[Federal Register Volume 79, Number 108 (Thursday, June 5, 2014)]
[Rules and Regulations]
[Pages 32464-32481]
[FR Doc No: 2014-13023]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 317

[Docket No. FDA-2012-N-1037]
RIN 0910-AG92

Establishing a List of Qualifying Pathogens Under the Food and
Drug Administration Safety and Innovation Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is issuing a
regulation to establish a list of ``qualifying pathogens'' that have
the potential to pose a serious threat to public health. This final
rule implements a provision of the Generating Antibiotic Incentives Now
(GAIN) title of the Food and Drug Administration Safety and Innovation
Act (FDASIA). GAIN is intended to encourage development of new
antibacterial and antifungal drugs for the treatment of serious or
life-threatening infections, and provides incentives such as
eligibility for designation as a fast-track product and an additional 5
years of exclusivity to be added to certain exclusivity periods. Based
on analyses conducted both in the proposed rule and in response to
comments to the proposed rule, FDA has determined that the following
pathogens comprise the list of ``qualifying pathogens:'' Acinetobacter
species, Aspergillus species, Burkholderia cepacia complex,
Campylobacter species, Candida species, Clostridium difficile,

Coccidioides species, Cryptococcus species, Enterobacteriaceae (e.g.,
Klebsiella pneumoniae), Enterococcus species, Helicobacter pylori,
Mycobacterium tuberculosis complex, Neisseria gonorrhoeae, N.
meningitidis, Non-tuberculous mycobacteria species, Pseudomonas
species, Staphylococcus aureus, Streptococcus agalactiae, S.
pneumoniae, S. pyogenes, and Vibrio cholerae. The preamble to the
proposed rule described the factors the Agency considered and the
methodology used to develop the list of qualifying pathogens. As
described in the preamble of this final rule, FDA applied those factors
and that methodology to additional pathogens suggested via comments on
the proposed rule.

DATES: This rule is effective July 7, 2014.

ADDRESSES: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Kristiana Brugger, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6262, Silver Spring, MD 20993-0002, 301-
796-3601.

SUPPLEMENTARY INFORMATION:

Table of Contents

Executive Summary
I. Background: FDASIA Requirements
II. Proposed Rule and Final Rule
    A. Finalization of Factors Considered and Methodology Used for
Establishing a List of Qualifying Pathogens
    B. Finalization of Statutory Interpretation
    C. Finalization of Proposed Pathogens for Inclusion on the List
    D. Summary of Additional Pathogens on the List of Qualifying
Pathogens
III. Comments to the Proposed Rule and FDA's Responses
    A. Statutory Interpretation and Proposed Factors for
Consideration
    B. Miscellaneous Comments
    C. Comments on Previously Proposed Pathogens
    D. Suggestions for Additional Qualifying Pathogens
IV. Environmental Impact
V. Analysis of Economic Impact
    A. Final Regulatory Impact Analysis
    B. Background
    C. Need for and Potential Effect of the Regulation
VI. Paperwork Reduction Act
VII. Federalism
VIII. References

Executive Summary

Purpose of the Regulatory Action

    Title VIII of FDASIA (Pub. L. 112-144), the GAIN title, is intended
to encourage development of new antibacterial and antifungal drugs for
the treatment of serious or life-threatening infections. Among other
things, GAIN requires that the Secretary of the Department of Health
and Human Services (and thus FDA, by delegation): (1) Establish and
maintain a list of ``qualifying pathogens'' that have ``the potential
to pose a serious threat to public health'' and (2) make public the
methodology for developing the list (see section 505E(f) of the Federal
Food, Drug, and Cosmetic Act (the FD&C Act), as amended by FDASIA) (21
U.S.C. 355f(f)). In establishing and maintaining the list of
``qualifying pathogens,'' FDA must consider the following factors: The
impact on the public health due to drug-resistant organisms in humans;
the rate of growth of drug-resistant organisms in humans; the increase
in resistance rates in humans; and the morbidity and mortality in
humans (see section 505E(f)(2)(B)(i) of the FD&C Act). FDA also is
required to consult with infectious disease and antibiotic resistance
experts, including those in the medical and clinical research
communities, along with the Centers for Disease Control and Prevention
(CDC) (see section 505E(f)(2)(B)(ii) of the FD&C Act). FDA issued a
proposed rule on June 12, 2013 (78 FR 35155), and, after analyzing
comments to that proposed rule, is issuing this final rule in
fulfillment of the statutory requirements described above.

Summary of the Major Provisions of the Regulatory Action

    After holding a public meeting and consulting with CDC and the
National Institutes of Health (NIH), and considering the factors
specified in section 505E(f)(2)(B)(i) of the FD&C Act, FDA proposed on
June 12, 2013, that the following pathogens comprise the list of
``qualifying pathogens:'' Acinetobacter species, Aspergillus species,
Burkholderia cepacia complex, Campylobacter species, Candida species,
Clostridium difficile, Enterobacteriaceae (e.g., Klebsiella
pneumoniae), Enterococcus species, Mycobacterium tuberculosis complex,
Neisseria gonorrhoeae, N. meningitidis, Non-tuberculous mycobacteria
species, Pseudomonas species, Staphylococcus aureus, Streptococcus
agalactiae, S. pneumoniae, S. pyogenes, and Vibrio cholerae. The
preamble to the proposed rule describes the factors FDA considered and
the methodology FDA used to develop this list of qualifying pathogens.
After analyzing comments to the proposed rule, FDA has decided to
retain the previously proposed methodology for developing the list of
qualifying pathogens and will include the pathogens identified in the
proposed rule on the list of qualifying pathogens. FDA also has applied
the methodology set forth in the proposed rule to additional pathogens
suggested by comments to the proposed rule. Based on these analyses,
FDA also will add Coccidioides species, Cryptococcus species, and
Helicobacter pylori to the list of qualifying pathogens. The table
below describes the pathogen lists for the proposed and final rule for
comparison:

------------------------------------------------------------------------
             Proposed rule                          Final rule
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Acinetobacter species..................  Acinetobacter species.
Aspergillus species....................  Aspergillus species.
Burkholderia cepacia complex...........  Burkholderia cepacia complex.
Campylobacter species..................  Campylobacter species.
Candida species........................  Candida species.
Clostridium difficile..................  Clostridium difficile.
Enterobacteriaceae.....................  Enterobacteriaceae.
Enterococcus species...................  Enterococcus species.
Mycobacterium tuberculosis complex.....  Mycobacterium tuberculosis
                                          complex.
Neisseria gonorrhoeae..................  Neisseria gonorrhoeae.
Neisseria meningitidis.................  Neisseria meningitidis.
Non-tuberculous mycobacteria species...  Non-tuberculous mycobacteria
                                          species.
Pseudomonas species....................  Pseudomonas species.
Staphylococcus aureus..................  Staphylococcus aureus.
Streptococcus agalactiae...............  Streptococcus agalactiae.

Streptococcus pneumoniae...............  Streptococcus pneumoniae.
Streptococcus pyogenes.................  Streptococcus pyogenes.
Vibrio cholerae........................  Vibrio cholerae.
                                         Coccidioides species.
                                         Cryptococcus species.
                                         Helicobacter pylori.
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Costs and Benefits

    The Agency has determined that this rule is not a significant
regulatory action as defined by Executive Order 12866.

I. Background: FDASIA Requirements

    Title VIII of FDASIA (Pub. L. 112-144), entitled Generating
Antibiotic Incentives Now, amended the FD&C Act to add section 505E,
among other things. This new section of the FD&C Act is intended to
encourage development of treatments for serious or life-threatening
infections caused by bacteria or fungi. For certain drugs that are
designated as ``qualified infectious disease products'' (QIDPs) under
new section 505E(d) of the FD&C Act, new section 505E(a) provides an
additional 5 years of exclusivity to be added to the exclusivity
periods provided by sections 505(c)(3)(E)(ii) to (c)(3)(E)(iv) (21
U.S.C. 355(c)(3)(E)(ii) to (c)(3)(E)(iv)), 505(j)(5)(F)(ii) to
(j)(5)(F)(iv) (21 U.S.C. 355(j)(5)(F)(ii) to (j)(5)(F)(iv)), and 527
(21 U.S.C. 360cc) of the FD&C Act. In addition, an application for a
drug designated as a QIDP is eligible for priority review and
designation as a fast track product (sections 524A and 506(a)(1) of the
FD&C Act (21 U.S.C. 356n-I and 556(a)(1)), respectively).
    The term ``qualified infectious disease product'' or ``QIDP''
refers to an antibacterial or antifungal human drug that is intended to
treat serious or life-threatening infections (section 505E(g) of the
FD&C Act). The term includes treatments for diseases caused by
antibacterial- or antifungal-resistant pathogens (including new or
emerging pathogens), or diseases caused by ``qualifying pathogens.''
    The GAIN title of FDASIA requires that the Secretary of the
Department of Health and Human Services (and thus FDA, by delegation)
establish and maintain a list of such ``qualifying pathogens,'' and
make public the methodology for the developing the list. According to
the statute, ``the term `qualifying pathogen' means a pathogen
identified and listed by the Secretary . . . that has the potential to
pose a serious threat to public health, such as[:] (A) resistant gram
positive pathogens, including methicillin-resistant Staphylococcus
aureus, vancomycin-resistant Staphylococcus aureus, and vancomycin-
resistant [E]nterococcus; (B) multi-drug resistant gram[-]negative
bacteria, including Acinetobacter, Klebsiella, Pseudomonas, and E. coli
species; (C) multi-drug resistant tuberculosis; and (D) Clostridium
difficile'' (section 505E(f)(1) of the FD&C Act). FDA is required under
the law to consider four factors in establishing and maintaining the
list of qualifying pathogens:
     The impact on the public health due to drug-resistant
organisms in humans;
     the rate of growth of drug-resistant organisms in humans;
     the increase in resistance rates in humans; and
     the morbidity and mortality in humans (section
505E(f)(2)(B)(i) of the FD&C Act).
    Further, in determining which pathogens should be listed, GAIN
requires FDA to consult with infectious disease and antibiotic
resistance experts, including those in the medical and clinical
research communities, along with the CDC, in determining which
pathogens should be included on the list of ``qualifying pathogens''
(section 505E(f)(2)(B)(ii) of the FD&C Act). To fulfill this statutory
obligation, on December 18, 2012, FDA convened a public hearing, at
which the Agency solicited input regarding the following topics: (1)
How FDA should interpret and apply the four factors FDASIA requires FDA
to ``consider'' in establishing and maintaining the list of qualifying
pathogens; (2) whether there are any other factors FDA should consider
when establishing and maintaining the list of qualifying pathogens; and
(3) which specific pathogens FDA should list as qualifying pathogens
(77 FR 68789, November 16, 2012). The transcript of this hearing, as
well as comments submitted to the hearing docket, are available at
http://www.regulations.gov, docket number FDA-2012-N-1037. FDA
considered carefully the input presented at this hearing, as well as
the comments submitted to the hearing docket, in creating the list of
qualifying pathogens.\1\ In addition, FDA consulted with experts in
infectious disease and antibiotic resistance at CDC and NIH during the
development of both the proposed and the final rule.
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    \1\ The public hearing and this rule share docket numbers
because they are part of the same rulemaking process. Accordingly,
the documents from the public hearing phase of Docket No. FDA-2012-
N-1037 are included in the docket for this rulemaking.
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II. Proposed Rule and Final Rule

