Scientific Review of a Modified Risk Tobacco Product Application (MRTPA): Technical 

Project Lead (TPL) Review 

SUBMISSION INFORMATION 

Applicant U.S. Smokeless Tobacco Company LLC 

Product Manufacturer U.S. Smokeless Tobacco Company LLC 

Submission Date March 19, 2018 FDA Receipt Date March 20, 2018 

Purpose ☒ Risk Modification (911(g)(1) order)

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

Claims USSTC is seeking a risk modification order under Section 911 (g)(I) of 

the FD&C Act for the pre-existing product Copenhagen Snuff Fine Cut 

(GF1200194), which the applicant has proposed to rename 

Copenhagen® Classic Snuff. USSTC requests that FDA designate the 

candidate product as a modified risk tobacco product and permit 

marketing of the candidate product with the following proposed 

modified risk claim, as provided in the proposed advertising and 

labeling: 

"IF YOU SMOKE, CONSIDER THIS: Switching completely to this product 

from cigarettes reduces risk of lung cancer." 

Amendments 

MR0000113, MR0000120, MR0000121, MR0000125, MR0000126, MR0000149, MR0000193, 

MR0000199 and MR0000202 

Cross-Referenced Submissions

 and GF1200194 

Attributes1,2,3 Tobacco Product 

STN MR0000108 

Product Name Copenhagen Classic Snuff 

Product Category Smokeless Tobacco 

Product Sub-Category Loose Moist Snuff 

Package Type Fiberboard Can/Metal Lid 

Package Quantity 34.02 grams 

Characterizing Flavor Tobacco 

Nicotine Source Tobacco 

Additional Properties Tobacco cut size: Cuts Per Inch (CPI) 

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

Discipline 

Cycle 1 Cycle 2 

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

Engineering Rashele Moore 3/22/2021 Cao Chung 2/23/2023 

1 Effective April 14, 2022, FDA’s authority to regulate tobacco products was extended to include tobacco products containing 

nicotine from any source. https://www.congress.gov/bill/117th-congress/house-bill/2471 

2 The characterizing flavor previously identified as “None” has been updated in FDA records to “Tobacco” to accurately reflect

that the product provides a tobacco characterizing flavor from the filler. As such, this product does not have any change in 

characterizing flavor. 

3 Finalized scientific reviews may not reflect the referenced product characterizing flavor and nicotine source. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 2 of 75 

Chemistry Stephanie Daniels 3/22/2021 Selena Russell 2/17/2023 

Microbiology Prashanthi Mulinti 3/24/2021 Not applicable (N/A) N/A 

Toxicology Mary Irwin 3/22/2021 Rebecca Danam 2/16/2023 

Social Science Aura Lee Morse 3/23/2021 Aura Lee Morse 2/16/2023 

Behavioral Clinical 

Pharmacology 

Steven Meredith 3/22/2021 Not applicable (N/A) N/A 

Medical Theresa WatkinsBryant 3/24/2021 Not applicable (N/A) N/A 

Epidemiology Hannah Day 3/25/2021 Terrence Lee 2/16/2023 

Statistics Juan C. Vivar 3/22/2021 Not applicable (N/A) N/A 

Environmental 

Science 

William E.Brenner 3/25/2021 William E. Brenner 10/21/2022 

OCE – DPAL Melissa R. View 3/22/2021 Adeola Obajemu 2/22/2023 

OCE – DEM/BIMO Arnon M. Dayak 3/22/2021 Abraham Agyapong 3/28/2022 

Consultations Cycle 1 Cycle 2 

(Discipline/ Office) Reviewer(s) Review Date Reviewer(s) Review Date 

TPST Not applicable (N/A) N/A Kimberly R. Lindsey 3/14/2022 

OHCE Not applicable (N/A) N/A Emily Talbert 2/21/2023 

Recommended Action(s) 

Issue a modified risk granted order for the product subject of this review. 

Technical Project Lead (TPL): 

S 

CAPT Robin Toblin, Ph.D., M.P.H. 

Director 

Division of Research and Knowledge Integration 

Signatory Decision: Concur with TPL recommendation and basis of recommendation 

S 

Todd Cecil, Ph.D. 

Acting Director 

Office of Science 
MR0000108 Page 3 of 75 

Table of Contents 

1. Executive Summary.................................................................................................................................. 4 

2. Regulatory Information............................................................................................................................ 8 

2.1 Regulatory History .............................................................................................................................. 8 

2.2 Public Availability .............................................................................................................................. 11 

2.3 TPSAC Meeting.................................................................................................................................. 12 

3. Scientific Review .................................................................................................................................... 13 

3.1 Potential Impact of Proposed MRTP to Individual Users - Product Characterization ...................... 13 

3.1.1 Engineering ................................................................................................................................ 14 

3.1.2 Chemistry ................................................................................................................................... 17 

3.1.3 Microbiology .............................................................................................................................. 24 

3.1.4 Conclusions: Product Characterization...................................................................................... 25 

3.2 Relative Health Risks to Individuals & Claim Substantiation ............................................................ 26 

3.2.1 Toxicology .................................................................................................................................. 26 

3.2.2 Clinical ........................................................................................................................................ 30 

3.2.3 Epidemiology.............................................................................................................................. 32 

3.2.4 Conclusions: Claim Substantiation and Individual Health Risks................................................. 34 

3.3 Consumer Understanding and Perceptions ...................................................................................... 35 

3.3.1 Social Science ............................................................................................................................. 35 

3.3.2 Social Science Support for TPL Deficiency ................................................................................. 41 

3.3.3 Conclusions: Consumer Understanding..................................................................................... 43 

3.4 Likelihood of Use and Impacts to Population ................................................................................... 44 

3.4.1 Impacts to Users ........................................................................................................................ 44 

3.4.2 Impacts to Non-users................................................................................................................. 50 

3.4.3 Population Modeling.................................................................................................................. 52 

3.4.4 Conclusions: Impact to the Population...................................................................................... 53 

4. Environmental Impact............................................................................................................................. 54 

5. Conclusions and Recommendation......................................................................................................... 54 

5.1 Statutory Requirements for Authorization ....................................................................................... 54 

5.2 Conclusions: Scientific Evidence ....................................................................................................... 55 

5.3 Recommendation for the Risk Modification Order Request ............................................................ 59 

6. References ............................................................................................................................................. 61 
 

 

 

 

 

 

 

MR0000108 Page 4 of 75 

7. Appendices............................................................................................................................................. 65 

1. Executive Summary 

On March 20, 2018, the Food and Drug Administration (FDA) received a Modified Risk Tobacco Product 

Application (MRTPA) from Altria Client Services LLC (ALCS), submitted on behalf of U.S. Smokeless 

Tobacco Company LLC (USSTC) for its pre-existing Copenhagen Snuff Fine Cut loose moist snuff 

smokeless tobacco product (GF1200194). The application requested authorization under Section 

911(g)(1) to market the product with the following risk modification claim: “IF YOU SMOKE, CONSIDER 

THIS: Switching completely to this product from cigarettes reduces risk of lung cancer.” 

. The MRTPA did not include 

(b) (4)

this information. The missing information was addressed in a deficiency along with seven other 

deficiencies sent on March 26, 2021. In response (MR0000199), the applicant presented a plan 

. 

(b) (4)

In examining the product characterization of the proposed MRTP, we found that the stability data did 

not raise microbial product stability concerns. However, I needed additional information to determine 

whether the product could be manufactured in a consistent way and to fully characterize the proposed 

MRTP, including its harmful and potentially harmful constituent (HPHC) quantities and any variation in 

those quantities, in order to determine whether the product, as actually used, would significantly reduce 

the risk to individual tobacco users and benefit the health of the population as a whole. This missing 

information was addressed in a deficiency. The applicant’s responses addressed the deficiencies in an 

acceptable manner to the disciplines who put forth the deficiencies (Engineering, Chemistry, and 

Toxicology). As TPL, I concur and find that the product can be manufactured consistently and can now 

be fully characterized. Therefore, the HPHC data initially submitted by the company is valid and can be 

analyzed as was submitted, and a definitive assessment of risk of the proposed MRTP relative to other 

ST products could be undertaken. 

4 

. (b) (4)
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 5 of 75 

In examining claim substantiation and the risks to individual health of the proposed MRTP, the applicant 

used data from the smokeless tobacco (ST) product category and bridged to the proposed MRTP, which 

is an acceptable approach. Compared to cigarette smoking, ST use poses lower risks of certain health 

outcomes. Specifically, those who completely switched from cigarettes to ST had generally lower risks 

for lung cancer, heart disease, oral cancer, and stroke (Henley et al. 2007). 

