Federal Register / Vol. 83, No. 151 / Monday, August 6, 2018 / Notices 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Draft Guidance for Industry; 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written comments on the draft guidance 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draft guidance before it begins work on 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 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 


sradovich on DSK3GMQ082PROD with NOTICES
38316 Federal Register / Vol. 83, No. 151 / Monday, August 6, 2018 / 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. 

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 

AGENCY: Office of the Secretary, HHS. 

ACTION: Notice. 

SUMMARY: 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 

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. 


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