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Technical Project Lead (TPL) Review of PMTAs 

New Products Subject to this Review' 

STNs PM0000630-PM0000631 

Common Attributes 

Submission date 

March 30, 2020 

Receipt date 

March 30, 2020 

Applicant NJOY, LLC 

Product manufacturer NJOY, LLC 

Application type Standard 

Product category ENDS (VAPES) 

Product subcategory Closed E-Cigarette 

Cross-Referenced Submissions 

All new products (b)(4) 

Supporting FDA Memoranda Relied Upon in this Review 

All STNs 

  Statistical Consultation finalized on May 6, 2021

  Tobacco Product Surveillance Team Consultations finalized on

September 30, 2020 and on February 2, 2022 

  OHCE Consultation finalized on February 24, 2022

Recommendation 

Issue marketing granted orders for the new products subject of this review. 

Technical Project Lead (TPL): 

Digitally signed by Luis G. Valerio -5 

Date: 2022.06.09 17:27:29 -04'00' 

Luis G. Valerio, Jr., Ph.D., ATS 

Associate Director 

Division of Nonclinical Science 

Signatory Decision: Concur with TPL recommendation and basis of recommendation 

Digitally signed by Matthew R. Holman -5 

Date: 2022.06.10 06:31:28 -04'00' 

Matthew R. Holman, Ph.D. 

Director 

Office of Science 

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 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 12 

3.2. PRODUCT CHARACTERIZATION 12 

3.2.1. Discipline key findings 12 

3.2.2. Synthesis 19 

3.3. ABUSE LIABILITY 20 

3.3.1. Discipline key findings 20 

3.4. USER POPULATIONS 22 

3.4.1. Discipline key findings 22 

3.4.2. Synthesis 29 

3.5. TOXICANT EXPOSURE 31 

3.5.1. Discipline key findings 31 

3.5.2. Synthesis 32 

3.6. HEALTH EFFECTS 33 

3.6.1. Discipline key findings 33 

3.6.2. Synthesis 38 

3.7. POPULATION AND PUBLIC HEALTH 40 

3.7.1. Discipline key findings 40 

3.7.2. Synthesis 41 

3.8. STATUTORY REQUIREMENTS 43 

3.8.1. Public health conclusion 43 

3.8.2. Tobacco product manufacturing practices 43 

3.8.3. Labeling 43 

3.8.4. Product standards 43 

4. ENVIRONMENTAL DECISION 43 

4.1. DISCIPLINE FINDINGS 43 

4.2. ENVIRONMENTAL CONCLUSION 43 

5. CONCLUSION AND RECOMMENDATION 43 

6. REFERENCES 46 

7. APPENDIX 51 
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LIST OF TABLES 

Table 1. Disciplines reviewed 8 

Table 2. Consultations 8 

Table 3. New products 51 

Table 4. Amendments 52 
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1. EXECUTIVE SUMMARY 

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

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

above ("new products" 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 premarket tobacco product 

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

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

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

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

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

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

Section 910(c)(4). FDA interprets the APPH standard to require 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 increase or decrease, the burden of 

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

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

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

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

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

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

raises unique considerations. 

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

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

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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TPL Review of PMTAs: PM0000630-PM0000631 Page 5 of 52 

type 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 tobacco-flavored 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 potentia1.4 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 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. 

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 their 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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1.2. SUBJECT APPLICATIONS 

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. The new products have UL 1642 Certification for the battery cell, and Engineering 

concluded there is a reduced risk of battery rupture. Based on the information provided in the 

PMTAs, the new products' abuse liability-Le., ability to promote continued use, addiction, or 

dependence-is lower than combusted cigarettes and is similar to, or lower than, that of other 

ENDS. The overall toxicological risk to the users of the new products is lower compared to 

combusted cigarette smoke due to significant reductions in aerosol harmful and potentially harmful 

constituents (HPHCs) of the new products compared to cigarettes, as evidenced by results of 

nonclinical and aerosol studies. The biomarker data provided by the applicant demonstrated that 

participants who had used only the new products had lower levels of measured biomarkers of 

exposure (e.g., carbon monoxide (CO), cotinine, 2-cyanoethylmercapturic acid (CEMA), 3-

hydroxypropylmercapturic acid {3-HPMA), and 4--{methylnitrosamino)-1-(3-pyridyl)-1-butanol 

(NNAL)) compared to the dual users of the new tobacco products and combusted cigarettes. Based 

on applicant submitted survey studies, curiosity and intention to try the new products was higher in 

current adult smokers compared to former adult smokers and never smokers. Estimates by the 

applicant of complete switching from cigarettes to the new products for current adult smokers at 

three months was 26.5%, a level higher than what is typically seen in the literature for estimates of 

complete switching to ENDS products. The applicant submitted an observational study, from which 

the epidemiology review estimated that more current smokers at baseline reported using the new 

tobacco-flavored products compared to non-tobacco flavored NJOY products. Therefore, the 

applicant has demonstrated that some current adult smokers are interested in the new products to 

assist in decreasing or quitting their cigarette use, and these products have the potential to benefit 

that group. 

Regarding human adverse experiences (AEs) with the new products, the applicant's submitted 

clinical studies did not have serious AEs or deaths. In addition, the applicant did not report any 

serious health outcomes related to misuse of the product. No definitive AEs related to the new 

products were found In FDA's Safety Reporting Portal. 

In terms of the risks to non-users, youth are considered a vulnerable populatron 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. In addition, the applicant's study findings 

demonstrated low intention to try and curiosity about using the new products among adult former 

smokers and never smokers. 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 post-market requirements to help ensure that youth 

exposure to tobacco marketing Is limited. Together, based on the information provided in the 

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

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

follows postmarket requirements aimed at reducing youth exposure and access to the products. 

Regarding product stability, the applicant proposed a I •b)W) shelf life for the new products. The

applicant provided complete chemical stability study data including test data for bulk e-liqulds, 

(b) (4)
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finished product e-liquids, and aerosols; extractables and leachables data for components, parts and 

container closure system (CCS) meeting product specifications. The applicant-provided data 

supports microbial stability of the products over! 1t, 4 J. The stability data provided by the 

applicant is acceptable and indicates that the products are low-risk for chemical instability and 

microbial growth over the period tested and there are no stability concerns. Therefore, the 

applicant's stated shelf life of! •tlC·'lfor the new products is supported by the submitted testing 

data. 

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 significantl'.y reduce their 

combusted cigarette use (or who switch completely to the new products) outweighs the risk to 

youth, provided that the applicant follows post-market requirements and implements marketing 

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

new products. 

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

of No Significant Impact (FONSI). 

2. BACKGROUND

2.1. NEW PRODUCTS 

The applicant submitted information for the two new products listed on the cover page and 

with more detail in the Appendix, sold under the product names NJOY DAILY Rich Tobacco 4.5% 

and NJOY DAILY EXTRA Rich Tobacco 6%. Briefly, the new products are disposable ENDS 

products wlth a prefilled e-liquid reservoir containing Rich Tobacco as a characterizing flavor 

with 4.5% nicotine (PM0000630) and 6% nicotine (PM0000631). The units are powered by a 

lithium ion, non-rechargeable battery with UL 1642 certification and atomizer subsystem. The 

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

2.2. REGULATORY ACTIVITY 

On March 30, 2020, FDA received two PMTAs (PM0000630-PM0000631) from NJOY LLC. FDA 

issued an Acceptance letter to the applicant on April 8, 2020. FDA issued a Filing letter to the 

applicant on April 21, 2020. FDA issued a Deficiency letter to the applicant on December 17, 

2020. 

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

2.3. SCOPE OF REVIEW 

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

subject of this review, as well as TPMFs !(b)(4) jand 

l<bX4\ 1- The TPMFs were referenced to support the new products in this application. 

(b) (4)

(b) (4)
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Table 1. Disciplines reviewed 

Discipline 

Cycle 1 Cycle 2 

Reviewers Review 

Date Reviewers Review Date 

Engineering Jim Melchiors 12/17/2020 Jim Melchiors 6/9/2022 

Chemistry Tianrong Cheng 12/14/2020 Tianrong Cheng 6/9/2022 

Microbiology Wen Lin 12/14/2020 Kristy HuynhNgo 6/9/2022 

Toxicology Prince Awuah 12/16/2020 Prince Awuah 6/9/2022 

Behavioral and 

Clinical 

Pharmacology 

Tyler Nighbor 12/14/2020 Steven Meredith 6/9/2022 

Medicals Kathy Jackson 12/17/2020 Not assigned N/A 

Epidemiology Arpi Terzian 12/16/2020 Amy Gross 6/9/2022 

Social science Dannielle Kelley 12/16/2020 Dannielle Kelley 6/9/2022 

Environmental 

Science 

Dilip Venugopal 12/16/2020 Dilip Venugopal 6/8/2022 

Table 2. Consultations 

Discipline or Office 

Cycle 1 Cycle 2 

Reviewer(s) Review 

Date Reviewer(s) Review Date 

Statistics Not assigned N/A Sapna Thakur 5/6/2021 

OCE — BIMOs Tara Singh 11/23/2020 Not assigned N/A 

OCE — 

Manufacturing/Lab 

Hiwot Kesi 11/19/2020 

Hiwot Kesi 04/30/2021 

OCE — DPAL5 Adeola Obajemu 11/5/2020 Not assigned N/A 

OHCE Emily Talbert 10/14/2020 

Allison O'Donnell 

Emily Talbert 

02/24/2022 

Tobacco Product 

Surveillance Team 

Susan Rudy 09/30/2020 Susan Rudy 

02/02/2022 

3. SCIENTIFIC REVIEW 

3.1. COMPARISON PRODUCTS 

3.1.1. Discipline key findings 

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

  Engineering:

o The applicant provided limited information on the comparator products 

STIG Cubano and STIG Mighty Mint. They have the same wick material and 

coil resistance as the new products, although the comparator products are 

slightly bigger, with 34% more e-liquid at 1.2 mL and 30% more battery at 

260 mAh. The STIG Cubano and STIG Mighty Mint are similar products to 

5 A second cycle review was not necessary as there was no new information or data to review for this discipline. 
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the new products with respect to the product design and are disposable 

ENDS like the new products. Therefore, they are appropriate comparators 

to the new products with respect to the product design. 

 Chemistry:

o All PMTAs provided aerosol constituent concentrations (generated from 

applicant-conducted testing) for Leap Go Smooth Tobacco 5% as a 

comparison product. Leap is a prefilled disposable tobacco flavored ENDS 

containing 5% nicotine salt. The rationale for this comparison was that Leap 

Go Smooth is also a disposable closed system ENDS with a non-rechargeable 

battery and single-use pod that is filled by the manufacturer with nicotine 

salt-containing e-liquid. Because the applicant also identified combusted 

cigarettes to compare to the new products, the chemistry reviewer also 

compared constituent yields from the new tobacco product aerosols to the 

mainstream smoke yields of 50 commercially available combusted 

cigarettes (FDA50 products). 

