U.S. Food & Drug Administration

10903 New Hampshire Avenue 

Silver Spring, MD 20993 

www.fda.gov 

PMTA Scientific Review: Technical Project Lead (TPL) 

SUBMISSION INFORMATION 

Applicant 22nd Century Group, Inc. 

Product Manufacturer NASCO Products, LLC 

Submission Date December 4, 2018 FDA Receipt Date December 4, 2018 

Cross-referenced 

Submission1 

1 The application contains a valid and active cross-reference, which contains appropriate authorization for the applicant to 

reference the entire file or certain sections thereof. 

Cross-referenced STN Primary STN(s) 

(b)(4) Applies to all STNs 

NEW TOBACCO PRODUCTS 

PM0000491: Moonlight ®2 

2 On December 4, 2018, FDA received original PMTAs for VLNTM King and VLNTM Menthol. On October 2, 2019, the applicant 

submitted a proposed name change for the products to Moonlight and Moonlight Menthol, respectively. The scientific reviews 

reflect the proposed names (VLNTM and VLNTM Menthol) in the original PMTA submissions. 

Product Category Cigarettes 

Product Sub-Category Combusted, Filtered 

Package Type Hard pack 

Package Quantity 20 per pack 

Characterizing Flavor None 

Length 83 mm 

Diameter 7.9 mm 

Ventilation 13% 

PM0000492: Moonlight ® Menthol2 

Product Category Cigarettes 

Product Sub-Category Combusted, Filtered 

Package Type Hard pack 

Package Quantity 20 per pack 

Characterizing Flavor Menthol 

Length 83 mm 

Diameter 7.9 mm 

Ventilation 13% 
STN PM0000491 – PM0000492 Page 2 of 89 

DISCIPLINES REVIEWED Primary Reviewer(s) DATE OF REVIEW 

Behavioral and Clinical Pharmacology Kia Jackson October 29, 2019 

October 29, 2019 

October 29, 2019 

October 30, 2019 

October 29, 2019 

October 30, 2019 

October 30, 2019 

October 30, 2019 

October 30, 2019 

October 30, 2019 

October 29, 2019 

October 30, 2019 

October 31, 2019 

Chemistry 

Environmental Science 

Engineering 

Epidemiology 

Medical 

Microbiology 

OCE – BIMO 

OCE – Manufacturing/Lab 

OCE – DPAL 

An Vu 

Rudaina Alrefai-Kirkpatrick 

Robert Meyer 

Joanne Chang 

Anna-Sophie Weidner 

Prashanthi Mulinti 

Tara Singh 

Eugene Chang 

Matthew Rohit 

Social Science 

Statistics 

Toxicology 

Katherine Margolis 

Chunfeng Ren 

Jonathan Fallica 

Recommendation

 Issue marketing order letters

 Issue denial letters 

Technical Project Lead (TPL): 

Iilun C. Murphy -S 

2019.11.20 15:52:43 -05'00' 

 Iilun Murphy, M.D.

 Director

 Division of Individual Health Science, Office of Science 

Signatory Decision: 

☒ Concur with TPL recommendation and basis of recommendation 

☐ Concur with TPL recommendation with additional comments (see separate memo) 

☐ Do not concur with TPL recommendation (see separate memo) 

Digitally signed by Matthew R. Holman -

S 

Date: 2019.11.22 16:13:51 -05'00' 

 Matthew R. Holman, Ph.D.

 Director

 Office of Science 
 

 

STN PM0000491 – PM0000492 Page 3 of 89 

TABLE OF CONTENTS 

1. EXECUTIVE SUMMARY ......................................................................................... 6 

2. REVIEW OF PMTAS............................................................................................. 11 

2.1. Regulatory History .......................................................................................................................... 11 

2.2. Product Composition, Design, and Manufacturing ......................................................................... 13 

2.2.1. Tobacco Ingredients................................................................................................................................... 14 

2.2.2. Non-tobacco Ingredients ............................................................................................................................ 16 

2.2.3. Product Design ........................................................................................................................................... 19 

2.2.4. Manufacturing, Process, and Controls ....................................................................................................... 21 

2.2.5. FDA Sample Testing .................................................................................................................................... 21 

2.2.6. Product Stability ......................................................................................................................................... 22 

2.2.7. Inspections of Manufacturing Facilities...................................................................................................... 24 

2.2.8. Summary of Composition, Design, and Manufacturing Findings ...............................................................24 

2.3. Toxicological Risk Assessment ........................................................................................................ 25 

2.3.1. Harmful and Potentially Harmful Constituents (HPHCs) ............................................................................ 25 

2.3.1.1. General Overview ......................................................................................................................... 25 

2.3.1.2. ISO Regimen HPHC Data ............................................................................................................... 26 

2.3.1.3. CI Regimen HPHC Data ................................................................................................................. 27 

2.3.1.4. Comparison Between VLNTM Cigarettes and SPECTRUM Research Cigarettes .............................29 

2.3.2. Nonclinical Studies and Literature Search.................................................................................................. 31 

2.3.3. Quantitative Risk Assessment (QRA).......................................................................................................... 31 

2.3.4. Summary of Toxicological Findings ............................................................................................................ 32 

2.4. Individual Health Impact ................................................................................................................ 34 

2.4.1. Overview of Behavioral and Clinical Pharmacology (BCP) Studies .............................................................34 

2.4.2. Nicotine Pharmacokinetics......................................................................................................................... 36 

2.4.3. Behavioral Pharmacology........................................................................................................................... 37 

2.4.3.1. Abuse Liability............................................................................................................................... 37 

2.4.3.2. Use Behavior and Topography...................................................................................................... 39 

2.4.3.3. Product Use/Consumption ........................................................................................................... 40 

2.4.3.4. Craving, Withdrawal, and Dependence........................................................................................42 

2.4.3.5. Cessation ...................................................................................................................................... 45 

2.4.4. Summary of Overall Behavioral and Clinical Pharmacology Findings.........................................................46 

2.4.5. Biomarkers of Exposure (BOE).................................................................................................................... 47 

2.4.5.1. Effect of Switching to VLNC Cigarettes on BOE ............................................................................47 

2.4.5.2. Dual Use and Non-compliance ..................................................................................................... 48 

2.4.5.3. Summary of BOE Findings............................................................................................................. 49 

2.4.6. Biomarkers of Potential Harm (BOPH) ....................................................................................................... 50 

2.4.7. Adverse Health Effects ............................................................................................................................... 51 

2.4.7.1. Health Risks to Non-Users ............................................................................................................ 52 
STN PM0000491 – PM0000492 Page 4 of 89 

2.4.7.2. Consumer Use and Potential Misuse............................................................................................52 

2.4.7.3. Health Risks Associated with Polyuse........................................................................................... 52 

2.4.7.4. Health Risks Associated with Switching to this Product Compared to Continued Smoking .........53 

2.4.7.5. Health Risks Associated with Switching to this Product Compared to Tobacco Cessation ..........53 

2.4.7.6. Health Risks Associated with Switching to Product Compared to Cessation Medication ............54 

2.4.7.7. Summary of Adverse Health Effects.............................................................................................54 

2.4.8. Likelihood of Product Misuse or Malfunction ............................................................................................ 54 

2.4.9. Bioresearch Monitoring (BIMO) Inspection ............................................................................................... 55 

2.4.10. Summary of Individual Health Findings...................................................................................................... 55 

2.5. Population Health .......................................................................................................................... 57 

2.5.1. Likelihood of Use by Current Cigarette Smokers........................................................................................ 57 

2.5.2. Summary of Likelihood of Use by Current Cigarette Smokers ...................................................................58 

2.5.3. Poly-use of VLNTM cigarettes and cigarettes or other tobacco products ....................................................58 

2.5.3.1. Summary of Poly-use.................................................................................................................... 59 

2.5.4. Use by Former or Never Smokers............................................................................................................... 59 

2.5.4.1. Summary of Use by Former or Never Smokers ............................................................................60 

2.5.5. Use by Vulnerable Populations (Youth and Mental Health Populations) ...................................................60 

2.5.5.1. Youth ............................................................................................................................................ 60 

2.5.5.2. Mental Health Populations........................................................................................................... 61 

2.5.5.3. Summary of Use by Vulnerable Populations ................................................................................62 

2.5.6. Population Modeling .................................................................................................................................. 63 

2.5.7. Summary of Population Health Findings .................................................................................................... 63 

2.6. Product Labeling, Consumer Comprehension, and Marketing Plan ................................................ 64 

2.6.1. Proposed PMTA Labeling............................................................................................................................ 64 

2.6.2. Consumer Perception ................................................................................................................................. 65 

2.6.3. Required Labeling....................................................................................................................................... 66 

3. ENVIRONMENTAL DECISION............................................................................... 66 

4. CONCLUSIONS AND RECOMMENDATIONS.......................................................... 67 

4.1. Conclusions .................................................................................................................................... 67 

4.2. Recommendation for Marketing .................................................................................................... 69 

4.3. Postmarketing Requirements ......................................................................................................... 69 

4.3.1. Recordkeeping and Retention .................................................................................................................... 70 

4.3.2. Periodic Reporting ...................................................................................................................................... 74 

4.3.3. Notifications............................................................................................................................................... 78 

4.3.4. Marketing Requirements............................................................................................................................ 79 

5. ACRONYMS........................................................................................................ 81 
 

STN PM0000491 – PM0000492 Page 5 of 89 

6. REFERENCES....................................................................................................... 83 

Table of Tables 

Table 1: Amendments Submitted by Applicant.......................................................................................... 12 

Table 2: Ingredients Other than Tobacco ................................................................................................... 17 

Table 3: Packaging Materials Used in VLNTM Cigarettes.............................................................................. 18 

Table 4: Cigarette Design Parameters ........................................................................................................ 20 

Table 5: STL Nicotine Test Results of VLNTM Cigarettes............................................................................... 22 
 

 

 

STN PM0000491 – PM0000492 Page 6 of 89 

1. EXECUTIVE SUMMARY

On December 4, 2018, FDA received PMTAs (PM0000491-PM0000492) from 22nd Century 

Group Inc. (also referred to as: applicant/22nd Century) for two products -- VLNTM King and VLNTM 

Menthol King cigarettes -- to be marketed in the U.S. upon receipt of a marketing authorization. 

Of note, on October 2, 2019, FDA received an amendment (PM0000594) requesting a name 

change for their proposed products from VLNTM King and VLNTM Menthol King cigarettes to 

Moonlight® and Moonlight® Menthol cigarettes, respectively. As this name change request was 

received after the scientific review had been completed, the related documents refer to the 

proposed products by the original proposed name VLNTM King and VLNTM Menthol King. 

The VLNTM King and VLNTM Menthol King cigarettes (together referred to as VLNTM cigarettes) are 

conventional cigarettes developed with the purpose of reducing cigarette smokers’ exposure to 

nicotine. The VLNTM King and VLNTM Menthol King cigarettes have similar adverse health risks as 

NNC cigarettes if used in a similar manner given that the proposed new products differ from 

NNC cigarettes only in nicotine content. Any potential reduction in risk in the proposed new 

tobacco product comes from reducing nicotine exposure and cigarette consumption. The 

applicant states that these cigarettes contain at least 95% less nicotine in the tobacco than 

typical commercial cigarettes. 

A new tobacco product, including a tobacco product modified in any way (“including a change 

in design, any component, any part, or any constituent, including a smoke constituent, or in the 

content, delivery, or form of nicotine, or any other additive or ingredient”) after February 15, 

2007, generally requires premarket authorization from FDA (sections 910(a)(1)(B) and 

910(a)(2)(A)). 

A PMTA must be submitted to FDA under section 910(b) of the FD&C Act and a marketing 

authorization order must be received from FDA under section 910(c)(1)(A)(i) prior to marketing 

any new tobacco product, unless FDA has found that the new tobacco product is substantially 

equivalent to a tobacco product commercially marketed in the U.S. as of February 15, 2007 (see 

section 910(a)(2)(A)(i)) or is exempt from a substantial equivalence determination pursuant to 

regulation (see section 910(a)(2)(A)(ii)). 

FDA will deny a PMTA and issue a no marketing authorization order stating that the product 

may not be introduced or delivered for introduction into interstate commerce under section 

910(c)(1)(A)(ii) where FDA finds that: 

● there is a lack of a showing that permitting the product to be marketed would be 

appropriate for the protection of the public health; 

● the methods, facilities, or controls used in manufacturing, processing, or packing do 

not conform to manufacturing regulations issued under section 906(e) (21 U.S.C. 

387f(e)); 

● based on a fair evaluation of all material facts, the proposed labeling is false or 

misleading; or 
 

 

 

 

 

STN PM0000491 – PM0000492 Page 7 of 89 

● it is not shown that the product complies with any tobacco product standard in effect 

under section 907 (21 U.S.C. 387g), and there is not adequate information to justify 

deviation from the standard. 

The statute provides that the finding as to whether the marketing of a product for which a 

PMTA is submitted would be appropriate for the protection of the public health shall be 

determined with respect to the risks and benefits to the population as a whole, including users 

and nonusers of the tobacco product, and taking into account: 

(A) the increased or decreased likelihood that existing users of tobacco products will

stop using such products; and

(B) the increased or decreased likelihood that those who do not use tobacco products

will start using such products.

Scientific review of these applications has demonstrated the following: 

● There is sufficient information to characterize the product composition and design. 

● There are adequate process controls and quality assurance procedures to help ensure VLNTM 

cigarettes are manufactured consistently to meet the applicant’s specifications. 

● The toxicological profiles of VLNTM King and VLNTM King Menthol are essentially identical 

except for the quantity of menthol. Overall toxicant-associated noncancer hazards and 

cancer risks due to use of VLNTM cigarettes are likely similar to the application’s six 

comparator NNC cigarettes that represent approximately 25% of the cigarette market, 

assuming that the VLNTM cigarettes will be used in the same way as the comparators. 

Evidence from clinical studies may indicate that the associated noncancer hazards and 

cancer risks could be lower compared to marketed cigarettes, as users of products very 

similar (SPECTRUM very low nicotine content [VLNC] cigarettes) to the VLNTM cigarettes tend 

to decrease their cigarettes per day (CPD) and puffing volumes if they switch from NNC 

cigarettes to VLNC cigarettes. This suggests that toxicological impacts may be 

proportionately decreased if users were to switch, due to a reduction in CPD. Clinical 

biomarkers of exposure (e.g., NNAL, CO, PheT, 3-HMPA) tend to support that acute and 

complete switching is associated with harmful and potentially harmful constituents (HPHC) 

and CPD reductions, whereas gradual switching is not, suggesting that reduction in HPHCs, 

and therefore associated hazards or risks, are likely via reduction in CPD. 

● Noncancer hazards and cancer risks to dual users of tobacco products, where at least one 

product is VLNTM King or VLNTM Menthol King cigarettes, are also likely to be similar or lower 

than smoking the six commercially marketed cigarette comparators, to the extent that the 

use of the other products, including nicotine replacement therapy (NRT) that are used with 

VLNTM King or VLNTM Menthol King cigarettes, is less harmful than the six commercially 

marketed cigarette comparators. However, using VLNTM cigarettes compared to quitting 

tobacco use or completely switching to NRT would increase harm, as toxicant exposures 

would be similar to exposure resulting from the use of NNC cigarettes. 

● The pharmacokinetic (PK) profile of VLNTM cigarettes indicates a lower abuse liability than 

the applicant’s usual brand-normal nicotine content (UB-NNC) cigarette comparator. 
 

STN PM0000491 – PM0000492 Page 8 of 89 

● VLNTM cigarettes are associated with lower positive subjective effects ratings (e.g., liking, 

pleasant, satisfaction) compared to UB-NNC cigarettes, reducing their abuse liability for 

youth and non-smokers. As menthol in NNC cigarettes facilitates experimentation and 

progression to regular smoking, it is unknown to what degree smoking VLNTM Menthol King 

cigarettes may influence progression to regular smoking compared to NNC menthol 

cigarettes in new and inexperienced users, particularly youth and young adults. Menthol 

and non-menthol NNC smokers who choose to switch to VLNC cigarettes would experience 

the benefit of significantly reducing their overall exposure to nicotine, potentially reducing 

their overall smoking, and subsequently, their exposure to non-nicotine HPHCs. Given that 

current adult smokers are the intended population for VLNTM cigarettes, reduced likelihood 

of use among adult smokers is likely to reduce youth access to these products and their 

availability for youth experimentation. 

● Youth may believe that VLNC cigarettes might be “safer” than NNC cigarettes, and youth 

who experimented with VLNTM cigarettes could transition to NNC cigarette smoking, 

although likelihood of uptake of VLNTM cigarettes by youth is anticipated to be low due to 

low appeal and abuse liability. The applicant did not provide information on how menthol 

VLNTM smoking could impact the likelihood of VLNTM use by youth, however, in the adult 

study of VLNTM Menthol King data showed these cigarettes have lower positive subjective 

effects than UB-NNC cigarettes although the reduction is less than compared to VLNTM King 

cigarettes. Existing data in adolescent and young adult smokers suggest VLNC cigarettes are 

associated with lower positive subjective effects ratings (e.g., liking, pleasant, satisfaction) 

compared to NNC cigarettes, and VLNC cigarettes are not associated with compensatory 

smoking (i.e., smoking topography, TNE levels) in this vulnerable population. While nicotine 

dependence has been shown to develop rapidly among adolescents following exposure to 

NNC cigarettes, the limited available evidence on VLNC cigarettes suggests that youth who 

experiment with VLNC cigarettes may find them less appealing and may be less likely to 

develop nicotine dependence and become established cigarette smokers due to their lower 

abuse liability profile. 

● Findings from the literature indicate that individuals who smoke VLNC cigarettes 

demonstrate either no significant differences in smoking topography relative to those who 

smoke UB-NNC or NNC cigarettes or reductions in tobacco smoke exposure (e.g., lower total 

puff volume); smoking VLNC cigarettes may lead to an overall reduction in CPD compared to 

smoking UB-NNC cigarettes. 

● Low subjective appeal, along with increased craving and withdrawal, may prevent current 

smokers from fully transitioning to VLNTM cigarettes. Data from the literature suggest that 

those who do switch to VLNC cigarettes reduce their exposure to nicotine and a range of 

non-nicotine HPHCs, may smoke fewer CPD, may reduce their nicotine dependence levels, 

and increase their quit attempts compared to those who continue to smoke UB-NNC 

cigarettes. It is anticipated that smokers who switch to VLNTM cigarettes and reduce their 

overall CPD would experience the greatest benefit of reducing their exposure to nicotine 

and non-nicotine HPHCs, though VLNTM smokers who do not reduce their CPD still reduce 

exposure to nicotine. 

● Switching to VLNC cigarettes may facilitate abstinence in smokers by increasing motivation 

to quit and quit attempts. Concurrent use of NRT and behavioral intervention may improve 
STN PM0000491 – PM0000492 Page 9 of 89 

these outcomes. However, among menthol smokers who switch to VLNC cigarettes, the 

potential effect on cessation may be less likely than with non-menthol VLNC cigarette 

smokers. Based on literature extrapolated from NNC menthol cigarettes, the reduced 

likelihood of cessation may occur even in smokers motivated to quit and who concurrently 

use pharmacotherapy for cessation. Nonetheless, both menthol and non-menthol NNC 

smokers who switch to VLNC cigarettes could experience the benefits of reduced exposure 

to nicotine, potential reductions in dependence therefore leading to reductions in CPD, 

increased quit attempts, and potential quitting in some smokers compared to smoking their 

UB-NNC cigarettes. 

● Literature indicates that dual use and noncompliance with smoking VLNC cigarettes in 

clinical studies is high; however, nicotine exposure remains significantly reduced in 

participants who smoke VLNC cigarettes compared to NNC cigarettes. Despite high levels of 

dual use/noncompliance, data suggest that smoking VLNC cigarettes can lead to an overall 

reduction in CPD compared to smoking UB-NNC cigarettes. 

● If smokers dual use VLNC and UB-NNC cigarettes, but primarily smoke VLNC cigarettes, 

studies suggest that smokers would still be exposed to lower nicotine levels than they 

would from smoking just the UB-NNC cigarettes, would likely reduce their overall CPD, and 

would experience the effects of reduced dependence on nicotine. Some consumers, in 

particular those who dual use VLNC and UB-NNC cigarettes, may not decrease their overall 

cigarette consumption; however, dual use of other nicotine-containing products, such as 

NRT or electronic nicotine delivery systems (ENDS), may aid in reducing CPD. 

● There have been no specific, short-term health-related or product quality issues unique to 

VLNTM cigarettes in the clinical studies or the published literature. While there are limited 

short-term and no long-term studies evaluating health effects of VLNTM cigarettes, the risks 

for adverse health effects are likely similar to those associated with NNC cigarettes, given 

that the proposed products differ from NNC cigarettes only in the nicotine content. As such, 

it is likely that the health risks of polytobacco use will not be any different for VLNTM 

cigarettes compared to NNC cigarettes. 

● If smokers who switch to VLNTM cigarettes decrease their use and/or ultimately quit, there 

would likely be improved health benefits. If, on the other hand, cigarette smokers who 

completely switch to VLNTM cigarettes use them in the same way as NNC cigarettes, it is 

possible that they may have weight gain, but with the added adverse health consequences 

of continued smoking. Based on existing clinical studies, the likelihood of this latter scenario 

is likely low. 

● Smoking increases the risk of cardiovascular disease and thrombosis. While in vivo and in 

vitro studies have indicated that VLNTM cigarettes may cause greater platelet activation 

compared to cigarettes with a higher nicotine content, which may contribute to potential 

increased risk of thrombosis compared to other cigarettes, adverse event data are 

insufficient to draw meaningful clinical conclusions regarding whether there is increased 

risk of thrombosis. At this time we do not have clinical information raising concern that 

there is substantive increased risk of thrombosis from use of VLNC cigarettes. If additional 

data becomes available elucidating this relationship, further consideration of risk and 

benefit to the population as a whole is warranted. Post market reporting requirements 

should include submitting any serious or unexpected adverse experiences reported to 22nd 
 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 10 of 89 

Century as well as summarizing any new significant findings on publications not previously 

reported relevant to VLNTM cigarettes. 

● While smokers who completely switch to VLNTM cigarettes may experience nicotine 

withdrawal, in brief exposure VLNC cigarette studies craving and withdrawal were 

suppressed relative to baseline following overnight abstinence, indicating that withdrawal 

will likely be less in people switching to VLNTM cigarettes than in those who quit smoking 

cold turkey (e.g., Barrett, 2010; Rose, Salley, Behm, Bates, & Westman, 2010; Tidey, 

Rohsenow, Kaplan, Swift, & Ahnallen, 2013). Adverse event data from company-sponsored 

studies and from the published literature are limited but suggest that some adverse events 

may relate to nicotine withdrawal. There is little experience with VLNTM cigarettes to 

determine whether they may have adverse public health consequences beyond relapse to 

NNC cigarettes or other nicotine sources, such as ENDS, or the use of other substances to 

mitigate withdrawal symptoms. 

● Non-users who are involuntarily exposed will likely experience similar adverse health effects 

as exposure to tobacco smoke from NNC cigarettes. 

● Although the data for VLNTM cigarette uptake by never smokers, former smokers, and youth 

is limited, similar products have been available on the U.S. market previously and uptake by 

youth and current nonsmokers was not evident and therefore does not likely appear to be 

of significant concern. Postmarket reporting may help to ensure this does not become 

problematic after the proposed products are marketed in the U.S. The population most 

likely to use VLNTM cigarettes is current NNC cigarette smokers, especially those motivated 

to quit. Additionally, the applicant will be required to monitor consumer use patterns and 

demographic information and provide FDA with regular reports. 

Overall the VLNTM King and VLNTM King Menthol cigarettes meet the following criteria specified 

in section 910(c)(2) of the FD&C Act: 

1. The methods used in, and the facilities or controls used for, the manufacture,

processing, and packing of these products do not fail to conform to the requirements in

section 906(e)3

3 FDA has not yet promulgated any regulations under Section 906(e) of the FD&C Act. 

 of the FD&C Act.

2. Based on a fair evaluation of all material facts, the labeling is not false or misleading in

any particular.

3. The products do not fail to conform to a tobacco product standard in effect under

section 907 of the FD&C Act.

4. Permitting the marketing of the products is at this time appropriate for the protection of

the public health, as described in section 910(c)(4) of the FD&C Act.

I recommend that FDA grant marketing authorization for the proposed products that are the 

subject of PM0000491 and PM0000492 for the reasons described above. 
 

 

 

 

 

STN PM0000491 – PM0000492 Page 11 of 89 

2. REVIEW OF PMTAs

2.1. Regulatory History

On December 4, 2018, FDA received two PMTAs (PM0000491-PM0000492) from 22nd Century 

for VLNTM King and VLNTM Menthol King cigarettes (together referred to as VLNTM cigarettes). On 

December 11, 2018, FDA received an unsolicited amendment (PM0000493) containing all 

content from the original PMTAs, including missing appendices from the original submissions. 

On December 19, 2018, FDA issued an Acknowledgement letter and conducted a 

teleconference with the applicant to convey technical issues with the submission files and 

options to rectify the issues needed to proceed with review. In response, FDA received an 

amendment (PM0000497) on January 10, 2019, requesting the withdrawal of amendment 

PM0000493 and resubmitting the original PMTAs in an FDA-accessible format. On January 24, 

2019, FDA issued a Filing letter. On February 11, 2019, FDA received an amendment 

(PM0000499) providing new analytical test data. On February 19, 2019, FDA conducted a 

teleconference requesting information to clarify product design, manufacturing acceptance 

criteria, HPHC testing regimens, and contact information. In response, FDA received an 

amendment (PM0000603) on February 25, 2019. 

On March 14, 2019, FDA received an amendment (PM0000506) containing a revised report 

related to the Consumer Perception and Intention Study, and data pertaining to a 9-month 

stability study. On March 15, 2019, FDA received two amendments (PM0000507, PM0000508) 

correcting previously submitted HPHC data, updating the quantitative risk assessment (QRA), 

and providing results from the Menthol Abuse Liability Study Report. On March 20, 2019, FDA 

received an amendment (PM0000509) clarifying information in the tobacco-specific 

nitrosamines (TSNAs) stability study report. On April 3, 2019, FDA received an amendment 

(PM0000511) providing raw data for the Consumer Perception Study. On April 4, 2019, FDA 

issued a Major Amendment letter notifying the applicant that the March 14, 2019, and March 

15, 2019, amendments received contain a substantial amount of new data that has not been 

previously submitted to or reviewed by FDA, such as new data from a previously unreported 

study or detailed new analyses of previously submitted data. This major amendment was 

reviewed by the review team and TPL. 

On June 27, 2019, FDA received an amendment (PM000514) that contained: 1. 12-month 

storage stability and water activity study results, 2. Summary reviews of four recently published 

studies available in the public literature involving VLNC cigarettes. As this amendment was 

received late in the scientific review cycle, this minor amendment was processed as a TPL-only 

review as the information submitted does not impact the scientific conclusions previously made 

by the review team. On July 18, 2019, FDA received an amendment (PM0000519) that 

contained a new clinical study report: A Longitudinal Ambulatory Study to Assess Changes in 

Cigarette Consumption Behavior and Biomarkers of Exposure during a 6-Week Switch to Very 

Low Nicotine Cigarettes. As the amendment contained significant amount of new data that 

required substantial additional FDA review team and TPL time, the amendment was 

determined to be a major amendment. A teleconference (t-con) was held with the applicant on 

August 2, 2019 to convey this information and a request was made to 22nd Century for 
 

 

 

 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 12 of 89 

additional clarifying information to be submitted related to the serious adverse experience that 

was reported associated with the new clinical study. On August 7, 2019, FDA received an 

amendment (PM0000524) that contained additional narrative related to the serious adverse 

experience reported in PM0000519. A t-con was held on September 9, 2019, with 22nd Century 

requesting clarification on the quantitative consumer perception study. An amendment 

(PM0000544) was submitted on September 13, 2019, explaining discrepancies observed 

between the study protocol and data submitted. 

A t-con was held with 22nd Century on September 23, 2019, with the applicant to discuss the 

potential for the name VLNTM to render the product a modified risk tobacco product given 

public communication available on applicant websites associating the product VLNTM and the 

words “very low nicotine”. A press release dated December 5, 2018 announcing the filing of the 

PMTA is titled “22nd Century Files Premarket Tobacco Application (PMTA) with the FDA.” The 

press release explains that the application is for cigarettes to be marketed “under the proposed 

brand name VLNTM (the product name is subject to FDA approval). 22nd Century’s proposed 

VLNTM cigarettes – the subject of the PMTA – are made with 22nd Century’s proprietary VLNTM 

tobacco and, as a result, contain very low levels of nicotine” (https://ir.xxiicentury.com/pressreleases/detail/356/22nd-century-files-premarket-tobacco-application-pmta). The December 5, 

2018 press release announcing the filing of an PMTA for “Very Low Nicotine Content 

Cigarettes” can also be found on the firm’s website (https://ir.xxiicentury.com/pressreleases/detail/356/22nd-century-files-premarket-tobacco-application-pmta). At this time, 

there are no modified risk orders in effect for these products. Additionally, a change in name 

does not create a new tobacco product. Therefore, an applicant may change their product 

name for many reasons, including if they are pending a decision on an MRTP application but 

seek to market a new product authorized under a PMTA. On October 2, 2019, 22nd Century 

submitted an amendment (PM0000549) proposing a name change from VLNTM King and VLNTM 

Menthol King cigarettes to Moonlight® and Moonlight® Menthol cigarettes respectively. 

Table 1: Amendments Submitted by Applicant 

STN Date 

Received 

Amendment 

Type 

Content 

PM0000493 12-11-2018 Major N/A – Amendment withdrawn 

PM0000497 01-10-2019 Major Majority of the PMTA submission 

including large number of files related to 

study documents, literature 

search/references, responsive electronic 

documents 

PM0000499 02-11-2019 Minor Analytical test data 

PM0000502 02-25-2019 Minor Analytical information, study contact 

information 

PM0000506 03-14-2019 Major Revised report and data pertaining to the 

Consumer Perception and Intention 
 

 

 

 

 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 13 of 89 

Study; 9-month storage and stability 

study results 

PM0000507 03-15-2019 Minor HPHC correction data, updated QRA 

PM0000508 03-15-2019 Major A new clinical study report: Evaluation of 

the Abuse Liability of Very Low Nicotine 

Mentholated Cigarettes 

PM0000509 03-20-2019 Minor TSNA in stability study report 

PM0000511 04-03-2019 Minor Raw data for Consumer Perception Study 

PM0000514 06-27-3019 Minor 12-month storage stability and water

activity study results; Reviews of four

recently published VLNC cigarettes

studies

PM0000519 07-18-2019 Major New six-week clinical study report: A 

Longitudinal Ambulatory Study to Assess 

Changes in Cigarette Consumption 

Behavior and Biomarkers of Exposure 

during a 6-Week Switch to Very Low 

Nicotine Cigarettes 

PM0000524 08-07-2019 Minor Additional narrative related to the serious 

adverse experience reported in 

PM0000519 

PM0000544 09-13-2019 Minor Supporting documentation for the 

quantitative consumer perception study 

PM0000549 10-02-2019 Minor Proposed name change and revised 

labeling 

2.2. Product Composition, Design, and Manufacturing 

22nd Century references products it previously manufactured that are similar to the proposed 

products in PM0000491-PM0000492 to support the requested authorization; the previously 

manufactured products were labeled as SPECTRUM and PARE cigarettes. The applicant’s very 

low nicotine content (VLNC) tobacco was developed in 1998 and has been used for producing 

cigarettes under different names, including SPECTRUM and PARE. In 2011, the applicant 

developed the SPECTRUM line of research cigarettes in collaboration with the National Institute 

on Drug Abuse (NIDA), FDA, the National Cancer Institute (NCI) and the Centers for Disease 

Control and Prevention (CDC). 

