;..-....... II U.S. Food & Drug Administration   10903 New Hampshire Avenu    Silver Spring, MD 20

www.fda.gov 

Scientific Review of Modified Risk Tobacco Product Application (MRTPA) Under 

Section 911 (d) of the FD&C Act -Technical Project Lead 

SUBMISSION INFORMATION 

Applicant 22nd Century Group Inc. 

Product Manufacturer NASCO Products, LLC 

Submission Date May 17, 2019 I FDA Receipt Date I May 20, 2019 

Purpose □ Risk Modification (911(g)(l) order 

~ Exposure Modification (911(g)(2) order 

Claims Claim #1: "95% less nicotine" •

• Claim #2: "Helps reduce your nicotine consumption" 

• Claim #3: " ... greatly reduces your nicotine consumption." 

PROPOSED MODIFIED RISK TOBACCO PRODUCTs 

MR0000159: VLNTM King 

Product Category Cigarettes 

Product Sub-Category Combusted, Filtered 

Package Type Hard Pack 

Package Quantity 20 Cigarettes

Characterizing Flavor None 

Length 83 mm 

Diameter 7.9mm 

13 % 

MR0000160: VLNTMMenthol King 

Product Category 

Ventilation 

Cigarettes 

Product Sub-Category Combusted, Filtered 

Package Type Hard Pack 

Package Quantity 20 Cigarettes 

Characterizing Flavor Menthol 

Length 83 mm 

Diameter 7.9mm 

Ventilation 13 %

Cross-referenced Cross-referenced STN Primary STN{s) 

Submission(s) f(6 ) (4) I APPLI ES TO ALL STNs ABOVE 
MR0000159- MR0000160 Page 2 of 90 

DISCIPLINES REVIEWED DATE OF REVIEW 

Engineering December 15, 2021 

Chemistry December 16, 2021 

Toxicology December 16, 2021 

Social Science December 16, 2021 

Behavioral Clinical Pharmacology December 16, 2021 

Medical December 17, 2021 

Epidemiology December 16, 2021 

Environmental Science December 15, 2021 

OCE Review (DEM) December 17, 2021 

Recommended Action(s) 

-12:J Issue a Modified Risk Grant letter 

D Issue a Denial letter 

Technical Project Lead (TPL): 

/Sf 

Cindy Tworek, Ph.D., M.P.H. 

Chief, Social Science 

Division of Population Health Science 

Signatory Decision: 

~ Concur with TPL recommendation and basis of recommendation 

□ Concur with TPL recommendation with addit ional comments (see separate memo) 

□ Do not concur w ith TPL recommendation (see separate memo) 

/Sf 

Matthew R. Holman, Ph.D. 

Director 

Office of Science 
MR0000159- MR0000160 Page 3 of 90 

Table of Contents 

I. Executive Summary............................................................................................................................... 5 

A. Background ....................................................................................................................................... 5 

B. Exposure Modification Order Request ............................................................................................. 5 

C. Summary of findings ......................................................................................................................... 8 

II. Regulatory Information.......................................................................................................................18 

A. Regulatory History ..........................................................................................................................18 

B. Proposed Modified Risk Tobacco Product......................................................................................19 

1. Proposed Modified Risk Claims...................................................................................................19 

2. Description of Product................................................................................................................20 

C. Tobacco Products Scientific Advisory Committee (TPSAC)............................................................21 

D. Public Availability of MRTPAs..........................................................................................................24 

III. Summary of Scientific Evidence......................................................................................................25 

A. Bridging from SPECTRUM NRC102/103 research cigarettes to VLNTM Cigarettes .......................... 27 

B. Relative Health Risks of the Proposed MRTPs to Individual Tobacco Users................................... 28 

1. Nicotine content on a dry weight basis (DWB)...........................................................................28 

2. Harmful and Potentially Harmful Constituents (HPHCs) and Toxicology Evaluation ................. 29 

3. Assessment of Potential Health Risks to Individual Tobacco Users and Non-Users...................40 

C. Consumer Understanding and Perceptions....................................................................................48 

1. Understanding of Nicotine Content............................................................................................48 

2. Understanding of Conditions of Use...........................................................................................50 

3. Understanding of Addiction Risk ................................................................................................51 

4. Understanding of health risks, other than addiction..................................................................51 

D. Tobacco Use Behavior and Impacts to the Population as a Whole ................................................56 

1. Impacts to Tobacco Users...........................................................................................................56 

2. Tobacco Users’ Likelihood of Use After Exposure to Proposed Modified Risk Claims ...............60 

3. Tobacco Nonusers’ Likelihood of Use After Exposure to Proposed Modified Risk Claims........65 

4. Population Health Impact Model ...............................................................................................68 

IV. Conclusions and Recommendations...............................................................................................71
MR0000159- MR0000160 Page 4 of 90 

A. Review Conclusions – Exposure Modification Order Request........................................................71 

B. Environmental Impact.....................................................................................................................79 

C. Postmarket Surveillance and Studies (PMSS) .................................................................................79 

1. PMSS Content .............................................................................................................................80 

2. Submitting PMSS Protocols and Reports ....................................................................................84 
 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 5 of 90 

I. Executive Summary 

A. Background 

On May 17, 2019, 22nd Century Group Inc. submitted modified risk tobacco product applications 

(MRTPAs) stating that it is seeking exposure modification orders under section 911(g)(2) of the Federal 

Food, Drug, and Cosmetic Act (FD&C Act) for its VLNTM King and VLNTM Menthol King combustible 

cigarettes, which were received by FDA on May 20, 2019. 

Under section 910 of the FD&C Act, the applicant submitted premarket tobacco product applications 

(PMTAs) and requested authorization of the same products that are the subject of these MRTPAs, 

named Moonlight and Moonlight Menthol1 combustible cigarettes, without modified risk claims. FDA 

authorized the marketing of the Moonlight and Moonlight Menthol combusted cigarettes without 

modified risk claims on December 17, 2019. The technical project lead (TPL) review for the 

accompanying PMTAs provides detail on the engineering, chemistry, stability, and manufacturing of the 

products, including the results of FDA inspections of manufacturing sites.2 Where relevant, the present 

review reflects determinations made in the PMTA TPL review. 

This review addresses the exposure modification pathway under section 911(g)(2) of the FD&C Act. The 

focus of this review of the MRTPAs is on evaluating: (1) the relative health risks of the proposed 

modified risk tobacco products (MRTPs) compared to combusted cigarettes to individual tobacco users; 

(2) consumer understanding and perception of VLNTM cigarettes marketed with the proposed claims; and 

(3) population health impact, including population health impact on tobacco users, tobacco users’ and 

nonusers’ likelihood of using the product after exposure to the proposed modified risk claims, and the 

applicant’s population health model. 

B. Exposure Modification Order Request 

The applicant has requested an exposure modification order under section 911(g)(2) of the FD&C Act to 

market these products with the following claims: 

• Claim #1: “95% less nicotine” 

• Claim #2: “Helps reduce your nicotine consumption” 

• Claim #3: “...greatly reduces your nicotine consumption.” 

Additionally, FDA identified the following claims in the advertising that was submitted by the applicant: 

1 On October 2, 2019, the applicant submitted an amendment to its PMTAs, notifying FDA the company was changing the 

product names from VLNTM King and VLNTM Menthol to Moonlight and Moonlight Menthol, respectively. 2 The PMTA TPL reviews are available at: https://www.fda.gov/tobacco-products/premarket-tobacco-productapplications/premarket-tobacco-product-marketing-orders
 

 

 

 

 

 

MR0000159- MR0000160 Page 6 of 90 

• Claim #4: “VLNTM cigarettes are substantially lower in nicotine content than any other cigarettes 

currently available to smokers in the United States. VLNTM cigarette contain an average of just 0.27 

mg of nicotine.” 

• Claim #5: “Without exception, VLNTM cigarettes contain at least 95% less nicotine than the top 100 

cigarette brands in the United States.” 

• Claim #6: “22nd Century’s VLNTM cigarettes contain an average of 0.27 mg nicotine - -at least 95% 

less nicotine compared to conventional cigarettes.” 

• Claim #7: “22nd Century’s VLNTM cigarettes feature the same nicotine content as the lowest nicotine 

style of the Company’s SPECTRUM research cigarettes.” 

• Claim #8: “VLNTM cigarettes contain 0.27 ± 0.1 mg nicotine.” 

• Claim #9: “As a result of our unique technology and plant breeding expertise, VLNTM tobacco grows 

with 95% less nicotine than conventional tobacco.” 

• Claim #10: Several examples utilize a graph depicting nicotine levels of VLNTM cigarettes compared to 

several other cigarette brands. 

Claims #1-3 appear on the submitted product labels, labeling, and advertising (LLA). Claims #4-10 appear 

only in the submitted product advertising. The labels and most of the advertising also include the 

following information, described by the applicant as a disclaimer3

: “Nicotine is addictive. Less nicotine 

does NOT mean safer. All cigarettes can cause disease and death.” 

We also note that both products include VLNTM in their name, which stands for ‘very low nicotine’. FDA 

has reviewed this language and finds it to be substantiated as descriptive for the amount of nicotine 

related to the product contents. Since the ‘low’ amount of nicotine contained in these products has 

been substantiated, we find that VLNTM is an accurate description for the product nicotine content and 

do not have concerns with it. 

Under section 911(g)(2) of the FD&C Act, exposure modification orders may be granted by FDA when 

the available evidence is not sufficient for a risk modification order under section 911(g)(1). Specifically, 

FDA may issue an exposure modification order under section 911(g)(2) (the "special rule") if it 

determines that the applicant has demonstrated that: 

• Such an order would be appropriate to promote the public health; 

• Any aspect of the label, labeling, and advertising for the product that would cause the 

product to be a modified risk tobacco product is limited to an explicit or implicit 

representation that the tobacco product or its smoke does not contain or is free of a 

3 The applicant refers to the statement, “Nicotine is addictive. Less nicotine does NOT mean safer. All cigarettes 

can cause disease and death.” variously as a “disclaimer” (Section V “Labels, Labeling, and Advertising,” p. 3; 

Section VII “Summary of All Research Findings,” p. 72) and “voluntary warning” (Section V “VLNTM Cigarettes: 

Labels, Labeling, and Advertising,” pp. 2, 8-9). In this review, the word “disclaimer” refers to the applicant’s use of 

this term and does not reflect FDA’s independent conclusion regarding characterization of the information. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 7 of 90 

substance or contains a reduced level of a substance, or presents a reduced exposure to a 

substance in tobacco smoke; 

• Scientific evidence is not available and, using the best available scientific methods, cannot 

be made available without conducting long-term epidemiological studies for an application 

to meet the standards for obtaining an order under section 911(g)(1); and 

• The scientific evidence that is available without conducting long-term epidemiological 

studies demonstrates that a measurable and substantial reduction in morbidity or mortality 

among individual tobacco users is reasonably likely in subsequent studies (section 

911(g)(2)(A) of the FD&C Act). 

Furthermore, for FDA to issue an exposure modification order, FDA must find that the applicant has 

demonstrated that: 

• The magnitude of overall reductions in exposure to the substance or substances that are the 

subject of the application is substantial, such substance or substances are harmful, and the 

product as actually used exposes consumers to the specified reduced level of the substance 

or substances; 

• The product as actually used by consumers will not expose them to higher levels of other 

harmful substances compared to the similar types of tobacco products then on the market 

unless such increases are minimal and the reasonably likely overall impact of use of the 

product remains a substantial and measurable reduction in overall morbidity and mortality 

among individual tobacco users; 

• Testing of actual consumer perception shows that, as the applicant proposes to label and 

market the product, consumers will not be misled into believing that the product is or has 

been demonstrated to be less harmful, or presents or has been demonstrated to present 

less of a risk of disease than one or more other commercially marketed tobacco products; 

and 

• Issuance of the exposure modification order is expected to benefit the health of the 

population as a whole taking into account both users of tobacco products and persons who 

do not currently use tobacco products (section 911(g)(2)(B) of the FD&C Act). 

In making the determinations under section 911(g)(2) of the FD&C Act, FDA must take into account: 

• The relative health risks to individuals of the modified risk tobacco product; 

• The increased or decreased likelihood that existing tobacco product users who would 

otherwise stop using such products will switch to using the modified risk tobacco product; 

• The increased or decreased likelihood that persons who do not use tobacco products will 

start using the modified risk tobacco product; 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 8 of 90 

• The risks and benefits to persons from the use of the modified risk tobacco product 

compared to the use of smoking cessation drug or device products approved by FDA to treat 

nicotine dependence; and 

• Comments, data, and information submitted to FDA by interested persons (section 911(g)(4) 

of the FD&C Act). 

Unlike the section 911(g)(1) standard, which requires scientific evidence showing actual risk reduction 

(e.g., a finding that the product, as actually used by consumers, will significantly reduce harm and risk to 

individual users; a finding that the product, as actually used by consumers, will benefit the health of the 

population a as whole), section 911(g)(2) establishes a lower standard, which allows FDA to issue an 

order when risk reduction has not yet been demonstrated but is reasonably likely based on 

demonstrated reductions in exposure (e.g., a finding that a reduction in morbidity or mortality among 

individual users is reasonably likely in subsequent studies; a finding that issuance of an order is expected 

to benefit the health of the population as a whole). 

Furthermore, FDA must ensure that the advertising and labeling of the MRTP enable the public to 

comprehend the information concerning modified risk and to understand the relative significance of 

such information in the context of total health and in relation to all tobacco-related diseases and health 

conditions (section 911(h)(1) of the FD&C Act). 

To the extent possible, the assessment integrates the various threads of evidence regarding the product 

and its potential effects on health and tobacco use behavior, including tobacco use initiation, to 

determine both the net effect of the product on overall tobacco-related morbidity and mortality and the 

distribution of the benefits and harms across the population. This determination also considers these 

product applications in the context of the current marketplace where menthol cigarette products are 

legally sold to consumers.4 In particular, the recommendation considers that VLNTM Menthol King 

provides an opportunity for menthol smokers to reduce their nicotine consumption and reduce their 

exposure to nicotine, potentially decreasing their cigarettes per day smoked. 

C. Summary of findings 

After conducting a thorough scientific review of: the information contained in the MRTPAs; the 

recommendations from the Tobacco Products Scientific Advisory Committee (TPSAC); comments, data, 

and information submitted to FDA by interested persons; and other scientific information identified by 

the agency from other sources, I conclude that: 

• With respect to the exposure modification order request, the applicant has demonstrated 

that the products sold or distributed with the proposed modified risk information meet the 

standard under section 911(g)(2) of the FD&C Act, including that a measurable and 

substantial reduction in morbidity or mortality among individual tobacco users is reasonably 

likely in subsequent studies, and issuance of an order is expected to benefit the health of 

4 In April 2021, FDA announced that it is working toward issuing a proposed product standard to prohibit menthol 

as a characterizing flavor in cigarettes. If a final rule banning menthol in cigarettes is issued, FDA will consider the 

impact of such action on the finding that VLNTM Menthol King meets the 911(g)(2) standard. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 9 of 90 

the population as a whole, taking into account both users of tobacco products and persons 

who do not currently use tobacco products. Currently, “scientific evidence is not available 

and, using the best available scientific methods, cannot be made available without 

conducting long-term epidemiological studies for an application to meet the standards set 

forth ...” in 911(g)(1) because issuance of an order under 911(g)(1) requires a demonstration 

that the product as actually used by consumers will “significantly reduce harm and the risk 

of tobacco-related disease to individual tobacco users” and “benefit the health of the 

population as a whole”. The applicant did not make such a demonstration for these 

products. There are outstanding questions about the manner in which consumers will use 

VLN, and if individual tobacco users use VLN cigarettes in the same frequency and manner 

as conventional cigarettes, they will not significantly reduce harm and their risk of tobaccorelated disease. However, as described in this review, cigarette smokers’ use of VLN 

cigarettes is likely to lead to reduced nicotine consumption, indicators of nicotine 

dependence, and likely overall cigarette consumption, which reasonably likely lead to 

reduced morbidity or mortality among these users, compared with continuing to smoke 

conventional cigarettes. 

Bridging from SPECTRUM NRC102/103 

Much of the evidence reviewed in these MRTPAs is based on studies of SPECTRUM NRC102 (nonmenthol) and NRC103 (menthol) very low nicotine cigarettes (VLNCs). The applicant stated SPECTRUM 

NRC102 is the same as VLNTM King, and SPECTRUM NRC103 is the same as VLNTM Menthol King. FDA 

found that the cigarette weight, cigarette length, cigarette diameter, and tipping paper permeability are 

the same between SPECTRUM and VLNTM cigarettes. SPECTRUM cigarettes and VLNTM cigarettes also 

share many identical 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. 

(b) (4)

The base tipping paper for both SPECTRUM and VLNTM cigarettes has the same 

porosity of CU and is produced by the same manufacturer. Thus, FDA finds it appropriate to bridge 

data from studies of SPECTRUM NRC102/103 (referred to as “VLNCs”) to the proposed MRTPs. In this 

review, the terms VLNC cigarettes and SPECTRUM NRC102/103 are used interchangeably. 

Reduced exposure claim substantiation 

After thoroughly examining the modified risk LLA, I find that, consistent with section 911(g)(2)(A)(ii), any 

aspect of the LLA that would cause VLNTM to be a modified risk tobacco product is limited to explicit and 

implicit representations that VLNTM (1) contains a reduced level of nicotine and (2) presents a reduced 

exposure to nicotine, compared to other cigarettes. This includes the applicant-submitted claims #1-3 

and the FDA-identified claims #4-10. 

Eight claims discussed the nicotine content (i.e., reduced level of a substance) of the proposed MRTPs: 

• Claim #1: “95% less nicotine” 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 10 of 90 

• Claim #4: “VLNTM cigarettes are substantially lower in nicotine content than any other cigarettes 

currently available to smokers in the United States. VLNTM cigarette contain an average of just 

0.27 mg of nicotine.” 

• Claim #5: “Without exception, VLNTM cigarettes contain at least 95% less nicotine than the top 

100 cigarette brands in the United States.” 

• Claim #6: “22nd Century’s VLNTM cigarettes contain an average of 0.27 mg nicotine - -at least 

95% less nicotine compared to conventional cigarettes.” 

• Claim #7: “22nd Century’s VLNTM cigarettes feature the same nicotine content as the lowest 

nicotine style of the Company’s SPECTRUM research cigarettes.” 

• Claim #8: “VLNTM cigarettes contain 0.27 ± 0.1 mg nicotine.” 

• Claim #9: “As a result of our unique technology and plant breeding expertise, VLNTM tobacco 

grows with 95% less nicotine than conventional tobacco.” 

• Claim #10: Several examples utilize a graph depicting nicotine levels of VLNTM cigarettes 

compared to several other cigarette brands. 

Two claims discussed how the proposed MRTPs affect the users’ consumption of nicotine (i.e., reduced 

exposure to a substance): 

• Claim #2: “Helps reduce your nicotine consumption” 

• Claim #3: “...greatly reduces your nicotine consumption.” 

Here, I summarize the evidence supporting the substantiation of each claim, grouped by topic area. 

First, I discuss claims related to nicotine content (Claims #1 and #4-10), and then I discuss claims related 

to reduction in nicotine consumption (Claims #2 and #3). After conducting a thorough assessment of the 

scientific evidence, I find that all exposure modification claims are substantiated by the evidence. 

Several lines of evidence substantiate the claims related to nicotine content (Claims #1 and #4-10). First, 

the chemistry review found that the applicant provided a survey of 100 top-selling cigarette brands that 

represent 87% of all cigarettes sold in the U.S. through convenience stores in 2017. These 100 cigarettes 

contain a reported average of 19.4 mg nicotine per gram of tobacco on a dry weight basis (DWB) and a 

reported average of 12.0 mg nicotine per cigarette. The applicant reported that the tobacco nicotine 

content of all 10 batches of the two new VLNTM 

specification of

(b) (4)

cigarettes met the applicant’s maximum nicotine 

 mg/g (DWB). Accordingly, the reported nicotine contents of the VLNTM cigarettes are 

98% lower than the average reported nicotine contents of the top 100 cigarette brands determined both 

per gram of tobacco and per cigarette. In addition, both applicant-contracted and FDA nicotine test 

results found that nicotine levels in tobacco and mainstream smoke of VLNTM cigarettes are at least 96% 

lower than the majority of marketed and market-leading conventional cigarette brands. 

Furthermore, batch analysis of eight batches of VLNTM cigarettes shows a slightly higher nicotine content 

than the 0.27 mg/cig reported by the applicant. The measured average VLNTM cigarette nicotine content 

was 0.29 mg/cig. However, this is within the advertised nicotine content lower and upper limit of 0.27 ± 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 11 of 90 

0.10 mg/cig (0.17 and 0.37 mg/cig lower and upper limit). Based on this evidence, Claims #1, 4, 5, 6, and 

8 are supported. Finally, the chemistry review notes that the two VLNTM cigarette products contain only 

Vector 21-41 Burley tobacco, which is a unique tobacco variety not present in any commerciallymarketed cigarette tobacco. This tobacco type is genetically engineered using the applicant’s 

proprietary technology to block several genes, which results in suppression of nicotine biosynthesis. 

This tobacco is also the filler in SPECTRUM research cigarettes NRC102 and mentholated NRC103. (b) (4)

SPECTRUM NRC102 and NRC 103 also have less than mg/g of nicotine on a DWB, and thus has at 

least 95% less nicotine than the reported nicotine content for conventional cigarette tobacco. Thus, 

Claims #7 and 9 are supported. 

Claims #1, 5, 6, and 9 all include the phrase “95% less nicotine.” All but one of these claims—Claim #1— 

indicates the product contains 95% less nicotine. Claim 1 does not use the word “contains” and could 

therefore be referring to nicotine exposure after using the product. Accordingly, the behavioral and 

clinical pharmacology (BCP) review evaluated the substantiation of this meaning. The applicant’s abuse 

liability studies, which contained actual use data in healthy adult smokers after ad libitum and controlled 

VLNTM cigarette smoking, indicate that exclusively smoking VLNTM cigarettes results in an approximate 

97% reduction in plasma nicotine levels compared to smoking usual brand (UB) normal nicotine content 

(NNC) cigarettes. Findings from the applicant’s submitted literature review on biomarkers of exposure 

(BOE) support these data, noting that smokers who primarily smoke or switch completely to smoking 

VLNC cigarettes (i.e., reduced nicotine content cigarettes that are identical or similar in nicotine content 

to VLNTM cigarettes) have reduced exposure to nicotine compared to smoking usual brand (UB) NNC 

cigarettes. The literature finds that exclusively smoking VLNC cigarettes across five days results in an 

average 94% reduction in urinary total nicotine equivalents (TNE). As such, by exclusively smoking VLNC 

cigarettes, consumers could reduce their exposure to nicotine by approximately 95%. As a result, I find 

this claim substantiated. 

Regarding the claims about reduced nicotine consumption (Claims #2 and #3), I find that both of these 

claims are substantiated, including by evidence discussed in the BCP review. First, to the extent that the 

claims refer to a reduction of nicotine consumption resulting from complete switching and exclusive use 

of VLN cigarettes over UB-NNC cigarettes (i.e., with or without a concomitant reduction in overall CPD), 

the claims are clearly substantiated based on the greatly reduced nicotine content of VLN over UB-NNC 

on a per-stick basis. Furthermore, given the 95% reduced nicotine content in VLNTM cigarettes, data 

support that menthol and non-menthol smokers who primarily smoke VLNTM cigarettes and occasionally 

dual use, with other tobacco or nicotine-containing products, still experience the benefit of substantially 

reducing their overall exposure to nicotine compared to exclusively smoking UB-NNC cigarettes. When 

considering the range of non-compliance across the sample of participants assigned to smoke VLNC 

cigarettes (i.e., the number of UB cigarettes smoked during the course of the study in addition to VLNTM 

cigarettes), studies in the literature report an average 59-60% reduction in nicotine exposure over 6 to 

20 weeks of VLNC cigarette use. In addition, the applicant’s 6-week longitudinal study supports that, as a 

result of substantially reducing nicotine exposure, switching to VLNC cigarettes can lead to smoking 

fewer overall cigarettes per day (CPD) compared to ongoing UB-NNC cigarette smoking. These findings 

are supported by several VLNC cigarette studies in the published literature, including a 20-week study of 

VLNC cigarette use among smokers, which is the longest study of VLNC cigarettes to date (Hatsukami et 

al., 2018). On average, smokers assigned to switch to VLNCs had half the CPD compared to those in the 

UB-NNC control group. The extent of cigarette reduction depends on the extent of switching to smoking 

VLNTM cigarettes, although smokers who occasionally smoke UB-NNC cigarettes still experience a 

significant reduction in CPD compared to smoking UB-NNC cigarettes exclusively. Studies support that as 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 12 of 90 

the duration of smoking VLNC cigarettes increases, the reduction in CPD increases. Thus, the available 

evidence supports the scientific substantiation of Claims #2 and #3. 

Relatedly, consistent with section 911(g)(2)(A)(i), I find that the magnitude of the overall reduction in 

exposure to nicotine in VLNTM is substantial, and VLNTM as actually used exposes consumers to the 

specified reduced level of nicotine (i.e., “95% less nicotine” in claim 1, “helps reduce” in claim 2, and 

“greatly reduced” in claim 3). Also, I find that nicotine is harmful. It is addictive and is a reproductive or 

developmental toxicant (RDT) in FDA’s established list of harmful and potentially harmful constituents. 

Individual health impact among tobacco users 

I find that while the proposed MRTPs may expose some smokers to higher levels of harmful and 

potentially harmful constituents (HPHCs), such increases are minimal; the reasonably likely overall 

impact of use remains a substantial reduction in morbidity among tobacco users, consistent with 

911(g)(2)(B)(ii). This is based on HPHC and BOE study data comparing the proposed MRTPs to 

conventional cigarettes on a per-stick basis; this approach is conservative since clinical studies find that 

people who smoke VLNCs decrease their CPD. Comparing HPHC yields on a per cigarette basis5 indicates 

that while the VLNTM products have higher levels of some HPHCs (acetaldehyde, ammonia, 4-

aminobiphenol, and acrylonitrile), they have lower levels of others (e.g., NNN, acrolein, formaldehyde, 

benzo[a]pyrene). Toxicology reviewers concluded that although there may be higher exposures to 

specific constituents, these higher levels do not appear to impact the overall relative product risks and 

hazards, given that other constituents associated with similar adverse health outcomes are lower in the 

VLNTM products compared to conventional cigarettes. The overall health risks and hazards of VLNTM 

cigarettes compared to conventional cigarettes are likely similar if smokers of VLNTM cigarettes smoke 

with the same frequency as conventional cigarettes or lower if smokers of VLNTM cigarettes significantly 

decrease their CPD. These findings are generally consistent with evaluations of BOE in the applicant’s 6-

week clinical study and Hatsukami et al.’s 2018 study: among smokers assigned to use VLNC or VLNTM 

cigarettes, there were significant reductions in nicotine levels and in some other HPHCs. These findings 

provide evidence that the products will not expose consumers to high levels of non-nicotine HPHCs 

compared to other conventional cigarettes. Additionally, this provides some support that reductions in 

exposure are reasonably likely to result in a measurable and substantial reduction in morbidity or 

mortality among individual tobacco users; additional evidence for this is discussed next. 

Consistent with section 911(g)(2)(A)(iv), I find that use of the proposed MRTPs is reasonably likely to 

translate to lower risk of tobacco-related morbidity and mortality among individual tobacco users in 

subsequent studies. The abuse liability of VLNTM cigarettes is low based on low plasma nicotine levels 

after using them and low subjective effects ratings. Because smokers assigned to use these products in 

the longest clinical study (20 weeks, Hatsukami et al., 2018) had a CPD that was 50% that of smokers 

assigned to smoke UB-NNC cigarettes and using the proposed MRTPs have lower dependence scores, I 

find it is reasonably likely that using this product reduces nicotine dependence. Nicotine dependence is 

a morbidity of tobacco use. Overall, reducing nicotine exposure can reduce nicotine dependence. This 

effect is anticipated to lead to long-term reductions in exposure to the smoking-related toxicants 

associated with morbidity and mortality through reducing smoking and increasing the potential for 

5 Toxicology assumes equal product use (same number of cigarettes per day (CPD), same puffing characteristics, 

etc.) between the VLNTM cigarettes and the comparison products. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 13 of 90 

cessation. Additionally, published epidemiological studies assessing the relationship between smoking 

reduction and disease risks suggested a potential benefit for some health endpoints, such as lung cancer 

risk, among those who reduced CPD by more than 50% compared to non-reducers. Past studies have not 

consistently demonstrated that a reduction in CPD reduces mortality; however, a recent study 

evaluating changes in smoking patterns over a longer period of time than previous studies found that 

all-cause mortality was lower among smokers who reduced their CPD compared to those who 

maintained their CPD, with greater reductions in CPD yielding greater benefits (Inoue-Choi et al., 2019). 