  Toxicology:

o The applicant provided comparisons between the new products and 

combusted cigarettes as a product category. The applicant used the average 

combusted cigarette mainstream smoke (MSS) concentration data from 

peer-reviewed scientific literature to represent the combusted cigarette 

category. This comparison was presented in the HPHC data. The 

applicant's rationale for this comparison is based on the premise of 

reduction of risk of overall adverse health effects from combusted cigarette 

for smokers who switch 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 

recently published and peer-reviewed, measured many of the same HPHCs, 

included cigarettes that are currently on the market, and were tested using 

common puffing protocols (e.g., International Organization of 

Standardization (ISO) and Health Canada Intense (FICI)) across the studies. In 

addition, aerosol HPHC yields from the new products compared to 

mainstream smoke (MSS) concentration data from FDA50 products was 

provided by the applicant (Section 2.3 in cycle 1 review). Based on the 

applicant-submitted data, an additional analysis was conducted by 

Chemistry comparing HPHCs in the MSS of FDA50 products and in the 

aerosols of the new products. The additional analysis by Chemistry found 

the level of the HPHC, acetaldehyde, to be higher in the MSS of FDA50 

products compared to that in the aerosols of the new products. The HPHCs 

acrylonitrile, benzene, NNN, NNK, and toluene were quantifiable (> limit of 

quantification) in the MSS of FDA50 products and were below the limit of 

detection in the aerosols of the new product PM0000631. The applicant did 

not measure acrylonitrile, benzene, NNN, NNK, and toluene in aerosols of 

the new products in PM0000630 because the measurement of these HPHCs 

from product shelf-life stability testing in PM0000631 was found to be 

below the limit of detection in the aerosols. The chemistry review found the 

shelf-life stability testing the applicant provided on PM0000631 to be 

acceptable. Since the only ingredient difference between PM0000631 and 

PM0000630 is the percentage of nicotine, 6% and 4.5%, respectively, the 
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toxicology review concluded that the levels of these HPHCs in PM0000630 

would be expected to be lower or at least similar (below the limit of 

detection) in comparison to PM0000631. Therefore, from a toxicological 

perspective, the applicant's rationale for using combusted cigarettes as a 

comparison product is appropriate because the data show the comparator 

is representative of the combusted cigarette category, and current adult 

cigarette smokers are the applicant's stated intended users. Moreover, the 

use of average cornbusted cigarette MSS concentration data from the 

published toxicology literature is an appropriate representative of the 

combusted cigarette category. 

o 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, 1R5F and 3R4F) to commercially marketed cigarettes have 

shown that reference cigarettes have 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., 

2008). 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 mutagenicity, 

cytotoxicity, and genotoxicity in a combusted tobacco product. 

o The applicant provided comparisons between the new products and the 

ENDS comparison product, Leap Go Smooth Tobacco with 5% nicotine. This 

comparison was presented in the HPHC data (Section 2.3 in cycle 1 review) 

and in the in vitro mutagenicity, cytotoxicity, and genotoxicity studies. The 

rationale for this comparison was that Leap Go Smooth is also a 

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

filled by the manufacturer with nicotine salt-containing e-liquid. The 

applicant also states that Leap Go Smooth Tobacco 5% flavor (Smooth 

Tobacco) and nicotine content (5% w/w nicotine) are similar to NJOY DAILY 

Rich Tobacco at 4.5% and 6% nicotine. From a toxicological perspective, the 

applicant's rationale for using Leap Go Smooth Tobacco with 5% nicotine is 

adequate. 

o 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-adjusted aerosol 

concentration data from peer-reviewed scientific literature to represent the 

other ENDS products categories. The applicant states that the rationale for 

using this comparison was to give insight into HPHC comparison between 

the new products and 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. Overall, comparison of 

HPHCs from the new products and other ENDS products showed lower 

levels in the new 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 this would allow for 

an ingredient normalized comparison since there are ingredient and design 

differences between the different ENDS products and the new products. 
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This method allows for a direct comparison of the new tobacco products 

and 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:

o The applicant used observational studies with comparison groups of both 

never users and current combusted cigarette users to support their 

application. According to the applicant, the intended user population is: 

"current adult users of nicotine-containing products who cannot or choose 

not to discontinue use of nicotine, particularly current combustible cigarette 

users and ENDS users". However, some non-users will likely use the product 

as well. Considering the applicant-submitted youth prevalence studies, 

although these studies had small sample sizes, the data suggest that 40.5% 

of youth who reported ever ENDS use started with "something other" than 

tobacco/menthol flavored products, compared to 41.5% of every ENDS 

users who reported initiating with mint or menthol, and 18% reported using 

tobacco flavored ENDS. The applicant's Youth Perceptions Study also 

indicated results specific to NJOY DAILY youth users. The applicant's study 

indicated 45.6% of ever NJOY DAILY youth users reported starting with Blue 

+ Black Berry, Tropical Twist, or Watermelon flavored NJOY DAILY products. 

The remaining respondents used tobacco flavored (13.3%), or menthol or 

mint flavored (32.8%) NJOY DAILY products, and 8% indicated they don't 

remember.. These data provide some evidence that the new products are 

less appealing to youth compared to other types of flavored products. 

Based on the applicant's description of the intended user population as 

current adult users of nicotine-containing products who cannot or choose 

not to discontinue use of nicotine, particularly current combustible cigarette 

users and ENDS users,, combusted cigarettes are an appropriate 

comparison product. 

  Medical:

o NJOY DAILY products were of the same product category (ENDS) as other 

products used as comparators in the applicant's clinical studies to collect 

data on adverse experiences (AE) and health effects (NJOY ACE Tobacco 5%, 

NJOY LOOP Rich Tobacco 4.5%, and JUUL Virginia 5%). Combusted cigarettes 

were also used as a comparator in clinical studies. All comparator products 

used by the applicant are appropriate as they provide AE and health effects 

data on products that represent the current tobacco market and generally 

contain similar amounts of nicotine as the new products, 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:

o ENDS comparator product (Leap Go Smooth Tobacco 5%) 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 
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comparison products is acceptable from a microbiology perspective. The 

new tobacco products have microbial content and endotoxin content below 

FDA and USP guidelines. 

  Social Science:

o The applicant-submitted studies included comparisons of the new products 

to combusted cigarettes, as well as to non-NJOY ENDS and nicotine 

replacement therapies (NRTs). Based upon available data on perceptions, 

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

the new products will include current adult smokers. The applicant 

examined perceptions of the tobacco products and measured intentions to 

try the new products among cigarette smokers. The data in the application 

support the applicant's assertion that the intended population of current 

adult smokers is a likely user population. Overall, the comparisons of the 

new products made by the applicant to cigarettes, non-NJOY ENDS, and 

NRTs are appropriate from a social science perspective because the 

intended user populations are users of nicotine-containing products, 

particularly adult cigarette users and adult ENDS users, and data from other 

ENDS and NRTs allows for a comparison where the new products fall on the 

risk continuum. 

  Behavioral & Clinical Pharmacology (BCP):

o Combusted cigarettes served as the comparison product in a clinical study 

submitted by the applicant. Other ENDS were also used as the comparison 

products in another clinical study. Results from the clinical study provided 

by the applicant suggest that the new products may have lower nicotine 

exposure and subjective effects than combusted cigarettes. Overall, these 

findings suggest that the abuse liability of the new products is likely 

sufficient to sustain addiction in nicotine-dependent populations, and thus 

the comparison products are appropriate. 

3.1.2. Synthesis 

The applicant used conibusted cigarettes and other ENDS products in the same category as 

the new products and a variety of other products outside the same category to compare to 

the new products. As TPL, I agree with the toxicology, engineering, chemistry, microbiology, 

medical, behavioral and clinical pharmacology, epidemiology, and social science conclusions 

that the comparison products selected by the applicant and the rationale for selection as 

well as the data from these products are appropriate. The principal comparator products 

were combusted cigarettes and ENDS products of the same category often with similar 

flavors. The comparators are appropriate because the applicant's stated intended user 

populations for the new products are current users of nicotine-containing products, 

including current ENDS users. Overall, the applicant provided adequate justification, 

rationale, and data to support the selections and comparisons made between the new 

products and their chosen representative and comparison products. 

3.2. PRODUCT CHARACTERIZATION 

3.2.1. Discipline key findings 

The following discussion is based on key findings provided in discipline reviews: 
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3.2.1.1. Product design and composition 

• Engineering:

Page 13 of 52 

o Each new tobacco product Is a closed non-rechargeable ENDS. The new

products are not serviceable by the user for any purpose, Including, but not

limited to, customizing the atom,zer, or modifying or refilling the e-llquld.

For a 3-second puff, the new products heat an e-llquid to produce 3 to 5 mg

of inhalabie aerosol.

o The new products contain an absorbent pad saturated with 0.84 to 0.94 ml

of e-llquld consisting of propylene glycol, vegetable glycerin. lactic acid. and

either 4.5% (PM0000630) or 6% (PM0000631) nicotine. A wick comprised of

I •blf4 ·I utilizes capillary action within the space

between th09 to transport e-Hquid from the absorbent pad to a

I 1

1

' 1

lheating element positioned dlametrfcally across the airway

where airflow transports the aerosol to the user. When the use, draws air

through the device (activation threshold iseiEZill cc/minute), the pressure

differential activates an alrflow sensor with an Application Specific

Integrated Circuit (ASIC) that outputs 3.4 VRMS from the non-rechargeable

200 mAh lithium-Ion battery cell to the coil for 0.4 seconds, after which 3.0

VRMS is output. The airflow sensor limits the maximum puff duration to

I to 11

1 In order to consume for longer than that, a user must take 

multiple puffs. When airflow is stopped, the negative pressure within the 

housing returns to atmospheric. and the sensor deactivates the output, 

returning the device to standby mode, When the battery cell is depleted 

I t 11" M, the airflow sensor flashes the LED to notify the user that the 

cell is depleted, and the device is no longer usable. 

o The device always remains on in standby mode with activation controlled by

the ASIC residing in the airflow controller waiting to detect airflow. The ASIC

on the new products does not require software or firmware, as the required

logic is integrated into the device. It has no user-adjustable parameters and

stores no data. The device cannot be accessed, altered, or adjusted through

any external connection.

o Specifications were provided for all of the components of the new products

that help to adequately characterize the new products. From an

engineering perspective, the information submitted regarding design and

principles of operation fully characterize the new products from an

engineering perspective.

o The new products have UL 1642 Certification for the battery cell reducing

the risk of fire and explosion. The devices also have short circuit protection.

The battery presents a minimal risk from an engineering perspective.

o The design minimizes the risk of poisoning by containing the e-liquid in a

manner that results in the e-liquid being inaccessible through customary or

reasonably foreseeable handling or use, consistent with the Child Nicotine

Poisoning Prevention Act of 2015. In addition, the e-liquid quantity is only

0.94 ml and it is contained in a sponge and is not free-flowing. Poisoning

presents a minimal risk from an engineering perspective. Although the

possibility of accidental exposure remains, these concerns have been

reduced by the product design (i.e., closed, pod-based, non-refillable

o

o

o

o

o

o

4

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)
Pa.ge 14 of 52 

TPL Review of PMTAs: PM0000630-PM0000631 Page 14 of 52 

system). In addition, post-market manufacturer reporting obligations wilt 

allow FDA to monitor and assess any issues with accidental exposure. 

o The new products have packaging components that could present a small

choking hazard if not properly disposed of. They have a silicon end tip side

cap and silicon mouthpiece side cap that are 9.2 mm in diameter. This risk is

being monitored by the applicant and no adverse experiences have been

recorded. Although this represents a potential concern, per the engineering

review, the risk is small and is being monitored by the applicant. Postmarket manufacturer reporting obligations will allow FDA to monitor and

assess any potential issues with accidental exposure.

o The new products do not have temperature control on the coil which could

result in elevated HPHCs under certain conditions ("dry puff"). These

conditions are that the atomizer fibers could deliver insufficient liquid to

heated zone, the e-liquid viscosity could be too high for wicking transport,

or an incorrect function of ASIC could cause over voltage at the atomizer.

This risk is being monitored by the applicant. This risk is minimal from an

engineering perspective.

o The new products have a coil resistance betwee O andEfil:DO with a

target of 0. The overall atomizer resistance is the same!JgO to[§! 0

which is a reasonable design of the atomizer.. The applicant does provide

data that demonstrates that the coil resistance meets the specification.

o The applicant performed a design failure modes and effects analysis

(dFMEA) for the new products. A risk assessment was completed by the

applicant to identify potential risks in the design of the product including

battery rupture. The engineering rev,ew concluded that the applicant's risk

assessment identified and Implemented control measures that adequately

mitigate foreseeable hazards.

• Chemistry:

o The source of nicotine is cross referenced to Tobacco Product Master Files

(TPMFs). According to the applicant, the nicotine used is extracted from

Nicotiona tobacum plant. Per the TPMFs fbl(4) I, the

nicotine specifications meet those in US Pharmacopeia monograph 41. The

new products contain nicotine salt (nicotine lactic acid).

o The 4.5% nicotine e-liquids contain 2.1% lactic acid, 40-44% (w/w)

propylene glycol (PG), and 42-44% (w/w) vegetable glycerin (VG). The 6.0%

nicotine e-liquids contain 3.2% lactic acid, 37-42% (w/w) PG, and 42-46%

(w/w) VG. With regard to nicotine salts in the new products, the applicant

used lactic acid to reduce e-liquid pH and protonate the nicotine to create a

nicotine salt. The applicant indicated the main purpose is to partition more

nicotine into the droplet phase of the aerosol for effective delivery and

palat<lbility. The applicant stated lactic acid is a weak acid naturally

occurring in the human body, is safe, and is able to vaporize during heating,

and compatible with the e-liquid formulation. Chemistry noted the nicotine

concentration and nicotine form are comparable between the new products

and the comparison ENDS product (leap Go Smooth Tobacco 5% nicotine

salts). Leap Go Smooth Tobacco 5% nicotine salts is in the same category

and subcategory (closed, non-rechargeable ENDS) as the new products.