Overall, consistent with the Tobacco Products Scientific Advisory Committee (TPSAC), I found that the 

claim was substantiated: switching completely to the proposed MRTP from cigarettes will confer a lower 

risk of lung cancer. The evidence also suggests switching completely to the proposed MRTP would lower 

HPHC exposure relative to smoking as well as reduce risk of morbidity and mortality for several other 

diseases relative to smoking. 

However, because the proposed MRTP is a harmful product, my final assessment of the individual health 

risks of the product, including risks relative to other ST products, was subject to the product chemistry. 

Well-characterized product chemistry is required to draw firm conclusions on individual health risk, 

especially compared to users of other ST products. Ultimately, the assessment of individual health is 

required to determine the impact of authorization to the population. A deficiency was sent requesting 

that the applicant provide scientific evidence and rationale about how exposure to HPHCs in the 

proposed MRTP may impact the population of tobacco users that may completely switch to the 

proposed MRTP or begin to dual use their current product(s) with the proposed MRTP, particularly in 

comparison to other ST products. In response, the applicant indicated that the appropriate comparison 

for HPHCs for the proposed MRTP was other moist smokeless tobacco (MST, also referred to as moist 

snuff) products based on its share of the ST marketplace. As TPL, I agree with this approach. Through an 

offsetting analysis, Toxicology determined that the higher levels of some HPHCs in the proposed MRTP 

relative to the MST category were offset by the lower levels of other HPHCs. Specifically, lower levels of 

NNK and free nicotine offset the higher levels of benzo[a]pyrene (BaP), and cadmium from a 

carcinogenic perspective. 

Next, I examined population-level effects of the proposed MRTP, including consumer understanding 

(e.g., whether the labeling and advertising would enable consumers to understand the modified risk 

information) and use behavior (e.g., the likelihood that current smokers would completely switch from 

cigarettes to the proposed MRTP). In examining consumer understanding, the Claim Comprehension and 

Intentions (CCI) study provided sufficient evidence to meet the basic statutory requirements that 

support appropriate consumer understanding of the proposed modified risk claim and its significance in 

the context of total health. After seeing the advertisement with the modified risk claim, participants 

understood that the absolute risk of developing lung cancer is lower for a person who exclusively uses 

the proposed MRTP daily than for a person who smokes cigarettes daily. Participants also understood 

that using the proposed MRTP still poses health risks, and that someone who only uses the proposed 

MRTP daily would likely experience a negative impact to their health. Finally, participants understood 

that using the proposed MRTP is not less risky than using other MST products, and that the risk of using 

the proposed MRTP is greater than that of using nicotine replacement therapy (NRT), quitting all 

tobacco, and never using tobacco products. I also examined if the applicant assessed a consumer’s 

understanding that a user must completely switch to the product (from cigarettes) in order to reap the 

benefit. The applicant did not do that. I believe that this limitation is mitigated by the fact that the claim 

itself directs potential users that they can reduce their risk by “switching completely.” Still, the extent to 

which consumers understand that the proposed MRTP must be used exclusively and that dual users 

must switch completely should be monitored in postmarket surveillance as has been the case in 

previous MRTP authorizations. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 6 of 75 

Although the CCI study suggested the modified risk claim did not significantly affect risk perceptions, it is 

understandable that participants’ beliefs did not change especially with a one-time exposure. It is 

difficult to change people’s beliefs and persistent misperceptions about the relative risks of ST 

compared to cigarettes, including the misperception that particular products are as harmful as 

cigarettes. This is seen in the literature and was supported by submitted data; on average, participants 

in the CCI study rated the overall health risk of using the proposed MRTP similarly to how they rated 

that of smoking cigarettes. Authorization would serve to increase the information’s credibility and 

believability to the public and help combat the persistent misperception. Because the statutory 

requirements were met and the repeated exposure in the real world to the claim following 

authorization would likely increase its effects on consumer perceptions and intentions (Hornik, 2002), 

the applicant demonstrated that the proposed MRTP enables the public to understand the modified risk 

information specific to the proposed MRTP and its relative significance in the context of total health and 

in relation to all of the diseases and health-related conditions associated with the use of tobacco 

products. 

While the basic requirements related to consumer understanding were met, the CCI study had 

limitations in its design and findings. I believe the applicant could have provided more compelling 

evidence through a number of changes. As noted above, one change would have been to assess 

consumer understanding of the need to switch completely; however, as explained above, that limitation 

is mitigated by the fact that the claim itself directs potential users that they can reduce their risk by 

“switching completely.” Another design limitation was that the applicant only required participants to 

examine the proposed labeling one time and did not assess if the participants opted to look at the 

exposure additional times to determine a dose-response relationship; requiring multiple exposures 

would have been optimal as would have determining the number and length of times that participants 

optionally examined the proposed labeling. It is likely that the findings do not reflect the full real-world 

impact of the claim, which is likely to happen over a period of time as the idea gains more credibility and 

general awareness among the public. Thus, the findings likely underestimate the potential impact of the 

claim on consumers’ perceptions. The applicant also assessed participants before and after exposure on 

a host of perception and intention items leaving participants subject to testing effects; testing only after 

exposure would have allowed a more definitive assessment of the impact of the claim and LLA itself. 

Section 3.3 and the Social Science review describe these methodological concerns in more detail. 

However, it is difficult to know to what extent this particular study design element affected results. 

Additionally, because this methodology has been used in similar studies and is a common study design, 

we believe the findings are informative; if anything, the applicant may have found fewer null effects had 

they used a post-test only design. Despite these limitations, I believe the applicant has met the statutory 

requirements for basic understanding of modified risk: participants understand that the proposed MRTP 

causes harm and that it is more harmful than quitting or NRT and the label directs users that they must 

switch completely to derive the benefits of the claim (in this case, a reduced risk of lung cancer relative 

to cigarettes). 

Epidemiology examined current use behavior, patterns of use, intentions to use, and modeling. It is 

worth noting that the model used inputs from the CCI study, including its aforementioned limitations, 

limiting its utility in weighing the evidence. Currently, ST use in the United States is low, but dual use 

with cigarettes is substantial. Patterns of switching indicate that the likelihood of completely switching 

from either exclusive cigarette or dual use to exclusive ST use remains quite low (Jackson, Ren et al. 

2021). Though the applicant’s CCI study corroborated the current patterns by demonstrating low to 

moderate levels of interest in using the proposed MRTP among those who stand to benefit (i.e., 

smokers, dual users), this must be examined in the context of misperceptions about the relative harms 

of ST relative to cigarettes also shown in the CCI study as noted above. The repeated exposure to the 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 7 of 75 

modified risk claim that would occur if the proposed MRTP were to be authorized would provide 

tobacco users with basic, substantiated information relevant to their health, opening the possibility of 

moving users of combustible products to a product with modified risk. 

Based on the broader literature and limited data from the CCI study and consistent with TPSAC’s 

concerns, I expect that the level of interest in using the proposed MRTP among those who stand to 

benefit most—current smokers—will be relatively low, and that exposure to the modified risk claim will 

have a limited effect on this. While ideally, the applicant could have demonstrated that some cigarette 

smokers were interested in switching, the literature finds a small group of smokers that do switch to ST. 

With the Copenhagen brand representing the largest market share among ST products, the MRTP may 

appeal to a large number of ST users though still a minority of smokers — those who are open to the 

category of ST. In examining whether the proposed MRTP provides a strong enough subjective effect 

and sensory experience to encourage complete switching, BCP found that the abuse liability for the 

proposed MRTP is greater than use of FDA-approved cessation aids, but less than that associated with 

cigarette smoking. This suggests that for those tobacco users who wish to reduce their tobacco-related 

risks, but do not wish or are not able to quit altogether, the proposed MRTP is a viable alternative. With 

targeted marketing toward cigarette smokers of brands of the applicant’s parent company, there is a 

large segment of current smokers who may receive direct marketing materials regarding the proposed 

MRTP, which may present them with new information about the relative lung cancer risk. Appealing to 

that group of smokers and persuading them to completely switch to a less harmful alternative presents 

an opportunity to benefit population health. 

The group that the proposed MRTP may be most likely to impact is current dual users who could reduce 

their individual risk by switching completely. Perhaps unsurprisingly, current dual users of smokeless 

products reported the highest mean levels of intentions to use the product. I expect that the MRTP will 

influence some proportion of these users to stop smoking and use the product exclusively, which would 

significantly reduce their individual risk and help benefit population health.

