[Federal Register Volume 65, Number 182 (Tuesday, September 19, 2000)]
[Proposed Rules]
[Pages 56511-56518]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-24007]


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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: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to require 
that all systemic antibacterial drug products (i.e., antibiotics and 
their synthetic counterparts) intended for human use contain additional 
labeling information about the emergence of drug-resistant bacterial 
strains. The proposal reflects a growing concern in FDA and the medical 
community that overprescription and inappropriate use of systemic 
antibacterials has contributed to a dramatic increase in recent years 
in the prevalence of drug-resistant bacterial infections. The proposal 
is intended to encourage physicians to prescribe systemic 
antibacterials more judiciously and only when clinically necessary. The 
proposal 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: Submit written comments by December 4, 2000. See section III of 
this document for the proposed effective date of a final rule based on 
this document.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Gary K. Chikami, Center for Drug 
Evaluation and Research (HFD-520), Food and Drug Administration, 9201 
Corporate Blvd., Rockville, MD 20852, 301-827-2120.

SUPPLEMENTARY INFORMATION:

I. Background

    Antimicrobial 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 antimicrobial drugs used to treat them. Several bacterial species 
have developed strains that are resistant to every approved 
antimicrobial drug, thus severely limiting the therapeutic options 
available for adequate treatment.
    Antimicrobial resistance in bacteria is not a new problem. For as 
long as antimicrobial drugs have been widely available--over 50 years 
now--bacteria have demonstrated an ability to develop resistance by a 
number of mechanisms, such as antibiotic-degrading enzymes. Over the 
past several years, however, the incidence of resistance in both 
hospital- and community-acquired

[[Page 56512]]

infections has increased dramatically, making many common illnesses 
more difficult to treat than they were only 5 or 10 years ago.
    The rise of resistance in the bacteriumStreptococcus pneumoniae 
provides a good example. S. pneumoniae is a common cause of middle-ear 
and sinus infections, as well as several life-threatening illnesses, 
including pneumonia, bacteremia, and meningitis. Strains of S. 
pneumoniae that are resistant to penicillin were observed as early as 
the 1960's. Over the following two or three decades, however, the 
frequency of drug-resistant S. pneumoniae strains remained relatively 
low. Even at the beginning of the 1990's, only about 5 percent of 
isolates showed decreased susceptibility to penicillin (Ref. 1). But in 
the past few years, that number has risen dramatically. In fact, in 
some parts of the country, up to 40 percent of all S. pneumoniae 
isolates are now intermediately or highly penicillin resistant (Ref. 
2).
    In the hospital setting, antimicrobial resistance is a particularly 
important problem. Each year in the United States, about 2 million 
patients acquire an infection while receiving treatment in a health 
care setting (Ref. 3). According to the Centers for Disease Control and 
Prevention (CDC), approximately 70 percent of those infections that are 
bacterial in nature are resistant to at least one of the antimicrobial 
drugs that have traditionally been used to treat them (Ref. 4).

A. Factors Contributing to the Emergence of Resistance

    Several factors contribute to the increasing prevalence of 
antimicrobial resistance. One of the most important is the overuse or 
inappropriate use of antimicrobial drugs. The amount of overuse is 
difficult to establish with accuracy; however, several studies have 
provided estimates that provide a picture of substantial overuse of 
these products. Office-based physicians in the United States write more 
than 100 million antibiotic prescriptions each year. According to the 
CDC, however, as many as half of those prescriptions--a total of 50 
million--are inappropriate, being prescribed for the common cold and 
other viral infections, including influenza, against which antibiotics 
are not active (Ref. 5). A recent study of paid Medicaid claims for 
treatment of respiratory tract infections in Kentucky found that 60 
percent of adults received antibiotics to treat the common cold (Ref. 
6). A survey of the prescribing patterns of office-based physicians in 
the United States in 1992 found that approximately 12 million 
antibiotic prescriptions, or 21 percent of all antibiotic prescriptions 
to adults, were written to treat colds, upper respiratory tract 
infections, and bronchitis, even though over 90 percent of these 
diseases are caused by viruses on which antibacterial drugs would have 
no effect (Ref. 7).
    A 1995 congressional report estimated that 25 to 35 percent of 
hospital patients receive antibiotics either to prevent infections 
associated with surgery or to treat disease (Ref. 8). Another study 
found that from 1980 to 1992, per capita consumption of antibacterial 
drugs remained relatively constant, but the total volume increased from 
86 million to 110 million prescriptions (Ref. 9). Moreover, the pattern 
of drug use changed over this period, with increased use of broad-
spectrum antimicrobial drugs such as cephalosporins and decreased use 
of narrow-spectrum drugs such as penicillins.
    Inappropriate antibiotic prescriptions can have serious 
consequences. Antimicrobial use increases the selective pressure on 
bacteria to develop and spread resistant strains. Thus, the more an 
antimicrobial is used, the more likely it is that bacteria will develop 
resistance to it.
    Incomplete treatment with antibiotics also leads to more rapid 
selection of resistant organisms (Ref. 10). Even when physicians 
properly prescribe antibiotics, antibiotic resistance is promoted when 
patients skip doses or do not complete the entire course of therapy. 
This is because suboptimal therapy may allow more resistant organisms 
to survive and spread in the community. Therefore, educating patients 
about how to take antibiotics is a necessary step in reducing 
antibiotic resistance (Ref. 11). Patients also need to be educated that 
antibiotics should not be used to treat viral illnesses.