The SPECTRUM product line consists of a series of cigarette styles that vary in nicotine content, 

from very low (0.4 mg/g tobacco) to relatively high (15.8 mg/g tobacco) nicotine contents. 

SPECTRUM products are available for research in 24 styles, in both regular and menthol 

versions, with eight levels of nicotine in their tobacco. SPECTRUM cigarettes are made with 

NNC tobacco and VLNC tobacco. 

PARE cigarettes were developed by 22nd Century for potential marketing in the U.S. pursuant to 
 

 

 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 14 of 89 

a premarket authorization in 2015 and were subsequently withdrawn. The applicant states that 

the PARE products are the same as the VLNC versions of SPECTRUM cigarettes (NRC102 and 

103). Most recently, 22nd Century developed the VLNTM cigarettes that are the subjects of these 

applications. According to the applicant, VLNTM cigarettes are “exactly the same as the NRC102 

and NRC103 SPECTRUM VLNC research cigarettes. They are also the same as the PARE 

cigarettes that were the subject products of the previous applications. The only difference 

between each respective regular or menthol VLNTM, PARE and SPECTRUM NRC102/NRC103 

brand style is the name of the product.” 

2.2.1. Tobacco Ingredients 

The two VLNTM cigarette tobacco products contain an tobacco blend that consists of 

approximately and . 

The blend also contains . 

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

The applicant states that Vector 21-41 tobacco is a unique tobacco variety not present in any 

commercially-marketed cigarette tobacco. The tobacco has been genetically engineered using 

the applicant’s proprietary technology to block several genes that result in suppression of 

nicotine biosynthesis. 

(b)(4)

Unlike typical American blended cigarette tobacco, which contains a mixture of Bright, Burley, 

data for the VLNTM cigarette tobacco products including all abbreviated HPHCs recommended 

for cigarette mainstream smoke.4

4 FDA Draft Guidance for Industry: Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco 

Smoke Under Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act, 2012. 

 See Section 2.3.1. of this review for evaluation of HPHC data. 

Oriental, and reconstituted tobaccos, tobacco blend consists of all tobacco.

 To address this concern, the applicant provided HPHC 

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

(b)(4)

The Vector 21-41 strain of

(b)(4)

 tobacco is produced through genetic engineering of quinolinic 

acid phosphoribosyltransferase (QPTase), a key enzyme in the biosynthetic pathway of nicotine 

production and related alkaloids. Based on the toxicology review, no chronic or sub-chronic 

toxicological assessments in any nonclinical species are currently available for the transgenic 

tobacco contained in VLNTM cigarettes; therefore, the consequences of inhaling transgenic 

tobacco from the transgenic plants are unknown. However, SPECTRUM Nicotine Research 

Cigarettes (NRCs), which are similar to VLNTM cigarettes, have been used in short-term clinical 

studies without any apparent alterations in smokers’ health in comparison to their UB-NNC 

cigarette to date. In addition, as noted by the applicant, the only new protein that is expected 

to be produced is neomycin phosphotransferase encoded by nptII; according to the applicant, 

neomycin phosphotransferase has no significant homology with proteins listed as food 

allergens or toxins (PMTA Section IV. Descriptive Information). From a toxicology perspective, 
 

 

 

 

STN PM0000491 – PM0000492 Page 15 of 89 

the breakdown of neomycin phosphotransferase during tobacco processing and burning is a 

reasonable expectation and therefore unlikely to raise concerns. 

Nonetheless, tobacco blend combustion is associated with HPHC production, impacting HPHC 

yields. In this case, the only tobacco variety in VLNTM King and VLNTM 

appears to be low alkaloid 

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

Menthol King cigarettes 

tobacco. tobacco is typically associated with elevated 

nitrogen, ammonia, and nitrogen oxides, which can serve as precursors in the formation of 

TSNAs such as NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) and NNN (nnitrosonornicotine) (Ding et al., 2006; Ding et al., 2008; D. Hoffmann, Djordjevic, & Hoffmann, 

1997; D. H. Hoffmann & Hoffmann, 2001).

(b)(4)

 However, given the disruption in nicotine 

biosynthesis in Vector 21-41 tobacco, it appears that nornicotine, total alkaloids, and 

TSNAs are partially reduced compared to wild-type tobacco plants. The toxicology review states 

that while inferences based on the tobacco blend in VLNTM cigarettes could be further discussed 

regarding specific HPHCs, such as TSNAs, the blend information alone is insufficient to make 

toxicological conclusions. As such, the applicant provided HPHC data for VLNTM King and VLNTM 

Menthol King cigarettes, which are further discussed below. In brief, the HPHC data for both 

VLNTM cigarettes indicates that noncancer hazards and cancer risks are likely similar to or 

slightly lower than NNC cigarettes, based on HPHC comparisons to top market-share cigarettes. 

For both VLNTM King and VLNTM Menthol King cigarettes, there are tobacco filler ingredients in 

the burned portion that may be associated with adverse health outcomes independent of the 

combustion process. Put differently, during cigarette combustion, ingredients may enter 

directly into the mainstream smoke (MSS), which can impact associated hazards and risks. 

Single ingredient additions and associated direct toxicities of concern are discussed in general 

below. Importantly, of the 

(b)(4)

(b)(4)

This is noteworthy, as these ingredients, such are 

, likely decompose into other byproducts, 

(b)(4)

including HPHCs such as aldehydes during combustion, emphasizing the utility of the HPHC 

comparisons to inform ingredient toxicity evaluation. However, depending on the volatility of 

ingredients and temperature gradient moving away from the cigarette coal, it is possible for 

certain amounts of ingredients to enter the MSS unchanged by combustion (U.S. Department of 

Health and Human Services, 2014). In addition, an evaluation of tobacco filler ingredient 

quantities is not on its own sufficient to resolve any potential toxicity concerns, as the potency 

of some ingredients may be much greater or the effect level much smaller, relatively speaking. 

In other words, small quantities of ingredients may still contribute to toxicity concerns. 

Available information on ingredients with known toxicities, such as 

, indicate that they may be associated with adverse respiratory effects and may 

not undergo full transformation during combustion, thus posing potential added risk based on 

(b)(4)

(b)(4)

their inherent respiratory toxicities. Tobacco filler ingredients such as these, therefore, may be 

of toxicological concern, but are not addressed by the applicant regarding their potential 

adverse health effects or their contribution to the relative risk profiles in their comparative 

assessment. The toxicology review includes the available toxicity information for these 

ingredients. Other examples of ingredients that may be of concern include 

(b)(4)
 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 16 of 89 

 which are associated 

with respiratory irritation; they are added to the filler in relatively larger quantities, but 

(b)(4)

available data indicate that these ingredients may transform during combustion, thus 

contributing, in part, to HPHCs. In acknowledgement of the fact that ingredients could impact 

product hazards and risks, FDA notes that the applicant does not have access to the ingredient 

information for the commercially marketed NNC cigarette comparators, which, in part, likely 

explains the absence of potential ingredients from the applicant’s submitted risk assessment. 

Based on information to date, which includes several reductions in HPHCs associated with 

respiratory toxicity, the toxicology review states that the tobacco filler ingredients are unlikely 

to increase the hazards or risks due to use of the VLNTM King and VLNTM Menthol King cigarettes 

compared to the use of commercially marketed NNC cigarettes. Furthermore, this conclusion is 

based on the potential of HPHC decreases to offset the inherent toxicities of the tobacco filler 

ingredients, assuming from a conservative perspective that some tobacco filler ingredients 

enter the MSS unchanged by combustion, at least to some extent. This concern may be further 

reduced if CPD reductions suggested by clinical data occur in practice, which would likely lead 

to comparative reductions in overall exposure and risks. 

2.2.2. Non-tobacco Ingredients 

The chemistry review notes that the applicant provided ingredients and their quantities for all 

casings, flavorings, components, and materials of the VLNTM cigarettes (see Table 2). Ingredient 

supplier, CAS number, purity, and function were also provided where available. The applicant 

also listed individual ingredients contained in complex purchased ingredients such as side seam 

(b)(4)

adhesive, tipping adhesive, adhesives and 

(b) (4)

adhesives. The ingredient information 

indicates that VLNTM cigarettes are composed of identical materials and components except for 

menthol in the filter of VLNTM Menthol King. As shown, these ingredients are commonly used in 

NNC cigarettes. Pyrolysis of many of these ingredients is known to produce HPHCs.

(b)(4)

 For 

example, pyrolysis of

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

 generates mainstream smoke carbonyls 

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

and hydrocarbons such as formaldehyde, acrolein, and benzene. Decrease in has been 

shown to increase NNN, NNK, and 4-aminobiphenyl (Ding et al., 2008). decomposes to 

acrolein, whereas thermally degrades to propylene oxide. In addition, 

combustion of and forms acetaldehyde, formaldehyde, and benzene. 

The VLNTM cigarettes contain approximately mg/cig of . is a 

 containing % (w/w) . The addition of to 

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

tobacco can increase the quantity of nicotine by less than 0.0024 mg/cig and is not expected to 

have a significant impact on the nicotine delivery of the VLNTM cigarettes. 
 

STN PM0000491 – PM0000492 Page 17 of 89 

Table 2: Ingredients Other than Tobacco 

Ingredient CAS # Function Purity 

Quantity (mg/cig) 

VLNTM 

King 

VLNTM 

Menthol 

King 

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

(b)(4)

Top Flavor

 Cigarette Paper 

Tipping Paper 

Filter Tow 

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

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

Plug Wrap 

Inner Plug Wrap

(b)(4)

 Filter 

(b)(4) (b)(4) (b)(4)
STN PM0000491 – PM0000492 Page 18 of 89 

. 

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

 

 

 

 

 (b)(4)

The reported menthol delivery of VLNTM Menthol King is comparable to those of the two 

market-leading king-sized mentholated cigarette brands. 

The VLNTM cigarettes are packed in flip-top hard packs in the same manner as NNC tobacco 

products, with 20 cigarettes per pack and 10 packs per carton. The materials used for packaging 

VLNTM cigarettes are listed in Table 3 below. The same pack and carton materials are used for 

both VLNTM tobacco products, but with different inks to differentiate between the menthol and 

regular products. All packaging components are provided by suppliers of packaging components 

for NNC tobacco products. 

Table 3: Packaging Materials Used in VLNTM Cigarettes 

Part Name Identifying Number Supplier 

Quantity (g/pack) 

VLNTM 

King 

VLNTM 

Menth 

ol King 

Foil (aluminized paper)

Inner frame (cardboard) 

Tear-Tape 

Cellophane 

Hinge-Lid Label (cardboard) 

Carton (cardboard) 

Packaging Glue 

Case (corrugated cardboard) 
 

STN PM0000491 – PM0000492 Page 19 of 89 

2.2.3. Product Design 

The chemistry and engineering relevant product features of the VLNTM cigarettes are shown in 

Table 4. These features include reported cigarette weight, tobacco filler mass, and filler nicotine 

content as well as their target values and upper and lower limits. Although both are king-sized, 

there is a small difference in target cigarette weight between the two VLNTM tobacco products.

 This results in the target cigarette weight of mg for 

VLNTM Menthol King and mg for VLNTM King. The applicant established a target tobacco filler 

nicotine level of mg/g on a dry weight basis, with lower and upper limits of and mg/g 

respectively. The average reported tobacco filler nicotine contents of the 100 top selling U.S. 

(b)(4)

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

cigarette brands and the top six U.S. market leading king-sized cigarette brands were 

determined to be 19.4 mg/g and 18.8 mg/g on a dry weight basis, respectively. Thus, the 

applicant’s statement that VLNTM cigarettes statement have 95% less nicotine when compared 

to the top 100 U.S. cigarette brands and top 6 U.S. market leading king-sized cigarette brands 

appear to be accurate. 

As stated in the engineering review, adequate target specifications and upper and lower range 

limits are provided by the applicant for the parameters listed in Table 4. The specifications 

provided do not raise any concerns from an engineering perspective, as they are recognized as 

specifications that are normal in the combustible filtered cigarette industry. Several range limit 

cells for the cigarette paper and filter are blank. The missing range limits for the paper are 

acceptable, 

, 

. The purchased materials 

are accepted based off certificates of conformance provided by each vendor. The filter 

parameters with blank range limit cells are acceptable as 

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

(b)(4)
 

 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 20 of 89 

Table 4: Cigarette Design Parameters 

VLNTM King VLNTM Menthol King 

Parameter Target Range 

Limits Target Range Limits 

Package Quantity 

20 N/A 20 N/A 

Overall Cigarette 

Length (mm) 

Diameter (mm) 

Puff Count 

Draw Resistance (mm H2O) 

Burn Rate (mm/min) 

Cigarette Mass (mg) 

Cut Size (mm) 

Tobacco 

Filler Mass (mg) 

Rod Density (g/cm3) 

Moisture (%) 

Filler nicotine dry weight 

basis (mg/g) 

Cigarette Paper 

Base Paper Basis Weight 

(g/m2) 

Base Paper Porosity (CU) 

Band Diffusion (cm/s) 

Band Width (mm) 

Band Space (mm) 

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

Filter 

Total Denier (g/9000m) 

Denier Per Filament (DPF) 

Density (g/cm3) 

Draw Resistance (mm H2O) 

Length (mm) 

Ventilation (%) 

Filter Efficiency (%) 

Filter Weight (mg) 

Tipping Paper 

Length (mm) 

N/A – not applicable; N/P – not provided 

(b)(4)

(b)(4)

(b)(4)
 

 

STN PM0000491 – PM0000492 Page 21 of 89 

2.2.4. Manufacturing, Process, and Controls 

VLNTM cigarettes are manufactured at NASCO Products, LLC located at 321 Farmington Road, 

Mocksville, North Carolina 27028. This facility is a wholly owned subsidiary of 22nd Century 

Group, Inc. The applicant provided flowcharts for every manufacturing step including 

. 

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

According to the applicant’s manufacturing information, 

. This 

manufacturing issue was referred to OCE for further investigation during the manufacturing site 

(b)(4)

(b)(4)

inspection. During the April 2019 inspection of the applicant’s NASCO manufacturing facility, 

NASCO’s general manager stated that 

(b)(4)

(b)(4)

(b)(4)

2.2.5. FDA Sample Testing 

The 22nd Century referenced Tobacco Product Master File (TPMF) (and 

amendments ) for all analytical methods used to test 

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

VLNTM and comparator cigarettes described in PM0000491-PM0000492. The owner of 

(b)(4)

, Enthalpy Analytical, provided a letter dated November 16, 2018 authorizing CTP to 

reference in support of all submissions by 22nd Century. The chemistry TPMF 

review evaluates applicable test methods described in and referenced in 

PM0000491-PM0000492. No substantive issues were identified. 

Four batches of VLNTM King and four batches of VLNTM Menthol King were analyzed by Enthalpy 

Analytical via validated testing methods for tobacco filler nicotine content, physical parameters, 

and tar, nicotine, and carbon monoxide (TNCO) measured under the International Organization 

for Standardization (ISO) smoking regimen. The applicant analyzed an additional batch of the 

two VLNTM cigarettes for tobacco filler nicotine content and ISO TNCO. The tobacco nicotine 

content of all tested batches of the two VLNTM

(b)(4)

 tobacco products met their nicotine specification 

of mg/g on a dry weight basis. 
 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 22 of 89 

In accordance with section 910(b)(1)(E) of the FD&C Act, the applicant submitted 22 cartons of 

VLNTM King and 25 cartons of VLNTM Menthol King cigarettes to FDA’s Southeast Tobacco 

Laboratory (STL) on December 4, 2018 in support of these PMTAs. Due to the reported nicotine 

levels of the two VLNTM cigarettes, CTP Office of Science (OS) requested that FDA’s STL analyze 

each tobacco product to confirm the nicotine data submitted in the PMTAs. STL performed the 

requested analysis on February 26 and 27, 2019. 

STL analyzed the VLNTM cigarettes to verify the nicotine data reported in the PMTAs. STL 

reported tobacco nicotine contents on an “as received” basis. Thus, “as received” tobacco 

nicotine contents of the two VLNTM cigarette products and the six market-leading king-sized 

comparator cigarette brands reported in the PMTAs are used for direct comparison. There are 

moderate differences between the STL and PMTA nicotine data for the VLNTM cigarettes. The 

STL data shows higher tobacco nicotine contents but lower nicotine deliveries than the PMTA 

data. However, the absolute nicotine quantity differences are minimal and are considered 

negligible relative to the broad market nicotine data. The STL data shows that the VLNTM 

cigarettes have 97-98% lower nicotine levels in tobacco and mainstream smoke than the top six 

comparator cigarette brands. Accordingly, the STL nicotine data also supports the applicant’s 

statement that the proposed products contain 95% less nicotine. 

Table 5: STL Nicotine Test Results of VLNTM Cigarettes 

HPHC 

STL Nicotine Data PMTA Nicotine Data % Change 

Mean SD N Mean SD N 

STL Data vs. 

PMTA Data 

STL Data vs. 6 

Comparator Data 

PM0000491 - VLNTM King 

Filler nicotine (mg/g)a 0.464 0.006 7 0.412 0.011 5 ↑ 13 ↓ 97 

ISO nicotine (mg/cig) 0.01940b

 0.00066 10 0.0246 0.0015 20 ↓ 21 ↓ 98 

CI nicotine (mg/cig) 0.04447 0.00231 10 0.0566 0.0043 20 ↓ 21 ↓ 98 

PM0000492 - VLNTM Menthol King 

Filler nicotine (mg/g)a

 0.499 0.008 7 0.411 0.011 5 ↑ 21 ↓ 97 

ISO nicotine (mg/cig) 0.02037 0.00116 10 0.0257 0.0012 20 ↓ 21 ↓ 98 

CI nicotine (mg/cig) 0.04518 0.00213 10 0.0551 0.0047 20 ↓ 18 ↓ 98 

CI – Canadian Intense machine smoking regimen 

ISO - International Organization for Standardization machine smoking regimen 

2.2.6. Product Stability 

The applicant conducted stability studies. Samples were analyzed for tobacco filler nicotine and 

mainstream smoke TNCO and water under the ISO smoking regimen. The applicant provided 

the following information: 

● Storage conditions prior to initiating testing: Stability studies were carried out under 

both standard (long-term) and accelerated conditions. These conditions follow the FDA 

Stability Testing Guidance and are appropriate. 

1. Standard evaluation: 25°C ± 2 °C, 60% relative humidity (RH) ± 5% RH for

initially 9 months followed by 3 months for a total 12 months duration

2. Accelerated evaluation: 40°C ± 2 °C, 75% RH ± 5% RH for 6 months
 

 

 

 

STN PM0000491 – PM0000492 Page 23 of 89 

● Testing laboratory and their accreditation(s): Enthalpy Analytical laboratory with 

appropriate accreditation. 

● Quantitative test protocols and methods used: Same as the HPHC test methods. 

● Number of replicates: Twenty replicates were performed for each TNCO analysis, and 

seven replicates were performed for tobacco filler nicotine. 

● Complete datasets: Complete stability datasets are provided in Appendix 11 of 

amendment PM0000497 and in amendments PM0000506, PM0000509, and 

PM0000514. 

● Standard deviation(s): Standard deviations (SD) of the mean were also provided. Mean 

and SD values were verified to be correctly determined. 

● Reference product datasets: 3R4F reference cigarette was tested alongside VLNTM 

cigarettes. 3R4F datasets are provided in Appendix 11 of amendment PM0000497. The 

applicant stated that all quality control samples were within limits. Moreover, the 

applicant’s 3R4F results are comparable to those reported by the University of Kentucky 

and Roemer et al. (Roemer et al., 2012; University of Kentucky)

 In the original application and amendments PM0000497 and PM0000506, the applicant stated 

that the stability studies for the two VLNTM cigarettes are on-going and submitted 9 months 

stability testing data measured under ambient (25°C ± 2 °C, 60% ± 5% RH) storage conditions 

and 6 months data measured under accelerated (40°C ± 2 °C, 75% RH ± 5% RH) storage 

conditions. The chemistry reviewer analyzed the data, including tobacco filler nicotine content 

and mainstream smoke TNCO and water content, and concluded that, except for water content 

in smoke, all stability yields relative standard deviation (RSD) values of the two VLNTM tobacco 

products under both ambient and accelerated storage conditions indicate acceptable variability 

after 9 and 6 months of product storage, respectively (see Section 3.9 of the chemistry review). 

However, the water reported in smoke varied moderately as shown by its RSD values (18-36%). 

Product storage conditions such as temperature, moisture (water content), and duration may 

affect the levels of TSNAs during storage. Based on the variability of water content in smoke of 

the two VLNTM cigarettes at various stability time points, FDA inquired during a teleconference 

on February 19, 2019 whether the applicant tested for TSNAs, over product storage time during 

stability studies. In response, the applicant submitted (PM0000509 and PM0000514) tobacco 

filler water activity (aw) data measured under ambient, for 12 months, and accelerated storage 

conditions, for 6 months. aw is a measure of the amount of water that is available for microbial 

growth in a product. Therefore, changes to aw could potentially affect microbial growth. 

Microbial-mediated nitrite production is a key determinant of carcinogenic TSNA levels in the 

final tobacco product (Brunnemann, Prokopczyk, Djordjevic, & Hoffmann, 1996). 

The applicant stated that as part of the storage stability study, retained samples were frozen for 

possible future analysis. The applicant indicated that the samples were defrosted and analyzed 

for aw by Enthalpy Analytical to determine if there was sufficient water for microbial growth. 

Based on the data provided by the applicant, the aw of all VLNTM cigarettes ranged from 0.465 – 

0.589 under ambient conditions and 0.465 – 0.672 under accelerated product storage 

conditions. It is generally recognized that the aw at which there is no microbial proliferation is 

<0.60 (Beuchat, 1983; Rockland et al., 1987). Additionally, as part of Amendment PM0000514, 
 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 24 of 89 

the applicant provided adequate aw data from a long-term stability study (twelve months under 

ambient conditions) measured over the proposed shelf life and recommended storage 

conditions of the two VLNTM products. Therefore, the aw levels of the two VLNTM products under 

ambient and accelerated conditions, and the increases in aw over the storage time of the 

products is not of concern from a microbiology perspective. Additionally, the chemistry review 

stated that the reported (single measurement) TSNA smoke yields of the two new VLNTM 

tobacco products are lower than the 6 comparator cigarettes, thus it is unlikely that TSNA 

deliveries of the two new VLNTM tobacco products would be higher than those of the market 

leading comparator cigarette brands during product storage. Therefore, the lack of TSNA data 

over complete storage time of the products does not raise any concerns from a chemistry 

perspective. 

In summary, both chemistry and microbiology evaluation of the submitted stability data 

concluded that the applicant provided adequate information for all VLNTM cigarettes to 

demonstrate stability of the products over complete shelf life of the products. 

2.2.7. Inspections of Manufacturing Facilities 

FDA conducted an inspection of the applicant’s manufacturing facility on April 23-26, 2019 to 

confirm the manufacturing information submitted in the PMTAs and determine whether the 

products can be consistently produced. No inspectional observations (Form FDA 483) were 

issued at the conclusion of the visit. The Establishment Inspection Report documents a “No 

Action Indicated” classification for this visit. 

2.2.8. Summary of Composition, Design, and Manufacturing Findings 

The engineering review concludes that the PMTAs contain adequate information with respect 

to the following: 

● A complete characterization of the design parameters that are typical for NNC cigarettes

other than nicotine content.

● An adequate description of manufacturing steps and quality control measures.

● Adequate process controls and quality assurance procedures to help ensure that the

products meet manufacturing specifications for VLNTM cigarettes and that the products

are manufactured in a consistent manner that minimizes the product quality variability.

● Performance testing to verify the product design.

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

information to characterize the product design and adequate processes and controls to help 

ensure that the products meet the manufacturer’s specifications. 

The chemistry review concludes these PMTAs contain adequate information with respect to the 

following: 

● A complete list of uniquely identified components, ingredients, and additives by 

quantity in each new tobacco product as well as the applicable specifications and a 

description of the intended function for each. 
 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 25 of 89 

● An adequate description of manufacturing/packaging steps and quality control 

measures in place. 

● Sufficient information to assure FDA that the products meet manufacturing 

specifications for the tobacco products (specifically target nicotine levels) and that the 

products are manufactured in a consistent manner that minimizes product quality 

variability. The tobacco nicotine content of all 10 batches of VLNTM cigarettes met the 

(b)(4)

nicotine specification of mg/g on a dry weight basis. 

● Data on chemical endpoints establishing the stability of the product through the stated 

shelf life. 

● Product analyses for verifying the product formulations. 

● Testing data to demonstrate that the new products contain significantly lower levels of 

nicotine compared to major combusted cigarettes on the U.S. market. 

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

to characterize the product composition and design and describe the manufacturing processes 

and controls that can affect the product composition, chemical stability, and HPHC levels to 

help ensure that the products meet the manufacturer’s specifications. 

The microbiology review concludes that the applicant provided adequate microbiology-related 

information to demonstrate product stability. As TPL, I agree with the microbiology conclusions. 

The OCE manufacturing review identified no significant compliance issues during the 

manufacturing inspection conducted, and no observations were issued at the time of 

inspection. 

2.3. Toxicological Risk Assessment 

2.3.1. Harmful and Potentially Harmful Constituents (HPHCs) 

2.3.1.1. General Overview 

The applicant tested and reported HPHC data including all abbreviated HPHCs recommended 

for cigarette mainstream smoke under both ISO and Canadian Intense (CI) machine smoking 

regimens.3 The applicant also reported mainstream smoke HPHCs for the six market-leading 

king-sized cigarette brands measured under the ISO smoking regimen. The applicant obtained 

CI HPHC data of the six comparator cigarette brands from the HPHC reports submitted by 

tobacco manufacturers pursuant to section 904(a)(3) of the FD&C Act. 

The HPHCs in the two VLNTM cigarettes and six comparator cigarette brands measured under 

the ISO and CI smoking regimens were analyzed using the “two one-sided tests” (TOST) 

methodology to determine analytical equivalence. For the TOST equivalence test, the 

recommended important analytical differences are 10% for tar and carbon monoxide, 15% for 

nicotine and 20% for other HPHCs.5 

5 Division of Product Science Memorandum “Equivalence Testing for SE Evaluations” 
 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 26 of 89 

The VLNTM cigarettes have lower reported yields of many HPHCs including nicotine, acrolein, 

formaldehyde, benzo[a]pyrene, and TSNAs than the six comparator cigarette brands under the 

ISO smoking regimen. Reported yields of other HPHCs including menthol are comparable. 

However, reported smoke yields of acrylonitrile, 4-aminobiphenyl and ammonia are higher for 

both VLNTM cigarettes, whereas benzene yield is also higher for VLNTM Menthol King cigarettes. 

The applicant explained that the Vector 21-41 VLNTM tobacco technology that inhibits nicotine 

and TSNA production pathways may cause accumulation of ammonia and other nitrogencontaining constituents such as 4-aminobiphenyl in the plant. The change in the HPHC smoke 

yields is reviewed by toxicology and discussed below. 

2.3.1.2. ISO Regimen HPHC Data 

Per the applicant’s submitted ISO regimen HPHC data and chemistry’s TOST analysis, there are 

three analytically non-equivalent HPHC increases for VLNTM King cigarettes and four analytically 

non-equivalent HPHC increases for VLNTM Menthol King cigarettes in comparison to the average 

of the six commercially marketed NNC cigarette comparators. In both cases, acrylonitrile is 

increased (49% and 55% respectively), 4-aminobiphenyl is increased (21% and 19% 

respectively) and ammonia is increased (120% and 150% respectively). The applicant states that 

the significant increases in 4-aminobiphenyl and ammonia are expected side-effects of the 

genetic engineering of the VLNTM

(b)(4)

 tobacco. Specifically, the applicant states, “the nicotine 

and TSNA production pathways in VLNTM tobacco plants are intentionally inhibited. This results 

in a slight accumulation of ammonia in the plant. It is hypothesized that the plant continues to 

assimilate nitrogen resulting in an increase in smoke ammonia as well as other nitrogen 

containing constituents, including 4-aminobiphenyl....” The HPHC data appear to reflect the 

applicant’s statement, as both nicotine and TSNAs are decreased, while 4-aminobiphenyl and 

ammonia are increased. 

Regarding the appropriateness of the commercially marketed NNC cigarette comparators, there 

are differences in design features that may impact MSS HPHC levels and comparisons. 

However, the applicant appears to employ sufficient selection criteria for marketed 

comparators, mainly based on market share analysis but also based on some design features. 

Per the applicant, the combined users of the commercially marketed NNC cigarette 

comparators represent around 25% of all smokers. In addition, all the products are king size, 

with similar yet small nuanced differences in lengths and weights that may or may not impact 

HPHC production. Conversely, filter ventilation, or pores in the filter, which allow for the 

dilution of MSS during ISO regimen machine smoking, can tend to lower the expected absolute 

yields of HPHCs (along with a decrease in puffing volume and increased interpuff interval) 

(Counts, Morton, Laffoon, Cox, & Lipowicz, 2005; Kozlowski & O'Connor, 2002; Song et al., 

2017). Aside from Newport Menthol Green cigarettes (2%) and Marlboro Red cigarettes 

(10.8%), commercially marketed NNC cigarette comparators have ventilation levels greater 

than 28%, while the VLNTM cigarettes are only ventilated at a level of 12.5%. Thus, in this specific 

case, increased HPHCs in the VLNTM cigarettes may potentially be overestimated by direct 

comparison to the averaged HPHC values in the commercially marketed NNC cigarette 

comparators. The change in ventilation may also impact product use behavior (Kozlowski et al., 
 

 

 

 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 27 of 89 

1998; O’Connor et al., 2008; Stephens, 2007), which is briefly noted here given that behavioral 

changes can impact exposure and, therefore, user toxicities. Specifically, in describing the 

exposure variables and assumptions in its whole product risk assessment, the applicant 

included behavioral components such as CPD and puff volume. Nonetheless, based on the 

individual product comparisons provided in the applicant’s Table 33, the HPHC differences 

between VLNTM King cigarettes and Marlboro Red cigarettes, and VLNTM Menthol King cigarettes 

and Newport cigarettes appear within range of the average values. 

Qualitatively, the ISO HPHC mean increases and decreases can be assessed, in part, based on 

the carcinogenic and noncarcinogenic effects of each HPHC, the number of HPHC decreases 

that occur concurrently with an increase, and the magnitude and potency or effect level of the 

HPHCs. Qualitative evaluation of HPHC data comparisons can indicate whether there may be an 

increase in potential toxicity between the products, prior to considering a quantitative risk 

assessment (QRA), which is also discussed below. In both cases—using a qualitative or 

quantitative approach—the product use behavior is considered to be the same between the 

VLNTM cigarettes and the commercially marketed NNC cigarette comparators, given unknowns 

surrounding actual use behavior that may occur in a real-world market landscape. This may be 

a conservative approach, given the applicant’s submission of two key studies demonstrating 

about a 25% reduction in product use in users that acutely and completely switch to SPECTRUM 

cigarettes, which are nearly identical to the VLNTM cigarettes. 

The toxicology review determined that overall, based on ISO regimen HPHC data, the 

noncancer hazards due to use of the VLNTM cigarettes are likely similar to those with use of the 

commercially marketed NNC cigarette comparators. In addition, based on the ISO regimen 

HPHC data, cancer risks due to use of the VLNTM cigarettes are likely similar and may be less 

than those associated with use of the commercially marketed NNC cigarette comparators. 