    On June 12, 2013, FDA published the proposed rule, ``Establishing a
List of Qualifying Pathogens Under the Food and Drug Administration
Safety and Innovation Act'' (78 FR 35155). In the proposed rule, the
Agency set forth the factors it proposed to consider and the
methodology it proposed to use in establishing the list of qualifying
pathogens, as well as its interpretation of statutory language. The
Agency concluded with extensive analyses of the 18 pathogens proposed
for inclusion on the list of ``qualifying pathogens.'' FDA's decisions
regarding the proposed rule are described in sections III.A, III.B,
III.C, and IV.

A. Finalization of Factors Considered and Methodology Used for
Establishing a List of Qualifying Pathogens

    After reviewing the comments submitted to the docket (see section
IV), the Agency has decided to finalize the proposed factors for
consideration and methodology for establishing the list of qualifying
pathogens, and has reiterated them below for convenience.
    As stated previously, section 505E(f)(2)(B)(i) of the FD&C Act
requires FDA to consider the following factors in establishing and
maintaining the list of qualifying pathogens:
     The impact on the public health due to drug-resistant
organisms in humans;
     the rate of growth of drug-resistant organisms in humans;
     the increase in resistance rates in humans; and
     the morbidity and mortality in humans.
    The Agency recognizes it is important to take a long-term view of
the drug resistance problem. For some pathogens, particularly those for
which increased resistance is newly emerging, FDA recognizes that there
may be gaps in the available data or evidence pertaining to

one or more of the four factors described in section 505E(f)(2)(B)(i)
of the FD&C Act. Thus, consistent with GAIN's purpose of encouraging
the development of treatments for serious or life-threatening
infections caused by bacteria or fungi, the Agency intends to consider
the totality of available evidence for a particular pathogen to
determine whether that pathogen should be included on the list of
qualifying pathogens. Therefore, if, after considering the four factors
identified in section 505E(f)(2)(B)(i) of the FD&C Act, FDA determines
that the totality of available evidence demonstrates that a pathogen
``has the potential to pose a serious threat to public health,'' the
Agency will identify the pathogen in question as a ``qualifying
pathogen.'' More detailed explanations of each factor identified in
section 505E(f)(2)(B)(i) of the FD&C Act are set forth in the
paragraphs that follow.
1. The Impact on the Public Health Due to Drug-Resistant Organisms in
Humans
    This first factor that section 505E(f)(2)(B)(i) of the FD&C Act
requires FDA to consider is also the broadest. Many factors associated
with infectious diseases affect public health directly, such as a
pathogen's ease of transmission, the length and severity of the illness
it causes, the risk of mortality associated with its infection, and the
number of approved products available to treat illnesses it causes.
Additionally, although the Agency did not consider financial costs in
its analyses for this proposed list of qualifying pathogens, we note
that the published literature supports the conclusion that
antimicrobial-resistant infections are associated with higher
healthcare costs (see, e.g., Refs. 1 and 2; Ref. 3 at pp. 807, 810,
812).
    In considering a proposed pathogen's impact on the public health
due to drug-resistant organisms in humans, FDA will assess such
evidence as: (1) The transmissibility of the pathogen and (2) the
availability of effective therapies for treatment of infections caused
by the pathogen, including the feasibility of treatment administration
and associated adverse effects. However, FDA also may assess other
public health-related evidence, including evidence that may indicate a
highly prevalent pathogen's ``potential to pose a serious threat to
public health'' due to the development of drug resistance in that
pathogen, even if most documented infections are currently drug
susceptible.
2. The Rate of Growth of Drug-Resistant Organisms in Humans and the
Increase in Resistance Rates in Humans
    The second and third factors that FDA must consider overlap
substantially with one another and, for the most part, are assessed
using the same trends and information. Therefore, the Agency will
analyze these factors together.
    In considering these factors with respect to a pathogen, FDA will
assess such evidence as: (1) The proportion of patients whose illness
is caused by a drug-resistant isolate of a pathogen (compared with
those whose illness is caused by more widely drug-susceptible
pathogens); (2) the number of resistant clinical isolates of a
particular pathogen (e.g., the known incidence or prevalence of
infection with a particular resistant pathogen); and (3) the ease and
frequency with which a proposed pathogen can transfer and receive
resistance-conferring elements (e.g., plasmids encoding relevant
enzymes, etc.). Given the temporal limitations on infectious disease
data, FDA also will consider evidence that a given pathogen currently
has a strong potential for a meaningful increase in resistance rates.
Evidence of the potential for increased resistance may include, for
example, projected (rather than observed) rates of drug resistance for
a given pathogen, and current and projected geographic distribution of
a drug-resistant pathogen. Furthermore, in acknowledgement of the
growing problem of drug resistance, FDA also may assess other available
evidence demonstrating either existing or potential increases in drug
resistance rates.
3. The Morbidity and Mortality in Humans
    Patients infected with drug-resistant pathogens are inherently more
challenging to treat than those infected with drug-susceptible
pathogens. For example, in some cases, a patient infected with a drug-
resistant pathogen may have a delay in the initiation of effective drug
therapy that can result in poor outcomes for such patients.
Consequently, in determining whether a pathogen should be included on
the list, FDA will consider the rates of mortality and morbidity (the
latter as measured by, e.g., duration of illness, severity of illness,
and risk and extent of sequelae from infections caused by the pathogen,
and risk associated with existing treatments for such infections)
associated with infection by that pathogen generally--and particularly
by drug-resistant strains of that pathogen.
    Setting quantitative thresholds for inclusion on the list based on
any prespecified endpoint would be inconsistent with FDA's approach of
considering a totality of the evidence related to a given pathogen, as
well as infeasible given the variety of pathogens under consideration.
Instead, in considering whether this factor weighs in favor of
including a given pathogen, the Agency will look for evidence of a
meaningful increase in morbidity and mortality rates when infection
with a drug-resistant strain of a pathogen is compared to infection
with a more drug-susceptible strain of that pathogen. The Agency may
also assess other evidence, such as overall morbidity and mortality
rates for infection with either resistant or susceptible strains of a
pathogen to determine whether that pathogen has the potential to pose a
serious threat to public health, in particular if drug-resistant
isolates of the pathogen were to become more prevalent in the future.

B. Finalization of Statutory Interpretation

    As FDA explained in the proposed rule (78 FR 35155 at 35156) and
affirms in this final rule, the statutory standard for inclusion on
FDA's list of qualifying pathogens is different from the statutory
standard for QIDP designation. QIDP designation, by definition,
requires that the drug in question be an ``antibacterial or antifungal
drug for human use intended to treat serious or life-threatening
infections'' (section 505E(g) of the FD&C Act). ``Qualifying
pathogens'' are defined according to a different statutory standard;
the term means ``a pathogen identified and listed by the Secretary . .
. that has the potential to pose a serious threat to public health''
(section 505E(f) of the FD&C Act) (emphasis added). That is, a drug
intended to treat a serious or life-threatening bacterial or fungal
infection caused by a pathogen that is not included on the list of
``qualifying pathogens'' may be eligible for designation as a QIDP,
while a drug that is intended to treat an infection caused by a
pathogen on the list may not always be eligible for QIDP designation.
After reviewing the comments to the docket on this point (see section
IV.A), FDA's understanding of these statutory standards remains
unchanged.
    To alleviate confusion regarding this issue, FDA also clarifies
that vaccine applications are ineligible for QIDP designation under the
GAIN title of FDASIA. Vaccines are biological products whose
applications for approval are submitted under section 351 of the Public
Health Service Act (the PHS Act) (42 U.S.C. 262). QIDPs,

however, must be human drugs whose applications are submitted pursuant
to section 505(b) of the FD&C Act. Thus, under the law, vaccines are
ineligible for QIDP designation.
    As stated in the proposed rule (78 FR 35156) and affirmed in this
final rule, FDA intends the list of qualifying pathogens to reflect the
pathogens that, as determined by the Agency, after consulting with
other experts and considering the factors set forth in FDASIA (see
section 505E(f)(2)(B)(i) of the FD&C Act), have the ``potential to pose
a serious threat to public health'' (section 505E(f)(1) of the FD&C
Act). FDA does not intend for this list to be used for other purposes,
such as the following: (1) Allocation of research funding for bacterial
or fungal pathogens; (2) setting of priorities in research in a
particular area pertaining to bacterial or fungal pathogens; or (3)
direction of epidemiological resources to a particular area of research
on bacterial or fungal pathogens. Furthermore, as section 505E of the
FD&C Act makes clear, the list of qualifying pathogens includes only
bacteria or fungi that have the potential to pose a serious threat to
public health. Viral pathogens or parasites, therefore, were not
considered for inclusion and are not included as part of this list.