Chemistry review found the applicant's justification for technical use of

(b)

(b) (b)

(b) (b)

n
Pa.ge 15 of 52 

TPL Review of PMTAs: PM0000630-PM0000631 Page 15 of 52 

lactic acid in the formulation acceptable. Toxicity from exposure to the 

ingredients including nicotine salt, was evaluated by toxicology; they had no 

concern based on the applicant's use of literature information and 

toxicology reference values. Regarding potential toxicity from lactic acid, 

toxicology evaluated estimates from the applicant for daily inhalation 

exposures to the new products. Toxicology estimated lactic acid to be 

fold and 370-fold lower than established toxicology reference values for a 

no-effect level in humans under acute and chronic periods of exposure, 

respectively. With this information and considering lactic acid is naturally 

occurring in the human body, toxicology concluded there was no concern 

from use of lactic acid in the new products. Further, as discussed in Sections 

3.3-3.6, the behavioral pharmacology review of clinical studies on the new 

products did not find any potential concerns in abuse liability specific to the 

nicotine salts that are used in the new products. 

o All PMTAs included single chemical and complex ingredient information for

e-liquids and the information is acceptable. All PMTAs included ingredient

information and extractables and leachables (E&l) study results for the

product structure materials that are in contact with e-liquids/aerosols. The

ingredient information and E&L study results did not raise concerns from a

chemistry perspective because chemistry concluded it is unlikely that

product characteristics negatively impact the aerosol constituent levels of

the new products as the aerosol constituent levels are significantly lower

than those of combusted cigarettes.

o The applicant provided uniquely identifying Information for materials and

ingredients for the CCS, and the Information ls acceptable from a chemistry

perspective. For all PMTAs, the applicant provided the material/Ingredient

quantities in percentages without providing the absolute quantity of the

materials/Ingredients. This llmltation does not Impact the outcome of this

review, because the applicant provided the time zero leachable data for all

bulk e-llqulds.

• Microbiology:

o The new products contain humectants (propylene glycol and vegetable

glycerin), which may impact microbial activity during product shelf life. The

stability of the new products is discussed in Section 3.2.1.3 of this review.

3.2.1.2. Manufacturing 

• Engineering:

o The applicant subcontracts the manufacturing of the products td

vlt4 · j

1t, • The applicant provided a description of 

.._,_ __________ _.___ the manuf-acturing process a tb .: including the manufacturing steps, 

the sources of the components assembled, the packing processes, and the 

associated quality control (QC) and safety mechanisms that are in place. 

10114• Then, the assembly is completed, and the product is packaged.

o The applicant states it audits thej tt>· ,, 11 of the 

suppliers and contract manufacturers periodically to ensure compliance 

with applicable internal and external standards and regulations. The 

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

3700-
16of 52 

TPL Review of PMTAs: PM0000630-PM0000631 Page 16 of 52 

cant supplied the relevant documentation for their including the 

documentation fo1 111'the information on the manufacturing 

steps and the quality control measures in place demonstrate that the 

products meet manufacturing specifications for the new products and that 

the products are manufactured in a consistent manner that minimizes the 

variability in product quality. 

o The above information submitted regarding the manufacturing process and

quality control measures is acceptable from an engineering perspective.

• Chemistry:

o The information submitted regarding manufacturing procedures for the new

product e-liquids and all e-liquids cartridge filling (by is

acceptable from a chemistry perspective. All PMTAs included

representative ingredient certificates of analysis (CoA), raw ingredient

quality control test results, batch verifications, liquid properties, and

constituent measurements.

o Quality control test data provided for all PMTAs are within the acceptance

criteria indicating batch consistency with respect to the provided e-liquid

properties. The applicant provided the test information (methods,

validation reports, and test laboratory quality management system) for the

lin-process and batch release testing and a valid laboratory 1509001

certificate for hat generates comparable data in quality compared to

ISO 17025 accredited laboratory for the targeted analysis. The

applicant provided pH and specific gravity acceptance criteria and included

specific gravity as a product quality measure for the new products

manufactured by The information provided demonstrated that each

new product's quality was controlled in a consistent manner and, therefore,

is acceptable from a chemistry perspective.

o The remote regulatory assessment (RRA) memo regarding inspections

stated that the RRA did not find any significant observations. The applicant

provided 22 exhibits, 14 of which address the chemistry relevant items

listed in the Firm Specific Package (FSP). All 14 exhibits were acceptable

from a chemistry perspective.

o The applicant provided "representative" data for in-process/batch release

testing and specifications for all PMTAs and the test information (test

methods, validation reports, and testing laboratory quality management

system) for manufacturing batches of the new products. There were minor

limitations in the testing results such as the slight difference between the

pH CoA specification range and the test data range. Chemistry found these

limitations negligible and not adversely impacting the batch release and

accepting testing. Overall, from a chemistry perspective, the data quality

information in the submission on in-process/batch release testing, liquid

properties, and constituent measurements demonstrates there is suitable

quality, data accuracy and reliability in test results, and therefore, the data

quality information provided by the applicant is acceptable from a chemistry

perspective.

• Microbiology:

o Bulk e-llquld manufacturers conduct e-llquid bl ending and fllling operations

by an A2LA ISO 17025:2005 certified laboratory, and an on-site

Page

appli

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

I (b)(4)

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

I (b)(4)

I (b)(4)

I (b)(4)

I (b)(4)

I (b)(4) I (b)(4)
17of 52 

TPL Review of PMTAs: PM0000630-PM0000631 Page 17 of 52 

laboratory, in an ISO and perform release

testing on the finished bulk e-liquids. The released finished bulk e-liquids are 

dispensed into nd sealed 

,...._ and shipped to the GMP certified ib I. to 

manufacture and package into finished new products. Ad 4'lsite, 

4 (ISO 9001:2015 

,...._ce_rti r-ei ---n,-p-ers-_on_n_e_,--sa_m_p-r-e_an t _ e,--st,

-

t:-r-e

-,,,-ni i-.-,-s e-rn-e ... w products

(organoleptic testing for e-liquids only). The new products that are 

compliant with NJOY specifications are released for shipment. This 

information submitted regarding manufacturing of the new products is 

acceptable from a microbiology perspective. 

3.2.1.3. Product stability 

• Chemistry:

o The applicant originally intended an I li-l shelf-life for finished

product, and shelf-life for bulk e-liquids. The applicant provided

complete stability study data including test data for bulk e-liquids, finished

product e-liquids, and aerosols; extractables and leachables data for

components and parts and CCS; the stability specifications; justifications for

the specifications; and justifications for bridging the bulk e-liquid stability

data from NJOY Daily Extra Rich Tobacco 6% nicotine to NJOY Daily Rich

Tobacco 4.5% product for sealed e-liquid shelf-life. In response to first cycle

deficiency, the applicant revised their intended shelf-life from I to 

I lb ,1 for all finished new products and the sealed bulk e-liquid in Extra 

Rich Tobacco 6% and from! b>W! tq ID 1

lfor sealed bulk e-liquid in 

Rich Tobacco 4.5%. All stability data show that the finished products (eliquids and aerosols) and bulk e-liquids in all PMTAs meet the stability 

specifications at the proposed shelf- life demonstrating that the shelf-life for 

finished products in all PMTAs is! 11, ,j whereas the shelf-life for sealed 

bulk e-liquids in NJOY Daily Extra Rich Tobacco 6% is! · 1>114J and for

NJOY Daily Rich Tobacco 4.5% i

l

1 · 41!

o The applicant provided homogeneity data demonstrating that the new

products remain homogeneous for up toj 0.11,! I during the! n, 411 

proces9 ,t>)c l

o For all PMTAs, one justification for bridging the bulk e•liquid shelf-life of

NJOY Daily Extra Rich Tobacco 6% nicotine to NJOY Daily Rich Tobacco 4.5%

is that the nicotine content in NJOY Daily Extra Rich Tobacco is the highest

(6.0%) and, therefore, is expected to generate the highest amount of

nicotine related substances (NRS). This justification is acceptable and is

supported by the bulk e-liquid stability data of the same flavor and of time

zero . Additionally, the specification of total NRS I lb 4 j μg/g) in 4.5%

nicotine content bulk e-liqu!d is lower compared to 6.0% nicotine content

bulk e-1,qulds I 11:1· .:,, μg/g) and thus, is not a concern.

• Microbiology:

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

bacterial communities change as a function of storage time. 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

(b)(4)

(b)(4)

(b)(4)

(b)(4)

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

(b)(4)

• _________ _,

(b)(4)

(b)(4)

(b)(4)

(b)(4)

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

(b)(4)

(b)(4)

(b)(4)

(b)(4)

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

n, 41 (b)(4) 1 

(b)(4)

(b)(4)

Page

s
Pa,ge 16 of 52 

TPL Review of PMTAs: PM0000630-PM0000631 Page 18 of 52 

(Chopyk et al. 2017; Djordjevic et al. 1993). The applicant provided stability 

testing data (water content, and total aerobic microbial count [TAMC)/ total 

yeast and mold count (TYMC)} that supports! \011,1 !of shelf life 

following new product storage at I o114 RH.Therefore, the data 

prov.ided are sufficient to demonstrate the microbial stability of the finished 

products over! 11, 1

3.2.1.4. Product test data 

• Engineering:

o The product performance testing provided demonstrates conformance with

the finished product release specifications set for the new products. The

applicant has provided adequate information to demonstrate that the new

products can be manufactured consistently and meet the manufacturer's

pre-defined quality controls and specifications, and they will operate

consistently throughout the life of the product.

• Chemistry:

o The aerosol HPHC yields of the new products are tested under intense and

non-intense regimens. There are significant reductions In HPHCs from the

new products' aerosols compared to combusted cigarette comparison data

under Intense and non-intense regimens.

o All analytical methods and valldatlons for chemical characterizations (of

e-aliqulds and aerosols) and product stability studies of all PMTAs are

sufficient to support the provided test data.

o The aerosol generation regimens (non-intense and intense) selected for all

PMTAs are appropriate and represent the range of emissions including the

emissions that could occur during heavy use of the new products.

o The constituents wrth increased yiefds in the new products relative to

combusted dgarette comparison data under both non-intense and intense

puffing regimens are discussed in Section 3.5.1.

• Toxicology:

o The toxicology review evaluated the increases of constituents in the

aerosols of the new products relative to combusted cigarette comparison

data noted by chemistry. The toxicology evaluation of the constituents with

increased yields in the new products relative to combusted cigarette

comparison data is discussed in Sections 3.5.1 and 3.7.1.1.

• Microbiology:

o Stability testing data (Water content. TAMC, TYMC) that supports [ili:Jl

I lb • llof shelf llfe were provided at time points (O.j tb. ••II and@:] 

l

•0114 ! following new product storage at I 1tJ1t4 % RH. From a

microbiology perspective, the provided stability testing is sufficient to

demonstrate the microbial stability of the products over the appllcantproposed shelf life oft ,t>JM l

o Endotoxln testing data at zero and! •t>lll I were provided for all new

products. All new products endotoxln content data are below acceptable

limits($ 0.5 EU/ml or $ 20 EU/device} as established by USP<l61> and

consistent with recommendations set out in FDA Guidance for Industry

(b)(4)

(b)(4)

(b)(4)

(b)(4)

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

(b)(4)

(b)(4)

(b)(4)

(b)(4)

(b)(4)

%
Pa£e 19oi 52 

TPL Review of PMTAs: PM0000630-PM0000631 Page 19 of 52 

3.2.2. Synthesis 

Pyrogen and Endotoxins Testing: Questions and Answers, June 

2012 (https://www.fda.gov/media/834 77 /download). 

o The information submitted regarding endotoxin content levels in the new

products is acceptable from a microbiological standpoint.

As TPL, I agree with engineering, chemistry, and microblology conclusions that these PMTAs 

contain sufficient information to characterize the product design and adequate 

manufacturing processes and controls to help ensure that the new products meet the 

manufacturer's specifications_ The product characterization Information submitted by the 

applicant fully characterizes the new products from an engineering, chemistry and 

microbiologlcal standpoint. 