B. Responding to the Resistance Problem

    Bacterial resistance can be reduced by decreasing the use of 
antibacterial drugs. For example, in response to increased erythromycin 
resistance of Group A streptococci, Finland implemented a nationwide 
campaign in 1992 to reduce the use of macrolide antibiotics (the class 
of which erythromycin is a member). Finnish consumption of this class 
of drug declined by about 43 percent in the first year and it has 
remained at a reduced level. By 1996, erythromycin-resistant Group A 
streptococci had declined in Finland by almost 48 percent (Ref. 12).
    Important steps in decreasing the prevalence of antibacterial 
resistance and slowing its future development and spread are to educate 
physicians and the public about the problem of antibiotic resistance 
and to encourage more judicious use of antimicrobial drugs. FDA 
believes that professional labeling can be used to accomplish these 
objectives. Therefore, FDA is proposing to require that the labeling 
for systemic antibacterial drug products include certain statements 
about the inappropriate use of antimicrobials and the link between 
inappropriate use and the emergence of drug-resistant bacterial 
strains. Under the proposal, the labeling would include the following 
reminders for physicians:
     Antibacterial drugs should only be used in situations 
where a bacterial infection is either proven or strongly suspected.
     The type of bacteria involved in an illness and its 
antimicrobial susceptibility pattern should generally be identified 
before an antibacterial is chosen.
     The antibacterial chosen should be targeted for the 
specific organism to be eradicated rather than opting for a more broad-
spectrum drug.
     Antimicrobial therapy should be modified once 
microbiologic results (both pathogen involved and susceptibility 
patterns) are available.
     Patients should be counseled about the proper use of 
antibacterials and the importance of taking them only as directed.

C. Scope of the Proposal

    The focus of this proposed rule is systemic antibacterial drug 
products. Bacteria, however, are not the only microorganisms that can 
develop resistance to the drugs designed to treat them. Viruses, fungi, 
and parasites have the same ability. Treatment of these infections 
raise some different and unique scientific and regulatory issues and 
the agency would like to receive comments on approaches for dealing 
with resistance problems that may exist for dealing with these 
situations. Similarly, the treatment of mycobacterial infections (e.g., 
tuberculosis or leprosy) raises unique issues and the drugs that are 
intended to treat these infections are not covered by this rule. The 
agency would also like to receive comments on approaches to dealing 
with these drugs as well. Finally, topical antibacterials and topical 
antiseptics are not covered by this proposal.

[[Page 56513]]