C. Finalization of Proposed Pathogens for Inclusion on the List

    FDA's proposed rule concluded with an analysis of the 18 pathogens
the Agency proposed to identify as qualifying pathogens. After
reviewing the comments to the docket (see section IV.C), FDA is
finalizing its analyses of the 18 proposed pathogens as written in the
proposed rule (see 78 FR 35155 at 35158 through 35166), which are
incorporated by reference herein, and is identifying all 18 proposed
pathogens as ``qualifying pathogens'' in Sec.  317.2 (21 CFR 317.2).

D. Inclusion of Additional Pathogens on the List of Qualifying
Pathogens

    In response to comments, FDA has added three additional pathogens
(Coccidiodes species, Cryptococcus species, and Helicobacter pylori) to
the list of qualifying pathogens (see section IV.D).

III. Comments to the Proposed Rule and FDA's Responses

    After the publication of the proposed rule on June 12, 2013, 18
comments from pharmaceutical companies, lawmakers and governmental
organizations, infectious disease specialists, public interest groups,
and other members of the public were submitted to the docket via http://www.regulations.gov during the 60-day comment period. FDA has
summarized and responded to these comments below. To make it easier to
identify the comments and FDA's responses, the word ``Comment,'' in
parentheses, appears before the comment's description, and the word
``Response,'' in parentheses, appears before the Agency's response. We
have numbered each comment to help distinguish between different
comments. Similar comments are grouped together under the same number,
and, in some cases, different subjects discussed in the same comment
are separated and designated as distinct comments for purposes of FDA's
responses. The number assigned to each comment or comment topic is
purely for organizational purposes and does not signify the comment's
value or importance or the order in which comments were received.

A. Statutory Interpretation and Proposed Factors for Consideration

    (Comment 1) One comment criticized FDA's interpretation of the
statute that not all treatments for infections caused by qualifying
pathogens will be eligible for QIDP designation, and that ``the
development of a treatment for an infection caused by a pathogen
included on the list of `qualifying pathogens' is neither a necessary
nor a sufficient condition for obtaining QIDP designation'' (78 FR
35515 at 35167). The comment first expressed concern that, because the
terms ``serious'' and ``life-threatening'' are not separately defined
by statute, their meanings could change in the future. The comment
contrasted this alleged uncertainty with the statute's detailed
definition and identification process for ``qualifying pathogens,''
asserting that the collective term ``serious or life-threatening
infections'' includes infections caused by qualifying pathogens. Thus,
the comment asserted, Congress intended the qualifying pathogen list to
provide ``some certainty and transparency'' regarding which products
may be eligible for QIDP designation.
    (Response) FDA agrees with the comment that the term ``serious or
life-threatening'' is not explicitly defined in the statute.
Nevertheless, the Agency has been interpreting and applying these terms
in the context of other programs under the Food, Drug, and Cosmetic Act
intended to expedite the development of drugs and biologics to address
unmet medical needs for several years. ``Serious or life-threatening''
is used in section 506 of the FD&C Act, in the context of expedited
programs, including fast track designation. The term ``serious'' is
further defined in a 2006 FDA guidance for industry, ``Fast Track Drug
Development Program--Designation, Development, and Application Review
(which will be superseded by the draft guidance for industry,
``Expedited Programs for Serious Conditions--Drugs and Biologics,''
when finalized) and in the preamble to a final rule pertaining to
accelerated approval (57 FR 58942, December 11, 1992). The term ``life-
threatening'' is defined in 21 CFR 312.81(a). The provisions related to
QIDPs in GAIN similarly seek to incentivize the development of drugs to
meet an unmet medical need and, indeed, QIDP-designated applications
are eligible for both priority review and fast-track designation (see
section 524A of the FD&C Act and section 506(b)(1) of the FD&C Act, as
amended). The Agency intends, therefore, to interpret serious or life-
threatening in a similar manner with respect to GAIN as it has in the
context of these expedited programs. While guidances and even
regulations may change, the Agency may not apply different definitional
standards to similarly situated applicants or applications. Thus,
concerns over lack of a statutory definition of ``serious or life-
threatening'' are an insufficient basis for FDA to change its
interpretation of the statute.
    Further, it may be true that many of the qualifying pathogens
listed by FDA may cause serious or life-threatening infections for
which treatments might be eligible for QIDP designation. However, the
comment's assertions cannot change the language that is in the statute,
which provides different standards for QIDPs and qualifying pathogens.
Qualifying pathogens are ``pathogen[s] . . . that ha[ve] the potential
to pose a serious threat to public health,'' whereas QIDPs are certain
human ``drugs . . . intended to treat serious or life-threatening
infections'' (emphasis added). Most importantly, many pathogens with
the potential to seriously threaten public health may cause varying
levels of morbidity and mortality in a given individual depending on
the site of infection, the person infected, the level of antimicrobial
resistance present in the infecting pathogen, and other factors.
    (Comment 2) One comment stated that only ``factors that can be
addressed through new drug development'' should be used as criteria for
including pathogens on the list. The comment does not specify which
factors these are, but the comment's concerns stem from an assertion
that new drugs contribute to antibiotic resistance due to their off-

label use, use in patients who do not need the drugs, or use in
patients whose underlying infection is unidentified.
    (Response) FDA agrees that good antibiotic stewardship is critical
in reducing antibiotic resistance rates. However, the mandatory
statutory considerations specified in section 505E(f)(2)(B)(i) of the
FD&C Act are not limited to factors that can be addressed only through
new drug development. FDA will make no changes to the rule based on
this comment.
    (Comment 3) One comment asserted that rarely used, non-``standard
of care'' drugs should be considered in assessing the therapies
available to treat a given pathogen. FDA understands this comment to
mean that FDA should include, in its assessment of available therapies
for infections by particular pathogens, drugs that may treat those
infections but nevertheless are not considered ``standard of care''
therapies.
    (Response) FDA considers the number of approved products available
to treat infectious diseases caused by a pathogen when assessing the
impact on the public health due to drug-resistant bacterial or fungal
pathogens in humans. For the purposes of this list of qualifying
pathogens, at this time, FDA will not consider unapproved products or
off-label use of products approved for another indication. FDA will
make no changes to the rule based on this comment.
    (Comment 4) One comment agreed that incentives authorized by GAIN
for the creation of new antibacterial and antifungal drugs should focus
on drugs that treat serious or life-threatening infections.
    (Response) FDA responds by confirming that QIDP designation, which
is a prerequisite to the incentives authorized by GAIN, may be made for
``antibacterial or antifungal drug[s] for human use intended to treat
serious or life-threatening infections'' (section 505E(g) of the FD&C
Act). FDA will make no changes to the rule in response to this comment.
    (Comment 5) Another comment found FDA's proposed methodology and
rationale for inclusion of qualifying pathogens to be favorable, and
agreed with the Agency that the statute provides different definitions
for ``qualifying pathogens'' and QIDPs. The comment also asserted that
having QIDP designation depend on intended indication (i.e., treatment
of serious or life-threatening infections) is what reflects statutory
intent, rather than having QIDP status depend on targeting specific
pathogens.
    (Response) FDA agrees with the points made in this comment. FDA's
interpretation and application of the GAIN provision is consistent with
the intent of the statute, which is to use exclusivity and other
incentives to spur development of the most urgently needed treatments,
i.e., those treating serious or life-threatening infections. The Agency
will make no changes to the proposed rule as a result.

B. Miscellaneous Comments

    (Comment 6) One comment pointed out that FDA did not provide a
basis for excluding the pathogens not listed on the qualifying pathogen
list. The comment also stated that FDA ``fails to mention'' how the
pathogens on the qualifying pathogen list and the pathogens not on the
qualifying pathogen list may relate to other pathogen lists (e.g.,
those pertaining to bioterrorism).
    (Response) FDA reiterates that the focus of this rulemaking is to
fulfill statutory requirements to: (1) Establish and maintain a list of
``qualifying pathogens'' that have ``the potential to pose a serious
threat to public health'' and (2) make public the methodology for
developing the list (see section 505E(f) of the FD&C Act). Other
pathogen lists, including CDC's list of bioterrorism agents/diseases,
have different purposes and standards. FDA will not, nor is it required
to, make comparisons between and among the qualifying pathogen list (or
the pathogens not appearing on the list) and ``additional lists'' of
pathogens.
    In responding to comments received on the proposed rule, however,
the Agency will explain why it either accepted or rejected comment
requests to add particular pathogens.
    For the foregoing reasons, FDA will make no changes to the contents
of the proposed rule based on this comment.
    (Comment 7) One comment asserted that pathogens with approved
``reserve antibiotics'' should ``not automatically count as qualifying
pathogens.'' FDA understands this comment to suggest that pathogens
whose infections may be treated with ``reserve antibiotics'' (i.e.,
antibacterial drugs that are placed ``in reserve'' for those patients
who have very limited options for treatment of their bacterial
infections, but are not widely used to treat patients who have many
antibacterial treatment options available to treat their bacterial
infections) should not be on the list of qualifying pathogens.
    (Response) In making its ``qualifying pathogen'' determinations,
FDA does consider the therapies--including ``reserve antibiotics''--
that are available and indicated to treat infections with a given
pathogen. Nevertheless, the fact that some pathogens already have
approved antimicrobial therapies available is not dispositive of
whether a particular pathogen meets the several statutory criteria FDA
must assess. Furthermore, as a general matter, subsequent new drug
development following the first drug approval could address important
public health issues in patients with unmet need based on one or more
of the following considerations:
     Alternative drugs may be needed to treat special
populations (e.g., renal impairment) or patients for whom drug
interactions are a concern.
     Some patients may experience an adverse drug effect and be
unable to complete the course of therapy.
     Some patients may have an allergy to certain drugs and
need alternatives.
     In some circumstances, drug production issues may arise
that affect supply for a drug.
     New information may become evident postmarketing that has
an impact on risk/benefit for some patients.

