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Technical Project Lead (TPL) Review of PMTAs 

New Products Subject to this Review; 

Submission tracking PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, and 

numbers (STNs) PM0004293 

Common Attributes 

Submission date April 2, 2020 (PM0000635, PM0000636, PM0004287) 

Receipt date April 2, 2020 (PM0000635, PM0000636, PM0004287) 

Submission date April 15, 2020 (PM0000646, PM0000712, PM0004293) 

Receipt date April 15, 2020 (PM0000646, PM0000712, PM0004293) 

Applicant R.J. Reynolds Vapor Company 

Product manufacturer R.J. Reynolds Vapor Company

Application type Standard 

Product category ENDS (VAPES) 

Product subcategory ENDS Component, Closed E-Liquid 

Cross-Referenced Submissions 

PM0000636, b (4 

PM0000712 

Supporting FDA Memoranda Relied Upon in this Review 

All STNs Remote Regulatory Assessment - Public Health Emergency (Pandemic), 

3/25/2021 

Recommendation 

Issue marketing granted order letter(s) for the new tobacco product(s) subject of this review. 

Technical Project Lead (TPL): Digitally signed by Lynn C. Hull -5 

Date: 2022.05.11 11 :27:20 -04100' 

Signatory Decision: 

Lynn C. Hull, Ph.D. 

Deputy Director 

Division of Individual Health Science 

Concur with TPL recommendation and basis of recommendation 

Digitally signed by Matthew R. Holman -S 

Date: 2022.05.12 06:34:21 -04'00' 

Matthew R. Holman, Ph.D. 

Director 

Office of Science 

; Tobacco product details, amendments, and dates provided in the Appendix. PMTA means premarket tobacco application. 

(b) (4)
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TABLE OF CONTENTS 

1. EXECUTIVE SUMMARY ..................................................................................................................... 4 

1.1. APPH STANDARD ............................................................................................................................. 4 

1.2. SUBJECT APPLICATIONS................................................................................................................... 6 

2. BACKGROUN D .................................................................................................................................. 7 

2.1. NEW PRODUCTS ..............................................................................................................................7 

2.2. REGULATORY ACTIVITY....................................................................................................................8 

2.3. SCOPE OF REVIEW ........................................................................................................................... 8 

3. SCIENTIFIC REVIEW .......................................................................................................................... 9 

3.1. COMPARISON PRODUCTS................................................................................................................ 9 

3.1.1. Discipline key findings ..................................................................................................... 9 

3.1.2. Synthesis........................................................................................................................ 11 

3.2. PRODUCT CHARACTERIZATION ..................................................................................................... 11 

3.2.1. Discipline key findings ................................................................................................... 11 

3.2.2. Synthesis........................................................................................................................ 16 

3.3. ABUSE LIABILITY............................................................................................................................. 20 

3.3.1. Discipline key findings ................................................................................................... 20 

3.3.2. Synthesis........................................................................................................................ 21 

3.4. USER POPULATIONS ...................................................................................................................... 21 

3.4.1. Discipline key findings ................................................................................................... 21 

3.4.2. Synthesis........................................................................................................................ 32 

3.5. TOXICANT EXPOSURE .................................................................................................................... 35 

3.5.1. Discipline key findings ................................................................................................... 35 

3.5.2. Synthesis........................................................................................................................ 35 

3.6. HEALTH EFFECTS ............................................................................................................................39 

3.6.1. Discipline key findings ...................................................................................................39 

3.6.2. Synthesis........................................................................................................................ 44 

3.7. POPULATION AND PUBLIC HEALTH ............................................................................................... 46 

3.7.1. Discipline key findings ................................................................................................... 46 

3.7.2. Synthesis........................................................................................................................ 47 

3.8. STATUTORY REQUIREMENTS......................................................................................................... 48 

3.8.1. Public health conclusion ................................................................................................ 48 

3.8.2. Tobacco product manufacturing practices .................................................................... 48 

3.8.3. Labeling ......................................................................................................................... 48 

3.8.4. Product standards ......................................................................................................... 48 

4. ENVIRONMENTAL DECISION........................................................................................................... 48 

4.1. DISCIPLINE FINDINGS.....................................................................................................................48 

4.2. ENVIRONMENTAL CONCLUSION ................................................................................................... 48 

5. CONCLUSION AND RECOMMENDATION ......................................................................................... 4 8 

6. REFERENCES................................................................................................................................... 51 

7. APPENDIX· ..................................................................................................................................... 54
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LIST OF TABLES 

Table 1. Disciplines reviewed ........................................................................................................................ 8 

Table 2. Consults ........................................................................................................................................... 8 

Table 3. New tobacco products subject to Granted Orders ....................................................................... 54 

Table 4. Amendments ................................................................................................................................. 56
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1. EXECUTIVE SUMMARY 

Based on the information provided in the application and other scientific data, as described in this 

Technical Project Lead (TPL) review, I find that permitting the marketing of the new products listed 

above ("new products") is appropriate for the protection of the public health (APPH) (subject to 

certain marketing restrictions) and that none of the other denial grounds specified in section 

910(c)(2) apply. Accordingly, I recommend that marketing granted orders be issued for the new 

products, subject to the marketing restrictions and post-market requirements. 

1.1. APPH STANDARD 

Section 910 of the FD&C Act requires that, for a product to receive a premarket tobacco product 

application (PMTA) marketing authorization, FDA must conclude, among other things, that 

permitting the product to be marketed would be APPH (Section 910(c)(2)(A)). The statute specifies 

that, in assessing APPH, FDA must consider the risks and benefits to the population as a whole, 

including both tobacco users and nonusers, taking into account the increased or decreased 

likelihood that existing users of tobacco products will stop using such products and the increased or 

decreased likelihood that those who do not use tobacco products will start using such products 

(Section 910(c)(4)). FDA interprets the APPH standard to require evidence that permitting the 

marketing of a new tobacco product would have a net benefit to public health based upon the risks 

and benefits to the population as a whole, which includes youth, young adults, and other vulnerable 

populations. In determining whether permitting the marketing of a new tobacco product would 

result in a net benefit to public health, FDA weighs the potential negative public health impacts (e.g., 

harm from initiation and use among nonusers, particularly youth) against the potential positive 

public health impacts (e.g., benefit from adult users of more harmful tobacco products completely 

switching). 

In making the APPH assessment for a noncombustible tobacco product such as an electronic 

nicotine delivery system (ENDS), FDA weighs, among other things, the negative public health impact 

stemming from youth initiation and use of the product against the potential positive public health 

impact stemming from adult cigarette smokers transitioning away from combustible cigarettes to 

the ENDS product. In order to show that an ENDS is APPH, an applicant must show that the benefits, 

including those to adult smokers, outweigh the risks, including those to youth, resulting in a net 

benefit to the public health. As the known risks of the product increase or decrease, the burden of 

demonstrating a substantial enough benefit likewise increases or decreases. For flavored ENDS;; (i.e., 

ENDS withe-liquid flavors other than tobacco or menthol, such as fruit), there is a known and 

substantial risk of youth initiation and use; accordingly, an applicant has a higher burden to establish 

that the likely benefits to adult smokers outweigh that risk. For tobacco-flavored ENDS the risk to 

youth is lower; accordingly, a lesser showing of benefit may suffice. Assessments for mentholflavored ENDS will be addressed separately. When it comes to evaluating the risks and benefits of a 

marketing authorization, the assessment for menthol ENDS, as compared to other flavored ENDS, 

raises unique considerations. 

In making the APPH assessment for a flavored ENDS, FDA has determined that it is appropriate to 

compare flavored ENDS with tobacco-flavored ENDS. Tobacco-flavored ENDS may offer the same 

type of public health benefit as flavored ENDS (i.e., increased switching and/or significant reduction 

ii Throughout this document, we use the term "flavored ENDS" to refer to ENDS with flavors other than tobacco or menthol. We 

use the term "menthol-flavored ENDS" or "menthol ENDS" to refer to ENDS flavored to impart a menthol flavor and the term 

"tobacco-flavored ENDS" or "tobacco ENDS" to refer to ENDS flavored to impart a tobacco flavor. 
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in smoking) but do not pose the same degree of risk of youth uptake. Whether other products, such 

as tobacco-flavored ENDS, give adult smokers comparable options for switching or cigarette 

reduction bears on the extent of the public health benefit that the subject ENDS arguably provide to 

that population. Therefore, in making the APPH determination for a flavored ENDS, FDA considers 

whether the applicant has provided acceptably strong evidence of an added benefit relative to that 

of tobacco-flavored ENDS in helping smokers completely switch from or significantly reduce their 

smoking. 

Before determining that permitting the marketing of a new tobacco product would be APPH, FDA 

also considers the impact of marketing restrictions and other mitigation efforts that aim to reduce 

the risk of youth initiation and tobacco use. Such mitigation efforts include advertising and 

promotion restrictions (e.g., measures such as limiting advertising to platforms that are 

predominantly used by adults and using advertising content and methods that are not known to 

resonate with youth); sales access restrictions (e.g., measures such as selling products only in face to 

face interactions, in adult-only facilities, or via websites that require robust age verification); and 

device access restrictions (e.g., technologies that require adult user identification by fingerprint or 

other biometric parameters in order to unlock and use a tobacco product). FDA evaluates these 

measures in the context of the overall public health evaluation of the product, weighing the known 

risks to youth against the benefit to adults. In the case of flavored ENDS, the risk of youth initiation 

and use is well documented and substantial. Experience shows that advertising and promotion 

restrictions and sales access restrictions cannot mitigate the substantial risk to youth from flavored 

ENDS sufficiently to reduce the magnitude of adult benefit required to demonstrate APPH. iii Rather, 

for flavored ENDS, only the most stringent mitigation measures - specifically device access 

restrictions - have such mitigation potential. iv In contrast, the risk of youth initiation and use with 

tobacco-flavored ENDS is lower. Restrictions on advertising and promotion and sales access for 

tobacco-flavored ENDS could mitigate that more limited risk and impact the overall net benefit 

assessment. In addition, rest rictions on advertising and promotion and sales access are important to 

include in marketing grant orders (MGOs) because t hey can help ensure that the marketing of a new 

tobacco product remains APPH after authorization. FDA has included such restrictions in MGOs 

issued to date. 

Finally, before determining that permitting the marketing of a tobacco product would be APPH, FDA 

also takes into account whether the applicant has provided sufficient information regarding product 

design, chemistry, stability, manufacturing controls including process controls and quality assurance 

procedures, toxicology, abuse liability, and other factors that can impact the product's risks and 

benefits to individual users, including relative to those of other tobacco products on the market. 

;;;See FDA, Enforcement Priorities for Electronic Nicotine Delivery Systems (ENDS) and Other Deemed Products on the Market 

Without Premarket Authorization (Revised): Guidance for Industry 44 (Apr. 2020) ("The reality is that youth have continued 

access to ENDS products in the face of legal prohibitions and even after voluntary actions by some manufacturers."); see also id. 

at 45 (noting "data that many youth obtain their ENDS products from friends or sources in their social networks"). 

iv Device access restrictions are novel and rare. To the extent flavored ENDS applicants purport to have device access 

restrictions (which, as components or parts of the product, would be discussed in the product formulation and engineering 

sections of a PMTA, rather than solely in the marketing plan), FDA's approach is to engage in further scientific review ofthose 

applications. 
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1.2. SUBJECT APPLICATIONS 

The new products are electronic nicotine delivery systems (ENDS) composed of disposable closed 

pre-filled e-liquid cartridges in Original flavor (PM0000636, Vuse Vibe Tank 3%; PM0000712, Vuse 

Ciro Cartridge 1.5%) and reusable/rechargeable power units (PM0000635, PM0004287 Vuse Vibe 

Power Units; PM0000646, PM0004293 Vuse Ciro Power Units). 

v 

FDA's evaluation of these PMTAs determined that they contain sufficient information to 

characterize the new products' composition and design, and that there are adequate process 

controls and quality assurance procedures to help ensure the new products are manufactured 

consistently. 

Based on the information provided in the PMTAs, the new products' abuse liability-Le., ability to 

promote continued use, addiction, or dependence- is lower than that of combusted cigarettes and 

higher than that of 4mg nicotine gum in ENDS na'ive exclusive smokers. The overall toxicological risk 

to the users of the new products is lower compared to cigarettes due to significant reductions in 

aerosol harmful and potentially harmful constituents (HPHCs) of the new products compared to 

cigarettes, as evidenced by results of nonclinical studies. Comparative HPHC analyses between 

combusted tobacco comparison products and the new products demonstrated that corresponding 

HPHCs from the new product aerosols were either below the limit of detection or substantially 

reduced on a unit per mg nicotine basis under both a non-intense and an intense puffing regimen. 

The available toxicological data indicates that the new products' aerosols are significantly less toxic 

than the combusted cigarette comparison data based on available HPHC data comparisons and 

results of nonclinical studies. Furthermore, HPHC levels observed from new product aerosols in eliquids (PM0000636 and PM0000712) were comparable to HPHC levels reported in twenty-two 

ENDS market comparison products. 

Furthermore, significant reductions in blood and urinary non-nicotine biomarkers of exposure (BOE) 

after switching from combusted cigarettes to the new products indicate that exposure to 

carcinogens and other toxicants present in cigarette smoke was greatly reduced in smokers who 

switched completely to use of the new products. No data was provided on the impact of long-term 

and dual use on BOE and the associated health risks. However, the currently available evidence 

indicates that smokers who switch completely to ENDS will have reduced toxic exposures and this 

likely leads to less risk of tobacco-related diseases. In the applicant's analysis, among all user groups 

(current established cigarette users, current established non-cigarette tobacco users, current 

tobacco experimenters, former tobacco users, and never tobacco users), current established 

cigarette users indicated among the highest intentions to purchase Vuse Vibe/Ciro products, and 

the most preferred flavor among these individuals was the tobacco (original) flavor compared to 

non-tobacco flavors (e.g., mint, tropical, nectar, melon, fusion, mango). Therefore, the applicant has 

demonstrated that current established adult cigarette users are particularly interested in the new 

tobacco-flavored products to assist in intended switching, and these products have the potential to 

benefit that group as compared to continued exclusive cigarette use. 

In terms of the risks to non-users, youth are considered a vulnerable population for various reasons, 

including that the majority of tobacco use begins before adulthood and thus youth are at particular 

risk of tobacco initiation. Existing evidence consistently indicates that use of tobacco-flavored ENDS 

v "Original" refers to the applicant-provided characterizing flavor for PM0000636 and PM0000712. FDA determined that no 

additional information regarding characterizing flavor was necessary. 
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is less common compared to non-tobacco flavored ENDS among youth. The applicant's study 

findings indicate that the tobacco flavor of the new products is less appealing (relative to the other 

flavors) to youth. In addition, the applicant's study findings indicated that appeal of the tobaccoflavored new products is low in adult non-users. Generally, nonusers view the new products as a risk 

to developing poorer health, rate them as unappealing, and a lower proportion of this group 

indicated interest in purchasing the new products compared to current tobacco users. Also, the 

applicant's study findings demonstrated lower intention to purchase the new products among adult 

never and former established tobacco users. Nonetheless, given the strong evidence regarding the 

impact of youth exposure to marketing on youth appeal and initiation of tobacco use, a marketing 

authorization should include marketing restrictions and post market requirements to help ensure 

that youth exposure to tobacco marketing is limited. Together, based on the information provided in 

the PMTAs and the available evidence, the potential to benefit smokers who switch completely or 

significantly reduce their cigarette use would outweigh the risk to youth, provided the applicant 

follows post-marketing requirements aimed at reducing youth exposure and access to the products. 

Regarding product s ·· applicant stated that the shelf-life of the new products (PM0000636

4 

and PM0000712) is The t::Jovided chemistry data to support that the new 

products are chemica y sta e over However, the applicant did not provide · · 

data that would allow FDA to evalua e w e er the products are microbially stable over

4 

icant instead provided data that suppor stability · of the products ave 

t:::.___j

4 

Because the m1crob1al stab1l1ty data for ts acceptable and 1nd1cates that t e 

products are low-risk for microbial growth over an . , 4 eriod, and because there are no other 

stability concerns, the lack of microbial data for oes not preclude an APPH finding for 

the products. 

Together, based on the information provided in the PMTAs and the available evidence, I find that 

permitting the marketing of the new products, subject to certain marketing restrictions, would be 

APPH. The potential of the new products to benefit smokers who significantly reduce their 

combusted cigarette use (or who switch completely and experience combusted cigarette cessation) 

outweighs the risk to youth, provided that the applicant follows post-marketing requirements and 

implements marketing restrictions to reduce youth exposure to marketing of the new products and 

youth access to the new products. 

FDA has examined the environmental effects of finding the new products APPH and made a Finding 

of No Significant Impact (FONSI). 

2. BACKGROUND

2.1. NEW PRODUCTS 

The applicant submitted information for the new products listed on the cover page (with more 

detail in the Appendix, Table 3), sold under the brand names Vuse Vibe and Vuse Ciro. The new 

products are electronic nicotine delivery systems (ENDS) comprised of disposable closed prefilled e-liquid cartridges in Originalv; (tobacco) flavor (PM0000636, Vuse Vibe Tank 3%; 

vi The applicant describes the "Original" products as tobacco-flavored throughout its PMTAs. For example, in Section A. (General

Information, Unique Identification Tables) and in Section C. (Descriptive Information, Unique Identification of the New Tobacco 

Products), the applicant describes the Vuse Vibe "Original" and the Vuse Ciro "Original" products as "a tobacco flavored eliquid." 

