Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile, 47911-47914 [2019-19643]

Download as PDF Federal Register / Vol. 84, No. 176 / Wednesday, September 11, 2019 / Proposed Rules substantial number of small entities under the criteria of the Regulatory Flexibility Act. Environmental Review This proposal will be subject to an environmental analysis in accordance with FAA Order 1050.1F, ‘‘Environmental Impacts: Policies and Procedures’’ prior to any FAA final regulatory action. List of Subjects in 14 CFR Part 71 Airspace, Incorporation by reference, Navigation (air). The Proposed Amendment Accordingly, pursuant to the authority delegated to me, the Federal Aviation Administration proposes to amend 14 CFR part 71 as follows: PART 71—DESIGNATION OF CLASS A, B, C, D, AND E AIRSPACE AREAS; AIR TRAFFIC SERVICE ROUTES; AND REPORTING POINTS 1. The authority citation for 14 CFR part 71 continues to read as follows: ■ Authority: 49 U.S.C. 106(f), 106(g); 40103, 40113, 40120; E.O. 10854, 24 FR 9565, 3 CFR, 1959–1963 Comp., p. 389. § 71.1 [Amended] 2. The incorporation by reference in 14 CFR 71.1 of FAA Order 7400.11C, Airspace Designations and Reporting Points, dated August 13, 2018, and effective September 15, 2018, is amended as follows: ■ Paragraph 5000 Class D Airspace. * * * * * jspears on DSK3GMQ082PROD with PROPOSALS ASO MS D Meridian, MS [Amended] Joe Williams NOLF, MS (Lat. 32°47′56″ N, long. 88°50′04″ W) That airspace extending upward from the surface to and including 3,000 feet MSL within a 4.2-mile radius of Joe Williams NOLF. This Class D airspace area is effective during the specific dates and times established by a Notice to Airmen. The effective date and time will thereafter be continuously published in the Chart Supplement. ASO MS D Meridian, MS [Amended] Key Field, MS (Lat. 32°19′57″ N, long. 88°45′07″ W) That airspace extending upward from the surface to and including 2,800 feet MSL within a 4.5-mile radius of Key Field. This Class D airspace area is effective during the specific dates and times established in advance by a Notice to Airmen. The effective date and time will thereafter be continuously published in the Char Supplement. ASO MS D Meridian, MS [Amended] NAS Meridian/McCain Field, MS (Lat. 32°33′13″ N, long. 88°33′19″ W) VerDate Sep<11>2014 17:49 Sep 10, 2019 Jkt 247001 Meridian TACAN (Lat. 32°34′42″ N, long. 88°32′43″ W) That airspace extending upward from the surface to and including 2,800 feet MSL within a 5.3-mile radius of NAS Meridian/McCain Field, and within 1 mile each side of the 009° bearing from the airport extending from the 5.3 mile radius to 5.5 miles north of the airport; and within 1.5 miles each side of the 189° bearing from the airport extending from the 5.3-mile radius to 6 miles south of the airport; and within 1.6 miles each side of the Meridian TACAN 331° radial extending from the 5.3-mile radius to 5.6 miles northwest the Meridian TACAN. This Class D airspace area is effective during the specific dates and times established in advance by a Notice to Airmen. The effective date and time will thereafter be continuously published in the Chart Supplement. Paragraph 6004 Class E Airspace Areas Designated as an Extension to a Class D or Class E Surface Area. * * * * * ASO MS E4 Meridian, MS [Amended] Key Field, MS (Lat. 32°19′57″ N, long. 88°45′07″ W) Meridian VORTAC (Lat. 32°22′42″ N, long. 88°48′15″ W) That airspace extending upward from the surface within 1 mile each side of the 009° bearing from Key Field extending from the 4.5-mile radius of Key Field to 4.9 miles north of Key Field, and within 1 mile each side of the 044° bearing from Key Field extending from the 4.5-mile radius of Key Field to 4.6 miles northeast of Key Field, and within 2.9 miles each side of the Meridian VORTAC 141° radial extending from the 4.5mile radius of Key Field to 11 miles southeast of the Meridian VORTAC, and within 1 mile each side of the 189° bearing from Key Field extending from the 4.5-mile radius of Key Field to 4.6 miles south of Key Field, and within 1 mile each side of the 224° bearing from Key Field extending from the 4.5-mile radius of Key Field to 4.6 miles southwest of Key Field. This Class E airspace area is effective during the specific dates and times established in advance by a Notice to Airmen. The effective date and time will thereafter be continuously published in the Chart Supplement. Paragraph 6005 Class E Airspace Areas Extending Upward From 700 Feet or More Above the Surface of the Earth. * * * * * Frm 00006 Fmt 4702 Sfmt 4702 of Key Field, and within 1 mile each side of the 009° bearing from Key Field extending from the 7-mile radius of Key Field to 12.5 miles north of Key Field; and within 3.4 miles each side of the 009° bearing from the Key Field: RWY 19–LOC extending from the 7-mile radius of Key Field to 11.1 miles north of the Key Field: RWY 19–LOC, and within 2 miles each side of the 044° bearing from Key Field extending from the 7-mile radius of Key Field to 11.6 miles northeast of Key Field, and within 3.6 miles each side of the Meridian VORTAC 141° radial extending from the 4.5-mile radius of Key Field to 13.9 miles southeast of the Meridian VORTAC, and within 1 mile each side of the 189° bearing from Key Field extending from the 7mile radius of Key Field to 12.6 miles south of Key Field, and within 3.4 miles each side of the 189° bearing from the Key Field: RWY 01–LOC extending