II. Description of the Proposed Rule

    The proposed rule would amend part 201 (21 CFR part 201) by adding 
new Sec. 201.24 requiring special labeling for all systemic drug 
products indicated to treat a bacterial infection, except a 
mycobacterial infection.
    Proposed Sec. 201.24(a) would require that at the beginning of the 
label, under the product name, the labeling must state that 
inappropriate use may increase the prevalence of drug resistant 
microorganisms and may decrease the effectiveness of the drug product 
and related antimicrobial agents, and that the drug product should be 
used only to treat infections that are proven or strongly suspected to 
be caused by susceptible microorganisms. Proposed Sec. 201.24(b) would 
require that the ``Clinical Pharmacology'' section state that 
appropriate use of the drug product includes, where applicable, 
identification of the causative microorganism and determination of its 
susceptibility profile.
    Proposed Sec. 201.24(c) would require that the ``Indications and 
Usage'' section state that local epidemiology and susceptibility 
patterns of the listed microorganisms should direct initial selection 
of the drug product for the treatment of the listed indications and 
that because of changing susceptibility patterns, definitive therapy 
should be guided by the results of susceptibility testing of the 
isolated pathogens.
    Proposed Sec. 201.24(d) would require that the ``Precautions'' 
subsection entitled ``General'' state that inappropriate use may 
increase the prevalence of drug resistant microorganisms and may 
decrease the future effectiveness of the drug product and related 
antimicrobial agents. This subsection would also include a statement 
that the drug product should only be used to treat infections that are 
proven or strongly suspected to be caused by susceptible 
microorganisms.
    Proposed Sec. 201.24(e) would require that the ``Precautions'' 
subsection entitled ``Information for Patients'' state that patients 
should be counseled that the drug product should be used only to treat 
bacterial infections and that it does not treat viral infections. The 
subsection would also advise physicians to counsel patients that the 
medication should be taken exactly as directed.

III. Effective Date and Proposed Implementation Plan

    FDA proposes that any final rule based on this proposed rule become 
effective 1 year after the date of its publication in the Federal 
Register. After that date, new drug applications (NDA's) submitted 
under 21 CFR 314.50 and abbreviated new drug applications (ANDA's) 
submitted under 21 CFR 314.94 for systemic antibiotic drug products 
intended for human use (except those intended to treat mycobacterial 
infections) would have to comply with the labeling requirements under 
proposed Sec. 201.24. Holders of approved NDA's or ANDA's would be 
encouraged to make the labeling changes prior to the effective date of 
the final rule and would submit supplements that do not require 
preapproval under 21 CFR 314.70(c) or 21 CFR 314.97. Holders of pending 
applications would submit amendments under 21 CFR 314.60 or 21 CFR 
314.96. To streamline the agency's review, these supplements and 
amendments would include only the labeling changes proposed in this 
rulemaking.

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 proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act (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 impact on a substantial 
number of small entities, an agency must analyze regulatory options 
that would minimize any significant impact of the rule on small 
entities. Section 202(a) of the Unfunded Mandates Reform Act of 1995 
requires that agencies prepare a written assessment 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 this proposed rule is consistent with the 
regulatory philosophy and principles identified in Executive Order 
12866 and in the two statutes cited above. The proposed rule would 
amend the content of the professional labeling for human prescription 
antibacterial drugs. Based on the analysis below, as summarized in 
table 1, FDA projects the annualized costs of complying with the 
proposed changes to be approximately $0.5 million. The agency also 
finds that if the proposed rule reduced the excess medical and 
productivity costs associated with antibacterial resistance by just 1 
percent, the annual benefits would exceed $4 million. While FDA has 
determined that the proposed rule is a ``significant regulatory 
action'' as defined in section 3(f)(4) of Executive Order 12866, the 
proposed rule is not an economically significant rule as described in 
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 proposed rule will not 
have a significant effect on a substantial number of small entities. 
The Unfunded Mandates Reform Act does not require FDA to prepare a 
statement of costs and benefits for the proposed rule, because the 
proposed rule is not expected to result in any 1-year expenditure that 
would exceed $100 million adjusted for inflation. The current 
inflation-adjusted statutory threshold is $110 million.

                        Table 1.--Summary of Quantifiable Benefits and Costs ($ Million)
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                                                                                                       Total
                       Benefits and Costs                            One-Time         Annual        Annualized
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Benefits\1\
    Avoided cost of hospital infections                                                 3.75            3.75
    Indirect cost of longer hospital stays                                              0.43            0.43
    Total Benefits                                                                      4.18            4.18
Costs
    One-time labeling revision                                          1.95                            0.28

[[Page 56514]]

 
    Annual incremental printing cost                                                    0.03            0.03
    Annual PDR costs                                                                    0.15            0.15
    Total Costs                                                         1.95            0.18            0.46
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\1\ Assumes medical and productivity costs now attribute to antibacterial resistance are reduced by 1 percent.

