Source: https://www.federalregister.gov/articles/2014/06/05/2014-13023/establishing-a-list-of-qualifying-pathogens-under-the-food-and-drug-administration-safety-and
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Federal Register | Establishing a List of Qualifying Pathogens Under the Food and Drug Administration Safety and Innovation Act
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Document Number: 2014-13023
Shorter URL: https://federalregister.gov/a/2014-13023 Related Topics
Reference 98 - Centers for Disease Control and Prevention,...
The Food and Drug Administration (FDA or Agency) is issuing a regulation to establish a list of “qualifying pathogens” that have the potential to pose a serious threat to public health. This final rule implements a provision of the Generating Antibiotic Incentives Now (GAIN) title of the Food and Drug Administration Safety and Innovation Act (FDASIA). GAIN is intended to encourage development of new antibacterial and antifungal drugs for the treatment of serious or life-threatening infections, and provides incentives such as eligibility for designation as a fast-track product and an additional 5 years of exclusivity to be added to certain exclusivity periods. Based on analyses conducted both in the proposed rule and in response to comments to the proposed rule, FDA has determined that the following pathogens comprise the list of “qualifying pathogens:”Acinetobacter species, Aspergillus species, Burkholderia cepacia complex, Campylobacter species, Candida species, Clostridium difficile,
Coccidioides species, Cryptococcus species, Enterobacteriaceae (e.g., Klebsiella pneumoniae), Enterococcus species, Helicobacter pylori, Mycobacterium
tuberculosis complex, Neisseria gonorrhoeae,
N. meningitidis, Non-tuberculous mycobacteria species, Pseudomonas species, Staphylococcus aureus,
S. pyogenes, and Vibrio cholerae. The preamble to the proposed rule described the factors the Agency considered and the methodology used to develop the list of qualifying pathogens. As described in the preamble of this final rule, FDA applied those factors and that methodology to additional pathogens suggested via comments on the proposed rule.
Establishing a List of Qualifying Pathogens That Have the Potential to Pose a Serious Threat to Public Health Under the Food and Drug Administration Safety and Innovation Act 3 actions from June 12th, 2013 to July 2014
(Comment 25) Zygomycetes (Mucor, Rhizopus,
Absidia, Cunninghamella)
Title VIII of FDASIA (Pub. L. 112-144), the GAIN title, is intended to encourage development of new antibacterial and antifungal drugs for the treatment of serious or life-threatening infections. Among other things, GAIN requires that the Secretary of the Department of Health and Human Services (and thus FDA, by delegation): (1) Establish and maintain a list of “qualifying pathogens” that have “the potential to pose a serious threat to public health” and (2) make public the methodology for developing the list (see section 505E(f) of the Federal Food, Drug, and Cosmetic Act (the FD Act), as amended by FDASIA) (21 U.S.C. 355f(f)). In establishing and maintaining the list of “qualifying pathogens,” FDA must consider the following factors: The impact on the public health due to drug-resistant organisms in humans; the rate of growth of drug-resistant organisms in humans; the increase in resistance rates in humans; and the morbidity and mortality in humans (see section 505E(f)(2)(B)(i) of the FD Act). FDA also is required to consult with infectious disease and antibiotic resistance experts, including those in the medical and clinical research communities, along with the Centers for Disease Control and Prevention (CDC) (see section 505E(f)(2)(B)(ii) of the FD Act). FDA issued a proposed rule on June 12, 2013 (78 FR 35155), and, after analyzing comments to that proposed rule, is issuing this final rule in fulfillment of the statutory requirements described above.
After holding a public meeting and consulting with CDC and the National Institutes of Health (NIH), and considering the factors specified in section 505E(f)(2)(B)(i) of the FD&C Act, FDA proposed on June 12, 2013, that the following pathogens comprise the list of “qualifying pathogens:”Acinetobacter species, Aspergillus species, Burkholderia cepacia complex, Campylobacter species, Candida species, Clostridium difficile, Enterobacteriaceae (e.g., Klebsiella pneumoniae), Enterococcus species, Mycobacterium tuberculosis complex, Neisseria gonorrhoeae,
S. pyogenes, and Vibrio cholerae. The preamble to the proposed rule describes the factors FDA considered and the methodology FDA used to develop this list of qualifying pathogens. After analyzing comments to the proposed rule, FDA has decided to retain the previously proposed methodology for developing the list of qualifying pathogens and will include the pathogens identified in the proposed rule on the list of qualifying pathogens. FDA also has applied the methodology set forth in the proposed rule to additional pathogens suggested by comments to the proposed rule. Based on these analyses, FDA also will add Coccidioides species, Cryptococcus species, and Helicobacter pylori to the list of qualifying pathogens. The table below describes the pathogen lists for the proposed and final rule for comparison:
Non-tuberculous mycobacteria species.