(b) (4)

 Given the brand’s market 

share and the over dual users of Copenhagen in the U.S., this is a particularly ripe population 

who would benefit from the proposed MRTP. In addition, it is notable that dual use Copenhagen users 

consume more of their Copenhagen product daily and smoke fewer cigarettes daily than do dual users 

of other ST products; this suggests that dual users of the applicant’s products may have an easier time 

switching to exclusive use of the proposed MRTP, since the balance of the use of the two products may 

be weighted more toward Copenhagen use compared to that of dual users of other ST products. Overall, 

by enabling people who smoke to switch completely, the proposed MRTP would benefit population 

health. Taken together the evidence provides support that the proposed MRTP would increase exclusive 

use of Copenhagen Classic Snuff among adult tobacco consumers who would benefit from complete 

switching, including both smokers and dual users of cigarette and ST products. 

While the applicant’s population model also supports this conclusion and indicates that the proposed 

MRTP would yield modest health benefits for the population, I assigned less weight to this evidence due 

to its limitations. Although I agree with the conclusion that the population modeling tools and approach 

were appropriate, a significant limitation is that many behavioral inputs into the model were derived 

from non-statistically significant findings in the CCI study, which led to considerable uncertainty 

regarding the model’s findings. While the applicant’s population health model indicates that the 

proposed MRTP would yield modest health benefits for the population, the results of the population 

model are dependent on the behavioral inputs and would therefore differ (and could even show a net 

negative impact) if the behavioral inputs were different. Because of this, I assigned minimal weight to 

the population model, and instead relied on other findings such as consumer understanding of the claim 
 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 8 of 75 

in the CCI study and the broader literature on tobacco use behavior to reach conclusions about the 

population health impact. 

Regarding the impact to non-users, specifically to youth, national estimates suggest that use of ST 

among youth is low (2.3%) and is declining over time and that the likelihood of youth initiating on an ST 

product is low. However, this varies by rurality with rural youth use of ST at roughly twice the rate of 

urban youth (Buettner-Schmidt et al., 2019), a concern substantial enough that the FDA’s Real Cost 

Campaign has a series of ads targeted at rural youth use of ST with the tag line “smokeless doesn’t mean 

harmless.” While Copenhagen appears to be perhaps the most popular brand among youth who use ST, 

the applicant’s CCI study, though it did not include youth, showed that non-users (including young 

adults) had virtually no intentions to try or use the proposed MRTP. However, given the association 

between risk perceptions and initiation, there is a potential risk of any MRTP to youth. Accordingly, if 

authorized, MRTP marketing should be targeted to maximize exposure to intended users and prevent 

exposure among youth, especially given the popularity of the applicant’s brand among youth ST users. 

In conclusion, I conducted a thorough scientific review of the information contained in the MRTPA, and 

considered the recommendations from TPSAC, comments, data, and information submitted to FDA by 

interested persons, and other scientific information identified by the agency from other sources. After 

examining the totality of evidence across scientific reviews, I found that the proposed modified risk 

claim is scientifically accurate: smokers who switch completely to the proposed MRTP will have a lower 

risk of lung cancer than if they continued to smoke. Furthermore, the data support a benefit to 

population health through reductions in overall morbidity and mortality associated with the use of the 

proposed MRTP, relative to cigarette smoking, that would not be offset by nonusers initiating with the 

product nor users of other ST products switching to the proposed MRTP. In addition, despite the 

limitations in the CCI study, the applicant demonstrated that consumers were able to sufficiently 

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

information in the context of total health. Therefore, I recommend issuing a Modified Risk Granted 

Order (MRGO) to USSTC for Copenhagen Classic Snuff, MR0000108. 

2. Regulatory Information 

2.1 Regulatory History 

On March 20, 2018, the Food and Drug Administration (FDA) received a Modified Risk Tobacco Product 

Application (MRTPA) from Altria Client Services LLC (ALCS), submitted on behalf of U.S. Smokeless 

Tobacco Company LLC (USSTC) for its Copenhagen Snuff Fine Cut tobacco product (GF1200194). The 

application requested authorization under Section 911(g)(1) to market the product with the following 

risk modification claim: “IF YOU SMOKE, CONSIDER THIS: Switching completely to this product from 

cigarettes reduces risk of lung cancer.” 

(b) (4)

(b) (4)
 

MR0000108 Page 9 of 75 

(b) (4) • March 20, 2018: FDA received an MRTPA (MR0000108) from the applicant for its pre-existing 

Copenhagen Snuff Fine Cut loose moist snuff smokeless tobacco product (GF1200194). 

• April 10, 2018: FDA received an unsolicited amendment (MR0000113) containing updates to 

Appendix 7.3.2-15 CCI Study SSAP Syntax Code in MR0000108. 

(b) (4)

• July 10, 2018: FDA issued an A/I Request letter for MR0000108. 

• July 11, 2018: FDA received an unsolicited amendment (MR0000120) containing a tabulated 

master bibliography index to the original application for MR0000108. 

• July 18, 2018: FDA received an unsolicited amendment (MR0000121) containing an updated 

version of Table 7.1-17 included in Section 7.1 of the original application for MR0000108. 
 

 

 

MR0000108 Page 10 of 75 

• August 8, 2018: FDA received the applicant’s response (MR0000125) to the July 10, 2018, FDA 

A/I Request letter for MR0000108. 

• August 23, 2018: FDA held a teleconference with the applicant to request the applicant check 

the formatting and resend the specific files and folders as some of the files and folders in 

amendment MR0000125 were unable to be located or opened for MR0000108. 

• August 27, 2018: FDA received a solicited amendment (MR0000126) containing responses to the 

information requested on August 23, 2018, for MR0000108. 

• September 14, 2018: FDA issued a Filing letter for MR0000108. 

• September 21, 2018: FDA opened a docket for public comment on MR0000108. 

• January 24, 2019: FDA held a teleconference with the applicant to request clarifications on 

minor modifications and HPHC data for MR0000108. 

• February 1, 2019: FDA received a solicited amendment (MR0000149) containing responses to 

the clarification questions requested on January 24, 2019, for MR0000108. 

• February 6-7, 2019: FDA held a TPSAC meeting at FDA White Oak Conference Center for 

MR0000108. 

•

• January 21, 2020: FDA closed the application docket for public comment for MR0000108. 

(b) (4)

• March 26, 2021: FDA issued a Deficiency Letter for MR0000108 

• April 8, 2021: USSTC responded that it would provide a response to the Deficiency Letter by 

September 30, 2021 (MR0000193) for MR0000108. 

• September 29, 2021: USSTC submitted a solicited amendment in response to the Deficiency 

Letter (MR0000199) for MR0000108. 

• On March 7, 2022, FDA sent an email to the applicant requesting they provide information 

regarding

(b) (4)

 by submitting a general 

correspondence letter to the FDA Document Control Center. The RHPM documented this in a 

telecon for MR0000108. 

• March 9, 2022: FDA received a solicited amendment (MR0000202) containing information 

requested on March 7, 2022, for MR0000108. 

• March 14, 2022: FDA re-opened the docket for public comment for the last three amendments 

received for MR0000108. 

• May 13, 2022: FDA re-closed the docket for public comment for MR0000108. 

(b) (4)
MR0000108 Page 11 of 75 

(b) (4)

In response to Deficiency #1 of the Deficiency letter issued on March 26, 2021, for MR0000108, the 

applicant

 discussion of that review is in section 3.3.2. 

(b) (4)

(b) (4)

As TPL, I find that Deficiency #1 was adequately addressed 

(b) (4)

. 

2.2 Public Availability 

Pursuant to Section 911(e) of the Food, Drug, and Cosmetic (FD&C) Act, FDA made the applicant’s 

MRTPA available to the public. Matters in the application that are trade secrets or otherwise 

confidential, commercial information were redacted in a manner consistent with other applications. The 

docket for public comment on this MRTPA was open from September 21, 2018, to January 21, 2020. 

During this period, FDA received a total of 58 (30 unique) submissions from individuals, academia, and 

other organizations. In addition to legal and advocacy issues, the comments included independent 
MR0000108 Page 12 of 75 

consumer perception information, critiques of the applicant’s studies and interpretation of findings, and 

concerns about potential appeal to youth. The docket was reopened on March 14, 2022, to May 13, 

2022, to receive comments about the amendments and all available application materials. FDA received 

a total of one finalized submission and one draft submission from non-profit organizations during this 

period. The comments largely focused on concerns about whether the applicant’s response addressed 

the deficiencies identified by FDA. The issues and concerns raised in both rounds of public comments 

were also identified during FDA’s scientific review of the applications. FDA considered all significant 

comments when making the final determination. Specific comments were addressed in the discipline 

reviews. 

2.3 TPSAC Meeting 

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

recommendations on the application during an open public committee meeting held on February 6-7, 

2019. TPSAC discussed FDA’s preliminary assessment of the MRTPA. FDA posed three specific questions 

to TPSAC for discussion; committee members were asked to vote on one of them. A brief summary, 

based on FDA’s meeting Summary Minutes, is provided below. Meeting materials, including complete 

meeting transcripts, are available on FDA’s website.