The engineering review found that these PMTAs contain sufficient information to 

characterize the product design, composition, manufacturing, and test data. The 

engineering review concluded that the devices were designed and tested to minimize the 

risk of fire, explosion, and accidental poisoning. A small choking hazard for packaging 

components was identified as a potential concern; however, no adverse experiences have 

been recorded and it is being monitored by the applicant. Because the risk cannot be 

eliminated, this small choking hazard represents a limitation on the new product from an 

engineering perspective. This limitation represents a low risk and is not significant enough to 

raise a concern. Post-market manufacturer reporting obligations will allow FDA to monitor 

and assess any potential issues with accidental exposure. A risk assessment for design 

failure modes was performed by the applicant which strengthened the evidence that there 

is a reduced risk of product malfunction, as well as safety or regulatory concerns resulting 

from materials of construction, system interactions, specification tolerances, degradation, 

and others as discovered during the design failure modes and effects analysis (dFMEA) 

process. The microbiology information submitted for manufacturing and stability data was 

found to be adequate. The applicant-provided stability testing for T AMC and TYMC and 

supports I tb of shelf life for finished product, and the endotoxin testing data was 

found to be below USP acceptable limits as well as FDA Guidance for Industry Pyrogen and 

Endotoxins Testing. Stability specification and justifications for bridging the bulk e-liquid 

stability data from NJOY Daily Extra Rich Tobacco 6% nicotine to NJOY Daily Rich Tobacco 

4.5% product for sealed e-liquid shelf-life was found to be adequate by chemistry. For 

chemistry and microbiology, materials and ingredient information was adequately 

described. A notable feature of the product composition is the presence of nicotine salt 

(nicotine lactate). The applicant indicated the main purpose of creating the nicotine salt is 

for delivery of nicotine in the droplet phase of the aerosol for effective nicotine delivery and 

palatability. The applicant stated the creation of nicotine salt reduces the pH of the nicotine 

solution and aerosolized vapor resulting in less throat irritation for the user. The applicant 

indicated that lactic acid is a weak acid that is naturally occurring in the human body, is able 

to vaporize upon heating, and is compatible with the e-liquid formula. The comparison ENDS 

product Leap Go Smooth Tobacco 5% also contains a nicotine salt at a similar nicotine 

strength compared to the new products. Chemistry found the applicant's provided 

information (source, quantity, grade, form, and function) for use of the nicotine salt 

adequate. Toxicology had no concerns with use of nicotine lactate noting lactate is 

endogenously produced at low levels in the body and found the applicant's use of literature 

(b)(4)
Page 20of 52 

TPL Review of PMTAs: PM0000630-PM0000631 Page 20 of 52 

information and toxicology reference values for ingredients to be adequate and to show no 

significant increased risk. As discussed in the Abuse Liability Section 3.3.1.1 below, BCP 

assessed whether the high nicotine salt formulations in the e-liquids of the new products 

would facilitate initiation and use of ENDS with high amounts of nicotine. Based on the 

applicant's submitted clinical studies, the abuse liability of the new products is somewhat 

lower than combusted cigarettes. Therefore, the use of nicotine salt in the new products is 

not a concern for enhancing addiction liability any greater than the comparator tobacco 

product, combusted cigarettes. Manufacturing procedures information provided by the 

applicant showed that the new products have consistent quality control with only negligible 

limitations regarding e-liquid batch release specification. The chemical stability data that 

was provided by the applicant for the new products support the applicant's intended@] 

I tt• 41!shelf-life for the finished products and sealed bulk e-liquid in Extra Rich Tobacco 

6.0%, and the applicant's intendeq tb «1j shelf-life for sealed bulk e-liquid in Rich Tobacco 

4.5%. Microbiological stability testing data supports a I 0114 ! shelf life for the finished 

product. 

3.3. ABUSE LIABILITY 

3.3.1. Discipline key findings 

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

3.3.1.1. Current tobacco users 

• Behavioral and Clinical Pharmacology:

o '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.

o The behavioral and clinical pharmacology review evaluated two applicantsponsored clinical studies on the new products and literature bridging

information submitted in the application to the new products and

concluded that current tobacco users who use the new products in these

PMTAs are likely to be dual users of the new products and combusted

cigarettes. The review further concluded the new products may produce

lower nicotine exposure and subjective effects than combusted cigarettes.

This conclusion is based on results of an acute clinical study submitted by

the applicant measuring nicotine pharmacokinetic data and urinary

biomarkers of exposure (BOE) information.

o According to the behavioral and clinical pharmacology review, the new

products have an abuse .liability lower than combusted cigarettes among

experienced ENDS users. Together with the published literature, the

submitted data for the new products suggests that individuals will maintain

their nicotine dependence and will have a low likelihood of complete

cessation from tobacco products. Results from a clinical study involving

acute exposure to the new products suggest that the new products may

(b)(4)

(b)(4)

(b)(4)

(b)(4)
Page 21 of 52 

TPL Review of PMTAs: PM0000630-PM0000631 Page 21 of 52 

produce lower nicotine exposure and subjective effects than combusted 

cigarettes, suggesting lower abuse liability for these new products than that 

of combusted cigarettes. This conclusion is based on clinical testing of the 

new product, Extra Rich Tobacco 6% nicotine (PM0000631), which was 

tested for nicotine pharmacokinetics and biomarkers of exposure. Bridging 

information on the tested Extra Rich Tobacco 6% nicotine concentration 

product was provided by the applicant to approximate the concentration of 

plasma nicotine measured by area under the curve over 120 minutes for the 

untested Rich Tobacco 4.5% nicotine concentration (PM0000630) new 

tobacco product. Based on the bridging information provided, compared to 

the tested product, the untested product is assumed to have nicotine Cmax 

approximating 96%, mean nicotine AUC0_120min approximating 99%, and 

mean nicotine Tmax approximating 128% of the tested product. Because the 

untested product has the same or lower amount of nicotine as the tested 

product, it is expected to have a similar mean plasma nicotine exposure to 

the tested products. Collectively, the information from the tested product 

and bridged product suggests that abuse liability for these products would 

be lower than combusted cigarettes. Furthermore, with respect to the 

bridged product, the information suggests that abuse liability would be no 

higher than the tested 6% nicotine product. 

o Results from the applicant's clinical study involving acute exposure to the 

new products PM0000630 and PM0000631 suggest these products may 

have lower nicotine exposure than the representative ENDS that were 

tested. However, it is unclear how the abuse liability of the new products 

compares to other ENDS. 

o Published literature shows that e-liquids with nicotine salts, like the new 

products in PM0000630 and PM0000631, 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 et al., 

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

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

liability of the new products is lower than combusted cigarettes, mitigating 

concern of greater nicotine exposure (addiction potential) than combusted 

cigarettes among youth. 

3.3.2 Synthesis 

Clinical studies measured nicotine pharmacokinetics for the new product, Extra Rich 

Tobacco 6%, which was appropriately selected by the applicant to bridge to the lower 

nicotine containing product, Rich Tobacco 4.5%. The data from these studies 

demonstrated an abuse liability that approaches that of combusted cigarettes. A study 

was submitted by the applicant demonstrating use of the new products by combusted 

cigarette smokers who had past month experience using ENDS suggesting that abuse 

liability would be lower than or comparable to combusted cigarettes for experienced 

users. Results from the applicant's clinical study provided evidence that the new 

products may have lower nicotine exposure than comparative ENDS products. Since 

nicotine exposure from the new products did not exceed that of combusted cigarettes, 

this supports a lower abuse liability for users of the new products which may be 

beneficial to population health. In addition, given that the submitted clinical evidence 
Page 22 01 52 

TPL Review of PMTAs: PM0000630-PM0000631 Page 22 of 52 

on the new product Extra Rich Tobacco 6%, which was bridged to Rich Tobacco 4.5%, 

which collectively shows an abuse liability approaching that of combusted cigarettes, 

there is support for a potential benefit of smokers trying to switch to the new products. 

Studies have demonstrated that experienced users can attain higher plasma nicotine 

concentrations than inexperienced users (Farsalinos et al., 2015; Hiler et al., 2017); 

however, there is also evidence that inexperienced ENDS users may also achieve plasma 

nicotine levels similar to own brand cigarettes (Hiler et al., 2017; Lopez et al., 2016; 

Maloney et al., 2019; O'Connell et al., 2019). Taken together, the inherent risk of 

addiction of the new products appear to be no higher than other currently available 

tobacco products. As TPL, I agree with the behavioral and clinical pharmacology 

conclusions that, based on data from the applicant's studies and published literature, 

the abuse liability of the new products is likely sufficient to sustain dependence in 

already nicotine-dependent populations. 

3.4. USER POPULATIONS 

3.4.1. Discipline key findings 

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

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

  The applicant states the intended users of the new products are "current adult users

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

nicotine, particularly current combustible cigarette users and ENDS users." 

3.4.1.2. Current tobacco users 

  Social Science:

o Based on data submitted by the applicant, curiosity about using NJOY 

products in general was 8.3% among current adult smokers, which was 

greater than curiosity among former smokers (3.5%) and never smokers 

(5.1%). Regarding curiosity, specific to the new products, the curiosity of 

current adult smokers was 7.2% for Rich Tobacco and 6.0% for Extra 

Rich Tobacco. Curiosity among former smokers for Rich Tobacco and 

Extra Rich Tobacco was at 1.9% and 2.6% respectively. Curiosity among 

never smokers for Rich Tobacco and Extra Rich Tobacco was 1.2% and 

2.3% respectively. 

o Intention to try any of the new products in the next year was 5.2% 

among adult current smokers and greater than intention to try among 

former smokers (0.8%) and never smokers (0.5%). A similar proportion 

of current adult smokers intended to try Rich Tobacco (5.2%) and Extra 

Rich Tobacco (7.0%) 

  Behavioral and Clinical Pharmacology:

o Based on a survey study provided by the applicant and findings in the 

literature, current tobacco users who use the new products in these 

PMTAs are likely to be dual users of the new products and combusted 

cigarettes. 

o Based on the literature submitted by the applicant, current tobacco 

users may learn to titrate their use of the new products in these PMTAs 
Page 23 of 52 

TPL Review of PMTAs: PM0000630-PM0000631 Page 23 of 52 

to their preferred nicotine exposures over time, thereby maintaining 

their nicotine dependence. 

o Based on a limited survey study provided by the applicant and findings 

in the literature, current tobacco users are unlikely to switch completely 

to the new products in the current PMTAs. Additional details were 

reviewed by epidemiology (discussed below). 

o Clinical data provided by the applicant suggest the new products have 

abuse liability lower than, but perhaps approximating, combusted 

cigarettes among experienced ENDS users. Together with the published 

literature, this suggests users of the new products will maintain their 

nicotine dependence and have a low likelihood of complete cessation 

from tobacco products. 

  Epidemiology:

o The prevalence of the use of NJOY DAILY products was approximately 

0.3% among adults in the applicant's Adults Prevalence Study. Overall, 

ENDS use prevalence in the Adult Prevalence Study (3.2%) was lower 

but generally similar to estimated national prevalence of ENDS use in 

adults from the 2018 National Health Interview Survey (NHIS) (4.1%). 

Similar to the published literature, ENDS use, specifically NJOY DAILY 

use, among adults was more common in current than former and never 

smokers. The evidence showed that the proportion of adult combusted 

cigarette users who reported NJOY ENDS use is 2.3%. 

o Based on the data presented by the applicant, a large number of NJOY 

DAILY users (78.6% baseline will dual use with combusted cigarettes, 

which is higher than other ENDS product dual use patterns reported in 

the literature (43.5%-54.1%). While the NJOY User Study suggests there 

may be a reduction in combusted cigarette use seen by NJOY DAILY 

users, data from the literature is mixed (Berry et al., 2019; Benmarhnia 

et al., 2018; Adriaens et al., 2017; Gomajee et al., 2019; Jackson et al., 

2020; Sweet et al., 2019). Published literature also currently shows that 

many adult dual users will discontinue ENDS use over time (43.5%-

54.1%), and few (3.4-5.9%) will transition to ENDS only use (Coleman et 

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

o The applicant's estimates for current smokers completely switching to 

NJOY use at one month was 24.6%, three months was 26.5%, and six 

months was 39%, 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). In support of the PMTAs, the applicant originally submitted five 

observational studies. The applicant submitted a flavor analysis (Primary 

Outcomes cohort, n=2103) to address a deficiency identified in the first 

cycle review of the lack of evidence of NJOY DAILY products assisting 

current smokers switching to ENDS use. Among current smokers at 

baseline, 24% reported using Rich Tobacco as their initial flavor, which is 

higher than each of the individual non-tobacco flavored NJOY DAILY 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 24 of 52 

products . It was also found from the study that 23% of current smokers 

reported using Rich Tobacco as their most used flavor at baseline 

(calculations by FDA epidemiology reviewers). 

