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a Submission Agreement, Submission systems, among others. (Compliance dissemination of ocean, coastal, and Information Form (SIF) or other, similar with this criterion can be demonstrated Great Lakes observation data. The RICE data producer-archive agreement. by referencing any existing grant, must identify to NOAA’s satisfaction: (g) Budget Plan. The Strategic cooperative agreement, or contract the The individual(s) responsible for overall Operational Plan shall include or RICE has with NOAA.) system management, as applicable, the reference a Budget Plan that: (c) The RICE shall document annually individual(s) responsible for (1) Identifies who supports the RICE the RICE’s operating and maintenance observations system management across financially; costs for all observing platforms and the region, and the individual(s) (2) Identifies how RICE priorities sensors, etc., owned and/or operated by responsible for management of data guide funding decisions; and the RICE. This information shall be operations across the region. In (3) Assesses funding constraints and made available to NOAA upon request. accepting certification, the RICE will the associated risks to the observing concede to NOAA the power to ensure § 997.26 Civil liability. System that the RICE must address for these individuals comply with the the future. (a) For purposes of determining requirements of this rule in their daily liability arising from the dissemination § 997.24 Gaps identification. operations and that they are responsive and use of observation data gathered to NOAA through the agreement the (a) To become certified, a RICE must pursuant to the ICOOS Act and these RICE has with NOAA. identify gaps in observation coverage regulations, any non-Federal asset or needs for capital improvements of regional information coordination entity [FR Doc. 2014–13034 Filed 6–4–14; 8:45 am] Federal assets and non-Federal assets of incorporated into the System by BILLING CODE 3510–JE–P the System, or other recommendations contract, lease, grant, or cooperative to assist in the development of annual agreement that is participating in the and long-terms plans and transmit such System shall be considered to be part of DEPARTMENT OF HEALTH AND information to the Interagency Ocean the National Oceanic and Atmospheric HUMAN SERVICES Observing Committee via the Program Administration. Any employee of such Food and Drug Administration Office. a non-Federal asset or regional (b) The application shall: information coordination entity, while 21 CFR Part 317 (1) Document that the RICE’s asset operating within the scope of his or her inventory contains up-to-date employment in carrying out the [Docket No. FDA–2012–N–1037] information. This could be purposes of this subtitle, with respect to RIN 0910–AG92 demonstrated by a database or portal tort liability, is deemed to be an accessible for public viewing and employee of the Federal Government. Establishing a List of Qualifying capable of producing a regional (b) The ICOOS Act’s grant of civil Pathogens Under the Food and Drug summary of observing capacity; liability protection (and thus the RICE’s Administration Safety and Innovation (2) Provide a regional Build-out Plan limited status as part of NOAA) applies Act that identifies the regional priorities for only to a RICE that: products and services, based on its (1) Is participating in the System, AGENCY: Food and Drug Administration, understanding of regional needs, and a meaning the RICE has been certified by HHS. description of the integrated system NOAA in accordance with the ICOOS ACTION: Final rule. (observations, modeling, data Act and these regulations; and management, product development, (2) Has been integrated into the SUMMARY: The Food and Drug outreach, and R&D). The RICE shall System by memorandum of agreement Administration (FDA or Agency) is review and update the Build-out Plan at with NOAA. issuing a regulation to establish a list of least once every five years; and (c) An ‘‘employee’’ of a regional ‘‘qualifying pathogens’’ that have the (3) Document the priority regional information coordination entity is an potential to pose a serious threat to gaps in observation coverage needs, as individual who satisfies all of the public health. This final rule determined by an analysis of the RICE following requirements: implements a provision of the asset inventory and Build-out Plan. The (1) The individual is employed or Generating Antibiotic Incentives Now RICE shall review and update the contracted by a certified RICE that has (GAIN) title of the Food and Drug analysis of priority regional gaps in been integrated into the System by Administration Safety and Innovation observation coverage needs at least once memorandum of agreement with NOAA, Act (FDASIA). GAIN is intended to every five years. and that is participating in the System, encourage development of new as defined in § 997.26(b); antibacterial and antifungal drugs for § 997.25 Financial oversight. (2) The individual is identified by the the treatment of serious or life- (a) To become certified, a RICE must RICE, as required in § 997.23(d)(3) and threatening infections, and provides comply with all financial oversight (f)(1)(i), as one of the individuals incentives such as eligibility for requirements established by the responsible for the collection, designation as a fast-track product and Administrator, including requirement management, or dissemination of ocean, an additional 5 years of exclusivity to be relating to audits. coastal, and Great Lakes observation added to certain exclusivity periods. (b) The application shall document data; and Based on analyses conducted both in compliance with the terms and (3) The individual is responsive to the proposed rule and in response to conditions set forth in 2 CFR Part 215— federal government control. comments to the proposed rule, FDA Uniform Administrative Requirements (d) The protection afforded to has determined that the following for Grants and Agreements with employees of a RICE with regard to pathogens comprise the list of Institutions of Higher Education, liability applies only to specific ‘‘qualifying pathogens:’’ Acinetobacter Hospitals, and Other Non-profit individuals employed or contracted by species, Aspergillus species, Organizations, Subpart C—Post Award a RICE who meet the requirements of Burkholderia cepacia complex, Requirements. Subpart C prescribes § 997.26(c) and who are responsible for Campylobacter species, Candida standards for financial management the collection, management, or species, Clostridium difficile,

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Coccidioides species, Cryptococcus III. Comments to the Proposed Rule and (see section 505E(f)(2)(B)(ii) of the FD&C species, Enterobacteriaceae (e.g., FDA’s Responses Act). FDA issued a proposed rule on Klebsiella pneumoniae), Enterococcus A. Statutory Interpretation and Proposed June 12, 2013 (78 FR 35155), and, after Factors for Consideration species, Helicobacter pylori, B. Miscellaneous Comments analyzing comments to that proposed Mycobacterium tuberculosis complex, C. Comments on Previously Proposed rule, is issuing this final rule in Neisseria gonorrhoeae, N. meningitidis, Pathogens fulfillment of the statutory requirements Non-tuberculous mycobacteria species, D. Suggestions for Additional Qualifying described above. Pseudomonas species, Staphylococcus Pathogens Summary of the Major Provisions of the aureus, Streptococcus agalactiae, S. IV. Environmental Impact Regulatory Action pneumoniae, S. pyogenes, and Vibrio V. Analysis of Economic Impact cholerae. The preamble to the proposed A. Final Regulatory Impact Analysis After holding a public meeting and B. Background rule described the factors the Agency C. Need for and Potential Effect of the consulting with CDC and the National considered and the methodology used to Regulation Institutes of Health (NIH), and develop the list of qualifying pathogens. VI. Paperwork Reduction Act considering the factors specified in As described in the preamble of this VII. Federalism section 505E(f)(2)(B)(i) of the FD&C Act, final rule, FDA applied those factors VIII. References FDA proposed on June 12, 2013, that the and that methodology to additional Executive Summary following pathogens comprise the list of pathogens suggested via comments on ‘‘qualifying pathogens:’’ Acinetobacter the proposed rule. Purpose of the Regulatory Action species, Aspergillus species, DATES: This rule is effective July 7, Title VIII of FDASIA (Pub. L. 112– Burkholderia cepacia complex, 2014. 144), the GAIN title, is intended to Campylobacter species, Candida encourage development of new species, Clostridium difficile, ADDRESSES: For access to the docket to antibacterial and antifungal drugs for Enterobacteriaceae (e.g., Klebsiella read background documents or the treatment of serious or life- pneumoniae), Enterococcus species, comments received, go to http:// threatening infections. Among other Mycobacterium tuberculosis complex, www.regulations.gov and insert the things, GAIN requires that the Secretary Neisseria gonorrhoeae, N. meningitidis, docket number, found in brackets in the of the Department of Health and Human Non-tuberculous mycobacteria species, heading of this document, into the Services (and thus FDA, by delegation): Pseudomonas species, Staphylococcus ‘‘Search’’ box and follow the prompts (1) Establish and maintain a list of aureus, Streptococcus agalactiae, S. and/or go to the Division of Dockets ‘‘qualifying pathogens’’ that have ‘‘the pneumoniae, S. pyogenes, and Vibrio Management, 5630 Fishers Lane, Rm. potential to pose a serious threat to cholerae. The preamble to the proposed 1061, Rockville, MD 20852. public health’’ and (2) make public the rule describes the factors FDA FOR FURTHER INFORMATION CONTACT: methodology for developing the list (see considered and the methodology FDA Kristiana Brugger, Center for Drug section 505E(f) of the Federal Food, used to develop this list of qualifying Evaluation and Research, Food and Drug, and Cosmetic Act (the FD&C Act), pathogens. After analyzing comments to Drug Administration, 10903 New as amended by FDASIA) (21 U.S.C. the proposed rule, FDA has decided to Hampshire Ave., Bldg. 51, Rm. 6262, 355f(f)). In establishing and maintaining retain the previously proposed Silver Spring, MD 20993–0002, 301– the list of ‘‘qualifying pathogens,’’ FDA methodology for developing the list of 796–3601. must consider the following factors: The qualifying pathogens and will include SUPPLEMENTARY INFORMATION: impact on the public health due to drug- the pathogens identified in the proposed resistant organisms in humans; the rate rule on the list of qualifying pathogens. Table of Contents of growth of drug-resistant organisms in FDA also has applied the methodology Executive Summary humans; the increase in resistance rates set forth in the proposed rule to I. Background: FDASIA Requirements in humans; and the morbidity and additional pathogens suggested by II. Proposed Rule and Final Rule mortality in humans (see section comments to the proposed rule. Based A. Finalization of Factors Considered and 505E(f)(2)(B)(i) of the FD&C Act). FDA on these analyses, FDA also will add Methodology Used for Establishing a List also is required to consult with Coccidioides species, Cryptococcus of Qualifying Pathogens B. Finalization of Statutory Interpretation infectious disease and antibiotic species, and Helicobacter pylori to the C. Finalization of Proposed Pathogens for resistance experts, including those in list of qualifying pathogens. The table Inclusion on the List the medical and clinical research below describes the pathogen lists for D. Summary of Additional Pathogens on communities, along with the Centers for the proposed and final rule for the List of Qualifying Pathogens Disease Control and Prevention (CDC) comparison:

