antibiotic for a particular patient in a particular context. Instead, 
FDA has revised the statement under the product name to directly link 
reducing antibiotic resistance with prescribing antibiotics only to 
treat or prevent infections that are proven or strongly suspected to be 
caused by bacteria. Similarly, the statement in the ``Precautions'' 
section indicates that prescribing antibiotics in the absence of a 
proven or strongly suspected bacterial infection increases the risk of 
developing resistance.
    (Comment 26) One comment offered the following examples of 
inappropriate use: (1) Using antibiotics for common respiratory viral 
infections, (2) using a broad-spectrum antibiotic when a narrower 
spectrum antibiotic would be more appropriate, (3) using an antibiotic 
with an excessively long half-life, and (4) using a less potent 
antibiotic when a more potent agent would be more appropriate. Another 
comment described inappropriate use as including the use of antibiotics 
to treat viral infections, failure to prescribe an adequate length of 
treatment, failure of patients to complete the entire course of 
treatment, and skipping doses. This comment stated that it is important 
for physicians and the public to understand the basic value of 
antibiotics and went on to say that only inappropriate usage should be 
highlighted as requiring further education and restraint.
    (Response) As discussed in the response to comment 25, the agency 
has decided not to use the words ``appropriate'' or ``inappropriate'' 
in the labeling statements required by this rule. The agency agrees, 
however, that examples of inappropriate use may include using 
antibiotics for viral infections, failure to prescribe an adequate 
length of treatment, failure of patients to complete the entire course 
of treatment, skipping doses, and using a broad-spectrum antibiotic 
when a narrower spectrum antibiotic would be more appropriate. The 
agency does not agree that it is never appropriate to use an antibiotic 
with a very long half-life. Half-life is a factor to be considered 
along with other many other specific factors involved in patient 
management, but it is not appropriate to make generalizations about it 
in the context of this rule. Furthermore, focusing on the potency of an 
antibiotic is not a helpful approach because there is no standard 
definition of the potency of an antibiotic.
    (Comment 27) The agency received the following five suggestions for 
wording to appear in place of that proposed to appear under the product 
name. Suggestions 1 through 4 were also proposed for the 
``Precautions'' section:
    1. ``Inappropriate use of antibiotic products may increase the 
prevalence of drug resistant microorganisms, leading to a potential 
decrease in the general overall effectiveness of antimicrobial 
agents.''
    2. ``Appropriate use of antimicrobial agents may help decrease the 
prevalence of drug resistant microorganisms, resulting in the continued 
effectiveness of this product and related agents. This product should 
be used only to treat infections that are strongly suspected or proven 
to be caused by susceptible microorganisms.''
    3. ``Inappropriate use of an antibiotic may increase the prevalence 
of drug-resistant microorganisms and may decrease the future 
effectiveness of the antibiotic and related antimicrobial agents. It is 
not appropriate to extrapolate the benefit/risk profile established in 
patients with documented bacterial infections to other patients (e.g., 
patients with viral infections). This antibiotic does not treat viral 
infections.''
    4. ``Appropriate antibiotic use requires the selection of an 
antibiotic, for a known or suspected bacterial infection, that 
optimizes clinical therapeutic effect by maximizing bacteriological 
eradication and minimizing the development of resistance and drug-
related toxicity. In order to eradicate the bacteria and minimize the 
development of bacterial resistance, it is important to administer the 
appropriate antibiotic at the right dose and for the right duration. 
See Dosage and Administration Section.''
    5. ``Inappropriate use of antibacterial agents, including (insert 
name of antibacterial drug product) may increase the prevalence of drug 
resistant bacteria and may decrease the effectiveness of antibacterial 
agents, including (insert name of antibacterial drug product). (Insert 
name of antibacterial drug product) should be used only to treat 
infections that are proven or suspected to be caused by indicated 
bacteria.''
    Suggestion 5 eliminates from the proposed phrase ``strongly 
suspected'' the word ``strongly,'' contending that it adds nothing.
    The agency also received a suggestion intended only for the 
``Precautions'' section:
    ``Inappropriate use of antibacterial agents, including (insert name 
of antibacterial drug product) may increase the prevalence of drug 
resistant bacteria and may decrease the effectiveness of antibacterial 
agents, including the drug product. Antibacterial agents, including the 
drug product, should be used to treat infections that are proven or 
suspected to be caused by indicated bacteria. The antibacterial agent 
chosen to treat a documented or presumptive bacterial infection should 
be targeted to the most likely bacterial pathogen(s) and should have 
the narrowest spectrum possible to cover the likely pathogen(s).''
    (Response) All of the previous wording suggestions are phrased in 
terms of either inappropriate or appropriate use. The agency has been 
persuaded by the comments that using the words ``inappropriate'' or 
``appropriate'' is confusing and unhelpful; therefore, the final rule 
does not use these terms. Because FDA has decided not to use the words 
``inappropriate'' or ``appropriate,'' the agency declines to adopt any 
of the wordings suggested in the comments. The agency disagrees with 
the opinion that there is no difference between ``suspected'' and 
``strongly suspected.'' Since many infections could theoretically be 
either viral or bacterial, the direction to use antibiotics for 
suspected bacterial infections could be interpreted as approving of 
antibiotic use whenever there is a possibility of a bacterial 
infection. Therefore, the final rule retains the word ``strongly.''

H. Culture and Susceptibility Tests

    Proposed Sec.  201.24(b) would have required the following 
statement in the ``Clinical Pharmacology'' section: ``Appropriate use 
of (insert name of antibacterial drug product) includes, where 
applicable, identification of the causative microorganism and 
determination of its susceptibility profile.''
    (Comment 28) Many comments objected to this statement, asserting 
that it is not always possible or advisable to do cultures. Comments 
stated that for the majority of infections, including respiratory tract 
infections, obtaining a specimen for a culture is not possible. One 
comment objected that diagnostic tests that immediately distinguish 
viral and bacterial infections are not available.
    (Response) The agency recognizes that it is not possible to obtain 
specimens for cultures for many common community-

[[Page 6069]]

acquired infections, including many respiratory tract infections and 
otitis media. FDA also agrees that there are no diagnostic tests that 
can immediately determine whether an infection is bacterial or viral. 
The revised statement for the ``Indications and Usage'' section 
recognizes these realities by advising that culture and susceptibility 
information should be considered in selecting or modifying 
antibacterial therapy when it is available.
    (Comment 29) Many comments stated that the majority of infections, 
especially those acquired in the community rather than in the hospital, 
are and should be treated empirically without waiting for 
identification of the causative microorganism. One comment asserted 
that antibiotics must be initiated empirically for a febrile 
neutropenic patient or a patient with pneumonia in an intensive care 
unit (ICU). Another comment stated that the American Thoracic Society 
Guideline for Pneumonia recommends empirical treatment of pneumonia and 
concludes that Gram stains of sputum, cultures, and susceptibility 
testing are not cost-effective, particularly for outpatient infection. 
One comment stated that to delay the start of treatment waiting for 
culture results would be unethical as well as impractical. Another 
comment maintained that when patients are at risk of serious 
complications from infection, they must be treated empirically, and 
broad-spectrum therapy may be used to avoid treatment failure. Another 
comment stated that the agency has not considered outcome data 
concerning the benefits of empiric treatment on mortality and 
morbidity. One comment stated that doctors should decide whether to 
change antibiotic therapy based on the clinical situation, not only on 
in vitro susceptibility data. Another comment stated that there are not 
many efforts to gather information on treatment outcomes in ambulatory 
settings. One comment asked what the agency meant by the phrase ``where 
applicable'' in the statement: ``Appropriate use of (insert name of 
antibacterial drug product) includes, where applicable, identification 
of the causative microorganism and determination of its susceptibility 
profile.''
    (Response) FDA agrees that antibiotic therapy must often be 
initiated empirically, including for patients with febrile neutropenia 
or ICU patients with pneumonia, and that it may be unethical to delay 
the initiation of therapy. FDA recognizes that in many situations 
physicians must make difficult choices about the need for empiric 
therapy and broad-spectrum agent use. Most clinical guidelines 
concerning the management of such situations also recommend taking 
measures to alter treatment to more targeted antimicrobial coverage, 
such as through the use of bacterial cultures, whenever possible.
    The agency did not intend to call for physicians to always refrain 
from initiating antibiotic therapy until the causative microorganism 
has been identified. The statement proposed for the ``Indications and 
Usage'' section recommended that initial selection of an antibiotic be 
guided by local epidemiology and susceptibility patterns, thus clearly 
contemplating that antibiotic therapy would be initiated before the 
results of culturing had been obtained. In addition, the modifier 
``where applicable'' was intended to indicate that it is not always 
possible to do culture and susceptibility testing.
    In response to comments, the agency has revised the statements 
about the role of culture and susceptibility tests and the use of local 
epidemiology and susceptibility patterns to make clear that FDA is not 
advising physicians that they should never prescribe antibiotics 
without first obtaining culture and susceptibility results or without 
referring to local epidemiology and susceptibility patterns. The agency 
has decided that the statement about culture and susceptibility 
information is more appropriate for the ``Indications and Usage'' 
section than for the ``Clinical Pharmacology'' section. The statement 
suggests that after initiating antibiotic therapy empirically, 
physicians should consider modifying therapy if susceptibility 
information becomes available and indicates that the microorganisms 
causing the infection are different from those initially suspected. FDA 
recognizes, however, that the physician must also weigh the clinical 
situation.
    (Comment 30) One comment asserted that there is no scientific 
consensus on the need to use narrow-spectrum antibiotics targeted at 
organisms that have been identified through cultures.
    (Response) FDA believes that using narrower spectrum, more targeted 
therapy, to treat a known organism can reduce the development of 
resistance. Narrower spectrum antimicrobials may have less impact on 
the normal organisms that colonize the body. Normal flora may protect 
the body from becoming colonized with other, more pathogenic bacteria. 
Also, normal flora exposed to an antimicrobial may become resistant to 
that antimicrobial and pass resistance genes on to more pathogenic 
bacteria. Therefore, prescribing narrower spectrum drugs may limit the 
spread of resistance while still treating the pathogenic organisms 
causing the disease. This subject was discussed by presenters and panel 
members at the January 8, 2003, Anti-Infective Drugs Advisory Committee 
meeting. However, the labeling statements in the final rule do not 
dictate the use of narrow-spectrum antibiotics.
    (Comment 31) Comments maintained that there are not enough 
laboratories to perform susceptibility testing for all of the 
antibiotics prescribed and that, in many parts of the country, 
physicians do not have access to susceptibility testing. One comment 
stated that few clinics have access to local microbiology labs; that 
the majority of microbiological diagnostic testing is done in central 
locations by a few laboratories, and that many hospitals do not have 
microbiology laboratories. This comment noted that the Infectious 
Disease Society of America has recently issued a position paper on the 
lack of access to microbiology laboratories and the threat that this 
lack of facilities poses to the public health. Two comments stated that 
the regulations of the Clinical Laboratory Improvement Act provide that 
Gram stains should be performed and interpreted by qualified lab 
technicians, not doctors.
    One comment stated that the infrastructure required to support 
diagnostic testing in primary care settings is not in place and that 
diagnostic testing is not likely to be funded unless there are data to 
support the cost-effectiveness of doing culture and susceptibility 
testing rather than using broad-spectrum antibiotics. This comment also 
stated that the pharmaceutical industry should not have to fund such 
testing. Another comment stated that managed care and third-party 
payers have not funded the infrastructure required for diagnostic 
testing in primary care settings.
    (Response) FDA agrees that some physicians lack access to 
facilities that perform susceptibility testing. The agency also agrees 
that it is not the responsibility of the pharmaceutical industry to 
make such testing available. The final rule's statement in the 
``Indications and Usage'' section takes into account that culture and 
susceptibility information may not always be available.