FDA will make no changes to the rule in response to this comment.

    (Comment 8) One comment stated that ``when new therapies are
created and used to treat qualifying pathogens, these should be removed
from the list.''
    (Response) FDA interprets this comment to mean that, as soon as FDA
approves a new drug to treat an infection caused by one of the
qualifying pathogens, that pathogen should be removed from the list.
FDA responds by noting that the availability of effective therapies for
treating infections with a given pathogen is merely one consideration
among many that FDA considers in determining whether a pathogen should
be designated a ``qualifying pathogen.'' While important to FDA's
assessment, the availability of effective therapies does not determine
whether a qualifying pathogen should remain on the list. FDA will
reassess the list of qualifying pathogens ``every 5 years, or more
often as needed,'' according to the requirements of the statute (see
505E(f)(2)(C) of the FD&C Act), and declines to establish a single-
standard trigger for removing pathogens from the list.
    (Comment 9) One comment asserted that regardless of QIDP
designation status, ``drugs intended to treat qualifying pathogens''
(which we assume to mean drugs intended to treat infections caused by
qualifying pathogens) should be required to prove reduction in
mortality or morbidity. The comment further asserted that clinical
trials in anti-infective drugs for

qualifying pathogens should have mortality as the primary endpoint.
    (Response) These concerns apply to approval standards for
particular drugs, which are required to be safe and effective within
the meaning of section 505 of the FD&C Act. These concerns do not apply
to the subject matter of the proposed rule, which is the method for
identifying qualifying pathogens and the resulting list. Thus, FDA
considers them irrelevant to the present rulemaking and will make no
changes to the rule as a result.

C. Comments on Previously Proposed Pathogens

    (Comment 10) One comment suggested edits and new literature
references to a paragraph in the preamble to the proposed rule
pertaining to the analysis of Enterobacteriaceae. These references are:
     A 2013 article by M. Sj[ouml]lund Karlsson et al.,
``Outbreak of Infections Caused by Shigella sonnei with Reduced
Susceptibility to Azithromycin in the United States,'' in Antimicrobial
Agents and Chemotherapy (Ref. 4);
     a 2010 article by M. R. Wong et al., ``Antimicrobial
Resistance Trends of Shigella Serotypes in New York City, 2006-2009,''
in Microbial Drug Resistance (Ref. 5); and
     a 2007 article by S. D. Alcaine et al., ``Antimicrobial
Resistance in Nontyphoidal Salmonella,'' in Journal of Food Protection
(Ref. 6).

The comment also made reference to CDC's National Antimicrobial
Resistance Monitoring System for Enteric Bacteria (NARMS), but did not
include specific data from NARMS in the comment.

    (Response) FDA appreciates the comment and suggested literature
references in support of FDA's decision to add Enterobacteriaceae to
the list of qualifying pathogens. We agree that the three suggested
literature references provide additional support for the inclusion of
Enterobacteriaceae on the list of qualifying pathogens. Specifically,
FDA agrees that the Karlsson and Wong references support recognition of
an increase in Shigella resistance in the United States, and that the
Alcaine reference supports recognition of an increase in Salmonella
resistance. FDA thus incorporates these references as part of its basis
for designating species in the Enterobacteriaceae family as qualifying
pathogens. The comment did not provide specific NARMS data or specific
references presenting relevant NARMS data, but rather made general
reference to the surveillance project. FDA, thus, declines to
incorporate the NARMS database in its entirety as part of its basis for
designating species in the Enterobacteriaceae family as qualifying
pathogens.
    (Comment 11) Two comments made suggestions in response to FDA's
inclusion of Clostridium difficile on the list of qualifying pathogens.
One advocated improvements in hospital hygiene (e.g., hand washing) and
staffing to reduce the spread of C. difficile. The other advocated an
unidentified procedure for treatment of C. difficile and expressed
concerns that the proposed rule would inhibit the use of this
treatment.
    (Response) FDA responds by thanking the commenters for their input.
The proposed rule, however, describes the Agency's methodology for
identifying qualifying pathogens and developing the resulting list. The
propose rule does not address matters on hospital hygiene standards and
non-pharmacologic procedures. Therefore, FDA will make no changes to
the rule in response to these comments.
    (Comment 12) One comment suggested adding Mycobacterium abscessus
to the list of qualifying pathogens.
    (Response) M. abscessus is a species of non-tuberculous
mycobacteria, a category of pathogens already on the proposed list of
qualifying pathogens in FDA's June 2013 proposed rule. As described in
the proposed rule, FDA believes that non-tuberculous mycobacteria
(including M. abscessus) meet the statutory standards for
identification as ``qualifying pathogens,'' and this final rule adds
non-tuberculous mycobacteria (including M. abscessus) to the list of
qualifying pathogens (see 78 FR 35155 at 35163).
    (Comment 13) One comment suggested adding Proteus mirabilis to the
list of qualifying pathogens.
    (Response) P. mirabilis is a species in the Enterobacteriaceae
family, a category of pathogens already on the proposed list of
qualifying pathogens in FDA's June 2013 proposed rule (see 78 FR 35155
at 35161). As described in the proposed rule, FDA believes that
Enterobacteriaceae (including P. mirabilis) meet the statutory
standards for identification as ``qualifying pathogens,'' and this
final rule adds Enterobacteriaceae (including P. mirabilis) to the list
of qualifying pathogens.
    (Comment 14) One comment stated that ``poor adherence to therapy,
overuse of currently available therapy, and empiric use'' should not be
used in support of identifying a pathogen for inclusion on the list of
qualifying pathogens--particularly M. tuberculosis--because these
``relate to clinical practice.''
    (Response) FDA considers antibiotic stewardship and attention to
patient adherence to therapy as important factors in determining
transmissibility. FDA explained in the preamble to the proposed rule
(see 78 FR 35155 at 35157) that a pathogen's ease of transmission is an
important consideration in evaluating ``the impact on the public health
due to drug-resistant organisms in humans'' (section 505E(f)(2)(B)(i)
of the FD&C Act). This factor is one of the four statutory factors
identified in section 505E(f)(2)(B)(i) of the FD&C Act. Therefore, FDA
will make no changes to the rule in response to this comment.

D. Suggestions for Additional Qualifying Pathogens

(Comment 15) Bacteroides, Fusobacterium, and Prevotella Species
    One comment suggested adding Bacteroides, Fusobacterium, and
Prevotella species to the list of qualifying pathogens.
    (Response) For the reasons that follow, FDA will not add these
species to the list of qualifying pathogens. A discussion of these
three bacterial pathogens is provided together for the following
reasons: (1) These bacterial pathogens are representative of a group of
medically-important gram-negative anaerobic rods (see Ref. 7 at pp.
3111-3120) and (2) common taxonomic characteristics (Ref. 8 at pp. 179-
194).
    These bacterial pathogens are commonly found in the mucous
membranes (Ref. 9), particularly in the mouth (Bacteroides,
Fusobacterium, and Prevotella), intestines (Bacteroides), and female
urogenital tract (Bacteroides, Fusobacterium, and Prevotella) (Ref. 7
at p. 3112). Each of these bacterial pathogens can cause the same
infectious diseases and are often implicated in odontogenic infections
(particularly for those with poor dental hygiene or periodontal
disease, as these bacteria populate dental plaque), peritonsilar
infections, and polymicrobial abdominal infections, among others.
Particularly when introduced into compromised tissue (e.g., via a wound
or break in mucous membranes), these pathogens can cause abscesses that
may require drainage or debridement in addition to antimicrobial
therapy (Ref. 7 at p. 3117). Infection prevention is often the focus
for these pathogens--either via ``avoiding conditions that reduce the
redox potential of the tissues'' or