Proposed rule Final rule

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.

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Proposed rule Final rule

Streptococcus pneumoniae ...... Streptococcus pneumoniae. Streptococcus pyogenes ...... Streptococcus pyogenes. Vibrio cholerae ...... Vibrio cholerae. Coccidioides species. Cryptococcus species. Helicobacter pylori.

Costs and Benefits vancomycin-resistant [E]nterococcus; with experts in infectious disease and The Agency has determined that this (B) multi-drug resistant gram[-]negative antibiotic resistance at CDC and NIH rule is not a significant regulatory action bacteria, including Acinetobacter, during the development of both the as defined by Executive Order 12866. Klebsiella, Pseudomonas, and E. coli proposed and the final rule. species; (C) multi-drug resistant II. Proposed Rule and Final Rule I. Background: FDASIA Requirements tuberculosis; and (D) Clostridium Title VIII of FDASIA (Pub. L. 112– difficile’’ (section 505E(f)(1) of the FD&C On June 12, 2013, FDA published the 144), entitled Generating Antibiotic Act). FDA is required under the law to proposed rule, ‘‘Establishing a List of Incentives Now, amended the FD&C Act consider four factors in establishing and Qualifying Pathogens Under the Food to add section 505E, among other things. maintaining the list of qualifying and Drug Administration Safety and This new section of the FD&C Act is pathogens: Innovation Act’’ (78 FR 35155). In the intended to encourage development of • The impact on the public health proposed rule, the Agency set forth the treatments for serious or life-threatening due to drug-resistant organisms in factors it proposed to consider and the infections caused by bacteria or fungi. humans; methodology it proposed to use in For certain drugs that are designated as • the rate of growth of drug-resistant establishing the list of qualifying ‘‘qualified infectious disease products’’ organisms in humans; pathogens, as well as its interpretation (QIDPs) under new section 505E(d) of • the increase in resistance rates in of statutory language. The Agency the FD&C Act, new section 505E(a) humans; and concluded with extensive analyses of provides an additional 5 years of • the morbidity and mortality in the 18 pathogens proposed for inclusion exclusivity to be added to the humans (section 505E(f)(2)(B)(i) of the on the list of ‘‘qualifying pathogens.’’ exclusivity periods provided by sections FD&C Act). FDA’s decisions regarding the proposed 505(c)(3)(E)(ii) to (c)(3)(E)(iv) (21 U.S.C. Further, in determining which rule are described in sections III.A, III.B, 355(c)(3)(E)(ii) to (c)(3)(E)(iv)), pathogens should be listed, GAIN III.C, and IV. requires FDA to consult with infectious 505(j)(5)(F)(ii) to (j)(5)(F)(iv) (21 U.S.C. A. Finalization of Factors Considered disease and antibiotic resistance 355(j)(5)(F)(ii) to (j)(5)(F)(iv)), and 527 and Methodology Used for Establishing experts, including those in the medical (21 U.S.C. 360cc) of the FD&C Act. In a List of Qualifying Pathogens addition, an application for a drug and clinical research communities, designated as a QIDP is eligible for along with the CDC, in determining After reviewing the comments priority review and designation as a fast which pathogens should be included on submitted to the docket (see section IV), track product (sections 524A and the list of ‘‘qualifying pathogens’’ the Agency has decided to finalize the 506(a)(1) of the FD&C Act (21 U.S.C. (section 505E(f)(2)(B)(ii) of the FD&C proposed factors for consideration and 356n–I and 556(a)(1)), respectively). Act). To fulfill this statutory obligation, methodology for establishing the list of The term ‘‘qualified infectious disease on December 18, 2012, FDA convened a qualifying pathogens, and has reiterated product’’ or ‘‘QIDP’’ refers to an public hearing, at which the Agency them below for convenience. antibacterial or antifungal human drug solicited input regarding the following As stated previously, section that is intended to treat serious or life- topics: (1) How FDA should interpret 505E(f)(2)(B)(i) of the FD&C Act requires threatening infections (section 505E(g) and apply the four factors FDASIA FDA to consider the following factors in of the FD&C Act). The term includes requires FDA to ‘‘consider’’ in establishing and maintaining the list of treatments for diseases caused by qualifying pathogens: establishing and maintaining the list of • antibacterial- or antifungal-resistant qualifying pathogens; (2) whether there The impact on the public health pathogens (including new or emerging are any other factors FDA should due to drug-resistant organisms in pathogens), or diseases caused by humans; consider when establishing and • ‘‘qualifying pathogens.’’ maintaining the list of qualifying the rate of growth of drug-resistant The GAIN title of FDASIA requires pathogens; and (3) which specific organisms in humans; • the increase in resistance rates in that the Secretary of the Department of pathogens FDA should list as qualifying Health and Human Services (and thus humans; and pathogens (77 FR 68789, November 16, • the morbidity and mortality in FDA, by delegation) establish and 2012). The transcript of this hearing, as maintain a list of such ‘‘qualifying humans. well as comments submitted to the The Agency recognizes it is important pathogens,’’ and make public the hearing docket, are available at http:// methodology for the developing the list. to take a long-term view of the drug www.regulations.gov, docket number resistance problem. For some pathogens, According to the statute, ‘‘the term FDA–2012–N–1037. FDA considered ‘qualifying pathogen’ means a pathogen particularly those for which increased carefully the input presented at this resistance is newly emerging, FDA identified and listed by the Secretary hearing, as well as the comments . . . that has the potential to pose a recognizes that there may be gaps in the submitted to the hearing docket, in available data or evidence pertaining to serious threat to public health, such as[:] creating the list of qualifying (A) resistant gram positive pathogens, 1 pathogens. In addition, FDA consulted rulemaking process. Accordingly, the documents including methicillin-resistant from the public hearing phase of Docket No. FDA– Staphylococcus aureus, vancomycin- 1 The public hearing and this rule share docket 2012–N–1037 are included in the docket for this resistant Staphylococcus aureus, and numbers because they are part of the same rulemaking.

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one or more of the four factors described 2. The Rate of Growth of Drug-Resistant Setting quantitative thresholds for in section 505E(f)(2)(B)(i) of the FD&C Organisms in Humans and the Increase inclusion on the list based on any Act. Thus, consistent with GAIN’s in Resistance Rates in Humans prespecified endpoint would be purpose of encouraging the inconsistent with FDA’s approach of development of treatments for serious or The second and third factors that FDA considering a totality of the evidence must consider overlap substantially life-threatening infections caused by related to a given pathogen, as well as with one another and, for the most part, bacteria or fungi, the Agency intends to infeasible given the variety of pathogens are assessed using the same trends and consider the totality of available under consideration. Instead, in information. Therefore, the Agency will considering whether this factor weighs evidence for a particular pathogen to analyze these factors together. determine whether that pathogen in favor of including a given pathogen, the Agency will look for evidence of a should be included on the list of In considering these factors with meaningful increase in morbidity and qualifying pathogens. Therefore, if, after respect to a pathogen, FDA will assess such evidence as: (1) The proportion of mortality rates when infection with a considering the four factors identified in patients whose illness is caused by a drug-resistant strain of a pathogen is section 505E(f)(2)(B)(i) of the FD&C Act, drug-resistant isolate of a pathogen compared to infection with a more drug- FDA determines that the totality of (compared with those whose illness is susceptible strain of that pathogen. The available evidence demonstrates that a caused by more widely drug-susceptible Agency may also assess other evidence, pathogen ‘‘has the potential to pose a pathogens); (2) the number of resistant such as overall morbidity and mortality serious threat to public health,’’ the clinical isolates of a particular pathogen rates for infection with either resistant Agency will identify the pathogen in (e.g., the known incidence or prevalence or susceptible strains of a pathogen to question as a ‘‘qualifying pathogen.’’ of infection with a particular resistant determine whether that pathogen has More detailed explanations of each pathogen); and (3) the ease and the potential to pose a serious threat to factor identified in section frequency with which a proposed public health, in particular if drug- 505E(f)(2)(B)(i) of the FD&C Act are set pathogen can transfer and receive resistant isolates of the pathogen were to forth in the paragraphs that follow. resistance-conferring elements (e.g., become more prevalent in the future. plasmids encoding relevant enzymes, 1. The Impact on the Public Health Due B. Finalization of Statutory etc.). Given the temporal limitations on to Drug-Resistant Organisms in Humans Interpretation infectious disease data, FDA also will As FDA explained in the proposed consider evidence that a given pathogen This first factor that section rule (78 FR 35155 at 35156) and affirms currently has a strong potential for a 505E(f)(2)(B)(i) of the FD&C Act requires in this final rule, the statutory standard meaningful increase in resistance rates. FDA to consider is also the broadest. for inclusion on FDA’s list of qualifying Evidence of the potential for increased Many factors associated with infectious pathogens is different from the statutory resistance may include, for example, diseases affect public health directly, standard for QIDP designation. QIDP projected (rather than observed) rates of such as a pathogen’s ease of designation, by definition, requires that drug resistance for a given pathogen, transmission, the length and severity of the drug in question be an ‘‘antibacterial and current and projected geographic the illness it causes, the risk of mortality or antifungal drug for human use distribution of a drug-resistant associated with its infection, and the intended to treat serious or life- pathogen. Furthermore, in threatening infections’’ (section 505E(g) number of approved products available acknowledgement of the growing to treat illnesses it causes. Additionally, of the FD&C Act). ‘‘Qualifying problem of drug resistance, FDA also pathogens’’ are defined according to a although the Agency did not consider may assess other available evidence financial costs in its analyses for this different statutory standard; the term demonstrating either existing or means ‘‘a pathogen identified and listed proposed list of qualifying pathogens, potential increases in drug resistance we note that the published literature by the Secretary . . . that has the rates. potential to pose a serious threat to supports the conclusion that public health’’ (section 505E(f) of the antimicrobial-resistant infections are 3. The Morbidity and Mortality in Humans FD&C Act) (emphasis added). That is, a associated with higher healthcare costs drug intended to treat a serious or life- (see, e.g., Refs. 1 and 2; Ref. 3 at pp. 807, Patients infected with drug-resistant threatening bacterial or fungal infection 810, 812). pathogens are inherently more caused by a pathogen that is not In considering a proposed pathogen’s challenging to treat than those infected included on the list of ‘‘qualifying impact on the public health due to drug- with drug-susceptible pathogens. For pathogens’’ may be eligible for resistant organisms in humans, FDA example, in some cases, a patient designation as a QIDP, while a drug that will assess such evidence as: (1) The infected with a drug-resistant pathogen is intended to treat an infection caused transmissibility of the pathogen and (2) may have a delay in the initiation of by a pathogen on the list may not the availability of effective therapies for effective drug therapy that can result in always be eligible for QIDP designation. treatment of infections caused by the poor outcomes for such patients. After reviewing the comments to the pathogen, including the feasibility of Consequently, in determining whether a docket on this point (see section IV.A), pathogen should be included on the list, treatment administration and associated FDA’s understanding of these statutory FDA will consider the rates of mortality adverse effects. However, FDA also may standards remains unchanged. and morbidity (the latter as measured To alleviate confusion regarding this assess other public health-related by, e.g., duration of illness, severity of issue, FDA also clarifies that vaccine evidence, including evidence that may illness, and risk and extent of sequelae applications are ineligible for QIDP indicate a highly prevalent pathogen’s from infections caused by the pathogen, designation under the GAIN title of ‘‘potential to pose a serious threat to and risk associated with existing FDASIA. Vaccines are biological public health’’ due to the development treatments for such infections) products whose applications for of drug resistance in that pathogen, even associated with infection by that approval are submitted under section if most documented infections are pathogen generally—and particularly by 351 of the Public Health Service Act currently drug susceptible. drug-resistant strains of that pathogen. (the PHS Act) (42 U.S.C. 262). QIDPs,