6 

To start, FDA asked TPSAC to discuss the available scientific evidence and vote on the extent to which 

the proposed modified risk claim is scientifically substantiated by that evidence (voting options were 

yes, no, or abstain). Overall, TPSAC agreed that the proposed claim was accurate based on the strength 

of the scientific evidence: eight of the nine voting members voted “yes”. The ninth member abstained, 

noting concerns about potential confounding factors (e.g., length of smoking history, genetic risk) that 

may impact the veracity of the statement on an individual basis, while also appreciating the simplicity 

and specificity of the statement. 

Next, TPSAC turned to the topic of consumer understanding and perception of the modified risk 

information in the proposed advertising. FDA asked TPSAC to discuss the potential implications of the 

proposed modified risk information on consumer understanding and perceptions. Overall, TPSAC 

expressed the opinion that this was a clear and focused statement that could inform consumers’ 

understanding of the relative risk of tobacco products. There was some concern about whether 

consumers understood the need for complete switching because it was not directly assessed in the 

applicant’s CCI study. TPSAC noted that the study failed to demonstrate that the claim affected 

perceptions. However, they also noted the context of pre-existing beliefs about the harms of ST use and 

the limited impact of a brief, single-sitting exposure as compared to a full marketing campaign. Overall, 

TPSAC found no evidence that the proposed claim would increase population harm or that people 

interpreted it as meaning the product was risk-free. 

Finally, TPSAC discussed potential users of the proposed MRTP. Specifically, FDA asked: “What is the 

likelihood that cigarette smokers will switch completely to Copenhagen Snuff Fine Cut?” and 

“Considering the health risks from the use of Copenhagen Snuff Fine Cut and those who may be likely to 

use the product, what are the groups of potential concern (e.g., users of smokeless tobacco products 

with lower HPHC quantities, youth)?” In response to these questions, the committee expressed concern 

that, given how difficult it is to quit smoking completely, and the product’s past lack of popularity 

relative to cigarettes, it seems unlikely that the proposed MRTP would lead to substantial change in 

smokers’ behavior. There was some speculation about whether smokers would see a tradeoff in 

6 https://www.fda.gov/advisory-committees/tobacco-products-scientific-advisory-committee/2019-tpsac-meeting-materialsand-information 
 

MR0000108 Page 13 of 75 

complete switching to the proposed MRTP between lower risk of lung cancer and a (perceived) 

increased risk of oral cancer. The committee also discussed concerns about the likelihood of dual use. 

TPSAC also discussed the challenges of predicting behavior and the importance of postmarket 

surveillance, especially for youth, former smokers, users of ST products with fewer HPHCs, and pregnant 

persons. These concerns are addressed in Section 3. 

3. Scientific Review 

Ten Office of Science (OS) scientific disciplines reviewed the applicant’s MRTPA -- Engineering, 

Chemistry, Microbiology, Toxicology, Medical, Behavioral and Clinical Pharmacology (BCP), 

Epidemiology, Social Science, Statistics, and Environmental Science -- and two Office of Compliance and 

Enforcement (OCE) divisions (Division of Product Compliance [DPC] and Division of Promotion, 

Advertising, and Labeling [DPAL]) to determine whether the MRTPA met the 911(g)(1) marketing 

authorization criteria. 

This assessment integrates the lines of evidence from the discipline reviews regarding the proposed 

MRTP and its potential effects on individual health and tobacco use behavior, including tobacco use 

initiation, to determine whether the applicant has demonstrated that marketing of the proposed MRTP, 

as actually used by consumers, will significantly reduce harm and the risk of tobacco-related disease to 

individual tobacco users and benefit the population as a whole, taking into account both users of 

tobacco products and persons who do not currently use tobacco products. 

3.1 Potential Impact of Proposed MRTP to Individual Users - Product Characterization 

This section describes the product design and composition and examines whether the application 

sufficiently describes the product itself, how it is made, and the consistency of the manufacturing of the 

product. This information is necessary to fully understand the product science, which, in turn, influences 

the potential health risks of the product. The section will summarize the findings of the Engineering, 

Chemistry, and Microbiology reviews. The OCE DEM review identified no significant compliance issues or 

process deficiencies during the manufacturing inspection conducted in 2016 and upon receipt of this 

MRTPA in 2018, concurred with the Office of Science’s (OS) recommendation that additional inspections 

were not necessary, and thus, were not performed. Upon receipt of the amendment (MR0000199), FDA 

learned of an additional manufacturing site. Based on its similarity and the use of the same processes 

and procedures, OCE DEM determined that an inspection was not necessary and was, therefore, not 

performed on this site. 

The applicant describes Copenhagen Classic Snuff as a loose, non-portioned, fine cut moist smokeless 

tobacco (MST) product. The applicant has been manufacturing variants of the proposed MRTP since 

1822, with the earliest documented manufacturing process dating back to 1905. The applicant states 

that a pinch of the product is intended to be placed into the mouth between the cheek or lip and gum. 

The user typically holds the product in the mouth, expectorates the “juice” produced during use, and 

removes the product from the mouth after use. Some users swallow the “juice” produced during use 

instead of spitting. 

MR0000108 

Product Name Copenhagen Classic Snuff 

Product Form Non-Portioned Loose 
 

 

 

 

 

 

 

 

 

 

MR0000108 Page 14 of 75 

Package Size 34.02 g per can 

Product ID/Universal Product Code (UPC) 0-731071-91 

Product Category Smokeless Tobacco Product 

Product Sub-Category Moist Snuff 

3.1.1 Engineering 

The Engineering review describes and examines the engineering design and principles of operation of 

the proposed MRTP as well as the manufacturing process and performance tolerances for the product. 

Product Design: All total moisture test data the applicant initially provided fell within the range limits. 

(b) (4)

Based on the test data, range limits, and method (CDC Method 095-3371), the applicant had 

demonstrated that the proposed MRTP’s total moisture, 

(b) (4)

, can be produced in a controlled process. 

The applicant provided the target specification for tobacco cut size and provided sufficient information 

on the cutting process to ensure that the fine cut snuff can be manufactured consistently. However, the 

applicant had not submitted the complete test data needed to fully characterize the product. Though 

the target specification and range limits were provided for the blend moisture and leaf moisture, the 

applicant did not provide the test data to confirm that the specifications are met. The assessment of 

these design parameters is necessary to understand the comprehensive design of the proposed MRTP as 

each parameter contributes to the overall constituent yields. Tobacco moisture may affect microbial 

growth in the product, extraction efficiency, and total exposure to nicotine, NNN, and NNK (US FDA, 

2013; Gale et al., 2013). Accordingly, the Engineering review concluded that the product had not been 

fully characterized because the application lacked test data for leaf moisture and blend moisture, which 

are obtained during the production process. This missing information was addressed in a deficiency. 

). Engineering 

also reviewed the manufacturing controls in place, which include 

. Based on this review, Engineering determined the 

Principles of Operation, Manufacturing Process, and Quality Control: The applicant had provided an 

adequate description of the principles of operation of the product from an Engineering perspective. 

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

Engineering reviewed the information provided describing the manufacturing process: from receiving 

and staging of the tobacco received from growers to the steps of producing the product (i.e., 

method and protocols used at the stages. These methods allow 

FDA to assess the quality control measures the applicant undertakes to ensure consistent 

manufacturing. Such information is necessary to confidently characterize the relative health risks of the 

product by ensuring that the levels of HPHCs reported through product testing reflect what an individual 

would be exposed to through regular use of the product. This missing information was addressed, along 

with related manufacturing information identified in the Chemistry review (discussed below), in 

deficiencies. 

In summary, the Engineering review concluded that the MRTPA did not contain adequate information 

with respect to the following: 

• Information to ensure that the product meets manufacturing specifications and that the 

product is manufactured in a consistent manner that minimizes the variability in product 

quality 

application was missing information regarding manufacturing process and controls including the test 

(b) (4)
 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 15 of 75 

• Manufacturing information such as quality control measures and performance testing to 

verify the product design including the leaf moisture and blend moisture parameters 

Engineering noted two deficiencies, one of which was combined with a Chemistry review deficiency. 