I. Background: FDASIA Requirements Back to Top
Title VIII of FDASIA (Pub. L. 112-144), entitled Generating Antibiotic Incentives Now, amended the FD Act to add section 505E, among other things. This new section of the FD Act is intended to encourage development of treatments for serious or life-threatening infections caused by bacteria or fungi. For certain drugs that are designated as “qualified infectious disease products” (QIDPs) under new section 505E(d) of the FD Act, new section 505E(a) provides an additional 5 years of exclusivity to be added to the exclusivity periods provided by sections 505(c)(3)(E)(ii) to (c)(3)(E)(iv) (21 U.S.C. 355(c)(3)(E)(ii) to (c)(3)(E)(iv)), 505(j)(5)(F)(ii) to (j)(5)(F)(iv) (21 U.S.C. 355(j)(5)(F)(ii) to (j)(5)(F)(iv)), and 527 (21 U.S.C. 360cc) of the FD Act. In addition, an application for a drug designated as a QIDP is eligible for priority review and designation as a fast track product (sections 524A and 506(a)(1) of the FD Act (21 U.S.C. 356n-I and 556(a)(1)), respectively).
The GAIN title of FDASIA requires that the Secretary of the Department of Health and Human Services (and thus FDA, by delegation) establish and maintain a list of such “qualifying pathogens,” and make public the methodology for the developing the list. According to the statute, “the term `qualifying pathogen' means a pathogen identified and listed by the Secretary . . . that has the potential to pose a serious threat to public health, such as[:] (A) resistant gram positive pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Staphylococcus aureus, and vancomycin-resistant [E]nterococcus; (B) multi-drug resistant gram[-]negative bacteria, including Acinetobacter, Klebsiella,
Pseudomonas, and E. coli species; (C) multi-drug resistant tuberculosis; and (D) Clostridium difficile” (section 505E(f)(1) of the FD&C Act). FDA is required under the law to consider four factors in establishing and maintaining the list of qualifying pathogens:
Further, in determining which pathogens should be listed, GAIN requires FDA to consult with infectious disease and antibiotic resistance experts, including those in the medical and clinical research communities, along with the CDC, in determining which pathogens should be included on the list of “qualifying pathogens” (section 505E(f)(2)(B)(ii) of the FD Act). To fulfill this statutory obligation, on December 18, 2012, FDA convened a public hearing, at which the Agency solicited input regarding the following topics: (1) How FDA should interpret and apply the four factors FDASIA requires FDA to “consider” in establishing and maintaining the list of qualifying pathogens; (2) whether there are any other factors FDA should consider when establishing and maintaining the list of qualifying pathogens; and (3) which specific pathogens FDA should list as qualifying pathogens (77 FR 68789, November 16, 2012). The transcript of this hearing, as well as comments submitted to the hearing docket, are available at http://www.regulations.gov, docket number FDA-2012-N-1037. FDA considered carefully the input presented at this hearing, as well as the comments submitted to the hearing docket, in creating the list of qualifying pathogens.
In addition, FDA consulted with experts in infectious disease and antibiotic resistance at CDC and NIH during the development of both the proposed and the final rule.
II. Proposed Rule and Final Rule Back to Top
The Agency recognizes it is important to take a long-term view of the drug resistance problem. For some pathogens, particularly those for which increased resistance is newly emerging, FDA recognizes that there may be gaps in the available data or evidence pertaining to one or more of the four factors described in section 505E(f)(2)(B)(i) of the FD&C Act. Thus, consistent with GAIN's purpose of encouraging the development of treatments for serious or life-threatening infections caused by bacteria or fungi, the Agency intends to consider the totality of available evidence for a particular pathogen to determine whether that pathogen should be included on the list of qualifying pathogens. Therefore, if, after considering the four factors identified in section 505E(f)(2)(B)(i) of the FD&C Act, FDA determines that the totality of available evidence demonstrates that a pathogen “has the potential to pose a serious threat to public health,” the Agency will identify the pathogen in question as a “qualifying pathogen.” More detailed explanations of each factor identified in section 505E(f)(2)(B)(i) of the FD&C Act are set forth in the paragraphs that follow.
