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Ii U.S. FOOD & DRUG 

ADMINISTRATION 

Technical Project Lead (TPL) Review of PMTAs 

Digitally signed by Zheng Tu -S 

Date: 2022.04.25 13:31 :56 -04'00' 

Zheng (Alex) Tu, Ph.D. 

Supervisory Pharmacologist 

Division of Nonclinical Science 

Concur with TPL recommendation and basis of recommendation 

New Products Subject to this Review1 

Submission tracking numbers (STNs) PM0000613.PD1 - PM0000615.PD1, and PM0000622.PD1 

Common Attributes of PMTAs 

Submission date March 10, 2020 

Receipt date March 10, 2020 

Applicant NJOY LLC 

Product manufacturer NJOY LLC 

Application type Standard 

Product category ENDS (VAPES) 

Product subcategory Closed E -Cigarette, Closed E-Liquid 

Cross-Referenced Submissions 

All STNs ll/h\/4\ I 

Supporting FDA Memoranda Relied Upon in this Review 

• OHCE Consultation finalized on 3/14/2022 

• TPST Search for AE Reports involving NJOY LLC ACE ENDS All STNs products finalized on 2/15/2022 

Recommendation 

Issue marketing granted order letter for PM0000613.PD1 - PM0000615.PD1, and PM0000622.PD1 

Technical Project Lead (TPL): 

Signatory Decision: 

Digitally signed by Matthew R. Holman -5 

1oate: 2022.04.25 13:57:22 -04'00' 

Matthew R. Holman, Ph.D. 

Director 

Office of Science 

1 Tobacco product details, amendments, and dates provided in the Appendix. PMTA means premarket tobacco application(s). 
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TABLE OF CONTENTS 

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

2. BACKGROUND..................................................................................................................................7 

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

2.2. REGULATORY ACTIVITY .................................................................................................................... 7 

2.3. SCOPE OF REVIEW ........................................................................................................................... 7 

3. SCIENTIFIC REVIEW ..........................................................................................................................8 

3.1. COMPARISON PRODUCTS ................................................................................................................8 

3.1.1. Discipline key findings ..................................................................................................... 8 

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

3.2. PRODUCT CHARACTERIZATION ..................................................................................................... 12 

3.2.1. Discipline key findings ...................................................................................................12 

3.2.2. Synthesis........................................................................................................................ 14 

3.3. ABUSE LIABILITY ............................................................................................................................. 15 

3.3.1. Discipline key findings ................................................................................................... 15 

3.3.2. Synthesis........................................................................................................................ 16 

3.4. USER POPULATIONS ...................................................................................................................... 16 

3.4.1. Discipline key findings ................................................................................................... 16 

3.4.2. Synthesis........................................................................................................................ 24 

3.5. TOXICANT EXPOSURE .................................................................................................................... 26 

3.5.1. Discipline key findings ................................................................................................... 26 

3.5.2. Synthesis........................................................................................................................ 27 

3.6. HEAL TH EFFECTS ............................................................................................................................ 27 

3.6.1. Discipline key findings ................................................................................................... 27 

3.6.2. Synthesis........................................................................................................................ 32 

3.7. POPULATION AND PUBLIC HEALTH ............................................................................................... 32 

3.7.1. Discipline key findings ................................................................................................... 32 

3.7.2. Synthesis........................................................................................................................ 33 

3.8. STATUTORY REQUIREMENTS ......................................................................................................... 34 

3.8.1. Public health conclusion ................................................................................................ 34 

3.8.2. Tobacco product manufacturing practices .................................................................... 34 

3.8.3. Labeling ......................................................................................................................... 34 

3.8.4. Product standards ......................................................................................................... 34 

4. ENVIRONMENTAL DECISION ...........................................................................................................34 

4.1. DISCIPLINE FINDINGS ..................................................................................................................... 34 

4.2. ENVIRONMENTAL CONCLUSION ................................................................................................... 35 

5. CONCLUSION AND RECOMMENDATION ......................................................................................... 35 

6. REFERENCES ...................................................................................................................................36 

7. APPENDIX ......................................................................................................................................42 

7.1. APPENDIX A: NEW PRODUCTS AND AMENDMENTS .....................................................................42 
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LIST OF TABLES 

Table 1. Disciplines reviewed ........................................................................................................................7 

Table 2. Consultations ...................................................................................................................................8 

Table 3. New tobacco products subject to Granted Orders ....................................................................... 42 

Table 4. Amendments received .................................................................................................................. 44 
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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 review, I find that permitting the marketing of the new products listed above 

("new products" or "subject ENDS") 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 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 a showing 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 increases or decreases, the burden of demonstrating a 

substantial enough benefit likewise increases or decreases. For flavored ENDS2 (i.e., ENDS withte-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 menthol-flavored 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 

2 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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of public health benefit as flavored ENDS, i.e., increased switching and/or significant reduction 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 tobaccoflavored ENDS in facilitating smokers in completely switching from or significantly reducing 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. 3 Rather, for flavored ENDS, only the most stringent mitigation measures -

specifically device access restrictions - have such mitigation potential. 4 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, restrictions on advertising and promotion and sales access are 

important to include in marketing granted orders (MGOs) because they 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. 

1.2. SUBJECT APPLICATIONS 

3 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 thei

r social networks"). 

4 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 of those 

applications. 
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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 both the device and e-liquids are manufactured consistently. 

Chemical testing submitted in the PMTAs was sufficient to determine that overall harmful and 

potentially harmful constituent (HPHC) levels in the aerosol of these products are lower than in 

combusted cigarette smoke. 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. Further, biomarker data provided by the applicant demonstrated that participants who had 

used only the NJOY ACE products had lower levels of biomarkers of exposure to HPHCs (e.g., CO, 

cotinine, CEMA, 3-HPMA, and NNAL) compared to the dual users of the new products and combusted 

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

ability to promote continued use, addiction, or dependence-is comparable to that of combusted 

cigarettes and other ENDS tested. Therefore, these products have the potential to benefit adult smokers 

who switch completely or significantly reduce their cigarette consumption. In the applicant's Prevalence 

and Perception Study, current adult smokers had the most interest in the Classic Tobacco 5% nicotine 

product. Further, the NJOY User Study demonstrated that switching from combusted cigarettes to the 

new ENDS products does occur among current adult smokers. The applicant has therefore 

demonstrated the potential for these products to benefit adult smokers 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 is less 

common compared to flavored ENDS among youth. Consistent with these findings, in the applicant's 

youth Prevalence and Perception studies, curiosity to use the tobacco-flavored products ..,kb:..:..:l<-'-4).__ ____,

(bl(4l The same studies also showed that the percentage of 

youth reporting ever using ENDS and started with tobacco-flavored ENDS was much lower than that of 

!lh\/4\ L Nonetheless, given the strong evidence regarding the impact of youth exposure to 

marketing on youth appeal and initiation of tobacco use, any marketing authorization should include 

marketing restrictions and postmarket requirements to help ensure that youth exposure to tobacco 

marketing is limited. 

Regarding product stability, the applicant stated that the shelf life of the new products is l�(b�

)(4

_) __ � 

However, the applicant only provided chemistry data to support that the new products are chemically 

stable over fbl(4l I. In addition, the applicant provided data that only supports microbial stability over 

!(b)(4) I for NJOY ACE POD 5% Rich Tobacco (PM0000622.PD1). The chemical and microbial stability 

data in the PMTAs is acceptable and indicates that the products are low-risk for chemical instability and 

microbial growth over the period tested. There are no other stability concerns, and therefore the lack of 

stability data for j(b)(4) jdoes 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 switch completely to the new products) 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. 
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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 TOBACCO PRODUCTS 

The applicant, NJOY LLC, submitted information for the four new tobacco products listed on the 

cover page and with more detail in the Appendix (Table 3), sold under the brand names NJOY 

and NJOY ACE. Briefly, a complete NJOY ACE ENDS is composed of a rechargeable Power Unit 

(closed device, PM0000613.PD1), a prefilled pod containing thete-liquids, and an accessory USB 

charger for the power unit. The power unit and cartridge settings are not adjustable by the user. 

The pods contain e-liquids identified by the applicant as containing the following flavors: Classic 

Tobacco flavor with 2.4% nicotine (PM0000614.PD1), Classic Tobacco flavor with 5% nicotine 

(PM0000615.PD1), and Rich Tobacco flavor with 5% nicotine (PM0000622.PD1). 

2.2. REGULATORY ACTIVITY 

On March 10, 2020, FDA received four PMTAs from NJOY LLC. FDA issued an Acceptance letter 

to the applicant on March 17, 2020. FDA issued a Filing letter to the applicant on March 26, 

2020. FDA issued a Deficiency letter to the applicant on July 29, 2020. 

Refer to the Appendix (Table 4) 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, as well as cross-referenced tobacco product master files (TPMFs) 

b)(4) 

Table 1. Disciplines reviewed 

Discipline 

Cycle 1 Cycle 2 

Reviewer(s) Review 

Date Reviewer(s) Review 

Date 

Regulatory Kristopher Van 

Amburg 3/17/2020 Dyamond Govan N/A 

Engineering Nashaat Rasheed 7/27/2020 Pritesh Darji 4/21/2022 

Chemistry Selena Russell 7/27/2020 Yougbang Liu 4/22/2022 

Microbiology David Craft 7/27/2020 Prashanthi Mulinti 4/25/2022 

Toxicology Kamau Peters 7/28/2020 Kamau Peters 4/25/2022 

Behavioral and 

Clinical 

Pharmacology 

Babita Das/ 

Marzena Spindle 7/27/2020 Arit Harvanko 4/21/2022 

Medical Edna Termilus 7/27/2020 Not assigned N/A 

Epidemiology Rebecca Jackson 7/27/2020 Maria Cooper 4/22/2022 

Social science Elisabeth Donaldson 7/27/2020 Lisa Lagasse 4/22/2022 

Environmental 

Science 

Rudaina AlrefaiKirkpatrick 7/27/2020 Ron Edwards 4/22/2022 
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Discipline 

Cycle 1 Cycle 2 

Reviewer(s) Review 

Date Reviewer(s) Review 

Date 

OCEt- BIMO5 Carlos Carmona 4/13/2020 Not assigned N/A 

OCEManufacturing/Lab Jiali He 4/8/2020 Not assigned N/A 

Table 2. Consultations 

Discipline or Office 

Cycle 1 Cycle 2 

Reviewer(s) Review 

Date Reviewer(s) Review 

Date 

Statistics Not assigned N/A Christopher Ellison 1/25/2021 

OCE - OPAL Rohit Mathew 7/2/2020 Not assigned N/A 

OHCE Emily Talbert 4/29/2020 Allison ODonnell 3/14/2022 

TPST Susan Rudy 4/7/2020 Susan Rudy 2/15/2022 

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: 