As TPL, I agreed with the Engineering conclusion that this MRTPA provided insufficient information for 

the FDA to fully understand what the product is, how it is made, and whether it is a product that can be 

manufactured in a consistent manner. I needed this information to fully evaluate the risk profile of the 

product. Because inconsistent manufacturing could potentially lead to varying quantities of HPHCs being 

delivered to an individual user, I needed this information to be able to make a complete assessment of 

individual health risks. FDA would be unable to fully evaluate the public health impact of the proposed 

MRTP related to tobacco-related diseases or abuse liability if a critical component such as HPHCs – as 

represented in the applications – is subject to change in unknown ways because of the applicant’s lack 

of raw tobacco and manufacturing controls. Thus, I recommended conveying the deficiencies to the 

applicant. 

Subsequently, in MR0000199, the applicant addressed all items in the deficiencies associated with 

Engineering (#2 and #5). 

 stage and for blend moisture collected during the stage of the manufacturing process. 

Test data for leaf and blend moisture were consistent and fell within the specified range limits. In 

Deficiency #2 requested test data for leaf moisture and blend moisture to confirm target specifications 

(b) (4)

were met to demonstrate that the applicant can manufacture the product consistently. 

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

The applicant 

provided %OV test data collected from 2012 to 2015 for leaf moisture during the

addition, the applicant provided work instructions and test protocols, including the current version of 

. The work 

instructions, test protocols, and test data demonstrate that the product can be manufactured 

(b) (4)

consistently and are sufficient from an Engineering perspective. 

Deficiency #5 (joint with Chemistry) requested 16 components of manufacturing and processing of the 

finished product such as steps, controls, and standard operating procedures (SOPs). This information 

was needed to fully characterize the proposed MRTP, including its HPHC quantities and any variation in 

those quantities, in order to determine whether the product, as actually used, will significantly reduce 

the risk to individual tobacco users and benefit the health of the population as a whole. Engineering 

found that the applicant provided information that is sufficient to demonstrate that product 

manufacturing is well-controlled. The calculation, clarification, descriptions, and documents provided by 

the applicant to address the 16-part deficiency are summarized below. Further evaluation of Deficiency 

#5 can be found in the Chemistry review. 

•

proposed MRTP are stored in warehouses 

Temperature and humidity controls affect product stability, however in their first cycle 

review, Microbiology concluded that stability data for the proposed MRTP are sufficient 

from a microbial product perspective. 

• Clarification that the 

(b) (4)

. 

Descriptions of their storage facilities stating that tobaccos used to manufacture the 

(b) (4) . 

• Test methods and protocols for the process, including and an 

. 

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

MR0000108 Page 16 of 75 

• Work instructions that include step-by-step details 

. 

•

 In addition, the applicant refers to Table 

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

(b) (4)

3.1-9 in Section 3.1 of the original submission (MR0000108) for clarification and calculations 

process. 

used to determine the amount of . 

•

• Work instruction to address 

(b) (4)

(b) (4)

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

• Clarification 

•

•

. The applicant receives Certificates of Analysis (COAs) from their suppliers 

and verifies with product specifications. 

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

(b) (4)

• All COAs for all non-tobacco ingredients listed in Table 3.1-4 in section 3.1 of their original 

meet the applicant’s specification using the 

submission (MR0000108). The applicant states that the supplier makes

(b) (4)

 flavor to 

(b) (4)

• Work instructions with procedures used to ensure that the raw materials, ingredients, 

additives, and incoming tobacco meet the applicant’s specifications include , 

. The applicant states 

. 

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

• Documents showing protocols for quality control and assurance programs ensuring the 

•

finished product meets the applicant’s specification. See the last bullet for details. 

Clarification that , 

. 

Work instructions 

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

•

• Work instructions and documents with protocols for the quality control and assurance 

programs used to ensure that the finished product meets the applicant’s specification and 

batch acceptance requirements throughout the production process, including 24, 

. 

(b) (4)

(b) (4)

In summary, the Engineering review concluded that the information provided by the applicant in 

response to Engineering’s deficiencies is adequate to fully characterize the proposed MRTP and 

demonstrate that the proposed MRTP is manufactured in a consistent manner from an Engineering 

perspective. 
 

 

 

 

 

 

 

 

 

 

MR0000108 Page 17 of 75 

As TPL, I agree with the Engineering conclusion. I find that the applicant now has provided sufficient 

information to fully characterize and evaluate the proposed MRTP from an Engineering perspective, has 

provided details on how it is manufactured, and demonstrated that it can be manufactured in a 

consistent manner. Now that I have this information, I am able to characterize the product and 

understand its potential risks relative to other ST products, in particular, to determine whether the 

product, as actually used, would significantly reduce the risk to individual tobacco users and benefit the 

health of the population as a whole. 

3.1.2 Chemistry 

The Chemistry review assessed the product’s ingredients, manufacturing processes, and controls that 

can affect the product composition, chemical stability, and HPHC analysis for the proposed MRTP. 

Product Formulation: The product design features relevant to chemistry are specifications and upper 

and lower limits for the final pH, the final percentage of oven volatiles (%OV), and container closure 

system (i.e., composition of the can and lid). While the applicant provided ingredient quantities and 

functions for the fiberboard can and metal lid materials used for the container closure system, the 

MRTPA lacked information such as inks, and grade of the container closure system ingredients and seal. 

This prevented Chemistry from fully evaluating the ingredients in the container closure system or 

evaluating the ability of the manufacturer to produce the product consistently. Without this 

information, FDA could not make a full assessment of individual health risks due to the potential 

variability in the product. This missing information was addressed in a deficiency. 

Copenhagen Classic Snuff is a loose moist snuff that consists of 34.02 grams of loose tobacco packaged 

in a fiberboard can with a metal lid. Based on the original MRTPA (MR0000108) and amendment 

(MR0000121), the candidate product tobacco blend comprises tobacco types: mg/g

 mg/g mg/g y and mg/g tobacco, along with other 

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

(4)

ingredients such as salts, flavorings, humectants, and buffering agents. 

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

The applicant indicates that the 

product is designed to contain between % %OV as moisture content and have a pH value 

between . 

Other than tobacco, the basic formulation for the proposed MRTP consists of flavorings, processing aids, 

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

various salts, and humectants. Of these, the two most abundant ingredients 

mg/g), reported as a ; and the complex flavor /g). Many of the 

ingredients other than tobacco are listed as flavors, which are mostly present at very low concentrations 

(parts per million or parts per billion levels). Many of the flavors are complex ingredients. However, the 

applicant did not provide a list of the individual ingredients and quantities for the complex ingredients 

regarding which ingredients are made to the applicant’s specifications and which are not, nor the 

necessary accompanying information from those distinctions as relates to health hazards (i.e., lung 

cancer). The absence of information on individual ingredients, grade, and quantities limited FDA’s ability 

to characterize the product and evaluate the potential impact of the complex flavors. This missing 

information was addressed in a deficiency. 

Finally, although many of the flavoring ingredients such as

 oil, and account for only % of the finished product by 

weight, these ingredients are potential permeation enhancers. Small amounts of permeation enhancers 

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

in an ST product may increase relative exposures and absorption of HPHCs relative to other ST products 

that do not contain these ingredients (Vaddi et al., 2002; Boukhatem et al., 2013). However, at this time, 

there is no conclusive evidence about any negative effects of these particular potential permeation 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 18 of 75 

enhancers; therefore, inclusion of these ingredients did not rise to the level of a deficiency. See Section 

3.2.1 for further discussion of this topic. 

Manufacturing Steps and Controls: The applicant has submitted some detailed information on the 

manufacturing practices and process for this product. However, like Engineering, Chemistry identified 

missing information regarding manufacturing steps and quality control measures specific to the 

proposed MRTP. The absence of this information prevented Chemistry from verifying that the leaf 

processing procedure for the proposed MRTP is consistent and the proposed MRTP can be 

manufactured on a consistent basis from lot to lot. This information is necessary to fully evaluate 

individual health risks. This missing information was addressed in a deficiency. 

Performance Criteria: The applicant describes the manufacturing performance criteria for the products. 

Performance criteria are parameters that reflect expected outcomes based on design specifications or 

other inputs and describe the functional performance criteria expected for a material, component, or 

product. The MRTPA has provided the design specifications for the finished product, which include 

target values and lower and upper limits for pH and moisture. The applicant has provided testing data as 

performance criteria on five different lots in section 7.1 of the MRTPA, demonstrating that the proposed 

MRTP meets the 

(b) (4)

, %OV, and pH specifications. However, the applicant did not provide 

information regarding the procedures undertaken when finished product batches exceed %OV and pH 

upper tolerance levels, which rendered Chemistry unable to determine the full variability of the product. 

The applicant also did not mention whether the final %OV and final pH were tested before or after 

packaging. This helps determine the duration of time prior to the product being placed on the shelf with 

the idea that after packaging may be better since there is less time between the last test and when a 

consumer purchases the product. Testing before packaging would also be acceptable if the applicant can 

demonstrate that the product is stable. For these reasons, specifications for final product moisture, pH, 

were insufficient to assure that product variability does not affect levels of 

Stability: The applicant submitted stability data for the shelf-life of the proposed MRTP. The purpose of 

the chemical stability testing is to ensure HPHC quantities are not changing over time (i.e., during 

storage and use). 