I. Local Epidemiology and Susceptibility Patterns

    Proposed Sec.  201.24(c) would have required the following 
statement in the ``Indications and Usage'' section:
    Local epidemiology and susceptibility patterns of the listed 
microorganisms should direct initial selection of (insert name of

[[Page 6070]]

antibacterial drug product) for the treatment of the following 
indications. Because of changing susceptibility patterns, definitive 
therapy should be guided by the results of susceptibility testing of 
the isolated pathogens.
    (Comment 32) One comment stated that the direction to use local 
epidemiology and susceptibility patterns is not practical because this 
information is not available to doctors. Another comment stated that 
lack of susceptibility data on a particular product in a particular 
geographic region should not contraindicate use of the drug. Several 
comments stated that various practice guidelines do not recommend the 
use of surveillance data to guide antibiotic therapy. Another comment 
stated that there are different datasets of susceptibility data and 
asked which set should be used. This comment also stated that 
susceptibility patterns can change rapidly, making data obsolete.
    (Response) FDA recognizes that surveillance data on microbial 
sensitivities may not be available in some settings and are not helpful 
in other situations. However, in many circumstances, the data provide a 
source of information that may assist the prescriber in the selection 
of empiric therapy. FDA suggests that physicians obtain epidemiology 
and susceptibility data from local hospitals or State health 
departments. Physicians who have access to such sources of information 
and make it a practice to update their information periodically can 
remain current on susceptibility patterns in their areas.
    (Comment 33) One comment contained the following detailed 
objections to the use of susceptibility data:
    [sbull] MIC data from in vitro testing are unproven as predictors 
of clinical outcome in many diseases.
    [sbull] Susceptibility data obtained from surveillance studies have 
limitations for prospective therapeutic decisions. These limitations 
include the fact that large national and international surveillance 
studies obtain data from hospitalized patients who are more likely to 
have resistant isolates. These data are unlikely to be linked to 
clinical data so that the relevance of the MIC values generated is 
limited.
    [sbull] Local surveillance data can be biased because of small 
sample sizes. The data that are likely to be available to physicians in 
the community come from clinical trials that exclude patients who would 
be at risk for resistant isolates.
    [sbull] Laboratory methodology and expertise can influence 
susceptibility testing, e.g., E tests often err for drugs that are 
highly dependent on pH for activity, which is a particularly important 
problem for macrolides such as erythromycin and clarithromycin.
    [sbull] Clinical outcome data are not the basis for current 
National Committee for Clinical Laboratory Standards (NCCLS) and FDA 
breakpoints for most drugs used for outpatient respiratory tract 
infections. The NCCLS changed the breakpoints for some beta-lactam 
antibacterials and that has altered the susceptibility rates.
    (Response) The agency agrees that surveillance data has 
limitations; however, data with limitations may still be useful. 
Accordingly, the revised statement in the ``Indications and Usage'' 
section states that local epidemiology and susceptibility patterns may 
contribute to the empiric selection of therapy when culture and 
susceptibility information are not available.
    (Comment 34) One comment contended that recommending the use of 
local epidemiology and susceptibility patterns will lead to the use of 
newer, possibly broad-spectrum agents that have lower rates of in vitro 
resistance, although older agents are still appropriate choices. This 
comment also stated that other factors may be useful in selecting 
antibiotic therapy. For example, molecular resistance mechanisms for 
particular bacteria may be useful to predict clinical efficacy, and the 
location of infection predicts response to therapy in some diseases.
    (Response) FDA agrees that it is not reasonable to focus solely on 
epidemiology and susceptibility patterns as the decisive factor in 
selecting an antibiotic. Most clinicians use this information as one of 
many factors considered in deciding which drug to use.
    (Comment 35) Two comments suggested alternative wording for the 
statement to appear in the ``Clinical Pharmacology'' section as 
follows:
    1. ``Appropriate use of this product may include, where applicable 
and practical, identification of the causative microorganism and the 
determination of its susceptibility profile.''
    2. ``Appropriate use of antibacterial agents includes, where 
applicable, identification of the causative bacteria and determination 
of its susceptibility profile. The pharmacokinetic and pharmacodynamic 
profile of the agent and the location of the infection should also be 
considered when selecting an appropriate antibiotic for treatment of a 
documented or presumptive infection.''
    (Response) The previous two wording suggestions are modified 
versions of the statement that was proposed for the ``Clinical 
Pharmacology'' section. The final rule does not require a statement in 
the ``Clinical Pharmacology'' section because the agency has decided 
that advice about obtaining cultures belongs in the ``Indications and 
Usage'' section rather than the ``Clinical Pharmacology'' section. 
Therefore, FDA declines to adopt either of these suggestions.
    (Comment 36) The agency received three suggestions for wording to 
appear in the ``Indications and Usage'' section as follows:
    1. ``Appropriate culture and susceptibility tests should be 
performed before treatment in order to isolate and identify organisms 
causing infection and to determine their susceptibility to (name of 
drug). Therapy with (name of drug) may be initiated before results of 
these tests are known; once results become available, appropriate 
therapy should be continued.''
    2. ``Appropriate specimens for bacteriological examination should 
be obtained, when indicated and feasible, in order to isolate and 
identify causative organisms and to determine their susceptibility to 
[name of product]. Therapy may be instituted while awaiting the results 
of these studies. Once these results become available, antimicrobial 
therapy should be adjusted accordingly.''
    3. ``The efficacy of this drug has been demonstrated when it is 
used as directed for the indications and susceptible pathogens listed 
below. Use of this drug in other regimens or for other indications or 
pathogens may be ineffective. Inappropriate use of this or other 
antibacterials may increase the prevalence of drug resistant 
microorganisms. The prescription of antimicrobial therapy should be 
guided, when possible, by the results of local or regional 
susceptibility testing of causative pathogens typically isolated during 
the infection. When microbiological data are not available for an 
individual patient, the decision to prescribe an antibiotic should be 
based on the clinician's assessment of the most likely etiology and 
optimal therapy based on the available clinical, pharmacodynamic, and 
in vitro information provided from clinical trials and post-marketing 
experience with antimicrobial agents.''
    (Response) The agency declines to adopt the specific wording in any 
of these suggestions. However, the revised statement for the 
``Indications and Usage'' section incorporates many ideas from these 
suggestions. The idea that therapy may be initiated before obtaining 
culture results is captured by the statement that antibiotics may be

[[Page 6071]]

used to treat infections that are strongly suspected to be bacterial. 
The statement that culture and susceptibility information should be 
considered when available captures the idea expressed by such phrases 
as ``where applicable and practical'' and ``when indicated and 
feasible.'' FDA's statement also includes the idea that physicians may 
wish to modify antibiotic therapy after obtaining the results of 
susceptibility testing.

J. Practice of Medicine

    (Comment 37) Many comments asserted that the proposal is outside 
the scope of labeling, the purpose of which is to provide the 
information necessary for the safe and effective use of drugs, not to 
tell physicians how to practice medicine. One such comment maintained 
that product labeling should not dictate medical practice, which 
requires individualized clinical assessment of the patient and the 
circumstances under which the patient is being treated, and that FDA's 
role does not include teaching medicine. Another comment asserted that 
the proposal interferes with the practice of medicine since the choice 
of antibiotic should be made by the physician after weighing the 
overall benefits and risks to the patient. Another comment stated that 
labeling should not impose a specific standard of care or practice that 
must be followed. Another comment maintained that there is no statutory 
basis for FDA to regulate physician conduct or train physicians and 
that the clinical knowledge gained from years of medical training and 
experience cannot be completely provided for in labeling.
    Several comments expressed concern that the proposed labeling 
statements would result in legal liability for physicians because in 
many cases they would not be able to follow the standard of practice 
required by the labeling, that is, obtaining cultures to identify 
microorganisms and determine their susceptibility profiles.
    (Response) The agency disagrees with comments maintaining that the 
proposed rule is outside the scope of labeling. As FDA has long 
recognized, its role is neither to regulate physician conduct, nor to 
train physicians. As FDA wrote in 1972:
    Throughout the debate leading to enactment (of the 1938 Act and 
the drug amendments of 1962), there were repeated statements that 
Congress did not intend the Food and Drug Administration to 
interfere with medical practice and referenced to the understanding 
that the bill did not purport to regulate the practice of medicine 
as between the physician and the patient . . . . 37 Fed. Reg. at 
16503.
    FDA's 1972 notice continues:
    {A{time} lthough it is clear that Congress did not intend the 
Food and Drug Administration to regulate or interfere with the 
practice of medicine, it is equally clear that it did intend that 
the Food and Drug Administration determine those drugs for which 
there exists substantial evidence of safety and effectivenss and 
thus will be available for prescribing by the medical profession, 
and additionally, what information about the drugs constitutes 
truthful, accurate, and full disclosure to permit safe and effective 
prescription by the physician. As the law now stands, therefore, the 
Food and Drug Administration is charged with the responsibility for 
judging the safety and effectiveness of drugs and the truthfulness 
of their labeling. The physician is then responsible for making the 
final judgment as to which, if any, of the available drugs his 
patient will receive in the light of the information contained in 
their labeling and other adequate scientific data available to him.
    Physicians have been concerned that the failure to follow the 
labeling of a drug may render them unduly liable for malpractice.
    Although labeling, along with medical articles, tests, and 
expert opinion, may constitute evidence of the proper practice of 
medicine, it is not controlling on this issue. The labeling is not 
intended either to preclude the physician from using his best 
judgment in the interest of the patient, or to impose liability if 
he does not follow the package insert. A physician should recognize, 
however, that the package insert represents a summary of the 
important information on the conditions under which the drug has 
been shown to be safe and effective by adequate scientific data 
submitted to the Food and Drug Administration.
    Given this framework, it is appropriate to include in labeling 
information necessary for the safe and effective use of the drug, 
including information about the context of product use. For example, 
labeling for anesthetic agents often includes very specific 
recommendations about the conditions under which the products should be 
used and the training of the personnel who administer them. 
Furthermore, many approved antibiotics already recommend that 
appropriate culture and susceptibility tests be performed.
    FDA has adopted revised statements to address concerns expressed in 
the comments that the proposed rule categorically dictated medical 
practice and held up a standard that physicians would be unable to 
meet. The revised statements take into account that culture and 
susceptibility information are not always available. In addition, 
rather than stating that local epidemiology and susceptibility patterns 
should help direct initial selection of antibiotic therapy, the final 
rule provides that information from these sources may contribute to the 
selection of therapy. With these changes, the agency believes that the 
statements required by the final rule cannot be interpreted as overly 
directive and thus do not interfere with the practice of medicine. The 
final rule is not intended to establish a standard of care. The rule is 
designed to provide information and context for health care providers 
to consider in prescribing certain medications.

K. Information for Patients

    The proposed rule provided that the following statement appear in 
the ``Precautions'' section under the ``Information for patients'' 
subsection:
    Patients should be counseled that (insert name of antibacterial 
drug product) should only be used to treat bacterial infections. It 
does not treat viral infections (e.g., the common cold).
    Patients should also be told that the medication should be taken 
exactly as directed. Skipping doses and not completing the full 
course of therapy may (1) decrease the effectiveness of the 
immediate treatment and (2) increase the likelihood that bacteria 
will develop that will not be treatable by (insert name of 
antibacterial drug product) in the future.
    (Comment 38) The comments were generally supportive of the proposal 
to educate patients. However, one comment stated that FDA's attempt to 
educate the public through labeling is misguided. The comment pointed 
to a study\1\ evaluating a medication guide that found that less than 
50 percent of the patients who received the guide read it; that of the 
patients who read the guide, only 50 percent could recall at least one 
issue discussed in it; and that only 20 percent of the patients who 
knew the contents of the guide said they had taken some action based on 
it. This comment stated that if the agency proceeded with the proposal 
to include a statement for patients, the statement should be: 
``Patients should be counseled to take all medicinal products exactly 
as directed.''
---------------------------------------------------------------------------

    \1\ Chianese, C. P., ``An Overview of an Initial Experience With 
a Medication Guide,'' Drug Information Journal, vol. 34, pp. 855-
859, 2000.
---------------------------------------------------------------------------

    (Response) The agency does not believe the medication guide study 
is relevant to the labeling proposal concerning antibiotic resistance 
because the agency has not proposed a medication guide or anything else 
for patients to read. The ``Information for patients'' subsection 
contains information that would be communicated to the patient by the 
prescriber. The agency disagrees with the suggestion that patient 
information be limited to advising patients to take all medications 
exactly as directed because that advice would not explain

[[Page 6072]]

the specific consequences of failure to take antibiotics as directed.
    (Comment 39) One comment asserted that, as written, the statement 
could suggest that patients are qualified and capable of diagnosing 
their own infections. Another comment stated that patient information 
should primarily reinforce the prescribed dosing because patients 
should not be expected to know how to distinguish between viral and 
bacterial infections. The comment also asserted that patients should be 
educated that at least one office visit is necessary to decide whether 
an antibiotic should be prescribed. Another comment stated that 
pharmacists should give patients the entire package insert rather than 
a summary, because patient demand for antibiotics often leads to 
unnecessary prescribing.
    (Response) FDA does not agree that its proposed language suggests 
that patients are capable of diagnosing their own infections or are 
able to tell the difference between a viral and a bacterial infection. 
Generally, FDA expects that information concerning the use of 
antibiotics would be communicated to the patient in the doctor's office 
after the patient had already decided to seek medical care. However, 
because antibiotics are prescribed in hospitals as well as on an 
outpatient basis, FDA declines to adopt the suggestion that patients be 
told that at least one office visit is necessary. It is not clear how 
giving the package insert to patients who are prescribed antibiotics 
would reduce patient demand for antibiotics. In any event, FDA usually 
requires patient package inserts only when there is a need to 
communicate detailed risk information about a drug product or 
instructions for using the product. Neither of these circumstances 
apply to systemic antibacterial drug products.
    (Comment 40) One comment stated that the patient information 
statement should not apply to any antibiotic administered solely via 
intravenous or intramuscular routes because patients do not self-
administer by these routes.
    (Response) FDA disagrees with the notion that patients never self-
administer antibiotics by intravenous or intramuscular routes. Patients 
who are started on intravenous antibiotics in the hospital sometimes 
continue to use injectable antibiotics on an outpatient basis. 
Therefore, the patient information section must be included in the 
labeling of systemic antibacterials administered intravenously or 
intramuscularly.
    (Comment 41) The agency received many specific suggestions for 
revisions to the proposed patient statement. One comment proposed the 
following language: ``Patients should be counseled about the 
differences between viral and bacterial infections.'' One comment 
suggested adding the phrase ``the oral antibiotic'' before the name of 
the product in the first sentence. Another suggestion was to add the 
words ``despite feeling better or `totally' well'' after the phrase 
``Skipping doses and not completing the full course of therapy.'' 
Another comment suggested using the phrase ``likelihood of selecting 
bacteria'' rather than the phrase ``likelihood that bacterial will 
develop.''
    Two comments suggested adding either ``antibacterial drugs, 
including'' or ``antibacterial agents including'' before the product 
name in the first sentence. One comment suggested replacing the 
specific product name in the last sentence with the phrase 
``antibacterial drugs,'' while another comment proposed to add ``or 
other antibacterials'' after the product name in the last sentence. In 
the sentence ``Skipping doses and not completing the full course of 
therapy may (1) decrease the effectiveness of the immediate treatment 
and (2) increase the likelihood that bacteria will develop that will 
not be treatable by (insert name of antibacterial drug product) in the 
future,'' one comment proposed to replace the first ``will'' with 
``may,'' while another comment suggested replacing both instances of 
the word ``will'' with the word ``may.''
    (Response) In the final rule, FDA has adopted a number of the 
suggestions made in the comments. FDA has adopted the suggestion to 
precede the name of the product in the first sentence with the phrase 
``antibacterial drugs including'' because the information applies to 
all antibacterial drugs. The agency also agrees with the idea of adding 
the phrase ``or other antibacterials'' to the last sentence, but has 
altered the wording slightly to state ``or other antibacterial drugs.'' 
FDA agrees with the concept that patients should be told to continue 
therapy even after they feel better and has included the phrase 
``Patients should be told that although it is common to feel better 
early in the course of therapy * * *'' in the statement.
    FDA declines to adopt other suggestions. The agency believes that 
the suggestion that patients be counseled about the differences between 
bacterial and viral infections is not as direct as and, therefore, not 
preferable to FDA's revised language. FDA does not agree that the 
phrase ``the oral antibiotic'' should be added because the implication 
of this suggestion is that patients are never responsible for using 
injectable antibiotics. As discussed previously, there are 
circumstances where injectable antibiotics are self-administered. The 
agency rejects the suggestion to use the phrase ``likelihood of 
selecting bacteria'' because most lay people are not familiar with the 
concept of bacterial selection. The agency declines to adopt the 
suggestions to use ``may'' rather than ``will'' in the phrases ``will 
develop'' and ``will not be treatable.'' The concept of possibility 
rather than certainty is already expressed by the words ``may'' and 
``likelihood'' earlier in the sentence.