• Comparison products used in specific studies or evaluations 

o Engineering: The applicant compared NJOY ACE products with JUUL and 

Vuse Alto. NJOY ACE and Vuse Alto have comparable design parameters 

such as e-liquid volume (ml), e-liquid pH, battery cell capacity (mAh), 

atomizer resistance (Q), and the same atomizer type. Although not all 

design parameters are comparable with comparison products, the 

applicant's rationale for selection of these comparison products is 

acceptable from an engineering perspective. 

o Chemistry: The applicant measured aerosol constituent concentrations of 

the comparison product Vuse Alto Original 5%. It is a tobacco product in the 

same product category and subcategory and with similar e-liquid flavors 

that contain nicotine salts as the new products. The Chemistry review also 

compared constituent yields from the new product aerosols to the cigarette 

mainstream smoke yields from 50 commercially available combusted 

cigarettes (FDAS0). The applicant's rationale for selection of the comparison 

product and data from the additional comparison with combustible 

cigarettes is acceptable from a Chemistry perspective. 

o Toxicology: • The applicant provided comparisons between the new products and 

combusted cigarettes. The applicant used the average combusted 

cigarette mainstream smoke (MSS) concentration data from peerreviewed scientific literature to represent the combusted cigarette 

5 Second cycle review was not necessary as there was no additional data that required review by Office of Compliance and 

Enforcement (OCE). 
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category. The applicant's rationale for this comparison is based on 

the premise of reduction of risk of overall adverse health effects for 

combusted cigarette smokers switching completely to the new 

products. The rationale and selection of average combusted 

cigarette data is an appropriate representative of the combusted 

cigarettes because the studies were peer-reviewed and selected 

studies that were recently published measured many of the same 

harmful and potentially harmful constituents (HPHCs), included 

cigarettes that are currently on the market, and tested the 

cigarettes using common puffing protocols (e.g., ISO and HCI) across 

the studies. An additional analysis by Chemistry compared HPHC 

yields from aerosol from the new products to MSS concentration 

data from FDAS0. Chemistry's analysis using FDAS0 showed similar 

HPHC profiles (i.e., the same HPHCs, with similar concentrations) to 

HPHCs concentrations from the applicant's comparison products, 

average combusted cigarette MSS. Therefore, from a toxicological 

perspective the applicant's rationale for using combusted cigarettes 

as a comparison product is acceptable, and the use of average 

combusted cigarette data from the published toxicology literature is 

an acceptable representative of the combusted cigarette category. 

• The applicant provided in vitro mutagenicity, cytotoxicity and 

genotoxicity studies that used the Kentucky Reference 1R6F 

cigarette as a comparison product. Several studies comparing other 

Kentucky reference cigarettes (e.g., 1R4F, lRSF and 3R4F) to 

commercially marketed cigarettes have shown similar HPHC 

profiles, and similar toxicological effects for in vitro cytotoxicity and 

mutagenicity, and an in vivo 90-day inhalation study (Vu et al., 2015; 

Roemer et al., 2004; Patskan et al., 2007). Therefore, from a 

toxicological perspective, the applicant's rationale for using the 

Kentucky Reference 1R6F cigarette as a comparison product in the 

in vitro studies is adequate to represent the overall content of 

HPHCs in a combusted tobacco product. • The applicant provided comparisons between the new products and 

the ENDS comparison product, Vuse Alto Original with 5% nicotine. 

The rationale for this comparison was that Vuse Alto is also a 

closed-system ENDS with a rechargeable battery and single-use pod 

that is filled by the manufacturer with nicotine salt-containing eliquid. The applicant also states that Vuse Alto flavors (Original, 

Menthol, Mixed Berry, and Rich Tobacco) and nicotine content (5% 

nicotine) are similar to the new products with selected flavors 

(Classic Tobacco, Rich Tobacco, Kbl(4) I 

l(b)(4) I at 2.4% and 5% nicotine). From a toxicological 

perspective, the applicant's rationale for using Vuse Alto Original 5% 

as a comparison product is acceptable and the product similarities 

make it a useful ENDS comparison product. 

• The applicant provided comparisons between the new products and 

other ENDS products (i.e., cig-a-like, fixed pods, variable pods, fixed 

tanks and variable tanks). The applicant used the average nicotine-
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o 

o 

o 

o 

adjusted aerosol concentration data from peer-reviewed scientific 

literature to represent the other ENDS products category. The 

applicant states that the rationale for using this comparison was to 

give insight into HPHC comparison between the new products to 

other ENDS products, and to allow for the consideration of possible 

HPHC exposures for non-users who may initiate use of the new 

products or other ENDS products. From a toxicological perspective, 

the applicant's rationale for using average nicotine-adjusted HPHC 

levels from other ENDS products as a comparison product is 

adequate because the comparison represents a variety of ENDS 

products, which may be considered as alternatives to the new 

products or may be used in conjunction with the new products. 

Epidemiology: The applicant's observational studies included both 

combusted cigarette smokers and never smokers as comparison groups. 

Based on the information provided in the application, current combusted 

cigarette smokers are among the intended user population for these new 

products. Therefore, comparisons between the new products and 

combusted cigarettes may assist FDA's determination of whether permitting 

the marketing of the new products is appropriate for the protection of 

public health (APPH) because combusted cigarette smokers are a likely user 

population. 

Medical: The applicant used NJOY DAILY Rich Tobacco 4.5%, NJOY DAILY 

Rich Tobacco 6%, NJOY Loop Rich Tobacco 4.5%, JUUL Virginia Tobacco 5% 

and subject's usual combusted cigarettes as comparison products in the 

clinical studies to collect data on adverse experiences (AE) and health 

effects. All products used were of the same product category as the new 

products and contained generally similar amounts of nicotine except for 

combusted cigarettes. It is acceptable to compare ENDS to combusted 

cigarettes in this analysis because combusted cigarettes provide AE and 

health effects data on products that represent the current tobacco market. 

Microbiology: ENDS comparator product (VUSE Alto) stability information 

was not provided for the PMTAs. Therefore, a comparison of how product 

characteristics affect stability, when compared to similar ENDS tobacco 

products, could not be completed. However, based on the stability data (pH, 

moisture contentment, total aerobic microbial counts (TAMC), total yeast 

and mold counts (TYMC) and Bacterial Endotoxin (BET) over shelf life of the 

new products, the lack of stability data for the ENDS comparison products is 

acceptable from a microbiology perspective. A literature review was 

provided to establish acceptable levels of microbial content in non-sterile 

inhalation solutions and endotoxin levels in sterile inhalation water 

solutions. The new products have microbial content and endotoxin content 

below FDA and USP guidelines. 

Social Science: The applicant-submitted studies included comparisons of the 

new products to combusted cigarettes, as well as to other ENDS and 

nicotine replacement therapies. Based upon available data on perceptions 

and curiosity about and intentions to try the new products, the likely users 

of the new products will include current adult smokers. Detailed discussion 
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about the impact of the new products on current adult smokers and youth is 

provided below in Section 3.4. 

o Behavioral & Clinical Pharmacology (BCP): 

• The applicant used Usual Brand (UB) cigarettes as the comparison 

product in one key clinical study that provided data on abuse 

liability, nicotine exposure, subjective effects, and puff topography. 

BCP determined that the data and rationale to support the 

applicant's chosen comparison product (UB cigarettes) was 

appropriate for comparison to the new products because cigarette 

smokers are the applicant's stated intended users of the new 

products and applicant-submitted survey data shows that cigarette 

smokers and dual users (of cigarettes and ENDS) are likely to use the 

new products. 

• The applicant used closed system ENDS containing nicotine salt 

formulations (i.e., NJOY Daily, Rich Tobacco; NJOY Extra, Rich 

Tobacco; NJOY Loop, Rich Tobacco; JUUL, Virginia Tobacco) as the 

comparison products in one key clinical study that provided data on 

abuse liability, nicotine exposure, subjective effects, and puff 

topography of one new product (PM0000615.PD1). BCP determined 

that these comparison products were appropriate as ENDS users are 

also the applicant's stated intended users, and likely to use the new 

products in this application. 

3.1.2. Synthesis 

The applicant provided comparisons between the new products and combusted cigarettes, 

as well as other ENDS products, in various studies and literature reviews. 

The applicant compared the new products with Vuse Alto and JUUL for engineering 

parameters. The applicant also provided comparison data for aerosol constituent 

concentrations between the new products and Vuse Alto Original with 5% nicotine, which is 

an ENDS product in the same product category and subcategory and with similar flavors and 

nicotine salts. For in vitro mutagenicity, cytotoxicity and genotoxicity studies, the applicant 

used the Kentucky Reference 1R6F cigarette as a comparison product. 

In their clinical studies, the applicant used subject's UB combusted cigarettes and NJOY 

DAILY Rich Tobacco 4.5%, NJOY DAILY Rich Tobacco 6%, NJOY Loop Rich Tobacco 4.5%, 

JUUL Virginia Tobacco 5%, as comparison products to collect data on AE, health effects, 

abuse liability, nicotine exposure, subjective effects, and puff topography. In their online 

survey studies, the applicant compared the new products to combusted cigarettes, as well 

as to other ENDS products and nicotine replacement therapies on product perceptions, 

appeal, and behavioral intentions. 

The applicant used peer-reviewed scientific literature to calculate the average combusted 

cigarette MSS concentration and the average nicotine-adjusted aerosol concentration from 

other ENDS products (i.e., cig-a-like, fixed pods, variable pods, fixed tanks and variable 

tanks). These data were compared to that of the new products to give insight into HPHC 

comparison between the new products to other comparison products. 
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As TPL, I agree with Chemistry, Toxicology, Epidemiology, Social Science, Medical and BCP 

conclusions that the applicant's rationale for the selection of combusted cigarettes and 

other ENDS as comparison products of the new products is appropriate because the 

applicant's stated intention is to market the new products to current adult tobacco users, 

including current cigarette smokers and current ENDS users. I further agree that the 

applicant provided adequate data to support the comparison between the new products 

and the chosen comparison products. 

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 

• Engineering: The applicant submitted the design parameters of the new products. 

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

for all of the design parameters for the new products. 

• Chemistry: The applicant provided sufficient details of the single chemical 

ingredients for all thete-liquids and structure materials to characterize the product 

composition. The information submitted regarding product composition is 

acceptable from a chemistry perspective. 