2.3.1.3. CI Regimen HPHC Data 

The applicant did not test mainstream smoke HPHCs of the six comparator cigarette brands 

under CI conditions. Under a Freedom of Information Act (FOIA) request, the applicant 

obtained the CI HPHC data of the six comparator cigarette brands from the HPHC reports 

submitted by tobacco manufacturers pursuant to section 904(a)(3) of the FD&C Act. The VLNTM 

cigarettes generated lower or comparable reported smoke yields of most HPHCs compared to 

the six comparator cigarette brands. Note that the reported 97% decrease in nicotine deliveries 

under the CI smoking regime supports the applicant’s “95% Less Nicotine” statement for its 

products. Besides the substantial reported increase in ammonia, there are moderate increases 

in acetaldehyde and acrylonitrile smoke yields for both VLNTM cigarettes. These additional 

reported HPHC increases observed under the CI smoking regimen were evaluated by toxicology 

for evaluation of health risks. 

Per the applicant’s submitted CI regimen data and chemistry’s TOST analysis, there are three 

HPHC increases for VLNTM King cigarettes and three increases for VLNTM Menthol King cigarettes 

in comparison to the average of the six commercially marketed NNC cigarette comparators. In 

both cases, there is an increase in ammonia (420% and 490% respectively) as well as increases 
 

 

 

 

STN PM0000491 – PM0000492 Page 28 of 89 

in acrylonitrile (43% and 44% respectively) and acetaldehyde (33% and 33% respectively). The 

increase in ammonia is consistent with the ISO results and likely expected, as stated by the 

applicant, given their hypothesis around the anticipated increases in nitrogen assimilation that 

still occur despite genetic modification of the nicotine biosynthesis pathway. 

The increases in both acrylonitrile and acetaldehyde are consistent with previous reports 

demonstrating that these HPHCs mainly occur in the gas phase of MSS, which, on average, 

tends to be increased relatively more than particulate-phase constituent yields, when 

comparing CI regimen data to ISO-regimen data (Counts et al., 2005). Higher levels of 

acetaldehyde may be expected given that increases in certain aldehydes are associated with 

larger puff volumes as well as the lack of ventilation during the CI regimen, which may intensify 

the combustion of added or natural sugars ( 

(b)(4)

; Pauwels et al., 2018). Lastly, the 

reductions in TSNAs, nicotine, formaldehyde, acrolein, and benzo[a]pyrene are consistent with 

the ISO-related results. 

While the applicant reported 33% more acetaldehyde in their product compared with the 

average of the 6 comparators in the CI measured yields, the values provided for the VLNTM 

cigarettes and the comparators are all within average values reported in literature for 

cigarettes in general (Talhout, Opperhuizen, & van Amsterdam, 2007). It is also possible that 

the 33% higher level of acetaldehyde in the VLNTM products compared to the six commercially 

marketed cigarette may be an artifact of the number of comparator products tested. When 

compared with the acetaldehyde values found in the FDA50, the OS analysis of 50 popular 

cigarettes in 2011 through a collaboration between CTP and CDC, the percent change between 

the FDA50 products and the VLNTM cigarettes under the CI measurement regime is reduced to 

6% less acetaldehyde in the VLNTM cigarettes compared with the FDA50. This is in line with the 

comparisons of the ISO regime values comparing the VLNTM cigarettes with both the 6 

comparator products provided by the company, as well as with the FDA50. Therefore, the 33% 

higher levels of acetaldehyde found by the applicant in their comparison is not a concern. 

Any assumptions pertaining to the discussion for the qualitative ISO evaluations above also 

apply to the evaluation of CI data here, specifically regarding the potential for carcinogenic and 

noncarcinogenic HPHCs to offset each other, as well as any available data pertaining to product 

usage. Conservatively, the VLNTM cigarettes and commercially marketed NNC cigarette 

comparators are assumed to be used the same by potential users. Specifically, the toxicology 

review defines VLNTM cigarettes users as completely switching, in acute fashion, from a 

commercially marketed cigarette. However, as the applicant did not provide evaluation 

regarding the potential risks based on CI data, discussion pertaining to the potency or degree to 

which toxic effects may be observed for a given HPHC is based on the magnitude of HPHC 

changes and the reference toxicity values as detailed in Table 3 of the toxicology review. 

The toxicology review noted that increases in acetaldehyde and acrylonitrile via the CI regimen 

likely do not raise cancer-risk-related concerns for the VLNTM cigarettes. Overall, based on these 

CI regimen HPHC data, cancer risks are likely similar with use of VLNTM cigarettes and use of the 

commercially marketed NNC cigarette comparators. The increase in ammonia via the ISO 
 

 

 

 

 

STN PM0000491 – PM0000492 Page 29 of 89 

regimen likely does not raise noncancer-hazard-related concerns for the VLNTM cigarettes. For 

example, any increase in respiratory effects due to ammonia, acetaldehyde, and acrylonitrile 

may be offset by other HPHCs that are decreased and broadly target the respiratory tract. In 

this case, these increased HPHCs occur concurrently with decreases in the respiratory irritants, 

formaldehyde, 1,3-butadiene, and acrolein that offset the increased respiratory hazards due to 

ammonia, acetaldehyde, and acrylonitrile. Overall, based on the CI regimen HPHC data, 

noncancer hazards due to use of the VLNTM cigarettes are likely similar to those with use of the 

commercially marketed NNC cigarette comparators. 

2.3.1.4. Comparison Between VLNTM Cigarettes and SPECTRUM Research 

Cigarettes 

Numerous clinical and nonclinical studies have been conducted using VLNC cigarettes. 

SPECTRUM research cigarettes NRC102 and its mentholated version NRC103 are among the 

VLNC products often studied in clinical research. Similar to the two new VLNTM cigarettes, 

Spectrum NRC102 and NRC103 also contain a tobacco filler with reported nicotine content of 

0.5 mg/g on a dry weight basis. The applicant states that SPECTRUM NRC102 is the same as 

VLNTM King cigarette, and SPECTRUM NRC103 is the same as VLNTM Menthol King cigarette. To 

bridge clinical data of Spectrum NRC102 and NRC103 to VLNTM King and VLNTM Menthol King 

cigarettes, respectively, their characteristics are compared and evaluated. Note that the main 

product performance attributes of VLNCs such as SPECTRUM cigarettes are nicotine and HPHC 

smoke yields. 

The chemistry review compared reported design features and product materials between 

SPECTRUM and VLNTM cigarettes. The cigarette weight, cigarette length, cigarette diameter, and 

tipping paper permeability are the same between SPECTRUM and VLNTM cigarettes. The two 

products also share many of the same components and materials including tobacco type, 

tobacco blend, cigarette paper, filter, seam adhesive, and tipping adhesive. The only material 

difference is that the SPECTRUM tipping paper has a silver line and the name SPECTRUM 

printed on it, whereas the VLNTM tipping paper does not have any markings. The base tipping 

paper for both tobacco products has the same porosity (100CU) and is produced by the same 

manufacturer, The slight 

(b)(4)

difference in tobacco weight (<2%) is not expected to 

significantly affect smoke deliveries. Ventilation levels are different: 30% for SPECTRUM and 

12.5% (target level) for VLNTM cigarettes. Behavioral and clinical pharmacology (BCP) evaluated 

the ventilation levels and determined that from the BCP perspective this difference in 

ventilation does not raise a concern. While the majority of information on BOE came from the 

SPECTRUM cigarette literature, the applicant-provided clinical studies show evidence of similar 

nicotine exposure, non-nicotine HPHC exposure, use behaviors, and subjective effects between 

VLNTM and SPECTRUM VLNC cigarette smokers. As nicotine is the driver of addiction, there is 

significantly lower nicotine delivery from VLNTM products and reduced abuse liability (e.g., 

satisfaction, liking) compared to UB-NNC cigarettes, similar to what is observed with SPECTRUM 

cigarettes. Although some HPHC yields are different, the reduction in non-nicotine BOE is based 

on the reduced content of some HPHCs in VLNTM products compared to conventional cigarettes, 

and on how people use the product (i.e., dependent upon smokers reducing their CPD). There is 
 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 30 of 89 

no evidence to suggest that individuals would use VLNTM products differently than SPECTRUM 

cigarettes. Therefore, the non-nicotine BOE reported in the SPECTRUM cigarette literature may 

be extrapolated to the VLNTM products. Although machine measured HPHC yields are slightly 

higher in VLNTM products compared to SPECTRUM, we expect people who switch to VLNTM 

products to smoke fewer cigarettes than their UB-NNC cigarettes. This would lead to reductions 

in BOE compared to UB-NNC cigarettes, and likely be comparable to the levels of BOE reported 

in SPECTRUM studies. 

The reported nicotine smoke yields of SPECTRUM NRC102 and NRC103 are slightly lower than 

those of VLNTM King and VLNTM Menthol King under both the ISO and CI smoking regimens (0.02 

mg/cig and 0.04 mg/cig vs. approximately 0.025 mg/cig and 0.056 mg/cig, respectively). The 

nicotine deliveries of SPECTRUM NRC102 and NRC103 cigarettes are overall similar to those of 

VLNTM King and VLNTM Menthol King, respectively, relative to NNC cigarettes. Reported carbon 

monoxide (CO) yields are equivalent between SPECTRUM NRC102 and NRC103 cigarettes and 

VLNTM cigarettes. Thus, SPECTRUM NRC102 and NRC103 are considered similar to VLNTM King 

and VLNTM Menthol King, respectively, based on TNCO deliveries, which are the main product 

performance attributes. Therefore, clinical and nonclinical data of SPECTRUM NRC102 and 

NRC103 cigarettes, which are based mainly on TNCO smoke yields and tobacco nicotine 

content, may be bridged to VLNTM King and VLNTM Menthol King cigarettes respectively. 

For other HPHCs, SPECTRUM NRC102 and NRC103 and VLNTM cigarettes generated similar 

smoke yields of crotonaldehyde under the ISO smoking regimen and acetaldehyde under the CI 

smoking regimen. Additionally, SPECTRUM NRC102 and VLNTM King generated similar smoke 

yields of acrolein and benzo[a]pyrene under the ISO smoking regimen, as well as acrolein, 1-

aminonaphthalene, and NNK under the CI smoking regimen. SPECTRUM NRC102 and NRC103 

cigarettes generated considerably higher smoke yields of most other HPHCs including 

benzo[a]pyrene compared to VLNTM King and VLNTM Menthol King respectively, which do not 

raise concerns for the VLNTM cigarettes. In contrast, SPECTRUM NRC102 and NRC103 cigarettes 

generated lower smoke yields of 4-aminobiphenyl and NNN under the ISO smoking regimen, 

and crotonaldehyde, formaldehyde, and NNN under the CI smoking regimen. Although the 

noted HPHC differences should be considered when bridging clinical and nonclinical data, the 

differences in these other HPHC yields do not raise concerns. Moreover, the chemistry review 

notes that the differences in the HPHC data between VLNTM and SPECTRUM cigarettes may be 

attributable to samples manufactured and tested four years apart using two different 

laboratories. If the applicant wishes to retest mainstream smoke HPHCs of VLNTM and 

SPECTRUM cigarettes for HPHC data comparison, FDA suggests that appropriate testing 

measures be taken including, but not limited to, using the same laboratory, the same methods, 

similar sample storage conditions and duration, and testing within similar timeframe to 

minimize HPHC data variability. 

Based on the overall product design features, components, materials, tobacco type, tobacco 

blend, tobacco filler nicotine, nicotine and tar deliveries, and many equivalent MSS HPHCs, 

SPECTRUM NRC102 and NRC103 research cigarettes are considered similar to VLNTM King and 

VLNTM Menthol King cigarettes. 
 

 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 31 of 89 

2.3.2. Nonclinical Studies and Literature Search 

The applicant submitted information detailing a comprehensive literature search (performed by 

Scitek Information Services) to identify all possible publications that relate to VLNTM or VLNC 

cigarettes from 1960 through May 2018. The databases included in the search were Medline, 

Embase, Biological Abstracts (BIOSIS), Chemical Abstracts, and ToxCenter. Overall, the 

toxicology review noted that the broad methodology and systematic approach appears to be 

sufficient for identifying key nonclinical and clinical studies that may be pertinent to the 

toxicology evaluation of VLNTM cigarettes. 

The applicant submitted eight nonclinical studies, including one that used SPECTRUM research 

cigarettes and seven that used Quest cigarettes. Although Quest cigarettes, as stated by the 

applicant, contain VLNC tobacco, virtually every other parameter, including the tobacco blend, 

design features, and HPHCs are different. As such, it is unclear how the data in the seven 

associated studies can be extrapolated to the VLNTM cigarettes. As noted by the applicant, the 

only Quest-related study that may be relevant is by Ramachandran, Rubenstein, Bluestein, and 

Jesty (2004), which demonstrates that low nicotine cigarettes may adversely sensitize platelets 

to flow-induced activation compared to higher nicotine cigarettes. The direct evidence in the 

study of an effect on platelets pertained to nicotine: nicotine was added back to the cigarette 

smoke extract sample derived from zero-nicotine Quest cigarettes, which appeared to reduce 

the platelet-activating potential. However, this study may have several methodological issues 

that preclude its meaningfulness, including the lack of detail and consistency pertaining to the 

cigarette smoke extraction process, as well as a lack of detail, criteria and subsequent 

methodologies pertaining to the collection of platelets from individual test subjects and how 

they were used or combined during experimentation. 

As stated above, the applicant also cites one study that used SPECTRUM® research cigarettes 

(Naik, Sajja, Prasad, & Cucullo, 2015). The overall conclusion by the study authors was that the 

toxicity of the SPECTRUM® cigarettes was equivalent to that of 3R4F cigarettes. This conclusion 

reached by the authors, that oxidative damage to cells and tissues is not different, is consistent 

with the qualitative discussion above that demonstrates that the potential toxicant-associated 

risks and hazards are likely similar. 

2.3.3. Quantitative Risk Assessment (QRA) 

The QRA provided by the applicant has limitations as detailed in the toxicology review; 

nonetheless, the conclusions generally support those of the qualitative HPHC evaluation. The 

toxicology review notes that the total absolute hazards and total absolute cancer risks provided 

by the applicant are likely inaccurate given the reasons stated below, which preclude the utility 

of the QRA to support the applicant’s conclusions. However, PM0000491 and PM0000492 each 

detail HPHC comparisons of the VLNTM cigarettes to the average HPHCs of six commercially 

marketed conventional cigarette comparators. Across the product comparisons, regarding the 

ISO and CI HPHC comparisons, it is assumed, by the applicant and in the toxicology review, that 

the VLNTM cigarettes are used in the same manner as the commercially marketed NNC cigarette 

comparators. As such, any differences identified by the applicant in its QRA simply reflect the 

differences in HPHC levels (i.e., not impacts due to differences in CPD, puffing behavior, etc.). In 
 

 

STN PM0000491 – PM0000492 Page 32 of 89 

other words, the applicant applied the same exposure assumptions and the same reference 

toxicity values to the HPHC levels for the VLNTM cigarettes and the commercially marketed NNC 

cigarette comparators. 

As such, the toxicology analysis focused on the HPHC yields, potencies, and magnitudes, 

concluding that the impact of the HPHC increases were likely not a concern, given the HPHC 

decreases with similar associated adverse health effects. In this case, a QRA is not necessary to 

quantify any potential hazard and risk differences due to the increased HPHCs in the VLNTM 

cigarette MSS compared to the average MSS HPHC levels of the commercially marketed NNC 

cigarette comparators chosen by the applicant. As noted in the HPHC evaluation, and by the 

applicant, the substantial reductions in TSNAs appear to be an important driver of the riskrelated conclusions. Overall, from a toxicology perspective, the combined hazards and risks are 

likely similar, and available data may indicate that potential reductions in toxicity-related 

endpoints that may occur would likely be due to potential decreases in product use. As 

throughout this review, this conclusion is likely dependent on cigarette use behavior. 

2.3.4. Summary of Toxicological Findings 

The applicant states that the health risk profile for the VLNTM cigarettes is the same as that for 

NNC cigarettes with the only difference being the low nicotine levels in the VLNTM cigarettes. 

The toxicology review provides this summary of key findings: 

● The applicant cited potential evidence from nonclinical and clinical studies in support of 

the HPHC comparisons between VLNTM cigarettes and six commercially marketed NNC 

cigarettes. The results of a toxicology evaluation demonstrate that the overall toxicantassociated noncancer hazards and cancer risks due to use of VLNTM cigarettes are likely 

similar to the six NNC cigarettes comparators that represent approximately 25% of the 

cigarette market, assuming that the VLNTM cigarettes will be used in the same way as the 

marketed NNC cigarette comparators in this application. 

● The only relevant behavior that can be extended to the toxicology review is the 

potential covering of filter ventilation holes as well as more intense puffing, which is 

available through the analysis of intense (CI regimen, ventilation holes covered) and less 

intense (ISO regimen, ventilation holes uncovered) MSS data. The ISO regimen HPHC 

data, and the associated HPHC evaluation and qualitative assessment discussed in this 

review, tends to support the applicant’s QRA conclusions that noncancer hazards and 

cancer risks are likely similar or lower for users of VLNTM cigarettes compared to top 

market-share commercially marketed cigarettes. The CI regimen HPHC data and the 

associated HPHC evaluation and qualitative assessment discussed in the review likely 

demonstrate that the noncancer hazards and cancer risks are similar, but the applicant 

did not submit a separate QRA to support any risk-related conclusions based on CI 

regimen HPHC data. Nonetheless, the overall toxicant risk to users, assuming they 

completely switch to VLNTM cigarettes, is likely similar or lower than the toxicant risk for 

users of the six comparator cigarettes currently on the market. 

● The applicant likely overestimated the potential noncancer and cancer reductions that 

occur in users of VLNTM King and VLNTM Menthol King cigarettes. Potential toxicant risks 
 

 

 

 

STN PM0000491 – PM0000492 Page 33 of 89 

for populations other than complete switchers, including dual users of VLNTM cigarettes 

and another tobacco product and non-users exposed to second hand smoke from VLNTM 

cigarettes, are likely similar as the risks to those populations posed by the six 

commercially marketed NNC cigarette comparators. Overall, the toxicological 

differences in hazards and risks between users of VLNTM cigarettes and users of the six 

comparators is likely impacted by anticipated changes in smoking behavior, if they 

occur, and not due to any inherent changes in HPHCs that, in part, arise as a result of 

genetic modifications that define the VLNTM tobacco. Tobacco filler and other material 

ingredients in the VLNTM cigarettes are, overall, likely similar to those in the six 

comparators, and any related impact due to their combustion, (i.e., HPHC production) 

are unlikely to raise toxicology concerns. Specifically, these ingredients likely do not 

raise additional concerns, given the relative reduction in HPHCs that may have similar 

adverse health effects to any increased ingredients potentially entering the MSS 

unchanged by combustion. Thus, overall, if there were evidence to support that users 

would switch to the VLNTM cigarettes, then toxicant-related health risks are likely to be 

similar to those due to the use of the six comparators. If switching resulted in reductions 

in CPD, then use of VLNTM cigarettes may result in lower toxicant exposure or health risks 

in comparison to those due to the use of the six comparators. 

● In addition, evidence from clinical studies may indicate that the associated noncancer 

hazards and cancer risks could be lower compared to the six NNC cigarette comparators, 

as users of products very similar (i.e., SPECTRUM VLNC cigarettes) to the VLNTM 

cigarettes tend to decrease their CPD and puffing volumes if they completely and 

acutely switch from their UB-NNC cigarettes to very low nicotine cigarettes. This 

suggests that toxicological impacts may be proportionately decreased if users were to 

switch, due to a reduction in CPD. To this latter point, clinical biomarkers of exposure 

(e.g., NNAL, CO, PheT, and 3-HMPA) tend to support that acute and complete switching 

is associated with HPHC and CPD reductions, whereas gradual switching is not, 

suggesting that the reduction in HPHCs, and therefore associated hazards or risks, likely 

occurs via the reduction in CPD. 

● Noncancer hazards and cancer risks to dual users of tobacco products, where at least 

one product is VLNTM King or VLNTM Menthol King cigarettes, are also likely to be similar 

or lower than hazards and risks to NNC cigarette smokers, to the extent that the use of 

such additional tobacco products, or NRT, is less harmful than the six comparators. By 

extension of the comparative risks for complete switchers, or for dual users in which 

one product is one of the VLNTM cigarettes, the associated exposures and risks posed to 

non-users through second hand smoke (SHS) are also likely similar to exposure to SHS 

from NNC cigarettes. The extent to which this is true for dual users is, however, also 

dependent on the likelihood that the use of additional tobacco products is less harmful 

than use of the six comparators. Using VLNTM cigarettes compared to quitting tobacco 

use or switching to NRT would increase harm, as toxicant exposures would be similar to 

exposures resulting from NNC cigarette use. The likelihood that users of VLNTM cigarettes 

switch to NRT or relapse back to VLNTM cigarettes is outside the scope of this review. For 

non-users seeking to initiate smoking by using VLNTM cigarettes, their toxicant exposures 

and risks would likely be similar to those of naïve users who initiate smoking with an 
 

 

 

STN PM0000491 – PM0000492 Page 34 of 89 

NNC cigarette such as the six comparators. 

● Overall, if there were evidence to support that users would switch to the VLNTM 

cigarettes, then toxicant health risks are likely to be similar to those of the six 

comparators that represent 25% of the cigarette market. If switching resulted in 

reductions in CPD, then use may result in lower toxicant or health risks in comparison to 

use of the six comparators. Given these conclusions, from the toxicology perspective, 

the information presented in the applications does not raise concerns about issuing 

marketing orders. 

As TPL, I agree with the toxicology review conclusion. After consideration of all the toxicological 

data presented, the overall toxicological risks of VLNTM cigarettes are likely similar to those 

associated with use of the six comparator products that represent a significant portion of the 

cigarette market. However, the potential for a relative benefit compared to NNC cigarettes 

exists for smokers who switch completely to VLNTM cigarettes, then reduce cigarette use, and 

eventually totally quit. 

2.4. Individual Health Impact 

2.4.1. Overview of Behavioral and Clinical Pharmacology (BCP) Studies 

The applicant originally submitted two completed abuse liability studies on VLNTM cigarettes as 

well as a literature review that allowed for an assessment of BCP outcomes. Amendment 

PM0000519 contained a third clinical study, a 6-week switching study, sponsored by the 

applicant that was also considered as part of the FDA scientific evaluation. 

The applicant’s studies on VLNTM cigarettes provided information on VLNTM King and VLNTM 

Menthol King cigarette abuse liability, including evaluations of subjective effects using visual 

analog scales (VAS), pharmacokinetics (PK), and product use behaviors (e.g., amount of product 

consumed, topography). 

The two abuse liability studies and one 6-week switching study were: 

1. NCT0359751: Evaluation of the Abuse Liability of Very Low Nicotine

Cigarettes

2. NCT03559725: Evaluation of the Abuse Liability of Very Low Nicotine

Mentholated Cigarettes

3. NCT03571724: A Longitudinal Ambulatory Study to Assess Changes in

Cigarette Consumption Behavior and Biomarkers of Exposure during a 6-

Week Switch to Very Low Nicotine Cigarettes

The first two studies evaluating abuse liability (NCT0359751 and NCT03559725) were designed 

in the same way but used different study products. A general summary of study design is as 

follows: 

Study products: VLNTM King cigarettes, UB-NNC cigarettes, 4 mg Nicorette® Original 

Flavor nicotine gum and VLNTM Menthol King cigarettes, UB-NNC menthol cigarettes, 4 
 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 35 of 89 

mg Nicorette® White Ice MintTM nicotine gum. The VLNTM cigarettes and nicotine gums 

were provided free of charge; participants supplied their UB-NNC cigarettes in both 

studies. 

Study design: Six-day, within-subject, confined, cross-over study. Phase A (Days 1-3) 

involved four-hour ad libitum use of one of the three study products. Phase B (Days 4-6) 

consisted of controlled use (10 puffs, 3 seconds per puff, 30 second interpuff interval; 

chew and park method for 10 minutes), followed by ad libitum use of the same product 

for 10 minutes. 

Relevant study outcomes: Phase A outcome measures included a self-reported VAS to 

assess “use product again” at the end of the session and product use behaviors (number 

of units consumed, time spent per unit). Phase B outcome measures included nicotine 

PK parameters (i.e., Cmax (maximum measured plasma nicotine concentration), Tmax (time 

of the maximum measured plasma nicotine concentration), T1/2 (apparent first-order 

terminal nicotine elimination half-life calculated as 0.693/Kel of the plasma 

concentration-time curve from time 0 to 180 minutes), AUC0-180 (area under the nicotine 

concentration-time curve calculated using linear trapezoidal summation from time 0 to 

180 minutes), VAS Tobacco/Nicotine Withdrawal Scale, VAS Direct Effects of Product 

Questionnaire, and topography (i.e., number of puffs, puff duration). 

A general summary of the third study evaluating BOE after 6 weeks of exposure (NCT03571724) 

is as follows: 

Study products: VLNTM King and Menthol King Cigarettes, participant’s UB-NNC 

cigarettes. VLNTM King and Menthol King cigarettes were provided free of charge at each 

visit; participants purchased their own UB-NNC cigarettes. 

Study design: An open-label, randomized, forced-switching study conducted at two 

United States study sites. All participants smoked their UB-NNC cigarettes for one week, 

then were randomized to either continue smoking their UB-NNC cigarettes (n=22 nonmenthol, n=20 menthol) or switch to smoking VLNTM King (n=50) or VLNTM Menthol King 

(n=50) cigarettes for 6 weeks. A subset of 18 non-menthol and 18 menthol smokers 

assigned to switch to smoking VLNTM cigarettes completed the topography assessments. 

A further subset of 12 non-menthol and 12 menthol smokers who completed the 

topography assessments also completed a nicotine PK assessment. Participants were 

confined overnight to collect 24-hour urine samples for BOE assessments and for 

nicotine PK and topography assessments in the selected participants. Measures were 

collected at the end of Week -1 (baseline), Week 2, Week 4 (subjective questionnaires 

only), and Week 6. 

The applicant analyzed the data based on a per protocol (PP) population (i.e., 

participants who were near complaint based on if their ratio of [plasma cotinine/CPD 

VLN]/[plasma cotinine/CPD baseline] exceeded 0.2; n=10 non-menthol, n=9 menthol) 

and an intent-to-treat (ITT) population (i.e., participants who had at least one valid 
 

 

 

 

 

STN PM0000491 – PM0000492 Page 36 of 89 

recording of cigarette consumption, with documented non-compliance; n=43 nonmenthol, n=42 menthol). The rationale for this analysis was to present the best possible 

outcome of completely switching to VLNTM cigarettes (PP population) and the more likely 

situation, where consumers who want to quit may have difficulty adhering to just

smoking VLNTM cigarettes and would alternate between UB-NNC cigarettes and VLNTM

cigarettes (ITT population). 

Relevant study outcomes: The primary study outcomes were CPD, number of collected 

cigarette butts to measure compliance and accuracy of self-report, and puff topography 

(puff duration, puff volume, peak puff flow rate, average flow rate and inter-puff 

interval). Secondary outcomes included changes in BOE (urinary NNAL [an NNK 

biomarker], NNN, 3-hydroxypropylmercapturic acid [3-HPMA, an acrolein biomarker], Sphenylmercapturic acid [S-PMA , a benzene biomarker], 1-hydroxypyrene [1-HOP, 

hydroxypyrene biomarker], TNE, blood carboxyhemoglobin [COHb], plasma cotinine), 

nicotine PK (Cmax, Tmax, AUC), and subjective measures of dependence (FagerstrÖm Test 

for Cigarette Dependence [FTCD]), smoking urges (Brief Questionnaire of Smoking 

Urges [QSU-Brief]), and withdrawal symptoms (Minnesota Nicotine Withdrawal Scale -

Revised [MNWS-R]).

Results of these three studies, as well as relevant findings from the literature, are discussed by 

outcome below. 

2.4.2. Nicotine Pharmacokinetics 

Abuse Liability Studies NCT0359751 and NCT03559725: 

During the controlled use portion of Phase B of the studies, the nicotine Cmax for VLNTM King 

cigarettes and VLNTM Menthol King cigarettes was significantly lower (0.47 ng/ml and 0.40 ng/ml 

at 7 minutes, respectively) than UB-NNC cigarettes (13.7 ng/ml at 7 minutes) (p < 0.0001) and 

Nicorette® Original Flavor or Nicorette® White Ice MintTM nicotine gum (3.5 ng/ml and 3.1 ng/ml 

at 20 minutes respectively) (p < 0.0001). There were no differences in nicotine Tmax between 

VLNTM King cigarettes and UB-NNC cigarettes or between VLNTM Menthol King and UB-NNC 

cigarettes. The plasma nicotine AUC0-180 for VLNTM King cigarettes was significantly lower (26.2 

ng*min/ml) than UB-NNC (770.8 ng*min/ml) (p < 0.0001) and nicotine gum (342.8 ng*min/ml) 

(p < 0.0001). The plasma nicotine AUC0-180 for VLNTM Menthol King cigarettes was also 

significantly lower (30.4 ng*min/ml) than UB-NNC (932.0 ng*min/ml) (p < 0.0001) and nicotine 

gum (359.3 ng*min/ml) (p < 0.0001). There were no statistically significant differences in 

nicotine T1/2 (controlled use) for any of the product comparisons in the VLNTM King cigarettes 

study. However, nicotine T1/2 was significantly shorter for the VLNTM Menthol King cigarettes 

compared with UB-NNC cigarettes (median difference = -67.7, 95% CI = -94.3, -12.3) and 

nicotine gum (median difference = - 68.0, 95% CI = -98.4, -13.8); a smaller sample size for VLNTM 

Menthol King cigarettes may have influenced these results; however, any potential differences 

in nicotine T1/2 did not appear to translate to differences in UB-NNC cigarette and VLNTM 

Menthol King cigarette use behavior or topography. 
 

 

 

 

 

 

 

 

 

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During the ad libitum portion of Phase B of the studies, the nicotine Cmax for VLNTM King 

cigarettes and VLNTM Menthol King cigarettes was significantly lower (0.57 ng/ml and 0.53 ng/ml 

at 7 minutes, respectively) than UB-NNC cigarettes (16.97 ng/ml and 19.2 ng/ml at 7 minutes, 

respectively) (p < 0.0001) and Nicorette® Original Flavor or Nicorette® White Ice MintTM nicotine 

gum (3.2 ng/ml and 2.0 ng/ml at 20 minutes, respectively) (p < 0.0001). There were no 

differences in nicotine Tmax between VLNTM King cigarettes or VLNTM Menthol King cigarettes and 

UB-NNC cigarettes. The plasma nicotine AUC0-180 for VLNTM King cigarettes was significantly 

lower (28.3 ng*min/ml) than UB-NNC cigarettes (879.75 ng*min/ml) (p < 0.0001) and nicotine 

gum (277.3 ng*min/ml) (p < 0.0001). Similarly, the plasma nicotine AUC0-180 for VLNTM Menthol 

King cigarettes was also significantly lower (33.5 ng*min/ml) than UB-NNC cigarettes (1035.3 

ng*min/ml) (p < 0.0001) and nicotine gum (231.7 ng*min/ml) (p < 0.0001). Furthermore, 

nicotine T1/2 was significantly shorter for the VLNTM King cigarette compared with UB-NNC 

cigarettes (median difference = -25.3, 95% CI = -41.3, -4.8) and nicotine gum (median difference 

= - 41.4, 95% CI = -68.0, -12.1). The nicotine T1/2 was also significantly shorter for the VLNTM 

Menthol King cigarettes (median difference = - 25.2, 95% CI = -73.0, -21.3) and UB-NNC 

cigarettes (median difference = 21.3, 95% CI = -3.7, 48.4) compared to nicotine gum. For both 

studies, a smaller sample size and large variability for the VLNTM cigarettes may have influenced 

these results; however, any potential differences in nicotine T1/2 did not appear to translate to 

differences in UB-NNC cigarette and VLNTM cigarette use behavior or topography. 

