[Federal Register Volume 84, Number 234 (Thursday, December 5, 2019)]
[Notices]
[Pages 66669-66671]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-26266]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-5464]


Novel Excipient Review Program Proposal; Request for Information 
and Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for information and comments.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
announcing the establishment of a docket to obtain information and 
comments that will assist the Agency in determining whether it should 
establish a pilot program for the toxicological and

[[Page 66670]]

quality evaluation of novel excipients intended for use in human drugs. 
The Agency hopes to obtain information and comments on several aspects 
of such a program before deciding whether to develop it.

DATES: Submit written or electronic comments and information on the 
notice by February 3, 2020.

ADDRESSES: 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 February 3, 2020. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of February 3, 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-5464 for ``Novel Excipient Review Program Proposal; Request 
for Information and Comments.'' 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: Karen Davis Bruno, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 6428, Silver Spring, MD 20993-0002, 301-
796-1199, karen.davisbruno@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background

    We use the term ``excipient'' in this notice to mean any ingredient 
intentionally added to a drug product (including biological drug 
products) that is not intended to exert therapeutic effects at the 
intended dosage, although it may improve product delivery (see FDA 
guidance for industry ``Nonclinical Studies for the Safety Evaluation 
of Pharmaceutical Excipients'' (Excipients guidance), May 2005, p. 1 
(available at https://www.fda.gov/media/72260/download)). The term 
``inactive ingredient'' is often used to mean the same thing. Examples 
of excipients include fillers, extenders, diluents, wetting agents, 
solvents, emulsifiers, preservatives, flavors, absorption enhancers, 
sustained-release matrices, and coloring agents (see Excipients 
guidance, pp. 1-2). For purposes of this notice, FDA would expect a 
novel excipient to be an excipient that has not been previously used in 
FDA-approved drug products and that does not have established use in 
food.
    FDA reviews excipients used in a drug product as part of an 
investigational new drug application (IND) or a marketing application 
to determine whether they are safe for use in human pharmaceuticals. 
Historically, FDA has not reviewed the safety of novel excipients 
outside the context of an IND, a new drug application (NDA), or a 
biologics license application (BLA) describing a finished product to 
which the excipient has been added.\1\
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    \1\ A proposed drug product that contains an excipient that 
would require clinical investigations to establish safety of the 
excipient for use in a particular drug product would not be 
permitted in an abbreviated new drug application (ANDA) but may be 
submitted in a 505(b)(2) application.
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    Stakeholders have encouraged FDA to establish a program for the 
submission and review of toxicological and quality data supporting the 
use of novel excipients in drug products outside the context of an IND, 
an NDA, or a BLA. They state that certain novel excipients may provide 
public health benefits, such as improved drug delivery or utility in 
abuse-deterrent opioid formulations, for example. Proponents of an FDA 
novel excipient review program believe FDA's recognition of a novel 
excipient would reassure drug developers that the novel excipient can 
be used in a drug development program

[[Page 66671]]

while minimizing the risk that safety concerns would be raised by FDA 
during application review. They have also cited a perceived risk 
aversion on the part of drug developers, such that novel excipients may 
be avoided in drug development programs, even when the excipients have 
potential public health benefits.
    With this information in mind, FDA's Center for Drug Evaluation and 
Research is considering developing a pilot program for the 
toxicological and quality evaluation of novel excipients. The Agency 
seeks information and comment on several aspects of such a program 
before deciding whether to develop it.

II. Possible Approach To Reviewing Novel Excipients

    FDA is considering establishing a pilot program that would review a 
limited number of submissions per year. Any program developed by the 
Agency would be voluntary. FDA recognition of a novel excipient would 
not be necessary for the novel excipient to be included in a finished 
drug product described in an IND, an NDA, or a BLA.
    Generally, FDA anticipates that a submission to a potential novel 
excipient review program would include toxicological studies supporting 
the safety of the novel excipient at anticipated levels and duration of 
exposure, by anticipated routes of administration. Additionally, FDA 
anticipates that submitters would provide identification and control 
information, including compositional and purity specifications for the 
novel excipient (see Excipients guidance).
    FDA recognition of a novel excipient would mean that, based on a 
review of safety, manufacturing, and compositional information, FDA has 
determined that the proposed context of use (e.g., acute or chronic 
exposure by specified route(s) of administration up to specified 
amounts) is expected to be safe. This determination would obviate the 
need for FDA review of the excipient in the context of an IND if its 
use in the investigational product is consistent with the recognized 
context of use. In the case of an NDA or a BLA seeking marketing 
approval or licensure of a finished drug or biological product 
containing a recognized excipient, FDA would review all information in 
the application relating to safety of the finished product. FDA expects 
that excipients reviewed under this program, after they are used in 
approved formulations, would be listed in the Inactive Ingredient 
Database.

III. Requested Information and Comments

    Interested persons are invited to provide detailed comment on all 
aspects of this issue. Please read the information above regarding the 
submission of comments and confidential information. FDA is 
particularly interested in responses to the following questions:
    1. What drug development challenges do drug sponsors encounter that 
could be addressed by using novel excipients?
    2. Can stakeholders identify examples (specific or general) of 
novel excipients that have potential public health benefits?
    3. FDA anticipates that a novel excipient recognition program would 
be limited to excipients that do not have a well-established history of 
safe use in food and that have potential public health benefits. We 
would be interested in stakeholder comment on these criteria.
    4. Would FDA recognition of a novel excipient be sufficient to 
overcome any reluctance on the part of drug developers to use the novel 
excipient in a drug development program? Do drug development sponsors 
also look for a history of safe use in marketed drug products?
    5. FDA envisions that an individual excipient manufacturer 
participating in a novel excipient recognition program would submit a 
complete package of safety data and certain chemistry, manufacturing, 
and controls information to support FDA's recognition of a novel 
excipient. This data and information would be based upon nonclinical 
studies of sufficient quality and quantity to allow for a safety 
evaluation, consistent with the Excipients guidance. We would be 
interested in stakeholder comment on this approach.
    6. Are there adequate incentives for excipient manufacturers to 
engage in this process, particularly in situations in which multiple 
manufacturers may be undertaking to develop closely related novel 
excipients? If not, what incentives would encourage excipient 
manufacturers to engage in this process?
    7. What information, if any, should FDA affirmatively disclose 
about a novel excipient evaluated under an eventual program in order to 
ensure the success of the program? For example, should FDA's evaluation 
be posted and explained publicly? Please note that FDA would handle 
disclosure of information submitted under the program in accordance 
with applicable law.

    Dated: December 2, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-26266 Filed 12-4-19; 8:45 am]
BILLING CODE 4164-01-P