°

3.4.1.3. Tobacco Non-users (including youth) 

  Social Science:

o Overall, the data submitted by the applicant on reported curiosity and 

intention to try NJOY DAILY among adult never (5.1% and 0.5%, 

respectively) and former (3.5% and 0.8%) smokers suggest that former 

and never smoking adults are not interested in trying the new products. 

o Among youth (age 13-17), curiosity to try Rich Tobacco was 11.26%, 

which is lower compared to non-tobacco flavored NJOY DAILY products. 

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

students reported current ENDS 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., 2020). These published findings indicate risk of ENDS use 

among youth. However, youth are less likely to initiate tobacco-flavored 

ENDS and subsequently progress to regular use than with non-tobacco 

flavored ENDS. For instance, in Wave 1 of the Population Assessment of 

Tobacco Health (PATH) Study, which is a longitudinal and nationally 

representative study covering the time period 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 nontobacco 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 

(Rose et al. 2020). 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 54.9% 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 nontobacco 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 

6 "Rich tobacco" and "Extra Rich tobacco" refer to the applicant-provided characterizing flavor for PM0000630-631, 

respectively. FDA determined that no additional information regarding characterizing flavor was necessary. 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 25 of 52 

Philadelphia, PA found initial use of a non-tobacco flavored vs. nonflavored ENDS (which is a flavor category not defined by the authors) 

was associated with progression to current ENDS use as well as 

escalation in the number of days ENDS were used across 18 months 

(Audrain-McGovern et al., 2019). Finally, similar effects have been 

found in the PATH study among young adults (18-24 years), where "ever 

use" of non-tobacco flavored ENDS at Wave 1 was also associated with 

increased odds of current regular ENDS use a year later at Wave 2 

(Villanti et al, 2015). Collectively, these findings indicate that while all 

ENDS pose risks to youth, youth are less likely to initiate with tobaccoflavored ENDS and subsequently progress to regular use, than with nontobacco flavored ENDS. 

o For the new products, the proportion of youth reporting both curiosity 

about and intention to try the new products is higher than the 

proportion of adult current smokers (p< 0.05). However, the interest in 

tobacco flavor is low among youth according to the literature. The 

available evidence (NYTS 2021) indicates that a higher percentage of 

middle and high school current users reported using flavored ENDS than 

tobacco-flavored ENDS (Park-Lee et al., 2021). 

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

middle and high school users reported prefilled or refillable pods or 

cartridge device, and 53.7% used a disposable device as the ENDS 

device types they used most often. Sleek design, ability to use products 

discreetly, and user-friendly nature make pod mod products appealing 

among youth. Although the new products are not pod mods, they are 

sleek and small in design, and appear to be user friendly. Although there 

is some risk of youth uptake of these products, in general, tobaccoflavored 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 nontobacco 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 (Morean et al., 2018; Harrell et al., 2017; Groom et al., 

2020). Moreover, the evidence indicates that tobacco flavored ENDS are 

less likely to be used by youth who initiate with or regularly use such 

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

2020 Monitoring the Future (MTF) survey provide evidence that youth 

use of tobacco flavored ENDS is less common compared to other 

flavored ENDS including mint (Miech et al., 2021). According to the 2020 

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

12th graders while mint was the second most often used flavor (26.9%) 

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

o In addition, Social Science anticipates that the digital marketing and TV 

and radio restrictions recommended by OHCE will help to mitigate the 

risk of youth initiation. 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 26 of 52 

  Behavioral and Clinical Pharmacology:

o Based on a survey study provided by the applicant, minimal use of the 

new products in the current PMTAs was observed among youth and 

non-tobacco users. 

o Due to the lower abuse liability of these products compared to 

cigarettes, former and non-tobacco users (including youth) who initiate 

use of the new products are less likely to progress to regular use of the 

new products than products with higher addiction potential (e.g., 

cigarettes). 

o Although tobacco non-users including youth were not included in the 

applicant-submitted clinical studies, the comparably low abuse liability 

of the new products relative to combusted cigarettes suggests initiation 

and sustained use of the new products among tobacco non-users is 

likely to be lower than initiation and sustained use of tobacco products 

with greater abuse liability (e.g., combusted cigarettes). 

o 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 and 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 DAILY products is somewhat lower than combusted 

cigarettes, mitigating concern of greater nicotine exposure (addiction 

potential) than combusted cigarettes among youth. 

  Epidemiology:

o FDA and Centers for Disease Control and Prevention's analysis of the 

2020 National Youth Tobacco Survey (NYTS) data found that, 33.2% of 

high school ENDS users reported using NJOY brand products in the past 

30 days, and 16.4% of high school ENDS users indicated that NJOY was 

their usual brand. However, it is not known which specific NJOY 

products were used. Analysis of the 2021 NYTS found that NJOY brand 

products were no longer in the top five usual brands used by high 

school and middle school ENDS users. In regard to youth initiation, the 

applicant analyzed the 2019 and 2020 NYTS findings. The applicant's 

analysis of the 2019 NYTS, found that no respondents indicated that 

they had used the new products. They argue that this is consistent with 

their Youth Prevalence Studies, which found only two respondents 

reported using the new products in the past 30 days. The applicant 

further cites results from the 2020 NYTS in which 8 respondents 

reported both that NJOY was their most frequently used brand in the 

past 30 days and that they most commonly used disposable ENDS. This 

represents 0.055% of unweighted respondents using NJOY DAILY. The 

2019 NYTS demonstrated a preference for fruit, mint, and menthol 

products among high school and middle school aged users of ENDS. No 

specific NJOY product is specified in these analyses, and it was noted by 

the epidemiology review that any given brand preference is subject to 

change as the market changes. As previously discussed, however, the 

published literature shows that prevalence of youth use of tobacco-
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TPL Review of PMTAs: PM0000630-PM0000631 Page 27 of 52 

flavored ENDS is low and that tobacco-flavored ENDS are less likely to 

be used by youth who initiate or regularly use ENDS compared to nontobacco flavors. 

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

whether ENDS use and specifically use of the new products by youth 

and young adults leads to regular smoking. While the literature supports 

an association between ever ENDS use and initiation of ever using 

combustible cigarettes or past 30-day cigarette use in youth, the 

available evidence to-date does not adequately address whether ENDS 

use in youth and young adults leads to regular established cigarette 

smoking. Additionally, cigarette smoking is now at an all-time low 

among youth, which suggests that the impact of tobacco-flavored ecigarette use on youth current, established smoking is likely minimal. 

The applicant did not include any evidence regarding combustible 

cigarette initiation among youth following use of their products. 

3.4.1.4. Vulnerable populations (other than youth) 

  Social Science and Epidemiology:

o It is possible, based on the applicant's submitted data, that there are 

gender and race/ethnicity differences in intention to try NJOY DAILY 

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 NJOY than females. In addition, White 

and Black non-users were less likely to intend to try than Hispanic and 

'other' non-user race respondents. However, the applicant did not 

provide information on use of the new products among other 

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. 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., 2017; Hawkins et al., 2020; Obisesan et al., 2020; Wheldon and 

Wiseman, 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). 

  Behavioral and Clinical Pharmacology:

o No clinical studies were provided or reviewed by the applicant 

addressing use of the new products among 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 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 28 of 52 

tobacco-related diseases, or decreased cessation. Due to insufficient 

information, from a BCP perspective, the impact of the new products in 

these PMTAs on abuse liability and product use behavior in vulnerable 

populations other than youth is unknown. 

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

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

OHCE reviewed the relevant marketing submissions and drafted a consult dated 

February 24, 2022. 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 age-gating functionality to restrict access to adults"; 

  Maintaining Distributor and Retailer Policies that govern the selection and oversight
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TPL Review of PMTAs: PM0000630-PM0000631 Page 29 of 52 

of tobacco retailers that carry NJOY Daily products; 

  Prohibiting the sale of NJOY Daily 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 sales; 

  Requiring retailers to only place NJOY Daily 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" 

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 BCP, social science, and epidemiology reviews indicate that the applicant states that 

current adult users of nicotine-containing products including combusted cigarette smokers 

and ENDS users are the intended users for the new products. As TPL, I agree with the 

reviews that the applicant has identified intended users to be adult users of nicotinecontaining products, particularly current combustible cigarette users and ENDS users. In 

making the APPH determination, it is important to understand population effects such as 

behavioral intentions, perceptions of harm and addiction, actual product use from clinical 

study, and the potential for switching from combusted cigarettes to the new products as 

well as potential for discontinuation from tobacco products. Effects on non-tobacco users 

including youth and vulnerable populations are also important to understand in a 

determination if the new products are appropriate for the protection of public health. 

To address how the new products are used by current smokers, the applicant conducted 

analyses from their study, "Additional Flavor Analysis". Current smokers were those who 

reported smoking combusted cigarettes during the past thirty days. Switching was assessed 

as the percentage of current smokers at baseline who became former smokers at one, two, 

three, and six months, respectively. Former smokers were those who either self-identified 

as a former smoker (baseline measure) or who reported no smoking during the past thirty 

days [30-day point prevalence abstinence (PPA)] at follow-up. A limitation to the study was 

that the applicant's analysis of switching did not provide information whether the 

participant was currently using NJOY DAILY. There was no way to distinguish between 

complete switching (cessation of combusted cigarettes and continued ENDS use) and 

cessation of combusted cigarettes while also discontinuing NJOY DAILY. However, the 

applicant reported that at three months, 35% of current smokers at baseline had 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 30 of 52 

transitioned to former smokers, and at six months, 48% of current smokers at baseline had 

switched to former smokers. These data show a possible benefit from the use of the new 

products in adult current smokers. To further estimate measures of change in smoking 

status, the applicant used different types of analyses on missing outcomes and showed that 

11.9-13.5% of everyday users and 26.3-32.3% of somedays users of the new products 

achieved 30-day PPA. According to the epidemiology review, these results are higher than 

what is typically reported in the literature for estimates of switching (3.4-5.9%) from other 

tobacco products to ENDS tobacco products and concludes the discrepancy is related to 

issues of study design. 

Similar to the published literature on ENDS use, use of the new products among adults was 

more common in current smokers than former and never smokers, and as the prevalence 

data in the application suggests, initiators are more likely to be current or former users than 

never users. Some of this could be due to cohort effects or generational differences in the 

marketplace when most adults initiated tobacco use. Overall, epidemiology found that the 

applicant presented several different measures of the association of the tobacco-flavored 

new products with smoking behaviors, including switching. Switching was defined as the 

percentage of current smokers at baseline who became former smokers at one, two, three, 

and six months. The measures of switching did not account for whether the participant was 

currently using the new products; therefore, the estimates did not distinguish between 

complete switching (cessation of combusted cigarettes and continued ENDS use) and 

cessation of combusted cigarettes while also discontinuing the new products. In addition, 

there was significant loss to follow-up. Despite limitations detailed in the epidemiology 

review, there was evidence of switching from current cigarette smokers to Rich Tobacco 

flavor NJOY DAILY product as assessed by z-tests and logistic regressions. Based on the 

applicant's User Study report, the percentage of baseline current smokers who reported 

former smoking and switched to NJOY DAILY Rich Tobacco product at one month was 24.6%, 

two months 38.6%, three months 26.5%, and six months 39.0%. 

The 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 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). The applicant asserted that a very small proportion of youth who use 

ENDS reported NJOY as their preferred brand citing the 2019 and 2020 NYTS, and therefore, 

youth use of the new product poses a minimal public health risk. The applicant's analysis of 

the 2019 NYTS found that no respondents indicated that they had used the new products 

which are tobacco flavored. The applicant states this is consistent with their Youth 

Prevalence Studies, which found only two respondents reported using the new products in 

the past 30 days. The applicant further cites results from the 2020 NYTS in which 8 

respondents reported both that NJOY was their most frequently used brand in the past 30 

days and that they most commonly used disposable ENDS. However, as noted in the 

epidemiology review, the popularity of any given brand is subject to change as the market 

changes. 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 31 of 52 

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 tobaccoflavored ENDS are less likely to be used by youth who initiate or regularly use ENDS 

compared to flavored ENDS. 

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. Accordingly, I 

recommend that the MGO letter include additional marketing requirements and 

recommendations. 

The evidence summarized ln this section describes relatively high interest among smokers in 

using tobacco-flavored products generally. Although nicotine delivery is lower than for 

cigarette smoking, available evidence indicates that experienced ENDS users can increase 

nicotine uptake compared to inexperienced users, which increases the likelihood of 

switching. Use of these products could :benefit smokers who switched completely or 

substantially reduced their cigarette smoking. The available information also shows that 

youth appeal/uptake of tobacco-flavored ENDS products is generally low among youth. 