(b) (4)

The analytical and microbial stability testing was conducted over the shelf-life of the 

proposed MRTP after manufacture). 

and 

exposure and risk to users. This missing information was addressed in a deficiency. 

(b) (4)

Evaluation of the potential impact of stability of the proposed MRTP for pH, %OV, nitrates, nitrites, NNN, 

NNK, and water activity (aw) demonstrated the expected microbiological stability of the candidate 

tobacco product through its shelf-life. There were decreases in pH, NNN, %OV, and a

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

w and increases in 

NNK, nitrate, and nitrite over the testing period. Though there was a 29% increase in nitrite 

over the period and nitrite concentration in ST can influence tobacco-specific nitrosamine 

(TSNA) production, Chemistry deferred to Microbiology on this assessment; Microbiology concluded this 

increase in nitrite of Copenhagen Classic Snuff is not of concern based on the decrease (1%) in NNN and 

a minor increase (3%) in NNK over the shelf life of the product. 

Product Analyses: The applicant reported quantities of nine HPHCs--acetaldehyde, arsenic, BaP, 

cadmium, crotonaldehyde, formaldehyde, NNN, NNK, and nicotine (total and free) -- in addition to 

moisture and pH for the proposed MRTP on a wet (“as is”) and dry weight basis. 

The initial Chemistry review evaluated the HPHCs of the candidate product relative to cigarette smoke 

and other ST products. Given the limited applicability of the former (e.g., differences in routes of 

administration affect exposure), the discussion below focuses on the comparison to other ST products. 
 

 

 

 

 

 

 

 

 

 

MR0000108 Page 19 of 75 

Chemistry compared the HPHC quantities reported by the applicant for the proposed MRTP in Section 

7.1 to published literature for different ST types (i.e., moist snuff, dry snuff, loose leaf, snus) (see Table 

1). Preliminary evaluation of one set of samples shows that quantities for some HPHCs in the proposed 

MRTP are similar to or lower than those of other currently marketed ST products, and some are higher 

(Table 1). This evaluation was contingent upon the findings of missing information regarding the 

analytical test methods used to generate the HPHC data information requested in the deficiencies. 

In particular, the proposed MRTP has lower quantities of the following HPHCs compared to other ST 

products: 

• Acetaldehyde (71% − 82%) compared to moist snuff and Swedish snus

• Formaldehyde (50% − 90%) compared to moist snuff, dry snuff, and Swedish snus

• NNN (6% − 31%) compared to other moist snuff and dry snuff 

• NNK (26% − 59%) compared to other moist snuff and dry snuff

• Total nicotine (21%) compared to dry snuff 

• Free nicotine (7% − 31%) compared to moist snuff and Swedish snus

The proposed MRTP has higher quantities of the following HPHCs compared to other ST products: 

• Acetaldehyde (85%) compared to dry snuff 

• Arsenic (9% − 122%) compared to moist snuff, dry snuff, and loose leaf 

• BaP (90% − 3,243%) compared to moist snuff, dry snuff, and loose leaf 

• Cadmium (46% − 165%) compared to moist snuff, dry snuff, loose leaf, and Swedish snus 

• Total nicotine (4% − 102%) compared to moist snuff, loose leaf, and Swedish snus

• NNN (113% − 427%) compared to loose leaf and Swedish snus 

• NNK (98% − 349%) compared to loose leaf and Swedish snus 

• Free nicotine (460% − 9,700%) compared to dry snuff and loose leaf 

Table 1. FDA Comparison of HPHCs in Copenhagen Classic Snuff Compared to Other ST Categories 

Constituent 

(Unit) 

Copenhagen 

Classic Snuff, 

Mean 

Quantity 

(5-lots 

combined) 

Moist 

Snuff, 

Mean 

Quantity 

% Difference 

Dry 

Snuff, 

Mean 

Quantity 

% Difference 

Loose 

Leaf, 

Mean 

Quantity 

% Difference 

Swedish 

Snus, 

Mean 

Quantity 

% Difference 

Acetaldehyde 

(μg/g) 6.3 35.7 ↓ 82 3.4 ↑ 85 N/P N/A 21.6 ↓71

Arsenic 

(ng/g) 

233 214 ↑ 9 179 ↑ 30 105 ↑ 122 N/P N/A 

Benzo[a]pyrene 

(ng/g) 117 61.6 ↑ 90 30.5 ↑

284 3.5 ↑3,243 N/P N/A 

Cadmium 

(ng/g) 

1537 1052 ↑ 46 879 ↑ 75 599 ↑ 157 579 ↑ 165 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 20 of 75 

Crotonaldehyde 

(μg/g) BLOQ 2.98 N/A 13.33 N/A N/P N/A N/P N/A 

Formaldehyde 

(μg/g) 1.58 8.43 ↓ 81 3.18 ↓ 50 N/P N/A 15.7 ↓90

NNN 

3825 4058 ↓6 5535 ↓ 31 1798 ↑ 113 726 ↑ 427

(ng/g) 

NNK 

1034 1394 ↓ 26 2522 ↓59 523 ↑ 98 230 ↑ 349

(ng/g) 

Total Nicotine 

(mg/g) 12.5 12 ↑ 4 15.8 ↓21 6.2 ↑ 102 8.71 ↑ 44

Free Nicotine 

(mg/g) 3.92 4.2 ↓ 7 0.7 ↑

460 0.04 ↑9,700 5.65 ↓31

*Data in Table 1: Carbonyl data for moist snuff and dry snuff are from Stepanov et al., 2008; TNSAs, metals, and 

nicotine data for moist snuff, dry snuff, and loose leaf are from Borgerding, MF et al., 2012; Swedish snus levels are 

reported as an average of data from Swedish Match 2014 MRTP application. Data reported on a dry weight basis 

(DWB) except for free nicotine, pH, and moisture which are reported “as is” (wet weight basis); N/P= Not Provided; 

N/A = Not Applicable; BLOQ= Below Limit of Quantitation 

FDA Product Analyses for HPHC Verification: To verify chemical and physical data submitted by the 

applicant, FDA requested that FDA’s Southeast Tobacco Laboratory (STL) independently perform testing 

on NNN and NNK on September 21, 2018. Chemical testing was conducted on fresh cans of the 

proposed MRTP and analysis of the samples were taken “as-is”. Analysis of NNN and NNK was 

performed using a STL in-house SOP (TSNA Analysis in Tobacco by UPLC/MS/MS). As seen in Table 2, 

mean quantities for NNN and NNK reported by STL are similar to data for NNN and NNK submitted by 

USSTC in the original MRTPA. There were minor differences in the methods between the two 

laboratories used to test NNN and NNK. However, a two one-sided test calculation determined the 

values reported from STL and USSTC for NNN and NNK to be analytically equivalent. 

Table 2. Verification of TSNAs in Copenhagen Classic Snuff (as is) 

Constituents Unit STL USSTC 

Mean Std. Dev N Mean Std. Dev N 

NNN ng/g 1689 103 21 1746 63 35 

NNK ng/g 452 79 21 472 65 35 

N= Number of Replicates 

Finally, the Chemistry review identified missing information related to the product analyses. In 

particular, the information provided by the applicant regarding SOPs used to determine the levels of the 

HPHCs in the proposed MRTP appeared to be adequate. However, the applicant did not provide 

validation reports (e.g., accuracy, precision, selectivity, linearity and range, limit of detection, limit of 

quantification) to demonstrate the validity of the methods for any of the SOPs. Clarification was also 

needed on the SOPs used to determine pH and %OV. Because the applicant did not include complete 

information on the analytical test methods used to generate the HPHC data for the proposed MRTP, 

Chemistry was not able to determine an accurate assessment of the differences in the HPHC quantities 
 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 21 of 75 

between the proposed MRTP and other ST products, which impacted the ability to fully weigh the 

impact on individual health risk. This missing information was addressed in a deficiency. 

Based on preliminary evaluation, Chemistry concluded that the increased quantities of the HPHCs in the 

proposed MRTP compared to other ST products raise potential concerns regarding the relative risks of 

the tobacco product. 

In summary, Chemistry concluded that the applicant did not provide sufficient information (e.g., 

composition, product design, manufacturing processes) to fully characterize the proposed MRTP and to 

ensure that the proposed MRTP will be manufactured in a consistent manner. This information is 

necessary to accurately determine the HPHC quantities in the product and any variation in those 

quantities. Without this information, I could not determine whether the product, as actually used, would 

significantly reduce the risk to individual tobacco users and benefit the health of the population as a 

whole. Accordingly, Chemistry noted five deficiencies, which are listed in Section 6. Two of these 

deficiencies were jointly submitted with other disciplines (Engineering and Toxicology, respectively). 

