Document ID: FDA-2019-N-3631-0001
Agency: fda
Document Type: Proposed Rule
Title: Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies; Public Hearing; Request for Comments
Posted Date: 2019-09-11T04:00Z

[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.

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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 
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-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