The total nicotine exposure and maximum level of nicotine in the blood was significantly lower 

for the VLNTM cigarettes in both studies compared with the UB-NNC cigarettes and the nicotine 

gum. The time it took to reach the maximum nicotine concentration in the blood was 

equivalent between the VLNTM cigarettes and UB-NNC cigarettes in each study, as expected 

when comparing two cigarette products delivering nicotine. The PK profile of both the VLNTM 

cigarettes indicates a lower abuse liability than their UB-NNC cigarette comparator. 

The 6 week Switching Study NCT03571724: 

Nicotine PK assessments indicated that for both VLNTM King and Menthol King cigarettes, the 

Cmax and AUC were significantly reduced from baseline UB-NNC cigarette smoking by ≥ 97% at 

Weeks 2 and 6 of the study (% reduction for these comparisons ranged from 96.9 – 99.0, all pvalues <0.0001). Nicotine Tmax values following use of VLNTM cigarettes were comparable to UBNNC cigarettes. 

2.4.3. Behavioral Pharmacology 

2.4.3.1. Abuse Liability 

The applicant provided a literature review of published acute laboratory studies that assessed 

nicotine abuse liability outcomes in participants using SPECTRUM or other VLNC cigarettes that 

are substantially similar to VLNTM cigarettes, but not exactly the same (i.e., Quest, Ultratech). A 

study in young adults (ages 18-25 years) showed that SPECTRUM non-menthol VLNC cigarettes 

are associated with reduced plasma nicotine levels compared to UB-NNC cigarettes, and these 

differences are not dependent upon differences in nicotine metabolism or sex (Faulkner et al., 

2017; Faulkner et al., 2018). Studies utilizing other VLNC cigarettes consistently support 
 

 

 

 

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significantly reduced levels of plasma nicotine in participants after ad libitum menthol and nonmenthol VLNC cigarette use compared to UB-NNC and NNC cigarettes (Cobb, Weaver, & 

Eissenberg, 2010; Pickworth, Nelson, Rohrer, Fant, & Henningfield, 1999; Rose & Behm, 2004). 

Self-reported subjective effects (e.g., drug “liking,” “satisfaction”) are widely used measures of 

reinforcing efficacy and abuse liability for drugs and tobacco products. Drug “liking” is 

associated with drug self-administration and has been shown to be the most sensitive and 

reliable subjective effects measure of abuse liability (Carter & Griffiths, 2009). Several studies 

compared the subjective effects of VLNC, NNC, or UB-NNC cigarettes using self-reported 

measures of drug effects (e.g., Cigarette Evaluation Scale, Smoking Effects Questionnaire, VAS 

items). Studies typically found that VLNC cigarettes were associated with lower subjective 

effects ratings compared to UB-NNC and NNC cigarettes. None of the studies reviewed found 

that VLNC cigarettes were associated with greater subjective appeal compared to UB-NNC or 

NNC cigarettes. 

In acute laboratory exposure conditions, several studies found that VLNC cigarettes were rated 

lower in cigarette “liking” compared to NNC cigarettes (Donny & Jones, 2009; Hatsukami, 

Heishman, et al., 2013; Lindsey et al., 2013; Perkins, Karelitz, & Kunkle, 2017, 2018; Rose & 

Behm, 2004; Schlagintweit & Barrett, 2016). However, other studies found no significant 

differences in “liking” as a function of nicotine content in cigarettes (Dallery, Houtsmuller, 

Pickworth, & Stitzer, 2003; Juliano, Donny, Houtsmuller, & Stitzer, 2006). Other subjective 

effects (e.g., “good” or “positive” effects; “bad” or “negative” effects) co-vary with drug 

“liking.” On average, VLNC cigarettes were rated lower on other positive subjective effects 

items (e.g., “satisfaction,” “pleasure,” “taste,” “strength,” “stimulation”) compared to NNC 

cigarettes (Hatsukami, Heishman, et al., 2013; Juliano, Fucito, & Harrell, 2011; Macqueen et al., 

2012; Perkins et al., 2017, 2018) and UB-NNC cigarettes (Cobb et al., 2010). VLNC cigarettes 

were also rated lower on “dizziness,” likely due to the low nicotine content in these products 

(Juliano et al., 2011), and higher on items such as “dislike” and “unpleasant” compared to UBNNC or NNC cigarettes (Donny & Jones, 2009; Hatsukami, Heishman, et al., 2013). 

Several studies assessed subjective effects of VLNC cigarettes following extended exposure, 

typically over the course of several weeks. Findings from these studies were relatively similar to 

findings from brief exposure studies. On average, VLNC cigarettes were rated as less appealing 

(e.g., lower ratings of “liking,” “satisfaction,” “pleasure”) compared to NNC cigarettes 

(Buchhalter, Acosta, Evans, Breland, & Eissenberg, 2005; Mercincavage et al., 2016). However, 

at least one study found no differences in subjective effects as a function of nicotine content in 

cigarettes (Benowitz et al., 2012). Positive subjective effects ratings for VLNC cigarettes were 

shown to remain constant or decrease over time (Buchhalter et al., 2005; Walker et al., 2012). 

Donny and colleagues (2007) conducted a study that examined the effects of Quest VLNC 

cigarettes on subjective effects in smokers who were confined to a residential research facility 

throughout the study, thereby permitting an assessment of appeal under conditions of 

complete substitution. During 11 days of exposure to study cigarettes, participants assigned to 

the VLNC cigarette group rated positive subjective effects of cigarettes (e.g., "enjoyable") lower 

and negative subjective effects (e.g., "unpleasant") higher than baseline subjective effects of 

UB-NNC cigarettes. Similarly, during the first few days of exposure to study cigarettes, 
 

 

 

 

 

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participants who received NNC cigarettes rated positive subjective effects of cigarettes lower 

and negative subjective effects higher than baseline subjective effects of UB-NNC cigarettes; 

however, these effects dissipated over time such that subjective ratings of NNC cigarettes were 

similar to UB-NNC cigarettes by the end of the study (Donny et al., 2007). 

BCP also identified two studies that assessed the effects of menthol on SPECTRUM VLNC 

cigarette perceptions. Perkins and colleagues (2018) investigated the effects of menthol on 

subjective and behavioral responses to VLNC cigarettes in 73 adult smokers. Subjective effects 

were measured after smoking each of five cigarettes. A main effect of menthol on subjective 

effects was observed; however, no significant interaction effect of nicotine content and 

menthol on subjective effects was observed. Participants chose significantly more puffs from 

NNC menthol cigarettes than VLNC menthol cigarettes, with no significant differences due to 

menthol or due to interactions between menthol and nicotine content. Greater differences in 

subjective effects between menthol NNC and VLNC cigarettes predicted choice for NNC 

cigarettes regardless of menthol content. Additionally, Hatsukami and colleagues (2013) 

assessed menthol’s influence on the subjective effects of three SPECTRUM cigarettes (i.e., 0.4 

mg nicotine/g, 5.7-5.8 mg/g, 11.4-12.8 mg/g) in 51 adult smokers. Regardless of nicotine 

content, VLNC non-menthol cigarette smokers rated the study cigarettes as having significantly 

higher positive subjective effects ratings (e.g., “satisfying,” “pleasing,” “liked”) than VLNC 

menthol cigarette smokers. VLNC non-menthol cigarettes were also associated with greater 

craving reduction than the menthol cigarettes; however, there was no interaction between 

nicotine content and menthol status. These findings suggest that VLNC menthol cigarettes have 

reduced positive subjective effect ratings compared to NNC menthol cigarettes and smokers 

are more likely to choose NNC menthol cigarettes compared to VLNC menthol cigarettes. 

2.4.3.2. Use Behavior and Topography 

The applicant-submitted abuse liability studies compared acute smoking topography (number 

of puffs, puff duration) of VLNTM King and VLNTM Menthol King cigarettes to UB-NNC cigarettes 

and showed that participants had similar puff durations; however, smokers took fewer puffs of 

the VLNTM cigarettes than UB-NNC cigarettes. The majority of studies in the applicant-submitted 

literature review support these findings; individuals who smoke VLNC cigarettes either 

demonstrate no significant differences in smoking topography relative to those who smoke UBNNC or NNC cigarettes, or they demonstrate changes in smoking topography measures that are 

associated with reductions in tobacco smoke exposure (e.g., lower total puff volume). Lack of 

compensatory smoking behavior was biochemically confirmed through exhaled CO 

measurements, which indicate no significant differences in CO boost between smoking VLNC 

and UB-NNC cigarettes. Smokers also do not compensate by increasing their overall CPD when 

switching to VLNC cigarettes. 

In the applicant-submitted 6-week switching study assessment of smoking topography during 1-

hour ad libitum sessions found that participants in both the VLNTM King and Menthol King 

cigarette groups significantly differed in some topography measures from their UB-NNC 

cigarette smoking (recorded at baseline), including shorter total puff durations, smaller total 

puff volumes, shorter inter-puff intervals, and decreased average number of puffs. 
 

 

 

 

 

 

 

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The applicant also provided a summary of smoking topography assessments from the VLNC 

cigarette literature. Single session studies suggest that participants may alter their smoking 

topography when smoking VLNC cigarettes compared to UB-NNC cigarettes; however, these 

use behaviors generally do not lead to an increase in exposure to nicotine or other HPHCs. 

Single session studies have found that smokers may increase puff duration and decrease the 

time between puffs when smoking VLNC cigarettes, but generally take fewer puffs from the 

cigarette, resulting in decreased total puff volume (e.g., Hammond & O'Connor, 2014; Higgins 

et al., 2017; Strasser, Lerman, Sanborn, Pickworth, & Feldman, 2007; Tidey, Cassidy, & Miller, 

2016). Although some smokers may partially compensate when smoking VLNC cigarettes (e.g., 

Kassel et al., 2007; Macqueen et al., 2012), this effect was present during initial cigarette 

exposures and diminished as participants smoked more cigarettes during single sessions 

(Macqueen et al., 2012). CO boost has also been examined to determine if compensatory 

smoking occurs with smoking VLNC cigarettes. Single session studies find no significant 

difference in CO boost between VLNC and NNC cigarettes, supporting that any differences in 

topography from smoking VLNC cigarettes do not lead to increased exposure (e.g., Juliano et 

al., 2011; Rose & Behm, 2004; Strasser et al., 2007). Longer-term studies (i.e., five or more days) 

also do not find significant differences in smoking topography or CO boost between smokers of 

VLNC and NNC cigarettes, supporting that any compensatory smoking associated with smoking 

VLNC cigarettes is transient and does not significantly affect exposure (e.g., Donny et al., 2015; 

Donny & Jones, 2009; Hatsukami, Heishman, et al., 2013; Hatsukami et al., 2018; Mercincavage 

et al., 2016; Vogel et al., 2014). 

The BCP review identified one study that assessed whether menthol moderated the effects of 

VLNC cigarettes on smoking topography (Davis et al., 2019). Smoking topography measures 

(i.e., puff volume, puff duration, interpuff interval, puff number, flow rate) were assessed in a 

total of 169 participants (36% menthol smokers) from three vulnerable populations (i.e., low 

socioeconomic status women, opioid maintained adults, adults with mental illness) after 

participants smoked each of four SPECTRUM research cigarettes (15.8, 5.2, 2.4, 0.4 mg/g) in an 

ad libitum manner. There were significant main effects of dose on puff volume, puff number, 

and flow rate, with higher nicotine doses associated with increased exposure. Menthol status 

did not moderate the effect of dose on these measures, suggesting that menthol would not 

differentially alter smoking topography in VLNTM cigarette smokers. 

Overall, findings indicate that, in general, individuals who smoke VLNC cigarettes demonstrate 

no significant differences in smoking topography relative to those who smoke UB-NNC or NNC 

cigarettes. Any observed differences in smoking topography measures are associated with 

reductions in tobacco smoke exposure (e.g., lower total puff volume). 

2.4.3.3. Product Use/Consumption 

The applicant-submitted abuse liability studies included 4-hour ad libitum use sessions, one for 

each of the three study products on separate days. In these ad libitum sessions product use 

behaviors such as number of units consumed and time spent per unit were recorded. They 

found that participants consumed slightly more VLNTM King cigarettes (M(SD) = 8.2 ± 4.3 vs. 7.8 
 

 

 

 

 

 

 

 

 

 

 

 

 

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± 2.6) than UB-NNC cigarettes, but smoked VLNTM King cigarettes for less time (M(SD) = 4.7 ± 1.7 

vs. 6.0 ± 2.1 minutes). Similarly, they found that participants consumed slightly more VLNTM 

Menthol King cigarettes (M(SD) = 6.8 ± 3.4 vs. 6.2 ± 1.9) than UB-NNC cigarettes, but smoked 

VLNTM Menthol King cigarettes for less time (M(SD) = 5.1 ± 2.4 vs. 6.3 ± 2.3 minutes). Overall, 

use behavior was similar for the study cigarettes and UB-NNC cigarette in both studies. 

The applicant submitted 6-week switching study found that, although there was an initial 

increase in mean CPD from baseline in Week 1 in VLNTM King cigarette smokers (17.94 to 20.02 

CPD), mean CPD was decreased from Week 3 to Week 6 in these smokers (16.84 to 15.13 CPD); 

however, the decreased CPD in VLNTM King cigarette smokers was not significantly different 

from baseline at any time point assessed in the study. In contrast, VLNTM Menthol King cigarette 

smokers significantly decreased CPD from baseline across the 6-week study period (Baseline14.75 to Week 6- 11.37 CPD). Of note, combined VLNTM cigarette data showed a significant 

reduction in CPD from baseline to Week 6. Regarding non-compliance, ITT participants reported 

smoking less than one non-study CPD during the study. Cigarette butt collection confirmed the 

findings on self-reported CPD and study compliance. 

The applicant also provided a summary of published studies ranging from six weeks to 20 weeks 

that evaluated CPD in participants who switched to smoking VLNC cigarettes. Both gradual and 

immediate reduction studies were included; given that the immediate reduction studies 

provide the most comparable situation to how VLNTM cigarettes would be introduced to the 

market, these studies hold the greatest weight. 

Some studies evaluating VLNC cigarette smoking over the course of six weeks to 20 weeks 

found that, compared to baseline, overall CPD is significantly reduced in participants who 

immediately switched to VLNC cigarettes. The largest study to date on VLNC cigarettes was 

conducted over 20 weeks. Despite high rates of non-compliance in smoking non-study 

cigarettes, there was an overall reduction in total CPD in smokers who switched to smoking 

VLNC cigarettes. Hatsukami et al. (2017) also conducted a study examining CPD and alternate 

tobacco product use following concurrent use of low nicotine content (LNC) cigarettes with 

non-cigarette combusted products, non-combusted products, and/or other nicotine-containing 

products. The study found that participants in LNC cigarette groups smoked fewer CPD overall 

and reported less combusted product use than those in the NNC cigarette group. LNC cigarette 

smokers reported higher use of alternative nicotine-containing products compared to NNC 

cigarette smokers, with ENDS being the highest reported dually used product. 

However, other studies of immediate reduction did not find a significant difference in CPD. 

Walker et al. evaluated participants (n=60) who smoked either their UB-NNC or VLNC cigarettes 

(Magic; 0.04 mg nicotine yield) for 12 weeks. While there was a reduction in CPD from baseline 

to six weeks in VLNC cigarette smokers compared to UB-NNC cigarette smokers, the change 

from baseline to 12 weeks was not significant. As a result, overall, participants in the VLNC 

cigarette group smoked a comparable amount of CPD as participants in the UB-NNC cigarette 

groups over the 12-week period; participants in the VLNC cigarette group replaced some of 

their UB-NNC cigarettes with VLNC cigarettes (Walker et al., 2015). Donny and Jones also did 

not find that VLNC cigarette smokers (n=68) reduced their CPD over a shorter time period (nine 
 

 

 

 

 

 

 

 

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days); however, VLNC cigarette smokers who also used nicotine patches did reduce their CPD 

compared to NNC cigarette smokers. One 5-day study of participants (n=31) confined to a hotel 

monitored the effects of exclusive smoking of VLNC cigarettes and noted an increase in CPD 

while at the hotel compared to baseline UB-NNC cigarette smoking (Denlinger et al., 2016); 

however, this effect was likely due to participants receiving free cigarettes while being confined 

to a hotel for five days. Despite the increase in CPD, total nicotine equivalent (TNE) levels were 

reduced by 92% compared to UB-NNC cigarette smoking. 

Regarding the role of menthol on CPD, evidence extrapolated from published studies of NNC 

menthol cigarettes does not suggest that menthol increases the number of CPD compared to 

non-menthol NNC cigarettes (Section 2.4.4.). Therefore, combined data on menthol and nonmenthol VLNC cigarettes can be extrapolated to VLNTM King Menthol cigarettes. One study 

submitted by the applicant conducted a subgroup analysis and found an overall significant 

reduction in CPD in smokers who switched from UB-NNC cigarette, with no significant 

interactions with menthol for total CPD (Donny et al., 2015). A 2019 Society for Research on 

Nicotine and Tobacco (SRNT) presentation that conducted a secondary analysis of the 20-week 

Hatsukami study (2018) for effects of menthol on trial outcomes also found that menthol 

smokers who switched from UB-NNC to VLNC cigarettes reduced their overall CPD, though 

reductions in CPD were to a lesser extent than non-menthol VLNC smokers (Delinger, 2019). 

Overall, these data suggest that smoking VLNC cigarettes may lead to an overall reduction in 

CPD compared to smoking UB-NNC cigarettes. Some consumers, in particular those who dual 

use VLNC and UB-NNC cigarettes, may not decrease their overall cigarette consumption; 

however, dual use of other nicotine-containing products, such as NRT or ENDS, may aid in 

reducing CPD (Donny & Jones, 2009; Hatsukami, Hertsgaard, et al., 2013; Hatsukami et al., 

2017). While one study found that some smokers increase CPD while using VLNC cigarettes, this 

effect is unlikely to be related to VLNC cigarettes themselves, but rather an effect of being 

confined to an environment with free cigarettes for several days. 

2.4.3.4. Craving, Withdrawal, and Dependence 

The applicant submitted 6-week switching study assessed subjective measures of dependence 

(FTCD), smoking urges (QSU-Brief), and withdrawal symptoms (MNWS-R). Results of the FTCD 

score comparison indicated that VLNTM King cigarette smokers had significantly higher 

dependence scores at Week 2 compared to baseline, though this effect subsided during the 

study, as there was no significant difference in FTCD score from baseline at Week 6. FTCD 

scores were significantly reduced in VLNTM Menthol King cigarette smokers at Week 6 compared 

to baseline. QSU-Brief results at Week 2 indicated that VLNTM King cigarette smokers 

experienced a greater urge to smoke and less anticipated relief from withdrawal compared to 

baseline; however, these effects were not significant at Week 6. In VLNTM Menthol King 

cigarette smokers, QSU-Brief scores indicated that urge to smoke was marginally decreased (p= 

0.06) and anticipated relief from withdrawal was significantly reduced from baseline at Week 6. 

Mean MNWS-R score in VLNTM King cigarette smokers was significantly higher at Week 2 

compared to baseline, indicating greater withdrawal symptoms, but did not significantly differ 

from baseline by Week 6. In VLNTM Menthol King cigarette smokers, mean MNWS-R score was 
 

 

 

 

 

 

 

 

 

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marginally decreased from baseline at Week 6 (p=0.05); this reduction in mean MNWS-R score 

was significant in UB-NNC menthol smokers at Week 6 compared to baseline (p=0.005). Of 

note, combined VLNTM King and Menthol King cigarette data at Week 6 did not detect a 

significant difference in FTCD, QSU-Brief, or MNWS-R score compared to baseline. 

The applicant provided a literature review of published acute laboratory studies that assessed 

nicotine/tobacco craving and withdrawal in participants using SPECTRUM or other VLNC 

cigarettes, which are substantially similar to VLNTM King and VLNTM Menthol King cigarettes but 

not exactly the same (i.e., Quest, Ultratech). Nicotine produces a characteristic withdrawal 

syndrome manifested by irritability, anxiety, depressed mood, difficulty concentrating, 

increased appetite, insomnia, and restlessness. Although craving is often characterized as a 

symptom of nicotine withdrawal, it can occur in the absence of other withdrawal symptoms. 

Thus, craving is usually measured and reported separately from withdrawal. Due to their lower 

nicotine content, VLNC cigarettes might be expected to increase craving and withdrawal 

relative to UB-NNC or NNC cigarettes. Study results suggest that while VLNC cigarettes may be 

associated with increased withdrawal compared to UB-NNC or NNC cigarettes, these effects 

appear to be transient and usually dissipate after the first week of use. VLNC cigarettes do not 

appear to be associated with sustained increases in cigarette craving compared to NNC 

cigarettes. 

In acute exposure laboratory studies, VLNC cigarettes initially suppressed craving and 

withdrawal symptoms relative to baseline measures that were typically assessed following 

overnight abstinence (Addicott et al., 2014; Barrett, 2010; Barrett & Darredeau, 2012; Tidey et 

al., 2013). This is likely due to the conditioned reinforcing effects of sensorimotor stimuli that 

are repeatedly paired with nicotine through the process of smoking, resulting in these stimuli 

being able to acutely ameliorate nicotine craving and withdrawal. Many studies showed that 

VLNC cigarettes can reduce craving and withdrawal to a similar degree as UB-NNC or NNC 

cigarettes (Cobb et al., 2010; Eid, Fant, Moolchan, & Pickworth, 2005; Higgins et al., 2017; 

Juliano et al., 2006; Perkins & Karelitz, 2015). However, some studies observed that suppression 

of craving and withdrawal symptoms was lower after smoking VLNC cigarettes than UB-NNC or 

NNC cigarettes (Hatsukami, Heishman, et al., 2013; Juliano et al., 2011). Notably, some of these 

brief exposure studies reported gender differences and generally found that female smokers 

experienced greater reductions in craving (Barrett & Darredeau, 2012; Hatsukami, Heishman, et 

al., 2013) or withdrawal (Barrett, 2010; Perkins & Karelitz, 2015) compared to male smokers 

after smoking VLNC cigarettes. 

During extended exposure, VLNC cigarettes tend to increase withdrawal symptoms during the 

initial week after switching; however, these differences do not persist (Donny & Jones, 2009; 

Hatsukami et al., 2010; Hatsukami et al., 2018). One study found that, after switching to VLNC 

cigarettes from UB-NNC cigarettes for one week, withdrawal symptoms increased with no 

reported change in craving. However, these effects were relatively brief, and within six weeks, 

withdrawal symptoms returned to baseline levels and craving steadily decreased below 

baseline levels. Another study demonstrated that six weeks of VLNC cigarette exposure resulted 

in less craving and no difference in other withdrawal symptoms compared to NNC cigarettes 

(Donny et al., 2015). A 20-week study showed higher withdrawal scores at Week 1 among those 
 

 

 

 

 

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switching to VLNC cigarettes compared to NNC cigarettes; however, these differences 

dissipated after the first week (Hatsukami et al., 2018). Craving scores were generally lower 

among those switching to VLNC cigarettes compared to NNC cigarettes. 

Craving and withdrawal symptoms were also assessed in several smoking cessation studies 

where participants were provided VLNC cigarettes along with pharmacotherapy (e.g., NRT, 

varenicline). One study showed that VLNC cigarettes plus NRT can produce persistent 

reductions in craving after three and six weeks of exposure (Walker et al., 2012). Another study 

provided participants with NNC or VLNC cigarettes plus a nicotine patch prior to a quit date. 

Those who received VLNC cigarettes and patches experienced less frequent and less intense 

cravings, as well as similar withdrawal symptoms before and after the quit date, compared to 

those who received NNC cigarettes before the quit date (Rezaishiraz, Hyland, Mahoney, 

O'Connor, & Cummings, 2007). Another study found that VLNC cigarettes plus either varenicline 

or NRT resulted in decreased craving compared to pharmacotherapy alone, with no differences 

in withdrawal across groups (McRobbie, Przulj, Smith, & Cornwall, 2016). 

Davis and colleagues (2019) assessed whether menthol status moderated the effects of VLNC 

cigarettes on withdrawal and craving. Each of the nicotine doses (15.8, 5.2, 2.4, 0.4 mg/g) 

reduced craving and withdrawal scores from baseline, and menthol status did not moderate the 

effect of dose on these measures. These findings suggest that VLNTM cigarettes would be 

associated with similar acute relief of craving and withdrawal in menthol and non-menthol 

smokers. 

The applicant also discussed studies from its literature review assessing dependence. Over the 

course of regular use, cigarette smoking can lead to symptoms of nicotine dependence, which 

may include tolerance to nicotine’s effects, withdrawal upon cessation of use, craving, and 

unsuccessful efforts to quit smoking. Because dependence takes time to develop or change, it 

is often measured under conditions of extended exposure. Studies typically assess dependence 

with the FagerstrÖm Test for Nicotine Dependence (FTND), FTCD, Nicotine Dependence 

Syndrome Scale (NDSS), and Wisconsin Inventory of Smoking Dependence Motives (WISDM). 

There is consistent evidence suggesting that switching to VLNC cigarettes for an extended 

duration of time is associated with decreased dependence scores among smokers interested 

and not interested in quitting. These findings support the applicant’s conclusions that using 

VLNC cigarettes reduce nicotine exposure and, therefore, may reduce nicotine dependence. 

Several studies gradually stepped down the nicotine content of cigarettes over the course of 

weeks or months. In a study that used Quest cigarettes to step down nicotine content weekly 

over the course of four weeks, there were no differences in overall dependence scores as a 

function of the cigarette’s nicotine content. Because not all study cigarettes were VLNC 

cigarettes, these products were only used for one week, and this short duration may have been 

insufficient to allow for observable changes in dependence (Hammond & O'Connor, 2014). 

Another study in 135 participants who smoked either gradually reduced nicotine content 

cigarettes (12mg to 1 mg, reduced monthly) or UB-NNC cigarettes over the course of six months 

found no difference in dependence when comparing data from baseline to week 26. However, 

when comparing only data from Week 14 to Week 26, when participants were primarily 
 

 

 

 

 

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smoking VLNC cigarettes, there was a significant decrease in dependence in participants who 

received gradually reduced nicotine content cigarettes (Benowitz et al., 2012). In a follow-up 

study, participants who received gradually reduced nicotine content cigarettes were given VLNC 

cigarettes for an additional six months (Benowitz et al., 2015), and dependence scores 

significantly decreased between baseline and 18 months. 

Immediate nicotine reduction from UB-NNC cigarettes to VLNC cigarettes consistently reduced 

dependence scores compared to those who smoked NNC or UB-NNC cigarettes for six (Donny 

et al., 2015), 12 (Walker et al., 2015), and 20 weeks (Hatsukami et al., 2018) in participants not 

interested in quitting smoking. In a smoking cessation study where participants endorsed 

wanting to quit, VLNC cigarettes were also associated with reductions in nicotine dependence 

at six weeks compared to baseline (Hatsukami et al., 2010). Finally, in a study that examined the 

effects of VLNC cigarettes on latency to smoke in smokers inhabiting a residential research 

facility, time to first cigarette, a strong predictor of dependence, was significantly longer among 

smokers who only had access to VLNC cigarettes for 11 days compared to those who only had 

access to NNC cigarettes (Donny et al., 2007). 

2.4.3.5. Cessation 

The applicant’s clinical studies on VLNC cigarettes evaluated the effect of smoking VLNC 

cigarettes on cessation. The X-22 VLNC cigarette was menthol flavored, while the Quest 

cigarette was non-menthol. These studies, in addition to the literature, were extrapolated to 

VLNTM Menthol King and VLNTM King cigarettes, respectively, to address the likelihood of 

improved cessation outcomes. One study of smokers motivated to quit found that, at four 

weeks, participants who smoked VLNC cigarettes and received NRT were more likely to be 

abstinent than those who smoked VLNC cigarettes alone or NNC cigarette with the patch. 

Neither study found a significant difference in longer-term quit rates (i.e., three- and six-month 

follow-up) compared to NNC cigarette smokers. Studies from the literature found that among 

smokers motivated to quit, VLNC cigarettes may facilitate abstinence due to reduced nicotine 

exposure. NRT and behavioral intervention with VLNC cigarettes may aid in cessation in some 

smokers motivated to quit. In smokers not motivated to quit, smoking VLNC cigarettes did not 

increase motivation to quit compared to NNC cigarette smokers; however, quit attempts were 

greater in VLNC cigarette smokers. 

In addition, several extended duration VLNC studies in the literature assessed self-reported quit 

attempts as a secondary study aim. While one study showed no significant differences in quit 

rates among nondaily smokers who used VLNC or NNC cigarettes for 10 weeks (Shiffman, 

Kurland, Scholl, & Mao, 2018), other studies showed that participants who smoked VLNC 

cigarettes were more likely to report a quit attempt after six weeks (Donny et al., 2015) and had 

a greater number of cigarette-free days after 18 weeks (Hatsukami et al., 2018) compared to 

those who smoked NNC cigarettes. 

These findings suggest that VLNTM cigarettes may appeal to smokers interested in quitting. This 

consumer subset may be motivated to use VLNTM cigarettes to reduce nicotine exposure, and as 

a result, potentially aid in facilitating cessation. It is unlikely that current tobacco users who are 
 

 

 

 

STN PM0000491 – PM0000492 Page 46 of 89 

not interested in quitting will switch to VLNTM cigarettes or to a smoking cessation product. 

However, this effect may differ among smokers motivated to quit smoking and who 

concurrently use NRT and behavioral intervention with VLNTM King cigarettes. Given that 

menthol in cigarettes contributes to reduced cessation success among NNC cigarette smokers 

(e.g., Delnevo, Gundersen, Hrywna, Echeverria, & Steinberg, 2011; Faseru et al., 2013; Levy et 

al., 2011; Trinidad, Perez-Stable, Messer, White, & Pierce, 2010), any potential effect on 

cessation may be less likely among smokers of VLNTM Menthol King cigarettes, including those 

who are motivated to quit and who concurrently use smoking cessation aids (Faseru et al., 

2013; Okuyemi et al., 2003) 

2.4.4. Summary of Overall Behavioral and Clinical Pharmacology Findings 

The BCP review concludes that the PMTAs contain adequate information to draw the following 

conclusions: 

● The PK profile of the VLNTM cigarettes indicates a lower abuse liability than the 

applicant’s UB-NNC cigarette comparator. 

● Based on the applicant’s submitted clinical studies, VLNTM King cigarettes are associated 

with significantly lower positive subjective effects ratings in adult smokers compared to 

UB-NNC cigarettes, reducing their abuse liability for youth and non-smokers. The 

applicant’s submitted studies also show that, among adult smokers, VLNTM Menthol King 

cigarettes have lower positive subjective effects than UB-NNC cigarettes. As menthol in 

NNC cigarettes facilitates experimentation and progression to regular smoking, it is 

unknown to what degree menthol may influence likelihood of progressing to regular 

smoking compared to smoking NNC menthol cigarettes among new and inexperienced 

users, in particular youth and young adults. 

● Menthol and non-menthol NNC smokers who choose to switch to smoking VLNC 

cigarettes could experience the benefit of significantly reducing their overall exposure to 

nicotine, potentially reduce their overall smoking, and subsequently, their exposure to 

non-nicotine HPHCs. 