The totality of evidence presented suggests that a measurable and substantial reduction in morbidity or 

mortality among individual tobacco users is reasonably likely in subsequent studies. This determination 

predominantly stems from: (1) the 95% reduction in nicotine exposure with exclusive use of VLNTM 

cigarettes and at least about 50% reduction in nicotine exposure with dual use with NNC cigarettes; (2) 

the reduced abuse liability of VLNTM cigarettes and reduced nicotine dependence among users; (3) the 

substantial reduction in CPD among smokers who predominantly use VLNTM cigarettes (an estimated 

50% reduction); and (4) the reduction in some tobacco morbidities (e.g., lung cancer) associated with at 

least a 50% reduction in CPD. The evidence also supports a finding under 911(g)(2)(A)(ii) that the LLA is 

limited to exposure claims; and a finding under 911(g)(2)(B)(i) that “the magnitude of the overall 

reductions in exposure to the substance or substances which are the subject of the application is 

substantial, such substance or substances are harmful, and the product as actually used exposes 

consumers to the specified reduced level of the substance or substances.” Consumer understanding 

In terms of consumer understanding, it is the TPL’s view that the applications support the findings 

required for authorization with the inclusion of the statement “Helps you smoke less” in the LLA. The 

social science review evaluated consumer understanding by assessing: (1) whether consumers 

comprehend the explicit meaning of the proposed modified risk information, as well as whether they 

understand (2) VLNTM cigarettes’ conditions of use, (3) addiction risk, and (4) health risks aside from 

addiction. Regarding (1), the social science review found that the claims are relatively simple and 

concrete (including the statement of “95% less”), and that each instance of LLA includes multiple 

statements reinforcing the main idea of substantially reduced nicotine. The applicant’s qualitative 

research examined consumer comprehension of the proposed claims and found support for using the 

“95% less” wording because it was brief and made clear that the reduction in nicotine was substantial. In 

the applicant’s quantitative research, most participants spontaneously brought up the low nicotine 

content when asked for an open-ended response about how they would describe the product to a friend 

or family member. Previously published research testing consumer comprehension of various reduced 

nicotine claims found that the inclusion of a percentage reduction (i.e., 95%) helped participants grasp 

the extent of the nicotine reduction (Byron, Hall, King, Ribisl, & Brewer, 2019). Dual-using the proposed 

MRTPs with other tobacco and nicotine-containing products results in a lesser nicotine exposure 

reduction (48-58% in the applicant’s study, 59-60% in the literature). It is reasonable to expect that 

consumers will interpret the claim “95% less nicotine” as referring to the content of the cigarettes or the 

exposure they will receive if they use these cigarettes in place of conventional cigarettes rather than 

dual use. The alternative interpretation would require consumers to believe that somehow use of the 

proposed MRTPs will block their exposure to nicotine from other sources, which is unlikely. Taken 

together, our findings suggest that the proposed LLA would indeed enable most consumers to 

comprehend the claims’ explicit meaning that VLNTM cigarettes contain much lower levels of nicotine 

than other cigarettes. 

Regarding consumer understanding of (2) conditions of use, the social science review examined whether 

consumers would understand that VLNTM cigarettes can help smokers reduce their smoking frequency or 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 14 of 90 

duration, which can reduce their exposure to nicotine and other HPHCs and potentially their disease 

risk. The social science review found that the proposed LLA include no information on conditions of use, 

such as how consumers should use VLNTM to reduce their exposure to HPHCs and potential disease risk. 

In qualitative in-depth interviews, some participants did not appear to understand the conditions of use: 

after viewing VLNTM cigarette packs with the proposed modified risk labeling, they did not understand 

the need to cut down or stop smoking in order to benefit from VLNTM cigarettes. In contrast, participants 

appeared to understand this better after viewing different packs that included the proposed claims plus 

an additional statement, “Helps you smoke less.” Given these findings, I recommend that the order 

require that VLNTM cigarette LLA include “Helps you smoke less,” if the LLA include one or more of the 

authorized exposure claims, as this statement is necessary to enable consumers to understand the 

manner in which they must use the product in order to obtain a benefit. 

Regarding consumer understanding of (3) addiction risk, the social science review examined whether 

consumers would understand that VLNTM cigarettes are less addictive than other cigarettes and similarly 

addictive as nicotine replacement therapies (NRT). In the applicant’s quantitative research, results found 

that this was the case: participants who viewed the proposed modified risk labeling perceived VLNTM 

cigarettes as substantially less addictive than other cigarettes but still perceived some risk of addiction 

(on a 5-point scale), placing them in a similar range as they placed NRT. This finding was also observed 

among participants who viewed VLNTM cigarette packs with the additional statement “Helps you smoke 

less.” The above findings held across adult current, former, and never smokers and are consistent with 

prior research finding that most U.S. adults believe that nicotine is the main addictive substance in 

tobacco (O’Brien et al., 2017). These findings indicate that the proposed LLA enable consumers to 

understand VLNTM cigarettes’ addiction risk. 

Finally, regarding consumer understanding of (4) health risks aside from addiction, social science 

reviewers examined whether consumers’ understanding is in line with the reasonably likely risks of the 

product. Specifically, social science reviewers examined whether consumers would understand that 

VLNTM cigarettes (a) pose moderate to high health risks, (b) are more harmful to health than NRT, (c) are 

reasonably likely to pose reduced disease risks (compared to other cigarettes) if consumers use them to 

smoke fewer cigarettes over time, and (d) are just as toxic as other cigarettes and would pose the same 

disease risks as other cigarettes if they are smoked in the same way (i.e., with the same frequency and 

duration). Importantly, findings from the applicant’s research supported (a) and (b); participants indeed 

perceived VLNTM cigarettes as presenting risks of tobacco-related diseases that were moderate to high 

and significantly higher than the risks posed by NRT. Regarding (c) and (d), prior published research 

suggests that, without corrective or clarifying information, many U.S. consumers are at risk of 

misinterpreting statements about reduced nicotine content cigarettes (e.g., “Imagine if tobacco 

companies were required to remove 95% of the nicotine from cigarettes”) to mean that the cigarettes 

would be less toxic and carcinogenic than other cigarettes on a per-cigarette basis (Byron et al., 2019; 

Bansal-Travers et al., 2010; Borrelli & Novak, 2007; Byron et al., 2018; Denlinger-Apte et al., 2017; Mutti 

et al., 2011; O’Brien et al., 2017). Indeed, the applicant’s quantitative research found that, after viewing 

VLNTM packs with the proposed modified risk information, participants perceived VLNTM cigarettes as 

presenting lower risks of tobacco-related diseases compared to other cigarettes, including lung cancer 

and 17 other tobacco-related health effects. However, in the applicant’s research, the survey questions 

did not specify frequency of use, and the research did not assess the assumptions participants made in 

answering disease risk questions (e.g., whether they assumed they would use the proposed MRTPs to 

reduce smoking). Therefore, it is unclear whether these perceptions reflect consumer misperceptions of 

toxicity or correct consumer understanding of the reasonably likely reduction in disease risks resulting 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 15 of 90 

from using VLNTM cigarettes, which are less addictive, and would lead to smoking fewer CPD with an 

increased likelihood of smoking cessation over time. TPSAC committee members stated it was unlikely 

that participants thought through the products’ addictiveness (and the corresponding effects on use 

frequency, duration, and, in turn, disease risks) when rating the risks of smoking VLNTM cigarettes. 

These findings and considerations regarding (c) and (d) underscore the need to recommend that the 

order require VLNTM’s modified risk LLA to include an explicit statement about how the product must be 

used in order to obtain a benefit (i.e., “Helps you smoke less”) in a way that will be noticed and read. 

Including this statement can help consumers understand how the product is used (i.e., to reduce 

smoking), which ensures their understanding of health risk reduction in line with what is reasonably 

likely to be demonstrated in subsequent studies. Additionally, by including this statement, the LLA will 

enable consumers to clearly understand the significance of the reduced nicotine claims, the relevance to 

their personal health (or the irrelevance, if the person does not wish to smoke less), and the reason why 

the manufacturer would be providing the information about nicotine to consumers. 

Under section 911(g)(2)(B)(iii) of the FD&C Act, to issue an exposure modification order, FDA must find 

that testing of actual consumer perception shows that, as the applicant proposes to label and market 

the product, consumers will not be misled into believing that the product is or has been demonstrated to 

be less harmful or is or has been demonstrated to present less of a risk of disease than one or more 

other commercially marketed tobacco products. FDA interprets this to mean finding that consumers do 

not hold inaccurate beliefs or are not misled regarding the definitiveness of the evidence regarding the 

relative risks or harm of the product. The totality of evidence on consumer understanding supports that 

if the LLA include the statement “helps you smoke less,” the LLA enable consumers to understand: (1) 

the explicit meaning of the proposed modified risk information; (2) the VLNTM cigarettes’ conditions of 

use; (3) the addiction risk; and (4) the health risks aside from addiction. Thus, it is my view that the 

testing of actual consumer perceptions showed that, overall, consumer understanding is generally in line 

with the health risks of the product that are reasonably likely and the current state of the evidence. 

Also, I recommend that the applicant include the disclaimer “Nicotine is addictive. Less nicotine does 

NOT mean safer...” on the VLNTM cigarette pack if the LLA include one or more of the authorized 

exposure claims, given that it was present on all of the labeling that the applicant tested in its 

quantitative consumer research. However, the social science review notes that several aspects of the 

disclaimer are inconsistent with expert recommendations for disclaimers, and prior research suggests 

that poorly designed disclaimers can confuse consumers and change their perceptions, attitudes, or 

decisions in a manner opposite of that intended (Green & Armstrong, 2012). Since the applicant 

submitted no evidence about the disclaimer’s independent effect on consumer understanding, I also 

recommend that the order require that the applicant conduct a postmarket study to provide FDA with 

evidence about the disclaimer. Such a study can provide evidence of whether the disclaimer helps 

enable consumers to understand that VLNTM cigarettes present the same disease risks as other cigarettes 

if smoked in the same way, or whether the disclaimer confuses people about the health risks of VLNTM 

cigarettes. 

Population health impact 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 16 of 90 

Regarding population health impact, the available scientific evidence demonstrates that the issuance of 

an exposure modification order for the proposed MRTPs would be appropriate to promote the public 

health and is expected to benefit the health of the population as a whole, taking into account both users 

of tobacco products and persons who do not currently use tobacco products. The social science review 

found that after viewing product labels with the exposure reduction claims, many current smokers were 

interested in VLNTM cigarettes (mean intentions were above the midpoint of the scale), and smokers had 

significantly higher intentions to purchase the proposed MRTPs compared to Marlboro Gold cigarettes. 

Current smokers also reported substantially higher intentions to use VLNTM cigarettes on a regular, 

ongoing basis compared to Marlboro GoldTM. Additionally, adult never smokers and former smokers had 

low intentions to buy and use VLNTM (mean intentions were near the bottom of the scale), and these 

intentions were similar to or slightly higher than their intentions to buy and use Marlboro Gold.TM 

Additionally, the epidemiology review evaluated the applicant’s population model estimating the public 

health impacts of the proposed MRTPs. The model assumes that the market share of conventional 

cigarettes (CC) and VLNTM will be equalized at around 25% by year 2050, meaning that approximately 

7.1% of CC smokers will initiate VLNTM smoking per year (i.e., if 7.1% of CC smokers switch to VLNTM 

cigarettes every year until 2050, then at least 25% of smokers will be using VLNTM cigarettes by 2050). 

Some model inputs were based on clinical studies; in a real-world setting, the uptake of VLNTM cigarettes 

among current smokers could be low. Thus, the projected benefits may be overestimated (e.g., high 

projected market share, dual users of CC and VLNTM cigarettes). Still, overall, epidemiology concluded 

that there are likely to be some benefits of smokers switching to VLNTM cigarettes and low uptake by 

nonusers. 

These findings are consistent with other reviews’ findings supporting a population health benefit: 

• The BCP review found that smokers who predominately used the proposed MRTPs significantly 

reduced their CPD over time, and the CPD of smokers assigned to switch to the proposed MRTPs 

was half that of smokers assigned to use UB-NNC cigarettes. Reviewers found that using the 

proposed MRTPs would be reasonably likely to reduce nicotine dependence. 

• The BCP review found that the proposed MRTPs have a low abuse liability, similar to NRT, 

reducing the risk that tobacco nonusers who initiate VLNTM use will have difficulty quitting the 

product. 

• The epidemiology and medical reviews found that a reduction in CPD of at least 50% is 

associated with a reduction in some tobacco-related diseases (e.g., lung cancer) but not others. 

Under section 911(g)(2)(A)(iii) of the FD&C Act, to issue an exposure modification order, FDA must find 

“that scientific evidence is not available and, using the best available scientific methods, cannot be made 

available without conducting long-term epidemiological studies for an application to meet the standards 

set forth in [section 911(g)(1)].” The available evidence is not sufficient to conclude that the applicant 

has demonstrated that the products, as actually used by consumers, will “significantly reduce harm and 

the risk of tobacco-related disease to individual tobacco users” and “benefit the health of the population 

as a whole.” There are no long-term epidemiological studies on cigarette consumption among VLNTM 

cigarette smokers and the CPD consumption evidence provided by the applicant was based on clinical 

studies where NNC smokers, with no intention to reduce their nicotine consumption nor quit smoking, 

were instructed to switch to use VLNTM cigarettes. It is not clear how well CPD findings from clinical 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 17 of 90 

studies will generalize to a real-world setting; they could be overestimates or underestimates. Thus, 

there are outstanding questions about the manner in which consumers will use VLN, and if individual 

tobacco users use VLN cigarettes in the same frequency and manner as conventional cigarettes, they will 

not significantly reduce harm and their risk of tobacco-related disease. In addition, while the applicantsponsored studies do not address biomarkers of potential harm (BOPH), one published study on the 

effect on BOPH of switching from conventional cigarettes to VLNC cigarettes was submitted (Hatsukami 

et al., 2019). This study did not identify robust changes between the study groups; therefore, no 

conclusions regarding the short- or long-term health risk of VLNTM cigarettes can be made based on the 

available BOPH data. In totality, conclusive scientific evidence to meet the standards set forth in section 

911(g)(1) is not available. 

However, it is reasonably likely that cigarette smokers who use VLN cigarettes will experience a 

reduction in nicotine dependence, which will also reduce tobacco dependence. Reductions in tobacco 

dependence can lead to increased tobacco cessation and are anticipated to lead to long-term reductions 

in exposure to the smoking-related toxicants associated with morbidity and mortality. Using the 

proposed MRTPs would be reasonably likely to reduce nicotine dependence and a reduction in CPD of at 

least 50% is associated with a reduction in some tobacco-related diseases (e.g., lung cancer), but not 

others, supporting a likely overall population health benefit. 

Additionally, the social science review describes some information suggesting that, depending on how 

VLNTM cigarettes are marketed, effects on youth may be limited. For example, youth cigarette smoking 

rates declined while Quest cigarettes were on the U.S. market and advertised as “low nicotine,” “extra 

low nicotine,” and “nicotine free.” Furthermore, one study found that after viewing ads for Quest, 

Marlboro cigarettes, and a heated tobacco product, college students rated Quest cigarettes as lowest on 

a scale of positive expectancies (e.g., “satisfying,” “fun”) that predicted willingness to try each product 

(O’Connor et al., 2007). However, given that youth are at increased risk, generally, for initiating tobacco 

use and the potential effect of modified risk information on youth use, it is critical that any marketing 

plans be designed to prioritize preventing youth exposure. Studies suggest that perceptions of risk 

predict tobacco product use among youth (Song et al., 2009) (Strong et al., 2019). FDA’s PMTA 

marketing authorization order for the products includes postmarket requirements to help ensure that 

youth exposure to tobacco marketing is being limited. This includes implementing plans to restrict youth 

access and limit youth exposure to the products’ labeling, advertising, marketing, and/or promotion, 

and requiring the applicant to track and measure actual delivery of all advertising impressions, including 

among youth. In addition, as described below, postmarket surveillance and studies should be 

conducted to monitor youth awareness and use of the proposed MRTPs to ensure that their marketing 

will not have the unintended consequence of leading to increased use of these products among youth. 

I recommend that this exposure modification order include both VLNTM King and VLNTM Menthol King 

combustible cigarettes. Although FDA announced in May 2021 that it would develop a proposed rule 

regarding menthol in cigarettes, menthol cigarettes are currently legal tobacco products in the 

marketplace and Moonlight Menthol cigarettes were previously found to be appropriate for the 

protection of public health (APPH) in that context. VLNTM Menthol King is identical to Moonlight 

Menthol, which was authorized under section 910 of the FD&C Act. FDA authorized the marketing of the 

Moonlight and Moonlight Menthol combustible cigarettes without modified risk claims on December 17, 

2019. This review has found that an exposure modification order for both products would be 

appropriate to promote public health and is expected to benefit the health of the population as a whole, 

including VLNTM Menthol King cigarettes, which will provide a reduced nicotine option for menthol NNC 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 18 of 90 

cigarette smokers. This recommendation considers the current marketplace without a rule regarding 

menthol cigarettes in effect; the previous authorization under section 910 of the FD&C Act for 

Moonlight Menthol cigarettes, which are identical to VLNTM Menthol King cigarettes; and the reduced 

nicotine option that an exposure modification order would provide for menthol cigarette smokers in the 

current marketplace. 

Section 911(g)(2)(C)(i) of the FD&C Act provides that an MRTP exposure modification order shall be 

limited for a term of not more than 5 years. I recommend authorization for a period of 5 years, given the 

low abuse liability of these products. Although this review has found that an exposure modification 

order for the products would be appropriate to promote the public health and is expected to benefit the 

health of the population as a whole, that determination may change over time as a function of how the 

products are actually used by consumers as well as how the marketplace changes. Therefore, 

monitoring use of the proposed MRTPs in terms of uptake, dual use, and complete switching should be 

required, including the potential for initiation among youth. As described below, postmarket 

surveillance and studies should be required in the order to include an assessment of MRTP users’ 

behavior and understanding over time. A 5-year period is a reasonable amount of time to assess 

whether there is appropriate consumer understanding and to generate preliminary data on behavior in 

postmarket surveillance and studies to assess whether the standard continues to be met and whether 

the order should be renewed. In addition, the order should require a study on the independent effects 

of the disclaimer; it is unclear whether the disclaimer benefits or reduces consumers’ ability to 

understand the risks of using the proposed MRTPs. 

II. Regulatory Information 

A. Regulatory History 

The following submissions from the applicant were received by FDA on the specified dates: 

• May 20, 2019: original MRTPAs. 

• May 23, 2019: an amendment containing updates to Section V. Labels, Labeling, and 

Advertising. 

• June 25, 2019: an amendment containing 12-month storage stability and water activity study 

results. 

• July 18, 2019: an amendment containing a new, 6-week clinical study sponsored by the 

applicant involving 140 subjects evaluating use behavior and biomarkers. 

• August 7, 2019: an amendment containing additional medical information on the serious 

adverse event experience in the 6-week clinical study. 

• August 28, 2019: an amendment containing clarification on the stimuli participants viewed in 

the study’s “VLNTM control” condition in the quantitative consumer perception M/A/R/C 

Research study. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 19 of 90 

• September 13, 2019: an amendment containing additional clarification on the “VLNTM control” 

condition in the quantitative consumer perception M/A/R/C Research study. 

• March 2, 2020: an amendment containing a tabular index of citations for the company’s 

MRTPAs. 

• March 10, 2020: an amendment submitting the applicant’s new tables VI.F-1, VIG-1, and VI.G-2 

for the Environmental Assessment for their MRTPAs. 

• February 5, 2021: an administrative amendment 

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

Under section 910 of the FD&C Act, the applicant requested authorization to market Moonlight and 

Moonlight Menthol1 combustible cigarettes without modified risk claims. FDA authorized the marketing 

of Moonlight and Moonlight Menthol1 combustible cigarettes without modified risk claims on 

December 17, 2019. The TPL review for the accompanying PMTAs provides detail on the engineering, 

chemistry, stability, and manufacturing of the products, including the results of FDA inspections of 

manufacturing sites, and is available at: https://www.fda.gov/tobacco-products/premarket-tobaccoproduct-applications/premarket-tobacco-product-marketing-orders. Where relevant, the present review 

reflects determinations made in the PMTA TPL review. 

The focus of this review of the MRTPAs is on the assessment of (1) the proposed modified risk claims, (2) 

relative health risks of the products, (3) consumer understanding, and (4) potential impact to the 

population from marketing the products with the proposed modified risk information. 

B. Proposed Modified Risk Tobacco Product 

1. Proposed Modified Risk Claims 

The applicant requested MRTP orders under section 911(g)(2) of the FD&C Act. The applicant proposed 

to disseminate the following three reduced exposure claims in the LLA for VLNTM cigarettes (Section V 

“Labels, Labeling, and Advertising,” p. 3): 

Exposure Modification Order Request Under 911(g)(2): 

• Claim #1: “95% less nicotine” 

• Claim #2: “Helps reduce your nicotine consumption” 

• Claim #3: “...greatly reduces your nicotine consumption.” 

In addition to disseminating this modified risk information on VLNTM cigarette packs, cartons, and cases, 

the applicant also proposed to disseminate this modified risk information in advertisements. The 

proposed advertising channels include a branded website, print ads, digital ads, direct mail, email, social 

media, brochures, point-of-sale ads, and earned media (Section V “VLNTM Marketing Outline,” p. 1). The 

applicant submitted screenshots of its draft website and examples of ads for each channel (Section V 
 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 20 of 90 

“VLNTM Marketing Outline,” pp. 3-41). FDA examined the applicant’s marketing examples and identified 

seven additional reduced exposure claims, in addition to Claims #1-3 described above: 

• Claim #4: “VLNTM cigarettes are substantially lower in nicotine content than any other cigarettes 

currently available to smokers in the United States. VLNTM cigarette contain an average of just 

0.27 mg of nicotine.” 

• Claim #5: “Without exception, VLNTM cigarettes contain at least 95% less nicotine than the top 

100 cigarette brands in the United States.” 

• Claim #6: “22nd Century’s VLNTM cigarettes contain an average of 0.27 mg nicotine - -at least 

95% less nicotine compared to conventional cigarettes.” 

• Claim #7: “22nd Century’s VLNTM cigarettes feature the same nicotine content as the lowest 

nicotine style of the Company’s SPECTRUM research cigarettes.” 

• Claim #8: “VLNTM cigarettes contain 0.27 ± 0.1 mg nicotine.” 

• Claim #9: “As a result of our unique technology and plant breeding expertise, VLNTM tobacco 

grows with 95% less nicotine than conventional tobacco.” 

• Claim #10: Several examples utilize a graph depicting nicotine levels of VLNTM cigarettes 

compared to several other cigarette brands. 

These statements appear to convey the same type of information as Claims #1-3. Specifically, the claims 

are limited to information about VLNTM cigarettes’ nicotine content and how it compares with that of 

other cigarettes, although some of the claims describe the nicotine content in absolute terms (e.g., “.27 

mg”), use qualitative comparisons (e.g., “substantially lower”), or include comparators (e.g., “the top 

100 cigarette brands”). 

The labels and most of the advertising also include the following disclaimer: “Nicotine is addictive. Less 

nicotine does NOT mean safer. All cigarettes can cause disease and death.” 

2. Description of Product 

The decision summary for the PMTA reviews of this product is included the product description below. 

The applicant’s VLNC tobacco was developed in 1998 and has been used for producing cigarettes under 

different names, including SPECTRUM and PARE. 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 content. 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 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 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 21 of 90 

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.” 

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

and reconstituted tobaccos, . 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) (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. The VLNTM cigarette tobacco products containing Vector 21-41 VLNTM

(b) (4)

 tobacco blend have a 

(b) (4)

target filler nicotine specification of mg/g of tobacco on a DWB, with an upper limit of mg/g and 

a per-cigarette target of 0.27 mg (± 0.10mg). The applicant reported that the tobacco nicotine content 

(b) (4)

of all 10 batches of the two new VLNTM cigarettes met a maximum nicotine specification o mg/g on a 

DWB. Furthermore, batch analysis of eight batches of VLNTM cigarettes shows a slightly higher nicotine 

content than the 0.27 mg/cig reported by the applicant. The measured average VLNTM nicotine content 

was 0.29 mg/cig. However, this is within the advertised nicotine content lower and upper limit of 0.27 ± 

0.10 mg/cig (0.17 and 0.37 mg/cig lower and upper limit). 

A more detailed description of the product by FDA, including ingredients, manufacturing process, FDA 

sample testing, and product stability information, can be found in the PMTA TPL review for the same 

products.6 

C. Tobacco Products Scientific Advisory Committee (TPSAC) 

Pursuant to section 911(f) of the FD&C Act, FDA referred the MRTPAs to TPSAC, and TPSAC reported its 

findings on the applications during an open public committee meeting held on February 14, 2020. At the 

meeting, the committee discussed the MRTPAs, including: consumer understanding of the labeling; the 

likelihood that reductions in dependence translate into reductions in morbidity and mortality; and 

likelihood of use among current, former, and never cigarette smokers. Information about the meeting, 

including the complete transcript, is available at: https://www.fda.gov/advisory-committees/tobaccoproducts-scientific-advisory-committee/2020-tpsac-meeting-materials-and-information 

FDA shared its preliminary assessment of the applications with the committee, focusing on: the scientific 

substantiation of the proposed modified risk claims; consumer understanding and perceptions of the 

proposed modified risk information; impact on morbidity and mortality; and impact on current cigarette 

smokers and nonsmokers. TPSAC was asked to discuss FDA’s preliminary assessment, including (1) the 

likelihood that reductions in dependence translate into substantial reductions in morbidities and 

6 https://www.fda.gov/tobacco-products/premarket-tobacco-product-applications/premarket-tobacco-productmarketing-orders
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 22 of 90 

mortality among individual tobacco users; (2) the extent to which never and former cigarette smokers 

are likely to try and progress to regularly using the proposed MRTPs; (3) the extent to which the 

cigarette smokers who do and do not want to quit will dual use the proposed MRTPs with their usual 

brand of cigarettes or exclusively use the proposed MRTPs; and (4) whether the labeling enables 

consumers to accurately understand the disease and addiction risks of using the products. A summary of 

TPSAC’s discussions, organized by these four topic areas, is presented below. FDA’s assessment of these 

discussions is included in Section III of this review, as well as in individual discipline reviews. 

1. The likelihood that reductions in dependence translate into substantial reductions in morbidities 

and mortality among individual tobacco users. 

TPSAC discussed questions about biomarkers and topographical data and whether enough data were 

available to substantially conclude that a reduction in dependence would then translate into a reduction 

in morbidity and mortality. 

One member said they thought that a reduction in smoking was likely to translate to a reduction in 

morbidity and mortality. Another member stated that there are actually two pathways to reduced 

morbidity and mortality: one is the reduction in cigarettes per day, and the other pathway is the 

reduction in dependence, which can lead to an increase in cessation. Another member noted that while 

there was a dose-response relationship for cancer, there was no such relationship for cardiovascular 

disease (CVD). Another agreed that not all morbidities would be reduced. I agree with their assessment; 

my assessment of the effects of using the product on morbidity and mortality can be found in Section 

(III)(B) of this review. 

The committee noted that the clinical studies on VLNC instructed participants to switch completely to 

VLNC cigarettes. Without instructions for VLNTM cigarette use, results obtained in these clinical studies 

are likely not representative of a situation in which individuals do not receive instructions for use. The 

committee recommended that information be added to VLNTM cigarettes to clarify that smokers should 

switch completely to the products in order to achieve results similar to those obtained in the clinical 

literature. The committee also discussed the dual use issue. While I agree there is some uncertainty in 

how clinical study findings will generalize to the real-world setting, I also note that dual use of VLNCs 

with UB-NNC was very common in clinical settings; smokers who did this, but predominately used 

VLNCs, were still able to benefit from using VLNCs. My discussion of this can be found in Section (III)(B) 

of this review. 

In summary, TPSAC discussed that there seemed to be some compelling information to make the 

inference that as dependence declines due to VLNC use, other things such as behavioral and 

physiological changes can follow, which may lead to some reductions in morbidities and likely lead to a 

reduction in mortality at the individual level. 

2. The extent to which never and former smokers are likely to try and progress to regularly using the 

proposed MRTPs. 

The committee expressed concerns about there being no evidence with testing or clinical data about use 

among young people. TPSAC members stated that they would like some kind of strategy developed to 

collect data from youth regarding these kinds of MRTPs, noting that there is a need for adolescent data, 

but that there are ethical issues with conducting this research. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 23 of 90 

The committee discussed the difference between trial and experimentation and progression to use. 

Although there are no direct data about product use among adolescents, there are data from adolescent 

models and other adult users to suggest that the lower nicotine products would not result in higher 

abuse liability among youth or adults, compared to normal nicotine level products. The committee felt 

that progression beyond initial trial to regular use of this product would be unlikely among never 

smokers, including youth. One committee member also stated that they thought former smokers would 

not be interested in the product and did not have concerns about relapse among them. Some TPSAC 

members noted that there is a lack of data and that more data are needed to draw conclusions on the 

likelihood of progression to either continued VLNTM or conventional cigarette use after experimentation 

with VLNTM cigarettes. I agree with the overall assessment that the likelihood of nonuser initiation is low 

and discuss this in Section (III)(D)(3). 

TPSAC expressed concerns regarding the advertising and imagery being appealing to youth. 

. There was discussion regarding the 

brand name of Moonlight and the committee mentioned that the word “light” has come up before in 

(b) (4)

previous meetings. FDA staff clarified that the application review is for products names VLNTM 

cigarettes, not Moonlight. 

3. The extent to which cigarette smokers (who do and do not want to quit) will dual use the proposed 

MRTPs with their usual brand of cigarettes or exclusively use the proposed MRTPs. 

TPSAC discussed how compliance might differ among smokers who do want to quit, noting that the 

committee members’ clinical studies on the topic did not look at this. TPSAC discussed that the 

probability of dual use is likely high in scenarios where both usual brand cigarettes and low nicotine 

content cigarettes are available. Dual use may occur for both smokers who want to quit and smokers 

who do not want to quit, and the extent of dual use may vary. TPSAC discussed that cigarette smokers 

who do not want to quit smoking may dual use VLNTM and usual brand cigarettes, believing that dual use 

may reduce their nicotine exposure and lower their health risks. They discussed that smokers who do 

want to quit may use the product on the road to quitting. 

TPSAC discussed that instruction of completely switching is missing, and if this information/instruction 

was provided, or clearer, it could potentially decrease dual use and cigarette-related diseases. 

While I agree that there is some uncertainty in how clinical study findings will generalize to the realworld setting, I also note that dual use of VLNCs with UB-NNC was very common in clinical settings. 

Smokers who did dual use, but predominately used VLNCs, were still able to benefit from using VLNCs. 

My discussion of this can be found in Section (III)(B) of this review. 

4. Whether the labeling enables consumers to accurately understand addiction and disease risks of 

using the products. 

Regarding addiction risk, TPSAC generally agreed that the labeling would enable consumers to 

understand the addiction risk from smoking VLNTM cigarettes. However, one member pointed out that 

addiction risk is different for everyone; that is, it’s not all equal. There are data to support this in genetic 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 24 of 90 

studies. Therefore, the response to nicotine and perceptions of risk will differ from individual to 

individual. 