from the 7-mile radius of Key Field to 11.2 miles south of the Key Field: RWY 01–LOC, and within 1.5 miles each side of the Meridian VORTAC 311° radial extending from the 7-mile radius of Key Field to 14.3 miles northwest of the Meridian VORTAC, and within a 6.7-mile radius of Joe Williams NOLF, and within a 7.8-mile radius of NAS Meridian/McCain Field, and within 6.7 miles each side of a line from Joe Williams NOLF to NAS Meridian/ McCain Field. Issued in Fort Worth, Texas, on September 4, 2019. Steve Szukala, Acting Manager, Operations Support Group, ATO Central Service Center. [FR Doc. 2019–19543 Filed 9–10–19; 8:45 am] BILLING CODE 4910–13–P DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 15 [Docket No. FDA–2019–N–3631] Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies; Public Hearing; Request for Comments AGENCY: Food and Drug Administration, HHS. ASO MS E5 Meridian, MS [Amended] Key Field, MS (Lat. 32°19′57″ N, long. 88°45′07″ W) Key Field: RWY 19–LOC (Lat. 32°18′54″ N, long. 88°45′25″ W) Meridian VORTAC (Lat. 32°22′42″ N, long. 88°48′15″ W) Key Field: RWY 01–LOC (Lat. 32°20′52″ N, long. 88°45′02″ W) Joe Williams NOLF, MS (Lat. 32°47′56″ N, long. 88°50′04″ W) NAS Meridian/McCain Field, MS (Lat. 32°33′13″ N, long. 88°33′19″ W) That airspace extending upward from 700 feet above the surface within a 7-mile radius PO 00000 47911 Notification of public hearing; request for comments. ACTION: The Food and Drug Administration (FDA, the Agency, or we) is announcing a public hearing to obtain input on the use of fecal microbiota for transplantation (FMT) to treat Clostridium difficile infection not responsive to standard therapies. FDA will consider scientific data and other information from the public hearing as we continue to consider ways to support the development of FMT to treat C. SUMMARY: E:\FR\FM\11SEP1.SGM 11SEP1 47912 Federal Register / Vol. 84, No. 176 / Wednesday, September 11, 2019 / Proposed Rules jspears on DSK3GMQ082PROD with PROPOSALS difficile infection not responsive to standard therapies and the impact of the enforcement policy on such development. DATES: The public hearing will be held on November 4, 2019, from 9 a.m. to 4 p.m. The hearing may be extended or may end early, depending on the level of public participation. Persons seeking to present or speak at the public hearing must register by October 8, 2019. Persons seeking to attend but not present at the public hearing must register by October 22, 2019. Section III of this document provides attendance and registration information. Electronic or written comments will be accepted after the public hearing until January 21, 2020. ADDRESSES: The public hearing will be held at the FDA White Oak Campus, 10903 New Hampshire Ave., Bldg. 31 Conference Center, the Great Room (Rooms 1503B and 1503C), Silver Spring, MD 20993–0002. Entrance for public hearing participants (non-FDA employees) is through Building 1, where routine security check procedures will be performed. For parking and security information, please refer to https:// www.fda.gov/about-fda/white-oakcampus-information/public-meetingsfda-white-oak-campus. You may submit comments as follows. Please note that late, untimely filed comments will not be considered. Electronic comments must be submitted on or before January 21, 2020. The https://www.regulations.gov electronic filing system will accept comments until 11:59 p.m. Eastern Time at the end of January 21, 2020. Comments received by mail/hand delivery/courier (for written/paper submissions) will be considered timely if they are postmarked or the delivery service acceptance receipt is on or before that date. Electronic Submissions Submit electronic comments in the following way: • Federal eRulemaking Portal: https://www.regulations.gov. Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to https:// www.regulations.gov will be posted to the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else’s Social Security number, or confidential business information, such as a manufacturing process. Please note VerDate Sep<11>2014 17:11 Sep 10, 2019 Jkt 247001 that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on https://www.regulations.gov. • If you want to submit a comment with confidential information that you do not wish to be made available to the public submit the comment as a written/ paper submission and in the manner detailed (see ‘‘Written/Paper Submissions’’ and ‘‘Instructions’’). Written/Paper Submissions Submit written/paper submissions as follows: • Mail/Hand Delivery/Courier (for written/paper submissions): Dockets Management Staff (HFA–305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. • For written/paper comments submitted to the Dockets Management Staff, FDA will post your comment, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in ‘‘Instructions.’’ Instructions: All submissions received must include the Docket No. FDA– 2019–N–3631 for ‘‘Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies.’’ Received comments, those filed in a timely manner (see ADDRESSES), will be placed in the docket and, except for those submitted as ‘‘Confidential Submissions,’’ publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday. • Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states ‘‘THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.’’ The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on https://www.regulations.gov. Submit both copies to the Dockets Management Staff. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as PO 00000 Frm 00007 Fmt 4702 Sfmt 4702 ‘‘confidential.’’ Any information marked as ‘‘confidential’’ will not be disclosed except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA’s posting of comments to public dockets, see 80 FR 56469, September 18, 2015, or access the information at: https://www.gpo.gov/ fdsys/pkg/FR-2015-09-18/pdf/201523389.pdf. Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to https:// www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the ‘‘Search’’ box and follow the prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. FOR FURTHER INFORMATION CONTACT: Shruti Modi, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993–0002, 240– 402–7911. SUPPLEMENTARY INFORMATION: I. Background and Purpose of the Public Hearing Fecal microbiota collected from healthy individuals are being investigated for use in the treatment of C. difficile infection. Published data suggest that the use of fecal microbiota to restore intestinal flora may be an effective therapy in the management of C. difficile infection not responsive to standard therapies. However, the efficacy and safety profiles of this intervention have not yet been fully evaluated in adequate and wellcontrolled clinical trials. FMT administered to treat C. difficile infection meets the definition of a biological product, as defined in section 351(i) of the Public Health Service (PHS) Act (42 U.S.C. 262(i)), and the definition of a drug within the meaning of section 201(g) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(g)). As a biological product, FMT administered to treat C. difficile infection is subject to the licensing requirements set forth in section 351 of the PHS Act. FDA has received public comments from some stakeholders suggesting that FMT might be regulated as a human cell, tissue, and cellular and tissue-based product (HCT/P; see 21 CFR part 1271). FMT is a live biotherapeutic product composed of microorganisms. Microorganisms are not human cells or tissues and do not meet the definition of HCT/P (see 21 CFR 1271.3(d)). The hearing will not E:\FR\FM\11SEP1.SGM 11SEP1 jspears on DSK3GMQ082PROD with PROPOSALS Federal Register / Vol. 84, No. 176 / Wednesday, September 11, 2019 / Proposed Rules include discussions about these comments. In the Federal Register of July 18, 2013 (78 FR 42965), following a public workshop, held on May 2 and 3, 2013, entitled ‘‘Fecal Microbiota for Transplantation,’’ FDA announced the availability of a guidance for industry entitled ‘‘Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies’’ (July 2013 Guidance) (available at: https:// www.fda.gov/media/86440/download). The July 2013 Guidance, which is still in effect, informed members of the medical and scientific communities and other interested persons that we intend to exercise enforcement discretion regarding the investigational new drug (IND) requirements for the use of FMT to treat C. difficile infection not responding to standard therapies, provided that the treating physician obtains adequate consent from the patient or his or her legally authorized representative for the use of FMT products. The guidance states that consent should include, at a minimum, a statement that the use of FMT products to treat C. difficile is investigational and a discussion of its potential risks. In the Federal Register of February 26, 2014 (79 FR 10814), we announced the availability of a draft guidance for industry entitled ‘‘Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies’’ (March 2014 Draft Guidance). The March 2014 Draft Guidance informed members of the medical and scientific communities and other interested persons that we intended to exercise enforcement discretion regarding the IND requirements for the use of FMT to treat C. difficile infection not responding to standard therapies, provided: (1) The licensed healthcare provider treating the patient obtains adequate consent from the patient or his or her legally authorized representative for use of the FMT product; (2) the FMT product is obtained from a donor known to either the patient or the licensed healthcare provider treating the patient; and (3) the stool donor and stool are qualified by screening and testing performed under the direction of the licensed healthcare provider for the purpose of providing the FMT product to treat his or her patient. FDA received many public comments in favor of patient access to FMT to treat C. VerDate Sep<11>2014 17:11 Sep 10, 2019 Jkt 247001 difficile, including access to FMT products from stool banks, but objecting to the provision that the donor be known to the patient or the treating licensed healthcare provider. After considering the comments on the March 2014 Draft Guidance, in the Federal Register of March 1, 2016 (81 FR 10632), FDA announced the availability of a revised draft guidance for industry entitled ‘‘Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies’’ (March 2016 Draft Guidance) (available at: https://www.fda.gov/media/96562/ download). The March 2016 Draft Guidance replaced the March 2014 Draft Guidance and proposed to revise our policy with regard to patient access to FMT product. We noted that centralized manufacturing in stool banks presents safety concerns related to the use of FMT from a limited number of donors administered to multiple