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

The appl

stability the

chemically stable over microbial

ts microbial r

h

d
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PM0000712, Vuse Ciro Cartridge 1.5%), a reusable/rechargeable power unit (PM0000635, 

PM0004287 Vuse Vibe Power Units; PM0000646, PM0004293 Vuse Ciro Power Units), and an 

accessory USB charger for the power unit. 

2.2. REGULATORY ACTIVITY 

On April 2, 2020 and April 15, 2020, FDA received 6 PMTAs from R.J. Reynolds Vapor Company. 

FDA issued Acceptance letters to the applicant on April 8, 2020, April 21, 2020, and 

December 11, 2020. FDA issued Filing letters to the applicant on April 17, 2020, May 4, 2020, 

and December 11, 2020. On November 9, 2020, FDA issued an Inspection Request Letter. A 

Deficiency letter was issued to the applicant on December 18, 2020. FDA issued a Correction 

Letter on February 17, 2021. FDA issued an Extension Denial Letter to the applicant on 

April 14, 2021. 

Refer to the Appendix for a complete list of amendments received by FDA. 

2.3. SCOPE OF REVIEW 

This review captures all compliance and scientific reviews completed for the new products 

subject to this review. 

Table 1. Disciplines reviewed 

Discipline Cycle 1 Cycle 2 

Reviewer(s) Review Date Reviewer(s) Review Date 

Regulatory Shireen Fotelargias 12/18/2020 Not Applicable 

(N/A) 

N/A 

Engineering Robert Meyer 12/17/2020 Robert Meyer 5/4/2022 

Chemistry Stephanie Daniels 12/15/2020 Stephanie Daniels 5/5/2022 

Microbiology Matthew Holman 12/15/2020 Prashanthi Mulinti 5/4/2022 

Toxicology Chad Brocker 12/15/2020 N/A N/A 

Behavioral and 

Clinical 

Pharmacology 

Rashmi Venkatesh 12/16/2020 Rashmi Venkatesh 5/5/2022 

Medical Omoye lmoisili 12/17/2020 Dara Lee 5/4/2022 

Epidemiology Gabriella Anic 12/16/2020 Bria Graham-Glover 5/9/2022 

Social Science Brittany Merson 12/21/2020 Brittany Merson 5/9/2022 

Environmental 

Science 

Bria Martin 12/14/2020 Bria Martin 5/5/2022 

OCE-BIMO Tara Singh 11/12/2020 Tara Singh 6/16/2021 

OCEManufacturing/Lab 

Jiali He 10/30/2020 N/A N/A 

Table 2. Consults 

Discipline Cycle 1 Cycle 2 

Reviewer(s) Review Date Reviewer(s) Review Date 

OCE- DPAL Julie Nguyen 11/23/2020 Julie Nguyen 5/5/2022 

OHCE Emily Talbert 10/21/2020 Allison O'Donnell 2/24/2022 

TPST Susan Rudy 10/1/2020 Susan Rudy 2/2/2022 
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3. SCIENTIFIC REVIEW 

3.1. COMPARISON PRODUCTS 

3.1.1. Discipline key findings 

The following discussion is based on key findings provided in the discipline reviews. 

3.1.1.1. Analytical evaluations and nonclinical studies 

Per the chemistry review: 

• The filtered cigarette, Newport Gold Non-Menthol KS Box (Newport Gold), was used 

as a comparison product to compare smoke yields of the cigarette to the aerosol 

yields of the new products. Newport Gold, which contains tobacco and uses burning 

coals as the heating source, is not in the same product category and subcategory as 

the new products. The applicant stated that the selection of Newport Gold as a 

comparison product was because it was the only R.J. Reynolds Tobacco Company 

(RJRT) cigarette with FDA marketing orders at the time the new products were 

tested. The chemistry review found Newport Gold to be an appropriate combusted 

tobacco comparison product as the applicant provided adequate data and rationale 

to support this choice. 

• HPHC aerosol yields of six currently marketed ENDS brands (Blu PLUS+ 2.4%, Logic 

Pro 2.4%, Mistie 2.0, JUUL 5.0%, myblu 2.4%, and Vuse Solo G2 4.8%), with a range 

of flavors for each brand, for a total of 22 e-cigarettes were used as comparison 

products to the new products. A reasonable justification for the six ENDS brand 

comparison products was provided stating these brands and flavors were market 

leaders in the U.S. as of 2017. 

Per the toxicology review: 

• Newport Gold cigarettes were chosen as the combusted tobacco comparison 

product. A reasonable justification was provided indicating this was the only RJRT 

cigarette available with an FDA marketing order at the time t he new product in vitro 

and in vivo studies were initiated. This combusted tobacco comparison product was 

used for the HPHC comparative analysis studies, in vitro toxicity studies, and in vivo 

inhalation studies. 

• Twenty-two closed e-cigarette market comparison products were chosen as the 

comparator ENDS to "ensure coverage ofa range ofaerosol deliveries as well as a 

range offlavors (tobacco, menthol, and fruit)" and because of their market 

leadership among closed e-cigarette ENDS at the time studies were initiated. The 

justification for the ENDS market comparison products is reasonable. These 22 ENDS 

market comparison products were compared to the new products in comparative 

HPHC analysis studies. For in vitro toxicity studies, select new products (i.e., 

PM0000636, PM0000712) were compared against select closed e-cigarette ENDS 

market comparison products (i.e., Blu PLUS+ Classic Tobacco, Magnificent Menthol, 

Cherry Crush; Logic Pro Tobacco, Menthol, Cherry; Vuse Solo G2 Original, Menthol, 

Mint, Tropical, Fusion, Melon, Nectar). 
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3.1.1.2. Clinical and Observational Studies 

Per the behavioral and clinical pharmacology (BCP) reviews: 

• The applicant used usual brand (UB) cigarettes and 4 mg nicotine gum in one clinical 

study intended to evaluate abuse liability of the Vuse Vibe and Ciro Original flavor 

products (PM0000636 and PM0000712). In another clinical study, the applicant 

provided historical pharmacokinetic data from UB regular cigarettes and UB 

menthol cigarettes as comparison data for the EViGO Original products and Menthol 

flavored products. The EViGO products are a precursor product to the Vuse Vibe. 

Finally, the applicant used non-menthol UB cigarettes in a clinical study to evaluate 

change in BOE after switching to the Vuse Vibe or Vuse Ciro products. 

• The rationale for choosing the comparison products in all studies was adequate. The 

applicant states that Vuse Vibe and Ciro products are intended as an alternative to 

combusted cigarettes; therefore, comparison to combusted cigarettes is 

appropriate. The comparison to nicotine gum was also appropriate since this 

product may be used by combusted cigarette smokers who are motivated to stop 

smoking and may use the Vuse Vibe and Ciro as an alternative to other nicotine 

replacement therapies such as nicotine gum. 

Per the toxicology review: 

• For clinical studies (such as BOE), select new products (i.e., PM0000635, 

PM0000636, PM0000646, PM0000712) were compared to the smokers' UB of 

combusted cigarette and the ENDS market comparison product Vuse Solo G2 

(Original flavor). 

Per the epidemiology review: 

• The observational studies do not have an explicit comparison product. However, the 

information provided suggests that adult current cigarette smokers are a likely user 

population of these new products; therefore, an important comparison is the use of 

the new products among cigarette smokers versus non-smokers. The observational 

st udies also evaluate whether the use of combusted cigarettes changes by different 

use patterns of the new products. Therefore, from an epidemiology perspective, the 

use of combusted cigarettes can be considered an important comparison product 

for these studies because current cigarette smokers are a likely user population. 

Per the medical review: 

• The rationale for choosing the comparison products, including other marketed ENDS 

as well as combusted cigarettes, was adequate from the medical perspective, across 

the eight submitted studies. 

Per the social science review: 

• The information provided by the applicant suggests that established combusted 

cigarette users are a likely user population of the new products. Therefore, from the 

social science perspective, comparisons between the new products and combusted 

cigarettes are appropriate. 
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3.1.2. Synthesis 

The applicant's rationale for the selection of combusted cigarette, 4mg nicotine gum, and 

other ENDS as comparison products of the new products is appropriate. The applicant 

provided adequate data to support the comparison between the new products and their 

chosen comparison products in their analytical, nonclinical, clinical, and observational 

studies to aid in the determination of whether the new products are APPH. 

As TPL, I agree with the chemistry, toxicology, and microbiology disciplines that the 

applicant provided adequate rationale for the selection of appropriate comparison products 

for their analytical and nonclinical studies. For these studies, including HPHC comparative 

analysis studies, in vitro toxicity studies, and in vivo inhalation studies, they used a filtered 

cigarette, Newport Gold Non-Menthol KS Box (Newport Gold) and currently marketed 

ENDSvii as their comparison products. The combusted cigarettes are not in the same product 

category and subcategory as the new products. Because the applicant states that the new 

products are intended for both current cigarette users and current ENDS users, the rationale 

for their selection of comparison products is appropriate. The rationale for selecting the 

ENDS comparison products is appropriate as they are in the same category and subcategory 

as the new products, were U.S. market leaders in 2017 for closed ENDS, and included a 

variety of flavors. 

As TPL, I agree with the BCP, toxicology, epidemiology, medical, and social science 

disciplines that the applicant's rationale for the selection of comparison products for their 

clinical studies is adequate. For the clinical and observational studies, the applicant used 

combusted cigarettes (UB cigarettes), ENDS product Vuse Solo G2 (Original flavor), and 

nicotine gum as the comparison products. The applicant has stated that the Vuse Vibe and 

Ciro products are intended as an alternative to combusted cigarettes; therefore, their 

rationale for selecting combusted cigarettes as comparison products is appropriate. The 

rationale for selecting nicotine gum as a comparison product was also appropriate as the 

applicant states that the new products may be used by combusted cigarette smokers who 

are motivated to stop smoking and may use the new products as an alternative to other 

nicotine replacement therapies such as nicotine gum. The rationale for selecting other 

marketed ENDS as comparison products is also appropriate as the applicant states that the 

target user population of the new products is other ENDS users. For the observational 

studies, the applicant examined the comparative health risks of the new products relative to 

combusted cigarettes, which is appropriate given that the applicant's stated target 

population of the new products includes combusted cigarette smokers. 

3.2. PRODUCT CHARACTERIZATION 

3.2.1. Discipline key findings 

The following discussion is based on key findings provided in the discipline reviews. 

3.2.1.1. Product design and composition 

Per the chemistry review: 

• Vuse Vibe products utilize a PET (polyethylene terephthalate; polyester) fiber disk 

and a polypropylene tank compared to a ceramic fiber disk and a polyetherimide 

vii Currently marketed ENDS as of 2017 when the studies were initiated. 
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tank in the EViGO (the predecessor product). Despite the material differences, the 

applicant justifies the use of chemical and toxicological study data for EViGO by 

adequately bridging it to Vuse Vibe products. 

• All data submitted for Vuse Solo+ can be used to evaluate the new product, Vuse

Ciro. The applicant stated that Vuse Solo+ and Vuse Ciro are identical in

·.,i ingredients and that the products only differed in name. Vuse Ciro uses

l 

(copolyester) tank that acts as the e-liquid reservoir.

• PM0000635, PM0000646, PM0004287, and PM0004293 are power units.

• PM0000636 and PM0000712 are disposable closed pre-filled e-liquid cartridges in

Original (tobacco) flavor.

• Both new product e-liquids contain nicotine (3% for Vibe (PM0000636) and

1.5% for Ciro (PM0000712)). These two products' ingredients vary in other

respects, namely various ratios of propylene glycol/glycerin (PG/VG), water,

and flavor ingredients.

• Both new product e-liquids contain

free-base nicotine. ,__ _____ _ 

• Both new product e-liquids contain lactic acid, which may form nicotine

salts. The applicant provided total nicotine aerosol quantities and pH under

non-intense and intense puffing regimens for both e-liquid new products.

The amounts of nicotine salts in the e-liquids were calculated by the

applicant from total nicotine and pH results. Although salts were

present Original tobacco-flavored ENDS productc_Jng/puff nonintenseQg/puff intense), the nicotine salt quantities in the Original

tobacco-flavored ENDS products were comparable to the nicotine salt

quantities reported in the ENDS market comparison products. Therefore,

the presence of lactic acid in the Original tobacco-flavored ENDS products is

not a concern from a chemistry perspective.

Per the engineering review: 

• The applicant adequately describes the Vuse Vibe and Vuse Ciro power unit and eliquid cartridge components and how they function together. The new products are

operated by connecting a specific disposable cartridge to the appropriate

rechargeable power unit. The system is activated by a user inhalation that is strong

enough to trigger an internal sensor that is imbedded in the power unit. The new

products are tamper-resistant and have no adjustable settings.

• The applicant provided the target specifications and upper and lower range limits

for all of the design parameters for the new products.

• The design specifications, defined by the applicant as a parameter with established

specifications that are measured and used to accept or reject products during

manufacture, are as follows:

• 

• 

• The new pro uc s o no con am empera ure con ro s an opera ea co1

temperatures ranging from 154-500°C for the Vuse Vibe and 115-264 •c for the Vuse 

Ciro when puffed at an 80 ml puff volume, 15 second puff interval, S second puff 

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

design and

nicotine

in the
Page 13of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 Page 13 of 56 

duration. BCP considers the applied intense smoke regime acceptable for evaluating 

the coil temperature. 

• From an engineering perspective, the information provided regarding design and

principles of operation adequately characterizes the new products and allows FDA

to evaluate the potential risk or injury that may be caused from using the new

products.

Per the microbiology review: 

• The new products contain humectants 1 

and which may impact mi e. 

However, the product stability data (see 3.2.1.3 below) indicates that the products 

are low risk for microbial growth. 

• The applicant provided adequate information on the type and concentration of

humectants that comprise the new products.

3.2.1.2. Manufacturing 

Per the chemistry review: 

• Target quantities forllJlt , , and used in the manufacturing of the e-liquid

formulations were provided. Ranges (maximum and minimum values) for n

used in the manufacturing of the e-liquid formulations were not provided. owever,

the applicant did providm "rejected low," "rejected high," and target e-liquid fill

weight for the cartridgec.Jo of the target value). The information provided is

acceptable for ensuring that the _ ___.and quantities in the finished

products are added in a consistent manner.

• The applicant provided sufficient details about the analytical testing methods used

to generate HPHC aerosol yields in the new products. The applicant also provided

sufficient information about the storage conditions and stability data to

demonstrate that the storage conditions for the finished products are adequate.

• Therefore, the information on the quantities o anc the finished

products, the HPHC aerosol data, the stability data, as well as the storage conditions

is considered adequate from a chemistry perspective and provides evidence that the

products are manufactured in a consistent manner that minimizes the variability in

product quality.

Per the engineering review: 

• The information on the manufacturing steps and the quality control measures in

place assure FDA that the products meet manufacturing specifications for the Vuse

Vibe and Vuse Ciro power units and cartridges. It is evident that the products are

manufactured in a consistent manner that minimizes the variability in product

quality.

• The applicant outlined how the batteries' manufacturers were asses

prior to their agreement and outlined how the batteries are verified

• e app ,cant prov, e stan ar operating proce ures or a attery

manufacturing and functional verifications. In addition, the applicant

(b)

(4)

(b) (4)

(b) (4)
Page 14of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 Page 14 of 56 

described how it is are involved in continuous monitoring of their battery 

manufacturers. 

• From review of the documents provided, the manufacturing information provided is

acceptable and demonstrates that the processes in place will ensure products are

manufactured properly and any non-conforming product will be identified and

removed from distribution.

Per the microbiology review: 

• A s

c

essrne

ct CB:

a

\

viii one at tbe ooao11 acturing and

pa

ckaging fac1h

t1est .... ...-,.. -__,,__ _ _,.._.,... __ Jwas conducted on 

March 08, 15, 22 and 25, 2021. No o jectionable conditions were found. 

3.2.1.3. Product stability 

Per the chemistry review: 

• The analytical methods used in the chemical stability studies were fit for purpose

and fully validated. '4 

• The a

;

rosol ields in PM0000636 and PM0000712 at t=O months, t=r

I and

t= w) .... emonstrate::J4 

· · • nt changes in the aerosol constituents over

their es a 1s ed shelf-lif or the new products. 

• The aerosol extractable an eac a e constituents' quantities from the e-liquid

replacement cartridge components (including simulated leachable study in artificial

saliva) and the aerosol leachables quantities from selected e-liquid replacement

cartridges were minor. Chemistry concluded that it is unlikely that product

characteristics negatively impact the aerosol extractable and leachable constituent

levels.

Per the microbiology review: 

• The microbial stability data is necessary for the proposed shelf-life as bacterial

communities change as a function of storage time. 1•

2 Increased microbial growth

over time can impact stability of the product and may result in an increased risk to 

public health as the product sits in storage.

• Microbial stability data (water activity, N-nitrosonornicotine [NNN], and 4-

(methylnitrosamino)-1- rid - I -1-butanone [NNK], endotoxin and (1➔3)-

glucan) measured over 4 of shelf-life was provided for PM0000636 and

PM0000712 (original to acco avored ENDS products). ThJ::l

. 