As FDA explained in the proposed rule (78 FR 35155 at 35156) and affirms in this final rule, the statutory standard for inclusion on FDA's list of qualifying pathogens is different from the statutory standard for QIDP designation. QIDP designation, by definition, requires that the drug in question be an “antibacterial or antifungal drug for human use intended to treat serious or life-threatening infections” (section 505E(g) of the FD Act). “Qualifying pathogens” are defined according to a different statutory standard; the term means “a pathogen identified and listed by the Secretary . . . that has the potential to pose a serious threat to public health” (section 505E(f) of the FD&C Act) (emphasis added). That is, a drug intended to treat a serious or life-threatening bacterial or fungal infection caused by a pathogen that is not included on the list of “qualifying pathogens” may be eligible for designation as a QIDP, while a drug that is intended to treat an infection caused by a pathogen on the list may not always be eligible for QIDP designation. After reviewing the comments to the docket on this point (see section IV.A), FDA's understanding of these statutory standards remains unchanged.
To alleviate confusion regarding this issue, FDA also clarifies that vaccine applications are ineligible for QIDP designation under the GAIN title of FDASIA. Vaccines are biological products whose applications for approval are submitted under section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262). QIDPs, however, must be human drugs whose applications are submitted pursuant to section 505(b) of the FD&C Act. Thus, under the law, vaccines are ineligible for QIDP designation.
As stated in the proposed rule (78 FR 35156) and affirmed in this final rule, FDA intends the list of qualifying pathogens to reflect the pathogens that, as determined by the Agency, after consulting with other experts and considering the factors set forth in FDASIA (see section 505E(f)(2)(B)(i) of the FD Act), have the “potential to pose a serious threat to public health” (section 505E(f)(1) of the FD Act). FDA does not intend for this list to be used for other purposes, such as the following: (1) Allocation of research funding for bacterial or fungal pathogens; (2) setting of priorities in research in a particular area pertaining to bacterial or fungal pathogens; or (3) direction of epidemiological resources to a particular area of research on bacterial or fungal pathogens. Furthermore, as section 505E of the FD Act makes clear, the list of qualifying pathogens includes only bacteria or fungi that have the potential to pose a serious threat to public health. Viral pathogens or parasites, therefore, were not considered for inclusion and are not included as part of this list.
FDA's proposed rule concluded with an analysis of the 18 pathogens the Agency proposed to identify as qualifying pathogens. After reviewing the comments to the docket (see section IV.C), FDA is finalizing its analyses of the 18 proposed pathogens as written in the proposed rule (see 78 FR 35155 at 35158 through 35166), which are incorporated by reference herein, and is identifying all 18 proposed pathogens as “qualifying pathogens” in § 317.2 (21 CFR 317.2).
III. Comments to the Proposed Rule and FDA's Responses Back to Top
(Response) FDA agrees with the comment that the term “serious or life-threatening” is not explicitly defined in the statute. Nevertheless, the Agency has been interpreting and applying these terms in the context of other programs under the Food, Drug, and Cosmetic Act intended to expedite the development of drugs and biologics to address unmet medical needs for several years. “Serious or life-threatening” is used in section 506 of the FD Act, in the context of expedited programs, including fast track designation. The term “serious” is further defined in a 2006 FDA guidance for industry, “Fast Track Drug Development Program—Designation, Development, and Application Review (which will be superseded by the draft guidance for industry, “Expedited Programs for Serious Conditions—Drugs and Biologics,” when finalized) and in the preamble to a final rule pertaining to accelerated approval (57 FR 58942, December 11, 1992). The term “life-threatening” is defined in 21 CFR 312.81(a). The provisions related to QIDPs in GAIN similarly seek to incentivize the development of drugs to meet an unmet medical need and, indeed, QIDP-designated applications are eligible for both priority review and fast-track designation (see section 524A of the FD Act and section 506(b)(1) of the FD Act, as amended). The Agency intends, therefore, to interpret serious or life-threatening in a similar manner with respect to GAIN as it has in the context of these expedited programs. While guidances and even regulations may change, the Agency may not apply different definitional standards to similarly situated applicants or applications. Thus, concerns over lack of a statutory definition of “serious or life-threatening” are an insufficient basis for FDA to change its interpretation of the statute.
Further, it may be true that many of the qualifying pathogens listed by FDA may cause serious or life-threatening infections for which treatments might be eligible for QIDP designation. However, the comment's assertions cannot change the language that is in the statute, which provides different standards for QIDPs and qualifying pathogens. Qualifying pathogens are “pathogen[s] .. . that ha[ve] the potential to pose a serious threat to public health,” whereas QIDPs are certain human “drugs .. . intended to treat serious or life-threatening infections” (emphasis added). Most importantly, many pathogens with the potential to seriously threaten public health may cause varying levels of morbidity and mortality in a given individual depending on the site of infection, the person infected, the level of antimicrobial resistance present in the infecting pathogen, and other factors.