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however, must be human drugs whose submitted to the docket via http:// term ‘‘serious’’ is further defined in a applications are submitted pursuant to www.regulations.gov during the 60-day 2006 FDA guidance for industry, ‘‘Fast section 505(b) of the FD&C Act. Thus, comment period. FDA has summarized Track Drug Development Program— under the law, vaccines are ineligible and responded to these comments Designation, Development, and for QIDP designation. below. To make it easier to identify the Application Review (which will be As stated in the proposed rule (78 FR comments and FDA’s responses, the superseded by the draft guidance for 35156) and affirmed in this final rule, word ‘‘Comment,’’ in parentheses, industry, ‘‘Expedited Programs for FDA intends the list of qualifying appears before the comment’s Serious Conditions—Drugs and pathogens to reflect the pathogens that, description, and the word ‘‘Response,’’ Biologics,’’ when finalized) and in the as determined by the Agency, after in parentheses, appears before the preamble to a final rule pertaining to consulting with other experts and Agency’s response. We have numbered accelerated approval (57 FR 58942, considering the factors set forth in each comment to help distinguish December 11, 1992). The term ‘‘life- FDASIA (see section 505E(f)(2)(B)(i) of between different comments. Similar threatening’’ is defined in 21 CFR the FD&C Act), have the ‘‘potential to comments are grouped together under 312.81(a). The provisions related to pose a serious threat to public health’’ the same number, and, in some cases, QIDPs in GAIN similarly seek to (section 505E(f)(1) of the FD&C Act). different subjects discussed in the same incentivize the development of drugs to FDA does not intend for this list to be comment are separated and designated meet an unmet medical need and, used for other purposes, such as the as distinct comments for purposes of indeed, QIDP-designated applications following: (1) Allocation of research FDA’s responses. The number assigned are eligible for both priority review and funding for bacterial or fungal to each comment or comment topic is fast-track designation (see section 524A pathogens; (2) setting of priorities in purely for organizational purposes and of the FD&C Act and section 506(b)(1) research in a particular area pertaining does not signify the comment’s value or of the FD&C Act, as amended). The to bacterial or fungal pathogens; or (3) importance or the order in which Agency intends, therefore, to interpret direction of epidemiological resources comments were received. serious or life-threatening in a similar manner with respect to GAIN as it has to a particular area of research on A. Statutory Interpretation and in the context of these expedited bacterial or fungal pathogens. Proposed Factors for Consideration Furthermore, as section 505E of the programs. While guidances and even FD&C Act makes clear, the list of (Comment 1) One comment criticized regulations may change, the Agency qualifying pathogens includes only FDA’s interpretation of the statute that may not apply different definitional bacteria or fungi that have the potential not all treatments for infections caused standards to similarly situated to pose a serious threat to public health. by qualifying pathogens will be eligible applicants or applications. Thus, Viral pathogens or parasites, therefore, for QIDP designation, and that ‘‘the concerns over lack of a statutory were not considered for inclusion and development of a treatment for an definition of ‘‘serious or life- are not included as part of this list. infection caused by a pathogen included threatening’’ are an insufficient basis for on the list of ‘qualifying pathogens’ is FDA to change its interpretation of the C. Finalization of Proposed Pathogens neither a necessary nor a sufficient statute. for Inclusion on the List condition for obtaining QIDP Further, it may be true that many of FDA’s proposed rule concluded with designation’’ (78 FR 35515 at 35167). the qualifying pathogens listed by FDA an analysis of the 18 pathogens the The comment first expressed concern may cause serious or life-threatening Agency proposed to identify as that, because the terms ‘‘serious’’ and infections for which treatments might be qualifying pathogens. After reviewing ‘‘life-threatening’’ are not separately eligible for QIDP designation. However, the comments to the docket (see section defined by statute, their meanings could the comment’s assertions cannot change IV.C), FDA is finalizing its analyses of change in the future. The comment the language that is in the statute, which the 18 proposed pathogens as written in contrasted this alleged uncertainty with provides different standards for QIDPs the proposed rule (see 78 FR 35155 at the statute’s detailed definition and and qualifying pathogens. Qualifying 35158 through 35166), which are identification process for ‘‘qualifying pathogens are ‘‘pathogen[s] . . . that incorporated by reference herein, and is pathogens,’’ asserting that the collective ha[ve] the potential to pose a serious identifying all 18 proposed pathogens as term ‘‘serious or life-threatening threat to public health,’’ whereas QIDPs ‘‘qualifying pathogens’’ in § 317.2 (21 infections’’ includes infections caused are certain human ‘‘drugs . . . intended CFR 317.2). by qualifying pathogens. Thus, the to treat serious or life-threatening comment asserted, Congress intended infections’’ (emphasis added). Most D. Inclusion of Additional Pathogens on the qualifying pathogen list to provide importantly, many pathogens with the the List of Qualifying Pathogens ‘‘some certainty and transparency’’ potential to seriously threaten public In response to comments, FDA has regarding which products may be health may cause varying levels of added three additional pathogens eligible for QIDP designation. morbidity and mortality in a given (Coccidiodes species, Cryptococcus (Response) FDA agrees with the individual depending on the site of species, and Helicobacter pylori) to the comment that the term ‘‘serious or life- infection, the person infected, the level list of qualifying pathogens (see section threatening’’ is not explicitly defined in of antimicrobial resistance present in IV.D). the statute. Nevertheless, the Agency the infecting pathogen, and other has been interpreting and applying factors. III. Comments to the Proposed Rule and these terms in the context of other (Comment 2) One comment stated FDA’s Responses programs under the Food, Drug, and that only ‘‘factors that can be addressed After the publication of the proposed Cosmetic Act intended to expedite the through new drug development’’ should rule on June 12, 2013, 18 comments development of drugs and biologics to be used as criteria for including from pharmaceutical companies, address unmet medical needs for several pathogens on the list. The comment lawmakers and governmental years. ‘‘Serious or life-threatening’’ is does not specify which factors these are, organizations, infectious disease used in section 506 of the FD&C Act, in but the comment’s concerns stem from specialists, public interest groups, and the context of expedited programs, an assertion that new drugs contribute other members of the public were including fast track designation. The to antibiotic resistance due to their off-

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label use, use in patients who do not interpretation and application of the that some pathogens already have need the drugs, or use in patients whose GAIN provision is consistent with the approved antimicrobial therapies underlying infection is unidentified. intent of the statute, which is to use available is not dispositive of whether a (Response) FDA agrees that good exclusivity and other incentives to spur particular pathogen meets the several antibiotic stewardship is critical in development of the most urgently statutory criteria FDA must assess. reducing antibiotic resistance rates. needed treatments, i.e., those treating Furthermore, as a general matter, However, the mandatory statutory serious or life-threatening infections. subsequent new drug development considerations specified in section The Agency will make no changes to the following the first drug approval could 505E(f)(2)(B)(i) of the FD&C Act are not proposed rule as a result. address important public health issues limited to factors that can be addressed B. Miscellaneous Comments in patients with unmet need based on only through new drug development. one or more of the following FDA will make no changes to the rule (Comment 6) One comment pointed considerations: based on this comment. out that FDA did not provide a basis for • Alternative drugs may be needed to (Comment 3) One comment asserted excluding the pathogens not listed on treat special populations (e.g., renal that rarely used, non-‘‘standard of care’’ the qualifying pathogen list. The impairment) or patients for whom drug drugs should be considered in assessing comment also stated that FDA ‘‘fails to interactions are a concern. the therapies available to treat a given mention’’ how the pathogens on the • Some patients may experience an pathogen. FDA understands this qualifying pathogen list and the adverse drug effect and be unable to comment to mean that FDA should pathogens not on the qualifying complete the course of therapy. include, in its assessment of available pathogen list may relate to other • Some patients may have an allergy therapies for infections by particular pathogen lists (e.g., those pertaining to to certain drugs and need alternatives. pathogens, drugs that may treat those bioterrorism). • In some circumstances, drug infections but nevertheless are not (Response) FDA reiterates that the production issues may arise that affect considered ‘‘standard of care’’ therapies. focus of this rulemaking is to fulfill supply for a drug. (Response) FDA considers the number statutory requirements to: (1) Establish • New information may become of approved products available to treat and maintain a list of ‘‘qualifying evident postmarketing that has an infectious diseases caused by a pathogens’’ that have ‘‘the potential to impact on risk/benefit for some patients. pathogen when assessing the impact on pose a serious threat to public health’’ FDA will make no changes to the rule the public health due to drug-resistant and (2) make public the methodology in response to this comment. bacterial or fungal pathogens in for developing the list (see section humans. For the purposes of this list of 505E(f) of the FD&C Act). Other (Comment 8) One comment stated qualifying pathogens, at this time, FDA pathogen lists, including CDC’s list of that ‘‘when new therapies are created will not consider unapproved products bioterrorism agents/diseases, have and used to treat qualifying pathogens, or off-label use of products approved for different purposes and standards. FDA these should be removed from the list.’’ another indication. FDA will make no will not, nor is it required to, make (Response) FDA interprets this changes to the rule based on this comparisons between and among the comment to mean that, as soon as FDA comment. qualifying pathogen list (or the approves a new drug to treat an (Comment 4) One comment agreed pathogens not appearing on the list) and infection caused by one of the that incentives authorized by GAIN for ‘‘additional lists’’ of pathogens. qualifying pathogens, that pathogen the creation of new antibacterial and In responding to comments received should be removed from the list. FDA antifungal drugs should focus on drugs on the proposed rule, however, the responds by noting that the availability that treat serious or life-threatening Agency will explain why it either of effective therapies for treating infections. accepted or rejected comment requests infections with a given pathogen is (Response) FDA responds by to add particular pathogens. merely one consideration among many confirming that QIDP designation, For the foregoing reasons, FDA will that FDA considers in determining which is a prerequisite to the incentives make no changes to the contents of the whether a pathogen should be authorized by GAIN, may be made for proposed rule based on this comment. designated a ‘‘qualifying pathogen.’’ ‘‘antibacterial or antifungal drug[s] for (Comment 7) One comment asserted While important to FDA’s assessment, human use intended to treat serious or that pathogens with approved ‘‘reserve the availability of effective therapies life-threatening infections’’ (section antibiotics’’ should ‘‘not automatically does not determine whether a qualifying 505E(g) of the FD&C Act). FDA will count as qualifying pathogens.’’ FDA pathogen should remain on the list. make no changes to the rule in response understands this comment to suggest FDA will reassess the list of qualifying to this comment. that pathogens whose infections may be pathogens ‘‘every 5 years, or more often (Comment 5) Another comment found treated with ‘‘reserve antibiotics’’ (i.e., as needed,’’ according to the FDA’s proposed methodology and antibacterial drugs that are placed ‘‘in requirements of the statute (see rationale for inclusion of qualifying reserve’’ for those patients who have 505E(f)(2)(C) of the FD&C Act), and pathogens to be favorable, and agreed very limited options for treatment of declines to establish a single-standard with the Agency that the statute their bacterial infections, but are not trigger for removing pathogens from the provides different definitions for widely used to treat patients who have list. ‘‘qualifying pathogens’’ and QIDPs. The many antibacterial treatment options (Comment 9) One comment asserted comment also asserted that having QIDP available to treat their bacterial that regardless of QIDP designation designation depend on intended infections) should not be on the list of status, ‘‘drugs intended to treat indication (i.e., treatment of serious or qualifying pathogens. qualifying pathogens’’ (which we life-threatening infections) is what (Response) In making its ‘‘qualifying assume to mean drugs intended to treat reflects statutory intent, rather than pathogen’’ determinations, FDA does infections caused by qualifying having QIDP status depend on targeting consider the therapies—including pathogens) should be required to prove specific pathogens. ‘‘reserve antibiotics’’—that are available reduction in mortality or morbidity. The (Response) FDA agrees with the and indicated to treat infections with a comment further asserted that clinical points made in this comment. FDA’s given pathogen. Nevertheless, the fact trials in anti-infective drugs for

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qualifying pathogens should have reference to the surveillance project. support of identifying a pathogen for mortality as the primary endpoint. FDA, thus, declines to incorporate the inclusion on the list of qualifying (Response) These concerns apply to NARMS database in its entirety as part pathogens—particularly M. approval standards for particular drugs, of its basis for designating species in the tuberculosis—because these ‘‘relate to which are required to be safe and Enterobacteriaceae family as qualifying clinical practice.’’ effective within the meaning of section pathogens. (Response) FDA considers antibiotic 505 of the FD&C Act. These concerns do (Comment 11) Two comments made stewardship and attention to patient not apply to the subject matter of the suggestions in response to FDA’s adherence to therapy as important proposed rule, which is the method for inclusion of Clostridium difficile on the factors in determining transmissibility. identifying qualifying pathogens and the list of qualifying pathogens. One FDA explained in the preamble to the resulting list. Thus, FDA considers them advocated improvements in hospital proposed rule (see 78 FR 35155 at irrelevant to the present rulemaking and hygiene (e.g., hand washing) and 35157) that a pathogen’s ease of will make no changes to the rule as a staffing to reduce the spread of C. transmission is an important result. difficile. The other advocated an consideration in evaluating ‘‘the impact unidentified procedure for treatment of on the public health due to drug- C. Comments on Previously Proposed C. difficile and expressed concerns that resistant organisms in humans’’ (section Pathogens the proposed rule would inhibit the use 505E(f)(2)(B)(i) of the FD&C Act). This (Comment 10) One comment of this treatment. factor is one of the four statutory factors suggested edits and new literature (Response) FDA responds by thanking identified in section 505E(f)(2)(B)(i) of references to a paragraph in the the commenters for their input. The the FD&C Act. Therefore, FDA will preamble to the proposed rule proposed rule, however, describes the make no changes to the rule in response pertaining to the analysis of Agency’s methodology for identifying to this comment. Enterobacteriaceae. These references qualifying pathogens and developing are: the resulting list. The propose rule does D. Suggestions for Additional Qualifying • A 2013 article by M. Sjo¨lund not address matters on hospital hygiene Pathogens Karlsson et al., ‘‘Outbreak of Infections standards and non-pharmacologic (Comment 15) Bacteroides, Caused by Shigella sonnei with procedures. Therefore, FDA will make Fusobacterium, and Prevotella Species no changes to the rule in response to Reduced Susceptibility to Azithromycin One comment suggested adding in the United States,’’ in Antimicrobial these comments. (Comment 12) One comment Bacteroides, Fusobacterium, and Agents and Chemotherapy (Ref. 4); Prevotella species to the list of • a 2010 article by M. R. Wong et al., suggested adding Mycobacterium abscessus to the list of qualifying qualifying pathogens. ‘‘Antimicrobial Resistance Trends of (Response) For the reasons that Shigella Serotypes in New York City, pathogens. (Response) M. abscessus is a species follow, FDA will not add these species 2006–2009,’’ in Microbial Drug to the list of qualifying pathogens. A Resistance (Ref. 5); and of non-tuberculous mycobacteria, a • category of pathogens already on the discussion of these three bacterial a 2007 article by S. D. Alcaine et al., pathogens is provided together for the ‘‘Antimicrobial Resistance in proposed list of qualifying pathogens in FDA’s June 2013 proposed rule. As following reasons: (1) These bacterial Nontyphoidal Salmonella,’’ in Journal pathogens are representative of a group of Food Protection (Ref. 6). described in the proposed rule, FDA believes that non-tuberculous of medically-important gram-negative The comment also made reference to mycobacteria (including M. abscessus) anaerobic rods (see Ref. 7 at pp. 3111– CDC’s National Antimicrobial meet the statutory standards for 3120) and (2) common taxonomic Resistance Monitoring System for identification as ‘‘qualifying characteristics (Ref. 8 at pp. 179–194). Enteric Bacteria (NARMS), but did not pathogens,’’ and this final rule adds These bacterial pathogens are include specific data from NARMS in non-tuberculous mycobacteria commonly found in the mucous the comment. (including M. abscessus) to the list of membranes (Ref. 9), particularly in the (Response) FDA appreciates the qualifying pathogens (see 78 FR 35155 mouth (Bacteroides, Fusobacterium, and comment and suggested literature at 35163). Prevotella), intestines (Bacteroides), and references in support of FDA’s decision (Comment 13) One comment female urogenital tract (Bacteroides, to add Enterobacteriaceae to the list of suggested adding Proteus mirabilis to Fusobacterium, and Prevotella) (Ref. 7 at qualifying pathogens. We agree that the the list of qualifying pathogens. p. 3112). Each of these bacterial three suggested literature references (Response) P. mirabilis is a species in pathogens can cause the same infectious provide additional support for the the Enterobacteriaceae family, a diseases and are often implicated in inclusion of Enterobacteriaceae on the category of pathogens already on the odontogenic infections (particularly for list of qualifying pathogens. proposed list of qualifying pathogens in those with poor dental hygiene or Specifically, FDA agrees that the FDA’s June 2013 proposed rule (see 78 periodontal disease, as these bacteria Karlsson and Wong references support FR 35155 at 35161). As described in the populate dental plaque), peritonsilar recognition of an increase in Shigella proposed rule, FDA believes that infections, and polymicrobial resistance in the United States, and that Enterobacteriaceae (including P. abdominal infections, among others. the Alcaine reference supports mirabilis) meet the statutory standards Particularly when introduced into recognition of an increase in Salmonella for identification as ‘‘qualifying compromised tissue (e.g., via a wound resistance. FDA thus incorporates these pathogens,’’ and this final rule adds or break in mucous membranes), these references as part of its basis for Enterobacteriaceae (including P. pathogens can cause abscesses that may designating species in the mirabilis) to the list of qualifying require drainage or debridement in Enterobacteriaceae family as qualifying pathogens. addition to antimicrobial therapy (Ref. 7 pathogens. The comment did not (Comment 14) One comment stated at p. 3117). Infection prevention is often provide specific NARMS data or that ‘‘poor adherence to therapy, the focus for these pathogens—either via specific references presenting relevant overuse of currently available therapy, ‘‘avoiding conditions that reduce the NARMS data, but rather made general and empiric use’’ should not be used in redox potential of the tissues’’ or