· ta indicates 

that the products are at low riskr::;· · I growth over ' However, the 

applicant's proposed shelf-life is " Therefore, the ata provided are 

sufficient to demonstrate microbia sta i ity over : ............. J. but not su!fticie?

t ta

demonstrate microbial stability over the applicant-proposed shelf-life of('

1 I 

3.2.1.4. Product test data 

Per the chemistry review: 

• The e-liquid ingredients and quantities in Vuse Vibe and EViGO (the predecessor

product) for the original characterizing flavor are similar. The applicant reported the

ingredients both in total mass (mg) per cartridge and in mass percent (mg

viii Due to the COVID-19 pandemic, an onsite inspection of the manufacturing facility was not possible.

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Remote Regulatory A of f

(3-py y β-D

tobacco fl
Page 15 of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 Page 15 of 56 

ingredient/mg total mass*lO0). Although the total mass of the e-liquid in the Vuse 

(Original) i4 l: ! Jng and the total mass of the e-liquid in Vuse Solo (Original) is 

g, the percentages of common ingredients in the Vuse Solo compared to the 

Vuse Vibe are similar. The similarities in e-liquid formulation for Vuse Solo and Vuse 

Vibe support bridging the results of studies of Vuse Solo to Vuse Vibe. The Vuse Solo 

products the applicant is referring to are Gl and G2. Vuse Solo G2 was used to 

bridge Vuse Vibe in the toxicology study and Vuse Solo Gl was used to bridge to 

Vuse Vibe in the Environmental Emission study. Chemistry reviewed the list of 

ingredients in EViGO and concluded that its ingredients and their quantities are 

similar to those of Vuse Vibe. EViGO was used to bridge to Vuse Vibe in thermal 

profiling and clinical studies. 

• The applicant stated that Vuse Solo+ and Vuse Ciro are identical in design and

ingredients and that the products only differ in name. Data submitted for Vuse

Solo+ can be used to evaluate the new product, Vuse Ciro.

• Compared to combusted filtered cigarettes, most of the aerosol yields under both

non-intense and intense smoking regimens in PM0000636 and PM0000712 were

lower, and chemistry did not have an issue with these values.

• The aerosol yields of constituents from the new products have higher mass

quantities of nicotine, acetaldehyde, and formaldehyde compared to those found

for the ENDS market comparison products. However, when reported in mass

percent (mg ingredient/mg total mass*lO0), the yields are comparable. The aerosol

yields of nicotine, acetaldehyde, and formaldehyde in the new products are

significantly below the levels present in cigarette smoke.

• The analytical methods used to test the aerosol HPHC quantities were fit for

purpose and fully validated.

• Aerosol HPHC yields reported for the new products under the intense puffing

regimen may not be representative of the maximum exposure to a consumer if the

maximum temperature of the heating element is reached. However, the applicant

provided a consumer topography report to adequately justify why it is unlikely that

a user will use a product to its functional limitations.

Per the engineering review: 

• The applicant provided test data for the battery design parameters for all batteries,

and it demonstrates the products are manufactured as intended. The batteries are

manufactured properly and function to meet International Electrotechnical

Commission (IEC) 62133, UN38.3, and UL 1642 battery standards.

• The PMTAs, PM0000635, PM0000636, and PM0004287 included thermal test

reports in which the test facility noted changes in wick color, and it was uncertain

whether the changes were due to dry puffing. FDA issued a deficiency to the

applicant to clarify whether these thermal test report results were due to dry

puffing. In response, the applicant submitted smoke testing data that applies an

intense smoking regimen, which FDA considers adequate and demonstrated the eliquid features associated with the new products adequately prevent a dry-puff

hazard from occurring. The test data also demonstrates that thermal temperatures

for PM0000635 and PM0004287 (the Vuse Vibe Power Units) are reasonably low

and do not pose a burn hazard to users. These concerns were not present for the

PM0000646 and PM0004293 Vuse Ciro power units.

(b)

(4)

(b)

(4) (b) (4)

Vibe (b) (4)

m
Page 16of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 Page 16 of 56 

• The test data demonstrates that the products will function as intended after

foreseeable conditions are applied.

• The leak test data provided in Amendment PM0004600 demonstrates that the eliquid cartridges are not likely to leak and that if a non-conforming product is

manufactured, leaking would likely be identified prior to distribution.

• The missing test data for coil diameter and coil len h is not a concern from an

engineering perspective, because

• Based on the information provided in the P MT As for the devices and cartridges,

adequate manufacturing processes and controls were used to ensure that the new

products meet manufacturer's specifications, and they will operate consistently

throughout the life of the product.

3.2.2. Synthesis 

As TPL, I agree with the engineering, chemistry, and microbiology conclusions that these 

PMTAs contain sufficient information to characterize the product design and adequate 

processes 

specifications. 

and controls 

The applicant 

to help 

only 

ensure 

s

that the products 

· robial stability 

meet the 

data 

man

for o 4 nd not 

for the entire proposed shelf-life of O 

'

4 However, because the torE:} 

m eptable and indicates at e products are low-risk for microbial growth over 

an -1 pef aod be use there are no other stability concerns, the lack of microbial 

sta , , y a a fo 

.... ___ __._ 

oes not preclude an APPH finding for the new products.

3.2.Z.1. Product Design and Composition 

The Vuse Vibe and Vuse Ciro new products are ENDS composed of closed pre-filled e-liquid 

cartridges (i.e., Vuse Vibe PM0000636, Vuse Ciro PM0000712) and a power unit (i.e., 

PM0000635, PM0004287 Vuse Vibe power units; PM0000646, PM0004293 Vuse Ciro power 

units). PM0000636 and PM0000712 consist of e-liquid cartridges in Original flavor with 3.0% 

nicotine in PM0000636 and 1.5% nicotine in PM0000712. The battery in the power units 

(PM0000635, PM0000646, PM0004287, and PM0004293) conform to product standards 

UN38.3, IEC 62133, and UL 1642. All four power units use a Universal Serial Bus (USB) 

charger to charge the power units. Two batteries are used in the Vuse Vibe Power Units with 

design parameter specifications that are not identical. Since both batteries can be used in 

the same power system assembly, to differentiate the Vu nits, PM0000635 is 

for the power unit that uses the battery manufactured by and PM0004287 is 

for the power unit that uses the battery manufactured b 

wo batteries were also used for the Vuse Ciro Power rn s; separa e num ers are 

used by CTP to differenti9-1,3. its: PM0000646 is for the power unit that uses the 

battery manufactured b and PM0004293 is for the power unit that uses the 

battery manufactured by 14 

The e-liquid formulations for the products in PM0000636 and PM0000712 are made up of 

PG, VG, nicotine, water, and flavor ingredients. Both e-liquids contair derived, 

=--------------;.1 free-base nicotine (3% for Vibe products and 1.5% for Ciro products). 

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b)

(4)

-1 (b) (4)

(b)(4) (4)(b)

(b) (b)(4)(b) (4)

(b) (b)(4)(b) (4)

1

4 

(b) (4)

submitted mic

onths is acc that the

period and because

stability data d

Vuse Vibe power units

T
Page 17 of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 Page 17 of 56 

Once the user has connected the power unit to a respective cartridge, the assembled unit is 

activated by inhaling air through the mouth-end of the cartridge. This puffing action and the 

resulting pressure differential activate the pressure sensor in the power unit. Activation of 

the pressure sensor signals the controller in the power unit to send power to the heater coil 

in the cartridge. The resistance of the cartridge is checked against a minimum threshold, and 

then the heater coil is powered for as long as the pressure sensor detects a pressure 

differential. PM0000635 and PM0004287 can be inhaled for a maximum of six seconds, and 

not be inhaled again for a roximatel three seconds. PM0000646 and PM0004293 can be 

inhaled for a maximum o and not be inhaled again for approximately three 

seconds. Users cannot alter t e power source battery or the cartridge reservoir without 

damaging the enclosures. The power units and cartridges are not user-adjustable, and this 

mitigates the potential for a consumer to change product characteristics, adjust product 

performance, or modify product ingredients. The cartridges are not designed to be opened, 

refilled, or otherwise modified by the consumer. The user can control how often they inhale 

and how much suction force is applied during inhalation. 

Summary 

As TPL, I agree with the engineering, chemistry, and microbiology conclusions that these 

PMTAs contain sufficient information to characterize the product design and composition of 

the new products. 

3.2.2.2. Manufacturing 

The applicant stated that the manufacturing of the ENDS in PM0000635, PM0000636, 

PM0000646, PM0000712, PM0004287, and PM0004293 consists of four processes (i

.

e., eliquid mixing, cartridge assembly and filling, power unit manufacturing, packaging). The eliquids in PM0000636 and PM0000712 were manufactured by RJRT in Tobaccoville, NC. The 

IV e

r , bulk e- I

1qu1 r units were shi 

( , 

.,._""'!'-._ __ 

car n ges 

s 

.,,,,,.,r,c 

. . . ere assembled. The 

L-------------------1=.-,----1----' or PM0000712, bulk eliquids were shipped from Tobaccoville, NC to bl 4 here cartridges (filled with eliquid, sealed in the blister packs) and packaging were completed. The applicant does not 

state where the USB charger for PM0000646 and PM0004293 is manufactured. However,

the USB charger's output is limited and controlled by the respective power units. In 

addition, the recharging function of the power unit and the associated charger were 

adequately demonstrated to function properly through testing. The finished ENDS are 

imported for distribution in the United States. 

For all new products (PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, and 

PM0004293), the applicant qualifies and monitors suppliers using processes governed by 

standard operating procedures. Processes are structured and implemented to prevent 

adverse material quality impact on finished products and to identifv events that reauire 

corrective and preventive action. These processes includerblt4

, 

14 (b) (4)

1

4 

(b) (4)

14 (b) (4)

(b) (4)

( , 

.,._""'!'-

.__

(b) (4)

(b) (4)

1

4 

(b) (4)

(b) (4)

(b) (4)

(b) (4)

d by

for PM0000636
Page 18of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 Page 18 of 56 

processes that effectively anticipate or manage process or 

uct issues. 

FDA/CTP completed a Remote Regulatory .Assessment (RRA) on December 15, 2020 of 

f

0 < l

a second-party supplier that manufactures the e-liquid

cartridges. The supplier does not manufacture the e-liquid, nor does it assemble power 

units. During the inspection, ORA did not find any significant findings. 

Summary 

As TPL, I agree with engineering, chemistry, and microbiology conclusions that the applicant 

demonstrates that the new products are manufactured in a consistent manner that 

minimizes variability in product quality. 

3.2.Z.3. Product Stability 

The applicant provided the chemical stability data for representative e-liquid flavors, 

including PM0000636 and PM0000712, by monitoring the changes in the aerosol 

constituent levels and aerosol pH levels over the intended shelf-life :: ]of the eliquid replacement cartridges. The aerosol yields in PM0000636 and 0001!:t at t=O 

months, t

4 land t

b 4

jde

r

wstrated no significant changes in the aerosol 

constituents over the established shelf-life 4 for the new products. 

The e-liauid formulations of all new products consist of five "core ingredients" 

-.., ___ _. an hat account for> 96% by weight, with 

representing the greatest proportion (> 89% by weight). The remaining ingre ients in each 

e-liquid are all flavoring ingredients and collectively represent< 4% by weight of each

formulation.

The applicant indicated that the expected shelf-life of all new products is .... ___ r ___. 

However, the applicant submitted finished product microbial stability data water activity, 

NNN, NNK, endotoxin and (1 ➔3)-13-D-glucan data) measured over onl ........ .,...._,._ 

of shelflife for PM0000636 and PM0000712 (Original tobacco flavored ENDS roducts). All pr

were tested at three time points (beginning [time zero], middle.....,___,..,......,,....,...___. 

nd end

r':'t !over anf· 4 ime p 

·,4. 

tability data indicates t at t e products are

low risk for microbial growth over -----;a--- As container-closure systems and product 

compo,;t;on 1;.e., humectants) cou potent,ally affect tobacco prnduct st•r

ty

,

:

;ng 

complete shelf-life of the products, additional stability testing data beyond j

O 4 

would be needed to determine the sta · · products for the entire s e - 1 e. 

,.. However, because the stability data fo ·

le and indicates that the 

products are low-risk for microbial growth over an....,_-,--....,.

__.Period and because there are 

no other stability concerns, the lack of microbial stability data forr 4 

oes not

preclude an APPH finding for the new products. 

The applicant does not specify a lifetime or expiration date for the Vuse Vibe and Vuse Ciro 

power units. In Amendment PM0004600 the applicant explained why a lifetime is not 

applicable to either power unit. As TPL, I agree with the engineering discipline's 

determination that the applicant's justification is acceptable; lifetime is not applicable 

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

P

= =

oducts

t

stability during

h life

d
Page 19 of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 Page 19 of 56 

because the products should stop powering e-liquid cartridges when their battery capacity 

reaches a lower limit, and this is not a safety hazard. 

Summary f\ The submitted microbial stability data covers art - beriod amll"T fOllnd r be

sufficient in demonstrating the new products' microbial stability over 

.. ___ ___.I

3.2.2.4. Product Test Data 

Compared to mainstream smoke of the comparison combusted cigarette, aerosol quantities 

for acrylonitrile, 4-aminobiphenyl, 1-aminonaphthalene, 2-aminonaphthalene, ammonia, 

anabasine, benzene, B[a]P, 1,3-Butadiene, cadmium, chromium, crotonaldehyde, diacetyl, 

diethylene, isoprene, lead, menthol, nickel, NNK, NNN, and toluene were below the limit of 

detection and acetaldehyde, acrolein, and formaldehyde aerosol quantities were lower 

under both non-intense (74% - 100% lower) and intense (34%-100% lower) puffing/smoking 

regimens. 

In some cases, PM0000636 and PM0000712 generated lower constituent quantities 

compared to the ENDS comparison products. However, the aerosol yields of constituents 

from the new products have higher absolute mass quantities of nicotine, acetaldehyde, and 

formaldehyde than those of the ENDS market comparison products (Siu PLUS+ 2.4%, Logic 

Pro 2.4%, Mistie 2.0, JUUL 5.0%, myblu 2.4% and Vuse Solo G2 4.8%) under non-intense and 

intense puffing regimens. However, I agree with the chemistry conclusion that when these 

constituents are reported in mass-to-mass ratio the differences are minor. For PM0000636 

and PM0000712, the aerosol quantities for the new products were lower compared to the 

cigarette mainstream smoke quantities. 

The applicant provided test data for the battery design parameters for all batteries, and it 

demonstrates that the products are manufactured as intended. Most importantly, the 

batteries are manufactured properly and function to meet IEC 62133, UN38.3, and UL 1642 

battery standards. 

The applicant also provided test data for airflow rate, puff count, atomizer tank/cartridge 

volume, inhaled aerosol temperature, heating element diameter, heating element 

temperature range, power delivery unit (POU) current operating range, POU current cut-off, 

PDU temperature cut-off, and e-liquid volume. The applicant provided test data for each of 

these parameters except for the atomizer tank/cartridge volume, coil diameter, current 

operating range, current cut-off, and POU temperature cut-off. For the parameters for 

which no test data is provided, the applicant provides adequate justification for why they 

are not provided (e.g., volume of cartridges is not tested because weight of e-liquid is 

measured, coil diameter is not tested because there is direct control of the resistance which 

indirectly controls the coil diameter). 

In Amendment PM0004600 the applicant provided leak test data demonstrating that the eliquid cartridges are not likely to leak and that if a non-conforming product is manufactured, 

leaking would likely be identified prior to distribution. 

(b) (4)

(b) (4)
Page 20 of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 Page 20 of 56 

Summary 

As TPL, I agree with the chemistry and engineering conclusions that the product test data 

indicated that adequate manufacturing processes and controls were used to ensure that the 

new products meet manufacturer's specifications. 

3.3. ABUSE LIABILITY 

The BCP review considered the seven applicant-sponsored clinical studies in adult smokers, 

six of which used the new products that are subject to the PMTAs, and one additional study 

using the EViGO, a predecessor of the Vuse Vibe products. Abuse liability-related outcomes 

from these studies included nicotine exposure, nicotine pharmacokinetics, product liking, 

and product use. The following discussion is based on key findings provided in the BCP 

discipline review. 

3.3.1. Discipline key findings 

Per the BCP review: 

• "Abuse liability" refers to the ability of the product to promote continued use and 

the development of addiction and dependence. This can be relevant to determining 

the likelihood that addicted users of one nicotine product would switch to another 

product. For example, if a new tobacco product has a low abuse liability, current 

addicted tobacco users may find it to be an inadequate substitute for a product they 

are currently using with higher abuse liability. On the other hand, low abuse liability 

makes it less likely that new users will become addicted. 

• In ENDS-na'ive exclusive combusted cigarette smokers, the abuse liability of Vuse 

Vibe (3.0% nicotine) and Vuse Solo+ (Ciro, 1.5% nicotine) Original tobacco-flavored 

ENDS products (PM0000636 and PM0000712, respectively) is significantly lower 

than that of combusted cigarettes and slightly greater than that of 4mg nicotine 

replacement therapy (NRT) gum, evidenced by similar nicotine uptake and 

subjective effects after acute use. This may increase the likelihood of use of and 

adherence to the new products compared to NRT in smokers interested in quitting 

combusted cigarette smoking. 

• Due to their puffing patterns, experienced ENDS users can obtain increased nicotine 

uptake from use of the Vuse Vibe products or Vuse Ciro products, which may 

promote switching, yet nicotine uptake remains lower than nicotine uptake from 

combusted cigarettes after acute use. With extended exclusive use of the Vuse Vibe 

or Vuse Ciro, the cumulative nicotine uptake could reach similar values as 

combusted cigarettes. 