IV. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

V. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Under the Regulatory 
Flexibility Act, if a rule has a significant economic impact on a 
substantial number of small entities, an agency must consider 
alternatives that would minimize the economic impact of the rule on 
small entities. Section 202(a) of the Unfunded Mandates Reform Act of 
1995 requires that agencies prepare a written statement of anticipated 
costs and benefits before proposing any rule that may result in an 
expenditure by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100 million in any one year (adjusted 
annually for inflation).
    The agency believes that the final rule is consistent with the 
regulatory philosophy and principles identified in Executive Order 
12866 and in these two statutes. The final rule will amend the content 
of the professional labeling for human prescription antibacterial 
drugs. Based on the analysis, summarized in table 1 of this document, 
FDA projects the annualized costs to comply with the final rule to be 
less than $600,000. The agency finds that if the revised labeling 
reduces direct and indirect costs attributable to resistant bacteria by 
1

[[Page 6073]]

percent, the annual benefit will exceed $10 million. Thus, while it has 
been determined that the final rule is significant under the Executive 
order, the final rule will not be economically significant as defined 
by the Executive order, because the annual impacts on the economy are 
substantially below $100 million. With respect to the Regulatory 
Flexibility Act, the agency certifies that this final rule will not 
have a significant effect on a substantial number of small entities. 
The effect of small entities is discussed in more detail in section V.D 
of this document. The Unfunded Mandates Reform Act does not require FDA 
to prepare a statement of costs and benefits for the final rule because 
the rule will not result in any 1-year expenditure that would exceed 
$100 million adjusted for inflation. The current inflation-adjusted 
statutory threshold is about $110 million.

     Table 1.--Summary of Quantifiable Benefits and Costs ($Million)
------------------------------------------------------------------------
   Benefits and
      Costs          One-Time       Annual          Total       Annualized
-------------------------------------------------------------- ------------
Benefits\1\        ............  ............  ...............
 Avoided cost of                 3.8           3.8
 hospital                        0.4           0.4
 infections                      6.6-11.8      6.6-11.8
 Indirect cost of
 longer hospital
 stays
 Indirect costs
 of mortality
 (discounted at
 3% and 7%)
Total Benefits     ............  10.8-16.0     10.8-16.0
                   ............  ............  ...............
Costs\2\           ............  ............  ...............
 One-time               2.9      ............  0.42
 labeling                        0.02          0.02
 revision                        0.123         0.123
 Annual
 incremental
 printing cost
 Annual
 Physicians Desk
 Reference (PDR)
 Costs
Total Costs             2.9      0.146         0.568
------------------------------------------------------------------------
\1\ Assumes medical, productivity, and mortality costs now attributable
  to antibacterial resistance are reduced by 1 percent.
\2\ May not sum to total because of rounding.

A. Objective of the Final Rule

    Drug-resistant bacteria pose a public health risk by reducing the 
effectiveness of prescription antibacterial drug products. Some 
disease-producing bacteria can adapt and become resistant to newly 
developed drugs within a couple of years. For example, a report of 
infections resistant to linezolid, the first drug in a new class of 
antibiotics, was published just 1 year after its approval (Ref. 6). To 
stress the need for continued vigilance against the emergence of 
resistant bacteria, the final rule requires that labeling of systemic 
antibacterial drug products include statements that encourage the use 
of antibiotics in a way that reduces the risk of developing drug-
resistant bacteria. The final rule requires that labeling for affected 
prescription drug products comply with the requirements by February 6, 
2004.

B. Costs of Regulation

    The agency received several comments about the costs of the 
proposed rule. One comment asked whether the economic analysis in the 
proposed rule included the cost of initial and followup doctor visits 
or the cost of culture and sensitivity tests. Because patients normally 
see a health care provider to obtain a prescription for an 
antibacterial drug, the agency's initial analysis of impacts did not 
include costs for health care visits.
    The agency also did not estimate the number or cost of laboratory 
tests that might have been ordered because of the proposed labeling 
change. Many doctors and hospitals currently order susceptibility 
tests, especially when there is a high incidence of resistant bacterial 
infections locally. In any event, in response to comments, the agency 
has revised the wording of the proposed statement that suggested a 
general need for susceptibility testing. Instead, the final rule adds 
statements to antibacterial labeling that remind health care providers 
to consider laboratory results, if available, when selecting drug 
therapy. Because the final rule does not require additional laboratory 
tests or visits to health care providers, this analysis of impacts does 
not include these patient health care costs as regulatory costs.
    Some comments questioned the cost-effectiveness of susceptibility 
testing. The agency did not evaluate the cost-effectiveness of 
laboratory tests. As stated elsewhere in the preamble, the agency has 
modified the language about susceptibility tests to clarify that 
initial drug therapy should be modified if available test results 
suggest the infection is caused by different microorganisms than 
initially suspected, not by testing each patient.
    One comment stated that waiting to initiate drug therapy would lead 
to additional health care, morbidity, and mortality costs. While the 
agency agrees that any delay in starting therapy can increase the 
direct and indirect costs of infection, the final rule does not suggest 
that health care providers postpone treatment once they strongly 
suspect that an infection is caused by a bacteria. The agency agrees 
that costs increase when resistant bacteria are not initially 
identified as the cause of an infection. In one study on bloodstream 
infections, the length of hospital stay increased by 6.4 days and 
mortality increased from 11.9 percent to 29.9 percent with inadequate 
treatment (defined as either giving an incorrect drug for an infection-
causing pathogen or giving the correct drug for an infection-causing 
pathogen that is resistant to the drug) (Ref. 7). The objective of the 
final rule is to reduce the prevalence of and costs associated with 
resistant bacteria and their associated costs. A more detailed 
discussion of avoided costs follows in section V.C of this document.
1. Affected Products
    The final rule will affect all systemic antibacterial drug products 
except those primarily indicated to treat a mycobacterial infection. 
Antifungal, antiviral, antiparasitic, and topical antibacterial 
products will not be subject to the labeling requirements of the final 
rule. FDA estimates that manufacturers will be required to modify 
labeling of 669 antibacterial drug products.\2\
---------------------------------------------------------------------------

    \2\ Derived from FDA's Approved Drug Products With Therapeutic 
Equivalence Evaluations, 2002, and 2001 Drug Information, American 
Hospital Formulary Service (AHFS). Products counted and active 
ingredients matching the AHFS lists of antibacterial agents, and a 
distinct manufacturer, active ingredient, or dosage form. Topical 
dosage forms were excluded. Products with different therapeutic 
equivalence codes for the same manufacturer were counted separately.

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

[[Page 6074]]

2. Professional Labeling Design Costs
    For a major revision in the content of professional labeling, FDA 
had estimated in its preliminary analysis that, on average, 
prescription drug manufacturers would incur costs of about $2,600 per 
product, including inventory loss, because the 12-month implementation 
period is shorter than the average useful life of pharmaceutical 
labeling. To derive this estimate, labeling costs for four categories 
of pharmaceutical manufacturers were weighted by their market share of 
all pharmaceutical products. Comments from a large pharmaceutical 
manufacturer, however, stated that labeling redesign costs to industry 
are more than three times FDA's estimate. In response, the agency has 
recalculated the market shares of the affected antibacterial products 
based on its current drug approval data (table 2). Adjusting for both 
inflation and market shares, FDA now estimates that manufacturers of 
antibacterial drugs will incur, on average, per product costs of 
approximately $4,380, including $1,040 in inventory loss. The weighted 
average cost to revise drug labeling is based on input from industry 
consultants on the time and materials required to modify the package 
insert accompanying pharmaceutical products. (Table 2a shows a 
breakdown, by firm size, of the labor and material costs used to derive 
the weighted average cost of $4,380.) While some firms may incur per 
product costs higher than the average estimate, the agency believes 
that the revised per product cost represents a reasonable estimate of 
industrywide costs.

               Table 2.--Market Share of Affected Antibacterial Drug Products by Category of Firm
----------------------------------------------------------------------------------------------------------------
              Category of Firm                   Number of Firms     Number of Products       Market Share\1\
----------------------------------------------------------------------------------------------------------------
Innovator\2\                                  ....................  ....................  ......................
 Small\3\                                             10                    18                      2.69%
 Medium                                                3                    27                      4.04%
 Large                                                45                   501                     74.89%
Generic\4\                                            43                   123                     18.39%
Totals                                               101                   669                    100.00%
----------------------------------------------------------------------------------------------------------------
\1\ May not sum to total because of rounding.
\2\ Includes firms manufacturing both innovator and generic products.
\3\ Includes 7 private firms without size data.
\4\ Includes firms manufacturing only generic products and 26 private firms without size data.