preventing the bacteria from entering wounds, often by administering
prophylactic antimicrobial agents prior to surgery or dental work (Ref.
9).
    In general, infections from these pathogens are not transmitted
from one person to another or acquired from the environment, but rather
occur from a person's own mucosal flora (id.). These infections, once
established, are generally able to be treated successfully with
surgical incision and drainage as well as administration of
antimicrobial agents and treatment of underlying comorbid conditions
(Ref. 7 at pp. 3111-3119 and Ref. 10). There have been reports of
increases in the incidence of bacteremia caused by anaerobic pathogens
(a classification that includes Bacteroides, Fusarium, and Prevotella
species) (Ref. 11). However, these increases appear more likely to
reflect the complex patient populations studied (id. at p. 898) rather
than, for example, underlying changes in the species' transmissibility,
pathogenicity or other characteristics that would likely signal a
potential for meaningful increase in colonization rates or active
infections.
    Resistance to antimicrobial agents has been reported in the species
of these genera, however (Ref. 9). For example, plasmid-mediated
resistance has been seen in Bacteroides species (id.). Beta-lactamase
production has been seen in Bacteroides species (see Refs. 12 and 13)
and in Prevotella isolates (albeit less frequently than in Bacteroides
isolates); Fusobacterium species have the lowest incidence of beta-
lactamase production of the three genera (Refs. 12, 13, 14, and 15).
Resistance to clindamycin and cefoxitin also has been noted in all
three genera (Ref. 15). Nevertheless, while there have been suggestions
of increasing resistance over time (Ref. 16), and while there is some
concern regarding rates of resistance to penicillin and clindamycin,
these bacteria still remain susceptible to many drugs (Refs. 12, 13,
and 14). Furthermore, persuasive clinical data that may indicate poorer
outcomes for resistant infections are lacking.
    Taken together, the available data do not provide a compelling
rationale for concluding that Bacteroides, Prevotella, or Fusobacteria
species have the potential to pose a serious threat to public health
within the meaning of the statute. Thus, FDA declines to include them
on the list of qualifying pathogens at this time.
(Comment 16) Brucella Species
    One comment suggested adding Brucella species to the list of
qualifying pathogens.
    (Response) Unlike the pathogens previously proposed as qualifying
pathogens, Brucella infections remain susceptible to and may be treated
by existing antibacterial drugs. Further, the incidence and prevalence
of brucellosis is low enough that Brucella species are unlikely to pose
a serious threat to public health--even if resistance were to emerge.
Thus, for these reasons and those that follow, FDA declines to identify
Brucella species as qualifying pathogens.
    Bacteria of the genus Brucella are gram-negative coccobacilli that
typically colonize animals (Ref. 7 at p. 2921). Rarely, certain
Brucella species (most frequently B. melitensis) may infect humans. In
these cases, infection often occurs when broken human skin comes in
contact with infected animals or animal fluids, when a person inhales
aerosolated bacteria, or when a person consumes unpasteurized dairy
products (id.). Brucellosis generally causes nonspecific constitutional
symptoms (e.g., malaise, fever, headache, anorexia) and can cause more
serious arthritis, central nervous system infection, and hepatitis,
among other conditions and symptoms (Ref. 7 at p. 2922). Brucella
infections are usually not transmitted person-to-person (Ref. 7 at p.
2921); therefore, the people at highest risk of Brucella infections
include those who consume unpasteurized dairy products or who work with
animals or the bacteria itself: Ranchers, veterinarians, lab
researchers, and slaughterhouse workers, i.e., isolated environmental
exposures (id.).
    The incidence of human brucellosis remained stable from 1990 to
2003 (Ref. 17), increased from 2003-2007, and decreased by 36 percent
in 2008 (Ref. 18). FDA is aware of no data that suggest a meaningful
post-2008 increase in Brucella infection in humans--to the contrary,
recent data suggest that infections have decreased from 2012 to 2013
(Ref. 19 at Table 1)--and the overall prevalence of brucellosis remains
low in the United States (Ref. 7 at p. 2921). Brucella species have
been listed as a category B (second-highest priority) bioterrorism
threat on CDC's list of bioterrorism agents (Ref. 20), but this
classification takes into account such elements as ease of
dissemination of the pathogen (e.g., it can be aerosolized) in a
bioterrorism setting, and the need for CDC's enhancement of diagnostic
and surveillance capabilities (id.). Importantly, this classification
also recognizes that brucellosis causes only ``moderate morbidity rates
and low mortality rates'' (id.). Indeed, although brucellosis may
require long courses of treatment (e.g., 6 weeks or more) and can
involve tissue sites that enhance the difficulty of treatment (e.g.,
central nervous system infection), the prognosis for Brucella infection
is generally favorable with appropriate treatment (Ref. 21).
    Treatment recommendations for brucellosis have remained unchanged
for many years and include the use of tetracycline or doxycycline plus
gentamycin, or doxycycline plus rifampin (id.). Despite occasional
overseas reports of resistance (Refs. 22 and 23), Brucella species
generally remain susceptible to the mainstays of brucellosis treatment,
even abroad (Refs. 24, 25, 26, and 97). In FDA's view, the currently
available data do not demonstrate widespread antimicrobial resistance
in Brucella infections, nor do they support the potential for a
meaningful increase in drug resistance for Brucella species.
    Thus, for the foregoing reasons, FDA will not identify Brucella
species as qualifying pathogens.
(Comment 17) Clostridium Species Other Than C. difficile
    One comment suggested adding Clostridium species other than C.
difficile to the list of qualifying pathogens.
    (Response) For the reasons that follow, FDA declines to add non-
difficile Clostridium species to the list of qualifying pathogens.
    There are over 200 non-difficile species of the bacterial genus
Clostridium. These toxin-producing, anaerobic rods are found in soil
and in normal human and animal flora, and often infect or intoxicate
humans via contaminated food or wounds (Ref. 7 at p. 3103), although
mother-to-child transmission has been identified for such pathogens as
C. tetani. These pathogens cause a variety of diseases or conditions,
including: Food poisoning (e.g., C. perfringens), including botulism
(C. botulinum); tetanus (C. tetani); clostridial myonecrosis, also
called gas gangrene (C. perfringens); bloodstream infections (C.
perfringens and C. septicum) (Ref. 7 at pp. 3091-3092, 3097-3098, 3106-
3107); and, less commonly, toxic shock syndrome (C. sordellii) (Ref.
27).
    Non-difficile Clostridium outbreaks are reported from time to time
(Ref. 28), but foodborne C. perfringens infections are the most common,
causing approximately 1 million cases of mostly mild to moderate
gastroenteritis in the United States each year (Ref. 29). C.
perfringens often colonizes meat or poultry, and illness may result
from large volumes of food kept warm for a long period of time (e.g.,
in buffets) (id.)

or in outbreaks associated with particular prepared foods (Refs. 30 and
31). C. botulinum, which also causes food poisoning, is relatively
rare, though much more severe--it is likely fatal if untreated (Refs.
29 and 32), whereas C. perfringens infections are often self-limited
and require simply oral rehydration and supportive care at home. Other
Clostridium-related diseases, such as tetanus, bloodstream infections,
and gas gangrene, are life-threatening and require immediate treatment.
    Some infections caused by Clostridium species are very rare. For
example, less than 200 cases of botulism were reported annually to the
CDC, and less than 50 cases of tetanus were reported annually to the
CDC, in each of the past 5 years (Ref. 19). While CDC does not require
reporting of other clostridial infections, antimicrobial susceptibility
studies ``have not changed significantly over the past 10 years''
(Refs. 19 and 33).
    In contrast with C. difficile, C. perfringens is not transmitted
from human to human (Refs. 34, 35, and 36),\2\ and FDA is unaware of
significant increases in incidence or prevalence of infections with C.
perfringens or other non-difficile Clostridium pathogens.
---------------------------------------------------------------------------

    \2\ See 78 FR 35155 (June 12, 2013).
---------------------------------------------------------------------------

    There have been reports of limited antimicrobial resistance in non-
difficile Clostridium species (Refs. 15, 37, 38, 39, and 40), and
studies have found that resistance genes may (or may potentially) be
transferred between C. perfringens species (Refs. 41 and 42). However,
many reports of resistant isolates do not offer a correlation either
with resistant infections seen in a clinical setting (Ref. 40) or with
suggestions of worse outcomes in patients with resistant infections
(Ref. 39) (particularly for C. perfringens, whose infections rarely
require treatment, and for which antibacterial therapy is not
recommended). Many therapies still remain available and effective for
treating the more severe non-difficile Clostridium infections, and,
limited in vitro resistance reports notwithstanding, FDA has not seen
evidence that there is a strong potential for a meaningful increase in
resistance rates in these pathogens.
    For the foregoing reasons--and particularly when contrasted with
the considerations described in the proposed rule pertaining to C.
difficile--FDA does not believe there are sufficient data available to
find that non-difficile Clostridium species meet the statutory standard
for listing as qualifying pathogens. Thus, FDA will not include these
pathogens on the list of qualifying pathogens.
(Comment 18) Coccidioides Species
    Six comments suggested adding Coccidioides immitis to the list of
qualifying pathogens. Six comments suggested adding C. posadasii to the
list of qualifying pathogens. One comment suggested adding Coccidioides
species (generally) to the list of qualifying pathogens. According to
the comments, Coccidioides species present a serious and growing public
health concern, particularly in the southwestern United States.
    (Response) FDA agrees with the comments and will include
Coccidioides species on the list of qualifying pathogens.
    Coccidioides species are pathogenic fungi that are endemic to
certain regions of southwestern United States (i.e., certain areas of
California, Arizona, New Mexico, Texas, Utah, and Nevada) and other
regions of the Western Hemisphere (Ref. 7 at pp. 3333-3334). The
pathogen is responsible for causing coccidioidomycosis, also known as
Valley Fever, with C. immitis and C. posadasii as the causative agents.
Coccidioides species is acquired via respiratory inhalation of spores.
    Infections caused by Coccidioides species have increased in the
past decade. It is estimated that up to 60 percent of people living in
the endemic areas of southwestern United States have been exposed to
the fungus (Ref. 43). According to a March 2013 report, the CDC found
that more than 20,000 cases of Valley Fever are reported annually in
the United States, but many cases go unreported (Ref. 44). Some
researchers estimate that the fungus infects more than 150,000 people
each year (Ref. 45). The CDC observed that the incidence of reported
Valley Fever increased substantially between 1998 and 2011, from 5.3
per 100,000 people in the endemic area in 1998 to 42.6 per 100,000 in
2011 (Ref. 44). Although some of the increase can be attributed to
changes in the case definition based on serologic evidence of infection
(Ref. 46), the incidence of infections caused by the fungi continued to
increase even after taking into account the change in the case
definition. Notably, the CDC found that the incidence of reported
Valley Fever increased in Arizona and California from 2009 to 2010 and
from 2010 to 2011 (Ref. 44).
    Of the infections, one-half to two-thirds are subclinical (Ref.
45). Symptomatic patients typically experience a self-limited acute or
subacute community-acquired pneumonia that becomes evident 1 to 3 weeks
after infection (id.), with fever, cough, headache, rash, muscle aches,
and joint pain as typical symptoms (Ref. 47). Some patients develop
severe or chronic pulmonary disease, and less than one percent of
patients experience extrapulmonary infection (Ref. 44). Chronic
pulmonary or disseminated disease can occur months or years after the
initial infection (Ref. 48). For extrapulmonary disease (also referred
to as disseminated disease), estimates range as high as 30 to 50
percent of ``infections for heavily immunosuppressed patients, such as
those with AIDS, lymphoma, receipt of a solid-organ transplant, or
receipt of rheumatologic therapies, such as high-dose corticosteroids
or anti-tumor-necrosis-factor (TNF) medications'' (Ref. 45).
    In a 2007 to 2008 population-based study in Arizona, over 40
percent of patients with Valley Fever required hospitalization, and
symptoms lasted a median of 120 days (Ref. 49). Furthermore, between
1998 to 2008, the annual number of coccidioidomycosis-related deaths
was about 163, with the highest risk of death associated with men,
persons aged 65 or greater, Hispanics, Native Americans, and residents
of Arizona or California (Ref. 50).
    Resistance mechanisms for Coccidioides species have not been
identified (Ref. 51). There is evidence of at least one report of
resistance to the azole class of antifungal agents (id.). In a
retrospective analysis of patients presenting with coccidioidal
meningitis at Los Angeles, CA, hospitals, researchers found that a
significant proportion of patients--40 percent--died, despite treatment
with fluconazole monotherapy or a combination of fluconazole and
intravenous amphotericin B (Ref. 52). Therefore, it is plausible that
resistance has increased given the increase in the rate of growth of
Valley Fever.
    For the reasons stated previously, FDA believes that Coccidioides
species has the potential to pose a serious threat to public health,
and FDA is including Coccidioides species on the list of qualifying
pathogens.
(Comment 19) Cryptococcus Species
    Two comments suggested adding Cryptococcus species to the list of
qualifying pathogens due to, among other things, C.gattii infections in
North America and concerns about worldwide morbidity and mortality from
cryptococcal infections generally.
    (Response) For the reasons that follow, FDA will include these
species as qualifying pathogens.