• The abuse liability of the new products following extended use cannot be 

determined as the switching studies were conducted over five-day in-clinic studies 

among exclusive smokers who used the new products over a short-term period. The 

abuse liability of these new products used long-term in one's naturalistic 

environment was not evaluated. However, previous research has shown that 

experienced ENDS users achieve comparable nicotine uptake from ENDS relative to 

combusted cigarettes3A; therefore, extended use of the new products may permit 

users to obtain higher nicotine uptake than what was observed in the applicant's 

clinical studies. Although more extended use may facilitate switching, long-term use 

of the new products was not explicitly examined by the applicant. 
Page 21 of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 Page 21 of 56 

3.3.2. Synthesis 

Although conclusions on long-term health benefits cannot be made at this point, as TPL, I agree 

with the BCP conclusion that based on the findings across all clinical studies included in the 

PMTAs, the abuse liability of the new products is lower than that of combusted cigarettes and is 

greater than that of 4mg nicotine gum. However, with experience, users might reach higher 

nicotine levels to satisfy their withdrawal and craving symptoms. Data from the applicant's BOE 

study showed that urine total nicotine equivalent (TNE) levels for the Vuse Vibe Original flavor 

(PM0000636) and Vuse Solo+ (Ciro, 1.5% nicotine) Original flavor (PM0000712) approached UB 

cigarette levels after 5 days of ad libitum use (see section 3.5.1.2. for more information on BOE). 

This is potentially beneficial for smokers trying to switch to ENDS as they are more likely to have 

satisfactory results and not resume cigarette smoking. In addition, slightly greater abuse liability 

of the new products than 4mg NRT gum may increase the likelihood of use of these products 

compared to nicotine gum among smokers interested in quitting. The applicant did not include 

ENDS comparison products in the clinical studies, so the abuse liability of the new products in 

direct comparison to other ENDS is unknown. However, data from the applicant's clinical studies 

show that the maximum measured plasma nicotine concentration (Cmax) for Vuse Vibe and 

Vuse Ciro Original flavored products are within the range of other ENDS products' Cmax values 

as reported in the published literature."5 Given the evidence from the literature, which indicates 

that the abuse liability of these new products is likely within the range of the abuse liability of 

other ENDS, as TPL I am satisfied with the information submitted by the applicant on abuse 

liability despite the lack of comparison to other ENDS. Collectively, the data suggest that the 

abuse liability ofthe Vuse Vibe and Vuse Ciro new products is lower than that of combusted 

cigarettes in current tobacco users. The nicotine levels that adult users of the new products 

might reach (and corresponding abuse liability) indicate that the addiction risk of the new 

products is no higher for adults than other currently available tobacco products. While the 

nicotine levels may pose an addiction risk for non-tobacco users, as discussed in 3.4.2.3 below, 

appeal of the new products is low in non-tobacco users and therefore the risk of addiction for 

non-tobacco users does not outweigh the potential benefits to current tobacco-using adults. 

3.4. USER POPULATIONS 

3.4.1. Discipline key findings 

The following discussion is based on key findings provided in the discipline reviews. 

3.4.1.1. Intended user population(s) (target population) 

Per the BCP review: 

• The applicant stated that the intended user population(s) for the Vuse Vibe products 

and Vuse Ciro products are current tobacco users, including current cigarette 

smokers and current ENDS users. The applicant submitted two clinical studies 

evaluating the PMTA products in exclusive cigarette smokers, and three clinical 

studies evaluating the PMTA products in ENDS and combusted cigarette dual users. 

These data provide adequate evidence to inform use behavior in those populations. 

Per the epidemiology review: 

• The applicant stated that the likely user population for Vuse Vibe and Vuse Ciro is 

current cigarette smokers. Data from observational studies characterizing users of 

these new products found that more than 90% of current established Vuse Vibe 
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users and more than 95% of current established Vuse Ciro users reported a history 

of cigarette smoking. The observational studies analyzed by the applicant provide 

sufficient information to evaluate the patterns of use of these new products in adult 

smokers. 

Per the social science review: 

• The applicant states that the intended user population is current tobacco users ages 

21+. The applicant does not describe any other audience demographics or 

psychographic characteristics for its intended user population. 

• The applicant provided "projected use" data indicating that current tobacco 

experimenters, established combustible cigarette users, and established noncigarette tobacco users are projected to use the new products. 

3.4.1.2. Current tobacco users 

3.4.1.2.1. Precursors of product use 

Per the social science review: 

• The applicant used two studies with nearly identical research methods and analyses 

to provide " precursor to use" data for Vibe and Ciro. Participants were only exposed 

to a single product line (e.g., Vibe, Ciro) within a given study and provided responses 

to either Vibe or Ciro products, but not both. Findings were similar for Vibe and Ciro. 

• The applicant asked participants to provide product appeal ratings for either Vibe or 

Ciro overall, not for each flavor within each product line. In other words, product 

appeal ratings were given for each product line as a whole (e.g., Vibe) but not for 

any specific flavor. The applicant study findings indicate that among all participants 

(adults ages 18-75) in all established tobacco user groups, the mean perceived 

product appeal for the new products was slightly above the midpoint of the 7-point 

appeal scale (Vibe 4.0-4.6; Ciro 4.2-4.4). Established cigarette users ages 18-75 

reported that they found cigarettes about 1 point more appealing than the new 

products on a 7-point scale. The applicant study findings indicate that among all 

participants (adults ages 18-30) in current tobacco user groups, the mean perceived 

product appeal for the new products was also slightly above the midpoint of the 7-

point appeal scale (Vibe 4.2-4.8; Ciro 4.5-4.8). Established cigarette users ages 18-30 

found the cigarettes about equally appealing as the new products on a 7-point scale. 

This was an assessment of product appeal perceptions for Vibe or Ciro overall. 

• The applicant asked participants to provide ratings of intention to buy the product 

for either Vibe or Ciro overall, not for each flavor within each product line. In other 

words, intention to buy ratings were given for the product line as a whole (e.g., 

Vibe) but not for any specific flavor. The applicant study findings indicate that for all 

participants (adults ages 18-75) among all current tobacco user groups, current 

tobacco experimenters (participants who have used one or more categories of 

tobacco products in the past 30 days but have not reached lifetime criteria of 100 

uses of the product(s)) reported the highest mean intentions to buy the product 

(Vibe 5.9 (5.5-6.3); Ciro 6.0 (5.7-6.4)) on a 10-point scale) and have the highest mean 

projected product use rates (Vibe 18.2% (13.0-24.7); Ciro 17.9% (12.7-24.3)). The 

applicant study findings indicate that for young adult participants {adults ages 18-

30) among all current tobacco user groups, current tobacco experimenters 

(participants who have used one or more categories of tobacco products in the past 
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30 days but have not reached lifetime criteria of 100 uses of the product(s)) 

reported the highest mean intentions to buy the product (Vibe 6.1 (5.6-6.6); Ciro 7.0 

(6.5-7.5)) on a 10-point scale). This was an assessment of intention to buy the 

products for Vibe or Ciro overall. 

• Current established cigarette users report various main reasons for their interest in 

using Vibe or Ciro. Among current cigarette users who selected Vibe Original flavor 

as their flavor of most interest, 47.4% selected "to reduce smoking" /"to stop 

smoking" as their main reasons for using Vibe. Among current cigarette users who 

selected Ciro Original flavor as their flavor of most interest, 46.8% selected "to 

reduce smoking"/"to stop smoking" as their main reasons for using Ciro. 

3.4.1.2.2. Product Use 

• Clinical or actual use studies 

Per the BCP review: 

• Dual/poly use 

• The abuse liability information provided suggests that Vuse Vibe 

products and Vuse Ciro products are less efficient at delivering nicotine 

than combusted cigarettes. Therefore, current combusted tobacco 

product users who initiate ENDS use with the new products are likely to 

dual-use the new products with cigarettes. 

• Complete switching 

• The abuse liability (i.e., nicotine exposure) of Vuse Vibe products and 

Vuse Ciro products is lower than that of combusted cigarettes; 

therefore, the likelihood that cigarette smokers who initiate use of the 

Vuse Vibe or Ciro will switch completely to the new products is low. 

• Cessation 

• Vuse Vibe 3.0% (Original) and Vuse Ciro 1.5% (Original) were associated 

with slightly greater abuse liability than 4mg NRT gum, which may 

increase the likelihood of use of the new products and adherence 

compared to NRT in cigarette smokers interested in quitting all tobacco 

products. 

• Observational studies or surveys 

Per the epidemiology review: 

• Dual/poly use 

• Dual use is very common among users of t hese new products. Based on 

data from the National Tobacco Behavior Monitor (NTBM) and Total 

Tobacco Migration Tracker (TTM) population surveys, over 92% of 

current established Vuse Vibe users had a history of cigarette smoking 

and most were current established cigarette smokers (70.6% in NTBM, 

77.7% in TTM). Vuse Vibe users who used the product daily reported 

slightly fewer cigarettes per day (CPD) than did non-daily users, 

although it was not reported whether these differences were 

statistically significant (NTBM: 9.7 CPD for daily users and 10.3 for non-
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daily users; TTM: 9.7 CPD for daily users and 12.8 CPD for non-daily 

users). 

• Almost all current established Vuse Ciro users had a history of smoking 

cigarettes in the NTBM (95.7%) and most were current established 

cigarette smokers (69.6%). Among current established smokers, the 

average number of CPD was 11.4 for daily Vuse Ciro users and 9.2 for 

non-daily users. 

• Complete switching 

• In Cycle 1, data from the Population Assessment of Tobacco and Health 

(PATH) Study and the Colorado Longitudinal Study were used to 

evaluate transitions in tobacco use behavior (i.e., the transition to dual 

use or switching) in adult smokers. These analyses were not brandspecific. To increase sample size, analyses were conducted that 

evaluated some tobacco use behaviors among all ENDS users in the 

study and the results were bridged to Vuse Vibe and Vuse Ciro users 

with the justification that users of these products are not different than 

all ENDS users. To support this, the applicant provided data to show that 

Vuse Vibe and Vuse Ciro users have demographic characteristics and 

tobacco use histories that are not significantly different than all ENDS 

users in these studies regardless of brand used. 

• Between Wave 1 and Wave 3 of the PATH study, 1.5% of adults who 

were exclusively smoking at Wave 1 transitioned to exclusive ENDS use. 

An additional 5.3% of adult dual users of cigarettes and ENDS at 

baseline became exclusive ENDS users. In the Colorado Longitudinal 

Study, 4.6% of baseline dual users had switched to ENDS at the 6-month 

follow-up. Among those who were dual users at Month 6, 6.7% 

switched to ENDS by Month 12. While this study was able to show 

switching behavior, we are not able to determine whether that behavior 

was sustained based on the length of time covered; therefore, the longterm impact cannot be determined. All data on switching were bridged 

to all ENDS users and no data were provided on switching rates among 

Vuse Vibe or Vuse Ciro users. These findings are aligned with prior 

abuse liability findings (discussed in section 3.3) and indicate that 

current adult combusted cigarette users who initiate use of the new 

products have low likelihood of completely switching to the new 

products as they are more likely to dual-use with cigarettes. 

• In the cited studies, daily ENDS users were more likely to transition from 

dual use to exclusive ENDS use than were non-daily users. In the PATH 

Study, the odds of switching from dual use was four times higher among 

those who used ENDS daily (14.6%) compared to those using ENDS less 

than daily (3.9%) (OR=4.2, 95% Cl: 3.1-5.8; p<0.0001). In the Colorado 

Longitudinal Study, dual users' rates of switching were nearly twice as 

high among daily ENDS users from baseline to Month 6 (7.3%) 

compared to non-daily users (4.1%). 

• Brand-specific longitudinal data were not provided, but the NTBM and 

TTM surveys were able to evaluate retrospective lifetime histories of 
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tobacco use among Vuse product users. In those studies, current Vuse 

Vibe users who were daily users were more likely than non-daily users 

to be former cigarette smokers (37.0% versus 13.3% in NTBM; 17 .3% 

versus 7.6% in TIM). In the NTBM survey, daily Vuse Solo users (a proxy 

for Vuse Ciro) were almost three times more likely than non-daily Vuse 

Solo users to be former cigarette smokers {36.6% versus 12.7%). 

Additionally, based on retrospective smoking histories collected in the 

NTBM and TIM surveys, daily ENDS users reported significantly greater 

reductions in cigarette consumption over the previous one-year period 

than did non-daily ENDS users. 

• The longitudinal data on switching submitted by the applicant are not 

brand-specific and show that a small percentage of smokers and dual 

users are able to switch to ENDS. Some cross-sectional brand-specific 

data were presented that found that daily users were more likely to 

report being a former smoker, suggesting that daily use may help with 

switching, but temporality between ENDS use patterns and quitting 

smoking cannot be established with these retrospective analyses. 

3.4.1.3. Tobacco non-users (including youth) 1

• 

3.4.1.3.1. Precursors of product use 

Per the social science review: 

• The applicant did not provide direct data on youth in its original submission or 

Amendment PM0004600. FDA determined in Cycle 1 that young adult data can 

be a proxy for youth data. 

• The applicant study findings indicate that among non-users (ages 18-75) •, the 

mean perceived risk of developing general poorer health from using each new 

product was high on the 7-point risk scale (range for both products: 5.9-6.0). 

Non-users rated the risk of developing generally poorer health from using 

cigarettes higher than that of the new products (.4-.8 points riskier than the 

new products on a 7-point scale). 

• The applicant study findings indicate that among non-users ages 18-75, the new 

products were rated as unappealing (mean perceived product appeal on a 7-

point scale; never users Vibe: 2.2/Ciro 2.3; former tobacco users Vibe 2.3/Ciro 

2.5). Young adult non-users (ages 18-30) also found the new products 

unappealing (young adult never users: Vibe 2.7 /Ciro 2.8; young adult former 

tobacco users: Vibe 3.0/Ciro 3.0); however, their ratings of the new products' 

appeal were higher than the ratings of the new products' appeal from the 

ix Determining whether marketing a new product is APPH includes evaluating the risks and benefits to the population as a 

whole. This requires FDA to balance, among other things, the negative public health impact for nonusers against the potential 

positive public health impact for current tobacco users. Accordingly, for marketing of a new product to be found to be APPH, 

any risks posed by a new product to youth would need to be overcome by a sufficient benefit to adult users, and as the known 

risks increase, so too does the burden of demonstrating a substantial enough benefit. In the case of a new flavored EN OS 

product, the risk of youth initiation and use is substantial, given the clearly documented published evidence. In contrast, the 

risk of youth initiation for tobacco-flavored ENDS products is less substantial, thus the level of evidence demonstrating a benefit 

to adult smokers may not need to be as high. 

• When reporting findings from its surveys, the applicant generally provided descriptive statistics for participants ages 18-75 in 

each tobacco user group; for some key measures, the applicant also provided descriptive statistics for only young adult (ages 

18-30} participants in each tobacco user group. 
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sample with older participants. These appeal ratings were reported for the new 

devices overall, not broken down by flavor. Therefore, these appeal ratings 

cannot be used on their own to evaluate youth appeal of the tobacco ENDS 

(Original flavored products) that are the subject of this review. These data 

should be interpreted along with the applicant submitted data that young adult 

non-users did not select tobacco ENDS (Original flavored products) as flavor of 

most interest (compared to the non-tobacco flavored products). Additionally, 

these appeal ratings should be interpreted along with published National Youth 

Tobacco Survey (NYTS) data indicating that youth find cartridge-based products 

appealing but find tobacco ENDS less appealing than non-tobacco flavored 

products. More details about youth perceptions of cartridge-based and tobacco 

ENDS products are provided below. 

• The applicant submitted one new analysis of overall product appeal for young 

adults under the age of tobacco sale (ages 18-20) to address concerns about the 

appeal of the new products for tobacco non-users, including youth. Due to 

statistical limitations of the linear regression analysis provided by the applicant 

(small sample sizes collected from only a subset of U.S. states; insufficient 

evidence that the applicant met the statistical assumptions for conducting this 

analysis; no reporting of key model specifications), the applicant's claim that 

"appeal for these products is unlikely to be higher among those under 18 years 

of age compared to those ages 18-30" is not supported. However, this data 

should be interpreted along with published NYTS data indicating that youth find 

cartridge-based products appealing but find tobacco ENDS less appealing than 

non-tobacco flavored products. More details about youth perceptions of 

cartridge-based and tobacco flavored ENDS products are provided below. 

• The applicant study findings indicate that the proportion of participants 

interested in purchasing Vibe or Ciro was significantly higher in tobacco user 

groups (current cigarette users: Vibe 61%/Ciro 66%; current non-cigarette 

tobacco users: Vibe 56%/Ciro 54%; current tobacco experimenters: Vibe 

76%/Ciro 73%), than in non-user groups (former users: Vibe 20%/Ciro 22%; 

never users: Vibe 8%/Ciro 9%). Compared to the sample of non-users ages 18-

75, young adult non-users (ages 18-30) indicated more interest in purchasing 

Vibe or Ciro (young adult former users: Vibe 40%/Ciro 40%; young adult never 

users: Vibe 16%/Ciro 17%). These interest in purchasing data are not broken out 

by flavor and cannot be used to evaluate youth appeal of these tobaccoflavored products on their own; therefore, these data should be interpreted 

along with published data that youth find cartridge-based products appealing 

but find tobacco-flavored products unappealing. In summary, social science 

does not expect that the tobacco-flavored products will be especially youthappealing. More details about youth perceptions of cartridge-based and 

tobacco ENDS products are provided below. According to National Youth 

Tobacco Survey (NYTS) 2021 data, 28.7% of middle and high school users 

reported prefilled or refillable pods or cart ridges as the ENDS device types they 

used most often.6 The ability to use products discreetly and the products' sleek 

design and user-friendly nat ure make pod mod (rechargeable cartridge-based 

ENDS) products appealing among youth. Although the new products are not pod 

mods, they are sleek and small in design, user-friendly cartridge-based, and 

easily rechargeable. 
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• Although there is some risk of youth uptake of these products, in general, 

tobacco-flavored ENDS are less appealing to youth compared to flavored ENDS, 

making the risk of youth initiation low for these Original tobacco ENDS products. 