Overall, I agree that the possible benefit of the new products to adult smokers is significant 

enough to overcome the risk to youth. 

Consistent with the epidemiology review, the behavioral and clinical pharmacology review 

suggests that current tobacco users are unlikely to switch completely to the new products. 

However, the applicant's data show that some smokers may completely switch. The 

behavioral and clinical pharmacology review concluded that, based on the submitted clinical 

study data, the new products do not have an abuse liability exceeding combusted cigarettes 

and that users of the new products w!II maintain their nicotine dependence and wlll have a 

low likelihood of complete cessation from tobacco products. As TPL, I agree with the 

conclusions of epidemiology, behavioral and clinical pharmacology. 

3.5. TOXICANT EXPOSURE 

3.5.1. Discipline key findings 

The following key findings were provided In discipline reviews. 

3.5.1.1. Toxicity 

• Overall, there were significant reductions in aerosol HPHCs tested using the new

products with their corresponding e-liquids (PM0000630, PM0000631) which had

been stored for up tol ,: 11-t ·I compared to cigarette comparison data under both 

non-intense and intense puffing regimens. Toxicology evaluated the applicant's 

submitted data on HPHC yields for the new products, combusted cigarettes, Leap 

Go Smooth Tobacco 5% nicotine salt, and other ENDS products. In the new 

products, compared to combusted cigarettes, HPHC increases for chromium, nickel, 

nicotine, PG, and VG are offset by HPHC decreases for acetaldehyde, diacetyl, acetyl 

propionyl, acroleinj 1r.x4 formaldehyde ID 1

1 and ethylene glycol, and 

are unlikely to raise toxicology concerns for users of the new products compared to 

average combusted cigarette yield. In comparisons of aerosols from the new 

products to the applicant's selected ENDS comparator product, Leap Go Smooth 

(b)(4)

(b)(4) (b)(4)
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TPL Review of PMTAs: PM0000630-PM0000631 Page 32 of 52 

Tobacco 5% nicotine salt, the HPHCs are comparable. In addition, all the nicotineadjusted HPHC yields (i.e., HPHC:nicotine ratios) were similar or decreased in the 

aerosols of the new products compared to average HPHC:nicotine ratios for other 

ENDS products {i.e., pod, and tank systems). Overall, these comparisons 

showing similar or reduced exposures to HPHCs from the new products do not raise 

toxicology concerns. 

3.5.1.2. Biomarkers of exposure (BOE) 

• BOE data submitted from a survey study conducted by the applicant found that

participants who had recently used only the new products had lower levels of the

measured BOE (i.e., CO, cotinine, CEMA, 3-HPMA, and NNAL) relative to recent

users of the new products and combusted cigarettes (i.e., dual users).

• ThE.' publishE.'d llterature suggests combusted cigarette smokers will likely experience

significant reductions in volatile organic compound (VOC} exposure upon complete

switching to ENDS (Gomewkz et al., 2017; Oliveri et al., 2020; Round et al., 2019).

The applicant did provide yields of some voe HPHCs (e.g., acrylonltrlle, benzene,

propylene oxide, toluene) using mainstream smoke (MS$) concentration data

derived from peer-reviewed scientific literature to represent the combusted

cigarette category and the levels of these voes from the new products. Overall, the

differences show lower levels of these voe yields from the new products compared

to the combusted cigarette MSS data.

• Heavy metal exposure is likely to stay the same or decrease upon complete

switching to ENDS (Goniewicz et al., 2018; Jain, 2019; Prokopowicz et al., 2019).

Dual users who do not significantly reduce combusted cigarette use will likely have

comparable tobacco-specific nitrosamine (TSNA) and voe BOE as combusted

cigarette smokers, or if cigarette use -is reduced, they may experience low to modest

reductions in these BOE (Pu Ivers et al., 2018).

• Changes in BOE and the associated health risks of dual use of cigarettes and the new

products In the PMTAs have not bE.'en evaluated in longitudinal studlE.'S or under

extended exposurE.' conditions, thus con cl us Ions on such long-term health risks

cannot be made at this point

3.5.2. Synthesis 

The toxicology review concludes that the majority of HPHC yields measured in the aerosols 

of the new products were decreased compared to literature-reported yields from 

combusted cigarettes, ENDS products of the same category (disposable ENDS) and 

subcategory (closed e-cigarette), and other ENDS products from different categories (i.e., 

cig-a-like, pod, and tank systems). NNK and NNN as well as volatile organic chemicals 

(acrylonitrile, benzene, propylene oxide, and toluene) were reported for the average 

combusted cigarette comparison product, however, these HPHCs were below the limit of 

detection or not quantifiable in the aerosol of the new products. Other HPHCs and toxicants 

such as acetaldehyde, diacetyl, acetyl propionyl, acroleinJ ll• -JL formaldehyde, 

j ll114 j and ethylene glycol yields in the aerosols of the new products were 65.3-100%

lower than average combusted cigarette smoke under both intense and non-intense puffing 

regimens. llt 4J and therefore, it -is 

unknown as to why it was detected in the aerosol of PM0000631. Diacetyl was not 

quantifiable but detected in PM0000630. The applicant provided supporting literature and 

(b)(4)

(b)(4)

(b)(4)

cig-a-like,
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TPL Review of PMTAs: PM0000630-PM0000631 Page 33 of 52 

analysis that indicates exposure to diacetyl from NJOY DAILY is at least two orders of 

magnitude lower than exposure to diacetyl from combusted cigarettes, and therefore, 

would represent a reduction in risk from acute exposure to diacetyl. In addition, the 

applicant demonstrated that the average of the 951h percentile of exposure to diacetyl from 

the new product (PM0000631) is several hundred fold lower compared to the average level 

of diacetyl documented in the literature for other comparator ENDS products including, heat 

not burn, tank fixed power, and tank variable power devices. Diacetyl was not quantifiable 

but was detected in the applicant's ENDS comparator Leap Go Smooth 5%. However, based 

on the applicant's risk evaluation and comparisons demonstrating higher levels of diacetyl 

from combusted cigarettes and other ENDS products compared to the new products, and 

considering that diacetyl is not added as such to the new products, toxicology concluded the 

low level of diacetyl detected in the aerosol of testing PM0000631 to be acceptable. Metals 

and humectants, chromium, nickel, nicotine, PG and VG yields were increased in aerosols of 

the new products compared to combusted cigarettes. However, the applicant's risk 

evaluation was found to be adequate in the toxicology review with no concerns. Overall, 

comparison of combusted cigarette smoke to the new products showed that combusted 

cigarette smoke has a higher number of HPHCs and many of the HPHCs present in cigarette 

smoke have comparatively higher potencies than HPHCs in the aerosols of the new 

products. In addition, compared to combusted cigarettes, the HPHC increases in the new 

products for chromium, nickel, nicotine, PG and VG are offset by HPHC decreases for 

acetaldehyde, diacetyl, acetyl propionyl, acrolein,! I, formaldehyd ·l>M'J 

and ethylene glycol, and are unlikely to raise toxicology concerns for users of the new 

products compared to average combusted cigarette yield. Comparisons of HPHC yields from 

the new products and the applicant's selected ENDS comparator product as well as other 

ENDS from different product categories, showed the aerosols from the new products have 

slmllar or reduced levels of HPHCs. Blomarkers of exposure (BOE) data were submitted from 

a survey study conducted for subjects that recently used only the new products. These 

subjects had lower levels of the measured BOE (I.e., CO, cotinine, CEMA, 3-HPMA, and 

NNAL) relative to recent users of both the new products and combusted cigarettes (i.e., dual 

users). 

I agree with the conclusion that available toxicological data, the demonstrated reductions In 

measured HPHC levels, other toxicants, and the reductions in measured BOEs indicate the 

potential for a relative benefit compared to cigarette smoking for smokers who completely 

or partially switch to the new products. 

3.6. HEAL TH EFFECTS 

3.6.1. Discipline key findings 

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

3.6.1.1. Toxic.ology 

• Aerosols from the new products and the ENDS comparison product, Leap Go Smooth

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

IVGT cells), nor cytotoxic (NRU assay) potential at the concentrations and under the

conditions tested. However, under the conditions tested, the combusted cigarette

comparison product, 1R6F Reference cigarette, showed significant mutagenicity,

cytotoxicity, and genotoxicity.

(b)(4) e (b)(4)
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TPL Review of PMTAs: PM0000630-PM0000631 Page 34 of 52 

• The applicant submitted a hazard analysis for In vitro studies comparing HPHCs (aB I tt> '

1

!tol tb llambient anq 11,.•,1jaccelerated versus! 1Dir1Jjambient) and

leachable compounds (at! ,n· ltol 1b· 41( to HPHCs and lea cha bl es compounds

a

11>1,1 {which were used In the in vitro studies), and used a toxicology literature

review to compare the hfghest Ineffective dose (HID) and the lowest effective dose

(LED) for Ames test and lvMN studies to the stability testing HPHC concentrations. Based

on relative stability of e-llqulds up to! 1>1t4 of storage under various conditions,

and lack of mutagenicity, cytotoxlcity, and genotoxlcity at! tt, L the in vitro study

hazard analysis of aerosol from the new product e-liquids stored for up tol •0114 j

under various conditions is acceptable from a toxicological perspective.

3.6.1.2. Bioresearch Monitoring (BIMO) inspection findings 

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

were not considered pivotal, and the reported adverse experiences (AEs) did not raise 

clinically significant concerns 

3.6.1.3. Addiction as a health endpoint 

• Results from a clinical study provided by the applicant suggest that the new product

in PM0000631 produced statistically significant lower area under the curves (AUCs)

for nicotine exposure compared to combusted cigarettes, indicating lower nicotine

exposure. However, overall, the data suggest that the abuse liability of the new

products is likely sufficient to sustain dependence in nicotine-dependent

populations.

• Based on a survey study provided by the applicant and findings in the literature,

current adult cigarette smokers may maintain their nicotine addiction severity via

dual use of the new products and combusted cigarettes and are unlikely to quit

using tobacco products overall.

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

concentrations (Caldwell et al., 2012; Omaiye et at., 2019; Prochaska and Benowitz,

2019; Talih et al., 2019) and may facilitate use and progression to regular use by

naTve users such as youth. However, based on data from the applicant submitted

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

lower than combusted cigarettes, mitigating concern of greater nicotine exposure

than combusted cigarettes among youth.

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

• Epidemiology:

o Users vs. Never Users: The a pp lie.ant 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

bias due to loss to follow-up, and the fact that most results are unadjusted

for potential confounding factors. Due to these limltations, the published

(b)(4)

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

(b)(4)

(b)(4)

(b)(4)

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

(b)(4) t
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TPL Review of PMTAs: PM0000630-PM0000631 Page 35 of 52 

literature provides a better source of information on potential health 

effects. There is currently some epidemiologic evidence suggesting 

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

cardiovascular disease, respiratory disease, 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 adjusting 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. 

o Battery-related adverse experiences and e-liquid nicotine poisonings are 

serious issues that have been reported with certain ENDS products. The new 

products have UL 1642 Certification for their integrated battery cells; 

battery cells that comply with UL 1642 have a reduced risk of fire and 

explosion. With respect to potential for e-liquid poisoning from the new 

products. Per the applicant information and engineering review, the new 

products are a closed system and non-refillable device or serviceable. 

Therefore, by design the risk of poisoning is comparably low. Another health 

risk is that ENDS users may have higher exposure to some chemical 

constituents such as VOCs than do non-tobacco users. 

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

users have been found to have higher levels of certain biomarkers of 

exposure associated with combusted cigarette use, including nicotine and 

its metabolites, compared to combusted cigarette smokers. This 

information is useful for discerning some biomarkers of exposure associated 

with dual use of ENDS and combusted cigarettes relative to users who 

completely switch to ENDS from combusted cigarettes. 

o 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 to ENDS, but levels of 

all other biomarkers significantly decreased after one week of using ENDS. 

Further information on possible short-term benefits of switching from 

combusted cigarettes to ENDS can be seen in published literature showing 

that ENDS users have lower levels of exposure to some constituents 

including TSNAs than combusted cigarette smokers. 

  Medical:

o Overall, the applicant submitted clinical studies which provided limited 

data to evaluate the short and long-term health effects of NJOY DAILY 

products. The applicant did not measure biomarkers of potential harm in 

any of the submitted studies. 

o Clinical studies submitted by the applicant did not identify short or longterm health effects specific to the NJOY products. The studies have small 

sample sizes and relatively short time periods of product exposure, limiting 

the generalizability of the health effects data to larger user populations 

and extrapolation of the long-term health effects of the NJOY products. 