A. 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. Moreover, many disease-producing 
bacteria adapt to environmental changes and develop resistance to new 
drugs within a few years of widespread use thereby reducing the 
effectiveness of new drug therapies (Ref. 13). 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.
1. Direct Costs of Bacterial-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. 14).
    Two studies of urban hospitals in the northeastern United States 
have 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 methicillin-resistant Staphylococcus 
aureus (MRSA) and those caused by methicillin-sensitive Staphylococcus 
aureus (MSSA). They estimated that each MRSA infection costs an 
additional $2,500 in direct medical costs and longer hospital stays 
(Ref. 15). The death rate attributable to the MRSA infection was more 
than double that of MSSA infections (i.e., 21 percent versus 8 
percent).
    In the second study, conducted at a Boston hospital, researchers 
examined the economic impact of antibiotic resistance in Pseudomonas 
aeruginosa (Ref. 16). This study compared the mortality rate, 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. 
Furthermore, length of stay and mortality rate were similar for 
patients infected with susceptible bacteria and those with baseline 
resistant bacteria. However, patients in which resistant bacteria 
emerged during hospitalization incurred additional costs of $7,340 for 
3.5 extra days and had a 250 percent higher mortality rate (27 percent 
versus 7.7 percent).
    The total number of annual infections caused by resistant bacteria 
is uncertain. Although diagnosis codes exist for infections with drug-
resistant microorganisms, they are intended only to supplement other 
codes for infectious conditions and may not always be included in 
patient data. As a result, these 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). For 1995 and 1997, respectively, NHDS 
estimates suggest about 18,000 and 43,000 cases of infections by 
resistant microorganisms (Refs. 19 and 20). Data from a larger national 
sample of hospital patients by the Healthcare Cost and Utilization 
Project estimate 84,000 diagnoses of resistant infections in community 
hospitals for 1997 (Ref. 21). Moreover, CDC hospital surveillance data 
of 5 known strains of resistant bacteria for 1995 suggest a much higher 
figure, projecting 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, assuming that patients incur additional hospital 
charges of $2,500 per resistant infection, the total hospital cost 
attributable to antibacterial resistance is estimated at $375 million 
annually.
2. Indirect Costs of Bacterial-Resistant Infections
    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 withPseudomonas, 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.
3. Reduced Direct and Indirect Costs
    In 1997, about 110 million antibacterial prescriptions were written 
by office-based physicians in the United States (Ref. 18), of which as 
many as half may have been inappropriate according to the CDC. The 
proposed rule would alter the professional labeling of these drugs to 
add concise information relating to the public health risks associated 
with their inappropriate use. The revised labeling would notify and 
remind physicians of these risks and prompt physicians to dissuade 
patients from using antibacterial drugs for diseases not caused by 
bacteria. These changes are expected to decrease the unnecessary 
consumption of antibacterial drugs and, in turn, to diminish the growth 
of antibacterial resistant bacteria. Although FDA cannot quantify the 
likely magnitude of these effects, if the proposed changes serve to 
avoid even 1 percent of the above estimated costs of antibacterial 
resistance, the potential hospital cost savings would amount to 
$3,750,000 per year in direct costs and $430,000

[[Page 56515]]

annually in indirect costs, for a total that exceeds $4 million 
annually. Moreover, the societal benefits of this rulemaking would be 
much higher than the economic cost savings because these figures do not 
include the value of reduced mortality or the benefits of decreasing 
the rate of development of resistant organisms over time.