Generally, the interest in tobacco flavor is low among youth. The available 

evidence from NYTS 2019 and 2021 indicates that a higher percentage of middle 

and high school current tobacco users reported using non-tobacco ENDS (e.g., 

menthol, mint, clove or spice, alcoholic drinks, candy, fruit, chocolate) than 

tobacco ENDS.6

,

7 Findings from a discrete choice experiment showed that nontobacco flavors were associated with more curiosity, less perceived danger, and 

greater perceived ease-of-use among high school students, compared to 

tobacco flavor. 8 Additionally, the published literature indicates that youth report 

significantly higher preference for non-tobacco flavored ENDS compared to 

tobacco-flavored ENDS.9

-

11 Moreover, the evidence indicates that tobaccoflavored ENDS are less likely to be used by youth who initiate or regularly use 

ENDS compared to non-tobacco flavored ENDS. The findings from the 2020 

Monitoring the Future (MTF) survey provide evidence that youth use of 

tobacco-flavored ENDS is less common compared to other flavored ENDS 

including mint.1 According to the 2020 MTF data, among ENDS users the 

prevalence of tobacco flavor was 2.9% among 10th and 12th graders while mint 

was the second most often used flavor (26.9%) after fruit (59.3%).

2

12 

• In addition, FDA believes the digital marketing and TV and radio restrictions 

recommended by OHCE will help to mitigate the risk of youth initiation. 

3.4.1.3.2. Product Use 

• Clinical or actual use studies 

Per the BCP review: 

• Progression 

• The abuse liability of the Vuse Vibe products and Vuse Ciro 

products is lower than that of cigarettes in current adult 

cigarette smokers. No clinical studies of progression to regular 

use were conducted in non-tobacco users. 

• Due to the lower abuse liability of these products compared to 

cigarettes, former tobacco and non-tobacco users (including 

youth) who initiate use of the new products are less likely to 

progress to regular use of the new products as compared to 

cigarettes. 

• The applicant-provided analysis of the PATH youth survey data 

showed slightly lower dependence scores for ENDS than for 

combusted cigarettes in dual users, though this difference was 

not statistically significant. Among youth exclusive combusted 

cigarette smokers vs. exclusive ENDS users, dependence scores 

among the ENDS group were statistically significantly lower than 

those of combusted cigarette smokers. 

• This analysis was limited because it examined general ENDS use 

and incorporated data collected until 2016. Therefore, the 

results of this analysis do not reflect the ENDS currently 
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available on the market, nor does this analysis apply directly to 

the new products, limiting its generalizability. 

• There were no clinical studies of initiation with the Vuse Vibe or 

Ciro conducted in non-tobacco users or adolescent tobacco 

users. Although tobacco non-users including youth were not 

included in the applicant-submitted clinical studies, the 

comparably low abuse liability of the new products relative to 

combusted cigarettes suggests that initiation and sustained use 

of the new products among tobacco non-users is likely to be 

lower than initiation and sustained use of tobacco products 

with greater abuse liability (e.g., combusted cigarettes). 

• Observational studies or surveys 

Per the epidemiology review: 

• Initiation 

• Use of these products among adult never smokers is not 

common; 8% of established Vuse Vibe users and 4% of 

established Vuse Ciro users were never cigarette smokers. 

Brand-specific data provide strong evidence that use among 

adult never smokers is likely limited. 

• The applicant also assessed initiation of ENDS use among never 

tobacco users in Waves 1-3 of the PATH Study. Initiation of 

tobacco use with ENDS was uncommon. Only 0.2% of adult 

never tobacco users and 1. 7% of youth never tobacco users 

initiated tobacco use with ENDS. However, it should be noted 

that these estimates were from data collected between 2013-

2014 (Wave 1) and 2015-2016 (Wave 3), which was before 

ENDS use became more common in youth. No data were 

provided for the initiation of tobacco use with specific brands of 

ENDS. 

• Youth 

• In 2021, Vuse was one of the five most commonly reported 

usual brands among middle and high school current ENDS 

users.6 Some evidence in the peer-reviewed literature on youth 

device type preferences suggests that youth report using closed 

systems (i.e., disposable devices or those that use pre-filled 

pods or cartridges, similar to the new products) most often.

13 

However, as previously discussed, the published literature 

shows that prevalence of youth use of tobacco-flavored ENDS is 

low and that tobacco-flavored ENDS are less likely to be used by 

youth who initiate or regularly use ENDS compared to nontobacco flavored ENDS. 

• The NTBM and TTM surveys that were analyzed by the applicant 

were composed of adults of legal age to purchase tobacco 

products, and thus do not include youth. Instead, the applicant 

proposed using information on young adults between the ages 

of 18-24 as a proxy for youth. Epidemiology considers this an 
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appropriate strategy in the absence of youth data. In these 

studies, increasing age was not associated with a change in the 

prevalence of young adults using Vuse Vibe (NTBM: OR=0.98, 

95% Cl: 0.93-1.04, p=S0; TTM: OR=l.02, 95% Cl: 0.90-1.41, 

p=0. 79). However, increasing age was associated with increased 

likelihood of using Vuse Solo (a proxy for Vuse Ciro) (NTBM: 

OR=l.11, 95% Cl: 1.03-1.19, p=0.005; TTM: OR=l.14, 95% Cl: 

1.01-1.29, p=0.0344), suggesting that younger people are less 

likely to use the product. Although the prevalence of Vuse Vibe 

use did not decrease with increasing age in young adults, most 

adult Vuse Vibe users are over age 30 (70.8% in NTBM, 73.8% in 

TTM). 

• Former tobacco users 

• Data from PATH Wave 1 to Wave 3 were used to evaluate the 

likelihood of ENDS use among former tobacco users. However, 

no brand specific data were evaluated, and the applicant did 

not provide a justification for bridging the results from the PATH 

data to the new products to indicate the weight of this 

evidence. In PATH, 1.1% of former adult tobacco users reported 

exclusive use of ENDS a year later. Furthermore, evidence from 

the broader peer-reviewed literature suggests that prevalence 

of ENDS use among former tobacco users (predominantly 

cigarette smokers) is low - generally, 3-5% across studies. 

• Progression 

• In an analysis conducted by the applicant using PATH youth 

survey data, 5.5% of never ENDS users at Waves 1-2, reported 

having ever used ENDS at Wave 3; however, 69.1% of those 

were not currently using ENDS at Wave 3, and the applicant 

states that the findings suggest that the use of ENDS in the 

youth population may be transient. Among youth who started 

using tobacco products as dual users, 25.6% stopped using any 

tobacco product a year later and another 9.5% stopped 

cigarette smoking but continued using ENDS. No brand-specific 

data were provided on the likelihood of progressing from ENDS 

use to cigarette smoking. 

• Some evidence in the peer-reviewed literature on youth device 

type preferences suggests that youth report using closed 

systems (i.e., disposable devices or those that use pre-filled 

pods or cartridges similar to the new products) most often.13 

The literature shows that non-tobacco flavored ENDS use is very 

common in both youth and adult ENDS users (irrespective of the 

device type). 

• Overall, the available evidence to date does not adequately 

address whether ENDS use in youth and young adults leads to 

regular smoking. Though youth use of ENDS is concerning, as 
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previously discussed, the published literature shows that 

prevalence of youth use of tobacco-flavored ENDS is low and 

that tobacco-flavored ENDS are less likely to be used by youth 

who initiate or regularly use ENDS compared to non-tobacco 

flavored ENDS. 

3.4.1.4. Vulnerable populations•

1 (other than youth) 

Per the BCP review: 

• No clinical studies were provided or reviewed by the applicant addressing use of the 

new products among vulnerable populations. Vulnerable populations have 

increased difficulties with smoking cessation.1

4-16 ENDS may serve as a harm 

reduction approach if users are able to completely switch or dramatically reduce 

combusted tobacco product use. However, from a BCP perspective, the impact of 

the new products on abuse liability and product use behavior in vulnerable 

populations other than youth is unknown. 

Per the epidemiology review: 

• Some published literature has found that the use and init iation of ENDS is higher 

among lesbian, gay, bisexual, and transgender (LGBT) youth and adults, people with 

a history of mental health problems, and American Indian/Alaskan Natives. The 

applicant did not provide information specific to vulnerable populations in its 

application; therefore, t he impact of the new products on vulnerable user groups 

other than youth is unknown from an epidemiology perspective. 

Per the social science review: 

• The applicant presented data for the new products by tobacco user group; the 

applicant did not provide demographic informat ion or a summary of the 

composition of these groups. No data was provided on vulnerable populations. 

• Published research indicates that individuals with substance use or mental health 

issues are more likely to use ENDS compared to those without those health 

11 concerns. -21 Additionally, the prevalence of ENDS use by LGBT individuals is higher 

than in heterosexual individuals.

22-25 Younger women and women who use 

28 combusted cigarettes may use ENDS during pregnancy.26 

· 

• The applicant did not provide data to determine how participant characteristics, 

including membership in vulnerable populations, affect perceptions and intentions 

to use the new products. From a social science perspective, the impact of the new 

products on vulnerable populations is unknown. 

3.4.1.5. Actions taken to mitigate risk to non-users, including youth 

Per the Office of Health Communication and Education (OHCE) consult: 

• The applicant submitted information on its proposed marketing in two letters dated 

November 9, 2018, and April 29, 2019. 

• OHCE raised some concerns with certain aspects of the applicant's marketing 

information and indicated support for other aspects. 

xi This term refers to groups that are susceptible to tobacco product risk and harm due to disproportionate rates oftobacco 

product initiation, use, burden of tobacco-related diseases, or decreased cessation. 
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• For example, OHCE's review raised concerns about the potential broad reach of the 

applicant's plan for digital and television marketing and concluded that, ifthe 

products are authorized to be marketed, FDA should place restrictions on digital 

marketing and TV and radio marketing to protect youth. 

• Additionally, OHCE noted concerns with the applicant's plans for print and point-ofsale advertising and recommended that any MGO letter encourage the applicant to 

take additional steps to limit youth exposure to print and point-of-sale advertising, 

including, for example, limiting advertising to print publications that do not overindex for youth, requiring advertising to be placed inside the store, and placing 

product displays near other age-restricted products and away from toys and candy. 

• Examples of measures OHCE expressed support for include the following: "Not use 

any social media platforms (e.g., Facebook, lnstagram, Twitter) or social media 

influencers for marketing and promotional purposes; No testimonials by sports 

figures or celebrit ies or any person with special appeal to persons under 21 years of 

age; No person appearing in any advertising materials shall be under age 25 or be 

styled to look under age 25; Content shall not include characters, images, or themes 

designed to target youth; Content shall not be related to youth or youth-oriented 

activities; Content shall not suggest that use of R.J. Reynolds Vapor Company's 

("RJRV") products is essential to social prominence, distinction, success or sexual 

attraction, nor shall any content picture a person using any RJRV products in an 

exaggerated manner; and Content shall not depict persons participating in, or 

obviously just having participated in, a physical activity requiring stamina or athletic 

conditioning beyond that of normal recreation." OHCE noted support for the use of 

these measures because they are likely to further help mitigate risks to youth. OHCE 

recommended that any MGO letter for these products encourage the applicant to 

implement these measures. 

3.4.1.6. Labeling and advertising 

Per the social science review: 

• The applicant provided proposed labeling. 

• The applicant made revisions to its "instruction insert" labeling in response to 

Deficiency 22. Revisions included changing the color of the labeling from colorful to 

predominately black and white, standardizing the text on the front panel, 

standardizing warning text font and content across products on the back panel, and 

changing the format and content of the use instructions for both products. 

• Based on the information presented at this time, we have not concluded that the 

proposed labeling is false or misleading in any particular way. We note that the 

"instruction insert" includes instructions for consumers to visit the applicantowned website "for important product information before use." Consumers who 

follow these instructions will be exposed to additional labeling/advertising 

materials when t hey search for product information. Additionally, the "Safety 

Information FAQs" that comprise the "important product information" include 

claims about product risk and appeal. This additional labeling/advertising includes 

information such as: "The ratio of vegetable glycerin (VG) and propylene glycol (PG) 

in Solo, Vibe, and Ciro liquids have been optimized to provide the optimal viscosity, 

flavor, and experience per device"; "We use food-grade flavorings designed for an 

adult palate"; and "Vuse products offer many advantages over traditional 
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cigarettes that adult tobacco consumers may find attractive- there's no ash and no 

burning odor." Although such statements could potentially convey modified risk, 

based on the information presented at this time there is insufficient information to 

conclude that they do. Accordingly, social science does not conclude that this 

labeling/advertising would cause the new tobacco products to be modified risk 

tobacco products (MRTPs). 

3.4.2. Synthesis 

The applicant states that the intended user population for the Vuse Vibe and Vuse Ciro new 

products is adult (ages 21+) current tobacco users, including current and former cigarette 

smokers and current and former ENDS users. The abuse liability of the new products, while 

sufficient for dual use or complete switching in those interested in quitting combusted 

cigarettes, is unlikely to support complete switching in a combusted cigarette user who is 

uninterested in quitting. The appeal of the tobacco-flavored new products is low in nontobacco users. Generally, nonusers view the new products as a risk to developing poorer 

health, rate them as unappealing, and have a lower proportion of the group indicating 

interest in purchasing any flavor of the new products than tobacco users. There is also 

evidence that the tobacco flavor of the new products pose less risk to youth uptake given 

their lower appeal to underage youth compared to other flavors. 

3.4.2.1. Intended User Population 

As TPL, I agree with the BCP and social science disciplines that the stated applicant intended 

user population for Vuse Vibe and Vuse Ciro new products is adult (ages 21+) current 

tobacco users, including current cigarette smokers and current ENDS users. I also agree with 

the epidemiology discipline that the applicant stated that the likely user population for the 

new products is current and former adult cigarette smokers. 

3.4.2.2. Current Tobacco Users 

The evidence indicates that established tobacco users, and in particular established 

cigarette smokers, are interested in the new products, indicate that tobacco flavor is their 

flavor of interest more frequently than flavored tobacco products, and are interested in the 

new products as a way to reduce or stop smoking. This evidence supports that these 

products, if authorized, would be acceptable to cigarette smokers looking to either switch 

completely to the new products or become dual users and thereby potentially decreasing 

their cigarette consumption. As noted in the abuse liability and toxicant 

exposure/biomarkers of exposure sections (3.3., 3.5.1.2.), with increased user experience, 

these new products have the ability to deliver nicotine near combusted cigarette levels, and, 

as noted in the toxicant exposure/biomarkers of exposure section (3.5.1.2.), have reduced 

toxicant exposure. This supports the evidence in this section that these products could be an 

acceptable substitute for combusted cigarettes and thereby reduce HPHC exposures for dual 

users or complete switchers. 

As TPL, I agree with the BCP and epidemiology disciplines that the abuse liability of the new 

products, while sufficient for dual use or in those interested in quitting combusted 

cigarettes, was unlikely to support complete switching in a combusted cigarette user who 

was uninterested in quitting. Given that the abuse liability of the new products in 

inexperienced users is lower than that of combusted cigarettes but higher than that of 
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nicotine replacement gum in ENDS-na'fve exclusive smokers, it is likely that among the target 

population of combusted cigarette smokers, those not interested in quitting would dual-use 

them along with cigarettes rather than completely switch. They may reduce their CPD, 

which could potentially improve the impact of smoking on their health. Smokers interested 

in quitting may find these products to be a better substitute for smoking than nicotine 

replacement gum. There is also potential to increase nicotine exposure with experience. 

Therefore, in adult combusted cigarette users, experimenting with the new products could 

lead to dual use in those uninterested in quitting (or they may return to exclusive cigarette 

use). For those interested in quitting, the abuse liability may be enough to maintain dual or 

exclusive use of the ENDS better than N RT, and therefore could lead to better cigarette 

cessation outcomes. 

3.4.2.3. Tobacco nonusers (including youth) 

Precursors ofProduct Use 

As TPL, I agree with the social science and epidemiology disciplines that the appeal of the 

new products is low in non-tobacco users. Generally, nonusers view the new products as a 

risk to developing poorer health, rate them as unappealing, and have a lower proportion of 

the group indicating interest in purchasing any flavor of the new products than tobacco 

users. Although youth and young adults generally find cartridge-based ENDS appealing, 

published research indicates that underage youth find tobacco-flavored ENDS less appealing 

than flavored ENDS. Therefore, the tobacco flavor of the new products likely poses less risk 

to youth uptake given their lower appeal to underage youth compared to other flavors. 