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

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or in outbreaks associated with not include these pathogens on the list weeks after infection (id.), with fever, particular prepared foods (Refs. 30 and of qualifying pathogens. cough, headache, rash, muscle aches, 31). C. botulinum, which also causes and joint pain as typical symptoms (Ref. (Comment 18) Coccidioides Species food poisoning, is relatively rare, though 47). Some patients develop severe or much more severe—it is likely fatal if Six comments suggested adding chronic pulmonary disease, and less untreated (Refs. 29 and 32), whereas C. Coccidioides immitis to the list of than one percent of patients experience perfringens infections are often self- qualifying pathogens. Six comments extrapulmonary infection (Ref. 44). limited and require simply oral suggested adding C. posadasii to the list Chronic pulmonary or disseminated rehydration and supportive care at of qualifying pathogens. One comment disease can occur months or years after home. Other Clostridium-related suggested adding Coccidioides species the initial infection (Ref. 48). For diseases, such as tetanus, bloodstream (generally) to the list of qualifying extrapulmonary disease (also referred to infections, and gas gangrene, are life- pathogens. According to the comments, as disseminated disease), estimates threatening and require immediate Coccidioides species present a serious range as high as 30 to 50 percent of treatment. and growing public health concern, ‘‘infections for heavily Some infections caused by particularly in the southwestern United immunosuppressed patients, such as Clostridium species are very rare. For States. those with AIDS, lymphoma, receipt of example, less than 200 cases of botulism (Response) FDA agrees with the a solid-organ transplant, or receipt of were reported annually to the CDC, and comments and will include rheumatologic therapies, such as high- less than 50 cases of tetanus were Coccidioides species on the list of dose corticosteroids or anti-tumor- reported annually to the CDC, in each of qualifying pathogens. necrosis-factor (TNF) medications’’ (Ref. the past 5 years (Ref. 19). While CDC Coccidioides species are pathogenic 45). does not require reporting of other fungi that are endemic to certain regions In a 2007 to 2008 population-based clostridial infections, antimicrobial of southwestern United States (i.e., study in Arizona, over 40 percent of susceptibility studies ‘‘have not changed certain areas of California, Arizona, New patients with Valley Fever required significantly over the past 10 years’’ Mexico, Texas, Utah, and Nevada) and hospitalization, and symptoms lasted a (Refs. 19 and 33). other regions of the Western median of 120 days (Ref. 49). In contrast with C. difficile, C. Hemisphere (Ref. 7 at pp. 3333–3334). Furthermore, between 1998 to 2008, the perfringens is not transmitted from The pathogen is responsible for causing annual number of coccidioidomycosis- human to human (Refs. 34, 35, and 36),2 coccidioidomycosis, also known as related deaths was about 163, with the and FDA is unaware of significant Valley Fever, with C. immitis and C. highest risk of death associated with increases in incidence or prevalence of posadasii as the causative agents. men, persons aged 65 or greater, infections with C. perfringens or other Coccidioides species is acquired via Hispanics, Native Americans, and non-difficile Clostridium pathogens. respiratory inhalation of spores. residents of Arizona or California (Ref. There have been reports of limited Infections caused by Coccidioides 50). antimicrobial resistance in non-difficile species have increased in the past Resistance mechanisms for Clostridium species (Refs. 15, 37, 38, 39, decade. It is estimated that up to 60 Coccidioides species have not been and 40), and studies have found that percent of people living in the endemic identified (Ref. 51). There is evidence of resistance genes may (or may areas of southwestern United States at least one report of resistance to the potentially) be transferred between C. have been exposed to the fungus (Ref. azole class of antifungal agents (id.). In perfringens species (Refs. 41 and 42). 43). According to a March 2013 report, a retrospective analysis of patients However, many reports of resistant the CDC found that more than 20,000 presenting with coccidioidal meningitis isolates do not offer a correlation either cases of Valley Fever are reported at Los Angeles, CA, hospitals, with resistant infections seen in a annually in the United States, but many researchers found that a significant clinical setting (Ref. 40) or with cases go unreported (Ref. 44). Some proportion of patients—40 percent— suggestions of worse outcomes in researchers estimate that the fungus died, despite treatment with fluconazole patients with resistant infections (Ref. infects more than 150,000 people each monotherapy or a combination of 39) (particularly for C. perfringens, year (Ref. 45). The CDC observed that fluconazole and intravenous whose infections rarely require the incidence of reported Valley Fever amphotericin B (Ref. 52). Therefore, it is treatment, and for which antibacterial increased substantially between 1998 plausible that resistance has increased therapy is not recommended). Many and 2011, from 5.3 per 100,000 people given the increase in the rate of growth therapies still remain available and in the endemic area in 1998 to 42.6 per of Valley Fever. effective for treating the more severe 100,000 in 2011 (Ref. 44). Although For the reasons stated previously, non-difficile Clostridium infections, some of the increase can be attributed to FDA believes that Coccidioides species and, limited in vitro resistance reports changes in the case definition based on has the potential to pose a serious threat notwithstanding, FDA has not seen serologic evidence of infection (Ref. 46), to public health, and FDA is including evidence that there is a strong potential the incidence of infections caused by Coccidioides species on the list of for a meaningful increase in resistance the fungi continued to increase even qualifying pathogens. rates in these pathogens. after taking into account the change in For the foregoing reasons—and the case definition. Notably, the CDC (Comment 19) Cryptococcus Species particularly when contrasted with the found that the incidence of reported Two comments suggested adding considerations described in the Valley Fever increased in Arizona and Cryptococcus species to the list of proposed rule pertaining to C. difficile— California from 2009 to 2010 and from qualifying pathogens due to, among FDA does not believe there are 2010 to 2011 (Ref. 44). other things, C.gattii infections in North sufficient data available to find that Of the infections, one-half to two- America and concerns about worldwide non-difficile Clostridium species meet thirds are subclinical (Ref. 45). morbidity and mortality from the statutory standard for listing as Symptomatic patients typically cryptococcal infections generally. qualifying pathogens. Thus, FDA will experience a self-limited acute or (Response) For the reasons that subacute community-acquired follow, FDA will include these species 2 See 78 FR 35155 (June 12, 2013). pneumonia that becomes evident 1 to 3 as qualifying pathogens.