(Comment 2) One comment stated that only “factors that can be addressed through new drug development” should be used as criteria for including pathogens on the list. The comment does not specify which factors these are, but the comment's concerns stem from an assertion that new drugs contribute to antibiotic resistance due to their off- label use, use in patients who do not need the drugs, or use in patients whose underlying infection is unidentified.
(Comment 9) One comment asserted that regardless of QIDP designation status, “drugs intended to treat qualifying pathogens” (which we assume to mean drugs intended to treat infections caused by qualifying pathogens) should be required to prove reduction in mortality or morbidity. The comment further asserted that clinical trials in anti-infective drugs for qualifying pathogens should have mortality as the primary endpoint.
(Response) FDA considers antibiotic stewardship and attention to patient adherence to therapy as important factors in determining transmissibility. FDA explained in the preamble to the proposed rule (see 78 FR 35155 at 35157) that a pathogen's ease of transmission is an important consideration in evaluating “the impact on the public health due to drug-resistant organisms in humans” (section 505E(f)(2)(B)(i) of the FD Act). This factor is one of the four statutory factors identified in section 505E(f)(2)(B)(i) of the FD Act. Therefore, FDA will make no changes to the rule in response to this comment.
These bacterial pathogens are commonly found in the mucous membranes (Ref. 9), particularly in the mouth (Bacteroides, Fusobacterium, and Prevotella), intestines (Bacteroides), and female urogenital tract (Bacteroides, Fusobacterium, and Prevotella) (Ref. 7 at p. 3112). Each of these bacterial pathogens can cause the same infectious diseases and are often implicated in odontogenic infections (particularly for those with poor dental hygiene or periodontal disease, as these bacteria populate dental plaque), peritonsilar infections, and polymicrobial abdominal infections, among others. Particularly when introduced into compromised tissue (e.g., via a wound or break in mucous membranes), these pathogens can cause abscesses that may require drainage or debridement in addition to antimicrobial therapy (Ref. 7 at p. 3117). Infection prevention is often the focus for these pathogens—either via “avoiding conditions that reduce the redox potential of the tissues” or preventing the bacteria from entering wounds, often by administering prophylactic antimicrobial agents prior to surgery or dental work (Ref. 9).
Non-difficile Clostridium outbreaks are reported from time to time (Ref. 28), but foodborne C. perfringens infections are the most common, causing approximately 1 million cases of mostly mild to moderate gastroenteritis in the United States each year (Ref. 29). C. perfringens often colonizes meat or poultry, and illness may result from large volumes of food kept warm for a long period of time (e.g., in buffets) (id.) or in outbreaks associated with particular prepared foods (Refs. 30 and 31). C. botulinum, which also causes food poisoning, is relatively rare, though much more severe—it is likely fatal if untreated (Refs. 29 and 32), whereas C. perfringens infections are often self-limited and require simply oral rehydration and supportive care at home. Other Clostridium-related diseases, such as tetanus, bloodstream infections, and gas gangrene, are life-threatening and require immediate treatment.
In contrast with C. difficile, C. perfringens is not transmitted from human to human (Refs. 34, 35, and 36),
and FDA is unaware of significant increases in incidence or prevalence of infections with C. perfringens or other non-difficile Clostridium pathogens.
(Response) For the reasons that follow, FDA will include these species as qualifying pathogens. Cryptococcus species are encapsulated yeast fungi (Ref. 7 at p. 3287). Although there are 19 species in the genus (Ref. 7 at p. 3287), C. neoformans and C. gattii are the two generally associated with human disease (Ref. 7 at pp. 3288-3289). Both species are found in soil, and infection typically occurs via inhalation of the fungi (Ref. 7 at p. 3290). Cryptococcal disease often presents as lung or central nervous system disease (Ref. 7 at p. 3293), although the pathogens also can infect other parts of the body (Ref. 53).
(Response) Preliminarily, FDA notes that the comment appears to have conflated the standards for qualifying pathogens (“pathogen[s] .. . that ha[ve] the potential to pose a serious threat to public health” (section 505E(f) of the FD&C Act)) and QIDPs (certain human “drugs .. . intended to treat serious or life-threatening infections” (section 505E(g) of the FD&C Act)) (emphasis added). For the reasons that follow, FDA declines to add Fusarium species to the list of qualifying pathogens.