• Microbiology: The new products contain humectants !(b)(4) t and 

!lh\/4\ I that may impact microbial activity during the applicant's proposed product 

shelf life. Microbiology stability data is discussed in detail in Section 3.2.1.3. 

3.2.1.2. Manufacturing 

• Engineering: The applicant submitted the manufacturing process for the new 

products, including nicotine manufacturing, i/bl/4) I manufacturing, bulk 

e-liquid manufacturing, and finished product (device and e-liquids) manufacturing 

and packaging. The information submitted regarding the manufacturing process is 

acceptable from an engineering perspective. 

• Chemistry: The applicant provided manufacturing procedures and quality control 

measures for all e-liquid products to ensure products are manufactured in a 

consistent manner that minimizes variability in product quality. The applicant also 

provided representative ingredient Certificate of Analysis (COAs), raw ingredient 

quality control test results, batch verification, liquid properties, pH, and constituent 

measurements. All the provided data are within the acceptance criteria indicating 

product batch consistency. Therefore, the information submitted regarding product 

manufacturing is acceptable from a chemistry perspective. 

• Microbiology: Bulk e-liquid manufacturers conduct e-liquid blending and filling 

operations in an International Organization for Standardization (ISO)t� clean 

room. l(b)(4) I is an A2LA ISO 17025:2005 certified laboratory that 

performs release testing on the bulk e-liquids. The information submitted regarding 

the manufacturing of the new products is acceptable from a microbiology 

perspective. 
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PM0000613.PD1 - PM0000615.PD1 and PM0000622.PD1 

3.2.1.3. Product stability 

• Chemistry: 

o The applicant proposes a l(b)(4) Ishelf life for the finished e-liquids. In 

order to support a Kb)(4) I product shelf life, the applicant is required to 

provide full j(b)(4) !finished product chemical stability data under 

ambient conditions (b)(4) RH) demonstrating that the finished e-liquids 

are chemically stable during a (b)(4) storage. Without full fbl(4) I 

ambient stability data, the applicant is required to provide an additional @El 

!(b)(4) lof chemical stability data under accelerated conditions l(b)(4) I 

RH) with statistical analysis to extrapolate to ambient storage time of at 

leastl(b)(4) However, the applicant provided only j(b)(4) lof

finished product chemical stability data under ambient conditions 

!/bl/4l !KH) and fh\14\ lof chemical stability data under accelerated 

conditionsl(b)(4) IRH) without extrapolation statistical analysis. The 

applicant would need to provide stability data for the last Kb)(4) !at

ambient conditions to ensure the new products are chemically stable fort

kb)(4) Ior statistical analysis of the l(b)(4) Iof chemical stability data 

under accelerated conditions to extrapolate to ambient storage time of at 

least Kb)(4) f The data provided supports a l(b)(4) I product stability

from a chemistry perspective. 

• Microbiology: 

o The microbial stability data is necessary for the proposed shelf life as 

bacterial communities change as a function of storage time (Chopyk et al., 

2017; Djordjevic et al., 1993). 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. Stability data (TAMC and TYMC) that 

spansfbl(4) lfor the finished e-liquids, and endotoxin data 

measured at the beginning of the tb)(4) I period was provided for 

PM0000614.PD1-PM0000615.PD1.6 Over that period, the TAMC and TYMC 

were not detected or )( cfu /ml. The stability data for TAMC and TYMC 

support (b)(4l stability from a microbiology perspective. 

o PM0000622.PD1 provided stability data (pH, water content, TAMC and 

TYMC) overfb)(4) I and endotoxin data measured at the beginning of 

that time period for the finished new product. The provided stability data is 

acceptable from a microbiology perspective. However, stability data 

provided only supports microbial stability forrb)(4) I The applicant 

stated that shelf life data from other tested products can be bridged to 

support a shelf life of fbl(4) !for PM0000622.PD1 because the products 

are expected to have similar water content based on composition and due 

to the antimicrobial properties of 5% nicotine. However, the flavor profile of 

these products are different and literature shows that flavor ingredients 

influence the antimicrobial activity of e-liquids (Fuochi et al., 2020). 

Therefore, FDA would not be able to bridge the data from other products to 

PM0000622.PD1. In conclusion, for PM0000622.PD1, although the applicant 

6 The new products contain endotoxin levels below Kb)(4IEU/ml. Based on the TAMC and TYMC data, further increase in 

endotoxin beyond time zero is unlikely. Therefore, the lack of endotoxin data beyond time zero of shelf life is not of concern for 

all new products. 
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PM0000613.PD1 - PM0000615.PD1 and PM0000622.PD1 

proposed that the product is stable for j(b)(4) the data only =:.....I,

supports that the product remains stable for fb)(4) I from a 

microbiology perspective. 

3.2.1.4. Product test data 

• Engineering: The power unit (PM0000613.PD1) contains a rechargeable 400 mAh 

lithium battery and printed circuit board assembly (PCBA) and is packaged with a 

universal serial bus (USB) charger. The NJOY ACE device does not include software. 

Charging and output power is controlled by the PCBA. The battery protection 

integrated circuit provides overcharging protection, over-discharging protection, 

overcurrent protection, short circuit protection, over-temperature protection, 

reverse charging protection, and reverse battery connection protection. The new 

products do not have user settings and cannot be modified by the user._The 

applicant submitted test data for all the required design parameters and the test 

data adequately demonstrate product consistency. 

• Chemistry: 

o Most analytical methods and method validation are sufficient to support 

this review. There were method validation issues for four analytes tested, 

b)(4) and b)(4) L However, 

the effect of the method validation issues is minimal because the 

concentrations of these four analytes are very low in thete-liquids. 

o Most constituents' aerosol yields are decreased in the products compared 

to the combusted cigarette and VUSE Alto Original 5% nicotine comparison 

products. The constituents with increased yields in the products are 

discussed in Toxicology Section 3.5.1. 

o The applicant also provided HPHC data for the product puff lifecycle for the 

5% nicotine e-liquids (PM0000615.PD1 and PM0000622.PD1). Although 

there is some observed HPHC variability between puff blocks, the results 

show no significant trends of increasing aerosol HPHC concentrations over 

the product puff lifecycle. Moreover, due to similarity in e-liquid 

formulations and similar HPHC exposures between the 2.4% and 5% 

nicotine e-liquids, the risk of aerosol HPHC increases during product puff 

lifecycle of the 2.4% NJOY ACE PODs is u nlikely to be meaningfully different 

from the data for the 5% nicotine e-liquids and is therefore acceptable from 

a chemistry perspective. 

3.2.2. Synthesis 

As TPL, I agree with the engineering conclusions that these PMTAs contain sufficient 

information on the target specifications, upper and lower range limits, manufacturing 

processes, and validation process for all of the design parameters for the new products. The 

test data submitted by the applicant adequately demonstrates that the products meet the 

manufacturer's specifications and are produced consistently. 

As TPL, I agree with the chemistry conclusions that these PMTAs contain sufficient 

ingredient information to characterize the product composition. In addition, the applicant 

implemented manufacturing procedures and quality control measures for all e-liquids to 
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PM0000613.PD1 - PM0000615.PD1 and PM0000622.PD1 

ensure products are manufactured in a consistent manner. NJOY ACE device 

(PM0000613.PD1) is a closed ENDS with no adjustable parameters. PM0000613.PD1 uses 

NJOY ACE pods (PM0000614.PD1, PM0000615.PD1 and PM0000622.PD1) which are sealed, 

pre-filled, and non-refillable. The aerosol HPHC measurement provided by the applicant 

reflects the combined effects of both the device and e-liquids. The HPHC data showed, 

when comparing to combusted cigarette mainstream smoke, the aerosols of the new 

products have a lower number of HPHCs and many of the HPHCs present in the aerosols 

have comparatively lower potencies (i.e., lower magnitude or severity of toxicological effect, 

at a given dose or exposure level) than HPHCs present in combusted cigarette smoke 

(discussed in details in Section 3.5). 

The applicant proposed a l(b)(4) I shelf life for the e-liquids, but only provided 

i<b)(4) pf finished product chemical stability data under ambient conditions. In addition, 

the applicant provided (b)(4) of microbial stability data for thete-liquids in 

PM0000614.PD1-PM0000615.PD1 an l(b)(4) lof microbial stability data for thete-liquid 

in PM0000622.PD1. Because the stability data provided by the applicant is acceptable and 

indicates that the products are low-risk for microbial growth over the period tested and 

because there are no other stability concerns, the lack of stability data for kb)(4) Idoes 

not preclude an APPH finding for the new products. Therefore, although the applicant 

proposed a b)(4) !

shelf life, an authorization for PM0000614.PD1-0000615 should note 

that stability data submitted by the applicant supported that the product would remain 

stable forl(b)(4) and for PM0000622.PD1, stability data submitted by the applicant 

supported that the product would remain stable for l(b)(4) I3.3. ABUSE LIABILITY 

3.3.1. Discipline key findings 

The following discussion is based on key findings provided in the BCP review: 

3.3.1.1. Current tobacco u sers (BCP} 

• '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. 

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 the product they are 

currently using. On the other hand, low abuse liability makes it less likely that new 

users will become addicted. 

• Based on evidence from the applicant-submitted studies on the new products and 

published literature on ENDS similar to the new products, BCP concludes that the 

abuse liability of the new products is lower than or comparable to combusted 

cigarettes for inexperienced ENDS users, and comparable to combusted cigarettes 

for experienced ENDS users. 

• Published literature shows that e-liquids with nicotine salts, like the new products in 

PM0000614.PD1, PM0000615.PD1, and PM0000622.PD1, can reach or exceed 

nicotine exposures associated with cigarettes (Goniewicz et al., 2019; Hajek et al., 

2020) and other ENDS with free-base nicotine formulations (Boykan, Goniewicz, et 
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PM0000613.PD1 - PM0000615.PD1 and PM0000622.PD1 

al., 2019; O'Connell et al., 2019; Yingst, Hrabovsky, et al., 2019). However, based on 

data from the applicant submitted clinical studies, BCP concluded that the abuse 

liability of NJOY ACE products is somewhat lower than or comparable to combusted 

cigarettes, mitigating concern of greater nicotine exposure (addiction potential) 

than combusted cigarettes. 

• Smokers who are inexperienced with ENDS took similar individual puff durations 

and puff volumes of NJOY ACE products and their Usual Brand (U B) cigarettes; 

smokers took longer total puff durations when using the tested NJOY ACE products 

compared to smoking cigarettes. Compared with ENDS-inexperienced cigarette 

smokers, experienced ENDS users may take significantly larger/longer puffs and 

thereby obtain more nicotine from the same ENDS than ENDS-inexperienced 

cigarette smokers (Farsalinos et al., 2015; Hiler et al., 2017). 