● Lower abuse liability reduces the likelihood that current adult smokers would transition 

to VLNTM cigarettes or switch completely. Given that current adult smokers are the 

intended population for VLNTM cigarettes, reduced likelihood of use among adult 

smokers is likely to reduce youth access to these products and their availability for 

youth experimentation. As discussed in the BCP review, it has been shown that indirect 

sources, including stealing or borrowing from an adult, are some of the most common 

means of youth access to cigarettes. Therefore, reduced adult use would likely reduce 

youth access through these means. 

● Findings from the literature indicate that individuals who smoke VLNC cigarettes 

demonstrate either no significant differences in smoking topography relative to those 

who smoke UB-NNC or NNC cigarettes or reductions in tobacco smoke exposure (e.g., 

lower total puff volume). 

● Findings from the literature suggest that smoking VLNC cigarettes may lead to an overall 

reduction in CPD compared to smoking UB-NNC cigarettes. 
 

 

 

 

 

STN PM0000491 – PM0000492 Page 47 of 89 

● Low subjective appeal, along with increased craving and withdrawal, may prevent 

current smokers from fully transitioning to VLNTM cigarettes. Data from the literature 

suggest that those who do switch to VLNC cigarettes reduce their nicotine exposure, 

may smoke fewer CPD, and lower their nicotine dependence levels compared to those 

who continue to smoke UB-NNC cigarettes. It is anticipated that smokers who switch to 

VLNC cigarettes and reduce their overall CPD would also reduce exposure to other nonnicotine HPHCs (see Section 2.4.5). 

● Switching to VLNC cigarettes may facilitate abstinence in smokers by increasing 

motivation to quit and quit attempts. Concurrent use of NRT and behavioral 

intervention may improve these outcomes. However, among menthol smokers who 

switch to VLNC cigarettes, the potential effect on cessation may be less likely than with 

non-menthol VLNC cigarette smokers. Based on literature extrapolated from NNC 

menthol cigarettes, the reduced likelihood of cessation may occur even in smokers 

motivated to quit and who concurrently use pharmacotherapy for cessation. 

As TPL, I agree with the BCP review conclusions that there is reduced abuse liability, no 

difference or a slight improvement in smoking topography, and reductions in CPD when using 

VLNC cigarettes, including the VLNTM cigarettes. I also agree with their conclusions that these 

factors may lead to an increase in abstinence in some smokers by increasing motivation to quit 

and quit attempts, but that the low appeal combined with increased craving and withdrawal 

may prevent other smokers from fully transitioning. 

2.4.5. Biomarkers of Exposure (BOE) 

BCP also evaluated BOE data, as the applicant provided both a 6-week switching study with BOE 

outcomes and a review of the VLNC cigarette clinical study literature relevant to BOE. 

In the 6-week switching study the BOE outcomes included (urinary NNAL [an NNK biomarker], 

NNN, 3-HPMA [an acrolein biomarker], S-PMA [a benzene biomarker], 1-HOP [hydroxypyrene 

biomarker], TNE, COHb, and plasma cotinine). Assessments indicated significant decreases from 

baseline in TNE and almost all other measured BOE in both VLNTM King and Menthol King 

cigarette smokers by Week 6 after switching from UB-NNC cigarettes (decreases in S-PMA and 

COHb at week six compared to baseline were not significant in the VLNTM King). 

A review of the relevant BOE literature cited by the applicant is below. 

2.4.5.1. Effect of Switching to VLNC Cigarettes on BOE 

Nicotine BOE 

Studies ranging from single exposure to 20 weeks of VLNC cigarette use consistently support 

significantly reduced levels of nicotine BOE, including significantly reduced total cotinine levels 

and TNE, in participants who switched to smoking VLNC cigarettes compared to NNC cigarettes. 

A study of smokers (n=31) confined to a hotel for five days confirmed that when participants 

exclusively switch to smoking VLNC cigarettes, there is a 94% reduction in TNE compared to 

baseline measurements of participants’ use of UB-NNC (Denlinger et al., 2016). The literature 
 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 48 of 89 

supports that the level of nicotine BOE remains significantly lower for VLNC cigarette smoking 

compared to smoking UB-NNC/NNC cigarettes even when there is no significant difference in 

CPD (Donny & Jones, 2009; Hammond & O'Connor, 2014; Hatsukami et al., 2018). 

A presentation from the 2019 SRNT Conference reported a secondary analysis on data from the 

20-week Hatsukami et al. study to determine if menthol flavoring affected trial outcomes

(Denlinger-Apte et al., 2019). These data are interpreted with caution, given that the findings

have not been peer-reviewed. Compared to baseline, VLNC menthol cigarette smokers had

smaller reductions in TNE compared to non-menthol smokers; TNE was reduced overall in

menthol smokers who switched from UB-NNC menthol to VLNC menthol cigarettes. These

findings suggest that menthol smokers who switch to VLNTM Menthol King cigarettes would also

reduce their nicotine exposure.

Non-Nicotine HPHC BOE 

Data on BOE for other HPHCs are also available in the literature (e.g., TSNAs [NNN, NNK, NNAL], 

3-HPMA [an acrolein metabolite], 1-HOP, mercapturic acid metabolites, PheT [indicator of

polycyclic aromatic hydrocarbons]). These studies evaluate outcomes from six weeks through

20 weeks of VLNC cigarette use. Studies of immediate switching to VLNC cigarettes, which,

should VLNTM King and VLNTM Menthol King cigarettes be marketed, are more comparable to the

marketplace situation, find significant reductions in all measured non-nicotine HPHCs. These

reductions in non-nicotine HPHCs are contingent upon a reduction in CPD. Preliminary data

from the SRNT presentation discussed above (Denlinger-Apte et al., 2019) also support that

VLNC menthol cigarette smokers have significant reductions in non-nicotine HPHCs compared

to baseline consistent with a reduction in CPD, although this effect may be to a lesser extent

than in VLNC non-menthol cigarette smokers.

2.4.5.2. Dual Use and Non-compliance 

Studies from the literature review note that non-compliance with exclusive VLNC cigarette 

smoking is observed in most participants. If smokers dual use VLNC and UB-NNC cigarettes but 

primarily smoke VLNC cigarettes, studies suggest that smokers would still be exposed to lower 

nicotine levels than they would from smoking just UB-NNC cigarettes, would likely reduce their 

overall CPD, and experience the effects of reduced dependence on nicotine. For example, 

despite a high rate of non-compliance in one study (76-78% of participants, based on 

biochemical verification) TNEs decreased, on average, by 60% from baseline to Week 6 in 

participants switched to VLNC cigarettes (Nardone et al., 2016). NNAL levels for participants in 

this study were reduced, but not significantly. Alternatively, participants who dual use VLNC 

and UB-NNC cigarettes but primarily smoke their UB-NNC cigarettes would have similar nicotine 

exposure as those who smoke the same number of only UB-NNC cigarettes. Studies do not 

suggest that smokers would increase their overall CPD or tobacco product consumption if they 

dual use VLNC and UB-NNC cigarettes. Therefore, dual use would not expose smokers to 

nicotine levels greater than smoking only UB-NNC cigarettes and is not anticipated to increase 

their overall exposure to non-nicotine HPHCs compared to UB-NNC cigarette smoking. 
 

 

 

 

 

STN PM0000491 – PM0000492 Page 49 of 89 

In the open marketplace, VLNTM cigarettes would not be free to consumers as they are in 

research studies, and this may impact the rate of VLNTM King and VLNTM Menthol King cigarette 

smoking compared to UB-NNC cigarettes. Satisfaction is a predictor of compliance (Nardone et 

al., 2016), and studies, including the applicant’s abuse liability study on VLNTM King cigarettes, 

find that VLNC cigarettes have lower abuse liability and are not as satisfying as UB-NNC/NNC 

cigarettes. Consumers who intend to use VLNTM cigarettes for the benefits of reduced nicotine 

exposure may dual use and smoke VLNTM cigarettes with UB-NNC cigarettes or other nicotine 

containing products; however, should this occur, studies still support a significant reduction in 

nicotine exposure compared to smoking UB-NNC /NNC cigarettes. Should participants smoke 

more UB-NNC than VLNC cigarettes, studies do not suggest that overall nicotine exposure 

would increase beyond what consumers would be exposed to if they only smoked their UB-NNC 

cigarettes. 

Higher rates of dual ENDS and VLNC cigarette use have been reported in VLNC cigarette 

smokers compared to NNC cigarette smokers. Dual use of other nicotine-containing products, 

such as NRT or ENDS, with VLNC cigarettes may aid in reducing overall CPD. Nicotine exposure 

is still reduced compared to UB-NNC cigarettes in participants who dual use VLNC cigarettes 

with NRT or non-combusted tobacco products (i.e., smokeless tobacco, snus, ENDS). Lower 

levels of total NNAL and NNN have also been observed over eight weeks in participants who 

used VLNC with non-combusted products compared to NNC cigarettes. 

Overall, findings from the literature support that dual use and non-compliance with smoking 

VLNC cigarettes is high [e.g., 1.46 non-study CPD, 95% confidence interval (0.87, 2.05) in 

Hatsukami et al. (2018); 1-2 UB-NNC CPD in Denlinger et al. (2016); 5.1 (SD 4.6) non-study CPD 

in Hatsukami et al. (2017)]; however, nicotine exposure remains significantly reduced in 

participants who smoke VLNC cigarettes compared to NNC cigarettes. 

2.4.5.3. Summary of BOE Findings 

While decreases in BOE were found, the extent to which these decreases affect clinical 

outcomes cannot be determined from the clinical studies. Therefore, no conclusions can be 

drawn about the long-term health effects associated with VLNTM cigarette use. In BCP’s 

assessment the methodologies used by the applicant to generate data and conduct the 

literature search to support its application were appropriate. 

The literature supports that the reduction in nicotine BOE remains significantly lower for VLNC 

cigarette smoking compared to smoking UB-NNC/NNC cigarettes even when there is no 

significant difference in CPD. There are some data suggesting that menthol smokers who switch 

to VLNTM Menthol King cigarettes would also reduce their nicotine exposure. Additionally, there 

is some data showing that VLNC menthol cigarette smokers have significant reductions in nonnicotine HPHCs compared to baseline consistent with a reduction in CPD, although this effect 

may be to a lesser extent than in VLNC non-menthol cigarette smokers. Overall, findings from 

the literature support that dual use and non-compliance with smoking VLNC cigarettes is high; 

however, nicotine exposure remains significantly reduced in participants who smoke VLNC 

cigarettes compared to NNC cigarettes. 
 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 50 of 89 

2.4.6. Biomarkers of Potential Harm (BOPH) 

In a recent publication by Hatsukami et al. (2019) the authors performed a secondary analysis 

of biomarkers of inflammation, oxidative stress, and hematological parameters collected in the 

previous described clinical trial (Hatsukami et al. (2018)) in which 1,250 daily smokers were 

randomized to 1. immediate nicotine reduction, 2. gradual nicotine reduction, or 3. normal 

nicotine content (control). Hatsukami et al. (2019) analyzed urinary prostaglandin E2 metabolite 

(PGEM), urinary (Z)-7-[1R,2R, 3R,5S]-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-

enyl]cyclopentyl]hept-5-enoicacid (8-iso-PGF2α), serum high-sensitivity C-reactive protein (hsCRP), and hematologic parameters. There were no significant differences in the levels of PGEM, 

8-iso-PGF2α, or hs-CRP between the study arms. Statistically significant differences were

identified in some hematologic parameters. Only red blood cell distribution width (RDW)

showed a consistently lower level in the immediate group versus the gradual and control

groups in both AUC and week 20 sensitivity analyses. The magnitude of the change in RDW was

small (-0.11 to -0.21%). The authors of the study concluded that “[i]t remains unclear whether

switching to very low nicotine cigarettes leads to a short-term reduction in biomarkers of

tobacco-related harm.”

FDA review noted that robust changes in biomarkers of inflammation, oxidative stress, or 

hematological parameters in smokers switched to VLN were not identified in this study. Many 

factors may have contributed to the absence of significant changes, including that 1. the study 

may have been insufficient duration, 2. the high rates of non-compliance in the VLN study arms 

may have obscured the results, and 3. the changes in exposure may not have been great 

enough to impact the chosen markers. The only consistent change detected was a reduction in 

RDW in the immediate nicotine reduction group versus gradual nicotine reduction and control 

groups. 

RDW is a measure of the degree of variation (anisocytosis) in red blood cell size with a normal 

range of approximately 11.0 to 15.6%. An increase in RDW indicates greater variation in red 

blood cell size. RDW may be elevated in a range of conditions, including anemias due to iron, 

vitamin B12, or folate deficiency. Studies have found an association between RDW and 

mortality; however, the association is strongest when values on the upper end of the range (≥

15%) are compared to those on the lower (<12.5%) (Pilling, Atkins, Kuchel, Ferrucci, & Melzer, 

2018). In Hatsukami et al. (2019) the AUC mean RDW value in each study group was between 

13.86 and 14.00%. The changes in RDW between groups ranged from -0.11 to -0.15% in the 

AUC analysis and -0.15 to -0.21% in sensitivity analysis. The clinical significance of changes of 

this magnitude within the normal range for RDW is uncertain. 

In the limited evaluation by Hatsukami et al. (2019) there is no indication that VLN use has a 

detrimental effect on inflammation, oxidative stress, or hematologic parameters compared to 

NNC cigarettes over 20 weeks. However, no conclusions regarding the short- or long-term 

health risks of VLN can be made based on the results of this study. 
 

 

 

 

 

STN PM0000491 – PM0000492 Page 51 of 89 

2.4.7. Adverse Health Effects 

Medical reviewers considered the available adverse event and study-related health endpoints 

from three applicant-sponsored clinical studies as well as adverse event and safety information 

from two clinical studies in the published literature to evaluate specific issues about the 

product as detailed below (Donny et al., 2015; Hatsukami et al., 2018). Long-term studies 

assessing health effects are not available. While there are limited short-term and no long-term 

studies evaluating health effects of VLNTM cigarettes, the risks for adverse health effects are 

likely similar as for those associated with NNC cigarettes given that the proposed products 

differ from NNC cigarettes only in the nicotine content. The applicant primarily relies upon two 

publications, Donny et al. (2015) and Hatsukami et al. (2018), to substantiate risk profile (2015) 

and Hatsukami et al., (2018), to substantiate safety of VLNTM cigarettes. 

It is expected that VLNTM cigarette users will have the same short- and long-term health effects 

as those that occur with NNC cigarette smoking. Cigarette smoking has well-documented 

“immediate adverse health consequences” (U.S. Department of Health and Human Services, 

2004). For example, respiratory symptoms such as cough, increased sputum production, and 

wheezing occur shortly after initiation of cigarette smoking (U.S. Department of Health and 

Human Services, 2004). Respiratory infections such as bronchitis and pneumonia are “more 

frequent and severe among smokers” (U.S. Department of Health and Human Services, 2004, 

2014). Smoking’s short-term effects also include acute cardiovascular events and exacerbation 

of asthma. 

Cigarette smoking also adversely affects long-term health. It is well documented that smoking 

increases all-cause morbidity and mortality. “Cigarette smoking accelerates the age-related 

decline in lung function that occurs among never smokers” (U.S. Department of Health and 

Human Services, 2004). Compared to non-smokers, cigarette smokers have higher risk for many 

chronic illnesses, such as heart disease, chronic obstructive pulmonary disease, stroke, and 

peripheral vascular disease. Smokers have a much higher risk for malignant diseases of all organ 

systems compared to non-smokers (U.S. Department of Health and Human Services, 2004). 

Many aspects of reproductive health are negatively impacted by smoking.6 

6 For example, the 2001 Surgeon General’s Report lists numerous adverse reproductive effects associated with smoking 

compared to never smoking: increased perinatal mortality—both stillbirth and neonatal deaths—and the risk for sudden infant 

death syndrome (SIDS), increased risk of preterm premature rupture of membranes, abruptio placentae, and placenta previa, 

preterm delivery, and delivery of low birth weight infants (U.S. Department of Health and Human Services, 2001). 

There was one serious adverse experience (SAE) reported during the 6-week switching study. 

The subject was a 50-year-old white female smoker with 28-year history of cigarette use who 

had a subarachnoid hemorrhage one day after study completion. Study investigator, Philip 

Mathew, determined the SAE to be unrelated to the study product because the subarachnoid 

hemorrhage was due to a ruptured aneurysm. The SAE was determined to be resolved by the 

date of hospital discharge. In summary, the subject had several underlying risk factors for 

aneurysmal subarachnoid hemorrhage. Her long history of cigarette smoking, and family history 
 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 52 of 89 

of aneurysm are more likely to have caused the aneurysm and subsequent SAE than her recent 

short term VLNTM use. 

2.4.7.1. Health Risks to Non-Users 

The applicant did not submit product specific information related to the effect of VLNTM 

cigarettes on non-users, but it anticipates it would be similar to NNC cigarettes. We agree with 

the applicant. The most important health risk to non-users from any combusted product is 

involuntary exposure to secondhand smoke (SHS) and thirdhand smoke (THS). Because VLNTM 

cigarettes are combusted tobacco products, it is expected that similar health effects will occur 

when non-smoking bystanders are exposed to SHS and THS from VLN cigarettesTM. In the event 

that a smoker exposing a non-user to SHS and THS reduces their CPD when using VLNTM 

cigarettes, a reduction in non-user exposure to SHS and THS would be expected. 

2.4.7.2. Consumer Use and Potential Misuse 

The applicant did not submit any information on human factor studies with VLNTM cigarettes. 

Per the applicant, these products “perform just like conventional cigarettes . . . [and] will be 

used in the same manner as conventional nicotine content cigarettes.” The human factor issues 

related to NNC cigarettes leading to misuse or injury are well documented: improper storage, 

allowing access to unused products by children; improper disposal of butts, i.e., “butt waste”, 

that when ingested may be hazardous to the health of small children and animals (Novotny et 

al., 2011); and incomplete extinguishment of lighted cigarette products leading to fires causing 

personal injury—the leading cause of fire deaths in the U.S.—and property damage (Leistikow, 

Martin, & Milano, 2000). 

The medical review does not expect any different human factor issues to arise with VLNTM 

cigarettes because these cigarettes have no unique use characteristics that differ from NNC 

cigarettes. 

2.4.7.3. Health Risks Associated with Polyuse 

Different tobacco products potentially have different levels of addiction and toxicity (Sung, 

Wang, Yao, Lightwood, & Max, 2016). Consumers who use multiple tobacco products 

“potentially have increased risks of nicotine dependence, adverse health effects, increased 

exposure to HPHCs, and increased healthcare utilization” (Sung et al., 2016; U.S. Department of 

Health and Human Services, 2014). The applicant does not address polytobacco use in the 

PMTA submission. No information is provided on BOPHs, adverse events, or published 

literature that addresses the health risks of use of VLNTM cigarettes when used with other 

tobacco products. Nonetheless, given that the unique factor is the difference in nicotine, it is 

likely that the health risks of polytobacco use will not be any different for VLNTM cigarettes 

compared to NNC cigarettes given the general similarities. 
 

 

 

 

STN PM0000491 – PM0000492 Page 53 of 89 

2.4.7.4. Health Risks Associated with Switching to this Product Compared to 

Continued Smoking 

The health risks are likely the same compared to continued smoking another brand of cigarette. 

Smokers who completely switch to VLNTM cigarettes may experience weight gain. If smokers do 

not otherwise decrease their smoking or switch to other nicotine-containing products, then 

VLNTM cigarette users may have weight gain in addition to the adverse health effects of 

continued smoking. The BCP review notes in its review (see section on Abuse Liability) that the 

likelihood that current tobacco product users would completely switch to VLNTM cigarettes is 

low. The BCP review also notes that this effect may differ in smokers who are motivated to 

reduce their nicotine exposure or quit smoking. In this scenario of smokers motivated to reduce 

or eliminate nicotine exposure, the health risks for those who switch to VLNTM cigarettes health 

risks are likely less harmful than continued smoking. Smoking increases the risk of 

cardiovascular disease and thrombosis. While in vivo and in vitro studies have indicated that 

VLNTM cigarettes may cause increased platelet activation compared to other cigarettes with 

higher nicotine content, which may contribute to the potential risk of greater thrombosis 

compared to other cigarettes, an increased risk of thrombosis has not borne out based on 

adverse event reporting in clinical studies. 

For smokers who switch to VLNTM cigarettes, either completely or incompletely, and decrease 

their CPD, adverse health outcomes may not improve. The relationship between the amount of 

cigarette smoking and disease is not strictly linear. Health risks are found even with consistent 

low-level smoking (10 or fewer cigarettes a day) (Rigotti, 2018). For example, small amounts of 

cigarette smoke exposure can still increase risk for coronary artery disease (U.S. Department of 

Health and Human Services, 2014) and at least two studies have shown no change in all-cause 

mortality when smokers halve their daily cigarette consumption (Godtfredsen, Holst, Prescott, 

Vestbo, & Osler, 2002; Tverdal & Bjartveit, 2006). 

 

2.4.7.5. Health Risks Associated with Switching to this Product Compared to 

Tobacco Cessation 

The applicant did not provide information comparing the short- and long-term health effects of 

complete or incomplete VLNTM cigarette switching to abstinence. As stated above, VLNTM 

cigarettes are likely to have similar short- and long-term health risks as NNC cigarettes if 

product use frequency and amount are the same. Abstinence from NNC cigarettes is far 

preferable because it is associated with substantial health benefits (U.S. Department of Health 

and Human Services, 2004). Abstinence from all tobacco, including cigarettes, is one of the 

most important factors in improving individual health. To be balanced, achieving abstinence 

(quitting) by going “cold turkey” or using other means such as behavioral methods or 

pharmacotherapy can have health risks (e.g., nicotine withdrawal syndrome, weight gain, 

depression, cough, mouth ulcers (Rigotti, 2018)) but the benefits of abstinence (quitting) far 

outweigh these risks. 

Lastly, VLNTM cigarettes could deter smokers from abstinence if these products are perceived as 

a safer choice than NNC cigarette smoking due to decreased nicotine exposure. This may be 

especially true in people who despite multiple quit attempts have not been able to quit 
 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 54 of 89 

smoking. The applicant did not address the issue of VLNTM cigarette use deterring abstinence 

attempts. 

2.4.7.6. Health Risks Associated with Switching to Product Compared to Cessation 

Medication 

The applicant did not provide clinical data to evaluate the relative health risks of switching to 

VLNTM cigarettes compared to using cessation medication. As mentioned above, smokers who 

switch to VLNTM cigarettes could gain weight from decreased nicotine exposure and, 

concurrently, have the same adverse consequences of continued smoking. There is no clinical 

data to support this scenario. Smoking cessation using FDA-approved medications is far 

preferable than smoking any combustible products, including VLNTM cigarettes. FDA-approved 

smoking cessation medications have risks, but these products have known records of safety and 

efficacy. Though there are risks with abstinence and cessation therapies, the benefits of 

quitting far outweigh these risks. Lastly, it is possible that VLNTM cigarettes could deter smokers 

from abstinence with or without FDA-approved smoking cessation medications. The applicant 

did not provide information on abstinence and did not address the issue of deterrence from 

FDA-approved smoking cessation therapies. While it is optimal for smokers who are interested 

in quitting to directly switch to FDA approved cessation therapies or quit without therapy, it is 

well established that cigarette cessation is difficult and that many are not able to successfully 

convert. For some individuals VLNC cigarettes can serve as an interim transition to reduce 

nicotine dependence levels and cut down, which may aid in future quite attempts. VLNC 

cigarettes are less reinforcing than NNC cigarettes and the likelihood of long-term use of VLNC 

cigarettes is lower than NNC cigarette use. 

2.4.7.7. Summary of Adverse Health Effects 

Overall, if smokers who switch to the VLNTM cigarettes decrease their use and/or ultimately quit, 

there would likely be improved health benefits. If, on the other hand, cigarette smokers who 

completely switch to VLNTM cigarettes use them in the same way as NNC cigarettes, it is possible 

that they may have weight gain, but with the added adverse health consequences of continued 

smoking. According to the BCP review (see section on Abuse Liability), the likelihood of this 

latter scenario is likely low. 

2.4.8. Likelihood of Product Misuse or Malfunction 

The applicant did not submit information on potential misuse or malfunction of the VLNTM 

cigarettes. The applicant states that these products perform like NNC cigarettes and will be 

used in the same manner. As discussed in the medical review, the human factors issues related 

to cigarettes leading to misuse or injury are well known: improper storage, allowing access to 

unused products by children; improper disposal of butts, i.e., “butt waste”, that when ingested 

may be hazardous to the health of small children and animals (Novotny et al., 2011); and 

incomplete extinguishment of lighted cigarette products leading to fires causing personal 

injury—the leading cause of fire deaths in the U.S.—and property damage (Leistikow et al., 

2000). Thus, there are not any different human factors issues expected to arise with VLNsTM 

cigarettes because they have no unique use characteristics that differ from NNC cigarettes. 
STN PM0000491 – PM0000492 Page 55 of 89 

2.4.9. Bioresearch Monitoring (BIMO) Inspection 

OS reviewers did not identify any substantive concerns pertaining to the submitted clinical 

studies and did not recommend BIMO inspection. FDA’s Office of Compliance (OCE) review of 

the submission did not reveal any data integrity or human subject protection concerns and 

agreed with OS reviewers that BIMO inspections for the protocols submitted and associated 

sites are not warranted. 

2.4.10. Summary of Individual Health Findings 

The BCP review concludes: 

● Smokers who switch to smoking VLNC cigarettes have reduced exposure to nicotine 

compared to smoking UB-NNC cigarettes. 

● As a result of reducing nicotine exposure, switching to smoking VLNC cigarettes can lead 

to smoking fewer overall CPD compared to UB-NNC cigarettes. Smokers who reduce 

their overall CPD by smoking VLNC cigarettes may subsequently reduce non-nicotine 

HPHCs (e.g., NNAL, NNK, 3-HPMA). 

● Nicotine exposure is also reduced in smokers who do not reduce their overall CPD when 

switching to VLNC cigarettes and in smokers who dual use UB-NNC cigarettes or other 

tobacco products; however, non-nicotine HPHCs are not reduced in smokers who do not 

reduce their overall CPD when switching to VLNC cigarettes. 

● The reduced nicotine exposure in smokers of VLNC cigarettes may be associated with 

reduced dependence levels and facilitate abstinence in smokers motivated to quit. 

Concurrent use of NRT and behavioral intervention may improve cessation outcomes in 

VLNC cigarette smokers motivated to quit. However, given the role of menthol in 

reduced cessation success among NNC menthol smokers, it is anticipated that any 

potential effect on abstinence would be less likely among VLNTM Menthol King cigarette 

smokers, even those who are motivated to quit and concurrently use NRT. 

● Despite high rates of non-compliance, studies still report an average 60% reduction in 

nicotine exposure over six weeks of use and a reduction in measured non-nicotine 

HPHCs; the effect on non-nicotine HPHCs remains contingent upon an overall reduction 

in CPD. 

● Some studies find that consumers who dual use VLNC and UB-NNC cigarettes may not 

decrease their overall cigarette consumption (i.e., smokers tend to replace some of the 

UB-NNC cigarettes with VLNC cigarettes). Nicotine exposure is reduced in consumers 

who primarily smoke VLNC cigarettes, but do not decrease their overall CPD compared 

to their UB-NNC cigarette consumption. However, levels of non-nicotine HPHCs are not 

reduced compared to UB-NNC cigarettes in VLNC cigarette smokers who do not reduce 

their overall cigarette consumption. 

As TPL, I agree with the BCP review conclusions that there is a reduction in nicotine BOE when 

smokers switch to VLNC cigarettes. When the switch to VLNC cigarettes results in a decrease in 

CPD, there is also a decrease in other, non-nicotine HPHC BOE. These reductions are seen 

despite high rates of non-compliance in studies. Together these results indicate that using 

either of the VLNTM cigarette products would be expected to reduce the nicotine exposure in 
 

 

 

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individuals, potentially leading to reductions in dependence and CPD. The reduction in CPD 

could lead to a decrease in other non-nicotine HPHC BOE. 

The medical review concludes: 

● Regarding individual health risk from use of VLNTM cigarettes, there are limited data 

available in the published literature. VLNTM cigarette users will likely have similar shortand long-term health effects as those that occur with NNC cigarette smoking if used in 

the same manner given that the unique aspect of these products is the low nicotine 

content. 

● Smokers who switch exclusively to VLNTM cigarettes may experience the adverse 

consequences of weight gain in addition to the adverse health effects of continued 

smoking. 

● Smoking increases the risk of cardiovascular disease and thrombosis. While in vivo and 

in vitro studies have indicated that VLNTM cigarettes may cause increased platelet 

activation than cigarettes with higher nicotine content, which may contribute to greater 

risk of thrombosis compared to other cigarettes, adverse event data are insufficient to 

draw meaningful clinical conclusions regarding whether there is increased risk of 

thrombosis. 

● Smokers who completely switch to VLNTM cigarettes may experience nicotine 

withdrawal. Adverse event data from applicant-sponsored studies and from the 

published literature are limited but suggest that some adverse events may relate to 

nicotine withdrawal. See Section 6 for more information about adverse events in the 

published literature. There is little experience with VLNTM cigarettes to determine 

whether they may have adverse public health consequences beyond relapse to NNC 

cigarettes or other nicotine sources, such as ENDS, or the use of other substances to 

mitigate withdrawal symptoms. 

● Non-users who are involuntarily exposed will likely experience the same adverse health 

effects as exposure to tobacco smoke from NNC cigarettes. 

The medical review concludes that VLNTM cigarettes are combusted tobacco products composed 

of tobacco leaves containing less nicotine. These products will likely have the similar adverse 

health effects as smoking NNC cigarettes if used in the same manner. It is possible that these 

products may decrease nicotine dependence among users. Smokers who completely switch to 

VLNTM cigarettes may experience nicotine withdrawal. Cigarette smokers who completely switch 

to VLNTM cigarettes and use them as their sole source of nicotine may, over time, have weight 

gain similar to smokers who quit, but with the added adverse health consequences of 

continued smoking. This is a theoretical risk, unsupported by current evidence. 

As TPL, I agree with the medical review. Low nicotine cigarettes are not new to the market. 

Several low nicotine cigarettes have been available in the past with limited public interest. 

There are limited data available related to short-term health effects of VLNTM cigarettes. As an 

example, per the medical review, smokers who switch exclusively to VLNTM cigarettes may 

experience the adverse consequences of weight gain in addition to the adverse health effects of 

continued smoking. That said, the likelihood that current tobacco users would switch 
 

 

 

 

 

 

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completely to these products is low, however, for those that are able to switch to VLNTM 

cigarette use, the reduction in nicotine exposure and dependence is thought to outweigh the 

potential weight gain associated with low nicotine tobacco product use. Furthermore, VLNTM 

cigarettes have been used in various clinical studies for several years; no health-related shortterm issues uniquely related to VLNTM cigarettes were identified. There are limitations to the 

clinical studies conducted by the applicant; however, there are practical limitations to the 

number, size, and nature/design of clinical studies that can realistically be completed during 

new product development. Although limited, the data available in the applicant’s clinical 

studies do not raise concerns or identify specific health-related issues uniquely related to VLNTM 

cigarettes compared to combusted cigarettes. 

2.5. Population Health 

2.5.1. Likelihood of Use by Current Cigarette Smokers 

The epidemiology review (section 3.2) states that the applicant did not submit any 

observational studies on the likelihood of use of VLNTM cigarettes for current tobacco users. 