patients. Therefore, we stated that FDA does not intend to extend enforcement discretion with respect to the IND requirements applicable to stool banks distributing FMT products. We stated that the sponsor’s compliance with the IND requirements would help to ensure that the stool donor and stool are appropriately qualified by screening and testing and that centralized processing of FMT adheres to appropriate current good manufacturing conditions. FDA received many public comments on this draft guidance, and we are continuing to evaluate our enforcement policy. The purpose of this public hearing is to obtain public input on the state of the science regarding FMT to treat C. difficile infection not responsive to standard therapies, including the available clinical evidence for safety and effectiveness of FMT for this use and to understand better the impact of FDA’s enforcement policy on product development. II. Issues for Consideration and Request for Data and Information FDA would like input from stakeholders, including patients, clinicians, research scientists, industry, healthcare providers, and stool banks. We encourage public comments and presentations at the public hearing. If submitting comments, data, and information to the docket, please identify available references for the data and information, as well as the general category area and specific question listed below. As noted above, fecal microbiota collected from healthy individuals are PO 00000 Frm 00008 Fmt 4702 Sfmt 4702 47913 being investigated for use in the treatment of C. difficile infection. Published data suggest that the use of fecal microbiota to restore intestinal flora may be an effective therapy in the management of refractory C. difficile infection. However, the efficacy and safety profiles of this intervention have not yet been fully evaluated in controlled clinical trials. To inform FDA’s understanding of the current scientific status of FMT, especially as it relates to the use of FMT to treat C. difficile infection not responsive to standard therapies, we are interested in obtaining information, including data and studies, from all stakeholders, including patients, clinicians, research scientists, industry, healthcare providers and stool banks on the following topics: 1. Clinical Evidence of Effectiveness • What is the strength of the evidence for the use of FMT to treat C. difficile infection not responsive to standard therapies? • Please identify any published data from rigorously conducted randomized controlled (placebo or non-FMT standard of care comparator) trials that support the use of FMT for: Æ Prevention of recurrent C. difficile infection. Æ Treatment of refractory C. difficile infection. 2. Safety Evaluation • What is the strength of evidence for the safety of FMT in patients with C. difficile infection not responsive to standard therapies? • Has meaningful safety information been collected under FDA’s enforcement policy? How can any deficiencies in safety data collection be remedied? • Are there particular safety issues FDA should consider regarding these products (e.g., donor screening/mixing donations)? 3. Impact of FDA’s current Enforcement Policy on FMT Product Development • What impact has FDA’s enforcement policy had on recruitment and ability to conduct clinical trials to assess safety and effectiveness of FMT for C. difficile infection not responsive to standard therapies? Æ Can specific examples be cited? Æ How can any negative impacts be remedied? • How does the existing availability of FMT affect the incentives for, and the feasibility of, FMT drug-development programs? • The use of FMT is addressed in some treatment guidelines (Infectious E:\FR\FM\11SEP1.SGM 11SEP1 47914 Federal Register / Vol. 84, No. 176 / Wednesday, September 11, 2019 / Proposed Rules Diseases Society of America and American Gastroenterological Association). What impact has this had on patient recruitment and conduct of clinical trials? jspears on DSK3GMQ082PROD with PROPOSALS 4. Future and Path Forward • What additional scientific information is needed to determine the safety and effectiveness of FMT for C. difficile infection not responsive to standard therapies? • How generalizable are the existing safety and effectiveness data on use of a specific FMT product for C. difficile infection not responsive to standard therapies to other FMT products for which safety and effectiveness data are not available? • Please comment on how FDA can facilitate patient access, protect patient safety, and include enough flexibility to support innovation for the development and licensure of safe and effective FMT products for C. difficile infection not responsive to standard therapies. III. Participating in the Public Hearing Registration and Requests to Speak and for Formal Oral Presentations: The FDA Conference Center at the White Oak location is a Federal facility with security procedures and limited seating. Attendance will be free. An agenda for the hearing and any other background materials will be made available on October 25, 2019, at https:// www.fda.gov/vaccines-blood-biologics/ news-events-biologics/workshopsmeetings-conferences-biologics. If you need special accommodations because of a disability, please contact Sherri Revell or Loni Warren Henderson at 240–402–8010 at least 7 days before the hearing. For those interested in speaking at the hearing or presenting at the hearing with a formal oral presentation, please register at https://www.eventbrite.com/ e/use-of-fecal-microbiota-fortransplantation-to-treat-clostridiumdifficile-infection-not-responsive-tickets63906239282 as ‘‘In-person presenter.’’ Speaker and presenter registrations are due October 8, 2019. FDA will try to accommodate all persons who wish to make a formal oral presentation. Formal oral presenters may use an accompanying slide deck. Individuals wishing to present should identify their name, which stakeholder group they represent (e.g., patient, clinician, research scientist, industry, stool bank), and the number of the specific question, or questions, they wish to address. FDA will consider this information when organizing the agenda. Individuals and organizations with common interests should consider VerDate Sep<11>2014 17:11 Sep 10, 2019 Jkt 247001 consolidating or coordinating their presentations and request time for a joint presentation. Individual organizations are limited to a single presentation slot. FDA will notify registered presenters of their scheduled presentation times on October 21, 2019. The time allotted for each presentation will depend on the number of individuals who wish to speak. If registered presenters are using an accompanying slide deck, those presenters must submit an electronic copy of their presentation (PowerPoint or PDF) to CBERPublicEvents@ fda.hhs.gov on or before October 28, 2019. Persons registered to present are encouraged to arrive at the hearing room early and check in at the onsite registration table to confirm their designated presentation time. Actual presentation times, however, may vary based on how the hearing progresses in real time. In-person attendance: For those who would like to attend in-person, but who are not making a formal presentation, please register at https:// www.eventbrite.com/e/use-of-fecalmicrobiota-for-transplantation-to-treatclostridium-difficile-infection-notresponsive-tickets-63906239282 as ‘‘Inperson attendee—no participation.’’ Seating is limited, and early registration is recommended to allow for broad participation. Streaming Webcast of the Public Hearing: For those unable to attend in person, FDA will provide a live webcast of the hearing. Please register at https:// www.eventbrite.com/e/use-of-fecalmicrobiota-for-transplantation-to-treatclostridium-difficile-infection-notresponsive-tickets-63906239282 as ‘‘online (webcast only)’’. Media: Please register at https:// www.eventbrite.com/e/use-of-fecalmicrobiota-for-transplantation-to-treatclostridium-difficile-infection-notresponsive-tickets-63906239282 as ‘‘Media’’ by October 28, 2019. Transcripts: Please be advised that as soon as a transcript is available, it will be accessible at https://www.fda.gov/ vaccines-blood-biologics/news-eventsbiologics/workshops-meetingsconferences-biologics and https:// www.regulations.gov. It may be viewed at the Dockets Management Staff (see ADDRESSES). IV. Notification of Hearing Under 21 CFR Part 15 The Commissioner of Food and Drugs is announcing that the public hearing will be held in accordance with part 15 (21 CFR part 15). The hearing will be conducted by a presiding officer, who will be accompanied by FDA senior PO 00000 Frm 00009 Fmt 4702 Sfmt 4702 management officials. Under § 15.30(f) (21 CFR 15.30(f)), the hearing is informal and the rules of evidence do not apply. No participant may interrupt the presentation of another participant. Only the presiding officer and panel members may question any person during or at the conclusion of each presentation. Public hearings under part 15 are subject to FDA’s policy and procedures for electronic media coverage of FDA’s public administrative proceedings (21 CFR part 10, subpart C). Under 21 CFR 10.205, representatives of the electronic media may be permitted, subject to certain limitations, to videotape, film, or otherwise record FDA’s public administrative proceedings, including presentations by participants. Persons attending FDA’s public hearings are advised that the Agency is not responsible for providing access to electrical outlets. The hearing will be transcribed as stipulated in § 15.30(b) (see section III of this document). To the extent that the conditions for the hearing, as described in this notification, conflict with any provisions set out in part 15, this notification acts as a waiver of those provisions as specified in § 15.30(h). Dated: September 5, 2019. Lowell J. Schiller, Principal Associate Commissioner for Policy. [FR Doc. 2019–19643 Filed 9–10–19; 8:45 am] BILLING CODE 4164–01–P ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 52 [EPA–R03–OAR–2019–0207; FRL–9999–64– Region 3] Approval and Promulgation of Air Quality Implementation Plans; District of Columbia; Reasonably Available Control Technology State Implementation Plan for Nitrogen Oxides Under the 2008 Ozone National Ambient Air Quality Standard Environmental Protection Agency (EPA). ACTION: Proposed rule. AGENCY: The Environmental Protection Agency (EPA) is proposing to approve a state implementation plan (SIP) revision submitted by the District of Columbia. This revision pertains to reasonably available control technology (RACT) requirements for nitrogen oxides (NOX) under the 2008 8-hour ozone national ambient air quality standard (2008 ozone NAAQS). The District of Columbia’s submittal for the NOX RACT SUMMARY: E:\FR\FM\11SEP1.SGM 11SEP1