                                 Table 2a.--Labeling Revision Costs by Firm Size
----------------------------------------------------------------------------------------------------------------
                                                                        Innovator Drug Manufacturers
                  Item                      Generic Drug   -----------------------------------------------------
                                            Manufacturers         Small            Medium             Large
----------------------------------------------------------------------------------------------------------------
Labor Cost                                       $830              $830            $1,242            $1,812
Material Cost                                    $740              $740            $2,230            $3,400
Total Cost to Revise Labeling                  $1,570            $1,570            $3,472            $5,212
----------------------------------------------------------------------------------------------------------------

3. Incremental Printing Costs for Professional Labeling
    No comments were received on FDA's estimate of incremental printing 
costs for longer labeling. Therefore, FDA maintains its estimate that 
an average of 100,000 package inserts are printed annually for each 
antibacterial drug product marketed in the United States.\3\ Compared 
to the proposed rule, the final rule requires fewer statements in the 
labeling, thus reducing the costs to print longer labeling. Adding new 
information on prudent use of antibacterial drug products to 
professional labeling will increase the size of current package inserts 
by an estimated 3.3 percent or 3.3 square inches (in\2\) for the 
average insert. Although few package inserts will change size, if all 
manufacturers had to increase the length of the package insert to 
accommodate the new statements, they would incur additional printing 
costs of about $37 per affected product.\4\ If all affected products 
had longer labeling, printing costs for the industry would increase by 
less than $25,000 annually.
---------------------------------------------------------------------------

    \3\ In 1996, there were approximately 133 million prescriptions 
for antibacterial drugs written by physicians in office and hospital 
settings (Government Accounting Office, 1999). An estimated 45.3 
million inserts were printed to accompany these drugs. (45.3 million 
= (106 retail prescriptions/3 prescriptions per container) + (19 
million hospital emergency prescriptions/2 prescriptions per 
container) + (8 million hospital outpatient prescriptions/(500 units 
per container/(28 units per prescription))). An average of 56,767 
inserts therefore accompanied each product (45.3 million / 798 
products). Also, we assume that 40,000 additional inserts per 
product are distributed annually by sales representatives as 
promotional material.
---------------------------------------------------------------------------

4. PDR Costs
    No comments were received on the impact of the rule on PDR costs 
for manufacturers. According to its publisher, a page in the print 
version of the PDR costs an average of $9,500 in 2001.\5\ Furthermore, 
according to the publisher of the electronic versions of the PDR, each 
full package insert published in the print version is also included in 
the Internet and CD-ROM versions of the PDR at no additional cost to 
the drug manufacturer. A search of the Internet version of the PDR 
showed that as many as 160 antibacterial drug products will have 
slightly longer descriptions in the PDR.\6\ The additional

[[Page 6075]]

language will add less than one-tenth of a page to an average PDR 
listing and cost about $842 more per product.\7\ The annual costs of 
printing the larger labels in the PDR, therefore, will increase by 
$0.13 million.
---------------------------------------------------------------------------

    \4\ Although the length of an average package insert will only 
increase by 3.3 in\2\, we rounded to 4 in\2\ to calculate costs. The 
1997 estimated incremental printing cost of $ 0.0086 per 100 in\2\ 
was adjusted for inflation by the producer price index for 
commercial printing (i.e., a 6 percent increase in costs between 
1997 and April 2001). $36.53 = 100,000 inserts per product x 1.06 x 
$0.000086 per in\2\ x 4 in\2\.
    \5\ $9,500 is the estimated average industry cost. Per page 
charges to an individual firm will decrease as more PDR pages are 
purchased. The maximum per page charge listed on Medical Economics' 
2001 rate card is $19,035 (i.e., less than eight pages purchased for 
the year).
    \6\ A search of the Internet version of the PDR by affected drug 
category and by indication found only 156 affected products. 
According to Micromedex (http://www.micromedex.com), all fully 
described products in the print version of the PDR are also included 
in the CD-ROM and Internet version.
    \7\ $842 per product = ($9,500 per page / columns per page) x 
0.266 column.
---------------------------------------------------------------------------

    Over 10 years, the agency estimates that the annualized compliance 
costs of the final rule will be approximately $580,000. These costs are 
summarized in table 3.

                 Table 3.--Costs to Revise Professional Labeling and Incremental Printing Costs
----------------------------------------------------------------------------------------------------------------
                       One-Time Labeling Revision Costs  Annual Incremental Printing Costs    Annual PDR Costs
----------------------------------------------------------------------------------------------------------------
Per product cost\1\              $4,379                                $37                        $842
Number of affected                  669                                669                         160
 products
Total                        $2,929,228                            $24,439                    $134,720
Total annualized               $417,056                            $24,439                    $134,720
 costs\2\
----------------------------------------------------------------------------------------------------------------
\1\ Rounding may affect totals.
\2\ One-time costs are annualized over 10 years at 7 percent.

C. Benefits

    Bacterial resistance to antibacterial drugs directly affects health 
care costs by requiring the use of newer and more expensive drugs and 
by requiring longer treatment and hospitalization periods for patients 
infected by resistant bacteria. The societal costs of the infections 
from these resistant bacteria include both the direct costs for 
additional drugs and medical care and the indirect costs of lost 
productivity for patients with extended illness and increased 
mortality. The agency did not receive any direct comments on the 
benefits estimate in the proposed rule. However, during the review of 
the proposed rule, the Office of Management and Budget (OMB) requested 
that the agency estimate mortality attributable to resistant bacteria 
for the final rule. Thus, the final analysis of impacts also includes 
an estimate of the number of lifeyears saved.
1. Direct Costs of Resistant Infections
    Most studies on the cost of hospital infections in the United 
States have not separated infections caused by resistant bacteria from 
those caused by susceptible bacteria. Researchers from the CDC, 
examining summary reports of outbreak investigations for 1971 through 
1980, as well as published and unpublished reports of infections caused 
by bacteria with known antibacterial resistance, found that infections 
from resistant bacteria were typically associated with substantially 
longer hospital stays. The examined studies, however, had too few 
subjects to allow statistical analysis (Ref. 8).
    Two recent studies on the effects of methicillin-resistant 
Staphylococcus aureus (MRSA) reported significantly different lengths 
of stay for patients infected with resistant bacteria compared to 
controls. The studies included only patients with similar underlying 
diseases. One study found that patients with infections from resistant 
bacteria stayed an average of 9.5 days in an intensive care unit (ICU) 
while control patients stayed there 5 days (Ref. 9). The other study 
found that patients with infections from resistant bacteria stayed an 
average of 21 days in an ICU compared to 12.5 days for control patients 
(Ref. 10).
    Three regional studies directly compared the costs of infections 
caused by resistant and susceptible bacteria. In the first study, using 
hospital discharge data from hospitals in New York City, researchers 
modeled differences between infections caused by MRSA and those caused 
by methicillin-susceptible S. aureus (MSSA). They estimated that each 
MRSA infection costs an additional $2,500 in direct medical costs and 
longer hospital stays (Ref. 11).
    The second study, performed at a university teaching hospital in 
North Carolina, also measured length of hospital stay and direct costs 
of hospitalization for patients with hospital-acquired bloodstream 
infections caused by MRSA and MSSA bacteria (Ref. 12). Patients 
infected with resistant bacteria stayed 8 additional days in the 
hospital (i.e., 12 days with MRSA infections compared to 4 days with 
MSSA infections), costing approximately $17,000 more in direct hospital 
costs.
    In the third study, conducted at a Boston hospital, researchers 
examined the economic impact of antibiotic resistance in Pseudomonas 
aeruginosa (Ref. 13). This study compared length of stay and costs for 
three groups: (1) Patients with susceptible bacteria, (2) patients with 
some baseline resistant bacteria, and (3) patients with resistance that 
emerged while hospitalized. Daily hospital charges of $2,059 were the 
same for all three groups. Also, the length of stay was similar for 
patients infected with susceptible bacteria and those with baseline 
resistant bacteria. However, patients in whom resistant bacteria 
emerged during hospitalization incurred additional costs of $7,340 for 
3.5 extra days.
    The total number of annual infections caused by resistant bacteria 
is uncertain. Although diagnosis codes exist for infections with drug-
resistant microorganisms, the codes are intended only to supplement 
other codes for infectious conditions and are not always included in 
patient data. As a result, hospital patient records may provide only an 
estimate of the minimum number of cases of drug-resistant infections in 
a given year. The U.S. National Center for Health Statistics publishes 
annual estimates of the number of diagnoses (by diagnosis code) in 
nonfederal short-stay hospitals from the National Hospital Discharge 
Survey (NHDS). NHDS estimates about 18,000 and 43,000 cases of 
infections by resistant microorganisms for 1995 and 1997, respectively 
(Refs. 14 and 15). On the basis of data from a larger national sample 
of hospital patients, the Healthcare Cost and Utilization Project 
(HCUP) estimates 84,000 diagnoses of resistant infections in community 
hospitals for 1997 (Ref. 16). CDC hospital surveillance data for 5 
known strains of resistant bacteria for 1995 suggest a much higher 
figure, approximately 279,000 cases (Ref. 17). For this analysis, FDA 
has assumed the average of the 1995 data, or that 150,000 hospital-
acquired infections per year are attributable to resistant bacteria. 
Thus, if patients incur additional hospital charges of only $2,500 per 
resistant infection, the total hospital cost attributable to 
antibacterial resistance is estimated at $375 million annually. 
However, these costs are likely understated because the more recent

[[Page 6076]]

