83 FR 38315 - Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug Products; Draft Guidance for Industry; Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 83, Issue 151 (August 6, 2018)

Page Range		38315-38316
FR Document		2018-16726

The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled ``Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug Products.''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.

Federal Register, Volume 83 Issue 151 (Monday, August 6, 2018)

[Federal Register Volume 83, Number 151 (Monday, August 6, 2018)]
[Notices]
[Pages 38315-38316]
From the Federal Register Online [www.thefederalregister.org]
[FR Doc No: 2018-16726]

[[Page 38315]]

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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Products; Draft Guidance for Industry; Availability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.

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

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the availability of a draft guidance for industry entitled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DATES: Submit either electronic or written comments on the draft
guidance by October 5, 2018 to ensure that the Agency considers your
comment on this draft guidance before it begins work on the final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:
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-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.
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.thefederalregister.org/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

38316 Federal Register / Vol. 83, No. 151 / Monday, August 6, 2018 / Notices

months or more exposure over a IV. References Neurological Disorders and Stroke
lifetime. Because of the duration of use, The following reference marked with (NINDS), National Institutes of Health
the nonclinical assessment for an asterisk (*) is on display at the (NIH), grants R01 NS039860 and R01
marketing approval should include Dockets Management Staff (see NS064976–01A2. The administrative
general toxicity studies, developmental ADDRESSES) and is available for viewing actions, including five (5) years of
and reproductive toxicity studies, an by interested persons between 9 a.m. debarment, were implemented
assessment of carcinogenic potential, and 4 p.m., Monday through Friday; it beginning on July 13, 2018, and are
and supporting toxicokinetic and also is available electronically at https:// detailed below.
pharmacokinetic studies. www.regulations.gov. References FOR FURTHER INFORMATION CONTACT:
FDA is aware of the serious risk Wanda K. Jones, Dr.P.H., Interim
without asterisks are not on display
associated with smoking and is Director, Office of Research Integrity,
because they have copyright restriction,
committed to facilitating the 1101 Wootton Parkway, Suite 750,
or they are available as published
development of therapies to support Rockville, MD 20852, (240) 453–8200.
articles and books. Please contact the
smoking cessation efforts. This guidance
person identified in the FOR FURTHER SUPPLEMENTARY INFORMATION:
focuses on novel components of the
INFORMATION CONTACT section to Christian Kreipke, Ph.D., Wayne State
drug product formulation, heat-
schedule a date to inspect references University: ORI issued a charge letter
generated products, and impurities that
without asterisks. enumerating findings of research
are generally not well characterized.
1. Madsen, L.R., N.H. Vinther Krarup, T.K. misconduct and proposing HHS
Orally inhaled nicotine-containing
Bergmann, et al., 2016, ‘‘A Cancer That administrative actions. Dr. Kreipke
tobacco products, including electronic
Went Up in Smoke: Pulmonary Reaction (‘‘Respondent’’) subsequently requested
nicotine delivery systems currently
to E-Cigarettes Imitating Metastatic a hearing before an Administrative Law
marketed in the United States, have Cancer,’’ Chest, 149(3):e65–67. Judge (ALJ) of the Departmental Appeals
already been associated with toxicity 2. Ghosh, A., R.C. Coakley, T. Mascenik, et Board to dispute these findings. A
concerns (Refs 1–4). An adequate al., 2018, ‘‘Chronic E-Cigarette Exposure hearing before the ALJ was held on July
nonclinical assessment, as described in Alters the Human Bronchial Epithelial
this guidance, can address the potential Proteome,’’ American Journal of
10–12, 2017. On May 31, 2018, the ALJ
toxicity of chemicals from orally Respiratory and Critical Care Medicine, issued his recommended decision,
inhaled nicotine-containing drug epub ahead of print February 26, 2018, finding that Respondent recklessly
products. As noted in the guidance, doi: 10.1164/rccm.201710–2033OC. caused or permitted twenty-three (23)
* 3. Olmedo, P., W. Goessler, S. Tanda, et al., instances of research misconduct in his
sponsors can use an alternative 2018, ‘‘Metal Concentrations in E-
approach if that approach provides three (3) grant applications, two (2)
Cigarette Liquid and Aerosol Samples: articles on which he was the first listed
adequate safety information. The Contribution of Metallic Coils,’’
This draft guidance is being issued Environmental Health Perspectives,
author, and two (2) posters on which he
consistent with FDA’s good guidance 126(2): doi: 10.1289/EHP2175. was the first listed author. The ALJ held
practices regulation (21 CFR 10.115). 4. Rubinstein, M.L., K. Delucchi, N.L. that appropriate administrative actions
The draft guidance, when finalized, will Benowitz, and D.E. Ramo, 2018, included a five-year debarment from
represent the current thinking of FDA ‘‘Adolescent Exposure to Toxic Volatile any contracting or subcontracting with
Organic Chemicals From E-Cigarettes,’’ any agency of the United States and
on nonclinical testing of orally inhaled Pediatrics, epub ahead of print March 5,
nicotine-containing drug products. It from eligibility for or involvement in
2018, doi: 10.1542/peds.2017–3557. nonprocurement programs of the United
does not establish any rights for any
Dated: July 31, 2018. States referred to as ‘‘covered
person and is not binding on FDA or the
public. You can use an alternative Leslie Kux, transactions.’’ 2 CFR parts 180 and 376.
approach if it satisfies the requirements Associate Commissioner for Policy. The ALJ held it was an appropriate
of the applicable statutes and [FR Doc. 2018–16726 Filed 8–3–18; 8:45 am] administrative action to also impose a
regulations. This guidance is not subject BILLING CODE 4164–01–P five-year prohibition from serving in
to Executive Order 12866. any capacity to the U.S. Public Health
Service (PHS), including but not limited
II. Paperwork Reduction Act of 1995 DEPARTMENT OF HEALTH AND to, service on any PHS advisory
This guidance refers to previously HUMAN SERVICES committee, board, or peer review
approved collections of information that committee, or as a consultant. The ALJ
are subject to review by the Office of Office of the Secretary noted that ORI also had proposed that
Management and Budget (OMB) under the publisher of certain articles be
Findings of Research Misconduct notified of the need to retract those
the Paperwork Reduction Act of 1995
(44 U.S.C. 3501–3520). The collections AGENCY: Office of the Secretary, HHS. articles and that retraction had already
of information in 21 CFR part 312 have ACTION: Notice. occurred by the time of his
been approved under OMB control recommended decision.
number 0910–0014. The collections of SUMMARY: Notice is hereby given that on Under the regulation, the ALJ’s
information resulting from special July 13, 2018, the U.S. Department of recommended decision went to the
protocol assessments have been Health and Human Services (HHS) Assistant Secretary for Health, who did
approved under OMB control number Debarring Official, on behalf of the not modify it and forwarded it to the
0910–0470. Secretary of HHS, issued a final notice HHS Debarring Official, who is the
of debarment based on an deciding official for the debarment. The
sradovich on DSK3GMQ082PROD with NOTICES