Initiation and Progression to use 

As TPL, I agree with the BCP and epidemiology disciplines that in inexperienced users the 

abuse liability of the new products is low relative to combusted cigarettes. For youth and 

non-users, the literature, combined with the abuse liability assessments of the new products 

in clinical studies of adult inexperienced ENDS users, suggests a low likelihood of initiation of 

Vuse Vibe or Vuse Ciro Original tobacco ENDS products; however, should non-users or youth 

initiate use of Vuse Vibe products or Vuse Ciro products, the likelihood of progression to 

regular use is low compared to combusted cigarettes. Though youth use of ENDS is 

concerning, as previously discussed, the published literature shows that prevalence of youth 

use of tobacco-flavored ENDS is low and that tobacco-flavored ENDS are less likely to be 

used by youth who initiate or regularly use ENDS compared to non-tobacco flavors. 

Vulnerable PopulationsError! Bookmark not defined. (other than youth) 

There is some evidence that indicates some vulnerable populations experience 

disproportionate ENDS use and have increased difficulties with smoking cessation. ENDS 

may serve as a harm reduction approach if users are able to completely switch or 

dramatically reduce combusted tobacco product use. However, as TPL, I agree that there is a 

lack of currently available evidence to show whether the new products would help facilitate 

adult combusted cigarette smokers from vulnerable populations to switch or reduce CPD. 

3.4.2.4. Summary of 3.4.2.1, 3.4.2.2, and 3.4.2.3 

The evidence summarized in these sections describes relatively high interest among adult 

smokers in using the tobacco products and demonstrates that switching from combusted 

cigarettes to ENDS does occur among current adult smokers-typically through a period of 

dual use. Use of these products would benefit smokers who switch completely or 
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substantially reduce their cigarette smoking due to significant reductions in HPHCs of the 

new products compared to cigarettes (discussed in detail in Section 3.5). In addition, the 

abuse liability ofthe new products is lower than that of combusted cigarettes, mitigating 

concern of greater nicotine exposure than combusted cigarettes among youth. The available 

information also shows that, compared to flavored ENDS, appeal/uptake of tobacco 

products is generally lower among youth. Overall, I agree that the benefit of the new 

products to adult smokers is significant enough to overcome the risk to youth. 

3.4.2.5. Actions taken to mitigate risks to non-users, including youth 

With respect to marketing, OHCE reviewed the marketing information provided by the 

applicant, including information about advertising and promotion and sales access. OHCE 

expressed concerns with certain aspects of the information that was provided and was 

supportive of other aspects. As TPL, I agree with OHCE's evaluation. I also agree that the 

marketing restrictions recommended by OHCE are necessary to ensure that the new 

products sufficiently mitigate the risk to youth, especially with potential changes to the 

ENDS marketplace. Accordingly, I recommend that the MGO letter include the marketing 

requirements and recommendations specified in the OHCE consult. 

3.4.2.6. Labeling and advertising 

As TPL, I agree with the social science discipline conclusions. Based on the information 

presented at this time, I have not concluded that the proposed labeling is false or misleading 

in any particular. The applicant has provided evidence that users will be able to comprehend 

the product labeling accurately, thereby reducing the likelihood of misuse. The applicant 

revised the "instruction insert" labeling in Amendment PM0004600 in response to the 

Deficiency letter, and this addition of the required nicotine warning statement to the 

"instruction insert" is compliant with federal law. 

Relatedly, the "instruction insert" includes instructions to visit the applicant-owned website 

"for important product information before use." Consumers who follow these instructions 

will be exposed to additional labeling materials when they search for product information. 

Additionally, the "Safety Information FAQs" that comprise the "important product 

information" include claims about product risk and appeal. These claims include "the ratio 

of vegetable glycerin (VG) and propylene glycol (PG) in Solo, Vibe, and Ciro liquids have been 

optimized to provide the optimal viscosity, flavor, and experience per device"; the products 

include "food-grade flavorings"; and that the products have an advantage over "traditional 

cigarettes" because there is "no ash and no burning odor." As TPL I also agree that, although 

such statements could potentially convey modified risk, based on the information presented 

at this time there is insufficient information to conclude that they do. Accordingly, I do not 

conclude that this labeling/advertising would cause the new tobacco products to be MRTPs. 
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3.5. TOXICANT EXPOSURE 

3.5.1. Discipline key findings 

The following discussion is based on key findings provided in the discipline reviews. 

3.5.1.1. Toxicity 

Per the toxicology review: 

• Two one-sided test (TOST) analyses indicated significant reductions in HPHCs from 

the new product aerosols compared to the combusted tobacco comparison 

products. Elevations in VG and PG in new product aerosols were outweighed by 

substantially lower yields of other respiratory toxicants (i.e., acetaldehyde, acetyl 

propionyl, ammonia, anabasine, acrolein, crotonaldehyde, diacetyl, ethylene glycol, 

formaldehyde) when compared to the combusted tobacco comparison products. 

Observed VG and PG levels were comparable to levels normally seen in other ENDS 

market comparison products. 

• There is a decrease in HPHCs from the new product aerosols compared to the 

combusted cigarette comparison products. This decrease is likely to result in 

reduced toxic exposures for smokers who either completely switch to the new 

products or dual-use combusted cigarettes and the new products. 

3.5.1.2. Biomarkers of exposure (BOE) 

Per the BCP review: 

• The applicant sponsored BOE study shows that non-nicotine BOE are significantly 

lower in combusted cigarette smokers who switch completely to the new products, 

and nicotine exposure is comparable to that of combusted cigarettes in smokers 

who switch to the new products for five days of ad libitum use. However, these data 

do not address smokers who dual use the new products with their combusted 

cigarettes. Therefore, the data the applicant provided for smokers are limited and 

may not reflect actual product use behaviors, such as dual use, for the new 

products. 

• Complete switching from combusted cigarette smoking to ad libitum use of the 

Vuse Vibe product or Vuse Ciro product for five days resulted in significant 

reductions in the urinary and blood non-nicotine BOE of similar magnitude to the 

reductions in the participants who abstained from smoking. While the long-term 

effects of complete switching were not assessed, these changes in systemic 

exposures are likely to provide the health benefit of reduced exposure to these 

HPHCs for the current adult smokers who completely switch to the new products. 

3.5.2. Synthesis 

As TPL, I agree with the toxicology and BCP disciplines' conclusions that the applicant 

supplied sufficient information to characterize the products' toxicity, the data indicate that 

the new products have significantly lower toxicity compared to combusted cigarettes, and 

users who completely switch to the new products will have significantly reduced levels of 

BOE compared to combusted cigarettes. 
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3.5.2.1. Toxicity 

3.5.2.1.1. Ingredients and HPHCs 

Many of the new product e-liquid ingredients, especially those that are known to cause 

respiratory irritation and/or toxicity, are also found in commercially available cigarettes. 29•30 

Similarly, many HPHCs are respiratory irritants/toxicants (e.g., acetaldehyde, formaldehyde). 

However, comparative HPHC analysisxi, between combusted tobacco comparison products 

Newport Gold or FDA-SO cigarettes (composed of HPHC and product design data from the 

50 top-selling cigarette brands from 2011) and the new products demonstrated that 

corresponding HPHCs from the new product aerosols were either below the limit of 

detection or substantially reduced on a unit per mg nicotine basis under both a non-intense 

and an intense puffing regimen. Taken together, in terms of carcinogenic and/or 

cardiovascular/respiratory/reproductive/developmental toxicant HPHCs, the new product 

aerosols consistently demonstrated reduced potential for overall toxicity compared to 

cigarette smoke from combusted tobacco comparison products. Furthermore, HPHC levels 

observed from new product aerosols in e-liquids PM0000636 and PM0000712 were 

comparable on a mass-to-mass basis with HPHC levels reported in 22 ENDS market 

comparison products. Given the magnitude and statistical significance of lower HPHC yields 

in the new product aerosols as compared to combusted cigarettes, I find that these new 

products are likely to result in reduced toxicity for smokers who switch to ENDS completely 

from combusted tobacco products. Furthermore, given the mass-to-mass comparability of 

HPHC levels with the ENDS market comparison products, any potential toxicities directly 

resulting from the specific ingredients found in these new products are unlikely to increase 

overall toxicological concern as compared to ENDS market comparison products. 

3.5.2.1.2. Extractables and Leachables 

The applicant also provided information regarding potential extractables and leachables 

from the components of the new products (PM0 - ,,d PM0000712). leachable 

compoun · were collected over a ' period under Ion -term storage 

conditioni E=d% relative humidity [RH] % RH) and at a 1 ime point 

where test articles were stored under accelerated storage conditions 4 

Data from the r) J )accelerated timepoint are used for e ... val --uat--io_n_s _as__t h_e_y __ .... 

d the hig hest leachable levels among timepoints measured. Over thee 4 ]

testing period leachable compounds in aerosols reported above the limit of quantitation 

(LOQ) and above the International Council for Harmonization (ICH) and FDA CDER/CBER 

M7(R1) analytical exposure threshold (AET) for mutagenic impurities in drug products (1.5 

μg/day) were assessed. Extractables and leachables were determined for PM0000636 and 

PM0000712. Mean leachable compound levels were converted to predicted exposures per 

day (μg/day) based on an estimated inhalation exposure equivalent of 80 puffs per day 

'11 The applicant provided select HPHCs from the USFDA Draft and Final Guidance for Industry on PMTAs for ENDS. 31

•

32 These

HPHCs included acetaldehyde; acetyl propionyl; acrolein; acrylonitrile; 4-aminobiphenyl; 1-aminonaphthalene; 2-

aminonaphthalene; ammonia; anabasine; benzene; benzo[a]pyrene (B[a)P); 1,3-butadiene; cadmium; chromium·

crotonaldehyde; diacetyl; diethylene glycol; ethylene glycol; formaldehyde; glycerin (also known as glycerol); soprene;

lead; menthol; nickel; nicotine (free and total); 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); N-nitrosonorn1cotine

( N N N); propylene glycol; and toluene. WJ.U

0

t; u,t;;,J,

ere reported in separate analytical studies or from

the e-liquid (If present).

(b) (4)

(b) (4) (b) (4)

1 (b) (4)

1 (b) (4)

((b) b) ((4) 4)

1 (b) (4) 1 (b) (4)

1 (b) (4) 1 (b) (b) (4) (4) 1 (b) (4) 1 (b) (4) 1 (b) (b) (4) (4) 1 (b) (4)

1 

u,t;;,J, 

(b) (4)

t; 1 (b) (4) 1 (b) (4)(b)4 (b)(4)

(b) (4) (4)

(b) (4) (b) (4)

000636 an

aerosol

exhibite

the above HPHCs were tested in the aerosol of the new products (PM0000636 and
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(PM0000635, PM0004287, PM0000636) or 100 puffs per day (PM0000646, PM0004293 

PM0000712). The estimated exposure equivalents were based on the reported mean user 

consumption of various ENDS platforms ranging from 78 to 250 puffs per day.33-

39 Nine 

organic and two elemental leachables were reported in the aerosols of PM0000636. Eight 

organic and one elemental leachable were reported in PM0000712. None of the compounds 

identified are listed as carcinogenic, genotoxic, or mutagenic by the European Chemicals 

Agency (ECHA) harmonized classification and labelling (CLH) database, the International 

Agency for Research on Cancer (IARC), or the US EPA's Integrated Risk Information System 

(IRIS). 

The majority of elevated extractable and leachable compounds from the new product 

cartridges are known constituents of cigarette smoke from 3R4F research cigarettes and 

commercially available cigarettes.29

.4° This includes the leachable compounds that are 

known to cause respiratory irritation and/or toxicity. 29,

30 The potential exposure to 

extractable and leachable compounds (including compounds that are also considered to be 

HPHCs) from the new product aerosols is substantially less than that observed from 

combusted cigarette smoke. Importantly, comparative HPHC analyses of combusted tobacco 

comparison products, Newport Gold or FDA-SO cigarette data, and the new products 

demonstrated that corresponding HPHCs from new product aerosols were either below the 

limit of detection or substantially reduced on a unit per mg nicotine basis under either a 

non-intense or intense puffing regimen. As discussed above, HPHC levels observed from the 

new products are also comparable on a mass-to-mass basis with the HPHC levels reported in 

the 22 ENDS market comparison products_ In terms of carcinogenicity and/or 

cardiovascular/respiratory toxicant HPHCs, the new product aerosols consistently 

demonstrated reduced potential toxicity compared to cigarette smoke from combusted 

tobacco comparison products and exhibit similar toxicological risk as the ENDS market 

comparison products. 

3.5.2.2. Biomarkers of exposure (BOE) 

The applicant submitted one sponsored inpatient clinical study (CSDl 70501) that allowed 

for an evaluation of BOE following actual use of the Vuse Vibe (3.0% nicotine) Original flavor 

and Vuse Solo+ (previous name of Vuse Ciro, 1.5% nicotine) Original flavor products 

(PM0000636, PM0000712) in current adult exclusive cigarette smokers compared to a 

cigarette abstinent group ("abst inence cohort"). The BOE measured in the study and 

corresponding HPHCs are listed in Table 2 of the BCP review. BOE data examines biomarkers 

of nicotine exposure by measuring a variety of nicotine metabolites. After five days of 

switching from smoking combusted cigarettes to using the Vuse Vibe Original flavor 

(PM0000636) or Vuse Solo+ Original flavor products {PM0000712), there was a statistically 

significant reduction in all examined non-nicotine urinary BOE in both groups_ The blood 

carboxyhemoglobin (COHb) percent saturation, a biomarker of exposure to carbon 

monoxide (CO), was statistically significantly reduced for all groups. The applicant concluded 

that these data demonstrate that complete switching from combusted cigarette smoking to 

the Vuse Vibe Original flavor (PM0000636) or Vuse Solo+ Original flavor (PM0000712) 

during five days of ad libitum use resulted in reductions in urinary and blood BOE of similar 

magnitude to the reductions in the abstinence cohort. While the applicant did not provide 

data on BOE in dual users of the new products and cigarettes, given the significant reduction 

in non-nicotine BOE in complete switchers similar in magnitude to the abstinence cohort, as 
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TPL I conclude that if dual users significantly reduce their CPD while using the new products, 

a reduction in non-nicotine BOE can be expected. 

Urinary TNE values were statistically significantly reduced in the Vuse Solo+ Original flavor 

(PM0000712) cohort by 31% and in the abstinence cohort by 96% between baseline and 

Day 5. Although the urinary TNE values in the Vuse Vibe (PM0000636) cohort was reduced 

9% compared to baseline, this change was not statistically significant from baseline. The 

difference in TNE reduction between the Vuse Vibe and Vuse Solo+ Original flavor products 

(PM0000636, PM0000712) could be due to the relative nicotine concentrations of the two 

products; while the Vuse Solo+'s accompanying e-liquid contains 1.5% nicotine, Vuse Vibe's 

accompanying e-liquid contains 3.0% nicotine, thereby delivering more total nicotine to 

users. Nicotine plasma concentrations measured in the evenings increased steadily in both 

the Vuse Vibe and Vuse Solo+ cohorts from Day 1 to Day 5, approaching UB cigarette 

baseline measurements by Day 5. Plasma cotinine levels also increased from Day -1 to Day 5 

in both the Vuse Vibe and Vuse Solo+ cohorts, parallel to plasma nicotine levels. The 

applicant concluded that these data demonstrate the potential for nicotine exposure in the 

new products to reach levels of UB cigarettes. Therefore, with extended, exclusive use of 

either of these products, nicotine exposure can reach levels similar to those in users of 

combusted cigarettes, which may promote complete switching. 

Summary 

As TPL, I agree with the toxicology and BCP disciplines' conclusions that the toxicant 

exposure of the new products is lower than that of the combusted cigarette comparison 

product and similar to other marketed ENDS. There were many more HPHCs, at much higher 

levels, found in the combusted tobacco comparison products when compared to HPHCs 

from all the new product aerosols under both non-intense and intense puffing regimens. 

Additionally, the potential exposure to extractable and leachable compounds (including 

compounds that are also considered to be HPHCs) from the new product aerosols was 

substantially less than that observed from combusted cigarette smoke. The clinical data 

submitted by the applicant support that systemic exposure to several HPHCs is lower for 

users of the Vuse Vibe (PM0000636) Original flavor product and the Vuse Solo+ 

(PM0000712) Original flavor product compared to combusted cigarette smoking; switching 

from UB smoking to the new products significantly reduced the majority of BOE measured 

related to combustion. These findings support the conclusion that, if a combusted cigarette 

smoker either switches completely to the new products, or through dual use significantly 

reduces their CPD, they would have reduced toxicant exposure as a result. 
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3.6. HEALTH EFFECTS 

3.6.1. Discipline key findings 

The following discussion is based on key findings provided in the discipline reviews. 

3.6.1.1. Toxicology 

Per the toxicology review: 

3.6.1.1.1. Nonclinical studies 

• Results from the in vitro toxicology studies demonstrated that combusted cigarette 

smoke fractions (total particulate matter (TPM) or gas vapor phase (GVP) fractions) 

were mutagenic, cytotoxic, and genotoxic. By contrast, neither the TPM nor GVP 

from any of the aerosols of the tested new products or ENDS market comparison 

products were mutagenic or genotoxic and exhibited no, or minimal, cytotoxicity 

except at the highest dose. 

• The applicant attempted to bridge from the in vivo studies using Vuse Solo G2 

comparison product aerosols. Vuse Solo G2 aerosols consistently resulted in 

substantially lower nonclinical toxicity and histopathological changes compared to 

Newport Gold cigarette smoke. Despite substantial overlap in ingredients, the new 

product aerosols were determined not to be equivalent to the Vuse Solo G2 

aerosols from a toxicology perspective because several HPHC constituent yields 

were not analytically equivalent between corresponding products. Nonetheless, the 

observed reductions in HPHC yields in the new products and the Vuse Solo G2 ENDS 

comparison products when compared to the Newport Gold combusted cigarette 

comparison product does indicate that the new products are most likely also 

considerably less toxic in vivo. 

