[Federal Register: September 19, 2000 (Volume 65, Number 182)]
[Proposed Rules]
[Page 56511-56518]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19se00-21]
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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
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One-Time Labeling Revision Annual Incremental
Costs Printing Costs Annual PDR Costs
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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%
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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%
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\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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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