    Cryptococcus species are encapsulated yeast fungi (Ref. 7 at p.
3287). Although there are 19 species in the genus (Ref. 7 at p. 3287),
C. neoformans and C. gattii are the two generally associated with human
disease (Ref. 7 at pp. 3288-3289). Both species are found in soil, and
infection typically occurs via inhalation of the fungi (Ref. 7 at p.
3290). Cryptococcal disease often presents as lung or central nervous
system disease (Ref. 7 at p. 3293), although the pathogens also can
infect other parts of the body (Ref. 53).
    Most C. neoformans occur in immunocompromised patients (Ref. 7 at
p. 3289), and C. neoformans meningitis cases are very rare in healthy
people, with an incidence of only 0.4 to 1.3 per 100,000 people (Ref.
54). Incidence of cryptococcal disease increased substantially with the
HIV/AIDS epidemic in the late portion of the 20th century and remains
high in developing countries, where antiretroviral therapy is scarce
(id.). In developed countries, the use of antiretroviral therapy has
reduced the number of end-stage HIV/AIDS patients susceptible to
cryptococcal infection (Ref. 55); incidence rates in this population in
the United States are between 2 and 7 infections per 100,000 people
(Ref. 54). Although HIV/AIDS-related cryptococcosis is declining, an
increasing population (Ref. 53) of immunosuppressed patients--including
solid organ transplant patients, cancer patients, and patients on
corticosteroids--remain at risk of C. neoformans infections (Ref. 56).
Non-HIV patients appear to bear an increasing burden of cryptococcal
disease, representing 16 percent of all U.S. cryptococcal meningitis
cases in 1997 but 29 percent of all U.S. cryptococcal meningitis cases
in 2009 (Ref. 55). Cryptococcosis is the third most common invasive
fungal infection in solid organ transplant patients after candidiasis
and aspergillosis (Ref. 56).
    C. gattii infections, however--which had been considered
geographically limited to areas such as Australia and New Zealand
because of an association with eucalyptus trees (Ref. 57)--have become
an increasing public health concern for healthy, rather than
immunocompromised, people in North America. Although C. gattii
infections also have been documented in HIV patients, ``[t]he emergence
of C. gattii infections in immunocompetent human and animal populations
in the Pacific Northwest region of North America is nothing short of
remarkable'' (Ref. 56). After an initial outbreak on Vancouver Island
in 1999, incidence rates of C. gattii infections were estimated to be
37 times higher than in the endemic areas of Australia and New Zealand
(Ref. 53). A retrospective analysis in the Pacific Northwest area of
the United States did not identify any patients with cryptococcal
infection due to C. gattii before 2000 (Ref. 58), while 100 infections
were documented in the United States between 2004 and 2011, mostly from
the Pacific Northwest area of the United States (Ref. 98).
    Both C. neoformans and C. gattii can cause life-threatening
infections, although the primary infection sites may differ. For
example, in the initial Vancouver Island outbreak of C. gattii
infections about 70 percent of patients had lung disease (Ref. 53), and
in C. neoformans infections in immunocompromised patients (who comprise
the majority of those infected), meningitis or other central nervous
system disease is the most common presentation of infection (id.).
Those C. gattii patients who have central nervous system involvement
may have more neurological sequelae than C. neoformans patients,
however (id.). These sequelae may require longer courses of antifungal
therapy to treat (id.), and may result in permanent neurological damage
(Ref. 59). Regardless of interspecies disease differences, infection
with either pathogen is likely to be very serious. In one study of C.
gattii infections, 91 percent of infected patients were hospitalized
and 33 percent died (Ref. 60). Mortality rates for C. neoformans
infections are approximately 12 percent in developed countries, and
that rate rises to 50 to 70 percent in sub-Saharan Africa, where
treatment is less accessible (Ref. 54).
    According to one set of clinical practice guidelines,
``[c]ryptococcosis remains a challenging management issue, with little
new drug development or recent definitive studies'' (Ref. 61). Both
pathogens require long courses of antifungal therapy for treatment,
although the success and components of therapy may differ somewhat
depending on the primary site of infection and the immunological
competence and underlying condition of the patient (id.). In recent
years, however, studies on both pathogens have indicated signs of
increasing resistance to antifungal therapies. For example, according
to a 10-year ARTEMIS Global Antifungal Surveillance Program (ARTEMIS)
survey, the proportion of C. neoformans isolates showing resistance to
fluconazole increased from 7.3 percent in 1997-2000 to 11.7 percent in
2005-2007 (Ref. 62). Furthermore, in one study, C. gattii isolates from
the Pacific Northwest were more resistant to antifungal drugs than non-
Pacific Northwest C. gattii isolates or C. neoformans isolates (Ref.
63). This result supports the observation that infection with C. gattii
strains from the Pacific Northwest may result in worse clinical
outcomes than infection with other C. gattii strains (e.g., a 33
percent mortality rate seen in Pacific Northwest infections versus a 13
percent mortality rate seen in infections in Australia) (id.).
    In sum, evidence of increasing resistance combined with increases
in immunocompromised patients, the emergence of C. gattii infections in
the Pacific Northwest in healthy individuals, and the seriousness of
cryptococcal disease, have led FDA to conclude that Cryptococcus
species have the potential to pose a serious risk to public health. FDA
thus will add these pathogens to the list of qualifying pathogens.
(Comment 20) Fusarium Species
    One comment suggested adding Fusarium species to the list of
qualifying pathogens because the fungal agent causes serious and life-
threatening infections.
    (Response) Preliminarily, FDA notes that the comment appears to
have conflated the standards for qualifying pathogens (``pathogen[s] .
. . that ha[ve] the potential to pose a serious threat to public
health'' (section 505E(f) of the FD&C Act)) and QIDPs (certain human
``drugs . . . intended to treat serious or life-threatening
infections'' (section 505E(g) of the FD&C Act)) (emphasis added). For
the reasons that follow, FDA declines to add Fusarium species to the
list of qualifying pathogens.
    Fusarium species are fungi found mainly as saprophytic organisms in
soil. Since the 1970s, the number of reports of human infection due to
Fusarium species has increased, mainly involving immuocompromised
patients (Ref. 7 at p. 3369). Infections caused by Fusarium species
occur most commonly in patients with acute leukemia and prolonged
neutropenia (id.). The fungi can cause localized infection, deep-seated
skin infections, and disseminated disease. The rare cases of
disseminated disease have been reported in the clinical settings of
severe burns, trauma, and heat stroke (id.). Reports of localized
infection in patients without leukemia or prolonged neutropenia are
infrequent and usually involve the skin (e.g., complication of a burn)
or ocular tissues (Ref. 64).
    Inhalation, ingestion, and entry through skin trauma have been
suggested as the portal of entry (Ref. 7 at p. 3369). More recently,
water has also been suggested as a source of these