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

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

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

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laboratory and are less frequent than regulation is necessary, to select provide for a defined period during invasive fungi caused by Aspergillus regulatory approaches that maximize which an approved drug is protected species. According to one report, net benefits (including potential from submission or approval of certain ‘‘[i]ncidence figures are difficult to economic, environmental, public health potential competitor applications. By collect as few national studies have and safety, and other advantages; securing additional guaranteed periods been undertaken, but for the United distributive impacts; and equity). The of exclusive marketing, during which a States, the annual incidence of Agency believes that this final rule is drug sponsor would be expected to zygomycosis has been estimated as 1.7 not a significant regulatory action as benefit from associated higher profits, infections per million people’’ (Refs. 92 defined by Executive Order 12866. drugs that might not otherwise be and 94). According to a 2002 report, the The Regulatory Flexibility Act developed due to unfavorable economic incidence of zygomycosis may be requires Agencies to analyze regulatory factors may become commercially increasing; researchers found an options that would minimize any attractive to drug developers. increase in the number of hematopoietic significant impact of a rule on small In recognition of the need to stimulate stem cell transplant recipients at the entities. Because the final rule would investments in new antibacterial or Fred Hutchinson Cancer Center in not impose direct costs on any entity, antifungal drugs, Congress enacted the Seattle, WA, infected with Zygomycetes regardless of size, but rather would GAIN title of FDASIA to create an from 1985–1989 to 1995–1999 (Ref. 95). clarify certain types of pathogens for incentive system. The primary Another study found that invasive which the development of approved framework for encouraging antibacterial fungal infections due to Zygomycetes treatments might result in the awarding or antifungal drug development became were associated with higher mortality of QIDP designation and exclusivity to effective on July 9, 2012, through a self- rates in adult hematopoietic stem cell sponsoring firms, FDA certifies that the implementing provision that authorizes transplant recipients at 64.3 percent, rule would not have a significant FDA to designate human antibacterial or with suboptimal therapeutic modalities economic impact on a substantial antifungal drugs that treat ‘‘serious or for the management of the infection as number of small entities. life-threatening infections’’ as QIDPs. one contributing factor to the high rates Section 202(a) of the Unfunded With certain limitations set forth in the (Ref. 96). Mandates Reform Act of 1995 requires statute, a sponsor of an application for Surgical debridement should be that Agencies prepare a written an antibacterial or antifungal drug that considered as an option early in statement, which includes an receives a QIDP designation gains an management of zygomycosis as the assessment of anticipated costs and additional 5 years of exclusivity to be evidence indicates that this intervention benefits, before proposing ‘‘any rule that added to certain exclusivity periods for improves survival (Ref. 92). includes any Federal mandate that may that product. Drugs that receive a QIDP Additionally, the agent of choice was result in the expenditure by State, local, designation are also eligible for conventional amphotericin B used at and tribal governments, in the aggregate, designation as a fast-track product and higher than normal doses (id.). FDA’s or by the private sector, of $100,000,000 an application for such a drug is eligible or more (adjusted annually for inflation) research did not identify any papers that for priority review. in any one year.’’ The current threshold suggest an increase in the resistance after adjustment for inflation is $141 C. Need for and Potential Effect of the rates to antifungal treatment. million, using the most current (2013) Regulation Zygomycetes are associated with high Implicit Price Deflator for the Gross Between July 9, 2012, when the GAIN morbidity and mortality rates. However, Domestic Product. FDA does not expect title of FDASIA went into effect, and there do not appear to be new or this final rule to result in any 1-year March 12, 2014, FDA granted 41 QIDP changing public health concerns with expenditure that would meet or exceed designations. As explained above, the infections caused by Zygomycetes. this amount. statutory provision that authorizes FDA Further, resistance data on clinical to designate certain drugs as QIDPs is pathogens are lacking. Therefore, FDA B. Background self-implementing, and inclusion of a will not add Zygomycetes to the list of Antibacterial research and pathogen on the list of ‘‘qualifying qualifying pathogens. development has reportedly declined in pathogens’’ does not determine whether IV. Environmental Impact recent years. A decrease in the number a drug proposed to treat an infection of new antibacterial products reaching caused by that pathogen will be given The Agency has determined under 21 the market in recent years has led to QIDP designation. However, section CFR 25.30(h) that this action is of a type concerns that the current drug pipeline 505E(f) of the FD&C Act, added by the that does not individually or for antibacterial drugs may not be GAIN title of FDASIA, requires that cumulatively have a significant effect on adequate to address the growing public FDA establish a list of ‘‘qualifying the human environment. Therefore, health needs arising from the increase in pathogens.’’ This final rule is intended neither an environmental assessment antibacterial or antifungal resistance. A to satisfy that obligation, as well as the nor an environmental impact statement number of reasons have been cited as statute’s directive to make public the is required. barriers to robust antibacterial drug methodology for developing such a list V. Analysis of Economic Impact development including smaller profits of ‘‘qualifying pathogens.’’ The final for short-course administration of rule identifies 21 ‘‘qualifying A. Final Regulatory Impact Analysis antibacterial drugs compared with long- pathogens,’’ including those provided as FDA has examined the impacts of the term use drugs to treat chronic illnesses, examples in the statute, which FDA has final rule under Executive Order 12866, challenges in conducting informative concluded have ‘‘the potential to pose a Executive Order 13563, the Regulatory clinical trials demonstrating efficacy in serious threat to public health’’ and Flexibility Act (5 U.S.C. 601–612), and treating bacterial infections, and proposes to include on the list of the Unfunded Mandates Reform Act of growing pressure to develop appropriate ‘‘qualifying pathogens.’’ 1995 (Pub. L. 104–4). Executive Orders limits on antibacterial drug use. As previously stated, this final rule 12866 and 13563 direct Agencies to One mechanism that has been used to would not change the criteria or process assess all costs and benefits of available encourage the development of new for awarding QIDP designation or for regulatory alternatives and, when drugs is exclusivity provisions that awarding extensions of exclusivity

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periods. That is, the development of a VI. Paperwork Reduction Act 2. Howard, D. H., R. D. Scott II, R. Packard, treatment for an infection caused by a et al., ‘‘The Global Impact of Drug FDA concludes that this rule does not pathogen included on the list of Resistance,’’ Clinical Infectious Diseases, contain a ‘‘collection of information’’ 2003;36(Suppl 1):S4–S10 (available at ‘‘qualifying pathogens’’ is neither a that is subject to review by the Office of http://cid.oxfordjournals.org/content/36/ necessary nor a sufficient condition for Management and Budget under the Supplement_1/S4.full.pdf+html). obtaining QIDP designation, and as Paperwork Reduction Act of 1995 (the 3. Niedell, M. J., B. Cohen, Y. Furuya, et al., stated in section 505E(c) of the FD&C PRA) (44 U.S.C. 3501–3520). This rule ‘‘Costs of Healthcare- and Community- Act, not all applications for a QIDP are Associated Infections With interprets some of the terms used in eligible for an extension of exclusivity. Antimicrobial-Resistant Versus section 505E of the FD&C Act and Relative to the baseline in which the Antimicrobial-Susceptible Organisms,’’ proposes ‘‘qualifying pathogen’’ exclusivity program under GAIN is in Clinical Infectious Diseases, candidates. Inclusion of a pathogen on 2012;55(6):807–815 (available at http:// effect, we anticipate that the the list of ‘‘qualifying pathogens’’ does cid.oxfordjournals.org/content/55/6/ incremental effect of this rule would be not confer any information collection 807.full.pdf+html). negligible. requirement upon any party, 4. Sjo¨lund Karlsson, M., A. Bowen, R. To the extent that this rule causes Reporter, et al., ‘‘Outbreak of Infections particularly because inclusion of a Caused by Shigella sonnei with Reduced research and development to shift pathogen on the list of ‘‘qualifying toward treatments for infections caused Susceptibility to Azithromycin in the pathogens’’ and the QIDP designation United States,’’ Antimicrobial Agents by pathogens on the list and away from process are distinct processes with and Chemotherapy, 2013;57(3):1559–60 treatments for infections caused by differing standards. (available at http:// other pathogens, the opportunity costs The QIDP designation process will be www.ncbi.nlm.nih.gov/pmc/articles/ of this rule would include the forgone PMC3591876/pdf/zac1559.pdf). net benefits of products that treat or addressed separately by the Agency at a 5. Wong, M. R., V. Reddy, H. Hanson, et al., prevent pathogens not included on the later date. Accordingly, the Agency will ‘‘Antimicrobial Resistance Trends of list, while recipients of products to treat analyze any collection of information or Shigella Serotypes in New York City, infections caused by pathogens on the additional PRA-related burdens 2006–2009,’’ Microbial Drug Resistance, 2010;16(2):155–161 (available at http:// list would receive benefits in the form associated with the QIDP designation process separately. online.liebertpub.com/doi/pdf/10.1089/ of reduced morbidity and premature mdr.2009.0130). mortality. Sponsoring firms would VII. Federalism 6. Alcaine, S. D., L. D. Warnick, and M. experience both the cost of product Wiedmann, ‘‘Antimicrobial Resistance in development and the economic benefit FDA has analyzed this rule in Nontyphoidal Salmonella’’ Journal of of an extension of exclusivity and of accordance with the principles set forth Food Protection, 2007;70(3):780–790 potentially accelerating the drug in Executive Order 13132. FDA has (available at (http://fdamedlibmd.library. ingentaconnect.com/content/iafp/jfp/ development and review process with determined that the rule does not contain policies that would have 2007/00000070/00000003/ fast-track status and priority review. If art00039?token=004f1d70bd125 this rule induces greater interest in substantial direct effects on the States, on the relationship between the ed42bda039412f415d763f252445744a6c seeking QIDP designation than would 246c514d25304829552c4b49266d656c). otherwise occur, FDA also would incur National Government and the States, or 7. Mandell, G. L., J. E. Bennett, R. Dolin, et additional costs of reviewing on the distribution of power and al., Mandell, Douglas, and Bennett’s applications for newly developed responsibilities among the various Principles and Practice of Infectious antibacterial or antifungal drug products levels of government. Accordingly, the Diseases. 7th Ed. Philadelphia: Churchill Livingstone Elsevier, 2010. under a more expedited schedule. Agency concludes that this rule does not contain policies that have 8. Shah, H. N., I. Olsen, K. Bernard, et al., Given that the methodology for federalism implications as defined in ‘‘Approaches to the Study of the including a pathogen on the list of the Executive order and, consequently, Systematics of Anaerobic, Gram- ‘‘qualifying pathogens’’ was developed negative, Non-sporeforming Rods: a federalism summary impact statement with broad input, including input from Current Status and Perspectives,’’ is not required. industry stakeholders and the scientific Anaerobe, 2009;15(5):179–194 (available and medical community involved in VIII. References at http://www.sciencedirect.com/science/ anti-infective research, we expect that article/pii/S1075996409001206). The following references have been 9. Feingold, S. M., Microbiology. 4th Ed. the pathogens listed in this final rule placed on display in the Division of Galveston: University of Texas Medical reflect not only current thinking Dockets Management (see ADDRESSES) Branch at Galveston, 1996, Ch. 20 regarding the types of pathogens that and may be seen by interested persons (available at http:// have the potential to pose serious threat www.ncbi.nlm.nih.gov/books/ between 9 a.m. and 4 p.m. Monday to the public health, but also current NBK8438/). through Friday, and are available thinking regarding the types of 10. Ngo, J. T., M. D. Parkins, D. B. Gregson, electronically at http:// pathogens that cause infections for et al., ‘‘Population-based Assessment of www.regulations.gov. (FDA has verified which treatments might be eligible for the Incidence, Risk Factors, and the Web site addresses, but FDA is not Outcomes of Anaerobic Bloodstream QIDP designation. To the extent that responsible for any subsequent changes Infections,’’ Infection, 2013;41(1):41–48 there is overlap between drugs to the Web sites after this document (available at http://link.springer.com/ designated as QIDPs and drugs publishes in the Federal Register.) article/10.1007%2Fs15010-012-0389-4/ developed to treat serious or life- fulltext.html). threatening infections caused by 1. Roberts, R. R., B. Hota, I. Ahmad, et al., 11. Lassmann, B., D. R. Gustafson, C. M. pathogens listed in this final rule, this ‘‘Hospital and Societal Costs of Wood, and J. E. Rosenblatt, final rule would have a minimal impact Antimicrobial-Resistant Infections in a ‘‘Reemergence of Anaerobic Bacteremia,’’ Chicago Teaching Hospital: Implications in terms of influencing the volume or Clinical Infectious Diseases, 2007; for Antibiotic Stewardship,’’ Clinical 44(7):895–900 (available at http:// composition of applications seeking Infectious Diseases, 2009;49:1175–1184 cid.oxfordjournals.org/content/44/7/ QIDP designation compared to what (available at http://cid.oxford 895.long). would otherwise occur in the absence of journals.org/content/49/8/ 12. Goldstein, E. J. C., D. M. Citron, S. A. this rule. 1175.full.pdf+html). Vaidya, et al., ‘‘In Vitro Activity of 11