1997 studies found even greater costs and longer hospital stays 
associated with infections from resistant bacteria than the 1995 
studies.
2. Indirect Costs of Resistant Infections
    a. Morbidity. In addition to direct medical costs, patients also 
incur indirect costs from lost productivity due to resistant bacterial 
infections. FDA does not know how long a typical hospital stay is 
extended due to antibacterial resistance. However, if just 1 extra day 
were needed for relatively simple cases, at an average hourly wage of 
$16 including benefits, each case would cost about $128 in lost 
productivity. For cases where few alternatives are effective against 
the disease-causing bacteria, as with Pseudomonas, patients might need 
an additional 3.5 days in the hospital, with lost productivity cost of 
about $448 per patient. Assuming the mean of these two estimates, 
150,000 cases of resistant bacterial infections would cost the economy 
about $43 million per year in lost productivity.
    b. Mortality. The threat of mortality appears to be greater from 
hospital-acquired infections than from community-acquired infections. 
According to the CDC, about 40 percent of all community-acquired 
infections from S. pneumoniae are penicillin-nonsusceptible (includes 
both intermediate-susceptible and resistant strains). These bacteria 
can cause infections such as bacteremia, pneumonia, meningitis, and 
otitis media. Until the mid-1990s, surveillance data for S. pneumoniae 
included few cases of resistant bacteria. Current surveillance data, 
however, show the incidence of resistant bacteria has dramatically 
increased, surpassing the incidence of intermediate-susceptible 
bacteria (Ref. 18). Several studies have reported higher crude 
mortality rates with infections caused by drug-resistant S. pneumoniae 
(DRSP) (Refs. 19, 20, 21, 22, and 23). However, once adjusted for age 
and severity of illness, mortality rates for patients with community-
acquired infections from DRSP and drug-sensitive S. pneumoniae strains 
are statistically similar. As the incidence of community-acquired 
infections from resistant bacteria increases, the differences in 
mortality rates may become statistically significant.
    In a report released last year, the World Health Organization 
estimated that 14,000 people die in the United States annually from 
drug-resistant infections acquired in hospitals (Ref. 24). Several 
published studies have reported higher crude mortality rates from 
hospital-acquired infections caused by resistant bacteria. However, 
direct comparison of the findings of these studies is difficult because 
of differences in definitions, base line mortality rates, and the 
characteristics of patients included in the studies. In most studies, 
age and severity of illness confound the mortality data. Furthermore, 
because the prevalence of resistant bacteria is not uniform throughout 
the United States, studies conducted in a specific hospital or region 
may not be representative of the whole country.
    To develop a rough estimate of the mortality that might be 
attributable to resistant bacterial infections, FDA estimated base line 
in-hospital mortality rates by age cohort, using hospital discharge and 
diagnosis data from HCUP (table 4 of this document). The number of 
life-years lost due to resistant bacterial infections was then derived 
from this base line mortality rate and from a weighted measure of the 
deaths attributable to resistant bacteria (27.1 percent).

                            Table 4.--1997 In-Hospital Mortality Rates by Age Cohort
----------------------------------------------------------------------------------------------------------------
                                                     Number of In-Hospital       In-Hospital Mortality as % of
        Age cohort           Population (000)\1\           Deaths)\2\              Population for Age Cohort
----------------------------------------------------------------------------------------------------------------
Birth-17                        69,603                    25,739                               0.04%
18-44                          108,553                    49,687                               0.05%
45-64                           55,441                   143,670                               0.26%
65-84                           30,272                   462,465                               1.53%
85+                              3,913                   185,868                               4.75%
Total                          267,782                   867,429               .................................
----------------------------------------------------------------------------------------------------------------
\1\ U.S. Department of Commerce, Census Bureau, Statistical Abstract of the United States: 2000, Table 12.
\2\ 1997 hospital discharge data from HCUPnet, Healthcare Cost and Utilization Project, Agency for Healthcare
  Research and Quality (AHRQ), Rockville, MD, http://www.ahrq.gov/data/hcup/hcupnet.htm.

    Table 5 of this document shows the number and monetary value of the 
life-years lost from resistant bacteria. The monetary values shown in 
columns 6 and 7 are derived by amortizing the value of a statistical 
life of $5 million\8\ over the average remaining life span of a 35-
year-old, which is estimated to be 44.3 years. At zero discount rate, 
this would be the equivalent of receiving a payment of $112,867 per 
year. However, applying discount rates of 3 percent and 7 percent\9\, 
to reflect more plausible rates of social time preference, results in 
life-year values equal to $205,493 and $368,404, respectively.
---------------------------------------------------------------------------

    \8\ The $5 million estimate is the aggregate amount society is 
willing to pay to save one life. Fisher, A., D. Violette, and L. 
Chestnut, ``The Value of Reducing Risks of Death: A Note on New 
Evidence,'' Journal of Policy Analysis and Management, vol. 8, pp. 
88-100, 1989.
    \9\ The Panel on Cost-Effectiveness in Health and Medicine 
convened by the U.S. Public Health Service recommends using a 
discount rate of 3 percent to calculate health benefits (Weinstein, 
M. C. et al. ``Recommendations of the Panel on Cost-Effectiveness in 
Health and Medicine,'' Journal of the American Medical Association, 
vol. 276, p. 1253-1258). OMB requires agencies to use a discount 
rate of 7 percent when calculating regulatory impacts.

[[Page 6077]]



             Table 5.--Estimated Number and Monetary Value of Life-Years Lost from Deaths Due to Infections with Drug-Resistant Bacteria\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                    Number of In-                                        Monetary Value   Monetary Value
                                                Average Life          Hospital          Number of      Number of Life    of Life Years    of Life Years
                                                    Years         [chyph]Diagnoses     Deaths From    Years Lost From       Lost--3%         Lost--7%
                 Age cohort                   [chyph]Remaining   With Drug-Resistant      Drug-            Drug-        [chyph]Discount  [chyph]Discount
                                                  for Each      [chyph]Infections\3,    Resistant     [chyph]Resistant  Rate ($ Mil)\6,  Rate ($ Mil)\6,
                                                  Cohort\2\              4\           Infections\5\  [chyph]Infections         7\               8\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Birth-17                                             69.2               3,056               0.3             21.2              $4.4             $7.8
18-44                                                48.1              10,372               1.3             62.0             $12.7            $22.8
45-64                                                26.8              16,807              11.8            317.1             $65.2           $116.8
65-84                                                12.3              39,857             165.2          2,039.5            $419.1           $751.3
85+                                                   4.2              13,838             178.4            750.6            $154.2           $276.5
Total                                         ................         83,930             357.0          3,190.3            $655.6         $1,175.3
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum or multiply due to rounding.
\2\ Anderson, R. N., ``United States Life Tables, 1997,'' National Vital Statistics Reports, vol. 47, Table 1, 1999.
\3\ 1997 hospital discharge data from HCUPnet, Healthcare Cost and Utilization Project, ``AHRQ, Rockville, MD (http://www.ahrq.gov/data/hcup/hcupnet.htm).
\4\ Includes all reported ICD-9 V09 diagnoses (i.e., infection with drug-resistant microorganisms).
\5\ Baseline mortality from table 4 of this document. The number of deaths from drug-resistant infections was derived from published reports and HCUP
  data. Drug resistance increased mortality rates across all age cohorts by a weighted average of 27.1 percent. The mean percent increase in mortality
  rates and the estimated share of infections caused by the bacteria (shown in parentheses) are: 88 percent (5.3 percent) for vancomycin resistant
  Enterococci (Refs. 24, 25, 26, 27, 28, 29, 30, 31, 32, and 33); 103 percent (7.4 percent) for methicillin resistant S. aureus (Refs. 9, 10, 27, and
  35); and 230 percent (6.5 percent) for P. aeruginosa (Refs. 12 and 36). No difference in mortality rates between resistant and susceptible strains was
  assumed for all other infection-causing bacteria. 27.1 percent = (0.053 x 0.88) + (0.074 x 1.03) + (0.065 x 2.30) + (0.808 x 0) (may not sum or
  multiply to total because of rounding.
\6\ $5 million = value of statistical life saved; 34.9 years = median age of population in 1997; 44.3 years remaining from 1997 Life Table, used to
  amortize $5 million (see footnote 2 of this table).
\7\ $205,493/life-year lost.
\8\ $368,404/life-year lost.

3. Reduced Direct and Indirect Costs
    Many factors can contribute to the development of antibiotic 
resistance, including the unnecessary use of antibiotics. The final 
rule adds statements to the professional labeling of these drugs that 
will encourage health care providers and patients to use antibiotics in 
a way that reduces the risk that antibiotic-resistant bacteria will 
develop, thus maintaining the effectiveness of these drugs.
    As discussed elsewhere in this document, some comments to the 
agency questioned the effectiveness of labeling as an information tool. 
Health care organizations and government, however, can employ a variety 
of ways to inform stakeholders of the serious public health threat 
posed by resistant bacteria. Labeling that prompts health care 
providers and patients to use antibacterial drugs prudently will 
complement the educational efforts of organizations such as the AMA and 
CDC. The agency finds that while many health care providers 
infrequently consult the actual package insert, they often refer to the 
PDR for information about available drugs. Both the print and 
electronic versions of the PDR reproduce the professional labeling 
verbatim. Moreover, many patients use the PDR to obtain information 
about the drugs they are taking.
    FDA cannot accurately quantify the magnitude of the impact that 
these changes in labeling will have on physician and patient behavior, 
or of its subsequent impact on the development of resistant bacteria 
and their societal costs. If, however, the changes avoid even 1 percent 
of the above estimated costs of antibacterial resistance, the annual 
cost savings will amount to $3.8 million in direct hospital costs, $0.4 
million in lost productivity, and from $6.6 million to $11.8 million in 
life-years lost (discounted at 3 percent and 7 percent respectively), 
for a total benefit exceeding $10 to $16 million annually.
    If the costs of increased antibiotic resistance were decreased as 
little as 0.01 percent, the benefits of this rule would exceed the 
compliance costs estimated in the previous paragraph. FDA believes it 
is extremely likely that the decrease in the excess cost of antibiotic 
resistance will be at least this large, and is likely to be 
significantly larger.