Agencies

[Federal Register Volume 84, Number 176 (Wednesday, September 11, 2019)]
[Proposed Rules]
[Pages 47911-47914]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-19643]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 15

[Docket No. FDA-2019-N-3631]


Use of Fecal Microbiota for Transplantation to Treat Clostridium 
difficile Infection Not Responsive to Standard Therapies; Public 
Hearing; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notification of public hearing; request for comments.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
announcing a public hearing to obtain input on the use of fecal 
microbiota for transplantation (FMT) to treat Clostridium difficile 
infection not responsive to standard therapies. FDA will consider 
scientific data and other information from the public hearing as we 
continue to consider ways to support the development of FMT to treat C.

[[Page 47912]]

difficile infection not responsive to standard therapies and the impact 
of the enforcement policy on such development.

DATES: The public hearing will be held on November 4, 2019, from 9 a.m. 
to 4 p.m. The hearing may be extended or may end early, depending on 
the level of public participation. Persons seeking to present or speak 
at the public hearing must register by October 8, 2019. Persons seeking 
to attend but not present at the public hearing must register by 
October 22, 2019. Section III of this document provides attendance and 
registration information. Electronic or written comments will be 
accepted after the public hearing until January 21, 2020.

ADDRESSES: The public hearing will be held at the FDA White Oak Campus, 
10903 New Hampshire Ave., Bldg. 31 Conference Center, the Great Room 
(Rooms 1503B and 1503C), Silver Spring, MD 20993-0002. Entrance for 
public hearing participants (non-FDA employees) is through Building 1, 
where routine security check procedures will be performed. For parking 
and security information, please refer to https://www.fda.gov/about-fda/white-oak-campus-information/public-meetings-fda-white-oak-campus.
    You may submit comments as follows. Please note that late, untimely 
filed comments will not be considered. Electronic comments must be 
submitted on or before January 21, 2020. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of January 21, 2020. Comments 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are postmarked or the delivery 
service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2019-N-3631 for ``Use of Fecal Microbiota for Transplantation to 
Treat Clostridium difficile Infection Not Responsive to Standard 
Therapies.'' Received comments, those filed in a timely manner (see 
ADDRESSES), will be placed in the docket and, except for those 
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Shruti Modi, Center for Biologics 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 240-
402-7911.

SUPPLEMENTARY INFORMATION: 

I. Background and Purpose of the Public Hearing

    Fecal microbiota collected from healthy individuals are being 
investigated for use in the treatment of C. difficile infection. 
Published data suggest that the use of fecal microbiota to restore 
intestinal flora may be an effective therapy in the management of C. 
difficile infection not responsive to standard therapies. However, the 
efficacy and safety profiles of this intervention have not yet been 
fully evaluated in adequate and well-controlled clinical trials.
    FMT administered to treat C. difficile infection meets the 
definition of a biological product, as defined in section 351(i) of the 
Public Health Service (PHS) Act (42 U.S.C. 262(i)), and the definition 
of a drug within the meaning of section 201(g) of the Federal Food, 
Drug, and Cosmetic Act (21 U.S.C. 321(g)). As a biological product, FMT 
administered to treat C. difficile infection is subject to the 
licensing requirements set forth in section 351 of the PHS Act. FDA has 
received public comments from some stakeholders suggesting that FMT 
might be regulated as a human cell, tissue, and cellular and tissue-
based product (HCT/P; see 21 CFR part 1271). FMT is a live 
biotherapeutic product composed of microorganisms. Microorganisms are 
not human cells or tissues and do not meet the definition of HCT/P (see 
21 CFR 1271.3(d)). The hearing will not

[[Page 47913]]