3.6.1.1.2. Clinical data with toxicity endpoints 

• From a toxicology standpoint, the comparison of select new products revealed that 

all urinary BOE, except for nicotine, are substantially lower when switching from 

combusted cigarettes to the new products. Moreover, BOE reductions in smokers 

who completely switched to the new products were similar to those measured in 

the abstinence cohort. 

3.6.1.1.3. Toxicant and study integration 

• The significantly lower aerosol HPHC yields in the new products compared to 

combusted cigarettes, and subsequent decrease in exposure to toxic and carcinogen 

constituents, are consistent with results from the corresponding nonclinical studies 

submitted by the applicant. 

• The applicant's findings indicate that after five days of completely switching from 

smoking combusted cigarettes to using the Vuse Vibe Original flavor {PM0000636) 

or Vuse Solo+ Original flavor products (PM0000712), smokers who switched to the 

new products exhibited BOE similar to those of the abstinence cohort, providing 

further support that exposure to new product aerosols, and lower levels of HPHCs, 

would likely result in fewer toxic exposures than combusted cigarettes, assuming 

equal puff profiles and other exposure parameters. 
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• The toxicological evaluation of ingredients, leachables, HPHCs, nonclinical studies, 

and BOE studies shows that results are consistent and supports the conclusion that 

risks to users ofthe new products who completely switch or significantly reduce 

CPD are likely to be lower relative to continued use of combusted cigarettes. 

3.6.1.2. BIMO inspection findings 

No Bioresearch Monitoring (BIMO) inspections were recommended or conducted during 

either cycle of substantive review. 

3.6.1.3. Addiction as a health endpoint 

Per the BCP review: 

• The abuse liability of the Vuse Vibe products and Vuse Ciro products is lower than 

that of combusted cigarettes, but higher than that of 4 mg nicotine replacement 

gum. Current combusted cigarette smokers (i.e., the applicant's stated intended 

user population for the new products) are likely to dual-use the new product with 

combusted cigarettes; however, combusted cigarette users who are motivated to 

quit smoking may use the Vuse Vibe products or Vuse Ciro products to reduce or 

quit smoking. Current cigarette smokers are likely to be able to maintain their 

nicotine addiction with the Vuse Vibe products or Vuse Ciro products, and smokers 

intending to use these products to aid in smoking cessation may find them more 

acceptable than nicotine replacement gum. 

• Although the Vuse Vibe products and Vuse Ciro products have abuse liability profiles 

that are lower than that of combusted cigarettes, both products deliver enough 

nicotine to sustain addiction in nicotine-dependent populations and can have risks 

of initiation and developing addiction in nonusers to a similar degree as combusted 

cigarettes. 

• The applicant's analysis of youth actual use behavior showed that youth who use 

ENDS exclusively may have lower nicotine dependence than those who use 

combusted cigarettes, though any level of youth nicotine dependence for ENDS use 

poses youth risk. This analysis was limited because it examined general ENDS use 

and incorporated data collected until 2016, before many of the ENDS currently used 

by youth, including the Vuse Vibe or Vuse Ciro products, were widely available, 

limiting its applicability to these new products. As previously discussed, the 

published literature shows that prevalence of youth use of tobacco-flavored ENDS is 

low and that tobacco-flavored ENDS are less likely to be used by youth who initiate 

or regularly use ENDS compared to non-tobacco flavored ENDS. 

3.6.1.4. Short and long-term health effects (clinical and observational) 

Per the epidemiology review: 

• The applicant did not submit any observational health effects studies. 

• Few observational studies have been published on the short- and long-term health 

effects of ENDS use. 

• Some published literature suggests that ENDS use compared to never tobacco use 

may be associated with a higher likelihood of some health outcomes such as 

cardiovascular disease, respiratory disease, and oral health. 41

•

43 However, many of 

these studies utilized cross-sectional surveys to examine these relationships; 
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therefore, the timing of ENDS use and disease onset cannot be established with 

certainty. 

• Bio marker data from observational studies generally show that ENDS users have 

higher exposure to nicotine, some volatile organic compounds (VOCs), and tobaccospecific nitrosamines (TSNAs) than do non-tobacco users.44•

45 Some biomarker data 

from observational studies have also found t hat dual users can have higher levels of 

certain BOE than exclusive cigarette smokers, including metabolites for nicotine, 

NNAL (4-(methylnitrosamino )-1-(3-pyridyl)-1-butanol ), 1-hydroxypyrene, acrolein, 

and 1,3-butadiene.

44•46 However, it has also been found that dual users have lower 

levels of some TSNAs and acrylonitrile.47 The number of cigarettes smoked per day 

among dual users and exclusive smokers likely impacts whether certain biomarkers 

of tobacco exposure are higher or lower in dual users compared to exclusive 

smokers across studies. 

• A meta-analysis found that, compared to heavy smokers, those who reduce their 

CPD by at least 50% had a significant reduction in lung cancer.48 However, 

reductions in cigarette smoking have not been found to lower the risk of all-cause 

mortality, all-cancer risk, or other smoking/tobacco related cancers. 48 These findings 

suggest that dual users who are able to reduce the number of cigarettes they smoke 

by at least 50% may be able to reduce their risk of lung cancer. 

• Switching likely reduces exposure to tobacco-related toxicants. In an observational 

study where smokers switched to ENDS for two weeks, total nicotine and some PAH 

metabolite levels did not change, but levels of all other biomarkers, including voes 

and TSNAs, significantly decreased after one week of using ENDS. 

49 

Per the medical review: 

• No definitive health conclusions can be drawn about the new products' impact on 

human healt h based on review of t he clinical data and health effects literature 

submitted by the applicant. Clinical study limitations preclude concluding that use of 

the proposed new products is not without potential human health risks, especially 

during long-term, chronic product exposure. 

• The likelihood of new product use leading to reduced incidence of chronic tobaccorelated disease such as pulmonary disease, cardiovascular disease, or cancer in 

cigarette smokers who switch to these products has not been established. Longterm studies demonstrating such findings are not available, and the current bridging 

literature and results of biomarkers of potential harm (BOPH) measurements in t he 

reduced exposure studies are not sufficiently robust to draw definitive conclusions 

about long-term health risks or disease from chronic product use and exposure. 

• Overall, the applicant provided data to evaluate the short- and long-term health 

effects of new products and, based on the provided information, no significant 

safety concerns were identified. There are currently no published data for the 

health effects of the new products. 

• Medical is not able to draw conclusions on the health effects of new products from 

the applicant's studies and published literature due to several study design 

limitations including: 

• Small sample sizes 

• Short study duration 

• Short-term exposure periods 
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• Enrollment of generally healthy subjects, which may under-estimate the 

incidence of real-world adverse experiences (AEs) in real-world ENDS consumers 

• Switching studies that assessed complete switching but did not assess partial 

incomplete switching (or dual use) 

• In general, the published literature on the health effects of ENDS suggests that 

many ENDS aerosol constituents (e.g., TSNAs, VOCs, PAHs) may be lower compared 

with combusted cigarettes.44,so,si The National Academies of Sciences, Engineering, 

and Medicine (NASEM) states that ENDS aerosol contains lower levels of most 

toxicants than combusted cigarette smoke. 52 Some literature also reports that not 

all ENDS aerosol constituents are reduced (e.g., acrolein, acrylamide, acrylonitrile, 

xylene),50,

53 which may potentially off-set the potential health benefit of short- and 

long-term reductions in exposure to other ENDS constituents. However, the ability 

to draw conclusions on the health effects of ENDS from the published literature is 

limited due to small sample sizes and short durations of exposure. 

• The literature is unclear regarding whether specific reductions in exposure to 

harmful constituents necessarily lead to a substantial or clinically significant 

reduction in tobacco-related health outcomes or disease risk. There continues to be 

a significant knowledge gap in the body of published literature regarding empirical 

morbidity and mortality data to fully characterize the range of potential short- and 

long-term health effects of ENDS use and aerosol exposure in users and nonusers. 

However, based on the currently available evidence, reducing CPD likely leads to 

less exposure to harmful toxicants than continued smoking and thus do not raise 

concerns from a medical perspective.

54 

3.6.1.5. Likelihood and effects of product misuse 

Per the BCP review: 

• The new products are closed-system, pod-style ENDS. The new product settings are 

non-adjustable and thee-liquid is enclosed in a cartridge, thereby reducing chances 

that users would be able to manipulate ENDS product settings and e-liquid 

constituents, including nicotine levels, which could influence exposure to nicotine 

and other HPHCs in the aerosol. 

Per the medical review: 

• Vuse Vibe and Vuse Ciro are closed systems consisting of a rechargeable power unit 

and disposable cartridge that is not intended to be opened. There is no childresistant packaging report or General Certificate of Conformity included in the 

applications. However, the cartridges are blister packaged and provide a tamper 

evident seal, and the health risk is likely mitigated for accidental exposure in 

children. 

3.6.1.6. Adverse experiences 

Per the chemistry review: 

• There were no chemist ry-related AEs due to product design and composition of 

the new products reported to FDA at this time. 
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Per the engineering review: 

• The applicant stated in a Failure Mode and Effects Analysis document that eliquid leakage hazards were considered and mitigated through robust design 

and manufacturing techniques. The applicant also outlined all of the design 

verification and continuous manufacturing verification steps that are in place to 

ensure e-liquid cartridges will not leak. 

• Engineering-related AEs from product design are adequately addressed. The 

applicant described 20 AEs in the original submission and in response to 

deficiencies, they explained that the AEs occurred only in the Vuse Vibe Power 

Units manufactured with the._...&,.;j""battery (PM0004287). The applicant 

adequately explains how it responded to the AEs: after determining that the AEs 

were a result of poor manufacturing practices, it instituted improved monitoring 

of battery production and increased the battery verification procedures. No AEs 

have been noted since the manufacturing oversight changes were applied. 

Per the medical review: 

• Short-term clinical studies submitted by the applicant demonstrate t hat the 

numbers of AEs were generally low and characterized overall as mostly mild, 

transient, and expected. No deaths or serious AEs were reported to be 

associated with use of the new products during the exposure studies. 

• Based on Tobacco Product Surveillance Team (TPST) AE data, thermal events 

were associated with PM0004287. Ofthe 23 AEs reported for Vuse Vibe, 20 

were reported to be associated with overheating/fire/explosions (OH/F/Ex). Of 

these, six were associated with burns. Reports of OH/F/Ex initiated a 2018 

market voluntary withdrawal of Vuse Vibe. No OH/F/Ex were reported in the 

PMTAs for Vuse Vibe or Vuse Ciro. 

• The potential for device malfunctions in the battery or coil temperat ure 

regulation could increase the potential health risk of thermal and aerosolrelated burn injury from ENDS should temperat ures rise above a 60°C 

threshold.

55 However, per the measurement values provided by the applicant 

and assessed by engineering, the temperatures are below 60°C. 

• The package insert states that the device may overheat, and vusevapor.com 

mentions the risk of fire, but none of the submitted language includes the risk of 

explosion, despite the multiple reported AEs of explosion documented for 

PM0004287 as acknowledged by the applicant. The current PMTA submission 

states that there are now inspection criteria and increased testing of batteries 

at mult iple process points, and improved and increased training of personnel is 

also reported; however, the applicant has not explicitly quantified the 

effectiveness of changes of that have been implemented. ENOS can explode and 

cause projectile injuries and burns to human users. However, the applicant 

provided sufficient information to demonstrate that the new products are not 

likely to explode or catch fire if they are used within the certified parameters 

tested (i. e., an 80 ml puff volume with a 5-second inhalation time and 15-

second interval smoking regimen). 

• E-cigarette, or vaping, product use-associated lung injury (EVALI) is still being 

fully characterized as a potential respiratory health effect that could occur in 

individuals who use vaping products. There were no reports of EVALI in this 
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PMTA, nor were there any subjects who experienced the full constellation of 

symptoms indicative of EVALI as an AE that required hospitalization. However, 

there were users who reported respiratory AEs to TPST, including one who 

required hospitalization after use of Vuse Vibe. EVALI is an emerging health 

issue associated with use of vaping products and could potentially occur with 

use of the new products. 

• While there were no seizures reported as an AE in the applicant-submitted 

clinical studies, there were multiple neurological AEs reported. However, across 

all studies, these AEs were generally mild, transient (i.e., resolved by study end) 

and expected (e.g., headache, nausea). No deaths or serious AEs were reported 

to be associated with use of the PMTA products in the clinical studies. Several 

neurological AEs were reported to the Safety Reporting Portal (SRP) as 

associated with both Vuse Vibe and Vuse Ciro. However, the strength of 

evidence for determining causality of these AEs is inconclusive based on TPST 

data due to incomplete or potentially confounding information. CTP has 

received multiple reports of seizures in youth and young adults associated with 

ENDS use. However, current SRP data are insufficient to fully evaluate the 

potential association of the new products with seizures. 

• Therefore, to further monitor and evaluate potential ENDS health effects such 

as EVALI and seizures, the medical discipline recommends that post-market 

reporting include a specific plan to monitor respiratory-related illnesses, 

neurological symptoms, and AEs related to thermal burns associated with the 

new products. 

• The use of blister-packaged cartridges prevents accidental exposure to the 

nicotine-containing e-liquid. However, there are no data to demonstrate 

adequate mitigation of accidental exposure in children, such as any childresistant packaging testing procedure reports or certifications. This limits the 

medical evaluation of the PMTA products in nonusers such as children. Oral, 

dermal, or ocular exposure toe-liquids containing nicotine can cause adverse 

health effects, including seizures, anoxic brain injury, vomiting and lactic 

acidosis, and can even be fatal. 

3.6.2. Synthesis 

Taken together the sum of the evidence for health effects of the new products is equivalent 

to the general health effects and risks of other ENDS and has the potential to improve 

health outcomes for a least a subset of smoking-related illnesses if combusted cigarette 

users completely switch or significantly reduce their cigarette consumption. 

The abuse liability of the new products is lower than that of combusted cigarettes, but 

higher than that of nicotine replacement gum. This makes it likely that smokers not 

interested in quitting who use these products would dual use them along with their 

cigarettes rather than completely switch. They may reduce their CPD, which would 

potentially improve the impact of smoking on their health. Smokers interested in quitting 

may prefer these products as a substitute for smoking over nicotine replacement gum. 

Because these products do have abuse liability, there is the risk that nonusers who 

experiment with these products may become established nicotine users and develop 

addiction to a similar degree as combusted cigarettes. 
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Consumers are unlikely to be able to misuse these products (using the product in ways other 

than intended such as product modifications, dripping, and stealth use) due to their closed 

design and pre-filled e-liquid cartridges. The settings are non-adjustable and the e-liquid is 

enclosed in a cartridge, reducing the chance that users can manipulate the product settings 

or e-liquid constituents. The applicant has also reduced the likelihood of accidental exposure 

in children by using blister packaging for the e-liquid cartridges. Concerns about the 

potential for battery case fires and explosions have been reduced to the level of general 

concern for these types of AEs (which exist for all ENDS) due to the applicant's efforts to 

improve its battery manufacturing and testing procedures. 

The new products show considerably less toxicity compared with combusted cigarettes. The 

nonclinical and clinical data indicate that there is less toxicity from the aerosols of the new 

products due to the reduction in HPHC yields and that the levels of BOE after smokers 

completely switched to the new products were similar to those measured in the abstinence 

cohort. Overall, it was concluded that the risks to users of the new products who completely 

switch or significantly reduce their CPD are likely to be lower relative to continued use of 

combusted cigarettes. 

Of the data that the applicant was able to provide on the short- and long-term health effects 

of the new products, no significant safety concerns were identified, although both the 

applicant's studies and published literature had several study design limitations that 

preclude strong conclusions. While epidemiology stated that reducing cigarette smoking can 

lead to a significant reduction of certain smoking-related diseases, such as lung cancer, they 

agree with medical that it is unclear whether specific reductions in exposure to harmful 

constituents will lead to clinically significant reductions in tobacco-related health outcomes 

or disease risk as a whole. This significant knowledge gap counters the potential for a 

positive outcome from dual use, as these new products are most likely to be used, 

compared with completely switching and stopping use of combusted cigarettes. However, 

based on available information, I agree that adult smokers who switch to these products 

(either completely or with a significant reduction in cigarette consumption) would benefit 

from reduced exposure to many HPHCs. While the effects of dual use were not assessed, 

significant reductions in systemic exposures after short-term switching and the available 

evidence suggest that even partial switching to the new products (assuming a significant 

reduction in cigarette consumption) may provide health benefits from a harm reduction 

perspective in terms of reducing exposure to HPHCs relative to continued use of cigarette 

smoking alone. 

There were 23 AEs for Vuse Vibe, of which 20 were associated with 

overheating/fire/explosions (OH/F/Ex); six of these associated with burns. These reports of 

OH/F/Ex initiated a 2018 voluntary market withdrawal of Vuse Vibe. There were no 

instances of OH/F/Ex reported in the PMTAs for Vuse Vibe or Vuse Ciro. As TPL, I agree with 

the engineering discipline that the applicant has supplied adequate evidence that it

to identify that the issue was with the Vuse Vibe Power Units manufactured with thc__j 

battery (PM0004287) and that the applicant has taken appropriate actions to remedy the 

issue including improved monitoring of the battery production process and increased 

battery verification procedures. I also agree with the medical discipline that the applicant 

has provided sufficient information to demonstrate that the new products are not likely to 

explode or catch fire if they are used within the certified parameters tested. 