3.3.2. Synthesis 

The applicant provided two clinical studies to examine the pharmacokinetics (PK), 

pharmacodynamics, subjective effects, and puffing behavior of the new products in this 

application. The submitted data demonstrated that, for inexperienced ENDS users, the new 

products are associated with a lower maximum nicotine concentration (Cmax) and areaunder-the-concentration-time-curve (AUC), and a greater time to maximum nicotine 

concentration (T max) compared to combusted cigarettes, indicating a lower abuse liability of 

the new products. Therefore, it is possible that an inexperienced ENDS user or non-user may 

not be able to achieve nicotine levels that would sustain ongoing use and the development 

of dependence. However, for experienced ENDS users, the study data and published 

literature showed that the new products have a Cmax and Tmax comparable to regular 

smokers of combusted cigarettes. The difference is likely due to experienced ENDS users 

taking significantly larger and longer puffs, thus attaining higher plasma nicotine 

concentrations compared to inexperienced ENDS users. 

Although the abuse liability of long-term use was not examined in the studies, I agree with 

BCP review that having comparable abuse liability to combusted cigarettes potentially helps 

reduce smokers' urge to smoke, and therefore may facilitate smokers switching. With 

experience, users might reach higher nicotine levels to satisfy the withdrawal and craving 

symptoms. 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, while being 

exposed to lower levels of HPHCs. 

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) 

o The applicant stated that the intended user population is "current adult users of 

nicotine-containing products who cannot or choose not to discontinue use of 

nicotine, particularly current combusted cigarette users and ENDS users." 
) 

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PM0000613.PD1 - PM0000615.PD1 and PM0000622.PD1 

o The applicant submitted two clinical studies that were conducted in current 

adult cigarette smokers and current adult ENDS users. 

3.4.1.2. Cutrrent tobacco users 

o Social Science: 

• Report of being "somewhat" or "very" curious about using the new 

products was low among current adult smokers�but was greater 

than curiosity among former smokers�an� smokerst� 

A similar proportion of current adult smokers were curious about the 

Rich Tobacco and Classic Tobacco flavors7 (b)(4) 

respectively). b)(4) 

b)

)(

(

b

(

4

4) 

• The proportion of adults who responded "definitely yes" to whether 

they intend to try the new products in the next year was low among 

adult current smokers b)(4) but was greater than intention to try 

among former smokers (b)(4) and never smokers b)(4) . (b)(4) 

(b)(4) 

(b)(4) 

�b)(4) �Atsimilar proportion of current adult 

smokers intended to try Rich and Classic Tobacco flavorsl(b)(4)land 

b)(4) I respectively).

• In summary, based on ratings of curiosity and intentions to use, the 

applicant's data suggest that !(b)(4) 

(b)(4) compared 

to the Classic and Rich Tobacco products. 

o Epidemiology: 

• The prevalence of the NJOY ACE products use was approximately l(b)(4)I 

among adults in the Adult Prevalence Study. The proportion of adult 

combusted cigarette users who reported use of the NJOY ACE products 

was fb)(4) I Overall, l(b)(4)I of respondents reported using any ENDS 

product, slightly higher than but similar to estimated national 

prevalence of adult ENDS use in the 2018 NHIS (3.2%) (Bao et al., 2019). 

Similar to the published literature, more current and former smokers 

used ENDS generally and the new products specifically. The applicant 

reported that most ENDS initiation in adults occurred after combusted 

cigarette initiation, and current or former combusted cigarette smokers 

were more likely to initiate than never tobacco users. However, some of 

these outcomes could be due to cohort effects or generational 

differences in the marketplace when most adults initiated tobacco use. 

• In the applicant's NJOY User Study, the estimates of complete switching 

from combusted cigarettes to ENDS at three months was 32%, which is 

higher than what is typically seen in the literature for estimates of 

complete switching from combusted cigarettes to ENDS (3.4% - 5.9%) 

(Coleman et al., 2019; Stanton et al., 2020; Piper et al., 2020). 

7 "Classic tobacco" and "Rich tobacco" refer to the applicant-provided characterizing flavor for PM0000614.PD1-615 and 

PM0000622.PD1, respectively. FDA determined that no additional information regarding characterizing flavor was necessary. 
b)(4) 

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Furthermore, the applicant's data suggests there was a decrease in 

complete switching (measured by 30-day point prevalence abstinence 

(PPA)) between two months and three months. These high estimates of 

complete switching in the applicant's NJOY User Study are possibly 

inflated due to use of a convenience sample with a low enrollment rate 

and considerable loss to follow-up. 

■ Based on the applicant's data, a large number of new product users 

(likely >40%} could become dual users with combusted cigarettes, 

similar to patterns of dual use reported in the literature (43.5% - 54.1%} 

(Coleman et al., 2019; Stanton et al., 2020; Piper et al., 2020). While the 

NJOY User Study suggests there may be a reduction in combusted 

cigarette smoking among smokers who also use the new products, data 

from the literature is mixed. Estimates from the published literature 

suggest that, among adult dual users, 43.5% - 54.1% will discontinue 

ENDS use over time, 3.4% - 5.9% will transition to ENDS only use, and 

1.4% - 11.0% will discontinue use of both products (Coleman et al., 

2019; Stanton et al., 2020; Piper et al., 2020). 

o BCP: 

• Among inexperienced ENDS users, abuse liability and nicotine exposures 

of the new products are somewhat lower than or comparable to 

combusted cigarettes. 

• Among experienced ENDS users, the abuse liability and nicotine 

exposures of the new tobacco products may be comparable to 

combusted cigarettes. 

• Cigarette smokers who initiate use of NJOY ACE likely will become either 

dual users of NJOY ACE and combusted cigarettes, or they will switch to 

NJOY ACE use completely. However, some cigarette smokers may 

temporarily adopt the new products before switching back to 

combusted cigarettes, which are rated higher in terms of liking and 

satisfaction compared with ENDS (e.g., Adriaens et al., 2018; Hajek et 

al., 2019; Stein et al., 2018; Stiles et al., 2017; Stiles et al., 2018). • Survey data provided by the applicant following dual-users of 

combusted cigarettes or exclusive users of the new products over a 

period of 3-months demonstrated that only 1% of users became 

completely abstinent from nicotine during this time period. This 

suggests that the vast majority of users of the applicant's product will 

not become completely abstinent from tobacco products. 

3.4.1.3. Tobacco non-users {including youth) 

o Social Science: 

• Overall, reported curiosity and intention to try the new product was low 

(<2%) among adult never and former smokers. These data suggest that 

former and never smoking adults are not interested in trying the new 

products. 

fb)(4) • 

(b)(4) 

I I 

l(b)(4) 

I 

I 
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PM0000613.PD1 - PM0000615.PD1 and PM0000622.PD1 

b)(4) 

b)(4)

• In 2021, 11.3% of high school students and 2.8% of middle school 

students reported current e-cigarette use (Park-Lee et al. 2021). It is 

possible that the number of youth who were current ENDS users was 

higher than reported in 2021; approximately half of the students took 

the survey at home, which may have resulted in an under-reporting of 

tobacco use behaviors (Biglan et al. 2004; HHS 2012). Additionally, 

longitudinal research using 2013-2015 PATH data indicated that 42.2% 

of past 30-day youth ENDS users remained past 30-day ENDS users one 

year later (Stanton et al., 2019). These published findings indicate risk of 

ENDS use among youth. However, youth are less likely to initiate with 

tobacco-flavored ENDS and subsequently progress to regular use than 

with non-tobacco flavored ENDS. For instance, in Wave 1 of the PATH 

Study from 2013-2014, over 80% of youth aged 12-17, 75% of young 

adults 18-24, and 58% of adults 25 and older reported that the first 

ENDS that they used was non-tobacco flavored. In another PATH study, 

more youth, young adults and adults who initiated ENDS use between 

Wave 1 and Wave 2 reported use of a non-tobacco flavored product 

than a tobacco-flavored product. Finally, in PATH Wave 4 from 2016-

2017, 93.2% of youth and 83.7% of young adult ever ENDS users 

reported that their first ENDS product was flavored compared to 52.9% 

among adult ever users 25 and older (Rostron et al. 2020). Additionally, 

existing literature on non-tobacco flavored product use suggests that 

non-tobacco flavors not only facilitate initiation, but also promote 

established regular ENDS use. For example, regional studies have found 

that the use of non-tobacco flavored ENDS was associated with a 

greater frequency of ENDS used per day among a sample of adolescents 

in Connecticut in 2014 (Morean et al., 2018) and continuation of ENDS 

use in a sample of adolescents in California from 2014-2017 (Leventhal 

et al., 2019). Use of non-traditional flavors (vs. tobacco, mint/menthol, 

flavorless) was associated with increased likelihood of continued use 

and taking more puffs per episode (Leventhal et al., 2019). Data from a 

regional survey in Philadelphia, PA found initial use of a non-tobacco 

flavored vs. tobacco flavored ENDS was associated with progression to 

current ENDS use as well as escalation in the number of days ENDS were 

used across 18 months. Finally, similar effects have been found in the 

PATH study among young adults (18-24 years), where "ever use" of nontobacco flavored ENDS at Wave 1 was also associated with increased 

odds of current regular ENDS use a year later at Wave 2. Collectively, 

these findings indicate that while all ENDS pose risks to youth, youth are 

less likely to initiate with tobacco-flavored ENDS and subsequently 

progress to regular use, than with non-tobacco flavored ENDS. 

• The interest in tobacco flavor is low among youth. The available 

evidence (NYTS 2021) indicates that a higher proportion of middle and 

high school current users reported using flavored ENDS than unflavored 

ENDS (including tobacco flavor) (Park-Lee, et al., 2021). 
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PM0000613.PD1 - PM0000615.PD1 and PM0000622.PD1 

o 

• According to National Youth Tobacco Survey (NYTS) 2021 data, 28.7% of 

middle and high school users reported prefilled or refillable pods or 

cartridges as the ENDS device types they used most often (Park-Lee, et 

al., 2021). Sleek design, ability to use products discreetly, and userfriendly nature make pod mod (rechargeable cartridge-based ENDS) 

products appealing among youth. Although there is some risk of youth 

uptake of the new products, in general, tobacco-flavored ENDS are less 

appealing to youth compared to non-tobacco flavored ENDS, making 

the risk of youth initiation low for these products. Findings from a 

discrete choice experiment showed that non-tobacco flavors were 

associated with more curiosity, less perceived danger, and greater 

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

tobacco flavor (Chaffee et al. 2020). Additionally, the published 

literature indicates that youth report significantly higher preference for 

non-tobacco flavored ENDS compared to tobacco flavored ENDS (Harrell 

et al. 2016; Groom et al. 2020). Moreover, the evidence indicates that 

tobacco flavored ENDS are less likely to be used by youth who initiate or 

regularly use ENDS compared to non-tobacco flavors. 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 (Miech et al. 2021). According to the 2020 

MTF data, the prevalence of tobacco flavor use was 2.9% among 10th 

and 12th graders while mint was the second most often used flavor 

(26.9%) after fruit (59.3%) (Miech et al. 2021). 