include discussions about these comments.
    In the Federal Register of July 18, 2013 (78 FR 42965), following a 
public workshop, held on May 2 and 3, 2013, entitled ``Fecal Microbiota 
for Transplantation,'' FDA announced the availability of a guidance for 
industry entitled ``Enforcement Policy Regarding Investigational New 
Drug Requirements for Use of Fecal Microbiota for Transplantation to 
Treat Clostridium difficile Infection Not Responsive to Standard 
Therapies'' (July 2013 Guidance) (available at: https://www.fda.gov/media/86440/download). The July 2013 Guidance, which is still in 
effect, informed members of the medical and scientific communities and 
other interested persons that we intend to exercise enforcement 
discretion regarding the investigational new drug (IND) requirements 
for the use of FMT to treat C. difficile infection not responding to 
standard therapies, provided that the treating physician obtains 
adequate consent from the patient or his or her legally authorized 
representative for the use of FMT products. The guidance states that 
consent should include, at a minimum, a statement that the use of FMT 
products to treat C. difficile is investigational and a discussion of 
its potential risks.
    In the Federal Register of February 26, 2014 (79 FR 10814), we 
announced the availability of a draft guidance for industry entitled 
``Enforcement Policy Regarding Investigational New Drug Requirements 
for Use of Fecal Microbiota for Transplantation to Treat Clostridium 
difficile Infection Not Responsive to Standard Therapies'' (March 2014 
Draft Guidance). The March 2014 Draft Guidance informed members of the 
medical and scientific communities and other interested persons that we 
intended to exercise enforcement discretion regarding the IND 
requirements for the use of FMT to treat C. difficile infection not 
responding to standard therapies, provided: (1) The licensed healthcare 
provider treating the patient obtains adequate consent from the patient 
or his or her legally authorized representative for use of the FMT 
product; (2) the FMT product is obtained from a donor known to either 
the patient or the licensed healthcare provider treating the patient; 
and (3) the stool donor and stool are qualified by screening and 
testing performed under the direction of the licensed healthcare 
provider for the purpose of providing the FMT product to treat his or 
her patient. FDA received many public comments in favor of patient 
access to FMT to treat C. difficile, including access to FMT products 
from stool banks, but objecting to the provision that the donor be 
known to the patient or the treating licensed healthcare provider.
    After considering the comments on the March 2014 Draft Guidance, in 
the Federal Register of March 1, 2016 (81 FR 10632), FDA announced the 
availability of a revised draft guidance for industry entitled 
``Enforcement Policy Regarding Investigational New Drug Requirements 
for Use of Fecal Microbiota for Transplantation to Treat Clostridium 
difficile Infection Not Responsive to Standard Therapies'' (March 2016 
Draft Guidance) (available at: https://www.fda.gov/media/96562/download). The March 2016 Draft Guidance replaced the March 2014 Draft 
Guidance and proposed to revise our policy with regard to patient 
access to FMT product. We noted that centralized manufacturing in stool 
banks presents safety concerns related to the use of FMT from a limited 
number of donors administered to multiple patients. Therefore, we 
stated that FDA does not intend to extend enforcement discretion with 
respect to the IND requirements applicable to stool banks distributing 
FMT products. We stated that the sponsor's compliance with the IND 
requirements would help to ensure that the stool donor and stool are 
appropriately qualified by screening and testing and that centralized 
processing of FMT adheres to appropriate current good manufacturing 
conditions. FDA received many public comments on this draft guidance, 
and we are continuing to evaluate our enforcement policy.
    The purpose of this public hearing is to obtain public input on the 
state of the science regarding FMT to treat C. difficile infection not 
responsive to standard therapies, including the available clinical 
evidence for safety and effectiveness of FMT for this use and to 
understand better the impact of FDA's enforcement policy on product 
development.

II. Issues for Consideration and Request for Data and Information

    FDA would like input from stakeholders, including patients, 
clinicians, research scientists, industry, healthcare providers, and 
stool banks. We encourage public comments and presentations at the 
public hearing. If submitting comments, data, and information to the 
docket, please identify available references for the data and 
information, as well as the general category area and specific question 
listed below.
    As noted above, fecal microbiota collected from healthy individuals 
are being investigated for use in the treatment of C. difficile 
infection. Published data suggest that the use of fecal microbiota to 
restore intestinal flora may be an effective therapy in the management 
of refractory C. difficile infection. However, the efficacy and safety 
profiles of this intervention have not yet been fully evaluated in 
controlled clinical trials. To inform FDA's understanding of the 
current scientific status of FMT, especially as it relates to the use 
of FMT to treat C. difficile infection not responsive to standard 
therapies, we are interested in obtaining information, including data 
and studies, from all stakeholders, including patients, clinicians, 
research scientists, industry, healthcare providers and stool banks on 
the following topics:

1. Clinical Evidence of Effectiveness

     What is the strength of the evidence for the use of FMT to 
treat C. difficile infection not responsive to standard therapies?
     Please identify any published data from rigorously 
conducted randomized controlled (placebo or non-FMT standard of care 
comparator) trials that support the use of FMT for:
    [cir] Prevention of recurrent C. difficile infection.
    [cir] Treatment of refractory C. difficile infection.

2. Safety Evaluation

     What is the strength of evidence for the safety of FMT in 
patients with C. difficile infection not responsive to standard 
therapies?
     Has meaningful safety information been collected under 
FDA's enforcement policy? How can any deficiencies in safety data 
collection be remedied?
     Are there particular safety issues FDA should consider 
regarding these products (e.g., donor screening/mixing donations)?

3. Impact of FDA's current Enforcement Policy on FMT Product 
Development

     What impact has FDA's enforcement policy had on 
recruitment and ability to conduct clinical trials to assess safety and 
effectiveness of FMT for C. difficile infection not responsive to 
standard therapies?
    [cir] Can specific examples be cited?
    [cir] How can any negative impacts be remedied?
     How does the existing availability of FMT affect the 
incentives for, and the feasibility of, FMT drug-development programs?
     The use of FMT is addressed in some treatment guidelines 
(Infectious

[[Page 47914]]

Diseases Society of America and American Gastroenterological 
Association). What impact has this had on patient recruitment and 
conduct of clinical trials?

4. Future and Path Forward

     What additional scientific information is needed to 
determine the safety and effectiveness of FMT for C. difficile 
infection not responsive to standard therapies?
     How generalizable are the existing safety and 
effectiveness data on use of a specific FMT product for C. difficile 
infection not responsive to standard therapies to other FMT products 
for which safety and effectiveness data are not available?
     Please comment on how FDA can facilitate patient access, 
protect patient safety, and include enough flexibility to support 
innovation for the development and licensure of safe and effective FMT 
products for C. difficile infection not responsive to standard 
therapies.