Regarding disease risks, TPSAC discussed the applicant’s study results showing that U.S. adults rated 

VLNTM cigarettes as lower in disease risks compared to other cigarettes. FDA presented two alternative 

interpretations of these findings to TPSAC and asked for committee members’ perspectives on whether 

one of these interpretations was more likely to be correct than the other: (1) participants incorrectly 

rated VLNTM cigarettes as lower in disease risks than other cigarettes because participants believed the 

lower nicotine content would allow people to smoke VLNTM cigarettes in the same way as other 

cigarettes without incurring the same disease risks, or (2) participants correctly rated VLNTM cigarettes as 

lower in disease risks than other cigarettes because participants understood that, because of VLN’s 

lower addiction risk, people would smoke fewer VLNTM cigarettes or would smoke VLNTM for a shorter 

duration than other cigarettes, causing fewer diseases. TPSAC members stated that the first 

interpretation is more likely to be correct, because it is unlikely that participants thought through the 

products’ addictiveness (and the corresponding effects on use frequency and duration) when rating the 

disease risks of smoking VLNTM cigarettes. TPSAC members suggested that participants’ lower ratings of 

disease risk from VLNTM cigarettes could be attributed to widespread misperceptions of nicotine, and 

that the proposed VLNTM labeling would not enable consumers to understand the products’ disease risks. 

Three members noted issues with the disclaimer/ “voluntary warning” and the need for more research 

on this warning. One member said more research is needed on what might reduce misperception of 

disease risk, because the “voluntary warning” is not sufficient. Another said that the “voluntary 

warning” was problematic because it looks like a legal disclaimer and there was no evidence of its 

impact. Another said there was a need to test ways to communicate that the product is equally risky, 

such as several reasonable strategies tested with the most promising one selected. 

There was consensus on the importance of providing accurate, specific information to the public about 

nicotine content, and that there are important benefits to educating the public about nicotine. The 

committee also noted, though, that nicotine misperceptions are common and that no one product is 

likely to overcome all the existing misperceptions about risk. Most members agreed that information 

about the product being low nicotine should not be withheld. Generally, I agree with this assessment, 

and my evaluation of consumer understanding is presented and discussed in Section (III)(C) of this 

review. 

D. Public Availability of MRTPAs 

Pursuant to section 911(e) of the FD&C Act, FDA made the applicant’s MRTPAs available to the public 

(except matters in the applications that are trade secrets or are otherwise confidential, commercial 

information). The docket for public comment on the MRTPAs for 22nd Century’s VLNTM King, VLNTM 

Menthol King, Combusted, Filtered Cigarettes was open from July 25, 2019, to May 18, 2020. FDA 

received 226 unique public comments from individuals, academia, health professionals, state and local 

governments, and other organizations. In addition to legal and advocacy issues, the comments included 

perspectives on consumer understanding, concerns about a lack of youth data, critiques of the 

applicant’s studies and interpretation of findings, concerns about potential appeal to youth, and 

concerns about marketing and advertising strategies. Many of the issues and concerns raised in the 
MR0000159- MR0000160 Page 25 of 90 

public comments were also identified during FDA' s scientific review of the applications; these issues are 

presented and discussed in discipline reviews. FDA considered all significant comments when making 

the final determination. 

We note that some comments pertained to the brand name " Moonlight" for the product, which is the 

subject of the PMTAs authorized in December 2019. Because the proposed brand name for these 

applications is VLNTM, w e do not discuss or address these comments here or in discipline reviews. 

Ill. Summary of Scientific Evidence 

The applicant argues that the proposed MRTPs represent a less harmful alternative for current cigarette 

smokers by providing evidence that the product contains about 95% less nicotine compared to 

conventional cigarettes on the market. They also provide evidence from: analyses of mainstream smoke 

HPHCs; nonclinical studies from the literature; and applicant and peer-reviewed clinical studies assessing 

CPD and BOE over 6 to 20 weeks. This section assesses the evidence on the relative health risks to 

individual users, including assessment of the scientific accuracy of the modified risk information 

proposed to be communicated by the applicant to consumers. Subsequent sections of the review 

address consumer understanding and perceptions of the proposed modified risk information and the 

potential impact of the products on the population as a whole, including both current users and nonusers of tobacco. In our evaluation, we bridge evidence from SPECTRUM NRC 102/ 103 to the proposed 

MRTPs. 

Throughout this section, I note w hen evidence provides support for specific proposed modified risk 

claims. Below is a table summarizing where supporting evidence can be found for each of the applicantrequested Claims (#1-3) and additional FDA identified Claims (#4-10). 

Claim Section of this review with substantiation information 

Claim #1: "95% less nicot ine" -Sect ion {lll)(B)(l ) Nicotine content on a dry weight basis 

-Sect ion (111 )(8)(2)(8) ISO and Cl HPHC data 

-Sect ion (lll)(B)(3)(a) Nicot ine BOE 

Claim #2: "Helps reduce your nicotine consumption" -Sect ion (111 )(8)(2)(8) ISO and Cl HPHC data 

-Sect ion (lll)(B)(3)(a) Nicot ine BOE 

Claim #3: " ... great ly reduces your nicotine 

consumption." 

-Sect ion (111 )(8)(2)(8) ISO and Cl HPHC data 

-Sect ion (lll)(B)(3)(a) Nicot ine BOE 

Claim #4: "VLNTM cigarettes a re substant ially lower in 

nicot ine content t han any other cigarettes currently 

available to smoke rs in the United States. VLNTM 

cigarett e contain a n average of just 0.27 mg of 

nicot ine." 

-Sect ion (111 )(8)(1) Nicotine content on a dry weight basis 

Claim #5: "Without exception, VLNTM cigarett es contain 

at least 95% less nicotine t han t he top 100 cigarett e 

brands in t he United States." 

-Sect ion (111 )(8)(1) Nicotine content on a dry weight basis 
MR0000159- MR0000160 Page 26 of 90 

Claim #6: “22nd Century’s VLNTM cigarettes contain an 

average of 0.27 mg nicotine - -at least 95% less nicotine 

compared to conventional cigarettes.” 

-Section (III)(B)(1) Nicotine content on a dry weight basis 

Claim #7: “22nd Century’s VLNTM cigarettes feature the 

same nicotine content as the lowest nicotine style of 

the Company’s SPECTRUM research cigarettes.” 

-Section (III)(A) Bridging from SPECTRUM NRC102/103 

research cigarettes to VLNTM Cigarettes 

Claim #8: “VLNTM cigarettes contain 0.27 ± 0.1 mg 

nicotine.” 

-Section (III)(B)(1) Nicotine content on a dry weight basis 

Claim #9: “As a result of our unique technology and 

plant breeding expertise, VLNTM tobacco grows with 

95% less nicotine than conventional tobacco.” 

-Section (III)(B)(1) Nicotine content on a dry weight basis 

Claim #10: Graphs depicting nicotine levels of VLNTM 

cigarettes compared to several other cigarette brands. 

-Section (III)(B)(1) Nicotine content on a dry weight basis 
 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 27 of 90 

A. Bridging from SPECTRUM NRC102/103 research cigarettes to VLNTM 

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. Like 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 DWB. 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

(b) (4)

 tipping paper does not have 

(b) (4)

any markings. The base tipping paper for both tobacco products has the same porosity CU) and is 

produced by the same manufacturer, . The slight difference in tobacco weight (<2%) is not 

expected to significantly affect smoke deliveries. Ventilation levels appeared different in testing: 30% for 

SPECTRUM and 12.5% (target level) for VLNTM cigarettes. 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 applicantprovided 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 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 tar, 

nicotine, and carbon monoxide (TNCO) deliveries, which are the main product performance attributes. 
 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 28 of 90 

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 a 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 mainstream smoke HPHCs, 

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

Menthol King cigarettes. In this review, the terms SPECTRUM NRC102/103 cigarettes and VLNC 

cigarettes are used interchangeably. 

This evidence supports Claim #7, “22nd Century’s VLNTM cigarettes feature the same nicotine content 

as the lowest nicotine style of the Company’s SPECTRUM research cigarettes.” 

B. Relative Health Risks of the Proposed MRTPs to Individual Tobacco Users 

In my evaluation of health risks to individual tobacco users, I also evaluated several lines of evidence for 

whether they supported the applicants’ statements in the applications related to: (1) nicotine content; 

(2) HPHCs; (3) BOE and the toxicology assessment; and (4) clinical studies examining dependence, abuse 

liability, CPD, and adverse health effects. 

1. Nicotine content on a dry weight basis (DWB) 

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. The VLNTM cigarette tobacco products containing Vector 21-41 VLNTM tobacco blend have a 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 29 of 90 

target filler nicotine specification of 

(b) (4)

 mg/g of tobacco on a DWB, with an upper limit of

(b) (4)

 mg/g and 

a per-cigarette target of 0.27 mg (± 0.10mg). 

The applicant provided a survey of 100 top-selling cigarette brands that represent 87% of all cigarettes 

sold in the U.S. through convenience stores in 2017. See Section VIIIB-1ii of the MRTPAs for a 

description of these 100 cigarette brands. These 100 cigarettes contain a reported average of 19.4 mg 

nicotine per gram of tobacco on a DWB, and a reported average of 12.0 mg nicotine per cigarette. The 

applicant reported that tobacco nicotine content of all 10 batches of the two new VLNTM 

(b) (4)

cigarettes met 

their maximum nicotine specification of mg/g on a DWB, and 0.27mg ± 0.10 nicotine per cigarette. 

Accordingly, the reported nicotine contents of the VLNTM cigarettes are 98% lower than the average 

reported nicotine contents of the top 100 cigarette brands determined both per gram of tobacco and 

per cigarette. 

The applicant also compared the two new VLNTM cigarettes to the four top-selling king-sized regular 

cigarette brands and two top-selling king-sized mentholated cigarette brands. These cigarette brands, 

whose unit sales rank is shown in parentheses, are Marlboro Gold King (1), Marlboro Red King (2), 

Newport Menthol Green King (4), Marlboro Special Blend Gold King (5), Camel Blue King (8), and 

Marlboro Menthol Gold King (17). The six top-selling king-sized cigarette brands contain a reported 

average tobacco filler nicotine content of 18.8 mg/g on a DWB and a reported average of 11.0 mg 

nicotine per cigarette. The applicant reported tobacco nicotine content of all 10 batches of the two new 

(b) (4)

VLNTM cigarettes met their maximum nicotine specification of mg/g on a DWB and 0.27 mg nicotine 

per cigarette. Thus, the reported nicotine contents of the VLNTM cigarettes are at least 97% lower than 

the average nicotine contents of the top six king-sized cigarette brands determined both per gram of 

tobacco and per cigarette. 

Overall, this information provides support for the required finding in 911(g)(2)(B)(i) that “the 

magnitude of the overall reductions in exposure to the substance or substances which are the subject 

of the application is substantial, such substance or substances are harmful, and the product as 

actually used exposes consumers to the specified reduced level of the substance or substances”; and 

also provides support for Claim #1 and Claims #4-10 regarding the nicotine content of the proposed 

MRTPs. 

2. Harmful and Potentially Harmful Constituents (HPHCs) and Toxicology 

Evaluation 

a. General Overview 

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

cigarette mainstream smoke under both International Organization for Standardization (ISO) and 

Canadian Intense (CI) machine smoking regimens (Chen et al., 2014). 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 for 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 
 

 

 

 

 

 

 

 

 

 

 

 

MR0000159- MR0000160 Page 30 of 90 

analytical equivalence. For the TOST equivalence test, the recommended important analytical 

differences are 10% for tar and CO, 15% for nicotine and 20% for other HPHCs.7 

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 ISO regimen smoke yields of acrylonitrile, 4-aminobiphenyl and ammonia are higher for VLNTM 

King cigarettes, whereas acrylonitrile, 4-aminobiphenyl, ammonia, and benzene yield are higher for 

VLNTM Menthol King cigarettes. In addition, available CI regimen smoke yields of acrylonitrile, 

acetaldehyde, and ammonia are higher for both VLNTM cigarettes. As discussed below, toxicology 

evaluated all provided HPHCs relative to the six conventional cigarette comparison products, and 

concluded that, “net HPHC exposure from VLNTM cigarettes is similar or lower relative to the comparison 

products”. While some individual HPHC yields from VLNTM cigarettes are higher relative to the 

comparison products, the net effect of HPHC changes, specifically the net impact of the lower HPHC 

yields, translates to similar or lower risks in using VLNTM cigarettes relative to the comparison products 

and therefore conventional cigarettes more broadly. This evaluation provides information about the 

individual health effects of using the proposed MRTPs, as well as substantiation of claims related to 

nicotine content. 

b. ISO and CI Regimen HPHC Data and Toxicology’s Qualitative Assessment 

ISO regimen data and qualitative assessment 

Per the applicant’s submitted ISO regimen HPHC data and Chemistry’s TOST analysis, in comparison to 

the average of the six commercially marketed NNC cigarette comparators, the two VLNTM cigarettes have 

nonequivalent 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. 

Specifically, nicotine content is 97% lower in the proposed MRTPs compared to the six comparator 

products. This information provides support for Claim #1, “95% less nicotine.” Reported yields of other 

HPHCs including menthol are equivalent. However, reported smoke yields of acrylonitrile, 4-

aminobiphenyl and ammonia are higher and not equivalent for both VLNTM cigarettes, whereas benzene 

yield is higher and not equivalent only for VLNTM Menthol King. 

In both ISO comparisons, acrylonitrile is higher (49% and 55% respectively), 4-aminobiphenyl is higher 

(21% and 19% respectively) and ammonia is higher (120% and 150% respectively). The applicant states 

that the significantly higher levels of 4-aminobiphenyl and ammonia are expected side effects of the 

genetic engineering of the VLNTM burley 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 lower, while 4-aminobiphenyl and ammonia are higher. 

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

differences in design features that may impact mainstream smoke HPHC levels and comparisons. 

7 Division of Product Science Memorandum “Equivalence Testing for SE Evaluations” 
MR0000159- MR0000160 Page 31 of 90 

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 mainstream smoke 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). 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 appear 

to be 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. Specifically, in describing exposure variables and 

assumptions in the 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 

application, 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 changes (i.e., relatively higher and lower HPHC yields) can be 

assessed, in part, based on the carcinogenic and noncarcinogenic effects of each HPHC, the number of

lower HPHCs that occur concurrently with higher HPHCs, and the magnitude and potency or effect level 

of the HPHCs. Qualitative evaluation of relative HPHC changes 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 assumed to be the same between the VLNTM cigarettes and the commercially 

marketed NNC cigarette comparators. This is a conservative approach, given the applicant’s submission 

of two key studies demonstrating a decrease in CPD in users that acutely and completely switch to 

SPECTRUM NRC102/103 cigarettes, which are nearly identical to the VLNTM cigarettes. Regarding cancer 

outcomes, the toxicology review noted that higher levels of 4-aminobiphenyl, acrylonitrile, and benzene 

via the ISO regimen likely do not raise cancer-risk-related concerns for the VLNTM cigarettes. Overall, 

based on these ISO regimen HPHC data, cancer risks are likely similar with use of VLNTM cigarettes and 

use of the commercially marketed NNC cigarette comparators. Regarding noncancer outcomes, the 

higher levels of 4-aminobiphenyl, acrylonitrile, ammonia, and benzene via the ISO regimen likely do not 

raise noncancer-hazard-related concerns for the VLNTM cigarettes. For example, any increase in 

respiratory effects due to ammonia and acrylonitrile or increases in cardiovascular effects or 

reproductive/developmental effects due to benzene, are offset by other HPHCs that are relatively lower 

and broadly target the respiratory tract, cardiovascular system, and reproductive/ developmental 

processes. Specifically, these relatively higher level HPHCs occur concurrently with relatively lower levels 

of the respiratory irritants: formaldehyde, 1,3-butadiene, and acrolein, that offset the increased 

respiratory hazards due to the higher levels of ammonia and acrylonitrile. Similarly, the increase in 

cardiovascular and reproductive/developmental effects due to higher levels of benzene tends to be 

offset by lower levels of nicotine and 1,3 butadiene respectively, although there is some uncertainty 

given available data used to develop the associated reference values. Overall, based on the ISO 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. 
MR0000159- MR0000160 Page 32 of 90 

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. 

CI regimen data and qualitative assessment

The applicant did not test the 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. With respect to 

nicotine, the reported nicotine smoke yields for the VLNTM cigarettes are 97% lower than the average 

reported nicotine smoke yield of the six market-leading king size comparator NNC cigarettes. This 

information provides support for Claim #1, “95% less nicotine,” and Claims #2 and 3 regarding reduced 

nicotine consumption. In addition, there are substantially higher amounts of ammonia in both VLNTM 

cigarettes; there are also moderately higher amounts of 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 are 

higher levels of ammonia (420% and 490% respectively) as well as acrylonitrile (43% and 44% 

respectively) and acetaldehyde (33% and 33% respectively). The higher level of ammonia is consistent 

with the ISO results and likely expected, as stated by the applicant, given its hypothesis around the 

anticipated increases in nitrogen assimilation that still occur despite genetic modification of the nicotine 

biosynthesis pathway. 

The higher levels of both acrylonitrile and acetaldehyde are consistent with previous reports 

demonstrating that these HPHCs mainly occur in the gas phase of mainstream smoke, 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 (Cheah et al., 2018; 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 its product compared with the average of the 

six 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 cigarettes may be an artifact of the 

number of comparator products tested. When compared with the acetaldehyde values found in the 

FDA50, an analysis of 50 popular cigarettes in 2011, conducted by CTP and CDC, there is 6% less 

acetaldehyde in the VLNTM cigarettes measured under the CI regimen. This is in line with the 
MR0000159- MR0000160 Page 33 of 90 

comparisons of the ISO regimen values comparing the VLNTM cigarettes with both the six comparator 

products provided by the company and with the FDA50. Therefore, the 33% higher levels of 

acetaldehyde found by the applicant in its comparison is not a concern, specifically because of the net 

HPHC changes indicated for these products that are lower than the comparison products. 

Any assumptions pertaining to the discussion of 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 the toxicology review. 

Regarding cancer outcomes, the toxicology review noted that higher levels of 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. Regarding noncancer outcomes,

higher levels of acetaldehyde, acrylonitrile, and ammonia via the CI 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 are offset by other HPHCs that are relatively 

lower and broadly target the respiratory tract. Specifically, these relatively higher level HPHCs occur 

concurrently with relatively lower levels of the respiratory irritants: formaldehyde, 1,3-butadiene, and 

acrolein that offset the increased respiratory hazards due to higher levels of 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. 

This information provides support for the required finding under 911(g)(2)(B)(ii) that “the product as 

actually used by consumers will not expose them to higher levels of other harmful substances compared 

to the similar types of tobacco products then on the market unless such increases are minimal and the 

reasonably likely overall impact of use of the product remains a substantial and measurable reduction in 

overall morbidity and mortality among individual tobacco users”. In summary, toxicology’s qualitative 

HPHC evaluation indicates that although there are likely higher exposures to some specific constituents, 

these higher levels do not appear to impact the overall relative product risks and hazards, given that 

other constituents associated with similar adverse health outcomes are lower in the VLNTM products 

compared to conventional cigarettes. The overall health risks and hazards are likely similar or lower in 

the VLNTM cigarettes versus the comparison products selected by the applicant. 

c. Toxicology assessment of applicant-submitted Quantitative Risk 

Assessment (QRA)

This section summarizes the toxicological studies provided by the applicant to compare the relative 

toxicity between VLNTM cigarettes and combusted cigarettes. This assessment focuses on non-nicotine 

mainstream smoke substances (e.g., added ingredients, HPHCs) and whether they raise toxicological 
MR0000159- MR0000160 Page 34 of 90 

concerns related to Section 911(g)(2)(B)(ii).

8 A summary of these studies and conclusions is presented

below. More detailed description and analysis can be found in the toxicology review.

For the applicant-submitted quantitative risk assessment, the VLNTM cigarettes are assumed to be used 

in the same manner as the comparison products. As such, any differences identified by the applicant in 

the submitted QRA simply reflect the differences in HPHC yields (i.e., not impacts due to differences in 

CPD or puffing behavior). The toxicology analysis focused on the HPHC yields, potencies, and 

magnitudes, concluding that the impact of the higher level HPHC yields for certain constituents were 

likely not a concern, given the lower level HPHC yields for other constituents with similar associated 

adverse health effects.

The ISO regimen HPHC data and associated HPHC evaluation discussed in this review tend to support the 

applicant’s QRA conclusions, which are that noncancer hazards and cancer risks are likely similar or

lower for users of VLNTM cigarettes compared to those for users of the comparison products. The CI

regimen HPHC data and the associated HPHC evaluation likely demonstrate that the noncancer hazards 

and cancer risks are similar, but the applicant did not submit a separate QRA to support any health riskrelated conclusions based on the CI regimen HPHC data. Importantly, the applicant did not include

details concerning the uncertainty associated with the reference toxicity values, specifically how they

pertain to the potency, effect level, or magnitude of individual HPHC contributions to the total risk or 

hazard. In particular, the applicant likely overestimated the impact of tobacco-specific nitrosamine 

(TSNA) reductions in reducing overall cancer risk, in part by extending the NNN cancer reference value 

to N-nitrosoanabasine (NAB), which is likely less carcinogenic than NNN (Edwards et al., 2017). While the 

concept of extending the same reference value to another HPHC could be a conservative approach, in 

this case NAB was lower, meaning that in the aggregate, the applicant’s estimated risk due to NAB may 

have inappropriately contributed to an overestimation of potential total cancer risk reductions. 

Nonetheless, from a toxicology perspective, the combined hazards and risks are likely similar.

d. Evaluation of literature review

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

) 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.

e. Evaluation of nonclinical studies 

The applicant submitted summarizing details of eight nonclinical studies, including one that used 

SPECTRUM® research cigarettes13 and seven that used QUEST cigarettes. Although QUEST cigarettes, as 

stated by the applicant, contain VLNC tobacco, virtually every other parameter, including the tobacco 

8 Tobacco Control Act section 911(g)(2)(B)(ii): “[T]he product as actually used by consumers will not expose them 

to higher levels of other harmful substances compared to the similar types of tobacco products then on the market 

unless such increases are minimal and the reasonably likely overall impact of use of the product remains a 

substantial and measurable reduction in overall morbidity and mortality among individual tobacco users.”

(b)(4) (b)(4)
MR0000159- MR0000160 Page 35 of 90 

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

associated studies can be extrapolated to the VLNTM cigarettes. 

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 FDA’s evaluation that finds that 

the overall health risks and hazards are likely similar or lower in the VLNTM cigarettes versus the 

comparison products selected by the applicant.

f. Summary and conclusion

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. Below I 

summarize toxicology’s key findings:

• Toxicology’s evaluation assumed the proposed MRTPs and comparator cigarettes would be used 

in the same way. This is a conservative approach, given that clinical studies indicate a reduction 

in CPD for smokers who predominantly use the proposed MRTPs. 

• Toxicology conducted a qualitative HPHC evaluation, based on ISO and CI regimens for assessing 

mainstream smoke. Findings indicate that although there are likely higher exposures to some 

specific constituents, these higher levels do not appear to impact the overall relative product 

risks and hazards, given that other constituents associated with similar adverse health outcomes 

are lower in the VLNTM products compared to conventional cigarettes. Thus, the overall health 

risks and hazards are likely similar or lower in the VLNTM cigarettes (on a per cigarette basis) 

versus the comparison products selected by the applicant.

• Toxicology evaluated the applicant’s QRA. The ISO regimen HPHC data and associated HPHC 

evaluation discussed in this review tend to support the applicant’s QRA conclusions, which are 

that noncancer hazards and cancer risks are likely similar or lower for users of VLNTM cigarettes 

compared to those for users of the comparison products. The CI regimen HPHC data and the 

associated HPHC evaluation likely demonstrate that the noncancer hazards and cancer risks are 

similar, but the applicant did not submit a separate QRA to support any health risk-related 

conclusions based on the CI regimen HPHC data. Nonetheless, the overall toxicant risk to users is 

likely similar or lower than the toxicant risk for users of the six comparator cigarettes currently 

on the market.

• The applicant conducted a literature review, and FDA identified one relevant nonclinical study of 

SPECTRUM VLNTM cigarettes (Naik et al., 2015). This study found that the toxicity of the 

SPECTRUM® cigarettes was equivalent to that of 3R4F cigarettes. These results are consistent 

with toxicology’s other findings. 

• In conclusion, net HPHC exposure from VLNTM cigarettes is similar or lower relative to the 

comparison products selected by the applicant. While some individual HPHC yields from VLNTM 

cigarettes are higher relative to the comparison products, the net effect of HPHC changes, 

specifically the net impact of the lower HPHC yields, translates to similar or lower risks in using 
MR0000159- MR0000160 Page 36 of 90 

VLNTM cigarettes relative to the comparison products and therefore conventional cigarettes 

more broadly. 

As TPL, I agree with the toxicology review findings. This information provides support for the finding 

under 911(g)(2)(B)(ii) that “the product as actually used by consumers will not expose them to higher 

levels of other harmful substances compared to the similar types of tobacco products then on the 

market unless such increases are minimal and the reasonably likely overall impact of use of the product 

remains a substantial and measurable reduction in overall morbidity and mortality among individual 

tobacco users”. 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, if used in the same way. The net impact of the 

lower HPHC yields, translates to similar or lower risks in using VLNTM cigarettes relative to comparison 

products or conventional cigarettes; therefore, from a toxicological perspective, there would also be the 

potential for a relative benefit compared to NNC cigarettes for. smokers who switch completely to VLNTM 

cigarettes; use VLNTM cigarettes to reduce their NNC cigarette use; and/or use VLNTM cigarettes to totally 

quit smoking. 

 

Clinical Assessment: Biomarkers of Exposure

In this section, we review clinical studies from the applicant and the literature to examine BOEs resulting

from using the proposed MRTPs. We also describe findings from one study in the literature examining 

biomarkers of potential harm (BOPH). More detailed description and analysis can be found in the 

medical, epidemiology, and BCP reviews.

a. Nicotine BOE

BCP 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 total nicotine 

equivalents (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 6 

compared to baseline were not significant in the VLNTM King).

Exclusive use of the proposed MRTPs

The applicant’s submitted abuse liability studies support that controlled and ad libitum use of VLNTM 

cigarettes in a confined setting results in approximately 97% lower plasma nicotine levels compared to 

smoking UB-NNC cigarettes. Similarly, Kamens et al. (2019) found that plasma nicotine levels were 

reduced by 94% in adult smokers following ad libitum use of one SPECTRUM non-menthol VLNC 

cigarette compared to smoking a UB-NNC cigarette. A study from the literature using SPECTRUM VLNC 

cigarettes found that when consumers exclusively switched to smoking VLNC cigarettes and had no 

access to other tobacco products for five days, there was a 94% reduction in urinary TNE compared to 

baseline measurements of participants’ UB-NNC cigarettes (Denlinger et al., 2016). These data support 
MR0000159- MR0000160 Page 37 of 90 

that use of VLNTM cigarettes instead of conventional cigarettes can lead to an approximate 95% 

reduction in exposure to nicotine in smokers, providing additional support for Claim #1 (“95% less 

nicotine”). This evidence demonstrates that Claim #1 is substantiated, whether “95% less nicotine” 

refers to the product itself containing 95% less nicotine (see Section III(B)(1) of this review), or to the 

fact that users would be exposed to 95% less nicotine if they use it to completely replace their use of 

conventional cigarettes. The only meaning of the claim that wouldn’t be substantiated is one that 

implies a 95% reduction in nicotine exposure during concomitant use with other nicotine containing 

products. However, this does not raise concerns because such an interpretation is unlikely. See related

discussion in the Social Science review regarding whether consumers would understand the extent of 

their nicotine reduction from dual using VLNTM with other tobacco or nicotine products. In their review, 

Social Science evaluated the possibility that smokers may incorrectly believe that, by using VLNTM, they 

would reduce their nicotine consumption by 95% even if they kept smoking their usual brand cigarettes 

in addition to smoking VLNTM. The applicant’s qualitative consumer research allowed participants to 

speak about their interpretations of the proposed claims, and participants’ statements suggested that 

they generally understood that “95% less nicotine” refers to the nicotine content of VLNTM cigarettes 

themselves, rather than users’ overall nicotine consumption, which would also depend on their use of 

other nicotine-containing products (see Section 4.1 of the Social Science review for additional details). 

We would also like to note that the “95% less nicotine” refers specifically to the content of VLNTM 

cigarettes themselves; whereas the dual use findings of reduced nicotine are about overall exposure; 

which, although not reduced by 95% in a dual use scenario, still provides substantially reduced nicotine 

exposure varying by the type, duration, and frequency of other products used. These findings support 

the finding under 911(g)(2)(B)(i) that “the magnitude of the overall reductions in exposure to the 

substance or substances which are the subject of the application is substantial, such substance or 

substances are harmful, and the product as actually used exposes consumers to the specified reduced 

level of the substance or substances”. Therefore, these findings support substantiation, understanding, 

and interpretation among consumers that Claim #1 (“95% less nicotine”) refers to the nicotine content 

of VLNTM cigarettes themselves, rather than users’ overall nicotine consumption. Additionally, these 

findings provide support that using the proposed MRTPs reduce nicotine consumption, providing 

support for Claims #2 (“helps reduce your nicotine consumption”) and #3 (“... greatly reduces your 

nicotine consumption”).

Dual use of the proposed MRTPs with other tobacco and nicotine products

Studies from the literature review note that non-compliance with exclusive VLNC cigarette smoking is 

observed in most participants (76-78%). Most participants instructed to switch completely to VLNCs still 

use non-study cigarettes (approximately 1-2 CPD). 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 

would be reasonably likely to experience the effects of reduced dependence on nicotine. 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. 

Therefore, dual use would not expose smokers to nicotine levels greater than smoking only UB-NNC 

cigarettes. 

Additionally, 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 
MR0000159- MR0000160 Page 38 of 90 

cigarettesfor the benefits of reduced nicotine exposure may dually 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. 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). 

As such, dual use of VLNTM cigarettes with other tobacco or nicotine-containing products (e.g., UB-NNC 

cigarettes, ENDS, NRT) is likely to occur in the open marketplace. When considering the range of nonstudy cigarette use across the sample of participants assigned to smoke VLNTM cigarettes (i.e., the 

number of UB cigarettes smoked during the course of the study in addition to VLNTM cigarettes), the 

applicant’s 6-week actual use study found that urinary TNE was reduced by averages of 48% and 58% in 

participants who switched from UB-NNC cigarettes to VLNTM King and Menthol King cigarettes, 

respectively. Findings from the literature indicate that after 6 and 20 weeks of smoking VLNC cigarettes, 

accounting for non-compliance, urinary TNE was reduced by an average of 59-60% in participants who 

switched from UB-NNC cigarettes (Hatsukami et al., 2018; Nardone et al., 2016). 