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

recommended by OHCE will help to mitigate the risk of youth initiation. 

BCP: 

• BCP's review of ENDS use in nonusers and youth is based solely on 

published literature. • ENDS use is highly prevalent among youth (Cullen et al., 2018), and the 

majority of youth use pod-style ENDS (Hammond et al., 2020; Lin et al., 

2020; Wang et al., 2020). Youth who use pod-style ENDS (i.e., Juul, 

Sourin, Phix, Bo) have nicotine exposures that are comparable to or 

higher than that of youth cigarette smokers (Goniewicz et al., 2019) and 

non-pod-ENDS users (Boykan, Messina, et al., 2019). The new products 

contain high nicotine concentrations (i.e., 2.4-5%), similar to the podstyle ENDS tested in the literature (approximate ranget= 2-5% based on 

product labeling (Goniewicz et al., 2019}); therefore, nicotine exposures 

across these products may be comparable. High nicotine exposure may 

facilitate continued nicotine use and development of nicotine 

dependence. • The new product e-liquids contain nicotine salt formulations, which may 

be easier (i.e., less irritating) to inhale at high nicotine concentrations 

(Caldwell et al., 2012; Omaiye et al., 2019; Prochaska & Benowitz, 2019; 

Talih et al., 2019), thereby facilitating initiation and use of ENDS with 

high amounts of nicotine. However, based on data from the applicant 

submitted clinical studies, BCP concluded that the abuse liability of 

NJOY ACE products is somewhat lower than or comparable to 
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PM0000613.PD1 - PM0000615.PD1 and PM0000622.PD1 

o 

combusted cigarettes, mitigating concern of greater nicotine exposure 

(addiction potential) than combusted cigarettes. 

• Youth users of pod-style ENDS report more symptoms of nicotine 

dependence than non-pod-ENDs users (Martinez et al., 2020; Morean et 

al., 2019). 

Epidemiology: 

• The applicant reports a low prevalence of new product use among 

adolescents in the Youth Prevalence Studies 1 and 2; however, these 

estimates are lower than what the literature suggests, and so should be 

interpreted with caution. In the applicant's Youth Prevalence studies, 

NJOY was the second most popular brand after JUUL. 

• Evidence from the peer-reviewed literature suggests that, while ENDS 

use among former tobacco users (predominantly former combusted 

cigarette smokers) has been observed across studies, prevalence is 

generally low (<5%), and one prospective study estimated the threeyear transition probability of ENDS initiation among previous tobacco 

users was 3.2%. There is some evidence to suggest that former smokers 

who begin to use ENDS may relapse to combusted cigarette smoking. 

• National surveillance data suggest that, within the ENDS category, there 

is variability in the popularity of device types among youth, suggesting 

there may be differential appeal of certain product styles. Still, across 

these different device types, the role of flavor is consistent. As 

described above, the majority of youth ENDS use involves flavored 

products: in 2020, the majority of high school and middle school current 

e-cigarette users reported use of non-tobacco-flavored products 

(82.9%) (Wang et al., 2020) and flavored use was favored among both 

users of closed (87%) and open (76%) ENDS (internal analysis). In 

particular, across device types, including prefilled pods/cartridges, 

disposables, tanks, and mod systems, fruit was the most commonly 

used flavor type among youth, with 66.0% for prefilled pods/cartridges, 

82.7% for disposables, 81.7% for tanks, and 78.9% for mod systems 

among youth reporting using a fruit flavor (Wang et al., 2020). It is also 

worth noting that the preference for device types and popularity of 

certain styles is likely fluid and affected by the marketplace, that is, the 

options, especially flavors, that are available for consumers to choose 

from. Some evidence for this was observed in the trends both leading 

up to, and coinciding with, the shifting marketplace following the 2020 

Enforcement Priorities Guidance. In particular, the enormous rise in 

youth ENDS use from 2017-2019 coincided with the ascendance of JUUL 

(and copy-cat devices) in the marketplace, suggesting a relationship 

between the availability of JUUL as an option, and the sudden 

popularity of pod-based devices. Then, as noted earlier, when FDA 

changed its enforcement policy to prioritize pod-based flavored ENDS, 

which were most appealing to youth at the time, we subsequently 

observed a substantial rise in use of disposable flavored ENDS--a tenfold increase (from 2.4% to 26.5%) among high school current ecigarette users (Wang et al., 2021). This trend illustrates that the 

removal of one flavored product option prompted youth to migrate to 
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PM0000613.PD1 • PM0000615.PD1 and PM0000622.PD1 

another ENDS type that offered the desired flavor options, underscoring 

the fundamental role of flavor in driving appeal. 

• Overall, the available evidence to date does not adequately address 

whether new product use in youth and young adults leads to regular 

smoking. 

3.4.1.4. Vulnerable populations (other than youth) 

o Epidemiology: The applicant did not provide information specific to vulnerable 

populations (i.e., groups that are susceptible to tobacco product risk and harm 

due to disproportionate rates of tobacco product initiation, use, burden of 

tobacco-related diseases, or decreased cessation) in their application. Evidence 

from the published literature indicates that all age groups with substance use or 

mental health issues are more likely to use ENDS compared to those without 

(Cho et al. 2018; Conway et al. 2018; Riehm et al. 2019). Additionally, the 

prevalence of ENDS use is higher among other vulnerable populations (e.g., 

pregnant persons, and lesbian, gay, and bisexual individuals) (Azagba et al. 

2019; Buchting et al. 2016; Hawkins et al. 2020; Obisesan et al. 2020; Wheldon 

et al. 2019). While the evidence indicates that some vulnerable populations 

experience disproportionate ENDS use, 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 

cigarettes per day (CPD). 

o Social Science: It is possible, based on the applicant's submitted data, that there 

are gender and race/ethnicity differences in intention to try NJOY ACE among 

adults. The applicant summarizes what appears to be intention to try data that 

they call "initiation" in a logistic regression model in their Adult Perceptions 

Study. The model findings suggest that males were more likely to intend to try 

the new products than females. In addition, White and Black non-users were 

less likely to intend to try than Hispanic and 'other' non-user race respondents. 

o BCP: 

• BCP's review of ENDS use in vulnerable populations is based solely on 

published literature and is limited to smokers with diagnosed mental 

illness. 

• Vulnerable populations have higher rates of current ENDS use 

compared to non-vulnerable populations suggesting they find ENDS 

appealing and may initiate and continue using the new products (Huang 

et al., 2016; Kasza et al., 2017; Miller et al., 2018). 

• Vulnerable populations have increased difficulties with smoking 

cessation (Bowden et al., 2011; Cook et al., 2014; Mcclave et al., 2010). 

ENDS may serve as a harm reduction approach if users are able to 

completely switch or dramatically reduce combusted tobacco product 

use. However the impact of the new products on vulnerable populations 

is unknown. ■ Studies have not been conducted to assess the abuse liability of podbased ENDS and e-liquids containing nicotine salts and/or flavors in 

vulnerable populations. 
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3.4.1.5. Actions taken to mitigate risk to non-users, including youth 

Per the Office of Health Communication and Education (OHCE) consult: 

OHCE reviewed the marketing information submitted as part of the PMTA applications for 

NJOY ACE products and finds that the applicant proposes directing its marketing to its target 

audience and proposes measures to limit youth exposure to the products' labeling, 

advertising, marketing, and promotion. However, it is noted that the applicant could alter its 

marketing plans following authorization. OHCE noted that if the products are authorized, 

this concern may be addressed by incorporating the marketing restrictions and reporting 

requirements described in section V of OHCE consult. Relatedly, OHCE supports certain 

aspects of the applicant's marketing plan, as described in the PMTAs, that are intended to 

help address the potential for youth use of the new products. Specifically, the applicant 

stated their intent to use the following measures to help reduce youth appeal of their 

marketing materials, restrict youth access to the new products, and limit youth exposure to 

their labeling, advertising, marketing, and promotion: 

• Not utilizing the following marketing practices: 

o Broadcast or digital radio advertising, 

o Television advertising, 

o Outdoor advertising, 

o Print advertising, 

o Direct mail advertising, 

o Search engine advertising, 

o Online display advertising, 

o Paid or unpaid product placements, 

o Public relations or earned media, 

o In-person engagements or activations, 

o Social media promotion, 

o Partners, sponsors, influencers, bloggers, or brand ambassadors, 

o Referral or affiliate programs, or 

o Product sampling; 

• Prohibiting the use of cartoon images or characters, fruit or food-related images, or imagery 

of any kind that is intended, designed, or otherwise likely to appeal to minors; 

• Limiting human portrayals to only depictions of models who are or appear to be over age 

45; 

• Limiting the use of NJOY-owned social media properties to the sole purpose of receiving 

inbound customer service communications and utilizing all available platform-native agegating functionality to restrict access to adults; 

• Maintaining Distributor and Retailer Policies that govern the selection and oversight of 

tobacco retailers that carry NJOY ACE products; 

• Prohibiting the sale of NJOY ACE products on third-party websites; 

• Limiting the number of products that can be purchased in a given time period or 

transaction; 

• Using competent and reliable third-party sources to verify the age and identity of users 

against public records before granting access to the product website or conducting online 
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sales; 

• Requiring retailers to only place NJOY ACE products in non-self-service areas of the store; 

and 

• Conducting quarterly audits of point-of-sale signage located in retail chains that carry NJOY 

to determine whether only NJOY-approved trade marketing materials are being utilized. 

OHCE encourages the applicant to implement these measures because they are likely to 

help further mitigate risks to youth. 

3.4.1.6. Labeling and advertising 

Social Science: 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. 

3.4.2. Synthesis 

The applicant stated that adult current tobacco users (including cigarette smokers and ENDS 

users) are the intended user population for the new products. The new e-liquid products are 

classic tobacco and rich tobacco flavored ENDS pods. The applicant conducted five 

observational studies, including two adult studies and three youth studies, to assess product 

perceptions, appeal, and behavioral intentions from adult tobacco users and youth. 