As TPL, I agreed with the Chemistry conclusion that the application provided insufficient information to 

fully characterize and evaluate the proposed MRTP, how it is manufactured, and whether it can be 

manufactured in a consistent manner. I needed this information to characterize the product and 

understand its potential risks relative to other ST products, in particular. I recommended conveying 

these deficiencies to USSTC. 

The applicant provided a response to these five deficiencies in MR0000199. Chemistry provided a 

second review specific to this response. 

Deficiency #3 requested three specific criteria, controls, and SOPs as relates to leaf processing 

procedures. This information was needed to fully characterize the proposed MRTP, including its HPHC 

quantities and any variation in those quantities, in order to determine whether the product, as actually 

used, will significantly reduce the risk to individual tobacco users and benefit the health of the 

population as a whole. The applicant provided work instructions, definitions, and acceptance criteria 

used 

. The information provided on

 steps, controls, and SOPs does not raise concerns from Chemistry’s perspective. As TPL, I 

find that this deficiency was adequately addressed. 

(b) (4)

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

Deficiency #4 requested specification %OV and pH protocols used throughout the entire manufacturing 

process in order to fully characterize the proposed MRTP, including its HPHC quantities and any 

variation in those quantities, in order to determine whether the product, as actually used, will 

significantly reduce the risk to individual tobacco users and benefit the health of the population as a 

adequately specified which %OV and pH protocols were used throughout the entire manufacturing 

whole. The applicant provided information on the %OV and pH protocols used in tobacco processing and 

manufacturing stages and corresponding work instructions. 

 The applicant 

(b) (4)
 

 

 

 

 

 

 

MR0000108 Page 22 of 75 

process for the in-process tobacco product. The information provided does not raise concerns from 

Chemistry’s perspective. As TPL, I find that this deficiency was adequately addressed. 

Deficiency #5 was joint with Engineering and requested 16 components of manufacturing and 

processing of the finished product such as steps, controls, and SOPs in order to fully characterize the 

proposed MRTP, including its HPHC quantities and any variation in those quantities, in order to 

determine whether the product, as actually used, will significantly reduce the risk to individual tobacco 

users and benefit the health of the population as a whole. The applicant provided clarifications, work 

instructions, and batch report forms addressing each part of this deficiency. The work instructions 

provide

 This information with the 

and requirements, provided in the original application, gives a more complete picture of 

, which do not raise concerns from this 

discipline’s perspective. The information provided demonstrates that the product is manufactured in a 

(b) (4)

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

consistent manner that minimizes the variability in product quality and does not raise concerns from 

Chemistry’s perspective. As TPL, I find that this deficiency was adequately addressed. 

Deficiency #6 was joint with Toxicology and requested clarification of complex ingredients made to the 

applicant’s specifications and those not, and for those made to the applicant’s specifications, to provide 

complete information. For those not made to the applicant’s specifications, specific information was 

requested. This information was requested in order to fully characterize the composition and evaluate 

the risks of the proposed MRTP. The applicant provided single chemical ingredients for all the complex 

flavors listed in the deficiency, including target values and ranges (in units of mg/g of product). The 

information provided on complex flavor does not raise concerns from Chemistry’s perspective. The 

toxicological impacts of the ingredients are deferred to Toxicology. As TPL, I find that this deficiency was 

adequately addressed from the Chemistry perspective. 

Deficiency #7 requested method validation summaries for each analytical method used for testing 

HPHCs in order to properly evaluate the proposed MRTP. The applicant provided 

This information does not raise concerns from 

Chemistry’s perspective. As TPL, I find that this deficiency was adequately addressed. 

(b) (4)

(b) (4)

The information provided by these deficiencies was necessary for Chemistry to be able to accurately 

determine the HPHC quantities in the product and any variation in those quantities. Because Chemistry 

found the applicant’s response to the deficiencies to be sufficient, Chemistry is now able to fully 

characterize the proposed MRTP, including its HPHC quantities and any variation in those quantities. 

To that end, upon request from Toxicology, Chemistry assessed the response to Deficiency #8 (originally 

put forth by Toxicology), which examined the individual health risks of the proposed MRTP relative to 

other ST products, including its HPHC quantities and any variation in those quantities. Based on the 

applicants’ assertion, which FDA accepted, regarding MST being the appropriate category, analyses 

during this second round of review used the MST sub-category as the comparator. Chemistry consulted 

Statistics who determined that the applicant’s comparisons of mean quantities to mean quantity ranges 

were not statistically appropriate because a range may indicate much more variability in the data than 

the true variability. Moreover, the applicant did not provide measures of range variability. Chemistry 

and Statistics instead provided appropriate nonparametric methods to analyze the data to ensure 

appropriate comparisons between HPHC yields from the proposed MRTP and published MST data. That 
 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 23 of 75 

analysis is contained in Table 3 below. That comparison shows that the proposed MRTP yielded higher 

BaP, higher cadmium, lower NNK, and lower free nicotine quantities than published MST data. 

Additionally, the proposed MRTP yielded equivalent (i.e., not statistically significantly different) 

quantities of arsenic, NNN, and total nicotine. This finding is consistent with the HPHCs discussed in 

Deficiency #8 for MST comparisons. Toxicology (see Section 3.2.1) evaluated whether the applicant 

provided scientific evidence and rationale about how exposure to these HPHCs may impact the 

population of tobacco users that may completely switch to or begin to dual use their current product(s) 

with the proposed MRTP. 

Table 3. HPHC quantity comparisons in the proposed MRTP and published moist snuff data24,25,[1] 

Constituent Unit 

Proposed MRTP Moist Snuff p- value 

(Wilcoxon 

rank-sum 

test) 

N Mean 

(SD) 

Median 

(IQR) N Mean 

(SD) 

Median 

(IQR) 

Acetaldehyde μg/g 35 6.3 

(2.5) 

4.67 

(4.35-9.27) 4 a 36.7 

(25.70) 

28.70 

(17.95- 55.45) NA 

Arsenic ng/g 35 232.7 

(23.6) 

225.00 

(218.00-245.00) 27 211.9 (70.1) 

226.00 

(151.00-261.00) 0.3560 

Benzo[a]pyrene ng/g 35 117.1 

(19.9) 

130.00 

(94.90-134.00) 32 57.7 

(51.5) 

58.80 

(1.85- 75.60) <.0001* 

Cadmium ng/g 35 1536.9 

(243.3) 

1660.00 

(1256.00-

1741.00) 

28 1014.4 

(401.8) 

1075.00 

(603.50-

1307.50) 

<.0001* 

Crotonaldehyde μg/g 2 b 0.11 

(0.01) 

0.11 

(0.11-0.12) 4 a 3.5 (2.2) 

3.26 

(2.11- 4.82) N/A 

Formaldehyde μg/g 35 1.6 

(0.2) 

1.58 

(1.46-1.70) 4a 8.4 

(2.0) 

8.24 

(6.76-10.07) N/A 

NNK ng/g 35 1033.7 

(139.2) 

944.00 

(919.00-1181.00) 26 1461.2 (1307.2) 

1260.00 

(887.00-

1476.00) 

0.0338* 

NNN ng/g 35 3824.6 

(152.6) 

3847.00 

(3656.00-

3944.00) 

32 3924.9 

(2595.8) 

4291.00 

(1102.50-

4772.00) 

0.3123 

Total Nicotine mg/g 35 12.5 

(0.2) 

12.50 

(12.30-12.60) 28 12.1 (2.0) 

12.90 

(11.07-13.37) 0.0732 

Free Nicotine mg/g 35 3.9 

(0.2) 

3.84 

(3.80-3.95) 28 4.5 (1.8) 

4.74 

(3.16-5.79) 0.0373* 

[1] a Data are only from Stepanova et al. (2008). b Low replicate number because many replicate measurements were BLOQ = 

below limit of quantitation. * Statistically significant. N/A = Not applicable because sample size is small. IQR = Interquartile 

range (25th percentile – 75th percentile). Nicotine and moisture quantities are in wet weight (“as-is”) and all other constituents 

dry weight basis (DWB). 