Despite these limitations, the applicant's data and published literature 

suggest that adult smokers who switch to these products (either 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 36 of 52 

completely or with a significant reduction in cigarette consumption) would 

benefit from reduced exposure to many HPHCs. 

o Limitations of the applicant's literature review included lack of NJOYspecific data and inclusion of ENDS products with various chemical 

compositions and testing methods with no rationale for bridging health 

effects data. 

o Based on review of the literature submitted by the applicant, the impact of 

ENDS use on cardiovascular disease, cancer, respiratory outcomes, 

developmental, and reproductive health outcomes, oral health, mental 

health, and other health topics are mixed and largely inconclusive. The 

risks of injury and poisonings have been consistently reported in the 

literature; however, no specific reports of serious injury related to use of 

the new products were identified. 

o The applicant provided limited data on biomarkers of potential 

harm; the information provided did not inform the health effects 

assessment. 

o There were no deaths, serious adverse experiences (AEs), or 

discontinuations due to AEs reported in the clinical studies. A few AEs 

associated with the new products were reported; those reported were 

found by the medical reviewer to be possibly related to the study product. 

Light headedness, mild nausea and vomiting were reported in one clinical 

study and no AEs in another study sponsored by the applicant. Reported 

AEs for the comparison products in the clinical studies were related to mild 

neurological (e.g., light headedness) or gastrointestinal symptoms (e.g., 

nausea, vomiting). No safety concerns were identified in these studies. 

3.6.1.5. Likelihood and effects of product misuse 

o Behavioral and Clinical Pharmacology: 

o The new products are closed, disposable "cigalike" ENDS with nonadjustable power settings. These device characteristics reduce the 

likelihood that users will manipulate ENDS device settings and e-liquid 

constituents, including nicotine. As discussed in the product design and 

composition section (see Section 3.2.1.1), the engineering review concluded 

the new products have UL 1642 certification for the battery cell and the 

devices have short circuit protection reducing the risk of fire and explosion. 

Regarding accidental e-liquid nicotine poisoning, the engineering review 

concluded the design of a closed pod-based, non-refillable system 

minimizes the risk of poisoning because the system is inaccessible through 

customary or reasonably foreseeable handling or use (see Section 3.2.1.1). 

o Design features of the new products make "stealth vaping" possible (i.e., 

discreet use of ENDS such as inhaling deeply to avoid forming visible aerosol 

clouds or swallowing of aerosol during exhalation) and based on findings in 

the literature, this behavior can influence nicotine and toxicant exposure. 

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

provide data evaluating the likelihood of misusing NJOY DAILY products. 

o Despite the lack of clinical data assessing product misuse, BCP concludes 

that the likelihood of misuse is low for NJOY DAILY products because they 

are closed-system ENDS. NJOY DAILY power settings are non-adjustable, and 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 37 of 52 

the e-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. 

3.6.1.6. Adverse experiences 

o Engineering: 

o The applicant supplied the consumer complaints (adverse experiences) for 

the new products for the calendar year 2020. The engineering related 

adverse experiences were reviewed and they were not significant or 

serious. 

o Medical: 

o There were no deaths, serious adverse experiences, or discontinuations of 

use due to AEs reported by the applicant in the two clinical studies. 

o Thirteen AEs were reported in the clinical studies. Eleven AEs were 

described by the applicant as mild and two were moderate. All AEs 

resolved prior to the end of the study. 

o Overall, gastrointestinal AEs were the most commonly reported and 

were consistent with the AEs reported in the literature related to 

nicotine intake. 

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 and were mostly minor in severity. 

o Analysis of FDA's Safety Reporting Portal data was performed on 

09/20/2020 with search inclusion dates 01/01/2014 to 09/21/2020, and a 

second search performed 02/02/2022 with search inclusion dates 

09/01/2020 to 01/31/2022. There were five reports related to NJOY 

products: one seizure while driving, one pulmonary embolism, one serious 

lung injury, and two respiratory issues (coughing and productive 

cough/sore throat). Product details were scant in the reports; hence it was 

unclear which NJOY ENDS products were used, the nicotine content or 

flavor of the products, and if the products were used in combination with 

other products. No definitive adverse experiences related to NJOY DAILY 

could be identified from the provided information. 

o Nine AEs were reported with the consumer report data provided by the 

applicant. One case of chest pain and one incident of difficulty breathing 

were reported by the applicant but were reported as non-serious 

experiences. Three reports of non-serious burns related to NJOY DAILY 

were reported by the applicant. 

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

specifically ENDS, or vaping, product use-associated lung injury (EVALI), 

seizures, and overheating/fire/explosion-related thermal burn injuries 

(OH/F/Exp): 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 38 of 52 

3.6.2. Synthesis 

o 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

foundational clinical studies and there did not appear to 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, FDA is interested in evaluating any additional

information related to respiratory illness in association with ENDS and

specifically the new products.

o There were no seizures reported as an AE in the applicant-submitted

clinical studies. One seizure was reported with NJOY products in FDA's

Safety Reporting Portal. However, it is unclear which NJOY ENDS products

were used with the provided reports. While this data is insufficient to fully

evaluate the potential association of the new products with seizures, FDA

is interested in monitoring an on.going evaluation of this potential health

consequence of ENDS use.

o No OH/F/Exp were reported in the PMTAs. Three reports of non-serious

burns related to NJOY DAILY were reported by the applicant. 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.

As TPL, I agree with the toxicology review that the aerosols of the new products have an 

overall lower level of toxicants and HPHCs compared to combusted cigarette.s. Comparison 

toxicity testing demonstrated the aerosols to be less toxic under the conditions tested 

compared to the research 1R6F combusted cigarette. The aerosols of the new products and 

smoke from a research combusted cigarette comparator were tested in short-term studies 

using in vitro mutagenicity, cytotoxicity, and DNA damage assays with and without 

metabolic activation. The results convincingly showed that the combusted cigarette 

comparator was more toxic than the new products. After! it>: «Jj storage, the 

from the new products showed a lack of genetic toxicity potential. Genetic toxicity is a 

commonly used toxicity endpoint used under short-term exposure conditions to help 

predict chronic cancer hazard potential. No long-term toxicology studies were submitted in 

the application. 

As TPL, I also agree with the behavioral and clinical pharmacology review which concluded 

from clinical studies that the addiction potential when assessing AUCs for nicotine exposure 

of the new product (PM0000631) is lower than that of combusted cigarettes. Bridging 

information provided by the appllcant for the untested new product (PM0000630) 

suggested that the nicotine exposure could be as high as, but no higher than, the tested 

product. The basis for this suggestion is that the nicotine concentration is lower in the 

bridged new product (4.5%) compared to the tested new product (6%). This conclusion is 

based on acute clinical pharmacokinetic data and biomarkers of exposure in which the 

findings overall suggest the new products would support nicotine-dependence for users 

who choose to completely switch from combusted cigarettes to the new products. 

(b)(4) e-liquids
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TPL Review of PMTAs: PM0000630-PM0000631 Page 39 of 52 

In an applicant-sponsored clinical study, biomarkers of exposure (e.g., CO, cotinine, CEMA, 3 

HPMA, and NNAL) were found at lower levels in users of the new products compared to 

dual users of the new products and combusted cigarettes. No biomarkers of harm were 

measured or reported in the applicant-sponsored clinical studies. No applicant-sponsored 

long-term clinical studies on addiction liability were submitted in the application. 

The applicant provided limited data on observational health outcomes from an 

epidemiological standpoint, and there are no data in the literature regarding long-term 

health effects of NJOY DAILY specifically. 

The medical review noted limitations with the applicant's sponsored studies in terms of the 

small sample size and short-term period of exposure. In addition, the medical review noted 

a lack of NJOY DAILY specific clinical data in the application. Although the applicant included 

assessment of various chemical compositions of other ENDS products, there was no 

rationale to bridge the information to the new products. The medical review also pointed 

out that based on literature findings, the impact of ENDS use on cardiovascular disease, 

cancer, respiratory outcomes, developmental, and reproductive health outcomes, oral 

health, mental health, and other health topics are mixed and largely inconclusive. The 

medical review indicated that the applicant reported non-serious burns in the provided 

consumer reports. As noted by epidemiology, battery-related adverse experiences and eliquid nicotine poisonings are serious issues that have been reported with certain ENDS 

products. However, as discussed in the product design and composition section (see Section 

3.2.1.1), the engineer review concluded the new products have UL 1642 certification for the 

battery cell and the devices have short circuit protection reducing the risk of fire and 

explosion. Regarding accidental e-liquid nicotine poisoning, the engineering review 

concluded the design as a closed pod-based, non-refillable system minimizes the risk of 

poisoning because the system is inaccessible through customary or reasonably foreseeable 

handling or use (see Section 3.2.1.1). 

Overall, there is a lack of available data to demonstrate a comprehensive health effects 

profile from chronic use of the new products. From a chemical toxicology standpoint, there 

is potential that use of these new products, along with significant reduction or quitting 

cigarettes, will result in a reduction in exposure to many HPHCs. This benefit will likely be 

greater for smokers who are able to switch completely to the new products. However, the 

applicant's switching studies did not assess the effects of long-term use and the impact of 

dual use which would be more likely to occur in real-world conditions. There are limited 

data about the long-term health effects of ENDS from large clinical studies or long-term 

epidemiological studies. In addition, the study design limitations (e.g., small sample size, 

generally healthy participants, short exposure periods) in the published literature make it 

difficult to draw definitive conclusions related to health effects of ENDS, specifically the new 

products. Therefore, the long-term health effects of completely switching to the new 

products and potential short and long-term health effects from dual use of the new 

products with combusted cigarettes could not be evaluated. However, based on available 

information, as TPL, I agree that adult smokers who switch to these products (either 

completely or with a significant reduction in cigarette consumption) could benefit from 

reduced exposure to many HPHCs. While the effects of dual use were not assessed, 

significant reductions in systemic exposures after short-term switching and the available 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 40 of 52 

evidence suggest that daily use of the new products with concomitant reduction in CPD may 

provide health benefits from a harm reduction perspective in terms of reducing exposure to 

HPHCs relative to continued use of cigarette smoking alone. 

From the standpoint of findings from clinical testing of the specific new products, I agree 

with the medical conclusion that there is inconclusive information for long-term health 

effects due to the limitations of clinical studies and lack of such specific information on NJOY 

DAILY products. Although adverse experiences (AEs) were reported in the applicantsponsored clinical studies and possibly related to the NJOY products, there were few and 

they were mostly mild involving gastrointestinal (e.g., nausea, vomiting) and neurological 

symptoms (e.g., headache and lightheadedness). Two AEs of moderate severity were 

reported, 1 per study. No serious AEs or deaths were reported in any of the applicant 

sponsored short-term clinical studies. Due to the product design as a closed ENDS product, 

there is minimal risk for accidental ingestion of the e-liquids. The applicant provided minimal 

information on observational health outcomes and the literature is limited regarding longterm health effects of use of NJOY DAILY products and other ENDS products. However, the 

epidemiology review points out that there is some epidemiologic evidence suggesting 

associations between ENDS use and some health outcomes including cardiovascular disease, 

respiratory disease, and oral health. 

For dual users of ENDS and combusted cigarettes, certain biomarkers of exposure may be 

similar or higher compared to combusted cigarette smokers. There is published literature 

reporting short-term benefits of switching from combusted cigarettes to ENDS with users 

showing lower levels of toxic and carcinogenic constituents such as tobacco specific 

nitrosamines. In the nonclinical testing, the toxicology endpoints measured are not 

indicators or predictors of short-term health effects. Genetic toxicity is designed to help 

predict cancer hazard and therefore, does not align with the AEs reported in the short-term 

clinical study. However, genetic toxicity assessment is accepted to understand carcinogenic 

potential of substances and products since DNA damage is the measured endpoint. The new 

products did not induce the DNA damage seen in the comparator combusted cigarettes in 

the studies conducted. 

As TPL, I agree that the nonclinical data suggest that use of the new products have the 

potential to have better outcomes for genetic damage compared to smoking combusted 

cigarettes. Given the lack of health effects information for long-term use and exposure to 

the new products, I agree with the medical review that, for the marketed new products, 

post-market reporting is needed to further monitor and evaluate potential health effects 

including EVALI, seizures, and OH/F/Exp. 

