Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug Products; Draft Guidance for Industry; Availability, 38315-38316 [2018-16726]

Download as PDF Federal Register / Vol. 83, No. 151 / Monday, August 6, 2018 / Notices Written/Paper Submissions 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Administration [Docket No. FDA–2018–D–2583] Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug Products; Draft Guidance for Industry; Availability AGENCY: Food and Drug Administration, HHS.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. The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled ‘‘Nonclinical Testing of Orally Inhaled Nicotine-Containing Drug Products.’’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 DATES: Submit either electronic or written comments on the draft guidance by October 5, 2018 to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance.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: sradovich on DSK3GMQ082PROD with NOTICES SUMMARY: 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’’). VerDate Sep<11>2014 17:36 Aug 03, 2018 Jkt 244001 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.gpo.gov/ fdsys/pkg/FR-2015-09-18/pdf/201523389.pdf. Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to https:// PO 00000 Frm 00043 Fmt 4703 Sfmt 4703 38315 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 nicotinecontaining 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 E:\FR\FM\06AUN1.SGM 06AUN1 38316 Federal Register / Vol. 83, No. 151 / Monday, August 6, 2018 / Notices sradovich on DSK3GMQ082PROD with NOTICES 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, heatgenerated 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/Guidance ComplianceRegulatoryInformation/ Guidances/default.htm or https:// www.regulations.gov. VerDate Sep<11>2014 17:36 Aug 03, 2018 Jkt 244001 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 ECigarette 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 DEPARTMENT OF HEALTH AND HUMAN SERVICES Office of the Secretary Findings of Research Misconduct Office of the Secretary, HHS. Notice. AGENCY: ACTION: Notice is hereby given that on July 13, 2018, the U.S. Department of Health and Human Services (HHS) Debarring Official, on behalf of the Secretary of HHS, issued a final notice of debarment based on an Administrative Law Judge’s findings of research misconduct against Christian Kreipke, Ph.D., former Research Associate Professor, Wayne State University. Dr. Kreipke engaged in research misconduct in research supported by National Institute of SUMMARY: PO 00000 Frm 00044 Fmt 4703 Sfmt 4703 Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), grants R01 NS039860 and R01 NS064976–01A2. The administrative actions, including five (5) years of debarment, were implemented beginning on July 13, 2018, and are detailed below. FOR FURTHER INFORMATION CONTACT: Wanda K. Jones, Dr.P.H., Interim Director, Office of Research Integrity, 1101 Wootton Parkway, Suite 750, Rockville, MD 20852, (240) 453–8200. SUPPLEMENTARY INFORMATION: Christian Kreipke, Ph.D., Wayne State University: ORI issued a charge letter enumerating findings of research misconduct and proposing HHS administrative actions. Dr. Kreipke (‘‘Respondent’’) subsequently requested a hearing before an Administrative Law Judge (ALJ) of the Departmental Appeals Board to dispute these findings. A hearing before the ALJ was held on July 10–12, 2017. On May 31, 2018, the ALJ issued his recommended decision, finding that Respondent recklessly caused or permitted twenty-three (23) instances of research misconduct in his three (3) grant applications, two (2) articles on which he was the first listed author, and two (2) posters on which he was the first listed author. The ALJ held that appropriate administrative actions included a five-year debarment from any contracting or subcontracting with any agency of the United States and from eligibility for or involvement in nonprocurement programs of the United States referred to as ‘‘covered transactions.’’ 2 CFR parts 180 and 376. The ALJ held it was an appropriate administrative action to also impose a five-year prohibition from serving in any capacity to the U.S. Public Health Service (PHS), including but not limited to, service on any PHS advisory committee, board, or peer review committee, or as a consultant. The ALJ noted that ORI also had proposed that the publisher of certain articles be notified of the need to retract those articles and that retraction had already occurred by the time of his recommended decision. Under the regulation, the ALJ’s recommended decision went to the Assistant Secretary for Health, who did not modify it and forwarded it to the HHS Debarring Official, who is the deciding official for the debarment. The ALJ decision constituted the findings of fact to the HHS Debarring Official in accordance with 2 CFR 180.845(c). On July 13, 2018, the HHS Debarring Official issued a final notice of debarment to begin on July 13, 2018, and end on July 12, 2023. E:\FR\FM\06AUN1.SGM 06AUN1

Agencies

[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]



[[Page 38315]]

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

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.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
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