[Federal Register Volume 85, Number 210 (Thursday, October 29, 2020)]
[Notices]
[Pages 68582-68584]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-23999]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-D-2583]


Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug 
Products; Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a final guidance for industry entitled 
``Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug 
Products.'' The document provides guidance about the nonclinical 
information FDA recommends to support development and approval of 
orally inhaled nicotine-containing drug products, including electronic 
nicotine delivery systems intended for smoking cessation and related 
chronic indications. This guidance finalizes the draft guidance of the 
same name issued August 6, 2018.

DATES: The announcement of the guidance is published in the Federal 
Register on October 29, 2020.

ADDRESSES: You may submit either electronic or written comments on 
Agency guidances at any time as follows:

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

[[Page 68583]]

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-2018-D-2583 for ``Nonclinical Testing of Orally Inhaled Nicotine-
Containing Drug Products.'' Received comments 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, 240-
402-7500.
     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.govinfo.gov/content/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, 240-402-7500.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of this guidance to the 
Division of Drug Information, Center for Drug Evaluation and Research, 
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale 
Building, 4th Floor, Silver Spring, MD 20993-0002. Send one self-
addressed adhesive label to assist that office in processing your 
requests. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Alina Salvatore, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, Rm. 5418, Silver Spring, MD 20903-0002, 240-
402-0379.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a final guidance for industry 
entitled ``Nonclinical Testing of Orally Inhaled Nicotine-Containing 
Drug Products.'' The recommended nonclinical assessment as outlined in 
the guidance addresses safety of novel chemicals of the drug product 
formulation, novel chemicals generated from any chemical of the drug 
product formulation by the delivery system, and novel impurities. As 
used in the guidance, the phrase novel chemicals of the drug product 
formulation refers to active and inactive ingredients intentionally 
added to the drug product that have not been approved in drugs at an 
equal or greater dose, for an equal or greater duration of use, or by a 
relevant route of administration sufficient to characterize toxicity 
via local and systemic exposure. FDA expects that in many cases use of 
the delivery system will generate novel chemicals (e.g., heat-generated 
products).
    Orally inhaled nicotine-containing drug products developed for 
smoking cessation and related chronic indications are expected to 
involve continuous use or chronic intermittent use resulting in 6 
months or more exposure over a lifetime. Because of the duration of 
use, the nonclinical assessment for marketing approval should include 
general toxicity studies, developmental and reproductive toxicity 
studies, an assessment of carcinogenic potential, and supporting 
toxicokinetic and pharmacokinetic studies.
    FDA is aware of the serious risk associated with smoking and is 
committed to facilitating the development of therapies to support 
smoking-cessation efforts. This guidance focuses on novel chemicals of 
the drug product formulation, heat-generated products, and impurities 
that are generally not well characterized. Orally inhaled nicotine-
containing tobacco products, including electronic nicotine delivery 
systems currently marketed in the United States, have already been 
associated with toxicity concerns. An adequate nonclinical assessment, 
as described in this guidance, can address the potential toxicity of 
chemicals from orally inhaled nicotine-containing drug products. As 
noted in the guidance, sponsors can use an alternative approach if that 
approach provides adequate safety information.
    This guidance finalizes the draft guidance of the same name issued 
August 6, 2018 (83 FR 38315). Changes from the draft to the final 
include the following:

 More information to guide the nonclinical development of an 
active ingredient in addition to nicotine
 Clarification on absorption, distribution, metabolism, and 
excretion studies, consistent with previous reference to the 
International Council for Harmonisation guidance for industry entitled 
``M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical 
Trials and Marketing Authorization for Pharmaceuticals'' (January 2010)
 Reference to the draft guidance for industry entitled ``Formal 
Meetings Between the FDA and Sponsors or Applicants of PDUFA 
[Prescription Drug User Fee Amendments] Products'' (December 2017), 
which describes the process through which sponsors can request meetings
 Clarification on how sponsors can compare the exposure to 
nicotine in an approved drug by providing

[[Page 68584]]

pharmacokinetic information (e.g., Cmax, Tmax, 
area under the curve) from the proposed drug product
 An example of how systemic toxicity could be addressed by a 
nonclinical toxicity study conducted with a noninhalation route of 
exposure
 Clarification that local effects in oral or respiratory tract 
tissues are best addressed with a nonclinical inhalation study

    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). The guidance represents the 
current thinking of FDA on ``Nonclinical Testing of Orally Inhaled 
Nicotine-Containing Drug Products.'' It does not establish any rights 
for any person and is not binding on FDA or the public. You can use an 
alternative approach if it satisfies the requirements of the applicable 
statutes and regulations.

II. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does 
refer to previously approved FDA collections of information. Therefore, 
clearance by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521) is not required 
for this guidance. The previously approved collections of information 
are subject to review by OMB under the PRA. The collections of 
information in 21 CFR part 312 have been approved under OMB control 
number 0910-0014. The collections of information resulting from special 
protocol assessments have been approved under OMB control number 0910-
0470.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at 
either https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs or https://www.regulations.gov.

    Dated: October 23, 2020.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2020-23999 Filed 10-28-20; 8:45 am]
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