[Federal Register Volume 83, Number 151 (Monday, August 6, 2018)]
[Notices]
[Pages 38315-38316]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-16726]



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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Products; Draft Guidance for Industry; Availability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the availability of a draft guidance for industry entitled 
``Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug 
Products.'' The document provides guidance regarding 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 other 
chronic uses.

DATES: Submit either electronic or written comments on the draft 
guidance by October 5, 2018 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 
version of the guidance.

ADDRESSES: You may submit comments on any guidance at any time as 
follows:

Electronic Submissions

    Submit electronic comments in the following way:
    <bullet> 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.
    <bullet> 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:
    <bullet> 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.
    <bullet> 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; Draft Guidance for Industry; Availability.'' 
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.
    <bullet> 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.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of the draft 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 draft 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 draft guidance for industry 
entitled ``Nonclinical Testing of Orally Inhaled Nicotine-Containing 
Drug Products.'' This document provides guidance on the nonclinical 
information FDA recommends to support development and approval of 
orally inhaled nicotine-containing drug products for smoking cessation 
and other chronic uses.
    The recommended nonclinical assessment as outlined in the guidance 
addresses safety of novel components of the drug product formulation, 
novel chemicals generated from any component of the drug product 
formulation by the delivery system, and novel impurities. As used in 
the guidance, the phrase novel component of the 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 other chronic uses are expected to involve 
continuous use or chronic intermittent use resulting in 6

[[Page 38316]]

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 components 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 (Refs 1-4). 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 draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent 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. This guidance 
is not subject to Executive Order 12866.

II. Paperwork Reduction Act of 1995

    This guidance refers to previously approved collections of 
information that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). 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 draft guidance 
at either https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or 
https://www.regulations.gov.

IV. References

    The following reference marked with an asterisk (*) is on display 
at the Dockets Management Staff (see ADDRESSES) and is available for 
viewing by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday; it also is available electronically at https://www.regulations.gov. References without asterisks are not on display 
because they have copyright restriction, or they are available as 
published articles and books. Please contact the person identified in 
the FOR FURTHER INFORMATION CONTACT section to schedule a date to 
inspect references without asterisks.

1. Madsen, L.R., N.H. Vinther Krarup, T.K. Bergmann, et al., 2016, 
``A Cancer That Went Up in Smoke: Pulmonary Reaction to E-Cigarettes 
Imitating Metastatic Cancer,'' Chest, 149(3):e65-67.
2. Ghosh, A., R.C. Coakley, T. Mascenik, et al., 2018, ``Chronic E-
Cigarette Exposure Alters the Human Bronchial Epithelial Proteome,'' 
American Journal of Respiratory and Critical Care Medicine, epub 
ahead of print February 26, 2018, doi: 10.1164/rccm.201710-2033OC.
* 3. Olmedo, P., W. Goessler, S. Tanda, et al., 2018, ``Metal 
Concentrations in E-Cigarette Liquid and Aerosol Samples: The 
Contribution of Metallic Coils,'' Environmental Health Perspectives, 
126(2): doi: 10.1289/EHP2175.
4. Rubinstein, M.L., K. Delucchi, N.L. Benowitz, and D.E. Ramo, 
2018, ``Adolescent Exposure to Toxic Volatile Organic Chemicals From 
E-Cigarettes,'' Pediatrics, epub ahead of print March 5, 2018, doi: 
10.1542/peds.2017-3557.

    Dated: July 31, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-16726 Filed 8-3-18; 8:45 am]
 BILLING CODE 4164-01-P