D. Impacts on Small Entities

    No comments on the initial regulatory flexibility analysis were 
received by the agency. The final rule affects manufacturers of 
systemic antibacterial drug products. The 1997 Economic Census found 
approximately 700 pharmaceutical preparation manufacturing firms in the 
United States (i.e., North American Industry Classification System 
(NAICS) code 325412). The Small Business Administration (SBA) considers 
firms with fewer than 750 employees to be small. As seen in table 6 of 
this document, Census data classify firms in size categories that do 
not permit a precise determination of the number of pharmaceutical 
firms that have fewer than 750 employees. However, Census data do show 
that more than 90 percent of pharmaceutical manufacturers have fewer 
than 500 employees, and thus are small businesses (Ref. 12).
    Approximately 101 large and small firms manufacture systemic 
antibacterial drug products\10\ and thus would be affected by the rule. 
The estimated annualized costs of $861 per product\11\ are relatively 
modest for most manufacturers of antibiotic drugs. Since small 
manufacturers of human prescription drugs already submit labeling to 
FDA, the labeling requirements of the rule will not require small firms 
to seek employees with additional special skills. As physicians and 
patients become more cautious in their use of antibiotics, some small 
antibiotic manufacturers could experience a decline in the demand for 
their products. The objective of the final rule is to safeguard the 
effectiveness of all antibiotic drug products. Thus, slowing the 
appearance of more resistant strains of bacteria will increase the 
demand for those antibiotic drugs that remain an effective treatment 
for those infections. More prudent use of

[[Page 6078]]

antibiotics therefore will protect small, as well as large, 
manufacturers against the decline in demand that would otherwise follow 
a drop in product effectiveness.
---------------------------------------------------------------------------

    \10\ Derived from FDA's Approved Drug Products With Therapeutic 
Equivalence Evaluations, 2001, and 2001 Drug Information, American 
Hospital Formulary Service.
    \11\ Total annulaized costs per product: $417,056 + $24,439 + 
$134,720 = $576,216. Average annualized costs: $576,216/669 = $861.
---------------------------------------------------------------------------

    Based on the previous analyses, any foreseeable significant adverse 
impacts of the rule would be incurred only by those small firms that 
manufacture many affected products and consequently would be required 
to change multiple package inserts at one time. We reviewed FDA's 
Approved Drug Products With Therapeutic Equivalence Evaluations, 2001, 
and identified only eight small domestic firms that manufacture more 
than three antibiotic products. These 8 small firms manufacture 11, 8, 
8, 6, 5, 4, 4 and 4 products respectively, 95 percent of which are 
generic products. At least 2 of the 3 firms with over 6 products are 
multi-million dollar firms with over 400 employees. Three of the eight 
firms also manufacture one reference listed drug product.
    Table 6 of this document compares the estimated annualized and 
first-year costs of compliance to reported average annual sales 
revenues for pharmaceutical firms of varying sizes and for the average 
firm that primarily manufactures antimicrobial drugs. Almost all 
manufacturers of antibiotic products in the United States have over 20 
employees.\12\ Thus, the last column of the table shows that the first-
year costs will be less than two-tenths of one percent of sales 
revenues for almost all small firms. Based on the minimal impact 
implied by these data, FDA certifies that this final rule would not 
have a significant adverse economic effect on a substantial number of 
small entities.
---------------------------------------------------------------------------

    \12\ Derived from FDA's Approved Drug Products With Therapeutic 
Equivalence Evaluations, 2001, and 2001 Drug Information, American 
Hospital Formulary Service.

[[Page 6079]]



   Table 6.--Examples of Annualized and First-Year Costs to Modify Professional Labeling as a Percentage of Average Annual Shipment Value by Number of
                                                        Employees for NAICS 325412 and 325412P\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                          Annualized
                                                                                          Annualized    Cost to Modify  Annualized Cost     First-Year
                                                    Value of       Average Annual Per   Cost to Modify   Two Products   to Modify Three  Costs to Modify
    No. of Employees             No. of         [chyph]Shipments  [chyph]Establishment  One Product as       as a        Products as a    Three Products
                         [chyph]Establishments       (mil$)          Shipment Value      a Percentage    Percentage of   Percentage of   as a Percentage
                                                                         (mil$)           of Shipment      Shipment         Shipment       of Shipment
                                                                                           Value\2\        Value\2\         Value\2\         Value\3\
--------------------------------------------------------------------------------------------------------------------------------------------------------
              NAICS 325412 (All Pharmaceutical Preparation Manufacturing) Small Businesses By SBA Size Standards (fewer than 750 employees)
 
--------------------------------------------------------------------------------------------------------------------------------------------------------
 1-4                             179                  90.0                 0.5                0.17%           0.34%            0.51%            2.76%
--------------------------------------------------------------------------------------------------------------------------------------------------------
5-9                               88                 137.5                 1.6                0.06%           0.11%            0.17%            0.89%
--------------------------------------------------------------------------------------------------------------------------------------------------------
10-19                            128                 451.6                 3.5                0.02%           0.05%            0.07%            0.39%
--------------------------------------------------------------------------------------------------------------------------------------------------------
20-49                            138               1,078.4                 7.8                0.01%           0.02%            0.03%            0.18%
--------------------------------------------------------------------------------------------------------------------------------------------------------
50-99                             85               2,486.1                29.2                0.00%           0.01%            0.01%            0.05%
--------------------------------------------------------------------------------------------------------------------------------------------------------
100-249                          107               7,846.8                73.3                0.00%           0.00%            0.00%            0.02%
--------------------------------------------------------------------------------------------------------------------------------------------------------
250-499                           62              15,217.1               245.4                0.00%           0.00%            0.00%            0.01%
--------------------------------------------------------------------------------------------------------------------------------------------------------
500-999                           29              13,720.8               473.1                0.00%           0.00%            0.00%            0.00%
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                             Large Businesses by SBA Size Standards (750 or more employees)
 
--------------------------------------------------------------------------------------------------------------------------------------------------------
 1,000-2,499                      15               9,163.3               610.9                0.00%           0.00%            0.00%            0.00%
--------------------------------------------------------------------------------------------------------------------------------------------------------
2500 +                             6              17,328.5             2,888.1                0.00%           0.00%            0.00%            0.00%
--------------------------------------------------------------------------------------------------------------------------------------------------------
                     NAICS 325412P (Primary Product Class = pharmaceutical preparations for human parasitic and infective diseases)
 
--------------------------------------------------------------------------------------------------------------------------------------------------------
 All                              28               6,480.3               231.4                0.00%           0.00%            0.00%            0.01%
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\U.S. Department of Commerce, Bureau of the Census, Pharmaceutical Preparation Manufacturing: 1997 Economic Census of Manufacturing, Industry Series,
  EC97M-3254B.
\2\Average annualized per product costs = $861.
\3\Average first-year per product costs = $4,616.


[[Page 6080]]

VI. Paperwork Reduction Act of 1995

    FDA concludes that this final rule does not require information 
collections subject to review by OMB under the Paperwork Reduction Act 
of 1995 (the PRA) (Public Law 104-13). FDA received no comments on its 
determination concerning information collections.
    FDA is amending its labeling regulations to require that the 
labeling for systemic antibacterial drug products include certain 
statements, specified by FDA, about the link between unnecessary use of 
antibiotics and the development of drug-resistant bacterial strains. 
These labeling statements are not subject to review by OMB because they 
are ``originally supplied by the Federal Government to the recipient 
for the purpose of disclosure to the public'' (5 CFR 1320.3(c)(2)) and 
therefore do not constitute a ``collection of information'' under the 
PRA of 1995.
    Holders of approved new drug applications (NDAs) and abbreviated 
new drug applications (ANDAs) are required to submit supplements and 
holders of pending NDAs and ANDAs are required to submit amendments to 
comply with the new labeling requirements. The final rule also requires 
that all new NDAs and ANDAs for systemic antibacterial drug products 
comply with the new labeling requirements. FDA regulations governing 
the submission and approval of NDAs and ANDAs, including the submission 
of product labeling, are in part 314 (21 CFR part 314). Recordkeeping 
and reporting requirements included in part 314 are approved by OMB 
until March 31, 2005, under OMB control number 0910-0001.