Therefore, as consumers dual use the product (i.e., occasional dual use with UB-NNC cigarettes or other 

tobacco or nicotine-containing products), nicotine exposure is still substantially reduced in consumers 

who dual use VLNTM cigarettes with UB-NNC cigarettes or other tobacco or nicotine-containing products

(e.g., NRT, ENDS). These findings provide additional support that using the proposed MRTPs, even 

along with UB-NNC cigarettes, reduce nicotine consumption, providing support for Claims #2 (“helps 

reduce your nicotine consumption”) and #3 (“... greatly reduces your nicotine consumption”).

The 22nd Century-sponsored studies do not address BOPH; however, the applicant submitted one 

published study on the effect on BOPH of switching from conventional cigarettes to VLNC cigarettes 

(Hatsukami et al., 2019). This study evaluated changes in biomarkers of inflammation and oxidative 

stress and hematologic parameters. No robust changes were identified between the study groups. No 

conclusions regarding the short- or long-term health risk of VLNTM cigarettes can be made based on the 

available BOPH data. Therefore, these findings provide further support for the required determination

in 911(g)(2)(A)(iii), which states that “scientific evidence is not available and, using the best available 

scientific methods, cannot be made available without conducting long-term epidemiological studies for 

an application to meet the standards set forth [section 911(g)(1)]”. 

A presentation from the 2019 Society for Research on Nicotine and Tobacco (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. 
MR0000159- MR0000160 Page 39 of 90 

b. Non-Nicotine HPHC BOE

Exclusive use

Epidemiology and BCP reviewed the Clinical Study Report on BOE of NNC smokers before, during, and 

after switching from UB to VLNTM cigarettes for the 6-week study. Epidemiology and BCP also evaluated 

the BOE results from the Hatsukami et al. (2018), which is a 20-week clinical study that assessed the 

effects of immediate and gradual reduction in nicotine content of cigarettes compared with NNC 

smokers. All tests in Hatsukami et al. (2018) and the 6-week study were 2-sided.

Hatsukami et al. (2018) found that those who were in the immediate reduction group had significantly 

lower levels of CO, 3-HPMA, PheT, total NNAL, CEMA, HMPMA, SPMA, and 2-HPMA compared to NNC 

smokers. Smokers assigned to immediately switch to VLNTM cigarettes had significant reduction in TNE 

compared to the control group. Smokers assigned to immediately switch to VLNTM cigarettes also had a 

significantly lower level of NNAL compared to the control group. 

In the applicant’s 6-week study, the applicant assessed the within-group comparison of changes of 

biomarkers from baseline, which generally showed a significant decrease in exposure by Week 6. 

Epidemiology confirmed that there was a significant decrease in urinary Tneq in smokers who switched 

to VLNTM cigarettes in both the intent to treat (ITT) and per protocol (PP) populations for the 6-week 

study compared to the baseline. In the PP population, urinary NNAL and 1-HOP were significantly lower 

in those who switched to VLNTM cigarettes. 

These reductions in BOE were also observed in VLNTM cigarette smokers who did not reduce their CPD, 

although to a lesser extent than in smokers who did reduce CPD. Smokers who reduce their CPD when 

switching to VLNTM cigarettes experience the greatest reductions in exposure to non-nicotine HPHCs and 

reduce exposure to a wider range of HPHCs. Studies indicate that dual use is not anticipated to increase 

overall exposure to non-nicotine HPHCs compared to exclusive UB-NNC cigarette smoking. These 

findings also provide support for the required finding under 911(g)(2)(B)(ii) that “the product as actually 

used by consumers will not expose them to higher levels of other harmful substances compared to the 

similar types of tobacco products then on the market unless such increases are minimal and the 

reasonably likely overall impact of use of the product remains a substantial and measurable reduction in 

overall morbidity and mortality among individual tobacco users”. 

Dual use of the proposed MRTPs with other tobacco and nicotine products

Studies from the literature review note that non-compliance with exclusive VLNC cigarette smoking is 

observed in most participants (76-78%). Based on the applicant’s 6-week study and the literature, if 

smokers primarily smoke VLNTM cigarettes and occasionally dual use with UB-NNC cigarettes, smokers 

would still be exposed to lower levels of some non-nicotine HPHCs compared to exclusively smoking UBNNC cigarettes; however, it is expected that reductions would be smaller compared to those who 

completely switch. For example, in one 6-week study (Nardone et al., 2016), NNAL levels for participants 

were reduced, but not significantly. Lower levels of total NNAL and NNN have also been observed over 8 

weeks in participants who used VLNC with non-combusted products compared to NNC cigarettes. 

Additionally, dual use is not anticipated to increase their overall exposure to non-nicotine HPHCs 

compared to UB-NNC cigarette smoking. 
MR0000159- MR0000160 Page 40 of 90 

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. 

c. Summary and conclusion

Below I summarize key BCP and epidemiology findings related to nicotine and non-nicotine biomarkers 

of exposure:

• Abuse liability studies from the applicant and the literature find that BOEs indicate nicotine 

exposure is reduced by about 95% with exclusive use of VLNTM or VLNC cigarettes. This provides

support for one meaning of Claim #1 (“95% less nicotine”)—that using the proposed MRTPs is 

associated with a 95% reduction in nicotine exposure. It also provides support for Claims #2 and 

3 regarding reduced nicotine consumption. In the applicant’s 6-week actual use study and the 

20-week study, noncompliance was high—most smokers (76-78%) used about 1-2 CPD of UBNNC cigarettes (Hatsukami et al., 2018). Among these dual users of the VLNTM or VLNC cigarettes 

and NNC cigarettes, nicotine BOEs are still reduced by at least half.

• Additionally, the BOE results of the applicant’s 6-week study and the 20-week study (Hatsukami 

et al., 2018) demonstrated significant reductions in some other non-nicotine HPHCs among 

smokers who were instructed to switch to VLNC or VLNTM cigarettes compared to NNC smokers. 

This was the case even for smokers who did not reduce their CPD.

• The applicant provided limited information about BOPH. While decreases in BOE were found, 

the extent to which these decreases affect clinical outcomes cannot be determined from the 

clinical studies. Therefore, based on the available BOPH data, no conclusions can be drawn 

about the long-term health effects associated with VLNTM cigarette use. 

As TPL, I agree with the BCP and epidemiology findings. Based on the available data, exclusive use of 

the product results in about a 95% reduction in nicotine exposure, and even dual use of the product 

with NNC cigarettes results in a reduction in nicotine consumption. This provides support for Claims #1-3 

and for the required finding in section 911(g)(2)(B)(i) of the FD&C Act. Additionally, using the proposed 

VLNCs is associated with a reduction in several non-nicotine BOEs, even among smokers who did not 

reduce their CPD. This provides support for the required finding in section 911(g)(2)(B)(ii) of the FD&C 

Act that the product as actually used by consumers will not expose them to higher levels of other 

harmful substances compared to the similar types of tobacco products. 

3. Assessment of Potential Health Risks to Individual Tobacco Users and Non-Users

In this section, the evidence from the clinical findings is integrated to assess the potential health risks of 

use of VLNTM cigarettes among current tobacco users and non-users. Specifically, this section discusses 

VLNTM cigarettes’: (a) dependence and abuse liability, (b) CPD reductions with complete switching, (c) 

CPD reductions and dual use, (d) adverse health effects from switching, (e) health risks compared to 

tobacco cessation, (f) health risks to nonusers, and (g) misuse. This information is from BCP, medical, 

and epidemiology discipline reviews. 

The health impact of reducing CPD based on epidemiological studies is discussed in Section III(D)(1)(b). 
MR0000159- MR0000160 Page 41 of 90 

a. VLNTM Cigarettes’ Use Patterns, Abuse Liability and User Dependence 

Below I summarize key findings related to VLNTM cigarette’s smoking topography, abuse liability, and 

user dependence. These findings are detailed in the BCP review and are also discussed in the PMTA TPL 

review: 

• Based on the applicant’s studies and the literature, individuals who smoke VLNC cigarettes 

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

smoke UB-NNC 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.

• VLNTM King and VLNTM Menthol King cigarettes are associated with reduced abuse liability 

compared to UB-NNC cigarettes. This conclusion is collectively supported by actual use data in 

healthy adult smokers after ad libitum and controlled VLNTM cigarette smoking and findings from 

the applicant’s literature review on VLNC cigarettes that show lower plasma nicotine and lower 

positive subjective effects ratings compared to UB-NNC cigarettes. The abuse liability of VLNTM 

cigarettes is comparable to NRT gum. 

• The literature suggests that use of VLNC cigarettes for an extended duration of time is 

reasonably likely to lead to significant reductions in CPD and decreased dependence scores 

among smokers interested and not interested in quitting (see Appendix 2 of the BCP review).

• Previous research has also found that reducing cigarette consumption can increase the 

likelihood that an individual will become cigarette abstinent in the future (Hughes & Carpenter, 

2006). Overall, reducing nicotine exposure can reduce nicotine dependence. This effect is

anticipated to lead to long-term reductions in exposure to the smoking-related toxicants 

associated with morbidity and mortality through reducing smoking and increasing the potential 

for cessation.

• Among smokers motivated to quit, switching to VLNC cigarettes may facilitate smoking 

abstinence as a result of reduced nicotine exposure, particularly when used in combination with 

NRT and behavioral intervention (Dermody, Donny, Hertsgaard, & Hatsukami, 2015; Hatsukami 

et al., 2010; Walker et al., 2012). Therefore, the target market for VLNTM cigarettes (i.e., current 

smokers interested in reducing their nicotine consumption) may have increased adherence with 

the products compared to participants in the applicant’s clinical studies and in the larger VLNC 

cigarette literature (i.e., current smokers not interested in quitting).

The BCP review concludes that use of VLNTM cigarettes results in a reduction in nicotine exposure and is 

reasonably likely to reduce nicotine addiction.
MR0000159- MR0000160 Page 42 of 90 

b. CPD Reductions and Complete Switching from NNC Cigarettes to VLNTM 

Cigarettes

The health risks of the proposed MRTPs are likely the same compared to continued smoking another 

brand of cigarette if smoked in the same way. However, the majority of available evidence supports that

switching to VLNC cigarettes can lead to an overall reduction in CPD compared to smoking UB-NNC

cigarettes (see Appendix 2 of the BCP review). Studies that evaluated CPD across various populations 

after 6 weeks of smoking VLNC cigarettes report reductions ranging from 11% to 46% (e.g., Donny et al., 

2015; Foulds et al., 2018; Pacek et al., 2016; Tidey et al., 2017). In the longest study of VLNC cigarettes 

to date, total CPD (including study and non-study cigarettes) was reduced by 46-53% in VLNC cigarette 

smokers compared to NNC cigarette smokers after 20 weeks of use (Hatsukami et al., 2018). When 

analyzing only the number of VLNC cigarettes smoked during the study, CPD decreased by 

approximately 57% in VLNC cigarette smokers compared to NNC cigarette smokers. These findings 

suggest that CPD is likely to gradually decrease the longer smokers use VLNTM cigarettes. 

c. CPD and Dual-Using VLNTM Cigarettes with Other Nicotine and Tobacco 

Products

Dual use with NNC cigarettes

Studies from the literature review note that non-compliance with exclusive VLNC cigarette smoking is 

observed in most participants (76-78%). If smokers dual use VLNC and UB-NNC cigarettes but primarily 

smoke VLNC cigarettes, studies suggest that smokers would still likely reduce their overall CPD. The

evidence does not suggest that smokers would increase their overall CPD or tobacco product 

consumption if they dual use VLNC and UB-NNC cigarettes. 

The applicant states that the target market for VLNTM cigarettes is current smokers interested in reducing 

their nicotine consumption. The applicant also acknowledges that the likely situation with VLNTM

cigarettes would be one where, upon initiation, consumers who want to quit may have difficulty 

adhering to just smoking VLNTM cigarettes and may initially alternate between UB-NNC cigarettes and 

VLNTM cigarettes; however, VLNTM/VLNC cigarette studies suggest that the level of dual use with UB-NNC 

cigarettes is low (two or fewer UB-NNC CPD) and occurs particularly during the early weeks of VLNC 

cigarette use. As such, dual use with UB-NNC cigarettes would likely subside over time as smokers 

acclimate to smoking VLNTM cigarettes. The applicant’s 6-week actual use study conducted among 

smokers not interested in quitting found that some VLNTM cigarette smokers initially increased their CPD 

in the first two weeks of the study, although smoking rates had returned to levels comparable to 

baseline UB-NNC CPD in these smokers by the end of the study. Because these individuals were more 

dependent at baseline (based on baseline CPD, smoking history, and Fagerström Test for Cigarette 

Dependence [FTCD] scores), this effect may be related to level of dependence, where individuals who 

are more dependent may have greater difficulty reducing CPD. Although in the applicant’s study VLNTM

CPD were not significantly reduced compared to baseline CPD in all study groups, nicotine exposure was 

still significantly reduced compared to UB-NNC cigarettes in these smokers.

The applicant’s 6-week longitudinal study supports that, as a result of substantially reducing nicotine 

exposure, switching to VLNC cigarettes can lead to smoking fewer overall cigarettes per day (CPD) 

compared to ongoing UB-NNC cigarette smoking. These findings are supported by several VLNC 
MR0000159- MR0000160 Page 43 of 90 

cigarette studies in the published literature, including a 20-week study of VLNC cigarette use among 

smokers, which is the longest study of VLNC cigarettes to date (Hatsukami et al., 2018). On average, 

smokers assigned to switch to VLNCs had half the CPD compared to those in the UB-NNC control group. 

The extent of cigarette reduction depends on the extent of switching to smoking VLNTM cigarettes, 

although smokers who occasionally smoke UB-NNC cigarettes still experience a significant reduction in 

CPD compared to smoking UB-NNC cigarettes exclusively. Studies support that as the duration of 

smoking VLNC cigarettes increases, the reduction in CPD increases. Although results support that 

participants who dual use VLNTM/VLNC cigarettes with their UB-NNC cigarettes still reduce their CPD and 

that dual use would likely subside over time as smokers acclimate to smoking VLNTM/VLNC cigarettes, it 

is unclear how these findings from clinical studies will generalize to the real-world setting. One

possibility is that CPD may be lower in the real-world setting than rates observed in clinical studies, since 

cigarettes would not be free to consumers as they are in clinical studies. This could be particularly the 

case as most clinical studies enrolled smokers not interested in quitting, and the target market for VLNTM

cigarettes (i.e., current smokers interested in reducing their nicotine consumption) may be more 

motivated to use more VLNTM cigarettes to reduce their nicotine consumption. However, it is also 

possible that dual use of the proposed MRTPs with NNC cigarettes would be even more prevalent than 

observed in clinical studies, and CPD reductions would be lower than observed in clinical studies. 

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. Additionally, in the clinical studies reviewed for CPD 

outcomes, participants were instructed to substitute their UB-NNC cigarettes with VLNTM/VLNC 

cigarettes or to switch completely to smoking VLNTM/VLNC cigarettes. Participants were also often 

incentivized for adherence to the study products. In the open marketplace, consumers will not be 

incentivized for product adherence and the applicant is not proposing to include conditions of use on 

the LLA. Given the uncertainty associated with how consumers will use the product and the significant 

effect of the manner of use on the risk of the product to human health, I recommend that the order 

include conditions of use on the LLA. Specifically, consumers should receive some type of instruction on 

how to use VLNTM cigarettes to obtain health benefits, which can occur from switching to VLNTM 

cigarettes, subsequently reducing their CPD, and ultimately increasing the likelihood that they will be 

able to quit smoking completely. To address this, I propose that the order require the statement “helps 

you smoke less” to appear in all LLA that include any of the proposed claims. “Helps you smoke less” 

directly states how consumers can use VLNTM to potentially achieve a health benefit. In contrast, 

alternative potential conditions of use such as “switch completely to VLNTM” or “use VLNTM exclusively” 

pose a risk of consumer misunderstanding because completely switching to VLNTM or exclusively using 

VLNTM are not necessarily sufficient given that smoking VLNTM cigarettes at the same rate as other 

cigarettes is unlikely to result in a health benefit. Additionally, the applicant tested consumer 

understanding of labeling that included “helps you smoke less” in its consumer research. This is further 

detailed in Section III(C)(2) and (4). 

Dual use with other nicotine-containing products

Higher rates of dual ENDS and VLNC cigarette use have been reported in VLNC cigarette smokers 

compared to NNC cigarette smokers. Dual use of VLNC cigarettes with ENDS or NRT may aid in reducing 

CPD in some individuals (Donny & Jones, 2009; Hatsukami, Hertsgaard, et al., 2013; Hatsukami et al., 

2017). Studies do not suggest that dual use of VLNC cigarettes with other tobacco or nicotine-containing 

products leads to increases in overall CPD or nicotine consumption; nicotine exposure is still reduced 

compared to UB-NNC cigarettes in participants who dual use VLNC cigarettes with NRT or non-
MR0000159- MR0000160 Page 44 of 90 

combusted tobacco products (i.e., smokeless tobacco, snus, ENDS). Among smokers motivated to quit, 

switching to VLNC cigarettes may facilitate smoking abstinence as a result of reduced nicotine exposure, 

particularly when used in combination with NRT and behavioral intervention (Dermody, Donny, 

Hertsgaard, & Hatsukami, 2015; Hatsukami et al., 2010; Walker et al., 2012). 

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 MRTPA submission. No information is provided on 

BOPH, adverse events, or published literature that addresses the health risks of use of VLNTM cigarettes 

when used with other tobacco products. Nonetheless, given 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. 

a. Morbidity and Mortality Reductions due to CPD Reductions

Morbidity and mortality reductions that are reasonably likely due to CPD reductions are discussed in 

detail in our evaluation of population health impact (Section III(D)(1)(b)). Briefly, published 

epidemiological studies assessing the relationship between smoking reduction and disease risks 

suggested a potential benefit for some health endpoints such as lung cancer risk in those who reduced 

CPD by more than 50% compared to non-reducers. Past studies have not consistently demonstrated that 

a reduction in CPD reduces mortality; however, a recent study that evaluated changes in smoking 

patterns over a longer period of time than previous studies found that all-cause mortality was lower 

among smokers who reduced their CPD compared to those who maintained their CPD. The evidence 

provided by the applicant also suggests that reduced cigarette consumption, rather than complete 

smoking cessation, is the main benefit of VLNTM cigarettes. However, it is also reasonably likely to infer 

that VLN would reduce users’ nicotine dependence, which in turn could also lead to reduced cigarette 

consumption, increased quit attempts, and greater likelihood of future smoking cessation. 

b. Adverse Health Effects from Switching to VLNTM Cigarettes

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 main difference between the proposed products and NNC cigarettes is the 

nicotine content. The applicant primarily relies upon two publications, Donny et al. (2015) and 

Hatsukami et al. (2018), to substantiate the risk profile and safety of VLNTM cigarettes, respectively. 

It is expected that VLNTM cigarette users who use the products in the same way as NNC cigarettes 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 
MR0000159- MR0000160 Page 45 of 90 

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.9 

Among smokers motivated to reduce or eliminate nicotine exposure, the health risks for those who 

switch to VLNTM cigarettes are likely less harmful than continued NNC cigarette smoking. Smokers who 

completely switch to VLNTM cigarettes may experience weight gain. If smokers dual use NNC cigarettes 

with VLNTM cigarettes, then they may experience some weight gain, in addition to the adverse health 

effects of continued NNC cigarette smoking. However, the BCP review notes (see section on abuse 

liability) that the likelihood that current tobacco product users would completely switch to VLNTM 

cigarettes is low. The medical review also notes that this weight gain effect may differ in smokers who 

are motivated to reduce their nicotine exposure or quit smoking. Smoking increases the risk of CVD 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, an increased risk of 

thrombosis has not been substantiated based on adverse event reporting in clinical studies. 

From available evidence, the adverse health effects caused by VLNCs or VLNTM cigarettes are likely to be 

similar to traditional cigarettes if smoked the same way. However, given the dramatically lower levels of 

nicotine in VLNTM cigarettes, switching from conventional cigarettes to the proposed MRTPs is 

reasonably likely to lead to reduced nicotine dependence, which could result in reduced CPD, and for 

some, increased likelihood of quitting cigarettes altogether; translating to a substantial and measurable 

reduction in morbidity and mortality. 

c. Health Risks Compared to Tobacco Cessation and Use of FDA-Approved 

Smoking Cessation Drug or Device Products

The applicant did not provide information comparing the short- and long-term health effects of 

complete or incomplete VLNTM cigarette switching to abstinence (quitting). 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 by going “cold turkey” or using other means 

such as behavioral methods or pharmacotherapy can have health risks (e.g., nicotine withdrawal 

9 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. 
MR0000159- MR0000160 Page 46 of 90 

syndrome, weight gain, depression, cough, mouth ulcers (Rigotti, 2020) but the benefits of abstinence 

(quitting) far outweigh these risks. 

The applicant did not provide clinical data to evaluate the relative health risks of switching to VLNTM 

cigarettes compared to using approved cessation products. 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 products is far preferable than smoking any combustible products, 

including VLNTM cigarettes. FDA-approved smoking cessation products 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, given the lower abuse liability of 

VLNTM cigarettes, it is not particularly likely that VLNTM cigarettes would deter smokers from abstinence 

with or without FDA-approved smoking cessation products. 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 FDAapproved cessation therapies or quit without therapy, it is well established that smoking 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 smoking, which may 

aid in future quit 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.

d. 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 that this effect would be similar to NNC cigarettes. FDA agrees 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 VLNTM 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. 

e. Misuse

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. 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. 

As discussed in the medical review, the human factors issues related to cigarettes leading to misuse or 

injury are well known: (1) improper storage, allowing access to unused products by children; (2) 

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 (3) 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 VLNTM cigarettes because they have no unique use characteristics that differ from 

NNC cigarettes. 
MR0000159- MR0000160 Page 47 of 90 

f. Summary and conclusion 

FDA’s assessment of potential health risks to individual tobacco users and nonusers from clinical studies

is summarized as follows: 

• VLNTM King and VLNTM Menthol King cigarettes are associated with reduced abuse liability 

compared to UB-NNC cigarettes. There is consistent evidence in the literature suggesting that 

use of VLNC cigarettes for an extended duration of time is associated with significantly 

decreased dependence scores among smokers interested and not interested in quitting. Among 

smokers motivated to quit, switching to VLNC cigarettes may facilitate smoking abstinence as a 

result of reduced nicotine exposure, particularly when used in combination with NRT and

behavioral intervention. Thus, VLNTM cigarettes are reasonably likely to reduce nicotine 

addiction, contributing to a reduction in morbidity and mortality. 

• The majority of available evidence supports that switching to VLNC cigarettes can lead to an 

overall reduction in CPD compared to smoking UB-NNC cigarettes. Reductions have ranged from 

11% to 46% in 6-week clinical studies. In the longest clinical study (20 weeks), total CPD in the 

group assigned to smoke VLNC cigarettes was about 50% of that of the NNC cigarette control 

group. However, most smokers instructed to use VLNC exclusively in clinical studies still use a 

few NNC cigarettes (two or less per day). Still, smokers who use predominantly VLNTM cigarettes

significantly reduce their CPD, though to a lesser extent than smokers who switch completely. 

Reductions in morbidity and mortality that are reasonably likely due to these reductions in CPD 

are discussed in Section III(D)(1)(b).

• Higher rates of dual ENDS and VLNC cigarette use have been reported in VLNC cigarette smokers 

compared to NNC cigarette smokers. Smokers who use VLNC along with ENDS or NRT may 

further reduce their CPD. Among smokers motivated to quit, switching to VLNC cigarettes may 

facilitate smoking abstinence as a result of reduced nicotine exposure, particularly when used in 

combination with NRT and behavioral intervention. 

• Uncertainty remains about how clinical study findings will generalize to the real-world setting. 

CPD reductions may be even greater as cigarettes would not be free to be consumers (as they 

are in clinical settings) and users may be smokers who are motivated to reduce their CPD 

(clinical studies only include smokers who do not intend to quit). CPD reductions may be lower, 

as studies have found smokers do not find VLNCs satisfying, and satisfaction predicts product 

uptake. CPD reductions also may be lower in the absence of instructions to use the product 

exclusively (as participants were given in clinical studies). 

• If smoked the same way, it is expected that VLNTM cigarette users will generally have the same 

negative short- and long-term health effects as those that occur with NNC cigarette smoking. 

The likelihood and extent to which smokers and nonsmokers (who are exposed to SHS and THS) 

experience risk reductions depend on the extent of the smokers’ CPD reduction. 

• Among smokers motivated to reduce or eliminate nicotine exposure, the health risks for those 

who switch to VLNTM cigarettes are likely less harmful than continued NNC cigarette smoking. 

Smokers who completely switch to VLNTM cigarettes may experience weight gain. If smokers dual 

use NNC cigarettes with VLNTM cigarettes, then they may experience some weight gain, in 
MR0000159- MR0000160 Page 48 of 90 

addition to the adverse health effects of continued NNC cigarette smoking; however, decreases

in NNC cigarette smoking will also likely decrease overall health risks. 

• The applicant did not provide information comparing the short- and long-term health effects of 

complete or incomplete VLNTM cigarette switching to abstinence or to using approved cessation 

products. 

• The applicant did not submit information on potential misuse or malfunction of the VLNTM 

cigarettes. The medical reviewer does not expect any different human factors issues to arise 

with VLNTM cigarettes because these cigarettes have no unique use characteristics that differ 

from NNC cigarettes. 

As TPL, I agree with these findings. If used in the same way, the health risks of using the proposed 

MRTPs are the same as NNC cigarettes, and the proposed MRTPs do not raise additional concerns 

regarding misuse and health effects compared to NNC cigarettes. However, the available evidence 

suggests the proposed MRTPs have reduced abuse liability and smokers who use them gradually reduce 

their CPD. Although a significant reduction in tobacco-related death and disease has not been 

demonstrated, I find that it is reasonably likely that switching to the proposed MRTPs would lead to a 

substantial and measurable reduction in death and disease through reduced nicotine dependence, 

cutting down on cigarettes, and for some, increasing the likelihood of quitting cigarettes altogether.

C. Consumer Understanding and Perceptions

Social science evaluated whether the proposed LLA would enable consumers to understand the 

proposed modified risk information and its significance in the context of total health, and whether the 

proposed labeling and marketing would mislead consumers about the demonstrated harms or disease 

risks of using the proposed MRTPs. See sections 911(h) and 911(g)(2)(B)(iii). This includes assessing 

whether consumers would understand (1) the nicotine content of the proposed MRTPs, (2) the 

conditions of use of the proposed MRTPs, (3) the addiction risks, and (4) the health risks other than 

addiction. This evaluation was informed by the applicant’s quantitative study of the product’s labeling 

with the proposed Claims #1-3 and the disclaimer, and four qualitative studies of different versions of 

the product’s labeling with proposed Claims #1-3 and other FDA-identified claims. The evaluation was 

also informed by peer-reviewed literature. I find that the totality of evidence on consumer 

understanding supports that if the LLA include the statement “helps you smoke less,” the LLA will enable 

consumers to understand the proposed modified risk information and will not mislead consumers into 

holding inaccurate beliefs about the products’ health risks or harms or the definitiveness of the evidence 

regarding the products’ relative risks or harms. 

1. Understanding of Nicotine Content

Regarding whether consumers would comprehend the explicit meaning of the proposed statements 

about reduced nicotine, social science examined the claims themselves, the applicant’s research on 

consumer responses to the claims, and previously published research on consumer responses to 

statements with wording similar to the wording in the proposed claims. We found that the claims are 

relatively simple and concrete (including the statement of “95% less”), and that each instance of LLA

includes multiple statements reinforcing the main idea of substantially reduced nicotine. The statements 
MR0000159- MR0000160 Page 49 of 90 

include a numeric description (“95% LESS NICOTINE”) as well as a verbal qualifier (“greatly reduces”) to 

convey the extent of the nicotine reduction, which may be helpful for consumers with lower levels of 

numeracy. The disclaimer “Nicotine is addictive. Less nicotine does NOT mean safer. All cigarettes can 

cause disease and death.” begins with a statement about nicotine being addictive, which gives 

additional context regarding the meaning of statements about reduced nicotine. The applicant

submitted four phases of qualitative research examining consumer comprehension of the applicantproposed claims’ explicit meaning as well as various other claims with different characteristics. These 

studies found support for using the “95% less” wording because it was brief and made clear that the 

reduction in nicotine was substantial. Other claims the applicant tested (e.g., “5% of the nicotine”) were 

misunderstood. In the applicant’s quantitative research, most participants spontaneously brought up 

the low nicotine content when asked for an open-ended response about how they would describe the 

product to a friend or family member (65%, 66%, and 67% of current, never, and former smokers, 

respectively), although the applicant did not submit any information to FDA about its methodology for 

analyzing or coding these open-ended responses. Previously published research also tested consumer 

comprehension of reduced nicotine claims with various phrasing, finding that the inclusion of a 

percentage reduction (i.e., 95%) helped participants grasp the extent of the nicotine reduction (Byron, 

Hall, King, Ribisl, & Brewer, 2019). 

Lastly, social science considered whether consumers would understand the extent of their nicotine 

reduction from dual-using VLNTM with other tobacco or nicotine products. In particular, social science

evaluated the possibility that smokers may incorrectly believe that, by using VLNTM, they would reduce 

their nicotine consumption by 95% even if they kept smoking their usual brand cigarettes in addition to 

smoking VLNTM. The applicant’s qualitative and quantitative consumer research did not directly address 

this question, nor could we find studies in the published literature directly addressing this question. 