infections, as the fungus was found in one hospital water supply system
and in several water sources at a dialysis clinic (id.). Infection
commonly presents with fever and myalgia not responsive to
antibacterial therapy during periods of profound neutropenia (id). Skin
lesions occur in 60 to 80 percent of infections and can occur within 1
day of the onset of fever (id.). Overall mortality in this infection
has been reported to be between 50 to 80 percent (Ref. 7 at p. 3370).
Survival is generally associated with the recovery from neutropenia
(id.). The high rates of morbidity and mortality are usually due to the
patients' underlying immune suppression and prolonged neutropenia (Ref.
65).
    Generally, while susceptibility varies among Fusarium species,
susceptibility to antifungal drugs generally is thought to be low (Ref.
7 at p. 3370). The management of fusariosis almost always includes
surgical debridement, so it is often difficult to ascertain the role of
antifungal drugs versus the role of surgical debridement when
considering the outcomes of patients with this infection (Ref. 65).
    While Fusarium species is associated with high morbidity and
mortality rates, there do not appear to be new or changing public
health concerns with infections caused by this fungi. Although
antifungal therapy plays a role, the standard of care is focused on
surgical debridement and reestablishment of the patient's immune
system. Therefore, FDA will not be adding Fusarium species to the list
of qualifying pathogens.
(Comment 21) Helicobacter Pylori
    One comment suggested adding Helicobacter pylori to the list of
qualifying pathogens because the pathogen is a major cause of
morbidity, specifically a range of gastroduodenal diseases.
    (Response) For the reasons that follow, FDA is adding H. pylori to
the list of qualifying pathogens.
    H. pylori is a gram-negative bacterium that survives in the gastric
epithelium or mucosal layer and occasionally in the duodenal or
esophageal mucosal epithelium. H. pylori is one of the most common
bacterial pathogens, estimated to infect about 60 percent of the
world's population (Ref. 66).
    About 20 percent of infected individuals develop gastroduodenal
disorders in their lifetime (Ref. 67). For symptomatic individuals, H.
pylori can cause severe gastric disease, including: Gastritis, duodenal
and gastric ulcers, duodenal and gastric cancers, and mucosal-
associated-lymphoid-type (MALT) lymphoma (Ref. 68). Approximately 15
percent of infected people will develop a peptic ulcer, and 1 to 3
percent will develop a gastric malignancy during their lifetime (Ref.
69). Persons infected with H. pylori also have a two- to six-times
greater risk of developing gastric cancer and MALT lymphoma compared
with uninfected individuals (Ref. 68).
    Transmission occurs fecal-oral, gastric-oral, or oral-oral from
human-to-human contact (Ref. 70). Risk factors include poor
socioeconomic conditions, family overcrowding, poor hygiene, and living
with an infected family member (id.). Incidence of new infections in
developing countries is 3 to 10 percent of the population each year,
compared to 0.5 percent in developed countries, due predominantly to
better hygiene practices (id.). In the United States, age-adjusted
prevalence of H. pylori is higher in Mexican-Americans at 62 percent
and non-Hispanic blacks at 53 percent, compared to non-Hispanic whites
at 26 percent (Ref. 71).
    H. pylori antibiotic resistance has been widely reported at a
global level. Resistance mechanisms against antibacterial drugs used to
treat H. pylori infections have been identified (Ref. 72). For
metronidazole, ``high intracellular redox potential of aerobe species
prevents the metronidazole reduction-activation and is responsible for
the intrinsic resistance'' (id.). Prevalence of antibacterial
resistance varies in different geographic regions, and it has been
correlated with the consumption of antibacterial drugs in the general
population (Refs. 73 and 74).
    A retrospective analysis of 31 worldwide studies concerning H.
pylori published between January 2006 and December 2009 showed
substantial rates of antibacterial drug resistance (Ref. 73). For
example, 9.6 percent of worldwide H. pylori isolates showed resistance
to two or more antibacterial drugs. A U.S. network of clinical sites
that tracked national prevalence rates of H. pylori, called the
Helicobacter pylori Antimicrobial Resistance Monitoring Program,
identified 347 clinical isolates of H. pylori to be analyzed for
resistance to antibacterial drugs (Ref. 67). The researchers observed
that 29.1 percent of isolates were resistant to one antibacterial drug
and 4.8 percent of isolates were resistant to two or more antibacterial
drugs. Other regions, such as China (Ref. 75) and Africa (Ref. 73),
have reported even greater resistance rates to antibacterial drugs.
Resistance to some classes of antibacterial drugs was associated with a
reduction in treatment efficacy (Ref. 76). Eradication of H. pylori in
humans is being challenged by the increasing rates of resistance to
current treatment (Ref. 77). For the reasons described previously, FDA
believes that H. pylori has the potential to pose a serious threat to
public health, and FDA will add Helicobacter pylori to the list of
qualifying pathogens.
(Comment 22) Pandoraea Species
    One comment suggested adding Pandoraea species to the list of
qualifying pathogens.
    (Response) For the reasons that follow, FDA declines to add
Pandoraea species to the list of qualifying pathogens.
    The Pandoraea bacterial genus was identified in 2000; as of 2011,
it contained five species (Ref. 78), all of which are aerobic gram-
negative rods (Ref. 79). Historically, proper identification of these
bacteria has been a challenge (id.), although a recent poster
presentation at an international meeting suggested that Pandoraea
species' production of carbapanem-cutting oxacillinase enzymes (which
suggests that these bacteria may have intrinsic resistance to
carbapanem antibiotics) may be a useful diagnostic tool (id.).
    These bacteria are generally opportunistic and tend to colonize or
infect patients with cystic fibrosis (CF) in particular (Ref. 78).
However, both the prevalence and the pathogenic role of Pandoraea
bacteria in patients with CF are unknown (Ref. 80). There have been
reports of sporadic Pandoraea-related bacteremia and lung infections,
including some in non-CF patients (Ref. 78). In addition, a 2003 report
describes six CF patients who acquired Pandoraea species infections and
four (out of the six) patients subsequently experienced a decline in
lung function (Ref. 81).
    Currently, there is too little information available about
Pandoraea species to support their inclusion on the list of qualifying
pathogens. Aside from a suggestion of intrinsic carbapanem resistance
(Ref. 79), FDA is unaware of data suggesting increasing resistance--or
any acquired resistance--to available therapies, or poorer outcomes
with resistant strains of these pathogens. Further, ``[t]he clinical
significance of colonization with these organisms remains unclear, and
there are limited and conflicting data available on the clinical
outcome of patients colonized with Pandoraea'' (Ref. 78). Thus, FDA
declines to add Pandoraea species to the list of qualifying pathogens
at the present time.

(Comment 23) Peptostreptococcus Species
    One comment suggested adding Peptostreptococcus species to the list
of qualifying pathogens.
    (Response) For the reasons that follow, FDA declines to add
Peptostreptococcus species to the list of qualifying pathogens.
    The Peptostreptococcus genus consist of anaerobic, gram-negative
bacteria that are a part of the normal flora of human mucocutaneous
surfaces, including the mouth, gastrointestinal track, female
genitourinary system, urethra, and skin (Ref. 7 at p. 3121). The
bacteria can cause a wide variety of infections, including respiratory,
oropharyngeal, sinus, ear, musculoskeletal, intraabdominal,
genitourinary, cardiovascular, dental, superficial, and soft tissue
infections (Ref. 82). Infection typically is associated with trauma or
disease (Ref. 83 at pp. 309-312) and has been identified to be a
significant component of mixed infections (Ref. 82).
    Notably, there is no evidence to show an increase in the rate of
incidence or prevalence with Peptostreptococci (Ref. 84). Until
recently, most clinical isolates of gram-positive anaerobic cocci were
identified as a species of Peptostreptococcus, but this genus is
currently being reclassified into three new genera: Micromonas,
Anaerococcus, and Peptoniphilus (Ref. 85). Some species are also being
transferred, for example, to the genus Streptococcus (Ref. 7 at p.
3121).
    While resistance to antibacterial drugs is rare, resistance
mechanisms have been identified as the transfer of plasmid-mediated
mechanisms (Ref. 86 at p. 878). Peptostreptococci are usually fully
susceptible to penicillin (Ref. 7 at p. 3122), though some isolates
have occasionally been found to be resistant to penicillin (Ref. 85).
Further, the genus has consistently reported no resistance to
metronidazole, clindamycin, and imipenem (Ref. 84). Surveillance data
from England and Wales do not support concerns regarding resistance to
antibacterial therapies (Ref. 85).
    There does not seem to be an emerging public health concern with
infections caused by Peptostreptococci. Although resistance mechanisms
have been identified, data on clinical pathogens are lacking and the
rates of incidence or prevalence have not been shown to be increasing.
Therefore, FDA will not be including Peptostreptococcus on the list of
qualifying pathogens.
(Comment 24) Scedosporium Species
    One comment suggested adding Scedosporium species to the list of
qualifying pathogens because the fungal agent causes serious and life-
threatening infections.
    (Response) FDA notes that the comment appears to have conflated the
standards for qualifying pathogens (``pathogen[s] . . . that ha[ve] the
potential to pose a serious threat to public health'' (section 505E(f)
of the FD&C Act)) and QIDPs (certain human ``drugs . . . intended to
treat serious or life-threatening infections'' (section 505E(g) of the
FD&C Act)) (emphasis added). For the reasons that follow, FDA declines
to add Scedosporium species to the list of qualifying pathogens.
    Scedosporium comprises a family of fungi that is responsible for an
increasing number of infections, particularly among immunocompromised
patients (Ref. 87). Two species of Scedosporium are medically relevant:
S. apiospermum and S. prolificans. These fungi are saprophytic agents
with worldwide distribution that are isolated from natural sources
(Ref. 88 at p. 4).
    The fungi are typically acquired via direct inoculations, through a
trauma wound or wound puncture (id.). Scedosporium infections are rare
but can cause human infectious diseases, including soft tissue
infections, septic arthritis, osteomyelitis, ophthalmic infections,
sinusitis, pneumonia, meningitis and brain abscesses, endocarditis, and
disseminated infection (Ref. 89). Disseminated infection has been
observed with both species of Scedosporium (Ref. 88 at p. 4).
    The overall incidence of Scedosporium infections is relatively low
in most geographic areas of the United States. Hospital-based
infections in patients with hematological malignancies have been
observed (Ref. 87). Most disseminated S. prolificans infections are
fatal due to persistent neutropenia and the intrinsic resistance to
available antifungal agents (Ref. 90). Additionally, the management of
invasive S. apiospermum infections is difficult because the pathogen
has intrinsic resistance to many antifungal agents, including
fluconazole and amphotericin (Ref. 91). A combination of chemotherapy
and surgery seems to be the best approach in treating the infection
(Ref. 88). Recovery from disseminated Scedosporium infections appears
to result from improvement of the underlying disease (e.g., recovery
from neutropenia) rather than from antifungal treatments (id.).
Therefore, rate of growth of resistant organisms and an evaluation of
rates of resistance would not provide meaningful evidence to support
inclusion on the list of qualifying pathogens.
    While Scedosporium is associated with high morbidity and mortality,
the incidence of disease associated with Scedosporium is rare, and
therefore there do not appear to be new public health concerns with
these infections. For these reasons, FDA will not add Scedosporium to
the list of qualifying pathogens.
(Comment 25) Zygomycetes (Mucor, Rhizopus, Absidia, Cunninghamella)
    One comment suggested adding Zygomycetes (specifically, Mucor,
Rhizopus, Absidia, and Cunninghamella) to the list of qualifying
pathogens because these fungal agents cause serious and life-
threatening infections.
    (Response) FDA notes that the comment appears to have conflated the
standards for qualifying pathogens (``pathogen[s] . . . that ha[ve] the
potential to pose a serious threat to public health'' (section 505E(f)
of the FD&C Act)) and QIDPs (certain human ``drugs . . . intended to
treat serious or life-threatening infections'' (section 505E(g) of the
FD&C Act)) (emphasis added). For the reasons that follow, FDA declines
to add Zygomycetes to the list of qualifying pathogens.
    The class of Zygomycetes is a large group of fungi that are mostly
opportunistic pathogens responsible for infections in high-risk
patients, such as immunocompromised and type 2 diabetes mellitus
patients (Ref. 92). There are two orders of Zygomycetes of medical
interest: the Mucorales, which cause the majority of illness, and the
Entomophthorales (Ref. 93 at p. 236). The main categories of human
disease associated with Mucorales are sinusitis/rhinocerebral,
pulmonary, cutaneous/subcutaneous, gastrointestinal, and disseminated
zygomycosis (Ref. 93 at p. 244).
    The host generally acquires the infectious spores through
inhalation, ingestion, or inoculation through breaches in or
penetrating injuries to the skin (Ref. 92). Host risk factors include
diabetes mellitus, neutropenia, sustained immunosuppressive therapy,
broad-spectrum antibiotic use, severe malnutrition, and primary
breakdown in the integrity of the cutaneous barrier such as trauma,
surgical wounds, needle sticks, or burn wounds (id.). Zygomycosis
occurs rarely in non-immunocompromised hosts.
    Zygomycetes are relatively uncommon isolates in the clinical

laboratory and are less frequent than invasive fungi caused by
Aspergillus species. According to one report, ``[i]ncidence figures are
difficult to collect as few national studies have been undertaken, but
for the United States, the annual incidence of zygomycosis has been
estimated as 1.7 infections per million people'' (Refs. 92 and 94).
According to a 2002 report, the incidence of zygomycosis may be
increasing; researchers found an increase in the number of
hematopoietic stem cell transplant recipients at the Fred Hutchinson
Cancer Center in Seattle, WA, infected with Zygomycetes from 1985-1989
to 1995-1999 (Ref. 95). Another study found that invasive fungal
infections due to Zygomycetes were associated with higher mortality
rates in adult hematopoietic stem cell transplant recipients at 64.3
percent, with suboptimal therapeutic modalities for the management of
the infection as one contributing factor to the high rates (Ref. 96).
    Surgical debridement should be considered as an option early in
management of zygomycosis as the evidence indicates that this
intervention improves survival (Ref. 92). Additionally, the agent of
choice was conventional amphotericin B used at higher than normal doses
(id.). FDA's research did not identify any papers that suggest an
increase in the resistance rates to antifungal treatment.
    Zygomycetes are associated with high morbidity and mortality rates.
However, there do not appear to be new or changing public health
concerns with infections caused by Zygomycetes. Further, resistance
data on clinical pathogens are lacking. Therefore, FDA will not add
Zygomycetes to the list of qualifying pathogens.

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 Economic Impact

A. Final Regulatory Impact Analysis

    FDA has examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct 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). The Agency believes that this final rule is not a significant
regulatory action as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the final rule would not impose direct costs
on any entity, regardless of size, but rather would clarify certain
types of pathogens for which the development of approved treatments
might result in the awarding of QIDP designation and exclusivity to
sponsoring firms, FDA certifies that the rule would not have a
significant economic impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $141 million, using the most current (2013) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.

B. Background

    Antibacterial research and development has reportedly declined in
recent years. A decrease in the number of new antibacterial products
reaching the market in recent years has led to concerns that the
current drug pipeline for antibacterial drugs may not be adequate to
address the growing public health needs arising from the increase in
antibacterial or antifungal resistance. A number of reasons have been
cited as barriers to robust antibacterial drug development including
smaller profits for short-course administration of antibacterial drugs
compared with long-term use drugs to treat chronic illnesses,
challenges in conducting informative clinical trials demonstrating
efficacy in treating bacterial infections, and growing pressure to
develop appropriate limits on antibacterial drug use.
    One mechanism that has been used to encourage the development of
new drugs is exclusivity provisions that provide for a defined period
during which an approved drug is protected from submission or approval
of certain potential competitor applications. By securing additional
guaranteed periods of exclusive marketing, during which a drug sponsor
would be expected to benefit from associated higher profits, drugs that
might not otherwise be developed due to unfavorable economic factors
may become commercially attractive to drug developers.
    In recognition of the need to stimulate investments in new
antibacterial or antifungal drugs, Congress enacted the GAIN title of
FDASIA to create an incentive system. The primary framework for
encouraging antibacterial or antifungal drug development became
effective on July 9, 2012, through a self-implementing provision that
authorizes FDA to designate human antibacterial or antifungal drugs
that treat ``serious or life-threatening infections'' as QIDPs. With
certain limitations set forth in the statute, a sponsor of an
application for an antibacterial or antifungal drug that receives a
QIDP designation gains an additional 5 years of exclusivity to be added
to certain exclusivity periods for that product. Drugs that receive a
QIDP designation are also eligible for designation as a fast-track
product and an application for such a drug is eligible for priority
review.

C. Need for and Potential Effect of the Regulation

    Between July 9, 2012, when the GAIN title of FDASIA went into
effect, and March 12, 2014, FDA granted 41 QIDP designations. As
explained above, the statutory provision that authorizes FDA to
designate certain drugs as QIDPs is self-implementing, and inclusion of
a pathogen on the list of ``qualifying pathogens'' does not determine
whether a drug proposed to treat an infection caused by that pathogen
will be given QIDP designation. However, section 505E(f) of the FD&C
Act, added by the GAIN title of FDASIA, requires that FDA establish a
list of ``qualifying pathogens.'' This final rule is intended to
satisfy that obligation, as well as the statute's directive to make
public the methodology for developing such a list of ``qualifying
pathogens.'' The final rule identifies 21 ``qualifying pathogens,''
including those provided as examples in the statute, which FDA has
concluded have ``the potential to pose a serious threat to public
health'' and proposes to include on the list of ``qualifying
pathogens.''
    As previously stated, this final rule would not change the criteria
or process for awarding QIDP designation or for awarding extensions of
exclusivity

periods. That is, the development of a treatment for an infection
caused by a pathogen included on the list of ``qualifying pathogens''
is neither a necessary nor a sufficient condition for obtaining QIDP
designation, and as stated in section 505E(c) of the FD&C Act, not all
applications for a QIDP are eligible for an extension of exclusivity.
Relative to the baseline in which the exclusivity program under GAIN is
in effect, we anticipate that the incremental effect of this rule would
be negligible.
    To the extent that this rule causes research and development to
shift toward treatments for infections caused by pathogens on the list
and away from treatments for infections caused by other pathogens, the
opportunity costs of this rule would include the forgone net benefits
of products that treat or prevent pathogens not included on the list,
while recipients of products to treat infections caused by pathogens on
the list would receive benefits in the form of reduced morbidity and
premature mortality. Sponsoring firms would experience both the cost of
product development and the economic benefit of an extension of
exclusivity and of potentially accelerating the drug development and
review process with fast-track status and priority review. If this rule
induces greater interest in seeking QIDP designation than would
otherwise occur, FDA also would incur additional costs of reviewing
applications for newly developed antibacterial or antifungal drug
products under a more expedited schedule.
    Given that the methodology for including a pathogen on the list of
``qualifying pathogens'' was developed with broad input, including
input from industry stakeholders and the scientific and medical
community involved in anti-infective research, we expect that the
pathogens listed in this final rule reflect not only current thinking
regarding the types of pathogens that have the potential to pose
serious threat to the public health, but also current thinking
regarding the types of pathogens that cause infections for which
treatments might be eligible for QIDP designation. To the extent that
there is overlap between drugs designated as QIDPs and drugs developed
to treat serious or life-threatening infections caused by pathogens
listed in this final rule, this final rule would have a minimal impact
in terms of influencing the volume or composition of applications
seeking QIDP designation compared to what would otherwise occur in the
absence of this rule.

VI. Paperwork Reduction Act

    FDA concludes that this rule does not contain a ``collection of
information'' that is subject to review by the Office of Management and
Budget under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C.
3501-3520). This rule interprets some of the terms used in section 505E
of the FD&C Act and proposes ``qualifying pathogen'' candidates.
Inclusion of a pathogen on the list of ``qualifying pathogens'' does
not confer any information collection requirement upon any party,
particularly because inclusion of a pathogen on the list of
``qualifying pathogens'' and the QIDP designation process are distinct
processes with differing standards.
    The QIDP designation process will be addressed separately by the
Agency at a later date. Accordingly, the Agency will analyze any
collection of information or additional PRA-related burdens associated
with the QIDP designation process separately.

VII. Federalism

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

VIII. References

    The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m. Monday through Friday, and
are available electronically at http://www.regulations.gov. (FDA has
verified the Web site addresses, but FDA is not responsible for any
subsequent changes to the Web sites after this document publishes in
the Federal Register.)

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List of Subjects in 21 CFR Part 317

    Antibiotics, Communicable diseases, Drugs, Health, Health care,
Immunization, Prescription drugs, Public health.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act, and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
317 is added as follows:

PART 317--QUALIFYING PATHOGENS

Sec.
317.1 [Reserved]
317.2 List of qualifying pathogens that have the potential to pose a
serious threat to public health.

    Authority:  21 U.S.C. 355f, 371.

Sec.  317.1  [Reserved]

Sec.  317.2  List of qualifying pathogens that have the potential to
pose a serious threat to public health.

    The term ``qualifying pathogen'' in section 505E(f) of the Federal
Food, Drug, and Cosmetic Act is defined to mean any of the following:
    (a) Acinetobacter species.
    (b) Aspergillus species.
    (c) Burkholderia cepacia complex.
    (d) Campylobacter species.
    (e) Candida species.
    (f) Clostridium difficile.
    (g) Coccidioides species.
    (h) Cryptococcus species.
    (i) Enterobacteriaceae.
    (j) Enterococcus species.
    (k) Helicobacter pylori.
    (l) Mycobacterium tuberculosis complex.

    (m) Neisseria gonorrhoeae.
    (n) Neisseria meningitidis.
    (o) Non-tuberculous mycobacteria species.
    (p) Pseudomonas species.
    (q) Staphylococcus aureus.
    (r) Streptococcus agalactiae.
    (s) Streptococcus pneumoniae.
    (t) Streptococcus pyogenes.
    (u) Vibrio cholerae.

    Dated: May 29, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-13023 Filed 6-4-14; 8:45 am]
BILLING CODE 4160-01-P