Per Social Science and Epidemiology reviews, the applicant's adult Prevalence and 

Perception Study showed that the prevalence of the new NJOY products use was low among 

adult combusted cigarette smokers, with 2.3% reported use of the new products. In adult 

current smokers, curiosity about and intention to try the NJOY ACE products were low !(b)(4) I l(b)(4) I respectively). Based on ratings of curiosity and intentions to try, the applicant's 

adult Prevalence and Perception data suggest that current adult smokers had the most 

interest in the Classic Tobacco 5% nicotine product b)(4)

(b)(4) 

l(b)(4) I The Rich Tobacco and Classic Tobacco flavors showed similar 

curiosity and intentions to try among adult smokers. The applicant's studies also 

demonstrated that a greater proportion of adult current smokers were curious about Rich 

and Classic Tobacco flavors as compared to youth. 

In the applicant's NJOY User Study, the estimated complete switching or abstinence rates at 

three months are 32%. These switching rates are higher than what is reported in published 

literature (3.4-5.9%). Per Epidemiology review, there were limitations to the NJOY User 

Study which may contribute to the high switching rates. The study limitations included: 1) 

the NJOY User Study recruited new purchasers of NJOY products using a convenience 

sampling approach and had a low enrollment rate, creating a likely source of selection bias 

in which the study population may not represent the target population; 2) the NJOY User 

Study had considerable loss-to-follow-up-i.e, incomplete follow-up observations were 

removed from the analyses which has the potential to bias results. Only 3,949 NJOY users 

out of 8,002 NJOY users (49.4%) completed the baseline survey and all follow-up time 

points. The incomplete surveys, which were excluded, were more likely from the 

participants who weren't completely switching to ENDS use. Even though the actual 
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switching rate may be lower than what is reported in the study, the NJOY User Study 

demonstrated that switching from combusted cigarettes to ENDS does occur among current 

adult smokers-typically through a period of dual use. In addition, current established 

cigarette smokers are more likely to prefer tobacco flavor relative to other flavors. In Wave 

2 of the PATH Study, tobacco flavor was used by 50.5% of adult ENDS users aged 25 years 

and older who used a single flavor while menthol/mint was used by 23.3%, fruit by 15.9%, 

and candy or sweets by 7.8% (Soneji et al., 2019). In addition, among adult dual users {18+) 

who used nonmenthol cigarettes, 32.3% reported exclusive tobacco flavor use (Rostron et 

al., 2020). I agree with the Social Science review that these tobacco-flavored ENDS products 

may provide an important option for adult smokers who want to transition away from 

smoking. 

The applicant's youth prevalence and perception studies showed that 18.0% of youth who 

reported ever ENDS use started with tobacco-flavored ENDS, 41.5% started with menthol or 

mint flavor, and 40.5% of youth who reported ever ENDS use started with "something 

other" than tobacco or mint menthol flavors. (b)(4) 

,....._______________. Rich and Classic Tobacco flavors had similar levels of 

curiosity in the studies, though the intention to try was higher for Rich Tobacco flavor. As we 

discussed in this section, evidence shows that tobacco-flavored ENDS are less likely to be 

used by youth who initiate or regularly use ENDS compared to non-tobacco flavors. 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 

(Miech et al., 2021). According to the 2020 MTF data, the prevalence of tobacco flavor use 

was 2.9% among 10th and 12th graders while mint was the second most often used flavor 

(26.9%) after fruit (59.3%). 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. 

With respect to youth appeal and mitigation, I agree with OHCE's evaluation of the 

applicant's marketing plans and all recommendations in the OHCE consult. The marketing 

information submitted by the applicant proposes directing marketing to its target audience 

and proposes measures to limit youth exposure to the products' labeling, advertising, 

marketing, and promotion. However, since the applicant could alter their marketing plans 

following authorization, I recommend that the MGO letter include those marketing 

requirements and recommendations in section V of OHCE consult. 

Product-specific information on vulnerable populations is lacking. However, based on 

published literature, vulnerable populations, such as lesbian, gay, and bisexual individuals 

and people with mental illness, have higher rates of ENDS use. I agree with BCP review that 

vulnerable populations have increased difficulties with smoking cessation (Bowden et al., 

2011; Cook et al., 2014; Mcclave et al., 2010). ENDS may serve as a harm reduction 

approach if users are able to completely switch or dramatically reduce combusted tobacco 

product use. However the impact of the new products on vulnerable populations is 

unknown. 
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The evidence summarized in this section describes relatively high interest among adult 

smokers in using the tobacco-flavored 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 

substantially reduce their cigarette smoking due to significant reductions in HPHCs of the 

new products compared to cigarettes (discussed in details in Section 3.5). In addition, the 

abuse liability of NJOY ACE products is somewhat lower than or comparable to combusted 

cigarettes, mitigating concern of greater nicotine exposure (addiction potential) than 

combusted cigarettes. The available information also shows that youth appeal/uptake of 

tobacco-flavored products is generally low among youth. Overall, I agree that the benefit of 

the new products to adult smokers is significant enough to overcome the risk to youth. 

3.5. 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 

o Overall, there were significant reductions in aerosol HPHCs tested using the device 

(PM0000613.PD1) withte-liquids (PM0000614.PD1, PM0000615.PD1, 

PM0000622.PD1) stored for up tofbl(4) !compared to cigarette comparison data 

under both non-intense and intense puffing regimens. Elevations in glycerin, 

propylene glycol, chromium and nickel of the new products aerosols are outweighed 

by decreases in other respiratory toxicants (e.g., acetaldehyde, diacetyl, acetyl 

propionide, acrolein,l(b)(4) I

, formaldehyde, fb)(4) land ethylene glycol) in 

the cigarette comparators. Observed glycerin, propylene glycol, chromium and 

nickel levels are comparable to levels seen in other ENDS market comparisons. 

o Overall, in comparisons of combusted cigarette smoke HPHC concentrations to the 

products, combusted cigarette smoke has a higher number of HPHCs and many of 

the HPHCs present in cigarette smoke have comparatively higher potencies (i.e., 

higher magnitude or severity of toxicological effect, at a given dose or exposure 

level) than HPHCs in the aerosols of the new products. Therefore, these HPHC 

increases for chromium, nickel and nicotine in the new products in comparison to 

combusted cigarettes are outweighed by the increased number and potency of 

HPHCs in cigarette smoke and are unlikely to raise toxicology concerns for users of 

the products in comparison to average combusted cigarette yields. 

3.5.1.2. Biomarkers of exposure 

o Biomarker data submitted from a survey study conducted by the applicant found 

that participants who had recently used only the new tobacco products had lower 

levels of biomarkers of exposure (e.g., CO, cotinine, CEMA, 3-HPMA, and NNAL) 

relative to recent dual users of the new tobacco products and combusted cigarettes 

(i.e., dual-users). 

o Published studies suggest that cotinine levels (i.e., nicotine exposures) in pod-style 

ENDS users are comparable or higher than that of cigarette smokers (Goniewicz et 

al., 2019) and non-pod-ENDS users (Boykan, Messina, et al., 2019). 
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o In youth, cotinine levels increase over time, particularly with increases in ENDS use 

frequencyt(Vogeltettal.,t2019). 

o Cigarette smokers will likely experience significant reductions of voe exposure upon 

complete switching to NJOY ACE products (Goniewicz et al., 2017; Oliveri et al., 

2020; Round et al., 2019). 

o Dual users likely will have comparable tobacco-specific nitrosamine (TSNA) and voe 

biomarkers of exposure (BOE) as cigarette smokers, or they may experience low to 

modest reductions in these BOE (Pulvers et al., 2018). 

o Exclusive users of NJOY ACE likely will be exposed to greater levels of TSNA and VOC 

BOE compared with non-tobacco users. 

o Based on published literature, heavy metal exposure is likely to stay the same or 

decrease upon complete switching to NJOY ACE (Goniewicz et al., 2018; Jain, 2019; 

Prokopowicz et al., 2019). 

3.5.2. Synthesis 

Toxicology review concludes that there were significant reductions in aerosol HPHCs of the 

new NJOY ACE products compared to the combusted cigarettes. Although the applicantprovided data showed elevations in glycerin, propylene glycol, chromium and nickel of the 

new products, these increases are outweighed by large decreases in other respiratory 

toxicants (e.g., acetaldehyde, diacetyl, acetyl propionide, acrolein,!(b)(4) I 

formaldehyde, !(bl(4l Iand ethylene glycol) in the cigarette comparators. Therefore, the 

overall toxicological risk to the users of the new products is lower compared to cigarettes 

due to significant reductions in HPHC yields in the new products compared to cigarette 

comparators. 

BCP review states that, based on biomarker data submitted from a survey study conducted 

by the applicant, participants who had recently used only the new products had lower levels 

of biomarkers of exposure (e.g., CO, cotinine, CEMA, 3-HPMA, and NNAL) compared to the 

dual users of the new products and combusted cigarettes. The data is consistent with other 

publications. 

As TPL, I agree with the Toxicology and BCP conclusions that smokers who completely 

switch to or significantly reduce cigarette consumption with the new NJOY ACE products can 

reduce overall exposures to HPHCs compared to users of combusted cigarettes. 

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 

• Nonclinical studies 

o The new product aerosols and the ENDS comparison product, Vuse Alto 

Original 5%, demonstrated no mutagenic (Ames assay), no genotoxic (ivMN 

assay in IVGT cells), nor cytotoxic (NRU assay) potential at the 
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concentrations and under the conditions tested. Meanwhile, under the 

conditions tested, the combusted cigarette comparison product, 1R6F 

Reference cigarette, showed: 

• Significant mutagenicity in Salmonella typhimurium strains TA98 

and TA1537. 

• Significant cytotoxicity and genotoxicity in IVGT cells. 

o The applicant submitted a hazard analysis for in vitro studies comparing 

HPHCs (at 1 month to 9 months) and leachable compounds (at 1 month to 6 

months) to HPHCs and leachable compounds at O month (which were used 

in the in vitro studies), and used a toxicology literature review to compare 

the highest ineffective dose (HID) and the lowest effective dose (LED) for 

Ames test and ivMN studies to the stability testing HPHC concentrations. 

Based on relative stability of e-liquids up to Kb)(4) Iof storage under 

various conditions, and lack of mutagenicity, cytotoxicity, and genotoxicity 

at O month, the in vitro study hazard analysis of aerosol from the new 

product e-liquids (PM0000614.PD1-PM0000615.PD1 and PM0000622.PD1) 

stored for up to t

b)(4) Iunder various conditions is acceptable from a 

toxicological perspective. 