B. Costs of Regulation

    The proposed rule would require that labeling of systemic 
antibacterial drug products include information about the inappropriate 
use of antimicrobial drugs and the link between inappropriate use and 
the emergence of drug-resistant bacterial strains. The proposed 
implementation plan would require that labeling for affected 
prescription drug products comply with the proposed requirements within 
1 year after the effective date of the final rule.
1. Affected Products
    The proposed rule would affect all systemic antibacterial drug 
products except those primarily indicated to treat a mycobacterial 
infection. Antifungal, antiviral, antiparasitic, and topical 
antimicrobial products would not be subject to the labeling 
requirements of this proposed rule. Of the approximately 5,300 marketed 
prescription drug products in the United States, FDA estimates that 737 
are antibiotic products, of which 89 are topical products excluded from 
these requirements.\1\ The agency estimates that an additional 113 
systemic antibacterial drug products would be required to conform to 
the labeling requirements.\2\ Thus, a total of 761 drug products may be 
affected by the proposed rule (table 2).
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    \1\ Derived from FDA's Approved Drug Products with Therapeutic 
Equivalence Evaluations, 1998. Products counted had NDA numbers in 
the 50,000 or 60,000 series (i.e., antibiotics) and a distinct 
dosage form or manufacturer. This number, however, may overestimate 
the number of antibiotic products with distinct labeling.
    \2\ Derived from FDA's Approved Drug Products with Therapeutic 
Equivalence Evaluations, 1998; and from the 1999 Drug Information, 
American Hospital Formulary Service (AHFS). Products counted had NDA 
numbers not in the 50,000 or 60,000 series, active ingredients 
matching the AHFS list of antibacterial agents, and a distinct 
manufacturer, active ingredient, or dosage form. Topical dosage 
forms were excluded.

                                      Table 2.--Number of Affected Products
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                                                                                                     Number of
                              Type of Antibacterial Drug Product\1\                                  Products
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Antibiotics with 50,000 or 60,000 series NDA numbers
    Aminoglycosides                                                                                    83
    Cephalosporins                                                                                    112
    Miscellaneous Beta-Lactam Antibiotics                                                              16
    Chloramphenicol                                                                                    17
    Macrolides                                                                                         56
    Penicillins                                                                                       148
    Tetracyclines                                                                                      75
    Miscellaneous Antibiotics\2\/Combination Drugs\3\                                                 141
Other antibacterial drug products
    Quinolones                                                                                         24
    Sulfonamides/Sulfones                                                                              38
    Urinary Anti-Infective Drugs                                                                       18
    Miscellaneous Anti-Infectives                                                                      33
Total number of affected drug products                                                               761
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\1\ Excludes antifungal drug products, topical drug products, and antibacterial drug products intended to treat
  a mycobacterial infection.
\2\ Includes 42 drug products with active ingredient(s) not on the AHFS list of antibiotics.
\3\ Combination drugs contain more than one antibacterial active ingredient.

2. Professional Labeling Design Costs
    Industry consultants estimate that, on average, prescription drug 
manufacturers would incur about $2,000 per product in design and 
implementation costs for a major revision in the content of 
professional labeling. Because changes must be made within 1 year of 
the effective date of the final rule, not all firms will have 
sufficient time to deplete their inventories of professional labeling. 
With a 12-month implementation period, consultants estimate per product 
inventory losses of approximately $570. Thus, including excess 
inventory losses, the cost to change professional labeling is estimated 
at $2,600 per product. In the first year, therefore, firms may incur 
one-time costs of about $2 million.
3. Incremental Printing Costs for Professional Labeling
    FDA estimates that an average of 100,000 package inserts may be 
printed annually for each prescription drug product marketed in the 
United States.\3\ Adding new information about prudent use of 
antibacterial drug products to professional labeling may increase the 
size of current package inserts by about 4 percent. With such a small 
change in the length of professional labeling (i.e., 0.4 inch for the 
average insert), it is unlikely that many package inserts would 
actually change size. Nevertheless, industry consultants estimate the 
cost of printing larger labels to be $0.0086 per 100 square inches. 
Therefore, if the affected products incurred additional printing costs 
for longer labeling, an estimated $35 per affected product \4\ would 
imply incremental printing costs of less than $30,000 annually.
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    \3\ In 1996, there were approximately 133 million prescriptions 
for antibacterial drugs written by physicians in office and hospital 
settings (General Accounting Office (GAO) 1999). An estimated 45.3 
million inserts accompanied these 761 drug products, or an average 
of 59,500 inserts per antibacterial product (45.3 million  
761 products). Moreover, an assumed 40,000 additional inserts per 
product may be distributed annually by sales representatives as 
promotional material.
    \4\ $34.40 = 100,000 inserts/product x $0.000086/square inch x 4 
square inches.
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4. Physicians' Desk Reference (PDR) Costs
    The agency estimates that up to 190 products may need slightly 
longer PDR listings.\5\ According to its publisher, a printed page in 
the PDR cost $8,000 in 1998. The additional language would add 
approximately one-tenth of a page to an average PDR listing, costing 
$800 per product.\6\ The annual costs of

[[Page 56516]]

printing the larger labels in the PDR, therefore, would increase by 
$0.15 million.
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    \5\ 190 products is the rounded up estimate from the following 
calculation: 761 (drug products affected by proposed rule) x .32 
(percentage of those products manufactured by innovators) x .75 
(percentage of innovator products listed in PDR) = 182.
    \6\ $800 per product = $8,000/page x 1/10 page.
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    Over 10 years, the agency estimates that the annualized compliance 
costs of the proposed rule would be approximately $455,000. These costs 
are summarized in table 3.