However, the applicant’s qualitative consumer research allowed participants to speak about their 

interpretations of the proposed claims, and participants’ statements suggested that they generally 

understood that “95% less nicotine” refers to the nicotine content of VLNTM cigarettes themselves, 

rather than users’ overall nicotine consumption, which would also depend on their use of other 

nicotine-containing products. For example, participants stated, “It’s saying exactly what it is. It’s 95 

percent less nicotine and because of that you’re not consuming the amount normally,” and, “It has less 

nicotine in it, therefore it absolutely would give you less nicotine consumption” (see Appendix in Section 

9 of the social science review). Among participants who smoked heavily, one of their main concerns with 

using VLNTM was that they “want their nicotine” and “might smoke more cigarettes to get the same 

amount of nicotine,” suggesting that they understood that their cumulative nicotine exposure depends 

on their overall level of use of nicotine-containing products. Also, consistent with the idea that 

consumers will understand “95% less nicotine” to refer specifically to the content of VLNTM cigarettes 

themselves, FDA maintains requirements for relative nutrient content claims on food labeling (e.g., 

“65% less fat than regular potato chips”), and these claims refer to products’ contents without reference 

to potential consumption of other products containing the same nutrients (see Appendix B in Institute of 

Medicine, 2010). Altogether, we believe smokers would understand that their total nicotine 

consumption will not be reduced by 95% if they dual use VLNTM with other nicotine-containing products. 

Taken together, these findings suggest that the proposed LLA would indeed enable most consumers to 

comprehend the claims’ explicit meaning that VLNTM cigarettes contain much lower levels of nicotine 

than other cigarettes. 
MR0000159- MR0000160 Page 50 of 90 

2. Understanding of Conditions of Use

Regarding conditions of use, social science examined whether consumers would understand that VLNTM 

cigarettes can help smokers reduce their smoking frequency or duration, which can reduce their 

exposure to nicotine and other HPHCs and potentially their disease risk. Reviewers found that the 

proposed LLA include no information on conditions of use, such as how consumers should use VLNTM to 

reduce their exposure to HPHCs and potentially disease risk. In qualitative in-depth interviews, some of 

the participants did not appear to understand the conditions of use: after viewing VLNTM cigarette packs 

with the proposed modified risk labeling, they did not understand the need to cut down or stop smoking 

in order to benefit from VLNTM cigarettes. In contrast, participants appeared to understand this better 

after viewing alternative packs that included the proposed claims plus an additional statement, “Helps 

you smoke less,” based on the applicant’s study reports and social science’s evaluation of a random 

sample of transcripts from the Phase 4 qualitative study. Participants found that this statement was 

“simple” and “to-the-point” and “uses verbiage that is easily understood.”

The applicant’s quantitative consumer research did not include items assessing whether the proposed 

LLA would enable consumers to understand the conditions of using VLNTM cigarettes, such as items 

asking about how much smokers would have to cut down on their cigarette smoking (e.g., cigarettes per 

day or number of days smoked) in order to reduce their HPHC exposure and potentially disease risk 

using VLNTM cigarettes. This was also the case for a study condition testing a different version of the 

labeling that the applicant did not propose to use; this version specifies the conditions for use that could 

lead to a benefit for consumers (“Helps you smoke less”). 

Among smokers who reported an intention to purchase VLNTM cigarettes, the quantitative study did ask 

about how their purchase of VLNTM cigarettes would affect their purchases of other tobacco products, 

finding that most smokers reported that VLNTM cigarettes would replace at least some of their current 

purchases of other cigarettes. However, it was unclear whether smokers intended to use VLNTM

cigarettes to cut down on their overall cigarette consumption or simply replace all or some of their 

current cigarette. Given these findings, it appears that instructions to convey how to use VLNTM 

cigarettes would benefit consumers. Appropriate statements to convey how the product should be used 

to obtain a benefit were considered, including detailed and explicit instructions about switching 

completely and reducing cigarette consumption; however, these types of explicit statements were not 

tested relative to improved understanding. Since the applicant qualitatively tested “helps you smoke 

less”, as instructions for use that demonstrated improved understanding for conditions to use the 

product to obtain the intended benefit, I recommend that the order require that VLNTM cigarettes’ LLA

include “Helps you smoke less,” as this statement is necessary to enable consumers to understand the 

manner in which they must use the product in order to obtain a benefit. 
MR0000159- MR0000160 Page 51 of 90 

3. Understanding of Addiction Risk

Social science posited that, if the proposed LLA enable people to understand the modified risk 

information in the context of total health, people will perceive VLNTM cigarettes as less addictive than 

other cigarettes and other nicotine-containing tobacco products (e.g., e-cigarettes and snuff) and 

similarly addictive as NRT. This is based on other FDA disciplinary reviews finding that VLNTM cigarettes’ 

abuse liability is substantially lower than that of other cigarettes and similar to that of NRT, and it is 

reasonably likely that smokers can use VLNTM cigarettes to reduce their nicotine dependence over time 

(see the BCP review). 

To examine whether the proposed LLA will enable consumers to understand the addiction risks of VLNTM 

cigarettes, the applicant conducted a quantitative study in which participants were randomly assigned 

to view either images of a VLNTM cigarette pack or a Marlboro GoldTM cigarette pack (total sample size 

n=29,219; Protocol #: 5180080-VLNTM-B2). The VLNTM cigarette pack either contained the proposed 

modified risk information or an alternative version of the information. Participants were also shown a 

brief description of VLNTM cigarettes that included modified risk information (see Figure 3 in the social 

science review). After viewing the cigarette pack images, participants reported their perceptions of the 

addictiveness of VLNTM cigarettes or Marlboro GoldTM cigarettes. Participants were also randomized to 

report their perceptions of health risk from using either conventional cigarettes in general (providing the 

brand examples of Marlboro, Camel, Newport, and Winston), snuff, e-cigarettes, or NRT. 

Findings suggest that the proposed LLA would enable consumers to understand the addiction risks of 

smoking VLNTM cigarettes. Consistent with VLNTM’s very low nicotine level, participants perceived VLNTM

cigarettes as substantially less addictive than other cigarettes after viewing the VLNTM pack image with 

the proposed modified risk claims and the alternative versions of the information. At the same time, 

participants still perceived some risk of addiction from smoking VLNTM cigarettes, placing them in a 

similar range as NRT (Ms = 3-4 on a 5-point scale). In an absolute sense, we expect that these ratings of 

addiction risk from VLNTM and NRT may reflect overestimates of abuse liability and dependence potential 

(which appear low; see the BCP review and, e.g., West et al., 2000), which could discourage use of VLNTM 

among people who are not already addicted to smoking cigarettes. The above findings held across 

current, former, and never smokers, and are consistent with prior research finding that most U.S. adults 

believe that nicotine is the main addictive substance in tobacco (O’Brien et al., 2017). 

As an example, adult current smokers had addiction risk perceptions that were lower for VLNTM

cigarettes than for either Marlboro GoldTM or conventional cigarettes in general. Perceptions of 

addiction risk for VLNTM cigarettes were also lower than those for snuff and e-cigarettes and higher than

those for NRT. These findings were also observed among former smokers. Among young adult never 

smokers, perceptions of addiction risk for VLNTM cigarettes were generally lower than those for 

conventional cigarettes, Marlboro GoldTM, snuff, and e-cigarettes; however, perceptions for VLNTM 

cigarettes were not significantly different from those for NRT. 

4. Understanding of Health Risks, other than Addiction

Social science posited that, if the proposed LLA enable people to understand the modified risk 

information, people will perceive VLNTM cigarettes as posing health risks that are (a) moderate or high, 

(b) higher than NRT, (c) similar to other cigarettes when smoked in the same way (i.e., same frequency 
MR0000159- MR0000160 Page 52 of 90 

and duration), and (d) lower than other cigarettes when used to reduce one’s smoking.10 As the 

applicant states, based on a toxicological risk assessment, VLNTM cigarettes “are not considered to be 

less hazardous than conventional cigarettes” (Executive Summary, pp. 18-20), but their use may lead to 

a population health benefit through reductions in smokers’ dependence on cigarettes. 

Social science evaluated the M/A/R/C Quantitative Study to make this assessment. In this study, 

participants rated the health risks of using VLNTM cigarettes, Marlboro GoldTM cigarettes, and other 

tobacco and nicotine products (total sample size n=29,219; Protocol #: 5180080-VLNTM-B2). Before rating 

the health risks of smoking VLNTM cigarettes, participants were shown VLNTM packs containing either the 

proposed modified risk information or alternative versions of the information. Participants were then 

asked, “Taking into consideration everything you know about [product], indicate what you believe is the 

risk of the following long-term or lifetime health-related issues” because of smoking VLNTM and using 

other products. The 18 health-related issues were: lung cancer, mouth/ throat cancer, heart disease, 

emphysema, earlier death, respiratory infections, aging faster, occasional wheezing, a bad cough that 

lasts for days, early morning cough, poor gum health, serious illness, other types of cancer, reduced 

stamina, losing some sense of taste, being physically unfit, sores of the mouth or throat, and frequent 

minor illnesses. 

Supporting (a), the applicant’s research found that participants indeed perceived VLNTM as presenting 

risks of tobacco-related diseases that were moderate to high (mean ratings between 3 and 4 on a 5-

point scale). Supporting (b), participants perceived VLNTM cigarettes’ risks as significantly higher than the 

risks posed by NRT. These findings on absolute risk perceptions of VLNTM and risk perceptions of VLNTM 

compared to NRT appear consistent with accurate consumer understanding of the proposed modified 

risk information and its significance in the context of total health. 

However, regarding (c) and (d), the applicant’s quantitative research found that, after viewing VLNTM 

packs with the proposed modified risk information, participants perceived VLNTM cigarettes as presenting 

lower risks of tobacco-related diseases -- including lung cancer, mouth/throat cancer, heart disease, and 

15 other tobacco-related diseases and health effects – compared to other cigarettes. However, in this 

research, the survey questions had limitations in that they did not include information regarding 

patterns or frequency of use, and the research did not assess the assumptions participants made in 

answering questions related to disease risks. Therefore, it is unclear whether these perceptions reflect 

consumer misperceptions of toxicity or correct consumer understanding of the reasonably likely 

reduction in disease risks resulting from using VLNTM cigarettes, which are less addictive, and smoking 

fewer of them over time. Social science’s evaluation of randomly selected transcripts from Phase 4 of 

the qualitative research found that some participants appeared to believe that VLNTM cigarettes were 

less toxic than other cigarettes because of the reduced nicotine content, while other participants 

believed that VLNTM cigarettes were less likely to cause disease because people would be less likely to 

smoke them long enough to get diseases (see Section 4.2 of the social science review for a more 

detailed discussion). Still, findings are generally consistent with prior published research that suggests

that, without corrective or clarifying information, many U.S. consumers are at risk of misinterpreting 

statements about reduced nicotine content cigarettes (e.g., “Imagine if tobacco companies were 

required to remove 95% of the nicotine from cigarettes”) to mean that the cigarettes would be less toxic 

and carcinogenic than other cigarettes (Byron et al., 2019; Bansal-Travers et al., 2010; Borrelli & Novak, 

10 Although the applicant also examined perceptions relative to snuff and e-cigarettes, we do not have data to 

evaluate the accuracy of consumer understanding of these comparisons. 
MR0000159- MR0000160 Page 53 of 90 

2007; Byron et al., 2018; Denlinger-Apte et al., 2017; Mutti et al., 2011; O’Brien et al., 2017). Indeed, 

TPSAC committee members also stated it was unlikely that participants thought through the products’ 

addictiveness (and the corresponding effects on use frequency, duration, and, in turn, disease risks) 

when rating the risks of smoking VLNTM cigarettes. 

Taken together, the published literature and the applicant’s findings support that, without additional 

information, many U.S. consumers, including smokers and non-smokers, would be at risk of 

misunderstanding the manner in which VLNTM cigarettes must be used in order to obtain a benefit. In 

light of these findings, it appears that instructions to convey the purpose of the product and how to use 

it would benefit consumers. Appropriate statements to convey how the product needs to be used to 

obtain a benefit were considered, including detailed and explicit instructions about switching completely 

to the product or reducing your cigarette consumption; however, to avoid overly complicated and 

untested instructions on the LLA without evidence of improved understanding, I am proposing to 

include “helps you smoke less”, which was part of the LLA tested by the applicant, as instructions of how 

to use the product to obtain the intended benefit. This statement was tested in the applicant’s 

submitted studies and communicates the way the product needs to be used to gain a benefit. Therefore, 

I find it necessary to require VLNTM cigarettes’ modified risk LLA to include an explicit statement about 

the manner in which the product must be used in order to obtain a benefit (“Helps you smoke less”).

By including this statement in a way that will be noticed and read, the LLA will enable consumers to 

better understand the significance of the reduced nicotine claims, the relevance to their personal health 

(or the irrelevance, if the person does not wish to smoke less), and the reason why the manufacturer 

would be providing the information about nicotine to consumers. 

Additionally, if FDA authorizes the applicant to market VLNTM cigarettes as modified risk products, the 

authorization letter should recommend that the applicant include the disclaimer “Nicotine is addictive. 

Less nicotine does NOT mean safer...” on VLNTM pack LLA given that it was present on all of the labeling 

that the applicant tested in its quantitative consumer research, and the letter should also require the 

applicant to test the disclaimer in a postmarket study. Several aspects of the disclaimer are inconsistent 

with expert recommendations for disclaimers, and prior research suggests that poorly designed 

disclaimers can confuse consumers and change their perceptions, attitudes, or decisions in a manner 

opposite of that intended (Green & Armstrong, 2012). Indeed, in a pre-submission meeting with the 

applicant, FDA recommended that the applicant conduct a study comparing consumer understanding

across participants who did and did not see the disclaimer, to assess the disclaimer’s effects on 

understanding of the modified risk information. However, the applicant submitted no evidence about 

the disclaimer’s effect on consumer understanding. Conducting a postmarket test can provide FDA with 

evidence about whether the disclaimer helps enable consumers to understand that VLNTM cigarettes 

present the same disease risks as other cigarettes if smoked in the same way, or whether it confuses 

people about the health risks of VLNTM cigarettes. 

Summary and Conclusion 

Social science evaluated whether consumers understood (1) the nicotine content of the proposed 

MRTPs, (2) the conditions of use of the proposed MRTPs, (3) the addiction risks, and (4) the health risks, 

other than addiction. Their evaluations were informed by one quantitative study and four qualitative 

studies submitted by the applicant, in addition to the published literature. Their findings are 

summarized below:
MR0000159- MR0000160 Page 54 of 90 

• (1) The applicant’s qualitative research suggested that consumers would understand the claims 

to mean the nicotine content of VLNTM is substantially lower compared to other cigarettes. In 

particular, “95% less nicotine” is brief and makes clear that the reduction in nicotine content is 

substantial. Claims #2 and #3 reinforce this point and provide a verbal qualifier (“greatly 

reduces”) to convey the substantial reduction in nicotine exposure, which may be helpful for 

consumers with lower levels of numeracy. Qualitative research also suggested that consumers 

generally understood that “95% less nicotine” refers to the nicotine content of VLNTM cigarettes 

themselves, rather than users’ overall nicotine consumption. Similarly, Claims #4-10 are clear 

that the statements about nicotine refer to the nicotine content of the cigarettes rather than 

users’ overall nicotine exposure, which is affected by their use of other nicotine-containing 

products. 

• (2) Reviewers found that the proposed LLA include no information on conditions of use, such as

how consumers should use VLNTM to reduce their exposure to HPHCs and potentially disease 

risk. In qualitative research, some participants did not appear to understand the need to cut 

down or stop smoking in order to benefit from VLNTM cigarettes. Based on the quantitative 

research, it was unclear whether smokers intended to use VLNTM to cut down on their overall 

cigarette consumption or simply replace all or some of their current cigarette use with VLNTM

cigarettes. 

• (3) Findings from the applicant’s quantitative study suggest the proposed LLA would enable 

consumers to understand the addiction risks of smoking VLNTM cigarettes. Consistent with VLNTM

cigarettes’ very low nicotine level, participants perceived VLNTM cigarettes as substantially less 

addictive than other cigarettes after viewing the VLNTM pack image with the proposed modified 

risk claims and the alternative versions of the information. At the same time, participants still 

perceived some risk of addiction from smoking VLNTM cigarettes, placing them in a similar range 

as NRT. 

• (4) Social science posited that, if the proposed LLA enable people to understand the modified 

risk information, then people will perceive VLNTM cigarettes as posing health risks that are (a) 

moderate or high, (b) higher than NRT, (c) similar to other cigarettes when smoked in the same 

way (e.g., same frequency and duration), and (d) lower than other cigarettes when used to 

reduce one’s smoking. While findings supported (a) and (b), results for (c) and (d) were unclear. 

Regarding (c) and (d), the applicant’s quantitative research found that, after viewing VLNTM 

cigarette packs with the proposed modified risk information, participants perceived VLNTM

cigarettes as presenting lower risks of tobacco-related diseases compared to other cigarettes, 

including lung cancer, mouth/throat cancer, heart disease, and 15 other tobacco-related 

diseases and health effects. However, it is challenging to evaluate these findings, given that the 

survey questions did not include information regarding patterns or frequency of use (i.e., 

whether VLNTM cigarettes would be used at the same rate or be used to cut down), and the 

research did not assess the assumptions participants made in answering these questions. Still, 

findings are generally consistent with prior published research that suggests that, without 

corrective or clarifying information, many U.S. consumers are at risk of misinterpreting 

statements about reduced nicotine content cigarettes.

As TPL, I agree with these findings. To address the issue outlined in (2) and (4) above, and in light of 

these findings, I recommend that the order require VLNTM cigarettes’ modified risk LLA to include an 
MR0000159- MR0000160 Page 55 of 90 

explicit statement about the manner in which the product must be used in order to obtain a benefit, 

“Helps you smoke less”. By including this statement in a way that will be noticed and read, the LLA will 

enable consumers to better understand the significance of the reduced nicotine claims, the relevance to 

their personal health (or the irrelevance, if the person does not wish to smoke less), and the reason why 

the manufacturer would be providing the information about nicotine to consumers. This will enable 

consumers to comprehend the information concerning modified risk and to understand the relative 

significance of such information in the context of total health.

Additionally, the authorization letter should recommend that the applicant include the disclaimer 

“Nicotine is addictive. Less nicotine does NOT mean safer...” on VLNTM pack LLA given that it was present 

on all of the labeling that the applicant tested in its quantitative consumer research, but the letter 

should also require the applicant to test the disclaimer in a postmarket study. Several aspects of the 

disclaimer are inconsistent with expert recommendations for disclaimers, and prior research suggests 

that poorly designed disclaimers can confuse consumers and change their perceptions, attitudes, or 

decisions in a manner opposite of that intended (Green & Armstrong, 2012). In a pre-submission 

meeting with the applicant, FDA recommended that the applicant conduct a study comparing consumer 

understanding across participants who did and did not see the disclaimer, to assess the disclaimer’s

effects on understanding of the modified risk information. However, the applicant submitted no 

evidence about the disclaimer’s effect on consumer understanding. Conducting a postmarket test can 

provide FDA with evidence about whether the disclaimer helps enable consumers to understand that 

VLNTM cigarettes present the same disease risks as other cigarettes if smoked in the same way, or 

whether it confuses people about the health risks of VLNTM cigarettes. Thus, I recommend that the order 

require the applicant to conduct such a study of the disclaimer as part of postmarket surveillance; this 

is discussed further in Section IV(C).

Social science did not specifically evaluate consumer understanding of FDA-identified Claims #4-10 in 

detail. These statements appear to convey the same information as applicant-identified Claims #1-3. 

Specifically, the claims are limited to information about VLNTM cigarettes’ nicotine content and how it 

compares with that of other cigarettes, although some of the claims describe the nicotine content in 

absolute terms (e.g., “.27 mg”), use qualitative comparisons (e.g., “substantially lower”), or include 

comparators (e.g., “the top 100 cigarette brands”). The applicant’s qualitative research on consumer 

understanding (described below in Section 4; M/A/R/C Qualitative Study) examined participants’ 

responses to claims with alternate phrasing similar to these variations. The one exception is Claim #9, 

which describes the source of VLNTM cigarettes’ reduced nicotine content (i.e., “unique technology and 

plant breeding expertise” allows the company to grow tobacco with different nicotine levels). This 

statement is similar to background information about VLNTM cigarettes viewed by participants in the 

applicant’s quantitative consumer perception research (see Sections 4 and 5 below; M/A/R/C Research 

Quantitative Study). The background information stated: “A new tobacco product called VLNTM (Very 

Low Nicotine) is currently in development... VLNTM cigarettes are made from a tobacco plant that has 

been altered to contain much lower levels of nicotine than the tobacco used in traditional cigarettes.” 

Thus, although the applicant did not specifically examine consumer responses to FDA-identified Claims 

#4-10, any potential concerns are mitigated by the fact that these claims appear to convey the same 

information as Claims #1-3 and the information that participants viewed in the applicant’s quantitative 

consumer research.
MR0000159- MR0000160 Page 56 of 90 

D. Tobacco Use Behavior and Impacts to the Population as a Whole

An assessment of the impact of an MRTP marketing authorization on the population as a whole is 

primarily a function of the relative health risks of the proposed product and the likelihood of tobacco 

use behavior change, including due to the modified risk marketing. Assessing the impact to the 

population as a whole includes an assessment of the potential impact of the product, including with the 

proposed modified risk information, on tobacco users and non-users if the product were to be 

authorized as an MRTP. 

Several lines of evidence were provided to inform the assessment of the impact of the proposed MRTPs 

on tobacco users and non-users, including abuse liability studies, pre- and post-market observational

studies, and consumer perception studies evaluating the impact of the proposed modified risk claims. In 

addition, the applicant provided a population model of the potential impact of the proposed MRTPs. A 

summary of these studies and conclusions is presented below.

1. Impacts to Tobacco Users

a. Review of CPD Reductions and Anticipated Patterns of Use

As described in Section III(B)(4)(a), individuals who smoke VLNC cigarettes either demonstrate no 

significant differences in smoking topography relative to those who smoke UB-NNC 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). 

Additionally, as described in Sections III(B)(4)(b-c), most smokers assigned to use VLNCs in clinical 

studies dual-used them with UB-NNC cigarettes. Smokers who predominantly use VLNCs—even when 

dual-using some UB-NNC cigarettes—experience a significant reduction in CPD and reduced dependence 

scores. The applicant also acknowledges that the likely situation with VLNTM cigarettes would be one 

where, upon initiation, consumers who want to quit may have difficulty adhering to just smoking VLNTM

cigarettes and may initially alternate between UB-NNC cigarettes and VLNTM cigarettes; however, dual 

use with UB-NNC cigarettes would likely subside over time as smokers acclimate to smoking VLNTM

cigarettes.

Previous research has also found that reducing cigarette consumption can increase the likelihood that 

an individual will become cigarette abstinent in the future (Hughes & Carpenter, 2006). Among smokers 

motivated to quit, switching to VLNC cigarettes may facilitate smoking abstinence as a result of reduced 

nicotine exposure, particularly when used in combination with NRT and behavioral intervention

(Dermody, Donny, Hertsgaard, & Hatsukami, 2015; Hatsukami et al., 2010; Walker et al., 2012). 

For these reasons, in Section III(B)(4), I conclude that it is reasonably likely that cigarette smokers will 

experience a reduction in nicotine dependence, which will also reduce tobacco dependence, from 

using these products. 

However, the evidence provided by the applicant suggests that reduced cigarette consumption, rather 

than complete smoking cessation, is the main benefit of VLNTM cigarettes. However, it is also reasonably 

likely to infer that reduced nicotine dependence, leading to reduced cigarette consumption, can also 

lead to increased quit attempts and increased likelihood of future smoking cessation. The applicant 
MR0000159- MR0000160 Page 57 of 90 

stated that the target market will be current smokers who wish to reduce their nicotine consumption 

and could potentially reduce cigarette consumption and quit smoking. Since there are no long-term 

epidemiological studies on cigarette consumption among VLNTM cigarette smokers, the CPD 

consumption evidence provided by the applicant was based on clinical studies where NNC smokers, with 

no intention to reduce their nicotine consumption nor quit smoking, were instructed to switch to use 

VLNTM cigarettes. It is not clear how well CPD findings from clinical studies will generalize to a real-world 

setting; they could be overestimates or underestimates (as discussed in Section III(B)(c). FDA used the

best evidence available—the longest study of VLNC cigarettes to date—to estimate CPD reductions 

from using the proposed MRTPs. In this study, total CPD (including study and non-study cigarettes) 

was reduced by 46-53% in VLNC cigarette smokers compared to NNC cigarette smokers after 20 weeks 

of use (Hatsukami et al., 2018). Thus, FDA evaluates the potential risk reductions associated with a 

50% or more reduction in CPD. However, it should be noted that smokers who do not reduce their CPD 

by at least 50% are not expected to reduce risks of negative health effects. Additionally, health risks are 

found even with consistent low-level smoking (10 or fewer CPD) (Rigotti, 2018). 

b. Risk Reductions that are Reasonably Likely Based on Reduced CPD

The medical and epidemiology reviews assessed potential health risk reductions (besides nicotine 

dependence) from reducing CPD.

While the health benefits of smoking reduction are not as well established as those of smoking 

cessation, the evidence suggests that 50%+ reductions in CPD may reduce some tobacco-related 

morbidities other than nicotine dependence, but not others. The relationship between the amount of 

cigarette smoking and disease is not strictly linear, and smoking reduction does not result in 

improvement in all health outcomes. For example, Godtfredsen et al. (2003, 2005) examined the effect 

of smoking reduction on lung cancer risk and found that heavy smokers (≥15 CPD) who reduced CPD by 

at least 50% had about a 25% reduction in lung cancer risk compared to continuing heavy smokers.

While some studies found that a decrease of at least 50% CPD was associated with beneficial effects in 

some cardiovascular risk factors, such as cholesterol levels, another study found that smoking reduction 

had no effect on the risk of myocardial infarction (Bollinger, 2000; Bollinger et al., 2002; Eliasson et al., 

2001; Hatsukami et al., 2005; Haustein et al., 2004; Godtfredsen et al., 2003). Similarly, while smoking 

reductions of at least 50% have resulted in improvement in some pulmonary symptoms, studies have 

not shown robust improvements in lung function or a reduction in the risk of hospitalization for chronic 

obstructive pulmonary disorder (COPD) (Hatsukami et al., 2005; Stein et al., 2005; Burchfiel et al., 1995; 

Godtfredsen et al., 2002). 

Lee (2013) reviewed 14 studies that examined the effect of smoking reduction on risks of lung cancer, 

COPD, and CVD. He found that compared to non-reducers, any reduction in cigarette consumption 

significantly lowered risk of lung cancer but did not significantly reduce risks of CVD, all-cause mortality, 

smoking-related cancer mortality, and COPD. However, he did not examine this smoking reduction in a 

specific category reflecting amount of smoking reduction (e.g., any reduction, <50% [reduction], ≥50%); 

many studies included in this meta-analysis had different smoking reduction categories. Taken together, 

published epidemiological studies (e.g., Godtfredsen et al., 2003; Godtfredsen et al., 2005; Lee, 2013; 

Inoue-Choi et al., 2019; Tverdal & Bjartveit, 2006) assessing the relationship between smoking 

reduction and disease risks suggest that a reduction in some morbidities is reasonably likely, such as 

lung cancer risk in those who reduced cigarette consumption by more than 50%, compared to non-
MR0000159- MR0000160 Page 58 of 90 

reducers (Godtfredsen et al., 2005); however, this is not the case for all morbidities (Lee, 2013; 

Tverdal & Bjartveit, 2006; Godtfredsen, 2008). 

Studies have not consistently demonstrated that a reduction in CPD reduces mortality. Godtfredsen et 

al. (2002) found no change in all-cause mortality, mortality from COPD/respiratory infections, or 

mortality from CVD in heavy smokers who reduced their tobacco consumption by at least 50% 

compared to continued heavy smokers in a prospective cohort study. Tverdal & Bjartveit (2006) found 

similar results with no change in all-cause mortality or mortality due to smoking-related cancer after 

smoking reduction. However, a recent study evaluating changes in smoking patterns over a longer time 

period than previous studies found that all-cause mortality was lower among smokers who reduced 

their CPD compared to those who maintained their CPD, with greater reductions in CPD yielding greater 

benefits (Inoue-Choi et al., 2019). 

These data suggest that compared to continued use of NNC cigarettes, some smokers who switch to 

VLNCs and reduce their CPD may achieve the health benefits that have been directly associated with a 

≥50% reduction in CPD, such as reductions in lung cancer risk. Thus, in absence of long-term 

epidemiological studies of the proposed MRTPs, I find that marketing the proposed MRTPs is 

reasonably likely to reduce some tobacco-related morbidities. 

c. Summary and Conclusion

Below are key findings from the medical and epidemiology reviews regarding potential risk reductions 

from reducing CPD:

• Smokers who predominantly use VLNCs—even when dual-using some UB-NNC cigarettes—

experience a significant reduction in CPD and reduced dependence scores. Previous research 

has also found that reducing cigarette consumption can increase the likelihood that an 

individual will become cigarette abstinent in the future. 

• Although there is uncertainty in how clinical study data will generalize to the real-world setting, 

the longest clinical study of VLNCs found that total CPD (including study and non-study 

cigarettes) was reduced by 46-53% in VLNC cigarette smokers compared to NNC cigarette 

smokers after 20 weeks of use (Hatsukami et al., 2018). Thus, FDA evaluates the potential risk 

reductions associated with a 50% or more reduction in CPD.

• Published epidemiological studies assessing the relationship between smoking reduction and 

disease risks suggests that a reduction in some morbidities is reasonably likely, such as lung 

cancer risk in those who reduced cigarette consumption by more than 50% compared to nonreducers; however, this is not the case for all morbidities.

• Previous studies have not consistently demonstrated that a reduction in CPD reduces mortality. 

However, a recent study evaluating changes in smoking patterns over a longer period of time 

than previous studies found that all-cause mortality was lower among smokers who reduced 

their CPD compared to those who maintained their CPD, with greater reductions in CPD yielding 

greater benefits (Inoue-Choi et al., 2019). 

As TPL, I agree with these findings. Based on these findings, and in absence of long-term 

epidemiological studies of the proposed MRTPs, I find that marketing the proposed MRTPs is 
MR0000159- MR0000160 Page 59 of 90 

reasonably likely to reduce some tobacco-related morbidities, in addition to nicotine dependence. 