However, a randomized-controlled trial, by Hatsukami et al. (2018), showed that in a forcedswitching environment, daily smokers who switched to VLNC cigarettes reduced their cigarette 

consumption by around 50% after 20 weeks of use. The immediate reduction group had greater 

withdrawal symptoms, greater use of non-study cigarettes and higher dropout rates compared 

to the gradual nicotine reduction group (32% vs 19%). Despite the success of nicotine reduction 

of these forced-switching studies, in a real-world setting where NNC cigarettes are available, it 

is unlikely that current smokers of NNC cigarettes will switch to this product due to the low 

appeal of VLNTM cigarettes. 

The applicant did not provide epidemiological evidence regarding the likelihood that tobacco 

users who adopt VLNTM cigarettes will switch to or switch back to other tobacco products, such 

as NNC cigarettes, that may present higher levels of individual risks if consumers increase the 

number of CPDs when switching to NNC cigarettes. In addition, the applicant did not provide 

observational data on the transition of VLNTM cigarette use back to NNC cigarette use. However, 

in a real-world setting where NNC cigarettes are available, there is a high likelihood that current 

smokers of NNC cigarettes who may adopt VLNTM cigarettes will switch to or switch back to 

other tobacco products such as NNC cigarettes due to the low appeal of VLNTM cigarettes. 

Epidemiologic data regarding the likelihood that users of any tobacco product who may have 

otherwise quit or switch to a smoking cessation product would instead use the VLNTM products 

is not available at this time. Available short-term data indicate that polytobacco use of VLNC 

and other tobacco products is likely and that, for some tobacco product users, availability of 

VLNC, despite polytobacco use, can lead to reduction in cigarette consumption, increased quit 

attempts, and in some cases spontaneous cessation of tobacco products. Long term 

epidemiologic data on use behavior of a proposed product is typically not available premarket, 

thus, postmarket reporting may assist in monitoring use transitions. 

The BCP review Section 4.1 discusses the results from applicant-submitted clinical studies, as 

well as the larger VLNC literature, to address the likelihood of use by current cigarette smokers. 
 

 

 

 

 

 

 

 

 

 

 

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After reviewing both the studies and the literature, BCP determined that VLNTM cigarettes were 

associated with lower abuse liability compared to UB-NNC cigarettes as evidenced by lower 

plasma nicotine uptake (Cmax, AUC), positive subjective effects ratings (e.g., pleasant, satisfying, 

calm), and likelihood of future use. VLNTM cigarettes were associated with a similar abuse 

liability profile as 4 mg nicotine gum, as evidenced by similar positive subjective effects ratings. 

As discussed in Section 3.2, the larger VLNC literature corroborates the applicant’s data on 

VLNTM cigarettes. In extended duration studies, when participants are provided with a sufficient 

supply of VLNC cigarettes at no cost, there are high levels of non-compliance wherein 

participants choose to pay for NNC cigarettes rather than use the VLNC cigarettes provided free 

of charge. Taken together, the data suggest that current smokers not interested in quitting or 

reducing their nicotine exposure have a low likelihood of initiating use of VLNTM cigarettes. 

However, current smokers interested in reducing their nicotine exposure and motivated to quit 

smoking may be the group most likely to start using VLNTM cigarettes. 

The applicant’s clinical abuse liability studies find that VLNTM cigarettes are associated with low 

subjective effects ratings and increases in cigarette craving and are not reliably chosen over UBNNC cigarettes. Specifically, VLNTM cigarettes have lower positive subjective effects ratings (e.g., 

pleasant, satisfying, calm) compared to UB-NNC cigarettes and a low likelihood of future use. 

These findings are supported by studies of VLNC cigarettes in the literature. Long-term studies 

on VLNC cigarettes (i.e., six to 20 weeks) indicate a high rate of non-compliance in smoking 

VLNC cigarettes, with product satisfaction being a predictor of non-compliance. Due to the low 

consumer satisfaction and low abuse liability of VLNTM cigarettes, the likelihood that current 

tobacco users would switch completely to these products is low. It is anticipated that some 

current tobacco users who adopt these products would switch back to smoking their UB-NNC 

cigarettes. However, this effect may differ in smokers who are motivated to reduce their 

nicotine exposure or quit smoking. For those individuals that are able to switch to using VLNTM 

cigarettes, studies show that there can be a reduction in nicotine exposure and dependence 

with a reduction in overall CPD use. 

2.5.2. Summary of Likelihood of Use by Current Cigarette Smokers 

As TPL I agree with the epidemiology and BCP reviews’ conclusion that it is unlikely that many 

current cigarette smokers would completely switch to VLNTM cigarettes. This is supported by the 

low appeal, consumer satisfaction, and abuse liability of VLNTM cigarettes found both in the two 

clinical studies provided as well as in the broader literature on VLNC cigarettes. Current 

smokers interested in reducing their nicotine exposure and motivated to quit smoking may be 

the group most likely to start using VLNTM cigarettes. 

2.5.3. Poly-use of VLNTM cigarettes and cigarettes or other tobacco products 

Both the epidemiology review (section 3.2) and the BCP review (section 4.1) note that there are 

very few clinical studies assessing the effects of VLNC cigarettes on other tobacco product use. 

One study was designed to assess other tobacco product use among smokers not interested in 

quitting; participants were assigned to smoke LNC cigarettes (1.3 mg nicotine per gram of 

tobacco) or NNC cigarettes and were provided with access to combusted or non-combusted 

tobacco products. Participants who received LNC cigarettes used more alternative combusted 
 

 

 

 

 

 

 

 

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and non-combusted tobacco products. However, these participants also smoked fewer total 

combusted tobacco products and had more quit-attempts. Furthermore, tobacco toxicant 

levels in participants who received LNC cigarettes and only non-combusted products were 

significantly lower than those in participants who received NNC cigarettes; toxicant levels in 

participants who received LNC cigarettes and had access to both combusted and noncombusted products did not differ from those in the NNC cigarette group. In addition, a study 

of nondaily smokers found that those randomized to receive LNC cigarettes for 10 weeks (1.3 

mg nicotine per gram of tobacco) were more likely to use ENDS compared to those randomized 

to an NNC group (Shiffman et al., 2018). Finally, clinical studies report high rates of noncompliance with VLNC cigarettes, even when provided free of charge, suggesting that dual use 

with UB-NNC cigarettes may be common. 

2.5.3.1. Summary of Poly-use 

As TPL I agree with the epidemiology and BCP reviews that there is evidence that smokers who 

use VLNTM cigarettes may use other tobacco products including NNC cigarettes; however, their 

total combusted tobacco product consumption and toxicant exposure are not likely to increase 

and may be lower if the polyusers reduce overall CPDs compared to those in smokers who 

continue to smoke UB-NNC cigarettes 

2.5.4. Use by Former or Never Smokers 

The epidemiology review notes that the applicant did not provide data from national surveys 

and epidemiological studies to suggest that never tobacco users (particularly youth or young 

adults) will not take up VLNTM cigarettes. The applicant also did not provide any evidence to 

address the likelihood that never users who take up VLNTM cigarettes will switch to other 

tobacco products that present higher levels of individual health risk. Even though VLNTM 

cigarettes are lower-nicotine products, VLNTM cigarettes are still combustible tobacco products, 

and never tobacco users would be exposed to all of the same non-nicotine HPHCs that are in 

the NNC combusted cigarettes. 

On the other hand, the BCP review, in order to discuss the potential impact on former or neversmokers, extrapolated from the literature on use and appeal in current smokers, as all studies 

in the literature assessing the use and appeal of VLNC cigarettes involved current cigarette 

smokers. The BCP review states that a large minority of subjects (over a third) of non-daily 

smokers provided with VLNC cigarettes at no cost were non-compliant with exclusive VLNC 

cigarette use. In extended duration studies, when participants are provided with a sufficient 

supply of VLNC cigarettes at no cost, there were high levels of non-compliance wherein 

participants choose to pay for NNC cigarettes rather than use the VLNC cigarettes provided free 

of charge. Additionally, in the applicant-submitted clinical studies with current smokers, VLNTM 

cigarettes were associated with lower abuse liability compared to UB-NNC cigarettes as 

evidenced by lower plasma nicotine uptake (Cmax, AUC), positive subjective effects ratings (e.g., 

“pleasant,” “satisfying,” “calm”), and likelihood of future use. Extrapolating from this limited 

literature and submitted clinical studies in current smokers, these data suggest a low likelihood 

that VLNTM King cigarettes would promote initiation and progression to regular use among 

consumers who have never used tobacco products. 
 

 

 

 

 

 

 

 

 

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2.5.4.1. Summary of Use by Former or Never Smokers 

As TPL I agree with the epidemiology review that there are no data that directly look at the 

likelihood that former or never users would take up VLNTM cigarettes, or the likelihood that 

those in this population who do use these products would switch to products with high levels of 

individual health risk (such as NNC combusted products). However, I agree with the BCP review 

that the information provided on current users may be informative to the former and never 

user population and that data suggest a low likelihood that VLNTM cigarettes would promote 

initiation and progression to regular use among consumers who have never used tobacco 

products. 

2.5.5. Use by Vulnerable Populations (Youth and Mental Health Populations) 

2.5.5.1. Youth 

The epidemiology review states that the applicant did not provide data on the impact of the 

name “VLNTM” or “Moonlight®” on never tobacco users including youth. It is possible that youth 

may believe that these cigarettes might be “safer” than NNC cigarettes, and youth who 

experimented with VLNTM cigarettes could transition to NNC cigarette smoking. Furthermore, 

the applicant did not provide information on how menthol VLNTM smoking could impact the 

likelihood of VLNTM use by youth. The applicant suggested that VLNTM cigarettes are less 

reinforcing and less appealing to youth; however, Epidemiology notes that menthol cigarette 

smoking among youth could facilitate progression or transition to more established smoking 

(U.S. Department of Health and Human Services, 2012). The 2012 Surgeon General Report 

“Preventing Tobacco Use Among Youth and Young Adults” shows that menthol use is 

disproportionally higher in youth and young adults compared to older adults. Initiating menthol 

smoking could put youth and young adults at risk for becoming established smoking later in life 

(U.S. Department of Health and Human Services, 2012). 

Section 4.1 of the BCP review notes that existing data in adolescent and young adult smokers 

suggest VLNC cigarettes are associated with lower positive subjective effects ratings (e.g., 

“liking,” “pleasant,” “satisfaction”) compared to NNC cigarettes, and VLNC cigarettes are not 

associated with compensatory smoking (i.e., smoking topography, TNE levels) in this vulnerable 

population. It is important to note that most of the data come from acute laboratory studies 

where participants have limited VLNC cigarette exposure. However, a secondary analysis of the 

Donny et al. study found no evidence of differential effects of VLNC cigarettes as a function of 

age (i.e., 18-24 years vs. 25+ years). While nicotine dependence has been shown to develop 

rapidly among adolescents following exposure to NNC cigarettes, the limited available evidence 

on VLNC cigarettes suggests that youth who experiment with VLNC cigarettes may find them 

less appealing and may be less likely to develop nicotine dependence and become established 

cigarette smokers due to their lower abuse liability profile. However, studies support that 

menthol in NNC cigarettes facilitates increased experimentation and progression to regular 

smoking among youth and young adults and contributes to greater dependence in youth 

smokers (e.g., Hersey et al., 2006; Wackowski & Delnevo, 2007). 

Additionally, the applicant submitted a summary of a recent published study as part of 
 

 

 

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amendment PM0000514, reviewed by TPL only as a late amendment, discussing youth 

perception of VLNC cigarettes. Cassidy and colleagues (2019) conducted a secondary analysis of 

Cassidy et al. (2018) to evaluate the abuse liability of VLNC cigarettes using a behavioral 

economic measure. Participants were 50 adolescent smokers who completed five hypothetical 

Cigarette Purchase Tasks (usual brand, and 15.8, 5.2, 1.3, 0.4 mg nicotine/g tobacco SPECTRUM 

cigarettes) after sampling a single cigarette of each dose. For each purchase task, participants 

were asked to estimate how many cigarettes they would smoke in a given day at escalating 

prices if the given cigarette was the only tobacco product available. Each of the SPECTRUM 

research cigarettes were associated with lower demand (i.e., abuse liability) compared to usual 

brand cigarettes; however, there were no differences in demand as a function of SPECTRUM 

cigarette dose. The Cassidy et al. (2019) study shows that among this group of adolescents, the 

reinforcing efficacy or appeal of all doses of SPECTRUM cigarettes was lower compared to UBNNC cigarettes. This result contrasts with primary outcomes showing reduced subjective effects 

as a function of reduced nicotine content in SPECTRUM cigarettes. The lack of a dose-response 

effect in this study may be due to adolescents’ sensitivity to cigarette branding, or their inability 

to discriminate between the research cigarettes after a single, blinded exposure. It is also 

possible that the Cigarette Purchase Task used in this study was less sensitive to dosedependent differences in appeal compared to measures that directly assess subjective 

response. In all, the current study supports the available evidence showing that VLNC cigarettes 

are not associated with increased appeal compared to UB-NNC or NNC cigarettes among 

adolescent smokers. In all, each of the SPECTRUM research cigarettes were associated with 

reduced abuse liability compared to usual brand cigarettes in this group of adolescent smokers. 

Given that current adult smokers are the intended population for VLNTM cigarettes, reduced 

likelihood of use among adult smokers is also likely to reduce youth access to these products 

and their availability for youth experimentation. Indirect sources, including stealing or 

borrowing from an adult, are some of the most common means of youth access to cigarettes 

(Castrucci, Gerlach, Kaufman, & Orleans, 2002; Cummings, Sciandra, Pechacek, Orlandi, & Lynn, 

1992; Lenk, Toomey, Shi, Erickson, & Forster, 2014). Therefore, reduced adult use would likely 

reduce youth access through these means. 

2.5.5.2. Mental Health Populations 

The epidemiology review did not identify analyses by the applicant that specifically focus on 

vulnerable populations that are at increased risk of using VLNTM cigarettes. The applicant 

provided an evaluation of the use of VLNC on smoking behaviors of a vulnerable population 

(i.e., individuals with depression, schizophrenia, psychiatric disorders). These studies showed 

that as a result of switching from traditional cigarettes to VLNC cigarettes, participants reduced 

CPD without compensatory smoking. 

The BCP review states that the evidence on vulnerable populations is extrapolated from the 

larger VLNC cigarette literature. The effects of VLNC cigarettes have been assessed in two 

vulnerable populations: smokers with mental health symptoms (e.g., depression, schizophrenia) 

and adolescent smokers. The literature supports that in smokers with mental health symptoms, 

as in the general population, VLNC cigarettes were associated with smaller reductions in craving 
 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 62 of 89 

and withdrawal symptoms compared to NNC cigarettes. Among this group, VLNC cigarettes 

were not associated with increased markers of compensatory smoking (e.g., smoking 

topography, CO) compared to the general population. Researchers also assessed psychiatric 

symptomatology as a function of VLNC cigarette use and found that VLNC cigarettes were 

associated with improvements in mood symptoms, likely due to nicotine’s anxiety-increasing 

properties. Studies also found no evidence that alcohol or marijuana use moderates the effects 

of VLNC cigarettes, and VLNC cigarette use does not increase compensatory alcohol or 

marijuana use. In sum, the available literature provides little to no evidence that VLNTM King 

cigarettes increase risk of adverse effects (e.g., exacerbations of psychiatric symptomatology, 

other substance use) in smokers with mental health symptoms. Extrapolating from the 

literature on NNC menthol cigarettes, evidence does not suggest that menthol would 

differentially influence outcomes in vulnerable populations evaluated for VLNC non-menthol 

cigarettes. As such, the literature can also be extrapolated to VLNTM Menthol King cigarettes and 

indicates little to no evidence that VLNTM Menthol King cigarettes would increase risk of adverse 

effects in vulnerable populations. There is no evidence of increased aversive effects (e.g., 

enhanced withdrawal, exacerbation of psychiatric symptoms) from smoking VLNC cigarettes 

(menthol or non-menthol) among vulnerable smoking populations (e.g., those with mental 

illness) compared to smoking NNC cigarettes. 

2.5.5.3. Summary of Use by Vulnerable Populations 

As TPL I note the concerns raised by the epidemiology review that information on perception of 

the name “VLN” was not provided. After the epidemiology review was initially completed, the 

applicant amended the PMTA to change the proposed brand name from “VLN” to “Moonlight.” 

There was no information on the perception of the new name provided. If individuals become 

aware that these products are low nicotine cigarettes, there may be individuals who consider 

that low nicotine products are “safer” tobacco products and experiment with these products 

first. While nicotine dependence has been shown to develop rapidly among adolescents 

following exposure to NNC cigarettes, I agree with the BCP review that the limited available 

evidence on VLNC cigarettes suggests that youth who experiment with VLNC cigarettes may 

find them less appealing and may be less likely to develop nicotine dependence and progress to 

established smoking due to their lower abuse liability profile. There is evidence that in NNC 

cigarettes menthol can facilitate progression to use and transition to established smoking due 

to the synergistic effect of menthol on the reinforcement of nicotine. However, as the VLNTM 

Menthol King cigarettes have ~95% less nicotine than NNC cigarettes currently on the market 

and at a dose that is considered minimally addictive, there would not likely be the same 

reinforcement of the menthol compared to NNC cigarettes. Stated alternatively, although the 

menthol in VLNTM Menthol King cigarettes will still have the effect of making it easier to tolerate 

the inhalation of the combusted product, youth will likely find both VLNTM products less 

appealing due to lower nicotine levels and be less likely to become established cigarette 

smokers. 

As TPL I agree with the epidemiology and BCP reviews that note for similar VLNC cigarettes 

there is no evidence of increased aversive effects (e.g., enhanced withdrawal, exacerbation of 

psychiatric symptoms) from smoking VLNC cigarettes (menthol or non-menthol) among 
 

 

 

 

 

 

 

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vulnerable smoking populations (e.g., those with mental illness) compared to smoking NNC 

cigarettes. 

2.5.6. Population Modeling 

The epidemiology review notes that the applicant did not conduct any population modeling of 

tobacco product use behavior. The applicant states that VLNTM cigarettes are not attractive to 

former smokers and never smokers, and that “the sales of the product without claims will be 

negligible and there will be no impact on the population as a whole.” The epidemiology review 

notes that in the real-world setting (in absence of any nicotine standard), where NNC cigarettes 

are available it is uncertain whether most current cigarette smokers will switch to VLNTM 

cigarettes. 

2.5.7. Summary of Population Health Findings 

The epidemiology review states that the PMTAs do not contain sufficient information about the 

VLNTM cigarettes as the applicant did not conduct or include observational studies or population 

modeling of tobacco product use behavior and concluded that marketing the product without 

claims would have no impact on the population as a whole. The epidemiology reviewer states 

that in the absence of a nicotine standard, where NNC cigarettes are available, it is uncertain 

whether most current cigarette smokers will switch to VLNTM cigarettes. Therefore, the 

likelihood of the use of VLNTM cigarettes among never tobacco users, including youth and young 

adults is unknown. Additionally, the applicant did not provide information on how VLNTM 

Menthol King cigarette smoking could impact the likelihood of VLNTM cigarette smoking by 

youth. The 2012 Surgeon General’s Report has summarized that use of NNC menthol cigarette 

smoking among youth may facilitate progression or transition to established cigarette smoking 

(U.S. Department of Health and Human Services, 2012). Given that VLNTM cigarettes are 

combustible cigarettes, never tobacco users including youth who start experimenting or using 

VLNTM cigarettes would be exposed to the same non-nicotine HPHCs that are in NNC cigarettes. 

As TPL I disagree that there is insufficient data related to VLNTM cigarettes and similar VLNC 

cigarettes to reasonably anticipate likely population health. VLNC cigarettes were on the U.S. 

market previously, in an environment where both NNC and VLNC cigarettes existed 

simultaneously. Furthermore, there are clinical studies evaluating VLNTM cigarettes and similar 

VLNC cigarettes manufactured by the applicant, although in controlled environments, related to 

tobacco use patterns and trends as well as consumer studies conducted by the applicant and 

other investigators. Thus, there is information about likely use by various populations to draw 

upon in this review. Overall, it is anticipated that uptake of VLNTM cigarettes without any claims 

would be low. Nevertheless, based on clinical studies, it appears that there is a portion of 

smokers that may be able to use VLNTM cigarettes as a transitional product to cut down CPD and 

eventually quit. Given the very low nicotine available from these cigarettes, which are nonreinforcing, and general low likeability of taste, it is not expected that youth or never smokers 

would experiment and transition to regular use even in the presence of menthol flavor and, at 

minimum, any transition would be less than in NNC cigarette experimenters. According to the 

2018 Monitoring the Future National Survey Results on Drug Use 1975-2018, cigarette smoking 

among youth was declining from 2002 to 2010 while Quest cigarettes were on the market 
 

 

 

 

 

 

 

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(Johnston et al., 2019). In addition, there is a study that examined college students’ preferences 

on light cigarettes or potential reduced exposure products including Quest and Eclipse that they 

found college students had lower positive expectancy (less likely to use) with Quest cigarettes 

(O'Connor et al., 2007). Cigarette smoking among youth has steadily continued to decline in the 

past few decades, including the time period that a VLNC cigarette (Quest) was on the market. 

The introduction of VLNC cigarettes did not appear to have had a negative impact on declining 

smoking rates with youth. 

2.6. Product Labeling, Consumer Comprehension, and Marketing Plan 

2.6.1. Proposed PMTA Labeling 

The applicant submitted specimens of proposed labeling for the PMTAs. OCE Division of 

Promotion, Advertising, and Labeling (DPAL) reviewed these specimens of proposed labeling 

and did not note issues of concern with the labeling, standing alone. However, DPAL noted 

concern that “VLN” displayed on the submitted labeling, which appears to stand for “very low 

nicotine,” in conjunction with other representations, may render the product a modified risk 

tobacco product. The applicant indicates that “VLNTM” stands for “Very Low Nicotine”, and has 

stated the following: 

1) In the text of the PMTA, under a subheading titled “Product Description,” the

applicant states “22nd Century developed the VLNTM cigarettes that are the subjects

of this application. The VLNTM cigarettes (Menthol King and regular King (nonmenthol) cigarettes) are also exactly the same as the NRC102 and NRC103

SPECTRUM® very low nicotine research cigarettes” (Page 32, PMTA)

2) The applicant also states, “Very Low Nicotine Tobacco destined for VLNTM brand

cigarettes is also tested for its nicotine content” (Page 93, PMTA).

3) A press release dated December 5, 2018 announcing the filing of the PMTA is titled

“22nd Century Files Premarket Tobacco Application (PMTA) with the FDA” The press

release explains the application is for cigarettes to be marketed “under the proposed

brand name VLNTM (the product name is subject to FDA approval). 22nd Century’s

proposed VLNTM cigarettes – the subject of the PMTA – are made with 22nd Century’s

proprietary VLNTM tobacco and, as a result, contain very low levels of nicotine”

(https://ir.xxiicentury.com/press-releases/detail/356/22nd-century-files-premarkettobacco-application-pmta) . The December 5, 2018 press release announcing the

filing of an PMTA for “Very Low Nicotine Content Cigarettes” can also be found on

the firm’s website. (https://ir.xxiicentury.com/press-releases/detail/356/22ndcentury-files-premarket-tobacco-application-pmta)

DPAL notes that labeling and/or advertising that represents explicitly or implicitly that a 

tobacco product contains a reduced level of a substance or presents a reduced exposure to a 

substance (e.g. nicotine) would render that product a Modified Risk Tobacco Product (“MRTP”) 

(sec. 911(b)(2)(A)(i)(II)). Additionally, tobacco product labeling and/or advertising that uses the 

descriptors “light,” “low,” or “mild” or similar descriptors would render that product an MRTP 

(sec. 911(b)(2)(A)(i)). It is the applicant’s responsibility to ensure that the products comply with 
 

 

 

 

 

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the FD&C Act, FDA’s implementing regulations, and all other applicable laws and regulations, 

such as the Federal Cigarette Labeling and Advertising Act. 

On October 2, 2019, the applicant amended their PMTAs to change the proposed brand name 

from “VLNTM” to “Moonlight” (PM0000549). This amendment also included specimens of 

proposed labeling which reflected the change in brand name. DPAL reviewed these specimens 

of proposed labeling and other representations made by the applicant and generally did not 

note any issues of concern. However, DPAL is concerned that the brand name “Moonlight” may 

appear on other labeling or advertising in a manner that highlights the descriptor “light,” and 

may potentially be marketed as such without an MRTP order in effect. It is the applicant’s 

responsibility to ensure that the products comply with the FD&C Act, FDA’s implementing 

regulations, and all other applicable laws and regulations, such as the Federal Cigarette Labeling 

and Advertising Act. 

As TPL I agree with OCE DPAL’s review that there is a potential for the applicant to use modified 

risk language in product communications related to VLNTM as well as Moonlight given publicly 

existing product communications language. However, I do not feel this is a limitation that 

should prevent a marketing authorization in that it is the applicant’s responsibility to ensure 

that the products in the United States comply with the FD&C Act, FDA’s implementing 

regulations, and all other applicable laws and regulations, such as the Federal Cigarette Labeling 

and Advertising Act. We may inform the applicant further on use of potential modified risk 

language by noting in a marketing order letter, should one be issued, that “light” and “very low 

nicotine” is considered modified risk language and may not be used to describe the proposed 

products without appropriate authorization in place. At this time, the labeling does not 

otherwise appear to be false or misleading. 

2.6.2. Consumer Perception 

22nd Century submitted one perception study conducted for the modified risk tobacco product 

application (MRTPA) for VLNTM cigarettes that examined outcomes relevant to the social science 

review for this PMTA: “Quantitative Study to Develop VLNTM Hypothetical Product Messages 

Among U.S. Adult Cigarette Smokers, Adult Former Cigarette Smokers and Adult Never 

Cigarette Users.” The purpose of this consumer perception study was to measure responses to 

versions of the VLNTM label and messaging within populations of: 1. adult smokers with an 

intention to quit, 2. adult smokers without any intention to quit, 3. adult former smokers, and 

4. adult never smokers. The applicant notes that the total sample was 29,219 participants, with

approximately 7,000 participants per concept. However, Table 1 of the application indicates

that there were approximately 3,500 participants per control condition and slightly more than

7,000 participants for each experimental condition. Specifically, the study aimed to assess risk

perceptions and intent to use for VLNTM, Marlboro Gold and four comparator categories (NNC

cigarettes, NRT, ENDS, and moist snuff). There were two control conditions. One control group

was shown a Marlboro Gold pack and the other group was shown a VLN pack without claims.

The data related to the VLNTM pack without claims is most pertinent for these PMTAs.
 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 66 of 89 

Secondary objectives were to estimate the impact of VLNTM cigarettes after exposure to the 

product among adult never smokers, adult never smokers legal age to 25 years old, adult 

former smokers (recent and long-term), adult smokers motivated to quit, and adult smokers 

with no intention to quit. 

However, in an amendment submitted on September 13, 2019 (PM0000544), the applicant 

noted 

. 

(b)(4)

perception study that examined outcomes potentially relevant to the evaluation of VLNTM 

cigarettes from the social science perspective. 

, there is no information to evaluate the 

appeal and perception of VLNTM specifically from the social science perspective in the content 

of this PMTA. 

(b)(4)

The applicant also submitted a literature review that addressed consumers’ beliefs about the 

health risk of using cigarettes relative to other tobacco products and the ability of consumers to 

understand modified risk claims. For the PMTA, only the first objective was examined by the 

social science review. 

The social science review concludes that the applicant submitted a literature review and one 

As TPL, I agree with the social science review that there are limitations to the consumer 

perception study provided for the PMTA and is not relevant provided the name change 

proposed. Useful conclusions can nonetheless be made related to potential impact of VLNTM 

cigarettes on the population as VLNC cigarettes are not a new product. Products similar to 

VLNTM cigarettes have been marketed in the US in early 2000s with limited marketing success, 

generally due to lack of desirable flavor and likeability. There is limited information available in 

the literature indicating that for some individuals, especially those motivated to quit, the VLNC 

cigarettes offer a way to cut down on tobacco products, which may lead to quitting. To date, 

significant transitions of undesirable behaviors such as youth or never user initiation of VLNC 

cigarettes and former users re-initiating do not appear to be of concern. In particular, the lower 

abuse liability profile of VLNC cigarettes make it less likely that experimentation of these 

cigarettes by youth would encourage regular use compared to NNC cigarettes. 

2.6.3. Required Labeling 

The cigarettes, if authorized, would bear the rotating Surgeon General’s warnings required 

under the Federal Cigarette Labeling and Advertising Act (FCLAA). 

3. ENVIRONMENTAL DECISION

A finding of no significant impact (FONSI) was signed by Dr. Kimberly Benson on October 29, 

2019. The FONSI was supported by an environmental assessment prepared by FDA on October 

29, 2019. 
 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 67 of 89 

4. CONCLUSIONS AND RECOMMENDATIONS

4.1. Conclusions 

In its applications for the VLNTM cigarettes, the applicant provided detailed information about 

the manufacturing process. This information describes adequate process controls and quality 

assurance procedures to help ensure that the VLNTM cigarettes are manufactured consistently 

to meet the applicant’s specifications. To verify nicotine data, confirmatory testing was 

conducted at FDA’s STL. Although there were methodological differences between the 

applicant’s testing and the FDA testing, the results were similar. The STL data shows that the 

VLNTM cigarettes have 97-98% lower nicotine levels in tobacco and mainstream smoke than the 

top six comparator cigarette brands. The STL nicotine data also supports the applicant’s 

statement that the proposed products contain 95% less nicotine. 

The results of a toxicology evaluation demonstrate that the overall noncancer hazards and 

cancer risks associated with toxicant exposure due to use of VLNTM King and VLNTM Menthol King 

cigarettes are likely similar to those due to use of the six commercially marketed NNC cigarette 

comparators in this application. Combining the submitted evidence, the overall toxicological 

risk to users (i.e., the potential health hazards and risks associated with toxicant exposure), 

assuming they completely switch to VLNTM King and VLNTM Menthol King cigarettes, are likely 

similar to those for users of the six commercially marketed NNC cigarette comparators. 

However, if there was evidence to support that users would switch completely to VLNTM 

cigarettes, then potential reductions in CPD may result in lower toxicant risks in comparison to 

the use of the six comparators.

Noncancer hazards and cancer risks to dual users of tobacco products, where at least one 

product is VLNTM King or VLNTM Menthol King cigarettes, are also likely to be similar or less than 

smoking the six commercially marketed NNC cigarette comparators, to the extent that the use 

of such additional tobacco products or NRT is less harmful than use of the six comparators. By 

extension of the comparative risks for complete switchers, or for dual users in which one 

product is VLNTM King or VLNTM Menthol King cigarettes, the associated exposures and risks 

posed to non-users through SHS are also likely similar to or less than what they may experience 

through exposure to SHS from the six comparators. The extent to which this is true for dual 

users is, however, also dependent on the likelihood that the additional tobacco products they 

use are less harmful than the six comparators. In other words, if by using VLNTM King or VLNTM 

Menthol King cigarettes the consumer dual uses less harmful products (i.e., non-combusted 

products) than the six comparator products, then the associated exposures and risks posed to 

non-users through SHS would be less. 

Using VLNTM King and VLNTM Menthol King cigarettes compared to quitting tobacco use or 

switching to NRT would increase harm, as toxicant exposures would be similar to exposure 

resulting from the use of the six comparators, if product use frequency and amount are the 

same. However, in the event that a regular cigarette user switched to VLNTM King and VLNTM 

Menthol King cigarettes, and reduced their CPD, their toxicant exposure would also be 

expected to be reduced. For non-users seeking to initiate smoking by using VLNTM King and 

VLNTM Menthol King cigarettes, if they proceeded to using the products similarly to those 
 

 

 

 

 

STN PM0000491 – PM0000492 Page 68 of 89 

initiating with NNC cigarettes, toxicant exposures and associated health risks would likely be 

similar as those of naive users who initiate smoking with one of the six comparators. However, 

due to the reduced nicotine levels, non-users experimenting with VLNTM King and VLNTM 

Menthol King cigarettes would be at less risk for developing dependence to these products and 

becoming established users than those initiating with NNC cigarettes. 