Inhalation, ingestion, and entry through skin trauma have been suggested as the portal of entry (Ref. 7 at p. 3369). More recently, water has also been suggested as a source of these infections, as the fungus was found in one hospital water supply system and in several water sources at a dialysis clinic (id.). Infection commonly presents with fever and myalgia not responsive to antibacterial therapy during periods of profound neutropenia (id). Skin lesions occur in 60 to 80 percent of infections and can occur within 1 day of the onset of fever (id.). Overall mortality in this infection has been reported to be between 50 to 80 percent (Ref. 7 at p. 3370). Survival is generally associated with the recovery from neutropenia (id.). The high rates of morbidity and mortality are usually due to the patients' underlying immune suppression and prolonged neutropenia (Ref. 65).
Currently, there is too little information available about Pandoraea species to support their inclusion on the list of qualifying pathogens. Aside from a suggestion of intrinsic carbapanem resistance (Ref. 79), FDA is unaware of data suggesting increasing resistance—or any acquired resistance—to available therapies, or poorer outcomes with resistant strains of these pathogens. Further, “[t]he clinical significance of colonization with these organisms remains unclear, and there are limited and conflicting data available on the clinical outcome of patients colonized with Pandoraea” (Ref. 78). Thus, FDA declines to add Pandoraea species to the list of qualifying pathogens at the present time. (Comment 23) Peptostreptococcus Species
(Response) FDA notes that the comment appears to have conflated the standards for qualifying pathogens (“pathogen[s] .. . that ha[ve] the potential to pose a serious threat to public health” (section 505E(f) of the FD&C Act)) and QIDPs (certain human “drugs .. . intended to treat serious or life-threatening infections” (section 505E(g) of the FD&C Act)) (emphasis added). For the reasons that follow, FDA declines to add Scedosporium species to the list of qualifying pathogens.
One comment suggested adding Zygomycetes (specifically, Mucor, Rhizopus,
Absidia, and Cunninghamella) to the list of qualifying pathogens because these fungal agents cause serious and life-threatening infections.
(Response) FDA notes that the comment appears to have conflated the standards for qualifying pathogens (“pathogen[s] .. . that ha[ve] the potential to pose a serious threat to public health” (section 505E(f) of the FD&C Act)) and QIDPs (certain human “drugs .. . intended to treat serious or life-threatening infections” (section 505E(g) of the FD&C Act)) (emphasis added). For the reasons that follow, FDA declines to add Zygomycetes to the list of qualifying pathogens.
Zygomycetes are relatively uncommon isolates in the clinical laboratory and are less frequent than invasive fungi caused by Aspergillus species. According to one report, “[i]ncidence figures are difficult to collect as few national studies have been undertaken, but for the United States, the annual incidence of zygomycosis has been estimated as 1.7 infections per million people” (Refs. 92 and 94). According to a 2002 report, the incidence of zygomycosis may be increasing; researchers found an increase in the number of hematopoietic stem cell transplant recipients at the Fred Hutchinson Cancer Center in Seattle, WA, infected with Zygomycetes from 1985-1989 to 1995-1999 (Ref. 95). Another study found that invasive fungal infections due to Zygomycetes were associated with higher mortality rates in adult hematopoietic stem cell transplant recipients at 64.3 percent, with suboptimal therapeutic modalities for the management of the infection as one contributing factor to the high rates (Ref. 96).
V. Analysis of Economic Impact Back to Top
As previously stated, this final rule would not change the criteria or process for awarding QIDP designation or for awarding extensions of exclusivity periods. That is, the development of a treatment for an infection caused by a pathogen included on the list of “qualifying pathogens” is neither a necessary nor a sufficient condition for obtaining QIDP designation, and as stated in section 505E(c) of the FD&C Act, not all applications for a QIDP are eligible for an extension of exclusivity. Relative to the baseline in which the exclusivity program under GAIN is in effect, we anticipate that the incremental effect of this rule would be negligible.
FDA concludes that this rule does not contain a “collection of information” that is subject to review by the Office of Management and Budget under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-3520). This rule interprets some of the terms used in section 505E of the FD Act and proposes “qualifying pathogen” candidates. Inclusion of a pathogen on the list of “qualifying pathogens” does not confer any information collection requirement upon any party, particularly because inclusion of a pathogen on the list of “qualifying pathogens” and the QIDP designation process are distinct processes with differing standards.
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List of Subjects in 21 CFR Part 317 Back to Top
PART 317—QUALIFYING PATHOGENS Back to Top
317.1 [Reserved]
21 U.S.C. 355f, 371.
§ 317.1 [Reserved]
§ 317.2 List of qualifying pathogens that have the potential to pose a serious threat to public health.
(l) Mycobacterium tuberculosis complex. (m) Neisseria gonorrhoeae.