Under section 911(g)(2)(A)(iii) of the FD&C Act, to issue an exposure modification order, FDA must 

find “that scientific evidence is not available and, using the best available scientific methods, cannot 

be made available without conducting long-term epidemiological studies for an application to meet 

the standards set forth in [section 911(g)(1)].” The available evidence is not sufficient to conclude 

that the applicant has demonstrated that the products, as actually used by consumers, will 

“significantly reduce harm and the risk of tobacco-related disease to individual tobacco users” and 

“benefit the health of the population as a whole.” There are no long-term epidemiological studies 

on cigarette consumption among VLNTM cigarette smokers and the CPD consumption evidence 

provided by the applicant was based on clinical studies where NNC smokers, with no intention to 

reduce their nicotine consumption nor quit smoking, were instructed to switch to use VLNTM 

cigarettes. It is not clear how well CPD findings from clinical studies will generalize to a real-world 

setting; they could be overestimates or underestimates. Thus, there are outstanding questions 

about the manner in which consumers will use VLN, and if individual tobacco users use VLN 

cigarettes in the same frequency and manner as conventional cigarettes, they will not significantly 

reduce harm and their risk of tobacco-related disease. In addition, while the applicant-sponsored 

studies do not address biomarkers of potential harm (BOPH), one published study on the effect on 

BOPH of switching from conventional cigarettes to VLNC cigarettes was submitted (Hatsukami et al.,

2019). This study did not identify robust changes between the study groups; therefore, no 

conclusions regarding the short- or long-term health risk of VLNTM cigarettes can be made based on 

the available BOPH data. In totality, conclusive scientific evidence to meet the standards set forth in 

section 911(g)(1) is not available.

However, it is reasonably likely that cigarette smokers who use VLN cigarettes will experience a 

reduction in nicotine dependence, which will also reduce tobacco dependence. Reductions in 

tobacco dependence can lead to increased tobacco cessation and are anticipated to lead to longterm reductions in exposure to the smoking-related toxicants associated with morbidity and 

mortality. Using the proposed MRTPs would be reasonably likely to reduce nicotine dependence and 

a reduction in CPD of at least 50% is associated with a reduction in some tobacco-related diseases 

(e.g., lung cancer), but not others, supporting a likely overall population health benefit.

Thus, although reduced risk has not been demonstrated, the totality of evidence presented 

suggests that a measurable and substantial reduction in morbidity or mortality among individual 

tobacco users is reasonably likely in subsequent studies. Therefore, these findings provide 

additional support for the applications submitted under the 911 (g) (2) reduced exposure standard: 

911(g)(2)(A)(iii), which states that where “scientific evidence is not available and, using the best 

available scientific methods, cannot be made available without conducting long-term 

epidemiological studies for an application to meet the standards set forth in paragraph (1) ...” 

[section 911(g)(1)] pursuant to modified risk 911 (g)(1) reduced risk standard.
MR0000159- MR0000160 Page 60 of 90 

2. Tobacco Users’ Likelihood of Use After Exposure to the Proposed Modified 

Risk Claims 

The applicant’s quantitative perception and intention study assessed adult smokers’ intentions to try or 

use the proposed MRTPs after exposure to its proposed modified risk labeling. The findings from these 

studies are summarized below. More detailed description and analysis can be found in the social science 

review.

a. Likelihood that Current Smokers will Start Using the Proposed MRTPs 

The applicant’s research found that many current smokers were interested in VLNTM after viewing pack 

labeling with the modified risk claims. The applicant’s M/A/R/C Quantitative Study (total sample size 

n=29,219; Protocol #: 5180080-VLNTM-B2) randomly assigned participants to view either images of a 

Marlboro GoldTM cigarette pack or a VLNTM cigarette pack with the proposed modified risk information. 

Specifically, among participants who viewed the VLNTM pack, they viewed multiple conditions that either

contained: Claims #1-3 and the disclaimer; Claims #1, and #3, the disclaimer and “helps you smoke less”; 

Claims #1, and #3, the disclaimer, and “ .”. After viewing the cigarette 

pack, participants reported their intentions to purchase VLNTM/ Marlboro GoldTM and their intentions to 

smoke VLNTM/ Marlboro GoldTM “on a regular, ongoing basis.” Current smokers reported moderate 

intentions to purchase both products, with mean intentions to purchase VLNTM well above the midpoint 

of the scale (mean intentions of approximately 3.4) and mean intentions to purchase Marlboro GoldTM 

slightly below the midpoint of the scale. 

Intentions to purchase VLNTM were substantially higher than intentions to purchase Marlboro GoldTM (by 

approximately 0.5 on the 5-point scale), a difference that reached statistical significance (M/A/R/C 

Quantitative Study Report, p. 104). Current smokers also reported substantially higher intentions to use 

VLNTM on a regular, ongoing basis compared to Marlboro GoldTM (mean intentions of approximately 3.7; 

M/A/R/C Quantitative Study Report, pp. 103-105). 

Intentions to use VLNTM on a regular, ongoing basis were especially high among current smokers 

intending to quit smoking (mean intentions of approximately 3.8-3.9; M/A/R/C Quantitative Study 

Report, p. 112). This finding is consistent with the potential for a population health benefit, if current 

smokers reduce their overall cigarette smoking when using VLNTM cigarettes. Note that the applicant 

used a broad definition of quit intentions that includes up to two-thirds of current smokers in the U.S. 

(Persoskie & Nelson, 2013), even though fewer than 10% of smokers might be expected to successfully 

quit smoking within the next year (Babb, Malarcher, Schauer, Asman, & Jamal, 2017; Messer, Trinidad, 

Ad-Delaimy, & Pierce, 2008).

Because of an issue in the study design (detailed in Section 5.2 of the social science review), the study’s 

estimates of current smokers’ intentions to purchase and use Marlboro GoldTM exclude all of the 

smokers who already smoke Marlboro GoldTM as their usual brand. Because of this, we do not expect 

that current smokers would be more likely to purchase and use VLNTM compared to Marlboro GoldTM. 

Rather, a more supportable conclusion is that, among current smokers who try a new brand, trial of 

VLNTM may exceed trial of Marlboro GoldTM.

(b) (4)
MR0000159- MR0000160 Page 61 of 90 

b. Likelihood that Current Smokers Will Use VLNTM to Cut Down or Quit 

Smoking 

Although the applicant’s research on its proposed labeling suggests that marketing VLNTM with the 

proposed modified risk information would increase use of VLNTM cigarettes among adult current 

smokers, the applicant provided limited information about how current smokers would use VLNTM

cigarettes, such as whether they would use VLNTM to substantially reduce their overall smoking 

frequency. 

As noted above in Section 3 (“Evaluating Consumer Understanding”), the proposed LLA do not include 

statements about using VLNTM to cut down on one’s overall cigarette smoking. Rather, the applicant 

argues that some smokers will choose to replace their current cigarettes with VLNTM and, depending on 

their efforts to primarily use VLNTM, will then reduce their overall smoking frequency (Section 7 

“Summary of All Research Findings,” p. 29). Indeed, the applicant summarized clinical studies showing 

that using VLNTM cigarettes leads to “decreased cigarette consumption, reduction in nicotine absorption, 

reduction in other biomarkers of exposure, more quit attempts, and abstinence” (Executive Summary, p. 

2). However, in these studies, smokers who were informed of VLNC cigarettes’ very low nicotine content 

were also given instructions for how to use VLNC cigarettes (e.g., they were told to smoke VLNC 

cigarettes and not smoke their usual brand cigarettes [6-Week Clinical Switching Study CA24914], or 

they were provided with VLNC cigarettes as part of a smoking cessation program [McRobbie et al., 

2016]). To our knowledge, none of those studies provided participants with information comparable to 

the proposed modified risk LLA, which inform people about the reduced nicotine content without 

instructing participants to use VLNTM cigarettes to cut down on their smoking (or to try to primarily use 

VLNTM cigarettes rather than their other cigarettes, which facilitates smoking fewer cigarettes overall). 

Without providing information about the conditions of use for VLNTM cigarettes (e.g., “Helps you smoke 

less”), it is unclear whether smokers will understand the intended conditions of use and the need to cut 

down in order to obtain benefits from the reduced nicotine content in VLNTM cigarettes. 

Beyond the clinical studies discussed above, the applicant’s consumer perception research provides 

limited additional information about smokers’ intentions to use VLNTM as a substitute for other 

cigarettes or to cut back on smoking. Specifically, the M/A/R/C Quantitative Study asked the following 

question among current smokers who reported that they might purchase VLNTM and Marlboro GoldTM: 

“Would your purchase(s) of [VLNTM/ Marlboro GoldTM] replace any tobacco or nicotine-replacement 

products that you currently use?” The majority of smokers who reported that they might purchase 

VLNTM responded, “Yes, buying VLNTM would result in fewer purchases of other tobacco or nicotinereplacement products.” Specifically, among current smokers intending to quit, over 80% expected that 

buying VLNTM would result in fewer purchases of other tobacco or nicotine-replacement products, 

compared to only 58% for Marlboro GoldTM; among current smokers not intending to quit, 64% expected 

that buying VLNTM would result in fewer purchases of other tobacco or nicotine-replacement products, 

compared to only 42% for Marlboro GoldTM. Smokers intending to quit were more likely than smokers 

not intending to quit to report that their VLNTM purchase would result in fewer purchases of other 

tobacco or nicotine-containing products (which was also observed for intended purchases of Marlboro 

GoldTM), which is consistent with the expectation that intended quitters would be unlikely to want to 

increase their overall cigarette consumption. 

When smokers were asked which products they would cut back on as a result of buying VLNTM, almost all 

chose cigarettes (approximately 90%), and few chose NRT (1-4% across smokers intending and not 
MR0000159- MR0000160 Page 62 of 90 

intending to quit; M/A/R/C Quantitative Study Report, p. 115). These findings suggest that, if VLNTM is 

marketed with the proposed modified risk information, many smokers would be interested in 

purchasing VLNTM to replace at least some of their cigarette purchases. However, the applicant’s 

consumer research provides no information about whether smokers intend to use VLNTM cigarettes to 

cut down on their overall cigarette consumption or simply replace all or some of their current cigarette 

use with VLNTM cigarettes. Including the phrase “Helps you smoke less” as discussed in Section III(C)(2)

of this review would address this issue. Findings also suggest that, after viewing the proposed 

modified risk labeling, few smokers planned to use VLNTM instead of NRT, including smokers intending 

to quit. 

c. Likelihood that Current Smokers Will Use VLNTM Instead of Quitting 

Smoking

The majority of studies on VLNC cigarettes were conducted in participants not interested in quitting, 

which does not accurately reflect the population of smokers most likely to use VLNTM cigarettes (i.e., 

those interested in reducing cigarette consumption). However, some studies from the literature 

discussed in Appendix 2 of the BCP review find that among smokers motivated to quit, VLNC cigarettes 

may facilitate abstinence due to reduced nicotine exposure. Using 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 UB-NNC cigarette 

smokers, although quit attempts were greater among those assigned to smoke VLNC cigarettes. 

However, VLNTM cigarettes may appeal to smokers interested in quitting. This consumer subset may be 

motivated to use VLNTM cigarettes to reduce nicotine consumption, and as a result, VLNTM cigarettes may 

potentially aid in facilitating cessation. It is unlikely that current tobacco users who are not interested in 

quitting will completely switch to VLNTM cigarettes or a smoking cessation product, such as NRT. 

However, smokers motivated to reduce their cigarette consumption may be more likely to switch 

completely to VLNTM cigarettes or attempt to quit smoking with concurrent use of NRT and behavioral 

intervention. 

In addition, given that quitting behaviors may also depend, in part, on whether smokers understand 

VLNTM cigarettes’ health risks and conditions of use, if FDA authorizes the applicant to market VLNTM 

cigarettes with the proposed claims, I recommend that the order require that all modified risk LLA 

display the intended conditions of use for VLNTM cigarettes, “Helps you smoke less,” to clarify the 

purpose of VLNTM cigarettes. If smokers misunderstand the proposed modified risk information to mean 

that VLNTM cigarettes are less toxic than other cigarettes and present lower risks even when smoked in 

the same way, previously published research suggests the theoretical possibility that this could reduce 

smokers’ intentions to quit. For example, in a nationally representative study of U.S. adult smokers, 

those who believed that VLNC cigarettes were less carcinogenic than other cigarettes were more likely 

than other smokers to say that a very low nicotine standard (i.e., a standard limiting the nicotine 

content in all cigarettes) would reduce their likelihood of quitting smoking (Byron et al., 2018). Also, 

prior research on cigarettes and other tobacco products has found that perceptions of product risk 

predict whether current users will continue using the products (e.g., Brose et al., 2015; Elton-Marshall et 

al., 2020). Thus, although data on VLNTM’s abuse liability and clinical effects suggest that VLNTM would not 

deter quitting, we expect that providing the intended conditions of use will enable smokers to 

understand VLNTM’s health risks and purpose and avoid negatively influencing smokers’ intentions to 

quit.
MR0000159- MR0000160 Page 63 of 90 

d. Vulnerable population: Impact of marketing on people with 

mental health issues

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 (individuals with depression, 

schizophrenia, and 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. Effects 

on adolescent smokers are further discussed in the subsequent section on ‘ Tobacco Nonusers’ 

Likelihood of Use After Exposure to the Proposed Modified Risk Claims: Impact of Marketing on Youth’. 

The literature supports that in smokers with mental health symptoms, as in the general population, 

VLNC cigarettes were associated with smaller reductions in craving 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.

e. Summary and Conclusion

Below I describe social science’s key findings related to tobacco users’ likelihood of use after exposure 

to the proposed modified risk information:

• Current smokers reported moderate intentions to purchase both VLNTM cigarettes and Marlboro 

GoldTM, with mean intentions to purchase VLNTM cigarettes well above the midpoint of the scale.

Among current smokers who try a new brand, trial of VLNTM cigarettes may exceed trial of 

Marlboro GoldTM. Intentions to purchase and intentions to use on a regular, ongoing basis were 

substantially higher for VLNTM cigarettes than for Marlboro GoldTM. Intentions to use VLNTM 

cigarettes on a regular, ongoing basis were especially high among current smokers intending to 

quit smoking.
MR0000159- MR0000160 Page 64 of 90 

• To evaluate the likelihood that current smokers will use the product to cut back or quit smoking, 

social science first evaluated the product labeling, and noted that it did not include information 

instructing users to cut down on their smoking or to try to primarily use VLNTM cigarettes. 

Without providing information about the conditions of use for VLNTM cigarettes (e.g., “Helps you 

smoke less”), it is unclear whether smokers will understand the intended conditions of use and 

the need to cut down or reduce cigarette smoking in order to obtain benefits from the reduced 

nicotine content in VLNTM cigarettes. 

• There is some evidence that smokers intending to quit expected that buying VLNTM cigarettes 

would result in them cutting back on buying other cigarettes. Among current smokers intending 

to quit who expressed they might purchase VLNTM, over 80% expected that buying VLNTM would 

result in fewer purchases of other tobacco or nicotine-replacement products, compared to only 

58% for Marlboro GoldTM; among current smokers not intending to quit, 64% expected that 

buying VLNTM would result in fewer purchases of other tobacco or nicotine-replacement 

products, compared to only 42% for Marlboro GoldTM. When smokers were asked which 

products they would cut back on as a result of buying VLNTM cigarettes, almost all chose 

cigarettes (approximately 90%), and few chose NRTs. 

• Most clinical studies of VLNCs are conducted among smokers who do not intend to quit. 

However, some studies indicate that among smokers motivated to quit, VLNC cigarettes may 

facilitate abstinence due to reduced nicotine exposure. Using NRT and behavioral intervention 

with VLNC cigarettes may aid cessation in some smokers motivated to quit.

• The literature supports that in smokers with mental health symptoms, as in the general 

population, VLNC cigarettes were associated with smaller reductions in craving 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.

As TPL, I agree with these findings. Based on this information, I find it likely that smokers will have 

interest in trying the proposed MRTPs when they are marketed with the proposed claims. Furthermore, 

I find it possible that consumers will not understand how to use the product to get the likely risk 

reduction; therefore, I recommend that the order require that all modified risk LLA display the 

intended conditions of use for VLNTM cigarettes, “Helps you smoke less,” to clarify the purpose of 

VLNTM cigarettes. Additionally, I find that smokers motivated to quit are not likely to engage in sustained 

use of this product instead of quitting, as smokers intending to quit who are interested in this product 

plan on cutting down purchases of NNC cigarettes, and as VLNC cigarettes may facilitate abstinence. 

Together, these findings are supportive that marketing VLNTM cigarettes with these reduced exposure 

claims could appeal to current smokers who are most likely to benefit from their use, and this

supports a likely benefit to population health. 
MR0000159- MR0000160 Page 65 of 90 

3. Tobacco Nonusers’ Likelihood of Use After Exposure to the Proposed 

Modified Risk Claims

The impact on tobacco use behavior among current users must be considered alongside the potential 

effects on tobacco use initiation among non-users. The applicant assessed the potential impact of

marketing VLNTM cigarettes with the proposed modified risk claims among current non-users by 

including adult former smokers and never smokers in its consumer perception studies. The applicant did 

not provide any direct data on the potential for use or appeal among U.S. youth. A summary of the 

relevant findings is presented below and provided in more depth in the social science and BCP reviews. 

a. Adult Never and Former Smokers, including Young Adults and Recent 

Quitters

The applicant’s research suggests that marketing VLNTM cigarettes with the proposed modified risk 

information on the product labeling has the potential to slightly increase the use of VLNTM cigarettes 

among never and former smokers, but that rates of use would be low. Specifically, the M/A/R/C 

Quantitative Study (total sample size n=29,219; Protocol #: 5180080-VLNTM-B2) randomly assigned 

participants to view either images of a Marlboro GoldTM cigarette pack or a VLNTM cigarette pack with the 

proposed modified risk information. Specifically, among participants who viewed the VLNTM pack, they 

viewed multiple conditions that either contained: Claims: #1-3 and the disclaimer; Claims #1, and #3, the 

disclaimer and “helps you smoke less;”; Claims # 1, and #3, the disclaimer, and

After viewing the cigarette pack, participants reported their intentions to “smoke [VLNTM/ 

Marlboro GoldTM] on a regular, ongoing basis,” and their intentions to purchase VLNTM/ Marlboro GoldTM. 

Former and never smokers’ mean intentions to purchase both products were near the bottom of the 

scale (for VLNTM, approximately 1.3-1.4 on the 6-point scale). Intentions to purchase VLNTM were slightly 

higher than intentions to purchase Marlboro GoldTM, a difference that reached statistical significance 

given the study’s large sample size (M/A/R/C Quantitative Study Report, p. 104). Never smokers (but not 

former smokers) also reported significantly higher intentions to smoke VLNTM on a regular, ongoing basis 

compared to Marlboro GoldTM, with mean intentions again near the bottom of the scale (for VLNTM, 

approximately 1.3-1.4 on the 5-point scale; M/A/R/C Quantitative Study Report, p. 103).

Results among subgroups at increased risk of tobacco use were similar to those above, with slightly

higher intentions among never smokers who are young adults (aged 18-25 years-old; compared to older 

adult never smokers; i.e., mean intentions to purchase VLNTM and use VLNTM of approximately 1.5;

M/A/R/C Quantitative Study Report, p. 108) and considerably higher intentions among former smokers 

who quit recently (compared to long-term quitters; i.e., mean intentions to use VLNTM cigarettes of 

approximately 2.0; M/A/R/C Quantitative Study Report, p. 109).

The above findings suggest the potential for a low, but still notable, level of trial of VLNTM cigarettes 

among adult former and never smokers if marketed with the proposed modified risk information. As the 

applicant states, Marlboro GoldTM was selected as a comparator product because it is currently on the 

market and has known use rates (M/A/R/C Quantitative Study Protocol, p. 18). Specifically, based on 

2017 sales data, Marlboro is the leading cigarette brand in the U.S., with sales volume accounting for 

approximately 40% of total cigarette sales and consumption (CDC, 2019; Sharma et al., 2016). Also, the 

item assessing intentions to use VLNTM included the following potentially biasing text: “By intent to use, 

we mean that you personally, as a non-smoker, now intend to smoke VLNTM on a regular, ongoing basis” 

(b) (4) (b) (4)
MR0000159- MR0000160 Page 66 of 90 

(emphasis added). This text may have implied to former and never smokers that they should not intend 

to smoke VLNTM cigarettes on a regular, ongoing basis because they are non-smokers. 

b. Impact of Marketing on Youth

The application did not provide information about the likelihood that youth would use VLNTM cigarettes 

if marketed with the proposed modified risk information. After considering the factors outlined below 

and considering the youth marketing restrictions outlined in the PMTA order letters, FDA has low 

concern about youth initiation and progression to regular use.

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. 

Additionally, 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 UB-NNC 

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 dose-dependent differences in appeal, compared to 

measures that directly assess subjective response. In all, this 2019 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 was associated 

with reduced abuse liability compared to usual brand cigarettes in this group of adolescent smokers.

Several additional factors suggest that, depending on how VLNTM cigarettes are marketed, effects on 

youth may be limited. Most notably, youth cigarette smoking rates declined between 2002 and 2010 

(Johnston et al., 2019), a period when Quest cigarettes were on the U.S. market and advertised as “low 

nicotine,” “extra low nicotine,” and “nicotine free,” and as products that allowed people to “enjoy 

smoking without all of the Nicotine” (Shadel et al., 2006; Strasser et al., 2008). In addition, a study in a 
MR0000159- MR0000160 Page 67 of 90 

convenience sample of college students found that, after viewing ads for Quest, Eclipse (a heated 

cigarette), and Marlboro, the students rated Quest cigarettes as lower than Marlboro Lights and Eclipse 

on a scale of positive expectancies (including, for example, satisfying, fun, exciting, interesting) that 

predicted willingness to try each type of cigarette (O’Connor et al., 2007). However, generalizability 

from such studies is limited because of potential differences in the proposed LLA for VLNTM cigarettes. 

For example, the applicant proposed to use different modified risk claims than those used for Quest, as 

well as ads that may differ in their appeal, targeting, and dissemination. Recent changes in the 

advertising landscape – in particular the rise of social media as a platform for reaching young audiences 

– also raise the possibility that VLNTM’s modified risk advertising could have different effects on youth 

compared to Quest’s advertising from the 2000s. Therefore, it is possible that the marketing of these 

products could increase youth appeal and the likelihood that youth may believe that these cigarettes 

might be “safer” than NNC cigarettes, initiate use with them, and even transition to NNC cigarette 

smoking. Accordingly, the marketing for VLNTM cigarettes should avoid the use of youth appealing ads 

or imagery and should be targeted to reach adult smokers. We also note that the PMTA order for these 

identical products, issued in December 2019, includes restrictions on marketing to limit youth exposure.

c. Summary and Conclusion 

Below I describe social science’s key findings related to tobacco nonusers’ likelihood of use after 

exposure to the proposed modified risk information:

• The applicant’s research suggests that marketing VLNTM with the proposed modified risk 

information on the product labeling has the potential to slightly increase the use of VLNTM

cigarettes among never and former smokers, but that rates of use would be low. Intentions to 

purchase and smoke VLNTM cigarettes on a regular, ongoing basis were low, though slightly 

higher than for Marlboro GoldTM. Intentions among young adults aged 18-25 were slightly 

higher, but still low. Recent quitters had slightly higher intentions to use VLNTM cigarettes, 

though they were still below the midpoint of the scale. 

• The application did not provide information about the likelihood that youth would use VLNTM 

cigarettes if marketed with the proposed modified risk information. However, at this time, 

based on the available evidence, the risk of youth initiation and progression to regular use

appears to be low because: the products have low abuse liability and youth may be less likely to 

develop nicotine dependence using them; young adults rate VLNCs as having lower subjective 

effects ratings compared to NNC cigarettes; and a study of adolescents found that the 

reinforcing efficacy or appeal of all doses of VLNC cigarettes was lower compared to UB-NNC 

cigarettes.

As TPL, I agree with these findings. Based on this information, I find it likely that nonsmokers will have 

low interest in trying the proposed MRTPs when they are marketed with the proposed claims. This

provides support for the required findings in section 911(g)(2)(A)(i) that “[the] order would be 

appropriate to promote the public health” and section 911(g)(2)(B)(iv) that “[the] order is expected to 

benefit the health of the population as a whole”) Concerns related to youth initiation and progression to 

regular use of these proposed MRTPs are low; however, given that youth are at increased risk, generally, 

for initiating tobacco use and the potential effect of modified risk information on youth use, it is critical 

that a marketing plan for the products be designed to target tobacco users and prioritize preventing 

youth exposure. Studies suggest that perceptions of risk predict tobacco product use among youth (Song 
MR0000159- MR0000160 Page 68 of 90 

et al., 2009) (Strong et al., 2019). It is important to note that FDA’s marketing authorization order for the 

same products (but without modified risk information) (PM0000491-PM0000492) includes requirements 

intended to help ensure that the marketing of the products will continue to be appropriate for the 

protection of the public health, taking into account initiation among non-users, particularly youth. This 

includes providing FDA with advertising and marketing plans, including plans to restrict youth access and 

limit youth exposure to the products’ labeling, advertising, marketing, and/or promotion. In addition, 

the applicant is required track and measure actual delivery of all advertising impressions, including 

among youth. 

4. Population Health Impact Model 

The applicant provided a population model estimating the public health impacts of VLNTM cigarettes. 

Epidemiology assessed the data inputs and assumptions concerning tobacco use behaviors including 

smoking prevalence, all-cause mortality, and life-years saved with and without use of VLNTM cigarettes. 

In Section VIII.F “Effect on the Population as a Whole,” the applicant presented two objectives, which 

were: (1) to predict conventional cigarette (CC) and VLNTM cigarette smoking according to the current 

regulatory framework; and (2) to show the effect of potentially increased smoking cessation and CPD 

reduction by VLNTM smokers, with the final endpoints being smoking prevalence and cigaretteattributable deaths (life-years gained) with VLNTM cigarettes on the market through year 2100. The

simulation model assessed the possible effects of the proposed VLNTM cigarettes on US population 

health. This model projects smoking prevalence (Figure VIII.F-5), avoided cigarette-attributable deaths 

(Figure VIII.F-6), and life-years gained (Figure VIII.F-6) with VLNTM products potentially on the market. 

The applicant also provided more details about the model inputs and results in the Summary Report, “A 

Simulation Model to Evaluate the Impact of VLNTM Cigarettes on the Population as a Whole.” The figures 

and table numbers in this part of the review reflect those used in applicant’s Summary Report.

The applicant used a Markov state dynamic population model to estimate the impact of introducing 

VLNTM cigarettes on the U.S. market. In terms of smoking inputs, the applicant used data from the 

National Health Interview Survey (NHIS) and National Survey on Drug Use and Health (NSDUH), which 

represent the U.S. population, to derive smoking initiation rates for CC smokers. For the VLNTM smoking 

initiation rate, the applicant assumes that the market share of CC and VLNTM will be equalized at 

approximately 25% by the year 2050, meaning that 7.1% of CC smokers will initiate VLNTM smoking per 

year (i.e., if 7.1% of CC smokers switch to VLNTM cigarettes every year until 2050, 25% of smokers will be 

using VLNTM cigarettes by 2050). 

Key model inputs include:

• Population: The applicant used 2015 U.S. Census estimates to project the population for years 

2016 to 2060 by age and sex.

• Smoking behavior: The applicant calculated conventional cigarette (CC) smoking initiation rates 

based on prevalence of established smoking from age 18-24 from the 2015 NHIS data. The 

applicant estimated quit rates for VLNTM cigarettes using the continued abstinence rates from 
MR0000159- MR0000160 Page 69 of 90 

Walker et al. (2012), which showed that 33% of VLNC smokers and 28% of non-VLNC smokers 

remained abstinent six months after quitting.

• Initiation: With regard to VLNTM cigarette smoking initiation, the applicant stated that former 

and never smokers would not be attracted to VLNTM cigarettes based on the consumer 

perception study. The applicant estimated the initial VLNTM cigarette uptake rate from CC rates 

based on the 25% market share by 2050: 50% of initial VLNTM cigarette smokers will sustain use 

after one year, and 10% of initial VLNTM cigarette smokers will relapse back to CC smoking per 

year.

• CPD changes: The applicant estimated that 80% of VLNTM cigarette smokers will reduce CPD by

50%. The applicant referenced Figure 2 of the Hatsukami et al. (2018) study, which depicted the 

proportion of smokers who will reduce CPD by at least 50%. All VLNTM smokers will experience 

the same excessive relative risk (ERR) as CC smokers.

• Mortality: The applicant estimated the all-cause mortality rates by age group, sex, and smoking 

status. Mortality rates for current smokers were based on CPD. The applicant used data from 

Poland et al. (2017), Thun et al. (2013), and Bjartveit et al. (2005), to estimate models on CPD 

consumption and mortality. 

Key model assumptions include:

• The applicant stated that use of CC or VLNTM cigarettes will be interpreted as predominant use 

rather than exclusive use. Instead, the applicant modeled the transition rates of CC smoking to 

“initial VLNTM smoking” and “initial VLNTM cigarette smoking” to “sustained VLNTM cigarette

smoking.” In the model, dual use of VLNTM cigarette and CC smoking was not considered 

explicitly.

• Non-combusted tobacco use (e.g., smokeless tobacco, ENDS) was not modeled. The applicant 

stated that declining rates of CC smoking over time could reflect dual use with non-combusted 

products. 

• VLNTM cigarette smokers could have different quit rates, CPD, and relative risks compared to CC 

smokers. 

• CC smokers have a fixed number of CPD over time; however, CPD reduction among VLNTM 

cigarette smokers vary. 

• Market share of VLNTM cigarettes will reach 25% by 2050 (i.e., if 7.1% of CC smokers switch to 

VLNTM cigarettes every year until 2050, 25% of smokers will be using VLNTM cigarettes by 2050).