3.7. POPULATION AND PUBLIC HEALTH 

3.7.1. Discipline key findings 

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

3.7.1.1. Toxicology 

  The applicant provided a risk assessment for ingredients in the e-liquids of the new

products (PM0000630, PM0000631), HPHCs in the aerosol for the new products, 

leachables and extractables for the new products, and alternative exposures 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 41 of 52 

(secondhand exposure to NJOY DAILY aerosol; oral and intentional ingestion of NJOY 

DAILY e-liquids; and incidental and accidental dermal exposures to NJOY DAILY). 

  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 DAILY, the potential health risks are likely to be similar (to use 

of other ENDS) or reduced (compared to combusted cigarettes) when compared to 

continued exclusive use of those tobacco products. In addition, secondhand 

exposures to HPHCs from ENDS aerosol is 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 means using these new products 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 depending on 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 other ENDS products, such as the comparison 

product, Leap Go Smooth Tobacco 5%, and other pods, cig-a-likes, and tank 

systems. 

3.7.1.2. Population health impact (PHI) model 

  The data inputs used in the population health modeling scenarios for ENDS use

generally and NJOY DAILY use specifically 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 particularly informative to the overall 

assessment. 

3.7.2. Synthesis 

As TPL, I agree with the toxicology conclusions that switching completely from use of 

combusted cigarettes to use of the new products will result in the greatest reduction in 

HPHC exposures. Dual use of combusted cigarettes and the new products or dual use of 

other ENDS and the new products would also likely result in decreases in HPHC exposures 

overall. Limited chronic inhalation toxicity data for the product ingredients are available in 

the public domain. However, the applicant assessed published toxicological studies to 

provide an understanding of the current state-of-the-science with respect to the toxicology 

and health effects associated with ENDS products. The systematic scientific literature 

searches provided by the applicant show that exposure to ENDS resulted in respiratory, 

cardiovascular, and immunological toxicity. However, the adverse events noted are 

comparatively less than those related to the use of combusted cigarettes. The applicant 

provided conservative risk assessments for ingredients in the e-liquids, HPHCs in the 
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aerosol, and extractables and leachable compounds from the new products. PG, VG, 

chromium, and nickel levels are higher in the aerosols of the new products than in the ENDS 

comparator. Additionally, for nickel and chromium, the reference exposure levels were 

higher than the California Office of Environmental Health Hazard Assessment (OEHHA) 

reference exposure level (REL) and the Agency for Toxic Substances and Disease Registry 

(ATSDR) acute toxicity minimum risk level (MRL) but below other reported regulatory 

reference values (Texas Commission on Environmental Quality and ICH Permitted Daily 

Exposure). Increases in chromium and nickel in the new products compared to average 

combusted cigarette smoke mainstream smoke levels were noted and suggest increased 

cancer risk. However, a user who completely switches from combusted cigarettes to the 

new products is expected to have lower exposures to several potent carcinogens (e.g., NNK, 

NNN, acrylonitrile, cadmium, lead) that will result in a large reduction in HPHC exposures to 

outweigh the increases in cancer risk in the new products due to chromium and nickel. 

Extractable and leachable organic and inorganic compounds were identified in some 

products but not all and highest levels were seen under accelerated conditions. There was 

no toxicology concern for the levels of these compounds due to genotoxicity testing results 

from the literature, the levels found in the e-liquid being below health-based guidance 

values (HGVs), and exaggerated conditions of the testing. Overall, as TPL, I agree with 

toxicology that based on the data submitted by the applicant on toxicants and HPHCs, 

switching from combusted cigarettes to the new products or dual use of combusted 

cigarettes and the new products with substantive reduction in combusted cigarette use is 

likely to result in significant reductions in HPHC exposures. Secondhand exposure studies 

were evaluated and showed increased indoor air nicotine, VOCs, particulate matter (i.e., 

PM2.5), polycyclic aromatic hydrocarbons (PAHs), aluminum, nickel, and silver 

concentrations after ENDS use, compared to background levels. However, several literature 

studies provided by the applicant reported that airborne black carbon, PAHs and TSNAs 

were not detected after ENDS use. In studies comparing secondhand ENDS aerosol exposure 

to secondhand combusted cigarette smoke exposure, airborne nicotine, VOCs, carbonyls, 

metals, nitrosamines, polyaromatic amines, PAH and carbon monoxide concentrations were 

low or undetected in ENDS aerosol, compared to combusted cigarette smoke. These 

secondhand exposures after ENDS use are not thought by the applicant to pose a risk for 

adverse health effects. The applicant concluded that secondhand exposures to HPHCs in 

aerosol of the new products are likely to not pose a risk for adverse health effects. As TPL, I 

do not unilaterally agree with the applicant that secondhand exposures to HPHCs in the 

aerosol does not pose a risk for adverse health effects as I believe this risk is still unknown. 

With respect to the new products, I find that secondhand exposure is likely to be much less 

harmful for this product than for cigarettes. 

The applicant developed a population health impact model for NJOY DAILY and ENDS use in 

general. As TPL, I agree with the epidemiology review on the limitations of the applicant's 

population health modeling methodology. The epidemiology review concluded that the 

applicant's model does not reflect real world data and likely overestimates whole 

population health benefits of the new products if marketed. Therefore, given the limitations 

associated with the model inputs, it is not particularly informative in the evaluation of 

whether marketing of the new products would be appropriate for the protection of the 

public health. However, the applicant provided data demonstrating some current cigarette 

smokers may switch completely to the new products which is supportive of an APPH 

determination. 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 43 of 52 

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 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. 

4.2. ENVIRONMENTAL CONCLUSION 

For PM0000630-PM0000631, a finding of no significant impact (FONSI) was signed by Hans 

Rosenfeldt, PhD on June 9, 2022. The FONSI was supported by an environmental assessment 

prepared by FDA on June 9, 2022. 

S. CONCLUSION AND RECOMMENDATION 

In making a determination about whether permitting the marketing of a product is APPH, Section 

910(c)(4) directs FDA to consider the risks and benefits to the population as a whole, including users 

and nonusers of tobacco products, taking into account, among other things, the likelihood that 

those who do not use tobacco products will start using them. FDA's scientific review is not limited to 

considering 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 product design and that there are adequate process controls and 
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TPL Review of PMTAs: PM0000630-PM0000631 Page 44 of 52 

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. 

Based on the information provided in the PMTAs, the abuse liability of the new products is lower 

than combusted cigarettes. Results from an applicant-submitted clinical study with the new 

products suggest that the new products may have lower nicotine exposure than the representative 

ENDS that were tested in the applicant's study. However, it is unclear how the abuse liability of the 

new products compares to other ENDS. Further, clinical biomarker data submitted by the applicant 

found statistically significant tower levels of biomarkers of exposure to HPHCs (e.g., CO, cotinine, 

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

new products and combusted cigarettes. A body of published literature suggests combusted 

cigarette smokers will likely experience significant reductions in volatile organic chemical {VOC) 

exposure upon complete switching to ENDS products. Consistent with this notion, the applicant 

provided voe HPHCs (e.g., acrylonitrile, benzene ,, lM toluene) using mainstream 

smoke (MSS) concentration data derived from peer-reviewed scientific literature to represent the 

combusted cigarette category. The applicant demonstrated lower levels of these voes from the new 

pfOducts compared to the combusted cigarette MSS literature data. The overall toxicological risk to 

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

aerosol HPHCs of the new products compared to cigarettes and as evidenced by results of 

nonclinical studies. The consideration of HPHC information provides compelling evidence that the 

new products have the potential to benefit smokers who switch completely or significantly reduce 

their cigarette consumption. The basis for this conclusion is that the biomarkers of exposure data to 

HPHCs and the HPHC aerosol yields suggest reduced exposure to carclnogens and other toxlcants. 

Therefore, the applicant has demonstrated the potential for these new products to benefit adult 

smokers who switch completely or slgnlficantly reduce their cigarette consumption as compared to 

continued exclusive cigarette use. 

The applicant's Adult Prevalence Study on NJOY DAILY use among adults showed use was more 

common in current than former and never smokers. Complete switching from combusted cigarettes 

to NJOY DAILY was estimated in the applicant's NJOY User Study with 39% of 2,533 adults using the 

tobacco flavored products at 6 months, a rate that Is much higher than typically seen (3-6%) In the 

pubHshed literature. Based on data presented by the applicant, dual use of the new products with 

combusted cigarettes was also observed (78.6% baseline) which 1s higher than other ENDS products 

reported in the literature (44-54%). 

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

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

risk of tobacco initiation. Existing evidence conslstently Indicates that use of tobacco flavored ENDS 

is less common than use of flavored ENDS among youth. The applicant submitted youth prevalence 

studies and although these studies had small sample sizes, the data suggest that 40.5% of youth 

who reported ever ENDS use started with "something other" than tobacco or menthol flavored 

products, and 45.6% of ever NJOY DAILY youth users reported starting with non-tobacco/nonmenthol flavored NJOY DAILY products. The remaining respondents used tobacco flavored (13.3%) 

or Menthol or Mint flavored (32.8%) NJOY DAILY products. These data provide some evidence that 

the new products which are tobacco-flavored are less appealing to youth compared to other types 

of flavored products. Nonetheless, given the strong evidence regarding the impact of youth 

marketing exposure to youth appecil and initiation of tobacco use, a marketing authorization should 

include post-market requirements to help ensure that youth exposure to tobacco marketing is 

(b)(4)
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TPL Review of PMTAs: PM0000630-PM0000631 Page 45 of 52 

limited_ 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-market requirements aimed 

at reducing youth exposure and access to the products. 

Regarding product stability, the applicant proposed a I lb. "'l shelf life for the new products. The 

applicant provided complete chemical stability study data including test data for bulk e-liquids, 

finished product e-liquids, and aerosols and extractables and leachables data for components, parts, 

and CCS meeting product specifications. The applicant's data supports microbial stability of the 

products overj The stability data provided by the applicant is acceptable and indicates 

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

and there are no stability concerns. Therefore, the applicant's stated shelf life of l lb' · !for the 

new products is supported by the submitted testing data. 

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 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 of this review, as identified 

on the cover page of this review. 

(b)(4)

(b)(4)

(b)(4)
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7. APPENDIX' 

Table 3. New products 

Common Attributes 

Submission date March 30, 2020 

Receipt date March 30, 2020 

Applicant NJOY, LLC 

Product manufacturer NJOY, LLC 

Product category ENDS (VAPES) 

Product subcategory Closed E-Cigarette 

Attributes New Product 

STN PM0000630.PD18

Product name NJOY DAILY Rich Tobacco 4.5% 

Package type Box 

Package quantity 1 E-cigarette 

Characterizing flavor Tobacco 

Length 106.9 mm 

Diameter 8.4 mm 

Nicotine concentration 4.5% w/w 

PG/VG ratio 46.56/46.00 

E-liquid volume 0.9 mL 

Wattage 4 W 

Battery capacity 200 mAh (lithium ion; non-rechargeable) 

Additional Properties Disposable E-Liquid Reservoir 

STN PM0000631.PD1 

Product name NJOY DAILY EXTRA Rich Tobacco 6% 

Package type Box 

Package quantity 1 E-cigarette 

Characterizing flavor Tobacco 

Length 106.9 mm 

Diameter 8.4 mm 

Nicotine concentration 6% w/w 

PG/VG ratio 43.96/46.00 

E-liquid volume 0.9 mL 

Wattage 4 W 

Battery capacity 200 mAh (lithium ion; non-rechargeable) 

Additional Properties Disposable E-Liquid Reservoir 

7 Brand/sub-brand or other commercial name used in commercial distribution. 

8 PD numbers were not used in previously issued letters 
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Table 4. Amendments 

Submission 

Date 

Receipt 

Date 

Applications 

being 

amended 

Reviewed Status Brief Description 

June 16, 

2020 

June 16, 

2020 

AV Yes Active Correction or 

clarification to update 

report: Adverse Events 

— NJOY Report DAILY — 

Qtr. 1 2020 Update: 

Adverse Experience 

(Module 5.5) 

July 13, 

2020 

July 14, 

2020 

AII9 Yes Active Correction or 

clarification to Study 

Reports: NJOY User 

Survey (Module 6.2.4) 

& Population Module 

(Module 6.6) 

November 

25, 2020 

November 

25, 2020 

AII9 Yes Active Response to 

November 12, 2020 

FDA Information 

Request 

March 04, 

2021 

March 04, 

2021 

AII9 Yes Active Response to 

December 17, 2020 

Deficiency Letter 

9 This amendment applies to all STN subject of this review.