((bb)) ((4) 4)

was able
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Summary 

Per the toxicology review, the new products' aerosols are significantly less toxic than the 

combusted tobacco comparisons based on available nonclinical, HPHC, and BOE data. Per 

the BCP review, short-term (five days) switching from cigarette smoking to the new products 

resulted in significant reductions in urinary and blood BOE. Per the medical review, the 

numbers of AEs were generally low and mostly mild and transient in short-term clinical 

studies. However, the applicant's switching studies assessed short-term complete switching 

but did not assess the effects of long-term use and the impact of dual use, which would be 

more likely to occur in real-world conditions. There is limited data about the long-term 

health effects of ENDS from large clinical studies or long-term epidemiological studies. 

Evidence from the published literature suggests that reducing CPD likely leads to lower 

exposure to harmful toxicants than continued smoking and exclusive ENDS users often have 

lower levels of nicotine, TSNAs, and voes compared to dual users of ENDS and combusted 

cigarettes. The study design limitations (e.g., small sample size, generally healthy 

participants, short exposure periods) in the published literature make it difficult to draw 

definitive conclusions related to health effects of ENDS, specifically the new products. 

Therefore, the long-term health effects and potential short- and long-term health effects 

from dual use of the new products could not be evaluated. However, based on available 

information, I agree that adult smokers who switch to these products (either completely or 

with a significant reduction in cigarette consumption) would benefit from reduced exposure 

to many HPHCs. While the effects of dual use were not assessed, significant reductions in 

systemic exposures after short-term switching and the available evidence suggest that even 

partial switching to the new products (assuming a significant reduction in cigarette 

consumption) may provide health benefits from a harm reduction perspective in terms of 

reducing exposure to HPHCs relative to continued use of cigarette smoking alone. 

3.7. POPULATION AND PUBLIC HEALTH 

3.7.1. Discipline key findings 

The following discussion is based on key findings provided in the discipline reviews. 

3.7.1.1. Toxicology 

Per the toxicology review: 

• From a toxicological perspective, given the magnitude and statistical significance of 

the decreases in HPHCs from the new product aerosols compared to combusted 

tobacco comparison products, the new products are likely to result in reduced 

toxicity due to reduced HPHC exposure among dual users (those who use 

combusted cigarettes and the new products) who significantly reduce CPD or who 

switch to ENDS completely. 

3.7.1.2. Population health impact (PHI} model 

Per the epidemiology review: 

• The applicant used the Dynamic Population Modeler (DPM) (+1), a statistical model, 

to estimate the effect of changes in tobacco use patterns across multiple age 

cohorts. The outcome was the difference in mean number of survivors-from age 

category 13-18 years to the end of the age category 68-72 years-for a 

counterfactual scenario where Vuse Vibe and Vuse Ciro products are available in the 
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marketplace compared to a base case without Vuse Vibe and Vuse Ciro products' 

availability. 

• Model inputs came from the 2018 National Survey on Drug Use and Health (NSDUH) 

data (smoking initiation) and 2015-2017 NSDUH data (cessation). Gender- and agespecific mortality rates for never, current, and former cigarette smokers were 

calculated based on data from the Kaiser-Permanente Cohort Study and 2000 U.S. 

Census. It was assumed that using the Vuse Vibe or Vuse Ciro compared to cigarette 

smoking would result in tobacco-related mortality risk reductions of 90% and 95%. 

Probabilities for all primary transitions were based on the likelihood of use testing 

specific to Vuse Vibe and Vuse Ciro (Section H.5.2.3 of the PMTAs). 

• The model suggests that the use of Vuse Vibe among tobacco users and nonusers 

would be projected to increase survival to age 72 for about 140,000 to 365,000 

individuals in the U.S. population over a 60-year period. For Vuse Ciro, an additional 

185,000 to 450,000 individuals would survive to age 72. 

• There are some limitations to the inputs used in this model that may overestimate 

the population health benefit. However, without running the model again with 

different inputs, the amount of overestimation is unknown. First, the model used 

likelihood of use data rather than prevalence data observed in real-world surveys 

(i.e., TTM, NTBM). Second, the model did not allow for periods of sustained dual 

use, which is a common use pattern before complete switching occurs. Finally, the 

main analyses are based on an optimistic risk reduction estimate (i.e., the 

assumption of a 95% lower excess relative risk compared to cigarettes). Despite 

these weaknesses, epidemiology generally agrees that the mortality rates due to 

combusted cigarette smoking will decrease and result in additional survivors in the 

population. However, as the model inputs do not rely on actual product use from 

surveys or real-world prevalence data (vs. likelihood of product use employed by 

the applicant) and do not account for periods of dual use, it does not help evaluate 

mortality rates and survival estimates and the potential public health impact. 

3. 7 .2. Synthesis 

As TPL, I agree with the epidemiology discipline that the population health impact model 

submitted by the applicant does not raise concerns in terms of model structure or tobacco 

use transitions; however, as it may overestimate actual product use, the model does not 

help evaluate whether the new products are APPH. 

As TPL, I also agree with the toxicology discipline's commentary on dual use of the new 

products with combusted cigarettes. They note that human dual use may be a highly 

heterogenous use scenario, with a wide range of use topographies. The applicant-submitted 

biomarker studies indicate a reduction in exposure to certain HPHCs among users who 

switch completely. If dual users significantly reduce the number of combusted cigarettes 

used per day, it can be expected that they will also reduce their exposure to certain HPHCs, 

although to a lesser degree than complete switchers. The risks to users of the new products 

who completely switch or significantly reduce their CPD are likely to be lower relative to 

continued use of combusted cigarettes. 

As TPL, I agree with toxicology discipline's conclusions that switching completely from 

combusted cigarette smoking to the new products will result in large reduction in HPHC 

exposures. I also agree with the epidemiology review on the limitations of the applicant's 
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population health modeling methodology. The limitations include overestimating the actual 

switching rate from combusted cigarette smoking to exclusive ENDS use, as well as 

overlooking the scenarios of ENDS use among young people. Therefore, given the limitations 

associated with the model inputs described in the epidemiology review, the model is not 

particularly informative in the evaluation of whether the new products are APPH. The 

determination ofAPPH will be made based on overall information evaluated. 

3.8. STATUTORY REQUIREMENTS 

3.8.1. Public health conclusion 

Based on the findings and evaluations discussed in Sections 3.1-3.7, I find that permitting 

the marketing of the new products in accordance with the requirements in the marketing 

granted orders is APPH. 

3.8.2. Tobacco product manufacturing practices 

The PMTAs contain sufficient information to characterize the products' design and adequate 

processes and controls to help ensure that the products meet the manufacturer's 

specifications. The methods used in, and the facilities or controls used for, the manufacture, 

processing, and packing of these products do not fail to conform to the requirements in 

Section 906(e) of the FD&C Act. 

3.8.3. Labe ling 

For all PMTAs, the applicant provided proposed labeling. Based on the information 

presented at this time, we have not concluded that the proposed labeling is false or 

misleading in any particular. 

3.8.4. Product standards 

There are no applicable product standards for these PMTAs. 

4. ENVIRONMENTAL DECISION 

4.1. DISCIPLINE FINDINGS 

Environmental science concluded that the environmental assessments for all PMTAs contain 

sufficient information to determine whether the proposed actions may significantly affect 

the quality of the human environment. As TPL, I agree with this conclusion. 

4.2. ENVIRONMENTAL CONCLUSION 

A finding of no significant impact (FONSI) was signed by Bria Martin on May 2, 2022. The 

FONSI was supported by an environmental assessment prepared by FDA on May 5, 2022. 

5. CONCLUSION AND RECOMMENDATION 

In making a determination about whether permitting the marketing of a product is APPH, 

Section 910(c)(4) directs FDA to consider the risks and benefits to the population as a whole, 

including users and nonusers of tobacco products, taking into account, among other things, the 

likelihood that those who do not use tobacco products will start using them. FDA's scientific review 

is not limited to considering information in a PMTA, and the agency may also consider any other 
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information before the agency, including the relevant existing scientific literature (see Section 

910(c)(2)). 

Based on its evaluation of these PMTAs, FDA determined that these PMTAs contain sufficient 

information to characterize the product design and that there are adequate process controls and 

quality assurance procedures to help ensure that both the device and e-liquids are manufactured 

consistently. Based on the information provided in the PMTAs, the abuse liability of the new 

products is lower than that of combusted cigarettes and higher than that of 4mg NRT gum. Evidence 

from the literature indicates that the new products likely have abuse liability that falls within the 

range of other ENDS based on nicotine pharmacokinetic data.5 The overall toxicological risk to the 

users of the new products is lower compared to cigarettes due to significant reductions in aerosol 

HPHCs of the new products compared to cigarettes and as evidenced by results of nonclinical 

studies. Furthermore, significant reductions in blood and urinary biomarkers of exposure (e.g., 

voes, TSNAs, PAHs) indicate that exposure to carcinogens and other toxicants present in cigarette 

smoke was greatly reduced in smokers who switched completely to the use of the new products. In 

addition, current established cigarette users indicated the highest intentions to purchase among all 

groups, and the most preferred products among current established cigarette users were the 

tobacco (Original) tobacco-flavored ENDS products. Therefore, the applicant has demonstrated the 

potential for these new products to benefit adult smokers. 

In terms of the risks to non-users, youth are considered a vulnerable population for various reasons, 

including that the majority of tobacco use begins before adulthood and thus youth are at particular 

risk of tobacco initiation. Although ENDS products are the most widely used tobacco products 

among youth, existing evidence consistently indicates that use of tobacco-flavored ENDS is less 

common than non-tobacco flavored ENDS. Nonetheless, given the strong evidence regarding the 

impact of youth marketing exposure on youth appeal and initiation of tobacco use, any marketing 

authorization for the new products should include post-market requirements to help ensure that 

youth exposure to tobacco marketing is limited. In addition, the applicant's study findings 

demonstrated low intention to purchase the new products among adult never and former 

established tobacco users. Together, based on the information provided in the PMTAs and the 

available evidence, the potential to benefit smokers who switch completely or significantly reduce 

their cigarette use would outweigh the risk to youth, provided the applicant follows post-marketing 

requirements aimed at reducing youth exposure and access to the products. 

I tr,n 

Regarding product stability, the applicant stated that the shelf-life of the new products i .__ ___ _,

;J;b

:nolicant provided chemistry data to support that the new products are chemically stable over E'

4 jHowever, the applicant did not provide !11icrobial data that would allow FDA to evaluate

whether the products are microbially stable over · 4 The applicant instead provided data 

that su · bial stability of the products over 4 Because the microbial stability 

data for is acceptable and indicates that tl'ie pro uc s are low-risk for microbial growth 

over an · 4 eriod and because there are no other stability concerns, the lack of microbial 

data fo · does not preclude an APPH finding for the new products. 

Based on my review of the subject PMTAs, I find that permitting the marketing of the new products, 

as described in the applications, and specified in Appendix Table 3, is APPH. The issuance of 

marketing granted orders confirms that the applicant has met the requirements of section 910(c) of 

the FD&C Act and authorizes marketing of the new products. Under the provisions of section 910, 

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4) ) (4)

e

supports micro
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the applicant may introduce or deliver for introduction into interstate commerce the products, in 

accordance with the marketing order requirements outlined in the marketing granted orders. 

FDA has examined the environmental effects of finding the new products APPH and made a Finding 

of No Significant Impact (FONSI). 

Marketing granted orders should be issued for the new products subject to this review, as identified 

on the cover page of this review. 
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Page 54 of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 

7. APPENDIXxiii, xiv

Table 3. New tobacco products subject to Granted Orders 

Common Attributes 

Applicant 

Product manufacturer 

Product category 

Attributes 

STN 

Submission date 

Receipt date 

Product name 

Product subcategory• 

Package type 

Package quantity 

Characterizing flavor 

Additional properties 

STN 

Submission date 

Receipt date 

Product name 

Product subcategory 

Package type 

Package quantity 

Characterizing flavor 

E-liquid volume

Nicotine concentration 

PG/VG ratio 

Additional properties 

R.J. Reynolds Vapor Company 

R.J. Reynolds Vapor Company 

ENDS {VAPES) 

New Product 

PM0000635 

April 2, 2020 

April 2, 2020 

Vuse Vibe Power Unit 

Closed E-Cigarette 

Paperboard Carton 

1 Power Unit 

Unflavored 

Length: 82.5 mm 

Diameter: 13.0 mm 

Wattage:•vi 4.0-6.5 W 

Battery capacity: 550 milliAmpere hour {mAh) 

Universal Serial Bus {USB) Charger 

Battery Manufacturer: f

bY4! 

PM0000636 

April 2, 2020 

April 2, 2020 

Vuse Vibe Tank Original 3.0% 

Closed E-Liquid 

Paperboard Carton/Blister Pack 

2 Cartridges 

Tobacco•vii 

1.9 ml per cartridge 

36.0 mg/ml 

20/80 

Length: 59.0 mm 

Diameter: 13.0 mm 

Nicotine content: 3.0% w/w 

I 

Page 54 of 56 

xiii We interpret package type to mean container closure system and package quantity to mean product quantity within the 

container closure system, unless otherwise identified. 

x

iv Brand/sub-brand or other commercial name used in commercial distribution. 

)(V FDA referred to these products as ENDS Components during the course of review to facilitate processing. However, at the 

close of review the accurate category and subcategory are reflected in the TPL review and supersede those listed in primary 

discipline reviews. 

xvi The applicant states the wattage listed represents the nominal operating range; the upper and lower wattages have a 

variation of 

xvii Labels may

,.__con-ta -.... in descriptive terms such as "Original". 

(b) (4)

(b) (4)

>=
Page 55 of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 

STN 

Submission date 

Receipt date 

Product name 

Product subcategory 

Package type 

Package quantity 

Characterizing flavor 

Additional properties 

STN 

Submission date 

Receipt date 

Product name 

Product subcategory 

Package type 

Package quantity 

Characterizing flavor 

Nicotine concentration 

PG/VG ratio 

E-liquid volume

Additional properties

STN 

Submission date 

Receipt date 

Product name 

Product subcategory 

Package type 

Package quantity 

Characterizing flavor 

Additional property 

PM0000646 

April 15, 2020 

April 15, 2020 

Vuse Ciro Power Unit 

Closed E-Cigarette 

Paperboard Carton 

1 Power Unit 

Unflavored 

Length: 83.5 mm 

Diameter: 9.2 mm 

Battery Capacity:> 260 milit!J'oero boj(mAh) 

Wattage: XVIII Expected Hir

: ,)(

Expected Low: tii,4) 

Universal Serial Bus (USB) Charger 

Battery Manufacturer:1

10

Ji-1J 

PM0000712 

April 15, 2020 

April 15, 2020 

Vuse Ciro Cartridge Original 1.5% 

Closed E-Liquid 

Paperboard Carton/Blister Pack 

3 Cartridges 

Tobacco•vii 

17.7 mg/ml 

29/71 

0.9 ml per cartridge 

Length: 50.0 mm 

Diameter: 9.2 mm 

Nicotine Content: 1.5% w/w 

PM0004287 

April 2, 2020 

April 2, 2020 

Vuse Vibe Power Unit 

Closed E-Cigarette 

Paperboard Carton 

1 Power Unit 

Unflavored 

Length: 82.5 mm 

Diameter: 13.0 mm 

Wattage:xvi4.0-6.5 W 

Battery capacity: 550 milliAmpere hour (mAh) 

Universal Serial Bus (USBl Chare:er 

·f.J;'4' Battery Manufacturer 

xviii The wattages listed represent the average of 15 samples± 95% confidence interval.

I 

Page 55 of 56 

l

(b) (4)

(b) (4)

(b) (4)

(b) (4)

>=
Page 56 of 56 

TPL Review of PMTAs: PM0000635, PM0000636, PM0000646, PM0000712, PM0004287, PM0004293 

STN PM0004293 

Submission date April 15, 2020 

Receipt date April 15, 2020 

Product name Vuse Ciro Power Unit 

Product subcategory Closed E-Cigarette 

Package type Paperboard Carton 

Package quantity 1 Power Unit 

Characterizing flavor Unflavored 

Additional property Length: 83.5 mm 

Diameter: 9.2 mm r

l(4) 

Wattage:•viiiExpected Hi2h: I

Expected Low:r t'l I Battery capacity: 260 m1111Ampere hour (mAh) 

Universal Serial Bus rh-,ra<=>r 

Battery Manufacturer: P')(41

Table 4. Amendments 

Submission Receipt Amendment Applications 

Date Date being 

amended 

November November PM0004271 PM0000635, 

23,2020 23,2020 PM0000636, 

PM0000646, 

PM0000712 

February February PM0004566 All';' 

18,2021 18,2021 

March 18, March 18, PM0004600 Allxix 

2021 2021 

xix This amendment applies to all STNs subject of this review. 

Reviewed 

Yes 

Yes 

Yes 

Status 

Active 

Active 

Active 

Page 56 of 56 

l I 

Brief 

Description 

Response to 

the Office of 

Compliance 

and 

Enforcement's 

Inspection 

Request 

Letter 

Request for 

Extension to 

Respond to 

FDA 

Deficiency 

Letter 

Response to 

Deficiency 

Letter 

(b) (4)

(b) (4)

(b) (4)

>=

(USB)