VII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

VIII. References

    The following references have been placed on display in the Dockets 
Management Branch (see ADDRESSES) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Centers for Disease Control, and American Academy of 
Pediatrics, edited by S. F. Dowell, ``Principles of Judicious Use of 
Antimicrobial Agents for Pediatric Upper Respiratory Tract 
Infections,'' Supplement to Pediatrics, vol. 101, pp. 163-164, 
January 1998.
    2. McCaig, L. F., R. E. Besser, and J. M. Hughes, ``Trends in 
Antimicrobial Prescribing Rates for Children and Adolescents,'' 
Journal of the American Medical Association, vol. 287, pp. 3096-
3102, 2002.
    3. Perz, J. F. et al., ``Changes in Antibiotic Prescribing for 
Children After a Community-Wide Campaign,'' Journal of the American 
Medical Association, vol. 287, pp. 3103-3109, 2002.
    4. Pichichero, M. E., ``Dynamics of Antibiotic Prescribing for 
Children,'' Journal of the American Medical Association, vol. 287, 
pp. 3133-3135, 2002.
    5. Interagency Task Force on Antimicrobial Resistance, A Public 
Health Action Plan to Combat Antimicrobial Resistance Part 1: 
Domestic Issues, 2001, available at http://www.cdc.gov/drugresistance/actionplan/html/index.htm.
    6. Gonzales, R. D. et al., ``Infections Due to Vancomycin-
Resistant Enterococcus Faecium Resistant to Linezolid,'' Lancet, 
vol. 357, p. 1179, 2001.
    7. Ibrahim, E. H. et al., ``The Influence of Inadequate 
Antimicrobial Treatment of Bloodstream Infections on Patient 
Outcomes in the ICU Setting, Chest, vol. 118, pp. 146-155, 2000.
    8. Holmberg S. D. et al, ``Health and Economic Impacts of 
Antimicrobial Resistance,'' Review of Infectious Disease, vol. 9, 
pp. 1065-1078, 1987.
    9. Singh, N. et al., ``Methicillin-Resistant Staphylococcus 
Aureus: The Other Emerging Resistant Gram-Positive Coccus Among 
Liver Transplant Recipients,'' Clinical Infectious Diseases, vol. 
30, pp. 322-327, 2000.
    10. Chaix, C. et al., ``Control of Endemic Methicillin-Resistant 
Staphylococcus Aureus: A Cost-Benefit Analysis in an Intensive Care 
Unit,'' Journal of the American Medical Assocation, vol. 282, pp. 
1745-1751, 1999.
    11. Rubin, R. J. et al., ``The Economic Impact of Staphylococcus 
Aureus Infection in New York City Hospitals,'' Emerging Infectious 
Diseases, vol. 5, pp. 9-17, 1999.
    12. Abramson, M. A., and D. J. Sexton, ``Nosocomial Methicillin-
Resistant and Methicillin-Susceptible Staphylococcus Aureus Primary 
Bacteremia: At What Costs?'' Infection Control and Hospital 
Epidemiology, vol. 20, pp. 408-411, 1999.
    13. Carmeli, Y. et al., ``Health and Economic Outcomes of 
Antibiotic Resistance in Pseudomonas Aeruginosa,'' Archives of 
Internal Medicine, vol. 159, pp. 1127-1132, 1999.
    14. Graves, E. J., and B. S. Gillum, ``Detailed Diagnoses and 
Procedures, National Hospital Discharge Survey, 1995,'' National 
Center for Health Statistics Vital Health Statisitics Series 13 
(130):115, 1997.
    15. Owings, M. F., and L. Lawrence, ''Detailed Diagnoses and 
Procedures, National Hospital Discharge Survey, 1997,'' National 
Center for Health Statistics Vital Health Statistics Series 13 
(145):118, 1999.
    16. HCUPnet, Healthcare Cost and Utilization Project, Agency for 
Healthcare Research and Quality, Rockville, MD (http://www.ahrq.gov/data/hcup/hcupnet.htm).
    17. U.S. General Accounting Office Report, ``Antimicrobial 
Resistance: Data to Assess Public Health Threat From Resistant 
Bacteria Are Limited,'' GAO/HEHS/NSIAD/RCED-99-132, pp. 5-6, April 
1999.
    18. Centers for Disease Control, Active Bacterial Core 
Surveillance (ABCs) Report; Emerging Infections Program Network, 
Streptococcus Pneumoniae, 1999 (http://www.cdc.gov/ncidod/dbmd/abcs).
    19. Feikin, D. R. et al., ``Mortality From Invasive Pneumococcal 
Pneumonia in the Era of Antibiotic Resistance, 1995-1997,'' American 
Journal of Public Health, vol. 90, pp. 223-229, 2000.
    20. Campbell, G. D., and R. Silberman, ``Drug-Resistant 
Streptococcus Pneumoniae,'' Clinical Infectious Diseases, vol. 26, 
pp. 1188-1195, 1998.
    21. Danila, R. N. et al., ``Addressing Emerging Infections: The 
Partnership Between Public Health and Primary Care Physicians,'' 
Emerging Infections, vol. 106, pp. 90-105, 1999.
    22. Castillo, E. M. et al., ``Streptococcus Pneumoniae: 
Bacteremia in an Era of Penicillin Resistance,'' American Journal of 
Infection Control, vol. 28, pp. 239-243, 2000.
    23. Jacobs, M. R., ``Drug-Resistant Streptococcus Pneumoniae: 
Rational Antibiotic Choices,'' American Journal of Medicine, vol. 
106, pp. 19S-25S, 1999.
    24. World Health Organization, ``Overcoming Antimicrobial 
Resistance,'' WHO Report on Infectious Diseases 2000, WHO/CDS/
2000.2, Chapter 4, http://www.who.int/infectious-disease-report/2000/.
    25. Stosor, V. et al., ``Enterococcus Faecium Bacteremia: Does 
Vancomycin Resistance Make a Difference?'' Archives of Internal 
Medicine, vol. 158, pp. 522-527, 1998.
    26. Bhavnani, S. M. et al., ``A Nationwide, Multicenter, Case-
Control Study Comparing Risk Factors, Treatment, and Outcome for 
Vancomycin-Resistant and -Susceptible Enterococcal Bacteremia,'' 
Diagnostic Microbiology and Infectious Disease, vol. 36, pp. 145-
158, 2000.
    27. Edmond, M. B. et al., ``Vancomycin-Resistant Enterococcal 
Bacteremia: Natural History and Attributable Mortality,'' Clinical 
Infectious Diseases, vol. 23, pp. 1234-1239, 1996.
    28. Gleason, T. G. et al., ``Prediction of Poorer Prognosis by 
Infection With Antibiotic-Resistant Gram-Positive Cocci Than by 
Infection With Antibiotic-Sensitive Strains,'' Archives of Surgery, 
vol. 134, pp. 1033-1040, 1999.
    29. Paladino, J. A., ``Pharmacoeconomics of Antimicrobial 
Therapy,'' American Journal of Health-System Pharmacy, vol. 56, 
supp. 3, pp. S25-28, 1999.
    30. Linden, P. K. et al., ``Differences in Outcomes for Patients 
With Bacteremia Due to Vancomycin-Resistant Enterococcus faecium or 
Vancomycin-Susceptible E.

[[Page 6081]]

Faecium,'' Clinical Infectious Diseases, vol. 22, pp. 663-670, 1996.
    31. Lucas, G. M. et al., ``Vancomycin-Resistant and Vancomycin-
Susceptible Enterococcal Bacteremia: Comparison of Clinical Features 
and Outcomes,'' Clinical Infectious Diseases, vol. 26, pp. 1127-
1133, 1998.
    32. Shay, D. K. et al., ``Epidemiology and Mortality Risk of 
Vancomycin-Resistant Enterococcal Bloodstream Infections,'' Journal 
of Infectious Diseases, vol. 172, pp. 993-1000, 1995.
    33. Garbutt, J. M. et al., ``Association Between Resistance to 
Vancomycin and Death in Cases of Enterococcus Faecium Bacteremia,'' 
Clinical Infectious Diseases, vol. 30, pp. 466-472, 2000.
    34. Lautenbach, E., W. B. Bilker, and P. J. Brennan, 
``Enterococcal Bacteremia: Risk Factors for Vancomycin Resistance 
and Predictors of Mortality,'' Infection Control and Hospital 
Epidemiology, vol. 20, pp. 318-323, 1999.
    35. Roghmann, M. et al., ``The Clinical and Economic Impact of 
Antimicrobial Resistance on Nosocomial Bloodstream Infections,'' 
Infection Control and Hospital Epidemiology, vol. 21, p. 97, 2000.
    36. Kollef, M. H., ``Ventilator-Associated Pneumonia: The 
Importance of Initial Empiric Antibiotic Selection,'' Infections in 
Medicine, vol. 17, pp. 265-268, 278-283, 2000.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
201 is amended as follows:

PART 201--LABELING

    1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.
    2. Add Sec.  201.24 to subpart A to read as follows:


Sec.  201.24  Labeling for systemic antibacterial drug products.

    The labeling of all systemic drug products intended for human use 
indicated to treat a bacterial infection, except a mycobacterial 
infection, must bear the following statements:
    (a) At the beginning of the label, under the product name, the 
labeling must state:
    To reduce the development of drug-resistant bacteria and 
maintain the effectiveness of (insert name of antibacterial drug 
product) and other antibacterial drugs, (insert name of 
antibacterial drug product) should be used only to treat or prevent 
infections that are proven or strongly suspected to be caused by 
bacteria.
    (b) In the ``Indications and Usage'' section, the labeling must 
state:
    To reduce the development of drug-resistant bacteria and 
maintain the effectiveness of (insert name of antibacterial drug 
product) and other antibacterial drugs, (insert name of 
antibacterial drug product) should be used only to treat or prevent 
infections that are proven or strongly suspected to be caused by 
susceptible bacteria. When culture and susceptibility information 
are available, they should be considered in selecting or modifying 
antibacterial therapy. In the absence of such data, local 
epidemiology and susceptibility patterns may contribute to the 
empiric selection of therapy.
    (c) In the ``Precautions'' section, under the ``General'' 
subsection, the labeling must state:
    Prescribing (insert name of antibacterial drug product) in the 
absence of a proven or strongly suspected bacterial infection or a 
prophylactic indication is unlikely to provide benefit to the 
patient and increases the risk of the development of drug-resistant 
bacteria.
    (d) In the ``Precautions'' section, under the ``Information for 
Patients'' subsection, the labeling must state:
    Patients should be counseled that antibacterial drugs including 
(insert name of antibacterial drug product) should only be used to 
treat bacterial infections. They do not treat viral infections 
(e.g., the common cold). When (insert name of antibacterial drug 
product) is prescribed to treat a bacterial infection, patients 
should be told that although it is common to feel better early in 
the course of therapy, the medication should be taken exactly as 
directed. Skipping doses or not completing the full course of 
therapy may (1) decrease the effectiveness of the immediate 
treatment and (2) increase the likelihood that bacteria will develop 
resistance and will not be treatable by (insert name of 
antibacterial drug product) or other antibacterial drugs in the 
future.

    Dated: October 4, 2002.
Mark B. McClellan,
Commissioner of Food and Drugs.
[FR Doc. 03-2969 Filed 2-5-03; 8:45 am]
BILLING CODE 4160-01-S