The applicant provided estimates of six scenarios with different CC quit rates of VLNTM cigarette smokers 

relative to CC smokers and long-term relapse rates of VLNTM cigarette smoking back to CC smoking:

• Scenario 1 (Base): 118% quit rate and 10% relapse rate

• Scenario 2 (Low-Low, Pessimistic): 100% quit rate and 20% relapse rate
MR0000159- MR0000160 Page 70 of 90 

• Scenario 3 (Low-Base, Intermediate 1): 100% quit rate and 10% relapse rate

• Scenario 4 (High-Base, Intermediate 2): 150% quit rate and 10% relapse rate

• Scenario 5 (High-High, Optimistic): 150% quit rate and 0% relapse rate

• Scenario 6 (Mandate in 2020): 100% quit rate and 0% relapse rate

The applicant proposed a population model that assumes that market penetration of VLNTM cigarettes 

will reach 25% by 2050 and predicts cumulative 340,000 avoided cigarette-attributable deaths by 2100 

in the base scenario with introduction of VLNTM cigarettes. However, when Quest 3 cigarettes (VLNC 

cigarettes) were on the U.S. market in the early 2000s, a lower uptake of this product (nearly zero) was 

observed compared to other cigarettes (O’Connor et al., 2007). Thus, the 25% market share of VLNTM

cigarettes is likely to be an overestimation. Additionally, the applicant stated that the target market is 

current CC smokers who wish to reduce their nicotine consumption; possible outcomes of switching to 

VLNTM cigarettes include reducing cigarette consumption and increasing cessation. However, some 

model assumptions are based on clinical studies that required participants to smoke VLNTM cigarettes 

(instructed to switch to VLNTM cigarettes), with no intention to quit smoking, and provided compensation 

to do so; these estimates may be different from observational studies. 

Additionally, the model did not address the dual use of CC and VLNTM cigarettes explicitly. Nardone et al.

(2016), showed that higher non-compliance was observed with VLNC cigarette smokers, which suggests 

that a higher proportion of dual use of CC and VLNTM cigarettes could occur. Additionally, if uptake of 

VLNTM cigarettes by consumers is lower and CC smokers do not switch completely to VLNTM cigarettes

right away, the outcomes noted above might take more time; dual use of CC and VLNTM cigarettes would 

be expected until complete switching occurs. On the other hand, assuming that dual use of CC and VLNTM 

cigarettes would not happen means that CC smokers would have to quit CC smoking completely before 

switching to VLNTM cigarettes. The applicant did not incorporate this information in the model 

assumption.

The applicant provided projections of avoided cigarette-attributable deaths and life-years gained (Table 

3 of the Summary Report) with six different scenarios. However, the applicant did not provide the 95% 

confidence intervals of these projections. It is possible that these projections could overlap with each 

other. Instead, the applicant provided sensitivity analysis results of different magnitudes of smoking 

reduction. Moreover, the applicant provided the relative risks of CPD consumption and mortality rate. 

Previous studies have shown that smoking reduction is not proportional to risk reduction (Godtfredsen

et al., 2005; US Centers for Disease Control and Prevention, 2010). Additionally, dual users of CC and 

VLNTM cigarettes may present different risks compared with exclusive VLNTM cigarette smokers. Thus, the 

applicant provided an overestimate of magnitudes of smoking reduction among VLNTM cigarette 

smokers. 

Additionally, it is unclear whether the population model forecasts the impact of the availability of 

proposed MRTP claims. Therefore, it is unclear whether the projected estimates are interpreted as 

resulting from introduction of the products into the marketplace through the PMTA marketing order or 

would also require authorization of the MRTPs.
MR0000159- MR0000160 Page 71 of 90 

a. Summary and Conclusion

Below are key findings regarding the applicant’s population model from the epidemiology review:

• According to the projected population health impact of VLNTM cigarettes presented by the 

applicant, the health impact of VLNTM cigarettes would result in 340,000 avoided cigaretteattributable deaths by year 2100, if the applicant’s projected market share of the product is 

attained. While clinical studies suggest that CC smokers could reduce cigarette consumption by 

switching to VLNTM cigarettes, as described in Section III(D)(1) of this review, it is unclear how 

these estimates will generalize to a real-world setting. 

• FDA is not aware of any observational studies examining the use of VLNTM cigarettes among 

adults and youth. The applicant did not account for youth and vulnerable populations in its

model. However, the uptake of VLNTM cigarettes among nonusers (including youth) is likely to be 

low because of the low abuse liability.

• Based on this model, there are likely to be some benefits of CC smokers switching to VLNTM 

cigarettes and low uptake of nonusers. However, the model’s projected benefits may be 

overestimated (e.g., high projected market share, dual users of CC and VLNTM cigarettes); model 

assumptions about tobacco use behavior and risks do not reflect what would likely happen in a 

real-world population. 

As TPL, I agree with these findings. While the applicant’s model likely overestimates population health 

benefit, I still expect the marketing of the proposed MRTPs to benefit the population as a whole, as 

nonsmokers are unlikely to initiate and progress to regular use with VLNTM cigarettes, and even smokers 

who dual use VLNTM cigarettes with NNC cigarettes are likely to reduce their CPD. Additionally, it is 

unclear whether the model considered the impact of marketing the product with modified risk claims; 

accounting for this may increase the estimated uptake of the proposed MRTPs by current smokers. 

IV. Conclusions and Recommendations

A. Review Conclusions – Exposure Modification Order Request

The applicant has requested an exposure modification order under section 911(g)(2) of the FD&C Act to 

market these products as follows:

Additionally, FDA identified the following claims in the advertising the applicant submitted:

• Claim #4: “VLNTM cigarettes are substantially lower in nicotine content than any other 

cigarettes currently available to smokers in the United States. VLNTM cigarette contain an 

average of just 0.27 mg of nicotine.”

• Claim #1: “95% less nicotine.” 

• Claim #2: “Helps reduce your nicotine consumption.” 

• Claim #3: “...greatly reduces your nicotine consumption.”
MR0000159- MR0000160 Page 72 of 90 

• Claim #5: “Without exception, VLNTM cigarettes contain at least 95% less nicotine than the 

top 100 cigarette brands in the United States.”

• Claim #6: “22nd Century’s VLNTM cigarettes contain an average of 0.27 mg nicotine - -at least 

95% less nicotine compared to conventional cigarettes.”

• Claim #7: “22nd Century’s VLNTM cigarettes feature the same nicotine content as the lowest 

nicotine style of the Company’s SPECTRUM research cigarettes.”

• Claim #8: “VLNTM cigarettes contain 0.27 ± 0.1 mg nicotine.”

• Claim #9: “As a result of our unique technology and plant breeding expertise, VLNTM tobacco 

grows with 95% less nicotine than conventional tobacco.”

• Claim #10: Several examples utilize a graph depicting nicotine levels of VLNTM cigarettes 

compared to several other cigarette brands.

FDA may issue an exposure modification order under section 911(g)(2) of the FD&C Act (the "special 

rule") if it determines that the applicant has demonstrated that:

• Such an order would be appropriate to promote the public health;

• Any aspect of the label, labeling, and advertising for the product that would cause the 

product to be a modified risk tobacco product is limited to an explicit or implicit 

representation that the tobacco product or its smoke does not contain or is free of a 

substance or contains a reduced level of a substance, or presents a reduced exposure to a 

substance in tobacco smoke;

• Scientific evidence is not available and, using the best available scientific methods, cannot 

be made available without conducting long-term epidemiological studies for an application 

to meet the standards for obtaining an order under section 911(g)(1); and

• The scientific evidence that is available without conducting long-term epidemiological 

studies demonstrates that a measurable and substantial reduction in morbidity or mortality 

among individual tobacco users is reasonably likely in subsequent studies (section 

911(g)(2)(A) of the FD&C Act).

Furthermore, for FDA to issue an exposure modification order, FDA must find that the applicant has 

demonstrated that: 

• The magnitude of overall reductions in exposure to the substance or substances that are the 

subject of the application is substantial, such substance or substances are harmful, and the 

product as actually used exposes consumers to the specified reduced level of the substance 

or substances;

• The product as actually used by consumers will not expose them to higher levels of other 

harmful substances compared to the similar types of tobacco products then on the market 

unless such increases are minimal and the reasonably likely overall impact of use of the 
MR0000159- MR0000160 Page 73 of 90 

product remains a substantial and measurable reduction in overall morbidity and mortality 

among individual tobacco users;

• Testing of actual consumer perception shows that, as the applicant proposes to label and 

market the product, consumers will not be misled into believing that the product is or has 

been demonstrated to be less harmful, or presents or has been demonstrated to present 

less of a risk of disease than one or more other commercially marketed tobacco products; 

and

• Issuance of the exposure modification order is expected to benefit the health of the 

population as a whole taking into account both users of tobacco products and persons who 

do not currently use tobacco products (section 911(g)(2)(B) of the FD&C Act).

In making the determinations under section 911(g)(2) of the FD&C Act, FDA must take into account:

• The relative health risks to individuals of the modified risk tobacco product;

• The increased or decreased likelihood that existing tobacco product users who would 

otherwise stop using such products will switch to using the modified risk tobacco product;

• The increased or decreased likelihood that persons who do not use tobacco products will 

start using the modified risk tobacco product;

• The risks and benefits to persons from the use of the modified risk tobacco product 

compared to the use of smoking cessation drug or device products approved by FDA to treat 

nicotine dependence; and

• Comments, data, and information submitted to FDA by interested persons (section 911(g)(4) 

of the FD&C Act).

In short, unlike the section 911(g)(1) standard, which requires scientific evidence showing actual risk 

reduction (e.g., a finding that the product, as actually used by consumers, will significantly reduce harm 

and risk to individual users; a finding that the product, as actually used by consumers, will benefit the 

health of the population a as whole); section 911(g)(2) establishes a lower standard, which allows FDA to 

issue an order when risk reduction has not yet been demonstrated but is reasonably likely based on 

demonstrated reductions in exposure (e.g., a finding that a reduction in morbidity or mortality among 

individual users is reasonably likely in subsequent studies; a finding that issuance of an order is expected

to benefit the health of the population as a whole). 

Furthermore, FDA must ensure that the advertising and labeling of the MRTP enable the public to 

comprehend the information concerning modified risk and to understand the relative significance of 

such information in the context of total health and in relation to all of the tobacco-related diseases and 

health conditions (section 911(h)(1) of the FD&C Act). 

To the extent possible, the assessment integrates the various threads of evidence regarding the product 

and its potential effects on health and tobacco use behavior, including tobacco use initiation, to 

determine both the net effect of the product on overall tobacco-related morbidity and mortality and the 

distribution of the benefits and harms across the population. This determination also considers these 
MR0000159- MR0000160 Page 74 of 90 

product applications in the context of the current marketplace where menthol cigarette products are 

legally sold to consumers. In particular, the recommendation considers that VLNTM Menthol King 

provides an opportunity for menthol smokers to reduce their nicotine consumption and reduce their 

exposure to nicotine, potentially decreasing their cigarettes per day smoked. 

After conducting a thorough scientific review of the information contained in the MRTPAs; the 

recommendations from the Tobacco Products Scientific Advisory Committee; comments, data, and 

information submitted to FDA by interested persons; and other scientific information identified by the 

agency from other sources, I conclude that:

• With respect the exposure modification order request, the applicant has demonstrated that 

the products sold or distributed with the proposed modified risk information meet the 

standard under section 911(g)(2) of the FD&C Act, including that a measurable and 

substantial reduction in morbidity or mortality among individual tobacco users is reasonably 

likely in subsequent studies, and issuance of an order is expected to benefit the health of 

the population as a whole, taking into account both users of tobacco products and persons 

who do not currently use tobacco products.

Reduced exposure claim substantiation

After conducting a thorough assessment of the scientific evidence, I find that the proposed modified risk 

claims are substantiated. This includes the applicant-submitted Claims #1-3 and the FDA-identified 

Claims #4-10. Here, I summarize the evidence supporting the substantiation of each claim, grouped by 

topic. First, I discuss claims related to nicotine content (Claims #1, 4, 5, 6, 7, 8, 9, and 10), and then I 

discuss claims related to reduction in nicotine consumption (Claims #2 and 3).

Several lines of evidence substantiate the claims related to nicotine content (Claims #1 and 4-10). First,

the chemistry review found that the applicant provided a survey of 100 top-selling cigarette brands that 

represent 87% of all cigarettes sold in the U.S. through convenience stores in 2017. These 100 cigarette

brands contain a reported average of 19.4 mg nicotine per gram of tobacco on a dry weight basis (DWB), 

and a reported average of 12.0 mg nicotine per cigarette. The applicant reported that the tobacco 

nicotine content of all 10 batches of the two new VLNTM cigarettes met the applicant’s maximum 

nicotine specification of mg/g on a DWB. Accordingly, the reported nicotine contents of the VLNTM 

cigarettes are 98% lower than the average reported nicotine contents of the top 100 cigarette brands

determined both per gram of tobacco and per cigarette. In addition, both applicant-contracted and FDA

nicotine test results found that nicotine levels in tobacco and mainstream smoke of VLNTM cigarettes are 

at least 96% lower than the majority of marketed and market-leading conventional cigarette brands. 

Furthermore, while batch analysis of eight batches of VLNTM cigarettes shows a slightly higher nicotine 

content than the 0.27 mg/cig reported by the applicant (it was 0.29 mg/cig), this is within the advertised 

nicotine content lower and upper limit of 0.27 ± 0.10 mg/cig (0.17 and 0.37 mg/cig lower and upper 

limit). Based on this evidence, Claims #1, 4, 5, 6, 8, and 10 are supported. Finally, the chemistry review 

notes that the two VLNTM cigarette products contain only Vector 21-41 Burley tobacco, which is a unique 

tobacco variety not present in any commercially-marketed cigarette tobacco. This tobacco type is 

genetically engineered using the applicant’s proprietary technology to block several genes, which results 

in suppression of nicotine biosynthesis. This tobacco is also the filler in SPECTRUM research cigarettes 

NRC102 and mentholated NRC103. SPECTRUM NRC102 and NRC 103 also have less than 0.7 mg/g of 

(b) (4)
MR0000159- MR0000160 Page 75 of 90 

nicotine on a DWB, and thus has at least 95% less nicotine than the reported nicotine content for 

conventional cigarette tobacco. Thus, Claims #7 and 9 are supported. 

Claims #1, 5, 6, and 9 all include the phrase “95% less nicotine.” All but one of these claims—Claim #1—

indicates the product contains 95% less nicotine. Claim 1 does not use the word “contains” and could 

therefore be referring to nicotine exposure after using the product. Accordingly, the behavioral and 

clinical pharmacology (BCP) review evaluated the substantiation of this meaning. The applicant’s abuse 

liability studies, which contained actual use data in healthy adult smokers after ad libitum and controlled 

VLNTM cigarette smoking, indicate that exclusively smoking VLNTM cigarettes results in an approximate 

97% reduction in plasma nicotine levels compared to smoking usual brand (UB) normal nicotine content 

(NNC) cigarettes. Findings from the applicant’s submitted literature review on biomarkers of exposure 

(BOE) support these data, noting that smokers who primarily smoke or switch completely to smoking 

VLNC cigarettes (i.e., reduced nicotine content cigarettes that are identical or similar in nicotine content 

to VLNTM cigarettes) have reduced exposure to nicotine compared to smoking usual brand (UB) NNC

cigarettes. The literature finds that exclusively smoking VLNC cigarettes across five days results in an 

average 94% reduction in urinary total nicotine equivalents (TNE). As such, by exclusively smoking VLNC 

cigarettes, consumers could reduce their exposure to nicotine by approximately 95%. As a result, I find 

this claim substantiated. 

Regarding the claims about reduced nicotine consumption (Claims #2 and #3), both these claims are 

supported by evidence included in the BCP review. Given the 95% reduced nicotine content in VLNTM

cigarettes, data support that menthol and non-menthol smokers who primarily smoke VLNTM cigarettes 

and occasionally dual use, with other tobacco or nicotine-containing products, still experience the 

benefit of substantially reducing their overall exposure to nicotine compared to exclusively smoking UBNNC cigarettes. When considering the range of non-compliance across the sample of participants 

assigned to smoke VLNC cigarettes (i.e., the number of UB cigarettes smoked during the course of the 

study in addition to VLNTM cigarettes), studies in the literature report an average 59-60% reduction in 

nicotine exposure over 6 to 20 weeks of VLNC cigarette use. The applicant’s 6-week longitudinal study 

supports that, as a result of substantially reducing nicotine exposure, switching to VLNC cigarettes can 

lead to smoking fewer overall cigarettes per day (CPD) compared to ongoing UB-NNC cigarette smoking. 

These findings are supported by several VLNC cigarette studies in the published literature, including a 

20-week study of VLNC cigarette use among smokers, which is the longest study of VLNC cigarettes to 

date (Hatsukami et al., 2018). On average, smokers assigned to switch to VLNCs had half the CPD 

compared to those in the UB-NNC control group. The extent of cigarette reduction depends on the 

extent of switching to smoking VLNTM cigarettes, although smokers who occasionally smoke UB-NNC 

cigarettes still experience a significant reduction in CPD compared to smoking UB-NNC cigarettes 

exclusively. Studies support that as the duration of smoking VLNC cigarettes increases, the reduction in 

CPD increases. Thus, the available evidence supports Claims #2 and #3. 

In sum, consistent with section 911(g)(2)(A)(i), I find that the magnitude of the overall reduction in 

exposure to nicotine in VLNTM is substantial, and VLNTM as actually used exposes consumers to the 

specified reduced level of nicotine. Also, I find that nicotine is harmful. It is addictive and is a 

reproductive or developmental toxicant (RDT) in FDA’s established list of harmful and potentially 

harmful constituents. 
MR0000159- MR0000160 Page 76 of 90 

Individual health impact among tobacco users

The totality of evidence presented suggests that a measurable and substantial reduction in morbidity or 

mortality among individual tobacco users is reasonably likely in subsequent studies. This determination 

predominantly stems from: (1) the 95% reduction in nicotine exposure with exclusive use of VLNTM 

cigarettes and at least about 50% reduction in nicotine exposure with dual use with NNC cigarettes; (2) 

the reduced abuse liability of VLNTM cigarettes and reduced nicotine dependence among users; (3) the 

substantial reduction in CPD among smokers who predominantly use VLNTM cigarettes (an estimated 

50% reduction); and (4) the reduction in some tobacco morbidities (e.g., lung cancer) associated with at 

least a 50% reduction in CPD. Specifically, in addition to the substantiation of claims about nicotine, FDA 

found that VLNTM cigarettes had low subjective effects ratings and lower dependence scores. Consistent 

with this, clinical studies of smokers who do not want to quit found that, even among smokers who 

continue to use NNC cigarettes, CPD decreases over the course of using VLNTM cigarettes. The longest 

clinical study, lasting 20 weeks, found that smokers assigned to use VLNC cigarettes had 50% lower CPD 

compared to smokers assigned to smoke NNC cigarettes (Hatsukami et al., 2018). Published literature 

finds that reducing cigarette consumption can increase the likelihood that an individual will become 

cigarette abstinent in the future. Additionally, as discussed further in our evaluation of population 

health impact, published epidemiological studies assessing the relationship between smoking reduction 

and disease risks suggested a potential benefit for some health endpoints such as lung cancer risk in 

those who reduced CPD by more than 50% compared to non-reducers. While past studies have not 

consistently demonstrated that a reduction in CPD reduces mortality, a recent study that evaluated 

changes in smoking patterns over a longer period of time than previous studies found that all-cause 

mortality was lower among smokers who reduced their CPD compared to those who maintained their 

CPD, with greater reductions in CPD yielding greater benefits (Inoue-Choi et al., 2019). Therefore, I find 

that the scientific evidence demonstrates that a measurable and substantial reduction in morbidity or 

mortality among individual tobacco users is reasonably likely in subsequent studies. 

Consumer understanding

In terms of consumer understanding, the applications support the findings required for authorization. 

Actual consumer perception testing overall supports that consumers understood the claims, including 

the applicant requested claims (#1-3) and the FDA identified claims (#4-10). Consumers understood that 

the claims refer to the nicotine content and nicotine exposure from VLNTM cigarettes themselves, rather 

than users’ overall nicotine consumption, and that exposure to nicotine from VLNTM cigarettes is 

substantially lower than from other cigarettes on the market. Findings from the applicant’s quantitative 

study suggest that the proposed LLA would enable consumers to understand the addiction risks of 

smoking VLNTM cigarettes. Consistent with VLNTM cigarette’s very low nicotine level, participants 

perceived VLNTM cigarettes as substantially less addictive than other cigarettes after viewing the VLNTM

cigarette pack image with the proposed modified risk claims. At the same time, participants still 

perceived some risk of addiction from smoking VLNTM cigarettes, placing them in a similar range as NRT. 

Participants also perceived health risks of using VLNTM cigarettes (other than addiction) as moderate to 

high, and higher than that of NRT. 

However, the proposed LLA include no information on conditions of use, such as how consumers should 

use VLNTM cigarettes to reduce their exposure to HPHCs and potential disease risk. It was unclear 

whether smokers intended to use VLNTM cigarettes to cut down on their overall cigarette consumption or 

simply replace all or some of their current cigarette use with VLNTM cigarettes. This made it challenging 
MR0000159- MR0000160 Page 77 of 90 

to evaluate the finding that after viewing VLNTM cigarette packs with the proposed modified risk 

information, participants perceived VLNTM cigarettes as presenting lower risks of tobacco-related 

diseases-- including lung cancer, mouth/throat cancer, heart disease, and 15 other tobacco-related 

diseases and health effects -- compared to other cigarettes. This was particularly challenging to evaluate 

because the survey questions did not include information regarding patterns or frequency of use (i.e., 

whether VLNTM cigarettes would be used at the same rate or be used to cut down), and the research did 

not assess the assumptions participants made in answering these questions. Thus, it was difficult to 

evaluate whether consumers believed using the products would result in lower risk because of smoking 

reduction and/or eventual abstinence (correct), or because lowering nicotine and smoking the same 

amount would lead to a risk reduction (incorrect). These findings indicate that without additional 

corrective or clarifying information, many U.S. consumers are at risk of misinterpreting statements 

about reduced nicotine content cigarettes. To address this issue, under section 911(h)(3)(B), I 

recommend that the order require VLNTM cigarettes’ modified risk LLA to include an explicit statement

about the manner in which the product must be used in order to obtain a benefit (“Helps you smoke 

less”). Some of the applicant’s research included this statement and found it to be generally well 

understood by consumers. By including this statement in a way that will be noticed and read, the LLA 

will enable consumers to better understand the significance of the reduced nicotine claims, the 

relevance to their personal health (or the irrelevance, if the person does not wish to smoke less), and 

the reason why the manufacturer would be providing the information about nicotine to consumers. This 

will enable consumers to comprehend the information concerning modified risk and to understand the 

relative significance of such information in the context of total health.

Additionally, the authorization letter for the proposed MRTPs should recommend that the applicant 

include the disclaimer “Nicotine is addictive. Less nicotine does NOT mean safer...” on VLNTM cigarette 

pack LLA, given that it was present on all of the labeling that the applicant tested in its quantitative 

consumer research. The letter should also require the applicant to test the disclaimer in a postmarket 

study. Several aspects of the disclaimer are inconsistent with expert recommendations for disclaimers, 

and prior research suggests that poorly designed disclaimers can confuse consumers and change their 

perceptions, attitudes, or decisions in a manner opposite of that intended (Green & Armstrong, 2012). In 

a pre-submission meeting with the applicant, FDA recommended that the applicant conduct a study

comparing consumer understanding across participants who did and did not see the disclaimer, to 

assess the disclaimer’s effects on understanding of the modified risk information. However, the 

applicant submitted no evidence of the disclaimer’s effect on consumer understanding. Conducting a 

postmarket test can provide FDA with evidence about whether the disclaimer helps enable consumers 

to understand that VLNTM cigarettes present the same disease risks as other cigarettes if smoked in the 

same way, or whether it confuses people about the health risks of VLNTM cigarettes. Thus, I recommend 

that the order require the applicant to conduct such a study of the disclaimer as part of postmarket 

surveillance; this is discussed further below in Section IV(C).

Social science did not specifically evaluate consumer understanding of FDA-identified Claims #4-10, in 

detail. These statements appear to convey the same information as applicant-identified Claims #1-3. 

Specifically, these claims are limited to information about VLNTM cigarettes’ nicotine content and how it 

compares with that of other cigarettes, although some of the claims describe the nicotine content in 

absolute terms (e.g., “.27 mg”), use qualitative comparisons (e.g., “substantially lower”), or include 

comparators (e.g., “the top 100 cigarette brands”). However, the applicant’s qualitative research on 

consumer understanding (described in the social science review Section 4; M/A/R/C Qualitative Study) 

examined participants’ responses to claims with alternate phrasing similar to these variations. The one 
MR0000159- MR0000160 Page 78 of 90 

exception is Claim #9, which describes the source of VLNTM cigarettes’ reduced nicotine content (i.e., 

“unique technology and plant breeding expertise” allows the company to grow tobacco with different 

nicotine levels). This statement is similar to background information about VLNTM cigarettes viewed by 

participants in the applicant’s quantitative consumer perception research (see Sections 4 and 5 of the 

social science review; M/A/R/C Research Quantitative Study). The background information stated: “A 

new tobacco product called VLNTM (Very Low Nicotine) is currently in development... VLNTM cigarettes are 

made from a tobacco plant that has been altered to contain much lower levels of nicotine than the 

tobacco used in traditional cigarettes.” Thus, although the applicant did not specifically examine 

consumer responses to Claims #4-10, any potential concerns are mitigated by the fact that these claims 

appear to convey the same information as Claims #1-3 and the information participants viewed in the 

applicant’s quantitative consumer research. 

Population Health Impact

The available scientific evidence demonstrates that the issuance of an exposure modification order for 

VLNTM cigarettes would be appropriate to promote the public health and is expected to benefit the 

health of the population as a whole, taking into account both users of tobacco products and persons 

who do not currently use tobacco products. The longest clinical study of VLNC cigarettes, lasting 20 

weeks, found that smokers assigned to use VLNC cigarettes had 50% lower CPD compared to smokers 

assigned to smoke NNC cigarettes (Hatsukami et al., 2018). Across clinical studies, most smokers 

instructed to exclusively use VLNTM cigarettes still used several NNC cigarettes per day, and still 

experienced CPD reductions. Published literature finds that reducing cigarette consumption can increase 

the likelihood that an individual will become cigarette abstinent in the future. Additionally, published 

epidemiological studies assessing the relationship between smoking reduction and disease risks 

suggested a potential benefit for some morbidities (such as lung cancer) in those who reduced CPD by 

more than 50% compared to non-reducers. While past studies have not consistently demonstrated that 

a reduction in CPD reduces mortality, a recent study evaluating changes in smoking patterns over a 

longer period of time found that all-cause mortality was lower among smokers who reduced their CPD 

compared to those who maintained their CPD, with greater reductions in CPD yielding greater benefits 

(Inoue-Choi et al., 2019). Therefore, I find it is reasonably likely that the scientific evidence demonstrates 

that a measurable and substantial reduction in morbidity or mortality among individual tobacco users is 

reasonably likely in subsequent studies. 

After viewing product labels with the exposure reduction claims, many current smokers were interested 

in VLNTM cigarettes (mean intentions were above the midpoint of the scale), and smokers had 

significantly higher intentions to purchase the proposed MRTPAs compared to Marlboro GoldTM 

cigarettes. Current smokers also reported substantially higher intentions to use VLNTM cigarettes on a 

regular, ongoing basis compared to Marlboro GoldTM. Additionally, adult never smokers and former 

smokers had low intentions to buy and use VLNTM cigarettes (mean intentions were near the bottom of 

the scale), and these intentions were similar to or slightly higher than their intentions to buy and use 

Marlboro GoldTM. Furthermore, while the applicant’s population model predicted 340,000 avoided 

cigarette-attributable deaths by year 2100, this model may have overestimated population benefits 

(e.g., due to overestimating market share). Still, overall, FDA concluded that there are likely to be some 

benefits of smokers switching to VLNTM cigarettes and low uptake of nonusers. 

The application did not provide information about the likelihood that youth would use VLNTM cigarettes 

if marketed with the proposed modified risk information. However, FDA has low concern about youth 
MR0000159- MR0000160 Page 79 of 90 

initiation and progression to regular use, because: the products have low abuse liability and youth may 

be less likely to develop nicotine dependence using them; young adults rate VLNCs as having lower 

subjective effects compared to NNC cigarettes; and a study of adolescents found that the reinforcing 

efficacy or appeal of all doses of VLNC cigarettes was lower compared to UB-NNC cigarettes (Cassidy et 

al., 2019). Still, as discussed below in Section IV(C), given that youth are at increased risk for tobacco 

initiation and the potential effect of modified risk information on youth use, it is critical that any 

marketing plans be designed to prioritize preventing youth exposure. Studies suggest that perceptions 

of risk predict tobacco product use among youth (Song et al., 2009) (Strong et al., 2019). FDA’s PMTA 

marketing authorization order for the products includes postmarket requirements to help limit youth 

exposure to product marketing. This includes: informing FDA of all marketing plans, restricting youth 

exposure to the products’ LLA, and requiring the applicant to measure actual delivery of advertising to 

youth. In addition, postmarket surveillance studies should be conducted to monitor youth awareness 

and use of the proposed MRTPs to ensure that their marketing will not have the unintended 

consequence of leading to increased use of these products among youth.

Section 911(g)(2)(C)(i) of the FD&C Act provides that an MRTP exposure modification order shall be 

limited for a term of not more than 5 years. I recommend authorization for a period of 5 years, given the 

low abuse liability of this product. Although this review has found that an exposure modification order 

for the products would be appropriate to promote the public health and is expected to benefit the 

health of the population as a whole, that determination may change over time as a function of how the 

products are actually used by consumers. Therefore, monitoring use of the proposed MRTPs in terms of 

uptake, dual use, and complete switching should be required, including the potential for initiation 

among youth. As described below, postmarket surveillance and studies must include an assessment of 

MRTP users’ behavior and understanding over time. A 5-year period is a reasonable amount of time to 

assess whether there is appropriate consumer understanding and to generate preliminary data on 

behavior in postmarket surveillance and studies to assess whether the standard continues to be met and 

whether the order should be renewed. In addition, this order should require a study on the independent 

effects of the disclaimer, since it is unclear whether the disclaimer benefits or reduces consumers’ ability 

to understand the risks of using the proposed MRTPs. 

B. Environmental Impact

A finding of no significant impact (FONSI) was signed by Luis Valerio Jr. Ph.D. on December 15, 2021. The 

FONSI was supported by an environmental assessment prepared by FDA on December 15, 2021. 