                 Table 3.--Costs to Revise Professional Labeling and Incremental Printing Costs
----------------------------------------------------------------------------------------------------------------
                              One-Time Labeling Revision      Annual Incremental
                                        Costs                   Printing Costs             Annual PDR Costs
----------------------------------------------------------------------------------------------------------------
Per product cost             $2,558                       $35                         $800
Number of affected products  761                          761                         190
Total                        $1,946,638                   $26,178                     $152,000
Total annualized costs1      $277,162                     $26,178                     $152,000
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\1\One-time costs are annualized over 10 years at 7 percent.

C. Impacts on Small Entities

    The proposed rule would affect manufacturers of systemic 
antibacterial drug products. There are 600 pharmaceutical manufacturers 
in the United States. The Small Business Administration (SBA) considers 
firms with fewer than 750 employees to be small. As seen in table 4 
below, 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.\7\
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    \7\ U.S. Department of Commerce, Bureau of the Census,1992 
Census of Manufactures, Industry Series, Drugs, MC92-1-28C.
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    Approximately 125 large and small firms manufacture systemic 
antibacterial drug products and thus would be affected by the proposed 
rule. The estimated annualized costs of $600 per product \8\ are 
relatively modest for most manufacturers of antibiotic drugs. 
Therefore, the impact of the proposed rule would be significant only 
for those firms that manufacture many affected products. FDA reviewed 
the list of approved products \9\ and identified only four small 
domestic firms that manufacture more than three antibiotic 
products.\10\ Table 4 compares the estimated costs of compliance to 
reported average annual sales revenues for pharmaceutical firms of 
varying sizes. Because almost all manufacturers of antibiotic products 
in the United States have over 10 employees, the next to the last 
column of the table shows that these annualized costs are less than 
one-tenth of one percent of sales revenues. As a result, FDA certifies 
that this proposed rule would not have a significant adverse effect on 
a substantial number of small entities.
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    \8\ Total annualized costs per product: $277,162 + $26,178 + 
$152,000 = $455,336. Average annualized costs: $455,336/761 = 
$598.34.
    \9\ FDA'sApproved Drug Products with Therapeutic Equivalence 
Evaluations, 1998.
    \10\ These four small firms manufacture 6, 6, 7, and 13 products 
respectively.

   Table 4.--Examples of Annualized and First-Year Costs to Modify Professional Labeling as a Percentage of Average Annual Shipment Value by Number of
                                                                      Employees\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                 Annualized   First-Year
                                                                                                       Annualized   Annualized    Cost to      Costs to
                                                                                          Average       Cost to      Cost to       Modify       Modify
                                                                                         Annual Per    Modify One   Modify Two     Three        Three
     Number of Employees       Number of  Establishments   Value of Shipments (mil$)   Establishment   Product as  Products as  Products as  Products as
                                                                                          Shipment         a            a            a            a
                                                                                        Value (mil$)   Percentage   Percentage   Percentage   Percentage
                                                                                                      of Shipment  of Shipment  of Shipment  of Shipment
                                                                                                        Value\2\     Value\2\     Value\2\     Value\3\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Small Businesses By SBA Size Standards (fewer than 750 employees)
--------------------------------------------------------------------------------------------------------------------------------------------------------
1-4                           152                         $115.60                             $0.76         0.08%        0.16%        0.24%        1.10%
5-9                           73                          $105.40                             $1.44         0.04%        0.08%        0.12%        0.58%
10-19                         101                         $284.60                             $2.82         0.02%        0.04%        0.06%        0.30%
20-49                         110                         $815.70                             $7.42         0.01%        0.02%        0.02%        0.11%
50-99                         65                          $1,966.80                          $30.26         0.00%        0.00%        0.01%        0.03%
100-249                       77                          $2,912.40                          $37.82         0.00%        0.00%        0.01%        0.02%
250-499                       56                          $11,394.60                        $203.48         0.00%        0.00%        0.00%        0.00%
500-999                       30                          $10,077.70                        $335.92         0.00%        0.00%        0.00%        0.00%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Large Businesses by SBA Size Standards (750 or more employees)
--------------------------------------------------------------------------------------------------------------------------------------------------------
1,000-2,499                   21                          $14,525.70                        $691.70         0.00%        0.00%        0.00%        0.00%
2,500 +                       6                           $8,219.40                       $1,369.90         0.00%        0.00%        0.00%       0.00%
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\U.S. Department of Commerce, Bureau of the Census,1992 Census of Manufactures, Industry Series, Drugs, MC92-1-28C.
\2\Average annualized per product costs = $598
\3\Average first-year per product costs = $2,792