III. Electronic Access Administrative Law Judge’s findings of ALJ decision constituted the findings of
Persons with access to the internet research misconduct against Christian fact to the HHS Debarring Official in
may obtain the draft guidance at either Kreipke, Ph.D., former Research accordance with 2 CFR 180.845(c). On
https://www.fda.gov/Drugs/Guidance Associate Professor, Wayne State July 13, 2018, the HHS Debarring
ComplianceRegulatoryInformation/ University. Dr. Kreipke engaged in Official issued a final notice of
Guidances/default.htm or https:// research misconduct in research debarment to begin on July 13, 2018,
www.regulations.gov. supported by National Institute of and end on July 12, 2023.

VerDate Sep<11>2014 17:36 Aug 03, 2018 Jkt 244001 PO 00000 Frm 00044 Fmt 4703 Sfmt 4703 E:\FR\FM\06AUN1.SGM 06AUN1

Document Created: 2018-11-06 10:36:45
Document Modified: 2018-11-06 10:36:45

Category		Regulatory Information
Collection		Federal Register
sudoc Class		AE 2.7: GS 4.107: AE 2.106:
Publisher		Office of the Federal Register, National Archives and Records Administration
Section		Notices
Action		Notice of availability.
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.
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.
FR Citation		83 FR 38315

83 FR 38315 - Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug Products; Draft Guidance for Industry; Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICESFood and Drug Administration

Federal Register Volume 83, Issue 151 (August 6, 2018)

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration