[Federal Register Volume 79, Number 108 (Thursday, June 5, 2014)]
[Rules and Regulations]
[Pages 32464-32481]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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,

[[Page 32465]]

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.

[[Page 32466]]

 
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

[[Page 32467]]

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,

[[Page 32468]]

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-

[[Page 32469]]

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

[[Page 32470]]

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

[[Page 32471]]

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.)

[[Page 32472]]

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.

[[Page 32473]]

    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

[[Page 32474]]

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.

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(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

[[Page 32476]]

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

[[Page 32477]]

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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at http://www.sciencedirect.com/science/article/pii/S1075996403000660).
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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.

[[Page 32481]]

    (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