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(m) Neisseria gonorrhoeae. 109–162, codified at 8 U.S.C. D. The Small Business Regulatory (n) Neisseria meningitidis. 1154(a)(1)(A)(vii), created an immigrant Enforcement Fairness Act of 1996 (o) Non-tuberculous mycobacteria visa classification for the parents of U.S. This rule is not a major rule as species. citizens, and the parents of former U.S. defined by 5 U.S.C. 804, for purposes of (p) Pseudomonas species. citizens who, within the past two years, congressional review of agency (q) Staphylococcus aureus. have lost or renounced U.S. citizenship rulemaking under the Small Business (r) Streptococcus agalactiae. status related to an incident of domestic Regulatory Enforcement Fairness Act of (s) Streptococcus pneumoniae. violence or died. (t) Streptococcus pyogenes. 1996, Public Law 104–121. This rule The Department currently identifies (u) Vibrio cholerae. would not result in an annual effect on applicants for this status using the the economy of $100 million or more; a Dated: May 29, 2014. ‘‘IB5’’ symbol, an existing symbol used major increase in costs or prices; or Leslie Kux, for parents of U.S. citizens who are at significant adverse effects on Assistant Commissioner for Policy. least 21 years old. The unique IB5 competition, employment, investment, [FR Doc. 2014–13023 Filed 6–4–14; 8:45 am] classification symbol will facilitate the productivity, innovation, or on the BILLING CODE 4160–01–P Department’s ability to identify ability of United States-based applicants for such status in various companies to compete with foreign- immigrant visa information databases. based companies in domestic and export markets. DEPARTMENT OF STATE Regulatory Findings E. Executive Order 12866 22 CFR Part 42 A. Administrative Procedure Act The Department does not consider [Public Notice: 8755] Since this rule concerns the this rule to be a ‘‘significant regulatory RIN 1400–AD52 administration of visas, which is a action’’ within the scope of section 3(f) foreign affairs function of the United of Executive Order 12866. Nonetheless, Visas: Documentation of Immigrants States, the Department publishes this the Department has reviewed the rule to Under the Immigration and Nationality rule as a final rule pursuant to 5 U.S.C. ensure its consistency with the Act, as Amended 553(a)(1). In addition, since this rule regulatory philosophy and principles set AGENCY: Department of State. implements the provisions of the forth in the Executive Order. Violence Against Women and ACTION: Final rule. F. Executive Order 13563 Department of Justice Reauthorization SUMMARY: Pursuant to the Violence Act of 2005, the Department finds that The Department of State has Against Women and Department of notice and public comment on this rule considered this rule in light of Justice Reauthorization Act of 2005, the are unnecessary, pursuant to 5 U.S.C. Executive Order 13563 and affirms that Department of State amends the 553(b)(B). Accordingly, this rule is this regulation is consistent with the immigrant visa classification table listed effective immediately. guidance therein. in the Department’s regulations to add B. Regulatory Flexibility Act/Executive G. Executive Orders 12372 and 13132: a symbol for an immigrant visa issued Order 13272: Small Business Federalism to to an alien who: is the parent of a This regulation will not have current U.S.citizen, or the parent of a Because this rule is exempt from substantial direct effects on the states, former U.S. citizen who, within the two- notice and comment rulemaking under on the relationship between the national year period prior to filing the petition, 5 U.S.C. 553, it is exempt from the government and the states, or the lost or renounced U.S. citizenship status regulatory flexibility analysis distribution of power and related to an incident of domestic requirements set forth at sections 603 responsibilities among the various violence or died; is a person of good and 604 of the Regulatory Flexibility moral character; is eligible to be levels of government. Nor will the rule Act (5 U.S.C. 603 and 604). Nonetheless, have federalism implications warranting classified as an immediate relative consistent with section 605(b) of the under the Immigration and Nationality the application of Executive Orders Regulatory Flexibility Act (5 U.S.C. 12372 and 13132. Act; resides, or has resided, with the 605(b)), the Department has reviewed U.S. citizen daughter or son; this regulation and certifies that this H. Executive Order 12988: Civil Justice demonstrates that he or she has been rule will not have a significant Reform battered or subject to extreme cruelty by economic impact on a substantial The Department has reviewed the the U.S. citizen daughter or son; and has number of small entities. an approved petition from the regulations in light of sections 3(a) and Department of Homeland Security. C. The Unfunded Mandates Reform Act 3(b)(2) of Executive Order 12988 to eliminate ambiguity, minimize DATES: of 1995 This rule becomes effective June litigation, establish clear legal 5, 2014. Section 202 of the Unfunded standards, and reduce burden. FOR FURTHER INFORMATION CONTACT: Mandates Reform Act of 1995, Public I. Executive Order 13175 Taylor W. Beaumont, Department of Law 104–4, 109 Stat. 48, 2 U.S.C. 1532, State, Bureau of Consular Affairs, Office generally requires agencies to prepare a The Department of State has of Visa Services, Legal Affairs, Division statement before proposing any rule that determined that this rulemaking will of Legislation and Regulations, 600 19th may result in an annual expenditure of not have tribal implications, will not Street NW., Washington, DC 20431, $100 million or more by State, local, or impose substantial direct compliance email ([email protected]). tribal governments, or by the private costs on Indian tribal governments, and SUPPLEMENTARY INFORMATION: Section sector. This rule will not result in any will not pre-empt tribal law. 816 of the Violence Against Women and such expenditure, nor will it Accordingly, the requirements of Department of Justice Reauthorization significantly or uniquely affect small Executive Order 13175 do not apply to Act of 2005, Title VIII of Public Law governments. this rulemaking.

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