VI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed rule does not require 
information collections subject to review by the Office of Management 
and Budget (OMB) under the Paperwork Reduction Act of 1995 (Public Law 
104-13).

[[Page 56517]]

    FDA is proposing to amend its labeling regulations to require that 
the labeling for systemic antibacterial drug products include certain 
statements, specified by FDA, about the inappropriate use of 
antimicrobials and the link between such inappropriate use and the 
emergence 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 
Paperwork Reduction Act of 1995.
    Holders of approved NDA's and ANDA's would be required to submit 
supplements and holders of pending NDA's and ANDA's would be required 
to submit amendments to comply with the new labeling requirements. The 
proposed rule would also require that all new NDA's and ANDA's for 
systemic antibacterial drug products comply with the new labeling 
requirements. FDA regulations governing the submission and approval of 
NDA's and ANDA's, 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 November 30, 2001, under 
OMB control number 0910-0001.

VII. Federalism

    FDA has analyzed this proposed rule in accordance with Executive 
Order 13132. Executive Order 13132 requires Federal agencies to 
carefully examine actions to determine if they contain policies that 
have federalism implications or that preempt existing State law. As 
defined in the Order, ``policies that have federalism implications'' 
refers to regulations, legislative comments on proposed legislation, 
and other policy statements or actions 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.
    The proposal would revise current regulations to require that all 
systemic antibacterial drug products (i.e., antibiotics and their 
synthetic counterparts) intended for human use contain additional 
labeling information about the emergence of drug-resistant bacterial 
strains. Because enforcement of these labeling provisions is a Federal 
responsibility, there should be little, if any, impact from this rule, 
if finalized, 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. In addition, 
FDA does not believe that this proposed rule preempts any existing 
State law.
    Accordingly, FDA has determined that this proposed rule does not 
contain policies that have federalism implications.

VIII. Request for Comments

    Interested persons may submit to the Dockets Management Branch 
(address above) written comments regarding this proposal by December 4, 
2000. Two copies of any comments are to be submitted, except that 
individuals may submit one copy. Comments are to be identified with the 
docket number found in brackets in the heading of this document. 
Received comments may be seen in the office above between 9 a.m. and 4 
p.m., Monday through Friday.