C. Postmarket Surveillance and Studies (PMSS)

I recommend that the order include the following language in the marketing authorization:

Under section 911(g)(2)(C)(ii) of the FD&C Act, an order under 911(g)(2) is conditioned on the applicant’s 

agreement to conduct postmarket surveillance and studies in order to “determine the impact of the 

order on consumer perception, behavior, and health, and to enable the [FDA] to review the accuracy of 

the determinations upon which the order was based in accordance with a protocol approved by the 

[FDA].” 
MR0000159- MR0000160 Page 80 of 90 

1. PMSS Content

a. MRTP Use Behavior and Consumer Understanding and Perception

After receiving authorization, the determination of whether the tobacco products, which are the subject 

of this order, continue to satisfy the requirements of section 911(g)(2)(A) and (B), is driven, in part, by 

use behavior. 

Your proposed postmarketing surveillance and studies (PMSS) include a 6-month cross sectional study 

(n=1,000) to assess product knowledge, use, and attitudes among people who started smoking VLNTM

cigarettes within the past 6 months (Section X “Postmarket Surveillance Program,” pp. 5-6). Primary 

objectives of the study would be to assess VLNTM product knowledge, use patterns, and demographic 

characteristics of VLNTM smokers (age, gender, ethnicity, three-digit zip code). Secondary objectives 

would be to assess the use of other tobacco products at the time of initiation of VLNTM cigarettes, 

describe how users learned about VLNTM cigarettes, and describe personal factors motivating initiation 

of VLNTM cigarette use. You also propose to recruit a subset of the cross-sectional study participants into 

a longitudinal study that would evaluate reductions in cigarette use among VLNTM smokers prospectively 

over a 12-month period. We agree with the constructs you propose to assess in your 6-month crosssectional study (e.g., knowledge of VLNTM’s product features – including understanding of the health 

risks associated with various patterns of use – as well as demographic characteristics and current, 

previous, and subsequent use patterns with VLNTM and other cigarettes). In your longitudinal study, 

monitoring use of the products that are the subject of this order in terms of uptake, dual use, and 

complete switching is required. In particular, your PMSS must assess the extent to which new MRTP 

users were never, former, or current smokers, or other tobacco product users before initiating the 

MRTPs and the extent to which new users of the MRTPs become exclusive VLNTM cigarette users, dual 

users with combusted cigarettes or other tobacco products, or transition to normal nicotine content 

(NNC) cigarette smoking over time. These studies must be designed to observe behavior over a 

sufficient period of time to examine, for instance, the extent to which dual use of VLNTM cigarettes and 

combusted cigarettes is a transitional versus stable pattern of use. 

Your studies must also include an assessment of consumers’ understanding of the modified risk claims 

and perceptions of the products. In particular, PMSS must assess the extent to which users of these 

products understand that VLNTM cigarettes are just as toxic as other cigarettes when used in the same 

way (i.e., with the same frequency and for the same duration). Additionally, you must assess the extent 

to which VLNTM cigarette users understand that to get long-term benefits, they have to use VLNTM 

cigarettes to substantially reduce the amount of cigarettes that they smoke. Thus, you must assess 

whether current smokers who take up VLNTM understand that they should cut down on their overall 

cigarette smoking and that replacing their other cigarettes with VLNTM without substantially cutting 

down is not sufficient to yield long-term benefits.

Your studies must have clear research objectives, including assessing whether the MRTPs are leading to 

changes in product use behaviors that are expected to benefit population health. Your protocol must 

include a statistical analysis plan describing, among other things, how you plan to conduct inferential 

statistical analyses to address these objectives. 
MR0000159- MR0000160 Page 81 of 90 

Your PMSS must also include a postmarket study testing the effects of the disclaimer11 (“Nicotine is 

addictive. Less nicotine does NOT mean safer. All cigarettes can cause disease and death.”) on consumer 

understanding of VLNTM cigarettes’ health risks and conditions of use. The disclaimer has several features 

that are inconsistent with expert recommendations for designing disclaimers, and poorly designed 

disclaimers have the potential to confuse consumers and change their perceptions, attitudes, or 

decisions in a manner opposite of that intended (Green & Armstrong, 2012). Conducting a postmarket 

study to test the disclaimer can provide FDA with evidence about whether the disclaimer helps enable 

consumers to understand that VLNTM cigarettes present the same disease risks as other cigarettes if 

smoked in the same way, or if it worsens existing misperceptions about the health risks of cigarettes

containing reduced nicotine levels. If FDA determines that the disclaimer causes such misperceptions, 

then FDA will require that you remove the disclaimer from the modified risk labels, labeling and 

advertising and any advertising where it is included. 

FDA also recommends that, if you seek to use any modified risk ads that are potentially youth-appealing, 

then you should conduct consumer testing of the ads to determine whether they would increase the 

likelihood of use among nonsmokers, particularly minors (under age 21).

we suggest that if you seek to use ads that are potentially youth appealing,

then you first study them to determine the effect on initiation by non-users, particularly youth; imagery 

and themes known to resonate with youth include aspirational content depicting tobacco use as “cool,” 

attractive, rebellious, or risky, or as a means to make one more popular, desirable, or independent (U.S. 

Department of Health and Human Services, 2012). 

In addition, FDA has determined that assessing the impact of your MRTP orders on uptake of the 

products requires surveillance of MRTP sales and distribution, which provide information to assess 

tobacco consumption at the population level. Your PMSS protocols must describe procedures for 

monitoring and reporting MRTP sales and distribution in the U.S. by product, major metropolitan areas, 

and channels where the products are sold (e.g., convenience stores, food and drug stores, internet and 

digital retailers, tobacco specialty shops). Your annual PMSS report must include:

• U.S. sales and distribution of the tobacco products by quarter since the date of issuance of your 

modified risk granted orders (for the initial reporting period) or the previous reporting period 

(for all reports that follow), including, for each MRTPA STN, total U.S. sales and distribution 

reported in dollars and units, and broken down by major metropolitan areas, and channels 

where the products were distributed and sold during the reporting period (e.g., convenience 

stores, food and drug stores, internet and digital retailers, tobacco specialty shops).

• A brief synthesis and summary of the sales and distribution data for the initial reporting period 

or the previous reporting period (for all reports that follow), including annual and quarterly 

11 In your MRTPAs, you refer to the statement, “Nicotine is addictive. Less nicotine does NOT mean safer. All 

cigarettes can cause disease and death.” variously as a “disclaimer” (Section V “Labels, Labeling, and Advertising,” 

p. 3; Section VII “Summary of All Research Findings,” p. 72) and “voluntary warning” (Section V “VLNTM Cigarettes: 

Labels, Labeling, and Advertising,” pp. 2, 8-9). In this order, the word “disclaimer” refers to your use of this term 

and does not reflect FDA’s independent conclusion regarding characterization of the information. 

(b) (4)
MR0000159- MR0000160 Page 82 of 90 

growth rate (percent change) in total U.S. sales and distribution of the tobacco products for 

each MRTPA STN, post-MRTP authorization. 

b. MRTP Use and Health Risk – Serious and Unexpected Adverse 

Experiences

In order for FDA to determine whether the tobacco products that are the subject of this order continue 

to be appropriate to promote the public health and continue to be expected to benefit the health of the 

population as a whole taking into account both users of tobacco products and persons who do not 

currently use tobacco products (section 911(g)(2)(A-B)), your PMSS must include ongoing surveillance of 

all adverse experiences. These experiences may become known to you through any source, including a 

customer complaint, request, or suggestion made as a result of an adverse experience; or tobacco 

product defect, or failure, reported to you, or identified in the literature or media. Your PMSS protocols 

must include procedures for monitoring and analyzing adverse experiences and your annual PMSS 

report must include: 

• A summary of reported serious and reported unexpected adverse experiences for the tobacco 

products, which includes a listing of all serious and unexpected adverse experiences during the 

reporting period and a cumulative list including all serious and unexpected adverse experiences 

previously reported. The summary must be accompanied by an analysis of the reports and a 

statement of any changes to risk information related to the products including nature, 

frequency, and potential aggravating factors. 

In addition, the PMTA order for your tobacco products, issued on December 17, 2019, requires you to 

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 the tobacco product within 15 calendar 

days after the report is received by you. These experiences may become known to you through any 

source, including a customer complaint, request, or suggestion made as a result of an adverse 

experience, tobacco product defect, or failure, reported to you, or identified in the literature or media. 

We request that when submitting such reports, you reference both your PMTAs and your MRTPAs for 

these products. Your information should be submitted with a cover letter that includes the following 

text in the subject line: SERIOUS ADVERSE EXPERIENCE REPORT FOR STNs PM0000491-PM0000492 and 

MR0000159-MR0000160. 

For purposes of this reporting, 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 of the ability to conduct normal 

life functions; 

• A congenital anomaly/birth defect; or 
MR0000159- MR0000160 Page 83 of 90 

• 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 this reporting, 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 the tobacco product as 

described in the PMTA (including the results of human subject investigations) 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 

person(s) experiencing the adverse experience and the person’s predisposing risk factor profile 

for the adverse experience; or 

• The results of nonclinical laboratory studies. 

c. Surveillance of New Research Study Findings on the MRTPs and 

Consumer Perception, Behavior, or Health 

In order for FDA to determine whether the tobacco products that are the subject of this order continue 

to be appropriate to promote the public health and continue to be expected to benefit the health of the 

population as a whole, your PMSS must include surveillance of new research study information about 

the MRTPs and consumer perceptions, behavior, or health. In particular, your PMSS protocol must 

include procedures for monitoring and assessing previously unreported (new) findings both in published 

or unpublished studies conducted by you or on your behalf and in published or otherwise available 

studies regarding the MRTPs and consumer perceptions, behavior, or health. Your annual PMSS report 

must include: 

• (1) A summary of significant findings about the tobacco products from research studies 

conducted by you or on your behalf, whether or not such studies were specifically required 

under this order. (2) A summary of significant findings in publications not previously reported 

and full copies of the articles. These must include any new scientific data (published or 

otherwise) on the MRTPs and consumer perception, behavior, or health. 

d. Modeling the Impact of the MRTP on Population Health

In order for FDA to determine whether the tobacco products that are the subject of this order continue 

to be appropriate to promote the public health and continue to be expected to benefit the health of the 

population as a whole, your PMSS must include computational modeling of the impact of the MRTPs on 

population health. Such modeling must incorporate data and information collected through PMSS, 

including the percentage of former smokers who start using VLNTM cigarettes; the percentage of current 

smokers who start using VLNTM cigarettes and become dual users; the percentage of current smokers 

who switch completely to VLNTM cigarettes; the percentage of youth and young adults under the federal 

minimum age of sale of tobacco products who start using VLNTM cigarettes; and the percentage of 

individuals who start using VLNTM cigarettes and then initiate or re-initiate NNC combusted cigarettes. 
MR0000159- MR0000160 Page 84 of 90 

Postmarket modeling must also incorporate the latest information on acute and long-term health 

effects of using the proposed MRTPs relative to NNC combusted cigarette smoking in order to assess the 

short and long-term population health impacts of the marketing. Your annual PMSS report must include:

• A description of the methodological approach used in the model;

• A copy of the model or its underlying code, such that FDA can independently run and verify the 

model inputs and outputs;

• A description of all model inputs, including the justification for input values and how they were 

derived from postmarket data and information; and

• A summary of the modeling results and their implications for assessing whether the MRTPs 

continue to be appropriate to promote the public health and continue to be expected to benefit 

the health of the population as a whole.

2. Submitting PMSS Protocols and Reports

As required under section 911(g)(2)(C)(ii) of the FD&C Act, your modified risk order is conditioned on 

your agreement to conduct PMSS under an approved protocol, and to submit the results for FDA to 

determine the impact of the order and review the accuracy of determinations on which the order is 

based. Within 30 days of receiving this notice, you must submit your agreement to conduct PMSS and 

complete protocols for your PMSS. Label your submission clearly as a “PMSS Protocol” and reference 

your MRTPA Submission Tracking Numbers (STNs). If you have more than one protocol, each protocol 

should be a separate submission. If applicable, each protocol should include the name(s) of the principal 

investigator(s) and materials that demonstrate the relevant professional credentials and training that 

qualify them to lead the study. Within 60 days of receipt of the protocol(s), FDA intends to review the 

protocol(s) and evaluate if the principal investigator proposed to be used in the surveillance has 

sufficient qualifications and experience to conduct the surveillance and if the protocol(s) will result in 

collection of data or other information that has the potential to enable FDA to accurately determine the 

impact of the order on consumer perception, behavior and health and to review the accuracy of the 

determinations upon which the order was based, pursuant to section 911(g)(2)(C)(ii) of the FD&C Act. 

FDA will notify you of, and provide opportunities to address, any deficiency in the submission. If the 

PMSS protocol is amended subsequent to FDA approval, FDA must receive the amended protocol 

promptly. For protocol amendments that are administrative in nature (e.g., corrections in punctuation 

or titles), the amended protocol must be received by FDA within 30 days of the update. For protocol 

amendments that seek to modify the study design (including endpoints, sites, questionnaires, 

methodology, etc.) or other scientific parameters, you may not initiate the change until you receive FDA 

approval.

As part of the requirement to conduct PMSS, you must initiate and conduct your PMSS per the 

timeframes established in your protocols and approved by FDA. Note that for PMSS that involve human 

subjects, the anticipated start date for each study must account for the time required for securing IRB 

approval, as needed. In addition to specifying the start date, your protocols must contain timelines for 

completion of major study milestones including, as applicable, the start and completion of participant 

recruitment, initiation of data collection (per wave, if applicable), completion of data collection, analysis, 
MR0000159- MR0000160 Page 85 of 90 

and report writing. If you deviate from these timelines, we request that you report the deviation within 

30 days to FDA.

Section 911(g)(2)(C)(iii) requires that the results of the PMSS be submitted on an annual basis. These 

reports must be identified as “PMSS Report” and the MRTPA STNs should be referenced for each report. 

The PMSS Report must indicate the beginning and ending date of the period covered by the report and 

must include accomplishments since the last reporting period. For quantitative updates on studies in 

progress (e.g., participant accrual), reports should describe both interim (since the last reporting period) 

as well as cumulative (since study initiation) accomplishments. The PMSS Report describing studies in 

progress must describe the status of PMSS, including, as applicable, the status of recruitment, data 

collection, and analysis; a summary of the study milestones achieved and any deviations from the 

approved timelines in the protocol; a summary of protocol amendments; and a summary of any 

preliminary analyses conducted. Once a study is completed, the PMSS Report should include the 

complete final study report.
MR0000159- MR0000160 Page 86 of 90 

References

Babb, S., Malarcher, A., Schauer, G., Asman, K., Jamal, A. (2017). Quitting smoking among adults - United 

States, 2000-2015. MMWR, 65(52), 1457-1464. doi:10.15585/mmwr.mm6552a1

Bansal-Travers, M., Cummings, K. M., Hyland, A., Brown, A., Celestino, P. (2010). Educating smokers 

about their cigarettes and nicotine medications. Health Education Research, 25(4), 678-686. doi: 

10.1093/her/cyp069

Bjartveit, K. & Tverdal, A. (2005). Health consequences of smoking 1-4 cigarettes per day. Tobacco 

Control, 14(5), 315-320.

Bolliger, C. T. (2000). Practical experiences in smoking reduction and cessation. Addiction, 95(Suppl 1), 

S19-S24.

Bolliger, C. T., Zellweger, J. P., Danielsson, T., van Biljon, X., Robidou, A., Westin, A., Perruchoud, A. P., 

Säwe, U. (2002). Influence of long-term smoking reduction on health risk markers and quality of 

life. Nicotine Tobacco Research, 4(4), 433-439.

Borrelli, B. & Novak, S. P. (2007). Nurses’ knowledge about the risk of light cigarettes and other tobacco 

“harm reduction” strategies. Nicotine Tobacco Research, 9(6), 653-661. doi: 

10.1080/14622200701365202

Brose, L. S., Brown, J., Hitchman, S. C., McNeill, A. (2015). Perceived relative harm of electronic 

cigarettes over time and impact on subsequent use. A survey with 1-year and 2-year follow-ups. 

Drug and Alcohol Dependence. 157, 106-111. doi: 10.1016/j.drugalcdep.2015.10.014

Burchfiel, C. M., Marcus, E. B., Curb, J. D., Maclean, C. S., Vollmer, W. M., Johnson, C. R., . . . Buist, A. S. 

(1995). Effects of smoking and smoking cessation on longitudinal decline in pulmonary function. 

American Journal of Respiratory Critical Care Medicine, 151(6), 1778-1785.

Byron, M. J., Jeong, M., Abrams, D. B., Brewer, N. T. (2018). Public misperception that very low nicotine 

cigarettes are less carcinogenic. Tobacco Control, 27(6), 712-714. doi: 10.1136/tobaccocontrol2017-054124

Byron, M. J., Hall, M. G., King, J. L., Ribisl, K. M., Brewer, N. T. (2019). Reducing nicotine without 

misleading the public: Descriptions of cigarette nicotine level and accuracy of perceptions about 

nicotine content, addictiveness, and risk. Nicotine Tobacco Research, 21(Suppl 1), S101-S107. 

doi: 10.1093/ntr/ntz161

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., Tidey, J. W., Cao, Q., Colby, S. M., McClernon, F. J., Koopmeiners, J. S., . . . Donny, E. C. 

(2019). Age moderates smokers' subjective response to very low nicotine content cigarettes: 

evidence from a randomized controlled trial. Nicotine & Tobacco Research, 21(7), 961-969. 

doi:10.1093/ntr/nty079

Cheah, N. P., Borst, S., Hendrickx L., Cremers, H., Jasen, E., Opperhuizen, A., Talhout, R. (2018). Effect of 

Adding Sugar to Burley Tobacco on the Emission of Aldehydes in Mainstream Tobacco Smoke. 

Tobacco Regulatory Science, 4(2), 61-72

Chen, M., Xu, Z., Chen, G., Wang, H., Yin, C., Zhou, Z., et al. (2014). The influence of exogenous fiber on 

the generation of carbonyl compounds in reconstituted tobacco sheet. Journal of Analytical and 

Applied Pyrolysis, 105, 227-233.

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: RTP, 41(3), 185-227.
MR0000159- MR0000160 Page 87 of 90 

Denlinger-Apte, R.L., Kotlyar, M., Koopmeiners, J.S., Tidey, J.W., Luo, X., Benowitz, N.L, et al. (2019). 

Effects of Very Low Nicotine Content Cigarettes on Smoking Behavior and Biomarkers of 

Exposure in Menthol and Non-menthol Smokers. Nicotine and Tobacco Research, 

21(Supplement 1), S63-S72.

Denlinger-Apte, R. L., Joel, D. L., Strasser, A. A., Donny, E. C. (2017). Low nicotine content descriptors 

reduce perceived health risks and positive cigarette ratings in participants using very low 

nicotine content cigarettes. Nicotine Tobacco Research, 19(10), 1149-1154. doi: 

10.1093/ntr/ntw320.

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. 

Tobacco Regulatory Science, 2(2), 186-203.

Dermody, S. S., Donny, E. C., Hertsgaard, L. A., & Hatsukami, D. K. (2015). Greater reductions in nicotine 

exposure while smoking very low nicotine content cigarettes predict smoking cessation. Tobacco 

Control, 24(6), 536-539. doi:10.1136/tobaccocontrol-2014-051797

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., & 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

Edwards, S.H., Rossiter, L.M., Taylor, K.M., Holman, M.R., Zhang, L., Ding, Y.S., Watson, C.H. (2017). 

Tobacco-Specific Nitrosamines in the Tobacco and Mainstream Smoke of U.S. Commercial 

Cigarettes. Chemical Research in Toxicology, 20(30), 540-551.

Eliasson, B., Hjalmarson, A., Kruse, E., Landfeldt, B., Westin, A. (2001). Effect of smoking reduction and 

cessation on cardiovascular risk factors. Nicotine Tobacco Research, 3(3), 249-255.

Elton-Marshall, T., Driezen, P., Fong, G. T., Cummings, K. M., Persoskie, A., Wackowski, O., ... Hyland, A. 

(2020). Adult perceptions of the relative harm of tobacco products and subsequent tobacco 

product use: Longitudinal findings from Waves 1 and 2 of the Population Assessment of Tobacco 

and Health (PATH) Study. Addictive Behaviors, 106, 106337. doi: 10.1016/j.addbeh.2020.106337

Foulds, J., Hobkirk, A., Wasserman, E., Richie, J., Veldheer, S., Krebs, N. M., Reinhart, L., Muscat, J. 

(2018). Estimation of compliance with exclusive smoking of very low nicotine content cigarettes 

using plasma cotinine. Preventive Medicine, 117, 24-29.

Godtfredsen, N. S., Lam, T.H., Hansel, T.T., Leon, M. E., Gray, N., Dresler, C., Burns, D. M., et al. (2008). 

COPD-related morbidity and mortality after smoking cessation: status of the evidence. European 

Respiratory Journal, 32, 844-83.

Godtfredsen, N. S., Osler, M., Vestbo, J., Andersen, I., Prescott, E. (2003). Smoking reduction, smoking 

cessation, and incidence of fatal and non-fatal myocardial infarction in Denmark 1976-1998: a 

pooled cohort study. Journal of Epidemiology and Community Health, 57(6), 412-416.

Godtfredsen, N. S., Prescott, E., Osler, M. (2005). Effect of smoking reduction on lung cancer risk. Journal 

of the American Medical Association, 294(12), 1505-1510

Godtfredsen, N. S., Vestbo, J., Osler, M., Prescott, E. (2002). Risk of hospital admission for COPD 

following smoking cessation and reduction: a Danish population study. Thorax. 57(11), 967-972.

Green, K. C. & Armstrong, J. S. (2012). Evidence on the effects of mandatory disclaimers in advertising. 

Journal of Public Policy and Marketing. 31(2), 293-304. doi: 10.1509/jppm.12.053

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
MR0000159- MR0000160 Page 88 of 90 

Hatsukami, D. K., Kotlyar, M., Allen, S., Jansen, J. M. S., Li, S., Le, C., Murphy, S. (2005). Effects of 

cigarette reduction on cardiovascular risk factors and subjective measures. Chest, 128(4), 2528-

2537.

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., Hecht, S. S., Shields, P. G., 

al’Absi, M. (2017). Reduced nicotine content cigarettes and use of alternative nicotine products: 

exploratory trial. Addiction. 112(1), 156-167.

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. Journal of the American Medical Association, 

320(9), 880-891. doi:10.1001/jama.2018.11473

Hatsukami, D. K., Luo, X., Heskin, A. K., Tang, M. K., Carmella, S. G., Jensen, J., Robinson, J. D., Vandrey, 

R., Drobes, D. J., Strasser, A. A., al'Absi, M., Leischow, S., Cinciripini, P. M., Koopmeiners, J., 

Ikuemonisan, J., Benowitz, N. L., Donny, E. C., and Hecht, S. S. (2019) Effects of immediate versus 

gradual nicotine reduction in cigarettes on biomarkers of biological effects. Addiction, 114, 

1824– 1833. https://doi.org/10.1111/add.14695. 

Haustein, K. O., Krause, J., Haustein, H., Rasmussen, T., Cort, N. (2004). Changes in hemorheological and 

biochemical parameters following short-term and long-term smoking cessation induced by 

nicotine replacement therapy (NRT). International Journal of Clinical Pharmacology 

Therapeutics, 42(2):83-92.

Hughes, J. R., & Carpenter, M. J. (2006). Does smoking reduction increase future cessation and decrease 

disease risk? A qualitative review. Nicotine & Tobacco Research, 8(6), 739-749. 

doi:10.1080/14622200600789726

Inoue-Choi, M., Hartge, P., Park, Y., Abnet, C. C., Freedman, N. D. (2019). Association Between 

Reductions of Number of Cigarettes Smoked per Day and Mortality Among Older Adults in the 

United States. American Journal of Epidemiology, 188(2), 363-371.

Institute of Medicine. (2010). Committee on Examination of Front-of-Package Nutrition Rating Systems 

and Symbols: Phase I Report. Washington, DC: National Academies Press. Retrieved from: 

https://www.ncbi.nlm.nih.gov/books/NBK209851/. 

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.

Kamens, H. M., Silva, C. P., Nye, R. T., Miller, C. N., Singh, N., Sipko, J., . . . Foulds, J. (2019). 

Pharmacokinetic profile of Spectrum reduced nicotine cigarettes. Nicotine & Tobacco Research, 

22 (2), 273-279. doi:10.1093/ntr/ntz045

Kozlowski, L. T. & O’Connor, R. J. (2002). Cigarette filter ventilation is a defective design because of 

misleading taste, bigger puffs, and blocked vents. Tobacco Control, 11, i40-i50.

Lee, P. N. (2013). The effect of reducing the number of cigarettes smoked on risk of lung cancer, COPD, 

cardiovascular disease and FEV(1)--a review. Regulatory Toxicology Pharmacology, 67(3), 372-

381.

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.

McRobbie, H. Przulj, D., Myers Smith, K., 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
MR0000159- MR0000160 Page 89 of 90 

Messer, K., Trinidad, D. R., Al-Delaimy, W. K., Pierce, J. P. (2008). Smoking cessation rates in the United 

States: A comparison of young adult and older smokers. American Journal of Public Health, 

98(2), 317-322.

Mutti, S., Hammond, D., Borland, R., Cummings, M. K., O’Connor, R.J., Fong, G. T. (2011). Beyond light 

and mild: Cigarette brand descriptors and perceptions of risk in the International Tobacco 

Control (ITC) Four Country Survey. Addiction, 106(6), 1166-1175. doi: 10.1111/j.1360-

0443.2011.03402.x

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.

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, 111(12), 2208-2216. doi:10.1111/add.13519

Novotny, T. E., Hardin, S. N., Hovda, L. R., Novotny, D. J., McLean, M. K., Safdar, K. (2011). Tobacco and 

cigarette butt consumption in humans and animals. Tobacco Control, 20(Suppl 1):i17-i20.

O’Brien, E. K., Nguyen, A. B., Persoskie, A., Hoffman, A. C. (2017). U.S. adults’ addiction and harm beliefs 

about nicotine and low nicotine cigarettes. Preventive Medicine, 96, 94-100. doi: 

10.1016/j.ypmed.2016.12.048

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. American 

Journal of Health Behavior, 31(4), 402-410.

Pacek, L. R., Sweitzer, M. M., McClernon, J. (2016). Non-cigarette tobacco and poly-tobacco use among 

persons living with HIV drawn from a nationally representative sample. Drug and Alcohol 

Dependence, 162, 251-255.

Pauwels, C. G. G. M., Klerx, W. N. M., Pennings, J. L. A., Boots, A. W., van Schooten, F. S., Opperhuizen, 

A., Talhout, R. (2018). Cigarette Filter Ventilation and Smoking Protocol Influence Aldehyde 

Smoke Yields. Chemical Research in Toxicology, 31(6), 462-471.

Persoskie, A. & Nelson, W. L. (2013). Just blowing smoke? Social desirability and reporting of intentions 

to quit smoking. Nicotine Tobacco Research, 15(12), 2088-2093. doi:10.1093/ntr/ntt101

Poland, B. & Teischinger, F. (2017). Population Modeling of Modified Risk Tobacco Products Accounting 

for Smoking Reduction and Gradual Transitions of Relative Risk. Nicotine Tobacco Research, 

19(11), 1277-1283.

Rigotti, N. (2020). Benefits and Risks of Smoking Cessation. In J. K. Stoller, M. D. Aronson (Eds.), 

UpToDate. Retrieved June 12, 202 from https://www.uptodate.com/contents/benefits-andconsequences-of-smoking-cessation. 

Shadel, W. G., Lerman, C., Cappella, J., Strasser, A. A., Pinto, A., Hornik, R. (2006). Evaluating smokers’ 

reactions to advertising for new lower nicotine Quest cigarettes. Psychology of Addictive 

Behaviors, 20(1), 80-84. doi: 10.1037/0893-164X.20.1.80

Song A.V., Morrell H.E.R., Cornell J.L., et al. (2009). Perceptions of smoking-related risks and benefits as 

predictors of adolescent smoking initiation. American Journal of Public Health, 99:487-492.

Stein, M. D., Weinstock, M. C., Herman, D. S., Anderson, B. J. (2005). Respiratory symptom relief related 

to reduction in cigarette use. Journal of General Internal Medicine, 20(10), 889-894.

Strasser, A. A., Tang, K. Z., Tuller, M. D., Cappella, J. N. (2008). PREP advertisement features affect 

smokers’ beliefs regarding potential harm. Tobacco Control, 17(Suppl 1), i32-i38. doi: 

10.1136/tc.2007.022426
MR0000159- MR0000160 Page 90 of 90 

Strong D.R., Leas E., Elton-Marshall T., Wackowski O.A., et al. (2019). Harm perceptions and tobacco use 

initiation among youth in Wave 1 and 2 of the Population Assessment of Tobacco and Health 

(PATH) Study. Preventive Medicine, 123:185-191.

Sung, H. Y., 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.

Talhout, R., Opperhuizen, A., van Amsterdam, J. G. C. (2007). Role of acetaldehyde in tobacco smoke 

addiction. European Neuropsychopharmacology, 17(10), 627-636.

Thun, M. J., Carter, B. D., Feskanich, D., Freedman, N. D., Prentice, R., Lopez, A. D., Hartge, P., Gaptur, S. 

M. (2013). 50-year trends in smoking-related mortality in the United States. New England 

Journal of Medicine, 368(4), 351-364.

Tidey, J. W., Denlinger, R., Hatsukami, D., Donny, E. (2017). Environmental smoke exposure among daily 

smokers with low vs. high educational attainment. Drug and Alcohol Dependence, 100(171). 

Tverdal, A. & Bjartveit, K. (2006). Health consequences of reduced daily cigarette consumption. Tobacco 

Control, 15(6), 472-480.

U.S. Department of Health and Human Services. (2004). The Health Consequences of Smoking: A Report 

of the Surgeon General. U.S. Department of Health and Human Services, Centers for Disease 

Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 

Office on Smoking and Health. Atlanta, GA. 

U.S. Department of Health and Human Services. (2012). Preventing Tobacco Use among Youth and 

Young Adults: A Report of the Surgeon General. U.S. Department of Health and Human Services, 

Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and 

Health Promotion, Office on Smoking and Health, Atlanta, GA. Retrieved from: 

https://www.surgeongeneral.gov/library/reports/preventing-youth-tobacco-use/full-report.pdf

U.S. Department of Health and Human Services. (2014). The Health Consequences of Smoking--50 Years 

of Progress: A Report of the Surgeon General. U.S. Department of Health and Human Services. 

Retrieved from Rockville, MD. 

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 

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