3.6.1.2. BIMO inspection findings 

BIMO inspection was not conducted at this time by FDA because the reported 

adverse effects (AEs) did not raise clinically significant concerns. 

3.6.1.3. Addiction as a health endpoint 

Per the BCP review: 

• Clinical study data submitted by the applicant suggests that, based on subjective 

effects and nicotine exposure, the new products have a somewhat lower or 

comparable addiction potential than combusted cigarettes among inexperienced 

ENDS users. 

• Clinical study data submitted by the applicant suggests that, based on subjective 

effects and nicotine exposure, PM0000615.PD1 has an addiction potential 

comparable to combusted cigarettes among experienced ENDS users. 

• Current cigarette smokers, (i.e., one of the applicant's stated intended user 

populations) who switch partially or completely to NJOY ACE products, are initially 

likely to achieve somewhat lower or comparable nicotine exposures and likely will 

maintain their nicotine addiction. After some period of experience with the 

applicant's products, however, nicotine exposure may become comparable to 

combusted cigarettes. 

• Dual users are likely to achieve slightly lower or comparable nicotine exposures 

from NJOY ACE products; some smokers may titrate, over time, to their preferred 

nicotine exposures (St Helen et al., 2020). Dual users are likely to maintain nicotine 

addiction, as with exclusive cigarette smoking. 

• Based on published literature and the applicant-submitted survey study, dual users 

of NJOY ACE and cigarettes likely will reduce their cigarette consumption, however 

the extent of the reduction is unclear (Czoli et al., 2019). 

• E-liquids with nicotine salts are easier (i.e. less irritating) to inhale at high nicotine 

concentrations (Caldwell et al., 2012; Omaiye et al., 2019; Prochaska & Benowitz, 
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2019; Talih et al., 2019) and may facilitate use and progression to regular use by 

na'ive users such as youth. Published literature suggest that youth who initiate use 

of nicotine salt-containing pod-style ENDS may have comparable or higher nicotine 

exposures compared with youth cigarette smokers and non-pod-ENDS users. Youth 

who use nicotine salt-containing pod-style ENDS may experience increased cotinine 

levels over time which may correspond with increases in nicotine dependence and 

progression to regular use. However, based on data from the applicant submitted 

clinical studies, BCP concluded that the abuse liability of NJOY ACE products is 

somewhat lower than or comparable to combusted cigarettes, mitigating concern of 

greater nicotine exposure than combusted cigarettes. 

3.6.1.4. Short and long-term health effects (clinical and observational) 

o Epidemiology: 

■ Users vs. Never Users: The applicant provided limited data on 

observational health outcomes. In the NJOY user study, participants 

were asked seven questions regarding respiratory symptoms, fatigue, 

and subjective health in the past 12 months. At each follow-up time 

point, the average number of self-reported respiratory symptoms, 

fatigue, and subjective health was provided by NJOY use status and 

smoking status. However, these results should be interpreted with 

caution due to the short time period, potential loss to follow-up bias, 

and the fact that most results are unadjusted for potential confounding 

factors. Due to these limitations, the published literature provides a 

better source of information on potential health effects. There is 

currently some epidemiologic evidence suggesting positive associations 

between ENDS use and some health outcomes (e.g., cardiovascular 

diseases, respiratory diseases, oral health); however, these studies are 

limited by lack of ability to discern temporality and the fact that most 

ENDS users included were former smokers whose past smoking might 

be related to these increased health risks, even after accounting for 

smoking status in multivariable models. Several cross-sectional 

Behavioral Risk Factor Surveillance System (BRFSS) studies in ENDS users 

who never smoked found associations between ENDS and respiratory 

outcomes. There is strong evidence that ENDS use is linked with ENDS 

battery explosion related burns and e-liquid nicotine poisoning. Ecigarette users have higher exposure to constituents such as VOCs than 

do non-tobacco users. 

• Dual Use: In general, data from the biomarker literature suggests that 

dual users have sometimes been found to have higher levels of certain 

biomarkers of exposure including nicotine and its metabolites compared 

to combusted cigarette smokers. 

■ Switching: One biomarkers study by Goniewicz et al. (2017) found levels 

of total nicotine and some polycyclic aromatic hydrocarbon metabolites 

did not change after switching from combusted cigarettes totecigarettes, but levels of all other biomarkers significantly decreased 

after one week of using e-cigarettes {Goniewicz et al., 2017). Further 

information on possible benefits of switching from combusted 

cigarettes tote-cigarettes can be seen in the biomarker literature 
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showing researchers have generally found that e-cigarette users have 

lower levels of exposure to some constituents including TSNAs than do 

combusted cigarette smokers. Nicotine levels among e-cigarette users 

have usually been found to be somewhat lower or comparable to levels 

among smokers. 

o Medical: ■ Based on the literature review, the impact of ENDS use on CVD, cancer, 

respiratory outcomes, developmental, and reproductive health 

outcomes, oral health, mental health, and other health topics are 

largely inconclusive. Risk of injury and poisonings have been 

consistently reported in the literature; however, no specific reports 

related to use of the new product were identified. 

■ The applicant provided minimal data on biomarkers of potential harm; 

the information provided did not inform the health effects assessment. 

■ Clinical studies submitted by the applicant did not identify short or long 

term health effects specific to the NJOY products. However, the studies 

have limitations, including small sample sizes and relatively short time 

periods of product exposure, thereby limiting the generalizability of the 

health effects data to a larger user population and extrapolation of the 

long-term health effects of the NJOY products. Despite these 

limitations, the applicant1

s data and published literature suggest 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. 

3.6.1.5. Likelihood and effects of product misuse 

o BCP: ■ The applicant-submitted clinical studies and literature review did not 

provide data evaluating the likelihood of misusing NJOY ACE products. 

Despite the lack of clinical data assessing product misuse (using the 

product in ways other than intended such as product modifications, 

dripping, and stealth use), BCP concludes that the likelihood of misuse is 

low for NJOY ACE products because they are closed-system pod-style 

ENDS. NJOY ACE power settings are non-adjustable, and thete-liquid is 

enclosed in a pod, thereby reducing chances that users may manipulate 

ENDS product settings and e-liquid constituents, including nicotine 

levels, which may influence exposure to nicotine and other HPHCs in the 

aerosol. 

o Medical: 

■ The applicant did not report any serious health outcomes related to 

misuse. Though reports of ENDS-related poisonings among children 

have increased in the literature, the closed-system design of NJOY ACE 

pods may mitigate the risk of accidental exposure. The majority of ENDS 

related injuries among children and adults have been minor with more 

extensive injuries related to the use of lithium batteries as a power 

source for devices; however, no serious adverse events related to 

lithium battery use was reported by the applicant. 
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• Warnings against use of this product in children and adolescents appear 

on the label to mitigate the risk of misuse but does not include the 

potential risk of poisoning. 

• The proposed labeling does not include recommendations for frequency 

of product use for these nicotine-containing products. 

3.6.1.6. Adverse experiences 

• Engineering: The AEs were discussed in the first cycle, where applicant evaluated 

the failure modes of the pods, device, and the complete system by calculating a risk 

priority number (RPN) to establish a standard risk scale. The medical discipline did 

not refer or defer any engineering-related design parameters associated with the 

adverse experiences of the NJOY ACE products. From an engineering perspective, no 

more information is needed. 

• Medical: 

o There were no deaths or other serious AEs reported in the two clinical 

studies. Subject 13 reported a moderate headache after receiving the study 

product and it is unclear if this AE contributed to the subject's withdrawal 

from the study. 

o Nineteen AEs were reported in the clinical studies and assessed as at least 

possibly related to NJOY products. The AEs reported were either mild or 

moderate in severity, with the majority being mild. 

o The most commonly reported AEs across all studies were gastrointestinal 

(nausea, vomiting, dyspepsia, and stomach ache) followed by neurological 

(dizziness and headache). All AEs resolved prior to the end of the study. 

o The four categories in the applicant's Adverse Experiences Summary Report 

containing the highest number of AEs were Respiratory System (n=71), 

Digestive System (n=48), General (n=30), and Nervous System (n=ll). The 

top four AEs across all organ systems were Sore Throat (n=23), Mouth 

Irritation (n=22), Cough/Sputum (n=19), and Feeling Sick (n=17). 

o The reports of gastrointestinal and neurological effects in clinical studies 

and in the Adverse Experiences Summary Report could indicate the 

potential for health effects of this nature when generalized to a larger 

population. These effects could potentially lead to further health 

complications or exacerbate underlying medical conditions in 

subpopulations of users (e.g., immunocompromised, diabetic, cardiac 

disease, respiratory disease). 

o In the applicant-submitted literature review on ENDS, AEs reported in 

published studies of ENDS products included cough, dry or irritated mouth 

or throat, dizziness or lightheadedness, headache or migraine, shortness of 

breath, change in or loss of taste, nausea, tight chest, and congestion. 

Several of these AEs were reported in the applicant-sponsored clinical 

studies. 

o FDA is aware of several health issues regarding the use of ENDS, specifically 

e-cigarette or vaping use-associated lung injury (EVALI), seizures, and 

overheating/fire/explosion-related thermal burn injuries (OH/F/Exp): 

• EVALI is a potential respiratory health effect that could occur in 

individuals who use vaping products. There were no reports of 

EVALI in the applicant's clinical studies and there did not appear to 
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be any subjects who experienced the constellation of symptoms 

indicative of EVALI as an AE that required hospitalization. However, 

since EVALI is associated with use of vaping products, CTP is 

interested in evaluating any additional information related to 

respiratory illness in association with ENDS and specifically the new 

products.

• There were no seizures reported as an AE in the applicantsubmitted clinical studies. CTP is interested in monitoring an ongoing evaluation of this potential health consequence of ENDS use. 

• No OH/F/Exp were reported in the PMTAs. However, the risk is still 

an issue regarding ENDS use overall. 

Therefore, to further monitor and evaluate potential ENDS health effects such 

as EVALI, seizures, and OH/F/Exp, medical recommends that post-market 

reporting include a specific plan to monitor respiratory-related illnesses, 

neurological symptoms, and AEs related to overheating and thermal burns 

associated with the products in the PMTAs. 

3.6.2. Synthesis 

As TPL, I agree with the BCP conclusions that the new tobacco products have a lower or 

comparable addiction potential than combusted cigarettes. Current cigarette smokers who 

switch partially or completely to NJOY ACE products will likely maintain their nicotine 

addiction. In terms of short- and long-term health effects, I agree with Epidemiology and 

Medical's conclusion that the association of ENDS use and CVD, cancer, respiratory disease, 

developmental, and reproductive health outcomes, oral health, mental health, and other 

health topics is largely inconclusive due to the limitations of clinical studies, such as small 

sample sizes and relatively short periods of product exposure. However, 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. 