IX. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Centers for Disease Control, ``Drug-Resistant Streptococcus 
Pneumoniae--Kentucky and Tennessee, 1993,'' Journal of American Medical 
Association, vol. 271, pp. 421-422, 1994.
    2. Centers for Disease Control, ``Summary of Notifiable Diseases, 
United States, 1998,'' Morbidity and Mortality Weekly Report, 47 (53), 
December 31, 1999.
    3. Centers for Disease Control, ``Public Health Focus: 
Surveillance, Prevention and Control of Nosocomial Infections,'' 
Morbidity and Mortality Weekly Report, vol. 41, pp. 783-787, 1992.
    4. Fridkin, S., S. F. Welbel, and R. A. Weinstein, ``Magnitude and 
Prevention of Nosocomial Infections in the Intensive Care Unit,'' 
Infectious Disease Clinics of North America, vol. 11, pp. 479-495, 
1997.
    5. 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.
    6. Mainous, A. G., III, W. J. Hueston, and J. R. Clark, 
``Antibiotics and Upper Respiratory Infection. Do Some Folks Think 
There Is a Cure for the Common Cold?,'' The Journal of Family Practice, 
vol. 42, pp. 357-361, 1996.
    7. Gonzales, R., J. F. Steiner, and M. A. Sande, ``Antibiotic 
Prescribing for Adults with Colds, Upper Respiratory Tract Infections, 
and Bronchitis by Ambulatory Care Physicians,'' Journal of American 
Medical Association, vol. 278, pp. 901-904, 1997.
    8. U.S. Congress, Office of Technology Assessment, Impacts of 
Antibiotic-Resistant Bacteria, OTA-H-269, U.S. Government Printing 
Office, Washington, DC, 1995.
    9. McCaig, L. F., and J. M. Hughes, ``Trends in Antimicrobial Drug 
Prescribing Among Office-Based Physicians in the United States,'' 
Journal of American Medical Association, vol. 273, pp. 214-219, 1995.
    10. World Health Organization, Overcoming Antimicrobial Resistance, 
WHO Report on Infectious Diseases, 2000, p. 27.
    11. WHO Report, pp. 55-56.
    12. Seppala, H. et al., ``The Effect of Changes in the Consumption 
of Macrolide Antibiotics on Erythromycin Resistance in Group A 
Streptococci in Finland,'' The New England Journal of Medicine, vol. 
337, pp. 441-446, 1997.
    13. Wenzel, R. P., and M. T. Wong, ``Editorial Response: Managing 
Antibiotic Use--Impact of Infection Control,'' Clinical Infectious 
Diseases, vol. 28, pp. 1126-1127, 1999.
    14. Holmberg, S. D., S. L. Solomon, and P. A. Blake, ``Health and 
Economic Impacts of Antimicrobial Resistance,'' Reviews of Infectious 
Diseases, vol. 9, pp. 1065-1078, 1987.
    15. Rubin, R. J. et al., ``The Economic Impact ofStaphylococcus 
Aureus Infection in New York City Hospitals,'' Emerging Infectious 
Diseases, vol. 5, pp. 9-17, 1999.
    16. Carmeli, Y. et al., ``Health and Economic Outcomes of 
Antibiotic Resistance in Pseudomonas Aeruginosa,'' Archives of Internal 
Medicine, vol. 159, pp. 1127-1132, 1999.
    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. GAO Report, p. 16.
    19. Graves, E. J., and B. S. Gillum, ``Detailed Diagnoses and 
Procedures, National Hospital Discharge Survey, 1995,'' National Center 
for Health Statistics Vital Health Statistics Series 13 (130):115.
    20. Owings, M. F., and L. Lawrence, ``Detailed Diagnoses and 
Procedures, National Hospital Discharge Survey, 1997,'' National Center 
for Health

[[Page 56518]]

Statistics Vital Health Statistics Series 13 (145):118.
    21. HCUPnet, Healthcare Cost and Utilization Project, Agency for 
Healthcare Research and Quality, Rockville, MD (http://www.ahrq.gov/data/hcup/hcupnet.htm).

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, it is 
proposed that 21 CFR part 201 be 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; 
required statements.

    The labeling of all systemic drug products 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:
    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.
    (b) In the ``Clinical Pharmacology'' section, the labeling must 
state:
    Appropriate use of (insert name of antibacterial drug product) 
includes, where applicable, identification of the causative 
microorganism and determination of its susceptibility profile.
    (c) In the ``Indications and Usage'' section, the labeling must 
state:
    Local epidemiology and susceptibility patterns of the listed micro 
organisms should direct initial selection of (insert name of 
antibacterial drug product) for the treatment of the indications listed 
below. Because of changing susceptibility patterns, definitive therapy 
should be guided by the results of susceptibility testing of the 
isolated pathogens.
    (d) In the ``Precautions'' section, under the ``General'' 
subsection, the labeling must state:
    Inappropriate use of (insert name of antibacterial drug product) 
may increase the prevalence of drug resistant microorganisms and may 
decrease the future effectiveness of (insert name of antibacterial drug 
product) and related antimicrobial agents.
    (Insert name of antibacterial drug product) should only be used to 
treat infections that are proven or strongly suspected to be caused by 
susceptible microorganisms. See Indications and Usage section.
    (e) In the ``Precautions'' section, under the ``Information for 
patients'' subsection, the labeling must state:
    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.

    Dated: August 25, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-24007 Filed 9-18-00; 8:45 am]
BILLING CODE 4160-01-F