The PK profile and lower positive subjective effects ratings of the VLNTM cigarettes indicate a 

lower abuse liability than the applicant’s UB-NNC cigarette comparator. Menthol and nonmenthol NNC smokers who choose to switch to VLNTM cigarettes would experience the benefit 

of significantly reducing their overall exposure to nicotine, potentially reducing their overall 

smoking, and subsequently, their exposure to non-nicotine HPHCs. However, the low subjective 

appeal, along with increased craving and withdrawal, may prevent current smokers from fully 

transitioning to VLNTM cigarettes. 

Youth may believe that VLNC cigarettes might be “safer” than NNC cigarettes, and some youth 

who experimented with VLNTM cigarettes could transition to NNC cigarette smoking. Existing 

data in adolescent and young adult smokers suggest VLNC cigarettes are associated with lower 

positive subjective effects ratings (e.g., “liking,” “pleasant,” “satisfaction”) compared to NNC 

cigarettes, and VLNC cigarettes are not associated with compensatory smoking (i.e., smoking 

topography, TNE levels) in this vulnerable population. While nicotine dependence has been 

shown to develop rapidly among adolescents following exposure to NNC cigarettes, the limited 

available evidence on VLNC cigarettes suggests that youth who experiment with VLNC 

cigarettes may find them less appealing and may be less likely to develop nicotine dependence 

and become established cigarette smokers due to their lower abuse liability profile. The 

applicant did not provide information on how menthol could impact the likelihood of VLNTM use 

by youth, however, in the adult study of VLNTM Menthol King data showed these cigarettes have 

lower positive subjective effects than UB-NNC cigarettes though the reduction is less than 

compared to VLNTM King cigarettes. 

Data provided in the literature cited in the application indicate that there is a reduction in 

nicotine BOE when smokers switch to VLNC cigarettes. When the switch to VLNC cigarettes 

results in a decrease in CPD, there is also a decrease in other, non-nicotine HPHC BOE. These 

reductions are seen despite high rates of non-compliance in studies. Together, these results 

indicate that using either of the VLNTM cigarette products would be expected to reduce the 

nicotine exposure in individuals, potentially leading to reductions in dependence and CPD. The 

reduction in CPD could lead to a decrease in other non-nicotine HPHC BOE. 

and specific appeal of VLNTM cigarettes could not be assessed. Nonetheless, evidence from the 

The applicant’s consumer perception study had 

(b)(4)

current smoker literature and studies, as well as previous U.S. markets that had VLNC cigarette 

products, may be used to reasonably anticipate outcomes of the availability of VLNTM cigarettes 

on current, former, and non-users of cigarettes. Overall, it is anticipated that uptake of VLNTM 

cigarettes without any claims would be low. Nevertheless, based on clinical studies, it appears 

that there is a portion of smokers who may be able to use VLNTM cigarettes as a transitional 

product to cut down CPD and eventually quit. Given the very low nicotine available from these 
 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 69 of 89 

cigarettes, which are non-reinforcing, and general low likeability of taste, it is not expected that 

youth, former, or never smokers would experiment and transition to regular use even in the 

presence of menthol flavor and, at a minimum, any transition would be less than that in NNC 

cigarette experimenters. 

If smokers who switch to the VLNTM cigarettes decrease their use, there would likely be 

improved health benefits. If smokers who switch to the VLNTM cigarette eventually quit tobacco 

product use, there would certainly be improved health benefits. If, on the other hand, cigarette 

smokers who completely switch to VLNTM cigarettes use them in the same way as NNC 

cigarettes, it is possible that they may have weight gain due to the lower nicotine but with the 

added adverse health consequences of continued smoking, although the likelihood of this 

scenario is likely low given the high prevalence of dual use in studies. While the risk of potential 

increased platelet activation was noted as a possible unintended consequence, limited clinical 

evidence to date does not indicate an increased risk of thrombosis relative to NNC cigarettes. 

Continued adverse event reporting may be informative. 

4.2. Recommendation for Marketing 

As discussed in this review, I recommend the PMTAs be authorized. None of the grounds 

specified in Section 910(c)(2) of the FD&C Act apply. Specifically, I find the following: 

1. Permitting the marketing of the products is appropriate for the protection of the public

health, as described in Section 910(c)(4) of the FD&C Act;

2. The methods used in, and the facilities or controls used for, the manufacture,

processing, and packing of these products do not fail to conform to the requirements in

906(e);7 

3. Based on a fair evaluation of all material facts, the labeling is not false or misleading in

any particular;8 and

4. The products do not fail to conform to a tobacco product standard in effect under

Section 907 of the FD&C Act.

I recommend FDA grant marketing authorization for the products described in the STNs, subject 

to the changes to the products’ package labels and advertisements, as described above: 

1. PM0000491

2. PM0000492

4.3. Postmarketing Requirements 

The following language should be included in the marketing authorization: 

7 FDA has not yet promulgated any regulations under Section 906(e) of the FD&C Act. 

8 When FDA promulgates a final rule with respect to health warnings for cigarettes, FDA will reevaluate the conditions of 

marketing with respect to warnings for the products subject to this order. 
 

 

 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 70 of 89 

4.3.1. Recordkeeping and Retention 

Under section 910(f) of the FD&C Act, we are requiring in these orders that you establish and 

maintain the records listed below. At any time during the retention period described in this 

order, FDA may request that you provide any of the documents described below. In addition, 

under section 704 of the FD&C Act, FDA may inspect your establishment(s) and request to 

inspect any record(s) described below. 

The following records must be retained cumulatively, that is, for a period of not less than four 

years from the date of distribution of the last batch of each product subject to this order, as 

described below. These records must be legible, in English, and available for inspection and 

copying by officers or employees duly designated by the Secretary, upon request. 

Type of Record Description Retention Period 

Prior PMTAs Each PMTA submitted prior to marketing order Four years from the 

date of distribution of 

the last batch of each 

product subject to this 

order 

Postmarket reports Postmarket periodic reports submitted to FDA, 

including documents such as: status report of 

ongoing studies conducted by, or on behalf of, the 

applicant; adverse experience reports and all 

relevant documentation associated with the 

experience; summary of how the new product 

continues to be appropriate for the protection of the 

public health 

Four years from the date 

of distribution of the last 

batch of each product 

subject to this order 

Correspondence with FDA Correspondence with FDA pertaining to each 

authorized product 

Four years from the 

date of distribution of 

the last batch of each 

product subject to this 

order 

Study data Nonclinical or clinical study documentation 

including: 

 Source data;

 Study protocols (including statistical analysis

plan); Amendments showing the dates and

reasons for each protocol revision;

 Institutional Review Board (IRB) or

Independent Ethics Committee (IEC)

approvals;

 Informed consent forms;

 Correspondence with study

monitors/investigators/contract research

organizations/sponsors/IRB/IEC;

 Investigator financial disclosure statements;

 Progress reports; Monitoring reports;

 Adverse experience reports;

 Case report forms/subject diaries/medical

records/laboratory reports;

 Subject data line listings/observations records;

 Test article accountability records;

Four years from the 

date of distribution of 

the last batch of each 

product subject to this 

order 
 

 

 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 71 of 89 

 Study results/protocol summaries/study 

reports; and 

 Certifications and amendments to 

certifications 

The following records must be retained on a rolling basis, that is, for a period of not less than 

four years from the date of distribution of each batch of each product subject to this order or 

four years from the date of initial dissemination of materials to the public, as specified below. 

These records must be legible, in English, and available for inspection and copying by officers or 

employees duly designated by the Secretary, upon request. 

Type of Record Description Retention Period 

Manufacturing records Records pertaining to the manufacture, in 

process and release testing, production 

process (including any changes to the 

process, facility, or controls), packaging, 

storage, and stability monitoring and testing 

(including protocol and results). 

Records and reports of all manufacturing 

deviations, investigations, and corrective and 

preventive actions including, but not limited 

to, those deviations associated with 

processing, testing, packing, labeling, storage, 

holding and distribution; and any deviation 

that may affect the characteristics of each 

final product.9 

9 For products that have been distributed, if a deviation occurs that you determine presents a reasonable probability that the 

tobacco product contains a manufacturing or other defect not ordinarily contained in tobacco products on the market that 

would cause serious, adverse health consequences or death you are required to report the deviation to FDA within 15 calendar 

days of identification. 

Four years from the date of 

distribution of each batch of each 

product subject to this order 

Sales and/or A list of distributors and retailers of the Four years from the date of 

distribution records products, including brick-and-mortar, and 

digital (including internet/online, and 

mobile); 

Any available information (not to include 

personally identifiable information) about 

product purchasers, such as purchasers’ 

demographics (e.g., age, gender, 

race/ethnicity, geographic region) and 

previous or current use of other tobacco 

products (i.e., dual use); 

Policies and procedures regarding restrictions 

on youth-access to the products, including 

purchaser age and identity verification 

processes. 

distribution of each batch of each 

product subject to this order 
 

 

STN PM0000491 – PM0000492 Page 72 of 89 

Complaints Records pertaining to any and all complaints 

associated with the tobacco product(s) that 

is/are the subject of this order(s). Such 

records may also include analysis of those 

complaints. 

Four years from the date of 

distribution of each batch of each 

product subject to this order 

Health hazard analyses Health hazard analyses, if performed 

voluntarily or directed by FDA 

Four years from the date of 

distribution of each batch of each 

product subject to this order 

Labeling Specimens of all labeling (including all 

labeling variations, such as those reflecting 

different required warnings), labels, 

inserts/onserts, instructions, and other 

accompanying information 

Four years from the date of 

dissemination to the public 

Advertising marketing 

and promotional 

materials and plans 

Copies of all advertising, marketing and/or 

promotional materials, published, 

disseminated to consumers, or for use in 

engaging or communicating with consumers 

Copies of all advertising and marketing plans 

including strategic creative briefs and paid 

media plans, by channel and by product, and 

the details, dollar amount(s) and flighting of 

such plans, by channel and by product, 

including any: 

 Use of competent and reliable data 

sources, methodologies, and 

technologies to establish, maintain, 

and monitor highly targeted advertising 

and marketing plans and media buys, 

including a list of all data sources used 

to target advertising and marketing 

plans and media buys; 

 Targeting of specific adult audiences by 

age-range(s), including young adult 

audiences, ages 18-24, and other 

demographic and psychographic 

characteristics that reflect your 

intended target audience(s), how the 

target audience(s) were defined, and 

the insights used to develop the target 

audience profiles(s) and the source of 

such insights; 

 Actions taken to restrict youth-access 

and limit youth-exposure to the 

products’ labeling, advertising, 

marketing, and promotion; 

 Use of owned, earned, shared/social, 

and/or paid media to create labeling 

for, advertise, market, and/or promote 

the products; 

Four years from the date of 

dissemination to the public 
 

 

 

STN PM0000491 – PM0000492 Page 73 of 89 

 Use of partners, influencers, bloggers, 

and/or brand ambassadors to create 

labeling for, advertise, market, and/or 

promote the products; 

 Consumer engagements – whether 

conducted by you, on your behalf, or at 

your directions - including events at 

which the products will be 

demonstrated and/or; 

 Use of public relations outreach to 

create labeling for, advertise, market, 

and/or promote the products. 

Copies of all records pertaining to media 

tracking and optimization, by channel, by 

product, and by audience demographics (e.g., 

age, gender, race/ethnicity, geographic 

region), and all post-launch deliveryverification reports submitted to you from an 

accredited source, by channel, by product, 

and by audience demographics. 

Policies and procedures for real-time digital 

media monitoring to identify, correct, and 

prevent any delivery of advertising 

impressions to youth, ages 17 years and 

under, including documentation of such 

monitoring activities and implementation of 

corrective and preventive measures. 

Formative consumer 

research 

Copies of any formative research studies 

conducted among any audiences, in the 

formation of the labeling, advertising, 

marketing, and/or promotional materials, 

including qualitative and quantitative 

research studies used to determine message 

effectiveness, consumer knowledge, 

attitudes, beliefs, intentions, and behaviors 

toward using the products, and including 

copies of the stimuli used in testing. 

Four years from the date of 

dissemination to the public 

Consumer Evaluation 

Research 

Copies of any consumer evaluation research 

studies conducted among any audiences to 

determine the effectiveness of the labeling, 

advertising, marketing, and/or promotional 

materials and any shifts in consumer 

knowledge, attitudes, beliefs, intentions, and 

behaviors toward using the products, and 

including copies of the stimuli used in testing 

Four years from the date of 

dissemination to the public 

Contractual Copies of any contractual agreements Four years from the date of 

agreements regarding the creation and/or dissemination 

of the products’ labeling, advertising, 

marketing, and/or promotional materials, 

dissemination to the public 
 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 74 of 89 

including, for example in print media, online 

or through digital platforms (e.g., social 

media and mobile applications), such as 

influencers, bloggers, and ambassadors, on 

your behalf, or at your direction. 

4.3.2. Periodic Reporting 

Per section 910(f) of the FD&C Act, these orders requires that you submit periodic reports every six 

months to FDA once during the month of June of each year and once during the month of December of 

each year, beginning June 2020, to help FDA determine whether continued marketing of each new 

tobacco product is appropriate for the protection of public health or whether there is or may be grounds 

for withdrawing or temporarily suspending such order. For the 6-month reporting period, the report 

must include: 

1. A single submission with a cover letter that includes the following subject line: PERIODIC 

REPORT for STN PM0000491 and PM0000492. The cover letter should include the STN(s) and 

corresponding tobacco product name(s), applicant name, date of report, and reporting period. 

2. All final printed labeling (including all variations, such as those reflecting different required 

warnings) not previously submitted (e.g., if previously submitted under section 905(i) or 

previously submitted at the last reporting period and no changes were made, please list the 

date and manner of submission), including the date the labeling was first disseminated and the 

date when the labeling was discontinued, and a description of all changes to the labeling. The 

labeling must include all the panels and be presented in the actual size and color with legible 

text. The labeling must include labels, inserts/onserts, instructions, and any other accompanying 

information or materials for the products. 

3. All final full-color advertising, marketing, and/or promotional materials, published, disseminated 

to consumers, or for use in engaging or communicating with consumers not previously 

submitted (e.g., if previously submitted under 905(i) or previously submitted at the last 

reporting period and no changes were made, list the date and manner of submission), along 

with the original date such materials were first disseminated and the date they were 

discontinued, and a description of all changes to the materials. The materials must be legible, 

include all panels where applicable (e.g., print ads, point of sale signs) and reflect the actual size 

and colors used. For any materials that would not fit on an 8.5” x 11” piece of paper, you may 

resize and submit electronic versions of such materials in a format that FDA can review and with 

sufficient resolution to allow FDA to read lettering clearly. If resizing the advertisement does not 

allow for text to be read easily, the complete text may be provided separately and clearly 

referenced. Digital media, such as videos must be submitted in a format that FDA is able to open 

and review. 

Per section 910(f) of the FD&C Act, these orders require that you submit the following postmarket 

reports to FDA on an annual basis, beginning November 2020, to help FDA determine whether 

continued marketing of each new tobacco product is appropriate for the protection of public health or 

whether there is or may be grounds for withdrawing or temporarily suspending such order. For the 12-

month reporting period, the report must include: 

1. A single submission with a cover letter that includes the following subject line: PERIODIC 

REPORT for STN PM0000491 and PM0000492. The cover letter should include the STN(s) and 
 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 75 of 89 

corresponding tobacco product name(s), applicant name, date of report, reporting period, and 

marketing status outside the United States. 

2. A summary of how the new product continues to be appropriate for the protection of 

the public health, including: 

a. A status report of ongoing studies and a summary of completed studies about 

the product conducted by, or on behalf of, the applicant; 

b. A summary of significant findings on publications not previously reported, with copies of 

the full articles included. Any new scientific data (published or otherwise) on the 

likelihood of product use by current users of tobacco products within the same tobacco 

product category, current users of tobacco products in other tobacco product 

categories, former users of any tobacco product, and use by youth and young adults 

must also be reported; 

c. All serious or unexpected adverse experiences reported to you, including a listing and 

analysis (accompanied by a statement of any changes to the reference risk information 

and a summary of important risks, including the nature, frequency, and potential risk 

factors) 

d. A summary of sales and distribution of the new product, including total U.S. sales 

reported in dollars, units, and volume with breakdowns by U.S. census region, major 

retail markets, and channels in which the product is sold (e.g., convenience stores, food 

and drug markets, big box retailers, digital platforms, tobacco specialty shops); 

e. Data on product purchasers. Report any data collected about new purchasers, those 

who have switched tobacco products, and/or multiple product users. The results must 

be broken down by purchaser demographics (e.g., age, gender, and race/ethnicity, 

geographic location) and must not include personally identifiable information. Also, any 

change in the intended target market for the product should be reported. The data 

described above may include sales data and post-marketing analyses. 

3. A summary of the implementation and effectiveness of your policies and procedures regarding 

verification of the age and identity of purchasers of the products. 

4. A summary of the implementation and effectiveness of your policies and procedures regarding 

restrictions on youth access to the products. 

5. A description of each change made to the manufacturing, facilities or controls during the 

reporting period, including: 

a. A comparison of each change to what was described in the PMTAs; 

b. The rationale for making each change; 

c. A certification that the reported change did not result in any modification (including a 

change in design, any component, any part, or any constituent, including a smoke 

constituent, or in the content, delivery or form of nicotine, or any other additive or 

ingredient) of the tobacco product; and the basis for concluding that each change did 

not result in any modification to the final product. Modifications to any component or 

part of the previously authorized tobacco product would render the modified tobacco 

product a new product, for which premarket authorization is required. These 

modifications should not be provided in a periodic report. 
 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 76 of 89 

6. A summary of any stability monitoring, and testing of the Moonlight® products, including the 

monitoring and testing protocol(s) (including batch/lot sampling) and results. 

7. A summary of all formative consumer research studies conducted– whether by you, on your 

behalf, or at your direction - among any audiences, in the formation of new labeling, advertising, 

marketing and/or promotional materials, not previously submitted, including qualitative and 

quantitative research studies used to determine message effectiveness, consumer knowledge, 

attitudes, beliefs, intentions and behaviors toward using the products, and including the findings 

or these studies and copies of the stimuli used in testing. 

8. A summary of all consumer evaluation research studies conducted – whether by you, on your 

behalf, or at your direction – among any audiences, not previously submitted, to determine the 

effectiveness of labeling, advertising, marketing and/or promotional materials and shifts in 

consumer knowledge, attitudes, beliefs, intentions, and behaviors toward using the products, 

and including the findings of these studies and copies of the stimuli used in testing. 

9. A summary of the creation and dissemination of the products’ labeling, advertising, marketing, 

and/or promotional materials – whether conducted by you, on your behalf, or at your direction 

– including a list of all entities involved and a description of their involvement, including a 

description of contractual agreements with such entities. 

10. A description of the implementation of all advertising and marketing plans not previously 

submitted, including strategic creative briefs and paid media plans– whether conducted by you, 

on your behalf, or at your direction - by channel and by product, and the dollar amount(s) and 

flighting of such plans, by channel and by product, including a description of any: 

a. Use of competent and reliable data sources, methodologies, and technologies to 

establish, maintain, and monitor highly targeted advertising and marketing plans and 

media buys, including a list of all data sources used to target advertising and marketing 

plans and media buys; 

b. Targeting of specific adult audiences by age-range(s), including young adults, 

ages 18-24, and other demographic and psychographic characteristics that reflect the 

intended target audience, including how the target audience(s) are defined and the 

insights used to develop the target audience profiles(s), including the source of such 

insights; 

c. Actions taken to restrict youth-access and limit youth-exposure to the products’ 

labeling, advertising, marketing, and/or promotion; 

d. Use of owned, earned, shared/social, and/or paid media to create labeling for, 

advertise, market, and/or promote the products; 

e. Use of partners, influencers, bloggers, and/or brand ambassadors to create labeling for, 

advertise, market, and/or promote the products; 

f. Consumer engagements – whether conducted by you, on your behalf, or at your 

direction – including events at which the products were demonstrated; and/or 

g. Use of public-relations outreach to create labeling for, advertise, market, and/or 

promote the products; including the original date such plans were first used and the 

date they were discontinued, and a description of all changes to such plans since the last 

periodic report, by channel and by product. 

11. An analysis of the actual delivery of advertising impressions, by channel, by product, and by 

audience demographics (e.g., age, gender, race/ethnicity, geographic location), including a 
 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 77 of 89 

breakout by age-group (i.e., adults, ages 25+; young adults, ages 18-24; and youth, ages 12-17 

and ages 11 and under), not previously submitted. This analysis must be verified against postlaunch delivery-verification reports submitted to you from an accredited source. 

12. A summary of media tracking and optimization, by channel, by product, and by audience

demographics (e.g., age, gender, race/ethnicity, geographic location), including a summary of

real-time digital media monitoring to identify, correct, and prevent delivery of advertising

impressions to youth, ages 17 and under, and including a summary of implementation of any

corrective and preventive measures, not previously submitted.

Serious Adverse Experiences Reporting 

Under section 910(f) of the FD&C Act, these orders require that you report to the FDA all adverse 

experiences that are serious, whether expected or unexpected, and your analysis of the association 

between the adverse experience and each new tobacco product within 15 calendar days after the 

report is received by you. These experiences may become known to you through a customer complaint, 

request, or suggestion made as a result of an adverse experience, a manufacturing deviation analysis, 

tobacco product defect, or failure reported to you; or identified in the literature or media. Your 

information should be submitted with a cover letter that includes the following subject line: SERIOUS 

ADVERSE EXPERIENCE REPORT for STN PM0000491 and PM0000492. 

For purposes of reporting under this order, serious adverse experience means an adverse experience 

that results in any of the following outcomes: 

● Death; 

● A life-threatening adverse event; 

● Inpatient hospitalization or prolongation of existing hospitalization; 

● A persistent or significant incapacity or substantial disruption in the ability to conduct 

normal life functions; 

● A congenital anomaly/birth defect; or 

● Any other adverse experience that, based upon appropriate medical judgment, may 

jeopardize the health of a person and may require medical or surgical intervention to 

prevent one of the other outcomes listed in this definition. 

For purposes of reporting under these orders, unexpected adverse experience means an adverse 

experience occurring in one or more persons in which the nature, severity, or frequency of the 

experience is not consistent with: 

● The known or foreseeable risks associated with the use or exposure to each tobacco 

product as described in the PMTA and other relevant sources of information, such as 

postmarket reports and studies; 

● The expected natural progression of any underlying disease, disorder, or condition of 

the persons(s) experiencing the adverse experience and the person’s predisposing risk 

factor profile for the adverse experience; or 

● The results of nonclinical laboratory studies. 
 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 78 of 89 

4.3.3. Notifications 

Under sections 910(c)(1)(B) and 910(f) of the FD&C Act, this order also requires that for the first six 

months after the date of your marketing granted orders you provide FDA a 30-day notification for all 

labeling, advertising, marketing, and/or promotional materials for which you plan on disseminating to 

the public. These notifications are not for pre-approval but are required so that FDA can have timely 

access to your marketing plans and materials, and if needed, provide you advisory comments, including 

any concerns about their possible impact on youth appeal and tobacco use initiation and, on the finding, 

that continued marketing of your products is appropriate for the protection of the public health. You 

may begin disseminating the materials 30 days after providing notification to FDA. This notification must 

be received by FDA at least 30 days prior to dissemination, which includes but is not limited to the 

publication, dissemination to consumers, or use in engaging or communicating with consumers of such 

materials. 

● Full-color copies of all such labeling, advertising, marketing, and/or promotional materials for 

the products. The materials must be legible, include all panels where applicable (e.g., print ads, 

point of sale signs) and reflect the actual size and colors used. For any materials that would not 

fit on an 8.5” x 11” piece of paper, you may resize and submit electronic versions of such 

materials in a format that FDA can review and with sufficient resolution to allow FDA to read all 

lettering clearly. If resizing the advertisement does not allow for text to be read easily, the 

complete text may be provided separately and clearly referenced. 

● All advertising and marketing plans, including strategic creative briefs and paid media plans, by 

channel and by product, and the details, dollar amount(s) and flighting of such plans, by channel 

and by product, including any plans to: 

o Use competent and reliable data sources, methodologies, and technologies to establish,

maintain, and monitor highly targeted advertising and marketing plans and media buys,

including a list of all data sources used to target advertising and marketing plans and

media buys;

o Target specific adult audiences by age-range(s), including young adults, ages 18-24, and

other demographic and psychographic characteristics that reflect your intended target

audience, including how the target audience(s) are defined and the insights used to

develop the target audience profile(s);

o Restrict youth-access and limit youth-exposure to the products’ labeling, advertising,

marketing, and/or promotion;

o Use owned, earned, shared/social, and/or paid media to create labeling for, advertise,

market, and/or promote the products;

o Use partners, influencers, bloggers, and/or brand ambassadors to create labeling for,

advertise, market, and/or promote the products;

o Conduct any consumer engagements – whether by you, on your behalf, or at your

direction – including events at which the products will be demonstrated; and/or

o Use public-relations outreach to create labeling for, advertise, market, and/or promote

the products – including the original date such plans were first used and the date they

were discontinued, and a description of all changes to such plans since the last periodic

report, by channel and by product.
STN PM0000491 – PM0000492 Page 79 of 89 

4.3.4. Marketing Requirements 

Under section 910(c)(1)(B) of the FD&C Act, this order requires: 

● For any digital sales – whether conducted by you, on your behalf, or at your direction – 

establish, maintain, and monitor use of independent age- and identity-verification service(s) 

that compare customer information against independent, competent, and reliable data sources, 

such as public records, to prevent the sale of the products to individuals who are under the 

federal minimum legal age to purchase tobacco products. 

● For any of the products’ labeling, advertising, marketing, and/or promotion appearing in your 

owned digital properties (e.g., your company-owned, consumer-directed, product-branded 

website(s) and/or mobile applications) – whether conducted by you, on your behalf, or at your 

direction – establish, maintain, and monitor use of independent age- and identity-verification 

service(s) that compare consumer information against independent, competent, and reliable 

data sources, such as public records, at the first point of access to such properties, to restrict 

access to such labeling, advertising, marketing, and/or promotion to only individuals who are at 

least of federal minimum legal age to purchase tobacco products. 

● For any of the products’ labeling, advertising, marketing, and/or promotion appearing in any 

shared digital properties (e.g., your product-branded social media accounts, pages and 

associated content; content promoting your products on your behalf disseminated through 

another entity’s social media accounts) – whether conducted by you, on your behalf, or at your 

direction – establish, maintain, and monitor use of the available site-, platform- and content-

(e.g., post, video) specific age-restriction controls (e.g., age-restrict an entire product-branded 

account and all associated content disseminated through such account; ensure age-restriction of 

a specific video disseminated by an influencer promoting the products on your behalf through 

the influencer’s account), at the first point of access to such properties, to restrict access to such 

labeling, advertising, marketing, and/or promotion to only individuals who are at least of federal 

minimum legal age to purchase tobacco products. 

● For any of the products’ labeling, advertising, marketing, and/or promotion appearing in paid 

digital media (e.g., paid digital banner advertisements for the product(s) running on another 

company’s website; paid advertising for the product(s) running in social media; paid distribution 

of influencer content) – whether conducted by you, on your behalf, or at your direction: 

o Establish, maintain, and monitor use of competent and reliable data sources,

methodologies, and technologies to precisely target delivery of such labeling, advertising,

marketing, and/or promotion to only individuals who are at least of federal minimum legal

age to purchase tobacco products. Such targeting must use only first- and/or second-party

age-verified data, where:

 “First-party” age-verified data is data owned by you (e.g., your customer registration

data collected via site traffic to your company-owned website; data you use in direct

marketing to your adult smoking customers) that you have age-verified through

independent, competent, and reliable data sources; and
 

 

 

STN PM0000491 – PM0000492 Page 80 of 89 

 “Second-party” age-verified data is first-party data owned and age-verified by another

competent and reliable entity (e.g., another company’s first-party user registration data)

to which you have access. Such data must be age-verified by the second party.

 “First-party” and “second-party” data does not include data obtained from data

aggregators who categorize consumers based on trackable activities and inferred

interests (e.g., internet search terms, video interactions, browsing history, purchasing

behaviors) to create demographic and psychographic profiles marketers may use to

enhance audience targeting. Such data is not considered age-verified and can only be

used in combination with first- and/or second-party age-verified data.

● Establish, maintain, and monitor use of competent and reliable data sources, methodologies, 

and technologies (e.g., using an embedded tracking pixel in all digital advertising) – whether 

conducted by you, on your behalf, or at your direction – to track and measure actual delivery of 

all advertising impressions, by channel, by product, and by audience demographics (e.g., age, 

gender, race/ethnicity, geographic location), including a breakout by age-group (i.e., adults, ages 

25+; young adults, ages 18-24; and youth, ages 12-17 and ages 11 and under). Such monitoring 

requires real-time digital media tracking, and identifying, correcting, and preventing delivery of 

advertising impressions to youth, ages 17 and under. Such monitoring also requires post-launch 

delivery verification reports be submitted to you from an accredited source. 

● For any use of partners, influencers, bloggers, and/or brand ambassadors to create labeling for, 

advertise, market, and/or promote the products – whether conducted by you, on your behalf, or 

at your direction – disclose to consumers or viewers, via the use of statements such as 

“sponsored by [firm name]” in such labeling, advertising, marketing, and/or promotional 

materials, any relationships between you and entities that create labeling for, advertise, market, 

and/or promote the products, on your behalf, or at your direction. 

At any time, FDA may request that you provide any of the documents described in Appendix D. In 

addition, under section 704 of the FD&C Act, FDA may inspect your establishment(s) and request to 

inspect any record(s) described in Appendix D. 

If you discontinue the manufacture, preparation, compounding or processing for commercial 

distribution of these tobacco products and later decide to reintroduce the products into the market, 

please contact the Office of Science prior to reintroduction. 