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 

• The applicant provided risk assessments for ingredients in thete-liquids for the new 

products (PM0000614.PD1, PM0000615.PD1, PM0000622.PD1), HPHCs in the 

aerosol for the new products, leachables and extractables from the NJOY ACE device 

(PM0000613.PD1), and alternative exposures (secondhand exposure to NJOY ACE 

aerosol; oral and intentional ingestion of NJOY ACE e-liquids; and incidental and 

accidental dermal exposures to NJOY ACE). 

• The increases in chromium, nickel, acrolein, and formaldehyde in the new product 

compared to average combusted cigarette smoke levels suggest that they would 

increase the cancer risk for users of the new products. Assuming that a potential 

user will be switching completely from combusted cigarette smoking to using the 
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new tobacco products, exposures to HPHCs such as NNK, NNN, acrylonitrile, 

cadmium and lead are expected to be decreased. HPHCs from cigarette smoke 

(NNK, NNN, acrylonitrile, cadmium and lead), for which exposure levels would be 

decreased with switching completely, have increased potencies (i.e., higher 

magnitude or severity of toxicological effect, at a given dose or exposure level) 

compared to the HPHCs from aerosols from the new product. Based on the 

comparatively increased potency of HPHCs from cigarette smoke, and the number 

and concentrations of HPHCs from cigarette smoke and new product aerosol yields, 

the reduction in cancer risk from switching completely from combusted cigarettes 

to the products would likely outweigh the increase in cancer risk in the products due 

to chromium, nickel and formaldehyde. Overall, it is likely that the total cancer risk 

for the new products, NJOY ACE (PM0000614.PD1- PM0000615.PD1, 

PM0000622.PD1), assuming additivity, is less than the cancer risk posed by the 

commercially marketed combusted cigarette comparison products (e.g., the 

applicant submitted average MSS HPHC levels from the literature, and FDAS0). 

• Overall, the risk assessments conclude that with complete switching from use of 

other tobacco products (i.e., other ENDS and combusted cigarettes) to use of the 

new products, NJOY ACE, the potential health risks are likely to be similar (to use of 

other ENDS) and reduced (compared to combusted cigarettes) when compared to 

continued exclusive use of those tobacco products. In addition, secondhand 

exposures to HPHCs from ENDS aerosol are likely to be less harmful than 

secondhand combusted cigarette smoke exposures, and although there is an 

increased risk of adverse health effects with exposures to the new product e-liquids 

from alternate sources (i.e., dermal, oral, and ingestion), the likelihood of being 

exposed through these pathways is low due to the design of the product (i.e., it is a 

closed ENDS product). Based on the proposed new product use scenarios, switching 

completely from combusted cigarette smoking to the new products will result in the 

greatest reduction in HPHC exposures. Dual use of combusted cigarettes and the 

new products may offer decreases in HPHC exposures if combusted cigarettes per 

day is reduced. Switching completely from smoking combusted cigarettes to using 

the new product may result in similar or greater reductions compared to switching 

completely to products such as the comparison product, Vuse Alto. 

3.7.1.2. Population health impact (PHI) model 

• The data inputs used in the applicant's population health modeling scenarios for 

ENDS generally and NJOY ACE specifically both present significant methodological 

and substantive challenges. Switching rates were calculated from cross-sectional 

instead of longitudinal data and may overestimate actual switching from combusted 

cigarette smoking to exclusive ENDS use. The scenarios also did not consider the 

possibility of ENDS use among young people, even though such use has become a 

matter of considerable public health concern. Given these limitations, the 

population modeling projections are not particularity informative to the overall 

assessment. 

3.7.2. Synthesis 
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As TPL, I agree with Toxicology conclusions that switching completely from combusted 

cigarette smoking to the new products will result in large reduction in HPHC exposures. I 

also agree with Epidemiology review on the limitations of the applicant's population health 

modeling methodology. The limitations include overestimating 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 appropriate for the protection of the public 

health. The determination of APPH 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 tobacco product design and 

adequate processes and controls to help ensure that the new products meet the 

manufacturer's specifications. The methods used in, and the facilities or controls used for, 

the manufacture, processing, and packing of the new products do not fail to conform to the 

requirements in Section 906(e) of the FD&C Act. 

3.8.3. Labeling 

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. 
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4.2. ENVIRONMENTAL CONCLUSION 

For PM0000613.PD1 - PM0000615.PD1, and PM0000622.PD1, a finding of no significant impact 

(FONSI) was signed by Luis G. Valerio on 4/22/2022. The FONSI was supported by an 

environmental assessment prepared by FDA on 4/22/2022. 

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, 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 

only information in a PMTA, but also extends to any other 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 new products' design and that there are adequate process controls 

and quality assurance procedures to help ensure both the device and e-liquids are manufactured 

consistently. FDA's evaluation also concluded that chemical testing was sufficient to determine that 

overall HPHC levels in the aerosol of these products are lower than in combusted cigarette smoke. 

Further, biomarker data provided by the applicant demonstrated that participants who had used 

only the NJOY ACE products had lower levels of biomarkers of exposure to HPHCs (e.g., CO, cotinine, 

CEMA, 3-HPMA, and NNAL) compared to the dual users of the new products and combusted 

cigarettes. In the applicant's Perception Study, current adult smokers had the most interest in the 

Classic Tobacco 5% nicotine product. Further, the NJOY User Study and published literature 

demonstrated that switching from combusted cigarettes to ENDS does occur among current adult 

smokers. The applicant has therefore demonstrated the potential for these products to benefit adult 

smokers who switch completely or significantly reduce their cigarette consumption 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. Although ENDS products are the most widely used tobacco products 

among youth, use of tobacco-flavored ENDS products by youth is reported to be significantly less 

common than flavored ENDS products in the published literature. Consistent with these findings, in 

the applicant's Youth Perception study, curiosity to use the tobacco-flavored products tb)(4) I 

b)(4) . The same study also showed that the 

percentage of youth reporting ever ENDS use who initiated tobacco use with tobacco flavored ENDS 

was much lower than that of other flavors. Despite the lower appeal of tobacco-flavored products to 

youth, a marketing authorization order for these products should include postmarket requirements 

to help ensure that youth exposure to tobacco marketing is being minimized, given the strong 

evidence regarding the impact of youth marketing exposure to youth appeal and initiation of 

tobacco use. Together, based on the information provided in the PMTAs and the available evidence, 

the potential to benefit adult 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 stability, the applicant proposed a l(b)(4) Ishelf life for the new products, 

but only provided r

b)(4) lof finished product chemical stability data under ambient 
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conditions. In addition, the applicant provided l(b)(4) Iof microbial stability data for the eliquids in PM0000614.PD1-PM0000615.PD1 and �b)(4) pf microbial stability data for the eliquid in PM0000622.PD1. Because the stability data provided by the applicant is acceptable and 

indicates that the products are low-risk for chemical stability and microbial growth over the 

eriod tested and because there are no other stability concerns, the lack of stability data forl�b)(I b)(4) 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 appropriate for the protection 

of the public health. The issuance of these 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, 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 tobacco products appropriate for 

the protection of public health 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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7. APPENDIX 

7.1. APPENDIX A: NEW PRODUCTS AND AMENDMENTS 

Table 3. New tobacco products subject to Granted Orders 8 

Common Attributes of PMTAs 

Date of Submission: March 10, 2020 

Date of Receipt: March 10, 2020 

Product Manufacturer: NJOY LLC 

Product Category: ENDS (VAPES) 

P00000613.PD1 : NJOY ACE Device 

Product Sub-Category: Closed E-Cigarette 

Package Type: Box 

Package Quantity: 1 E-Cigarette 

Length: 74.12 mm 

Diameter: 29.8 mm 

Wattage: 6.5W 

Battery Capacity: 400 mAh 

E-liquid Volume: Not applicable 

Nicotine Concentration: Not applicable 

PG/VG Ratio: Not applicable 

Characterizing Flavor: None 

Additional Properties: 

Thickness: 13.5 mm 

Universal Serial Bus (USB) 

PM0000614.PD1t: NJOY ACE POD Classic Tobacco 2.4% 

Product Sub-Category: Closed E-Liquid 

Package Type: Cartridge 

Package Quantity: 2 Cartridges 

Characterizing Flavor: Tobacco 

E-liquid Volume: 1.9ml 

Nicotine Concentration: 2.4%w/w 

PG/VG Ratio: 0.839 

Additional Properties: Length: 34.75 mm 

Thickness: 11.57 mm 

Width: 29.59 mm 

8 Brand/sub-brand or other commercial name used in commercial distribution. 

9 Applicant provided value. Additionally, applicant provided PG and VG values as percentages of ingredient formula for each 

product. 
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PM0000615.PD1 : NJOY ACE POD Classic Tobacco 5% 

Product Sutb-Category: 

Package Type: 

Package Quantity: 

Characterizing Flavor: 

E-liquid Volume: 

Nicotine Concentration: 

PG/VG Ratio: 

Additional Properties: 

Closed E-Liquid 

Cartridge 

2 Cartridges 

Tobacco 

1.9 ml 

5%tw/w 

0.759 

Length: 34.75 mm 

Thickness: 11.57 mm 

Width: 29.59 mm 

PM0000622.PD1t: NJOY ACE POD Rich Tobacco 5% 

Product Sutb-Category: 

Package Type: 

Package Quantity: 

Characterizing Flavor: 

E-liquid Volume: 

Nicotine Concentration: 

PG/VG Ratio: 

Additional Properties: 

Closed E-Liquid 

Cartridge 

2 Cartridges 

Tobacco 

1.9 ml 

5%tw/w 

0.779 

Length: 34.75 mm 

Thickness: 11.57 mm 

Width: 29.59 mm 
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Table 4. Amendments received 

Submission Date Receipt Date Amendmen 

t 

Applications 

being 

amended 

Reviewed Brief Description 

June 16, 2020 June 16, 2020 PM0000824 All Yes Technical update to new 

adverse experiences 

reporting, updated user 

survey, and updated 

population model 

August 11, 2020 August 11, 2020 PM0000882 All Yes Response to July 29, 2020 

Deficiency Letter 

August 26, 2020 August 26, 2020 PM0000906 All Yes Follow up phone call for 

July 29, 2020 Deficiency 

Letter 

September 30, 2020 September 30, 2020 PM0003401 All Yes Clarification to previously 

submitted data 

December 17, 2020 December 17, 2020 PM0004434 All Yes Notification of 

new/current literature to 

support PMTA 

applications