III. Participating in the Public Hearing

    Registration and Requests to Speak and for Formal Oral 
Presentations: The FDA Conference Center at the White Oak location is a 
Federal facility with security procedures and limited seating. 
Attendance will be free. An agenda for the hearing and any other 
background materials will be made available on October 25, 2019, at 
https://www.fda.gov/vaccines-blood-biologics/news-events-biologics/workshops-meetings-conferences-biologics. If you need special 
accommodations because of a disability, please contact Sherri Revell or 
Loni Warren Henderson at 240-402-8010 at least 7 days before the 
hearing.
    For those interested in speaking at the hearing or presenting at 
the hearing with a formal oral presentation, please register at https://www.eventbrite.com/e/use-of-fecal-microbiota-for-transplantation-to-treat-clostridium-difficile-infection-not-responsive-tickets-63906239282 as ``In-person presenter.'' Speaker and presenter 
registrations are due October 8, 2019.
    FDA will try to accommodate all persons who wish to make a formal 
oral presentation. Formal oral presenters may use an accompanying slide 
deck. Individuals wishing to present should identify their name, which 
stakeholder group they represent (e.g., patient, clinician, research 
scientist, industry, stool bank), and the number of the specific 
question, or questions, they wish to address. FDA will consider this 
information when organizing the agenda. Individuals and organizations 
with common interests should consider consolidating or coordinating 
their presentations and request time for a joint presentation. 
Individual organizations are limited to a single presentation slot. FDA 
will notify registered presenters of their scheduled presentation times 
on October 21, 2019. The time allotted for each presentation will 
depend on the number of individuals who wish to speak. If registered 
presenters are using an accompanying slide deck, those presenters must 
submit an electronic copy of their presentation (PowerPoint or PDF) to 
[email protected] on or before October 28, 2019. Persons 
registered to present are encouraged to arrive at the hearing room 
early and check in at the onsite registration table to confirm their 
designated presentation time. Actual presentation times, however, may 
vary based on how the hearing progresses in real time.
    In-person attendance: For those who would like to attend in-person, 
but who are not making a formal presentation, please register at 
https://www.eventbrite.com/e/use-of-fecal-microbiota-for-transplantation-to-treat-clostridium-difficile-infection-not-responsive-tickets-63906239282 as ``In-person attendee--no 
participation.'' Seating is limited, and early registration is 
recommended to allow for broad participation.
    Streaming Webcast of the Public Hearing: For those unable to attend 
in person, FDA will provide a live webcast of the hearing. Please 
register at https://www.eventbrite.com/e/use-of-fecal-microbiota-for-transplantation-to-treat-clostridium-difficile-infection-not-responsive-tickets-63906239282 as ``online (webcast only)''.
    Media: Please register at https://www.eventbrite.com/e/use-of-fecal-microbiota-for-transplantation-to-treat-clostridium-difficile-infection-not-responsive-tickets-63906239282 as ``Media'' by October 
28, 2019.
    Transcripts: Please be advised that as soon as a transcript is 
available, it will be accessible at https://www.fda.gov/vaccines-blood-biologics/news-events-biologics/workshops-meetings-conferences-biologics and https://www.regulations.gov. It may be viewed at the 
Dockets Management Staff (see ADDRESSES).

IV. Notification of Hearing Under 21 CFR Part 15

    The Commissioner of Food and Drugs is announcing that the public 
hearing will be held in accordance with part 15 (21 CFR part 15). The 
hearing will be conducted by a presiding officer, who will be 
accompanied by FDA senior management officials. Under Sec.  15.30(f) 
(21 CFR 15.30(f)), the hearing is informal and the rules of evidence do 
not apply. No participant may interrupt the presentation of another 
participant. Only the presiding officer and panel members may question 
any person during or at the conclusion of each presentation. Public 
hearings under part 15 are subject to FDA's policy and procedures for 
electronic media coverage of FDA's public administrative proceedings 
(21 CFR part 10, subpart C).
    Under 21 CFR 10.205, representatives of the electronic media may be 
permitted, subject to certain limitations, to videotape, film, or 
otherwise record FDA's public administrative proceedings, including 
presentations by participants. Persons attending FDA's public hearings 
are advised that the Agency is not responsible for providing access to 
electrical outlets.
    The hearing will be transcribed as stipulated in Sec.  15.30(b) 
(see section III of this document). To the extent that the conditions 
for the hearing, as described in this notification, conflict with any 
provisions set out in part 15, this notification acts as a waiver of 
those provisions as specified in Sec.  15.30(h).

    Dated: September 5, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-19643 Filed 9-10-19; 8:45 am]
 BILLING CODE 4164-01-P