You may be eligible to submit a supplemental PMTA for modification(s) made to tobacco products that 

received marketing granted orders, by cross-referencing content in the PMTA and postmarket reports 

for the original tobacco products subject of this letter. Applicants that have questions about whether it 

would be appropriate to submit a supplemental PMTA for modification(s) they are seeking to implement 

should contact their Regulatory Health Project Manager (RHPM) within the Office of Science for more 

information. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 81 of 89 

5. ACRONYMS

1-HOP 1-hydroxypyrene

2R4F reference cigarette 

3-HMPA 3-hydroxypropylmercapturic acid

8-iso-PGF2α (Z)-7-[1R,2R, 3R,5S]-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopentyl]hept-5-

enoicacid 

AUC0-180 area under the nicotine concentration-time curve 

aw water activity 

BCP Behavioral and Clinical Pharmacology 

BIMO Bioresearch Monitoring 

BIOSIS Biological Abstracts 

BOE biomarkers of exposure 

BOPH biomarkers of potential harm 

CAS number Chemical Abstracts Service number 

CDC Centers for Disease Control and Prevention 

CI Canadian Intense smoking regimen 

Cmax maximum measured plasma nicotine concentration 

CO carbon monoxide 

COHb blood carboxyhemoglobin 

CPD cigarettes per day 

CTP Center for Tobacco Products 

DPAL Division of Promotion, Advertising, and Labeling 

DPF Denier Per Filament 

ENDS electronic nicotine delivery systems 

FCLAA Federal Cigarette Labeling and Advertising Act 

FD&C Act Federal Food Drug and Cosmetic Act 

FDA Food and Drug Administration 

FDA50 study that characterized 50 cigarettes in 2011 

FOIA Freedom of Information Act 

FONSI finding of no significant impact 

FTCD FagerstrÖm Test for Cigarette Dependence 

FTND FagerstrÖm Test for Nicotine Dependence 

HPHC harmful and potentially harmful constituents 

hs-CRP high-sensitivity C-reactive protein 

ISO International Organization for Standardization machine smoking regimen 

ITT intent-to-treat population 

Kel 

Apparent first-order terminal elimination rate constant calculated from a semi-log plot 

of the plasma concentration-time curve of the controlled/uncontrolled use condition 

LNC low nicotine content 

M mean 

MNWS-R Minnesota Nicotine Withdrawal Scale - Revised 

MRTP Modified Risk Tobacco Product 

MSS mainstream smoke 

N/A not applicable 

N/P not provided 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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

STN PM0000491 – PM0000492 Page 82 of 89 

NCI National Cancer Institute 

NDSS Nicotine Dependence Syndrome Scale 

NIDA National Institute on Drug Abuse 

NNAL 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 

NNC Normal Nicotine Content 

NNK 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 

NNN n-nitrosonornicotine

NRC Nicotine Research Cigarettes 

NRT nicotine replacement therapy 

OCE Office of Compliance and Enforcement 

OS Office of Science 

PGEM prostaglandin E2 metabolite 

PheT phenanthrene tetraol 

PK pharmacokinetic 

PMTA premarket tobacco application 

PP per protocol population 

QPTase quinolinic acid phosphoribosyltransferase 

QRA quantitative risk assessment 

QSU-Brief Brief Questionnaire of Smoking Urges 

RH relative humidity 

RIM random iterative method 

RSD relative standard deviation 

SAE serious adverse experience 

SD Standard Deviation 

SDA specially denatured alcohol 

SGR Surgeon General’s Report 

SHS second hand smoke 

SIDS 

S-PMA

sudden infant death syndrome 

S-phenylmercapturic acid

SRNT Society for Research on Nicotine and Tobacco 

STL Southeast Tobacco Laboratory 

STN Submission Tracking Number 

T1/2 apparent first-order terminal nicotine elimination half-life 

t-con teleconference 

THS thirdhand smoke 

Tmax time of the maximum measured plasma nicotine concentration 

TNCO tar, nicotine, and carbon monoxide 

TNE total nicotine equivalent 

TOST two one-sided tests 

TPL Technical Project Lead 

TPMF Tobacco Product Master File 

TSNA tobacco-specific nitrosamines 

UB-NNC Usual Brand- Normal Nicotine Content 

VAS visual analog scales 

VLNC Very low nicotine content 

WISDM Wisconsin Inventory of Smoking Dependence Motives 
 

 

 

STN PM0000491 – PM0000492 Page 83 of 89 

6. REFERENCES 

Addicott, M. A., Froeliger, B., Kozink, R. V., Van Wert, D. M., Westman, E. C., Rose, J. E., & McClernon, F. 

J. (2014). Nicotine and non-nicotine smoking factors differentially modulate craving, withdrawal 

and cerebral blood flow as measured with arterial spin labeling. Neuropsychopharmacology, 

39(12), 2750-2759. doi:10.1038/npp.2014.108 

Barrett, S. P. (2010). The effects of nicotine, denicotinized tobacco, and nicotine-containing tobacco on 

cigarette craving, withdrawal, and self-administration in male and female smokers. Behavioral 

Pharmacology, 21(2), 144-152. doi:10.1097/FBP.0b013e328337be68 

Barrett, S. P., & Darredeau, C. (2012). The acute effects of nicotine on the subjective and behavioural 

responses to denicotinized tobacco in dependent smokers. Behavioral Pharmacology, 23(3), 

221-227. doi:10.1097/FBP.0b013e328353431c 

Benowitz, N. L., Dains, K. M., Hall, S. M., Stewart, S., Wilson, M., Dempsey, D., & Jacob, P., 3rd. (2012). 

Smoking behavior and exposure to tobacco toxicants during 6 months of smoking progressively 

reduced nicotine content cigarettes. Cancer Epidemiology, Biomarkers & Prevention, 21(5), 761-

769. doi:10.1158/1055-9965.epi-11-0644 

Benowitz, N. L., Nardone, N., Dains, K. M., Hall, S. M., Stewart, S., Dempsey, D., & Jacob, P., 3rd. (2015). 

Effect of reducing the nicotine content of cigarettes on cigarette smoking behavior and tobacco 

smoke toxicant exposure: 2-year follow up. Addiction, 110(10), 1667-1675. 

doi:10.1111/add.12978 

Brunnemann, K. D., Prokopczyk, B., Djordjevic, M. V., & Hoffmann, D. (1996). Formation and analysis of 

tobacco-specific N-nitrosamines. Critical Reviews in Toxicology, 26(2), 121-137. 

doi:10.3109/10408449609017926 

Buchhalter, A. R., Acosta, M. C., Evans, S. E., Breland, A. B., & Eissenberg, T. (2005). Tobacco abstinence 

symptom suppression: The role played by the smoking-related stimuli that are delivered by 

denicotinized cigarettes. Addiction, 100(4), 550-559. doi:10.1111/j.1360-0443.2005.01030.x 

Carter, L. P., & Griffiths, R. R. (2009). Principles of laboratory assessment of drug abuse liability and 

implications for clinical development. Drug and alcohol dependence, 105 Suppl 1, S14-25. 

doi:10.1016/j.drugalcdep.2009.04.003 

Cassidy, R. N., Colby, S. M., Tidey, J. W., Jackson, K. M., Cioe, P. A., Krishnan-Sarin, S., & Hatsukami, D. 

(2018). Adolescent smokers' response to reducing the nicotine content of cigarettes: Acute 

effects on withdrawal symptoms and subjective evaluations. Drug and alcohol dependence, 188, 

153-160. doi:10.1016/j.drugalcdep.2018.04.006 

Cassidy, R. N., Miller, M. E., Tidey, J. W., Diguiseppi, G., Denlinger-Apte, R., & Colby, S. M. (2019). The 

impact of nicotine dose on the reinforcing value of cigarettes in adolescents. Tob Regul Sci, 5(2), 

105-114. doi:10.18001/TRS.5.2.2 

Castrucci, B. C., Gerlach, K. K., Kaufman, N. J., & Orleans, C. T. (2002). Adolescents' acquisition of 

cigarettes through noncommercial sources. J Adolesc Health, 31(4), 322-326. 

(b)(4)

Cobb, C. O., Weaver, M. F., & Eissenberg, T. (2010). Evaluating the acute effects of oral, non-combustible 

potential reduced exposure products marketed to smokers. Tobbaco Control, 19(5), 367-373. 

doi:10.1136/tc.2008.028993 

Counts, M. E., Morton, M. J., Laffoon, S. W., Cox, R. H., & Lipowicz, P. J. (2005). Smoke composition and 

predicting relationships for international commercial cigarettes smoked with three machinesmoking conditions. Regulatory Toxicology and Pharmacology, 41(3), 185-227. 

doi:10.1016/j.yrtph.2004.12.002 
 

 

 

STN PM0000491 – PM0000492 Page 84 of 89 

Cummings, K. M., Sciandra, E., Pechacek, T. F., Orlandi, M., & Lynn, W. R. (1992). Where teenagers get 

their cigarettes: A survey of the purchasing habits of 13-16 year olds in 12 US communities. . Tob 

Control, 1(4), 264-267. Retrieved from http://www.jstor.org/stable/20206836 

Dallery, J., Houtsmuller, E. J., Pickworth, W. B., & Stitzer, M. L. (2003). Effects of cigarette nicotine 

content and smoking pace on subsequent craving and smoking. Psychopharmacology (Berl), 

165(2), 172-180. doi:10.1007/s00213-002-1242-8 

Davis, D. R., Miller, M. E., Streck, J. M., Bergeria, C. L., Sigmon, S. C., Tidey, J. W., . . . Higgins, S. T. (2019). 

Response to Reduced Nicotine Content in Vulnerable Populations: Effect of Menthol Status. Tob 

Regul Sci, 5(2), 135-142. doi:10.18001/TRS.5.2.5 

Delnevo, C. D., Gundersen, D. A., Hrywna, M., Echeverria, S. E., & Steinberg, M. B. (2011). Smokingcessation prevalence among U.S. smokers of menthol versus non-menthol cigarettes. American 

Journal of Preventive Medicine, 41(4), 357-365. doi:10.1016/j.amepre.2011.06.039 

Denlinger-Apte, R., Kotlyar, M., Koopmeiners, J., Tidey, J., Luo, X., Jensen, J., . . . Hatsukami, D. (2019). 

The effects of menthol flavoring on smoking behavior and biomarkers of exposure in smokers 

using very low nicotine content cigarettes for 20 weeks: Podium presentation February 21, 2019. 

Paper presented at the Society for Research on Nicotine and Tobacco. 

Denlinger, R. L., Smith, T. T., Murphy, S. E., Koopmeiners, J. S., Benowitz, N. L., Hatsukami, D. K., . . . 

Donny, E. C. (2016). Nicotine and anatabine exposure from very low nicotine content cigarettes. 

Tob Regul Sci, 2(2), 186-203. Retrieved from 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870904/pdf/nihms946129.pdf 

Ding, Y. S., Yan, X. J., Jain, R. B., Lopp, E., Tavakoli, A., Polzin, G. M., . . . Watson, C. H. (2006). 

Determination of 14 polycyclic aromatic hydrocarbons in mainstream smoke from U.S. brand 

and non-U.S. brand cigarettes. Environmental Science & Technology, 40(4), 1133-1138. 

Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16572766 

http://pubs.acs.org/doi/pdfplus/10.1021/es0517320 

Ding, Y. S., Zhang, L., Jain, R. B., Jain, N., Wang, R. Y., Ashley, D. L., & Watson, C. H. (2008). Levels of 

tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons in mainstream smoke from 

different tobacco varieties. Cancer Epidemiology Biomarkers & Prevention, 17(12), 3366-3371. 

Donny, E. C., Denlinger, R. L., Tidey, J. W., Koopmeiners, J. S., Benowitz, N. L., Vandrey, R. G., . . . 

Hatsukami, D. K. (2015). Randomized trial of reduced-nicotine standards for cigarettes. New 

England Journal of Medicine, 373(14), 1340-1349. doi:10.1056/NEJMsa1502403 

Donny, E. C., Houtsmuller, E., & Stitzer, M. L. (2007). Smoking in the absence of nicotine: behavioral, 

subjective and physiological effects over 11 days. Addiction, 102(2), 324-334. Retrieved from 

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1360-0443.2006.01670.x 

Donny, E. C., & Jones, M. (2009). Prolonged exposure to denicotinized cigarettes with or without 

transdermal nicotine. Drug and alcohol dependence, 104(1-2), 23-33. 

doi:10.1016/j.drugalcdep.2009.01.021 

Eid, N. C., Fant, R. V., Moolchan, E. T., & Pickworth, W. B. (2005). Placebo cigarettes in a spaced smoking 

paradigm. Pharmacology Biochemistry and Behavior, 81(1), 158-164. 

doi:10.1016/j.pbb.2005.03.007 

Faseru, B., Nollen, N. L., Mayo, M. S., Krebill, R., Choi, W. S., Benowitz, N. L., . . . Sanderson Cox, L. 

(2013). Predictors of cessation in African American light smokers enrolled in a bupropion clinical 

trial. Addict Behav, 38(3), 1796-1803. doi:10.1016/j.addbeh.2012.11.010 

Faulkner, P., Ghahremani, D. G., Tyndale, R. F., Cox, C. M., Kazanjian, A. S., Paterson, N., . . . London, E. D. 

(2017). Reduced-nicotine cigarettes in young smokers: impact of nicotine metabolism on 

nicotine dose effects. Neuropsychopharmacology, 42(8), 1610-1618. doi:10.1038/npp.2017.18 

Faulkner, P., Petersen, N., Ghahremani, D. G., Cox, C. M., Tyndale, R. F., Hellemann, G. S., & London, E. 

D. (2018). Sex differences in tobacco withdrawal and responses to smoking reduced-nicotine 
 

 

 

 

STN PM0000491 – PM0000492 Page 85 of 89 

cigarettes in young smokers. Psychopharmacology (Berl), 235(1), 193-202. doi:10.1007/s00213-

017-4755-x 

Godtfredsen, N. S., Holst, C., Prescott, E., Vestbo, J., & Osler, M. (2002). Smoking reduction, smoking 

cessation, and mortality: A 16-year follow-up of 19,732 men and women from the copenhagen 

centre for prospective population studies. American Journal of Epidemiology, 156(11), 994-1001. 

doi:10.1093/aje/kwf150 

Hammond, D., & O'Connor, R. J. (2014). Reduced nicotine cigarettes: smoking behavior and biomarkers 

of exposure among smokers not intending to quit. Cancer Epidemiology, Biomarkers & 

Prevention, 23(10), 2032-2040. doi:10.1158/1055-9965.epi-13-0957 

Hatsukami, D. K., Heishman, S. J., Vogel, R. I., Denlinger, R. L., Roper-Batker, A. N., Mackowick, K. M., . . . 

Donny, E. (2013). Dose-response effects of spectrum research cigarettes. Nicotine & Tobacco 

Research, 15(6), 1113-1121. doi:10.1093/ntr/nts247 

Hatsukami, D. K., Hertsgaard, L. A., Vogel, R. I., Jensen, J. A., Murphy, S. E., Hecht, S. S., . . . Allen, S. S. 

(2013). Reduced nicotine content cigarettes and nicotine patch. Cancer Epidemiology, 

Biomarkers & Prevention, 22(6), 1015-1024. doi:10.1158/1055-9965.EPI-12-1439 

Hatsukami, D. K., Kotlyar, M., Hertsgaard, L. A., Zhang, Y., Carmella, S. G., Jensen, J. A., . . . Hecht, S. S. 

(2010). Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and 

cessation. Addiction, 105(2), 343-355. doi:10.1111/j.1360-0443.2009.02780.x 

Hatsukami, D. K., Luo, X., Dick, L., Kangkum, M., Allen, S. S., Murphy, S. E., . . . al'Absi, M. (2017). 

Reduced nicotine content cigarettes and use of alternative nicotine products: exploratory trial. 

Addiction, 112(1), 156-167. doi:10.1111/add.13603 

Hatsukami, D. K., Luo, X., Heskin, A. K., Tang, M. K., Carmella, S. G., Jensen, J., . . . Hecht, S. S. (2019). 

Effects of immediate versus gradual nicotine reduction in cigarettes on biomarkers of biological 

effects. Addiction. doi:10.1111/add.14695 

Hatsukami, D. K., Luo, X., Jensen, J. A., al'Absi, M., Allen, S. S., Carmella, S. G., . . . Donny, E. C. (2018). 

Effect of immediate vs gradual reduction in nicotine content of cigarettes on biomarkers of 

smoke exposure: A randomized clinical trial. JAMA, 320(9), 880-891. 

doi:10.1001/jama.2018.11473 

Hersey, J. C., Ng, S. W., Nonnemaker, J. M., Mowery, P., Thomas, K. Y., Vilsaint, M. C., . . . Haviland, M. L. 

(2006). Are menthol cigarettes a starter product for youth? Nicotine & Tobacco Research, 8(3), 

403-413. doi:10.1080/14622200600670389 

Higgins, S. T., Heil, S. H., Sigmon, S. C., Tidey, J. W., Gaalema, D. E., Stitzer, M. L., . . . Pacek, L. R. (2017). 

Response to varying the nicotine content of cigarettes in vulnerable populations: An initial 

experimental examination of acute effects. Psychopharmacology (Berl), 234(1), 89-98. 

doi:10.1007/s00213-016-4438-z 

Hoffmann, D., Djordjevic, M. V., & Hoffmann, I. (1997). The changing cigarette. Preventive Medicine, 

26(4), 427-434. doi:10.1006/pmed.1997.0183 

Hoffmann, D. H., & Hoffmann, I. (2001). The changing cigarette: Chemical studies and bioassays. In 

National Cancer Institute: Smoking and Tobacco Control Monograph (Vol. 13, pp. 159-191). 

Johnston, L. D., Miech, R. A., O’Malley, P. M., Bachman, J. G., Schulenberg, J. E., & Patrick, M. E. (2019). 

Monitoring the Future national survey results on drug use 1975-2018: Overview, key findings on 

adolescent drug use. University of Michigan: Ann Arbor: Institute for Social Research. 

Juliano, L. M., Donny, E. C., Houtsmuller, E. J., & Stitzer, M. L. (2006). Experimental evidence for a causal 

relationship between smoking lapse and relapse. Journal of Abnormal Psychology, 115(1), 166-

173. doi:10.1037/0021-843x.115.1.166 

Juliano, L. M., Fucito, L. M., & Harrell, P. T. (2011). The influence of nicotine dose and nicotine dose 

expectancy on the cognitive and subjective effects of cigarette smoking. Exp Clin 

Psychopharmacol, 19(2), 105-115. doi:10.1037/a0022937 
 

 

 

 

STN PM0000491 – PM0000492 Page 86 of 89 

Kassel, J. D., Greenstein, J. E., Evatt, D. P., Wardle, M. C., Yates, M. C., Veilleux, J. C., & Eissenberg, T. 

(2007). Smoking topography in response to denicotinized and high-yield nicotine cigarettes in 

adolescent smokers. Journal of Adolescent Health, 40(1), 54-60. 

doi:10.1016/j.jadohealth.2006.08.006 

Kozlowski, L. T., Mehta, N. Y., Sweeney, C. T., Schwartz, S. S., Vogler, G. P., Jarvis, M. J., & West, R. J. 

(1998). Filter ventilation and nicotine content of tobacco in cigarettes from Canada, the United 

Kingdom, and the United States. Tob Control, 7(4), 369-375. doi:10.1136/tc.7.4.369 

Kozlowski, L. T., & O'Connor, R. J. (2002). Cigarette filter ventilation is a defective design because of 

misleading taste, bigger puffs, and blocked vents. Tob Control, 11(suppl 1), i40-i50. 

doi:10.1136/tc.11.suppl_1.i40 

Leistikow, B. N., Martin, D. C., & Milano, C. E. (2000). Fire injuries, disasters, and costs from cigarettes 

and cigarette lights: A global overview. Preventive Medicine, 31(2), 91-99. 

doi:https://doi.org/10.1006/pmed.2000.0680 

Lenk, K. M., Toomey, T. L., Shi, Q., Erickson, D. J., & Forster, J. L. (2014). Do sources of cigarettes among 

adolescents vary by age over time? J Child Adolesc Subst Abuse, 23(2), 137-143. 

doi:10.1080/1067828x.2012.750972 

Levy, D. T., Blackman, K., Tauras, J., Chaloupka, F. J., Villanti, A. C., Niaura, R. S., . . . Abrams, D. B. (2011). 

Quit attempts and quit rates among menthol and nonmenthol smokers in the United States. 

American Journal of Public Health, 101(7), 1241-1247. doi:10.2105/ajph.2011.300178 

Lindsey, K. P., Bracken, B. K., Maclean, R. R., Ryan, E. T., Lukas, S. E., & Frederick, B. D. (2013). Nicotine 

content and abstinence state have different effects on subjective ratings of positive versus 

negative reinforcement from smoking. Pharmacology Biochemistry & Behavior, 103(4), 710-716. 

doi:10.1016/j.pbb.2012.11.012 

Macqueen, D. A., Heckman, B. W., Blank, M. D., Janse Van Rensburg, K., Evans, D. E., & Drobes, D. J. 

(2012). Transient compensatory smoking in response to placebo cigarettes. 

Psychopharmacology (Berl), 223(1), 47-54. doi:10.1007/s00213-012-2685-1 

McRobbie, H., Przulj, D., Smith, K. M., & Cornwall, D. (2016). Complementing the standard 

multicomponent treatment for smokers with denicotinized cigarettes: A randomized trial. 

Nicotine & Tobacco Research, 18(5), 1134-1141. doi:10.1093/ntr/ntv122 

Mercincavage, M., Souprountchouk, V., Tang, K. Z., Dumont, R. L., Wileyto, E. P., Carmella, S. G., . . . 

Strasser, A. A. (2016). A randomized controlled trial of progressively reduced nicotine content 

cigarettes on smoking behaviors, biomarkers of exposure, and subjective ratings. Cancer 

Epidemiology, Biomarkers & Prevention, 25(7), 1125-1133. doi:10.1158/1055-9965.epi-15-1088 

Naik, P., Sajja, R. K., Prasad, S., & Cucullo, L. (2015). Effect of full flavor and denicotinized cigarettes 

exposure on the brain microvascular endothelium: a microarray-based gene expression study 

using a human immortalized BBB endothelial cell line. BMC Neuroscience, 16, 38. 

doi:10.1186/s12868-015-0173-3 

Nardone, N., Donny, E. C., Hatsukami, D. K., Koopmeiners, J. S., Murphy, S. E., Strasser, A. A., . . . 

Benowitz, N. L. (2016). Estimations and predictors of non-compliance in switchers to reduced 

nicotine content cigarettes. Addiction. doi:10.1111/add.13519 

Novotny, T. E., Hardin, S. N., Hovda, L. R., Novotny, D. J., McLean, M. K., & Khan, S. (2011). Tobacco and 

cigarette butt consumption in humans and animals. Tob Control, 20(Suppl 1), i17-i20. 

doi:10.1136/tc.2011.043489 

O'Connor, R. J., Ashare, R. L., Fix, B. V., Hawk, L. W., Cummings, K. M., & Schmidt, W. C. (2007). College 

students' expectancies for light cigarettes and potential reduced exposure products. Am J Health 

Behav, 31(4), 402-410. doi:10.5555/ajhb.2007.31.4.402 

O’Connor, R. J., Hammond, D., McNeill, A., King, B., Kozlowski, L. T., Giovino, G. A., & Cummings, K. M. 

(2008). How do different cigarette design features influence the standard tar yields of popular 
 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 87 of 89 

cigarette brands sold in different countries? Tob Control, 17(Suppl 1), i1-i5. 

doi:10.1136/tc.2006.019166 

Okuyemi, K. S., Ahluwalia, J. S., Ebersole-Robinson, M., Catley, D., Mayo, M. S., & Resnicow, K. (2003). 

Does menthol attenuate the effect of bupropion among African American smokers? Addiction, 

98(10), 1387-1393. 

Pauwels, C. G. G. M., Klerx, W. N. M., Pennings, J. L. A., Boots, A. W., van Schooten, F. J., Opperhuizen, 

A., & Talhout, R. (2018). Cigarette Filter Ventilation and Smoking Protocol Influence Aldehyde 

Smoke Yields. Chemical Research in Toxicology, 31(6), 462-471. 

doi:10.1021/acs.chemrestox.7b00342 

Perkins, K. A., & Karelitz, J. L. (2015). Sex differences in acute relief of abstinence-induced withdrawal 

and negative affect due to nicotine content in cigarettes. Nicotine & Tobacco Research, 17(4), 

443-448. doi:10.1093/ntr/ntu150 

Perkins, K. A., Karelitz, J. L., & Kunkle, N. (2017). Sex differences in subjective responses to moderate 

versus very low nicotine content cigarettes. Nicotine & Tobacco Research. 

Perkins, K. A., Karelitz, J. L., & Kunkle, N. (2018). Evaluation of menthol per se on acute perceptions and 

behavioral choice of cigarettes differing in nicotine content. Journal of Psychopharmacology, 

32(3), 324-331. 

Pickworth, W. B., Nelson, R. A., Rohrer, M. S., Fant, R. V., & Henningfield, J. E. (1999). Pharmacodynamic 

effects of new de-nicotinized cigarettes. Nicotine & Tobacco Research, 1(4), 357-364. 

Pilling, L. C., Atkins, J. L., Kuchel, G. A., Ferrucci, L., & Melzer, D. (2018). Red cell distribution width and 

common disease onsets in 240,477 healthy volunteers followed for up to 9 years. PLoS One, 

13(9), e0203504. doi:10.1371/journal.pone.0203504 

Ramachandran, J., Rubenstein, D., Bluestein, D., & Jesty, J. (2004). Activation of platelets exposed to 

shear stress in the presence of smoke extracts of low-nicotine and zero-nicotine cigarettes: the 

protective effect of nicotine. Nicotine & Tobacco Research, 6(5), 835-841. 

Rezaishiraz, H., Hyland, A., Mahoney, M. C., O'Connor, R. J., & Cummings, K. M. (2007). Treating smokers 

before the quit date: Can nicotine patches and denicotinized cigarettes reduce cravings? 

Nicotine & Tobacco Research, 9(11), 1139-1146. doi:10.1080/14622200701684172 

Rigotti, N. A. (2018, February 6 ). Benefits and risks of smoking cessation. UpToDate. Retrieved from 

https://www.uptodate.com/contents/benefits-and-risks-of-smoking-cessation/print 

Roemer, E., Schramke, H., Weiler, H., Buettner, A., Kausche, S., Weber, S., . . . Wittke, S. (2012). 

Mainstream smoke chemistry and in vitro and in vivo toxicity of the reference cigarettes 3R4F 

and 2R4F. Beiträge zur Tabakforschung International/Contributions to Tobacco Research, 25(1), 

316-335. doi:https://doi.org/10.2478/cttr-2013-0912 

Rose, J. E., & Behm, F. M. (2004). Effects of low nicotine content cigarettes on smoke intake. Nicotine & 

Tobacco Research, 6(2), 309-319. doi:10.1080/14622200410001676378 

Rose, J. E., Salley, A., Behm, F. M., Bates, J. E., & Westman, E. C. (2010). Reinforcing effects of nicotine 

and non-nicotine components of cigarette smoke. Psychopharmacology (Berl), 210(1), 1-12. 

doi:10.1007/s00213-010-1810-2 

Schlagintweit, H. E., & Barrett, S. P. (2016). Does acute tobacco smoking prevent cue-induced craving? 

Journal of Psychopharmacology, 30(5), 468-473. doi:10.1177/0269881116639288 

Shiffman, S., Kurland, B. F., Scholl, S. M., & Mao, J. M. (2018). Nondaily smokers’ changes in cigarette 

consumption with very low-nicotine-content cigarettes: A randomized double-blind clinical trial. 

JAMA Psychiatry. 

Song, M., Benowitz, N. L., Berman, M., Brasky, T. M., Cummings, K. M., Hatsukami, D. K., . . . Shields, P. 

G. (2017). Cigarette filter ventilation and its relationship to increasing rates of lung 

adenocarcinoma. Journal of the National Cancer Institute, 109(12), djx075-djx075. 

doi:10.1093/jnci/djx075 
 

 

 

 

 

 

 

 

 

STN PM0000491 – PM0000492 Page 88 of 89 

Stephens, W. E. (2007). Dependence of tar, nicotine and carbon monoxide yields on physical 

parameters: implications for exposure, emissions control and monitoring. Tob Control, 16(3), 

170-176. doi:10.1136/tc.2006.017491

Strasser, A. A., Lerman, C., Sanborn, P. M., Pickworth, W. B., & Feldman, E. A. (2007). New lower nicotine 

cigarettes can produce compensatory smoking and increased carbon monoxide exposure. Drug 

and alcohol dependence, 86(2-3), 294-300. doi:10.1016/j.drugalcdep.2006.06.017 

Sung, H., Wang, Y., Yao, T., Lightwood, J., & Max, W. (2016). Polytobacco use of cigarettes, cigars, 

chewing tobacco, and snuff among US adults. Nicotine & Tobacco Research, 18(5), 817-826. 

doi:10.1093/ntr/ntv147 

Talhout, R., Opperhuizen, A., & van Amsterdam, J. G. (2007). Role of acetaldehyde in tobacco smoke 

addiction. European Neuropsychopharmacology, 17(10), 627-636. 

doi:10.1016/j.euroneuro.2007.02.013 

Tidey, J. W., Cassidy, R. N., & Miller, M. E. (2016). Smoking topography characteristics of very low 

nicotine content cigarettes, with and without nicotine replacement, in smokers with 

schizophrenia and controls. Nicotine & Tobacco Research, 18(9), 1807-1812. 

doi:10.1093/ntr/ntw089 

Tidey, J. W., Rohsenow, D. J., Kaplan, G. B., Swift, R. M., & Ahnallen, C. G. (2013). Separate and 

combined effects of very low nicotine cigarettes and nicotine replacement in smokers with 

schizophrenia and controls. Nicotine & Tobacco Research, 15(1), 121-129. 

doi:10.1093/ntr/nts098 

Trinidad, D. R., Perez-Stable, E. J., Messer, K., White, M. M., & Pierce, J. P. (2010). Menthol cigarettes 

and smoking cessation among racial/ethnic groups in the United States. Addiction, 105 Suppl 1, 

84-94. doi:10.1111/j.1360-0443.2010.03187.x

Tverdal, A., & Bjartveit, K. (2006). Health consequences of reduced daily cigarette consumption. Tob 

Control, 15(6), 472-480. doi:10.1136/tc.2006.016246 

U.S. Department of Health and Human Services. (2001). 2001 Surgeon General's Report-- Women and 

Smoking. Retrieved from Rockville, MD: 

https://www.cdc.gov/tobacco/data_statistics/sgr/2001/complete_report/index.htm 

U.S. Department of Health and Human Services. (2004). 2004 Surgeon General's Report--The Health 

Consequences of Smoking. Retrieved from Rockville, MD: 

http://www.surgeongeneral.gov/library/reports/preventing-youth-tobacco-use/execsummary.pdf 

U.S. Department of Health and Human Services. (2012). Preventing tobacco use among youth and young 

adults: A report of the Surgeon General. Retrieved from 

https://www.surgeongeneral.gov/library/reports/preventing-youth-tobacco-use/index.html 

U.S. Department of Health and Human Services. (2014). The Health Consequences of Smoking--50 Years 

of Progress: A Report of the Surgeon General. . Retrieved from Rockville, MD: 

University of Kentucky. 3R4F PReliminary Analysis. Retrieved from 

https://ctrp.uky.edu/assets/pdf/webdocs/3R4F%20Preliminary%20Analysis.pdf 

Vogel, R. I., Hertsgaard, L. A., Dermody, S. S., Luo, X., Moua, L., Allen, S., . . . Hatsukami, D. K. (2014). Sex 

differences in response to reduced nicotine content cigarettes. Addictive Behaviors, 39(7), 1197-

1204. doi:10.1016/j.addbeh.2014.03.021 

Wackowski, O., & Delnevo, C. D. (2007). Menthol cigarettes and indicators of tobacco dependence 

among adolescents. Addictive Behaviors, 32(9), 1964-1969. doi:10.1016/j.addbeh.2006.12.023 

Walker, N., Fraser, T., Howe, C., Laugesen, M., Truman, P., Parag, V., . . . Bullen, C. (2015). Abrupt 

nicotine reduction as an endgame policy: A randomised trial. Tob Control, 24(e4), e251-257. 

doi:10.1136/tobaccocontrol-2014-051801 

Walker, N., Howe, C., Bullen, C., Grigg, M., Glover, M., McRobbie, H., . . . Whittaker, R. (2012). The 

combined effect of very low nicotine content cigarettes, used as an adjunct to usual Quitline 
 

STN PM0000491 – PM0000492 Page 89 of 89 

care (nicotine replacement therapy and behavioural support), on smoking cessation: A 

randomized controlled trial. Addiction, 107(10), 1857-1867. doi:10.1111/j.1360-

0443.2012.03906.x