In summary, following the applicant’s response to the deficiencies laid out by Chemistry, the applicant 

adequately addressed the Chemistry aspects of Deficiencies 3-8 in their amendment. From a Chemistry 

perspective, the applicant provided manufacturing and testing information to fully characterize the 

proposed MRTP, including demonstrating consistent manufacturing by providing %OV and pH of the 

finished product and throughout manufacturing steps, HPHC quantities in the finished product, finished 

product stability data, and demonstrated the reliability of the testing methods and results. This allows 

FDA to understand the product’s risk relative to cigarettes and other MST products. Manufacturing 

information was also evaluated by Engineering. Ingredients and HPHC differences between the 

proposed MRTP and other products were further evaluated by Toxicology (see Section 3.1.2). 
MR0000108 Page 24 of 75 

As TPL, I agree with the Chemistry conclusions. I find that the applicant now has provided sufficient 

information to fully characterize and evaluate the proposed MRTP, has provided adequate details on 

how it is manufactured, and demonstrated that it can be manufactured in a consistent manner. Now 

that I have this information, I can characterize the product and understand its potential risks relative to 

cigarettes and other ST products, in particular, to determine whether the product, as actually used, 

would significantly reduce the risk to individual tobacco users and benefit the health of the population 

as a whole 

3.1.3 Microbiology 

The Microbiology review focused on characterizing the product stability of the MRTP (as it relates to 

microbiology), factors that can potentially affect the microbial stability of the product (e.g., 

manufacturing processes, ingredients, additives), and ensuring well-controlled manufacturing of the 

product. 

Product Description and Formulation: From a Microbiology perspective, the tobacco product ingredients 

of most concern are those that could affect microbial growth, such as humectants and preservatives. 

Based on the product stability data in the application, the additions of a humectant 

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

 and 

preservative to the proposed MRTP do not raise concerns from a microbial 

product stability perspective. 

Manufacturing Steps and Controls: The key manufacturing step of the proposed MRTP, as related to 

microbiology, is the process (i.e., ). The applicant provided 

detailed information on the f process including 

. In 

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

(b) (4)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

closure system of the proposed MRTP but did not indicate whether a formal method exists 

. However, product 

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

addition, the applicant also provided adequate information on the storage conditions and container 

stability information submitted by the applicant, as described below, adequately addressed this 

concern. 

Product Stability: Microbiology also evaluated the stability testing evaluated by Chemistry to ensure that 

the product is microbiologically stable during the expected storage period and does not result in an 

increased risk to public health as the product sits in storage. The review concluded that the stability data 

do not raise microbial product stability concerns. 

Product Analyses: To further assess the product stability data submitted by the applicant, 

microbiological (total aerobic microbial count (TAMC) and total yeast and mold count (TYMC)) and 

physical (aw) testing of the proposed MRTP was performed by FDA’s A2LA-certified Southeast Food and 

Feed Laboratory (SFFL) and compared to the applicant’s stability testing data. The aw, TAMC, and TYMC 

data submitted by the applicant were verified by testing performed by FDA SFFL. aw and TYMC data 

provided by SFFL is comparable to data provided by the applicant. The TAMC measured by SFFL is lower 

when compared to that of the applicant, but that difference is acceptable from a Microbiology 

perspective and does not raise concerns from a microbial product stability perspective. 

Additionally, the physical, chemical, and microbiological stability attributes of the proposed MRTP were 

compared to other comparator (ST) products. After analyzing the physical, chemical, and microbiological 

stability data of the proposed MRTP submitted by the applicant and comparing it with the data from 

published journals on several moist snuff products, FDA concluded that the pH and OV% of the 

proposed MRTP are similar to other moist snuff products on the U.S. market. However, the nitrate level 

of the proposed MRTP is higher than the average level observed in other moist snuff products, and the 
 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 25 of 75 

levels of nitrite, NNN and NNK are lower than that of other moist snuff products. 

(b) (4)

The high TAMC count 

of 106 is not unexpected because it is a tobacco product. Moreover, the TAMC levels are 

comparable to other moist snuff products on the U.S. market. The undetectable TYMC in the proposed 

MRTP (as measured by SFFL) further confirmed the applicant’s claim that USSTC’s MST products are 

inherently non-supportive to the proliferation of yeasts and molds. 

In summary, the Microbiology review concluded that the applicant provided adequate microbiologyrelated information to demonstrate full product characterization and stability over product shelf life and 

to address factors that can potentially affect the microbial stability of the product. Microbiology also 

concluded that the application had adequate quality control information. 

As TPL, I agree with the Microbiology conclusion. 

3.1.4 Conclusions: Product Characterization 

The applicant describes Copenhagen Classic Snuff as a loose, non-portioned, fine cut moist snuff ST 

product. The product is made with a tobacco blend comprising 

(b) (4)

, along with 

ingredients such as salts, flavorings, humectants, and buffering agents. The applicant reported quantities 

of nine HPHCs in one set of samples --acetaldehyde, arsenic, BaP, cadmium, crotonaldehyde, 

formaldehyde, NNN, NNK, and nicotine (total and free). 

Microbiology concluded that the stability data did not raise microbial product stability concerns. 

Engineering and Chemistry found missing information related to manufacturing and controls across 

numerous constructs, which prevented FDA from determining if the product could be manufactured 

consistently as well as from fully characterizing the product. These analyses, in turn, would allow 

Toxicology to examine toxicities associated with HPHCs, which would impact individual health risk, and 

ultimately population health benefit. The missing information was conveyed through six deficiencies 

(one of which was joint with Toxicology). Accordingly, in MR0000199, the applicant responded to the 

conveyed deficiencies. As described above, the applicant’s responses addressed the deficiencies in an 

acceptable manner to both Engineering and Chemistry allowing full product characterization and 

ensuring consistent manufacturing. To support Toxicology’s analyses, Chemistry also examined HPHC 

levels and quantities relative to other MST products. This test found the BaP and cadmium quantities in 

the proposed MRTP to be significantly higher than those in MST, whereas NNK and free nicotine 

quantities are significantly higher in MST than in the proposed MRTP. 

In summary, as TPL, I agree with the conclusions of Engineering, Chemistry, and Microbiology and find 

that the product can be manufactured consistently and can now be fully characterized. Therefore, the 

HPHC data initially submitted by the company is valid and can be analyzed as was submitted. I also 

concur with the joint decision of Epidemiology, Statistics, Chemistry, and Toxicology that, as requested 

and stated by the applicant, it is appropriate to compare HPHCs in the proposed MRTP to only other 

MST products as opposed to the whole class of ST products given that MST comprises the vast majority 

of the ST marketplace. Analyses conducted following the applicant’s response to the deficiency letter 

were done using the MST sub-category as the comparator for HPHCs. With these data, we now have 

complete product analysis information to fully characterize the proposed MRTP, including its HPHC 

quantities and any variation in those quantities, which allows FDA to understand the product’s risk 

relative to other ST products, which have implications for an individual user’s health risk. 
 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 26 of 75 

3.2 Relative Health Risks to Individuals & Claim Substantiation 

This section examines the evidence provided by the applicant in order to evaluate the statutory 

requirements for an MRTPA to demonstrate that the proposed MRTP—as actually used by consumers— 

will significantly reduce the harm and risk of tobacco-related disease to individual tobacco users. This 

section includes an assessment of the health risks relative to non-use and use of other tobacco products. 

It will also examine whether the proposed modified risk information is scientifically accurate in order to 

substantiate the claim. The section will review evidence provided by Toxicology, BCP, Medical, and 

Epidemiology reviewers. OCE’s review did not reveal any data integrity or human subject protection 

concerns. OCE concurred with OS’s recommendation that a BIMO inspection for the protocol and 

associated sites is not needed at this time and this conclusion remained unchanged after an additional 

site was identified in MR0000199. No additional inspections were conducted. 

3.2.1 Toxicology 

This subsection describes the Toxicology review of the scientific information contained in the MRTPA, 

including review of HPHC information, published nonclinical toxicology studies submitted, and published 

literature regarding the marketplace of cigarettes and ST products. 

Comparison to cigarettes: The applicant provided HPHC data for one set of samples for the proposed 

MRTP. To compare this preliminary information to the marketplace of cigarettes, contingent upon the 

findings of missing information regarding the analytical test methods requested in the deficiencies, 

potential daily intake levels were calculated using the 90th percentile use information provided by the 

applicant in section 3.2 of the application and published literature. Compared to cigarettes, the potential 

daily intakes of acetaldehyde and formaldehyde with the use of the proposed MRTP were lower, but 

were higher (~325-5700-fold) for arsenic, B[a]P, cadmium, NNN, and NNK. Differences in route of 

exposure between cigarettes (i.e., inhalation of combustible product) and the proposed MRTP (i.e., oral 

absorption and a lack of direct pulmonary exposure) would affect the overall toxicity of the HPHCs 

present in the proposed MRTP relative to cigarettes. In nonclinical animal models, oral exposure to 

arsenic, BaP, NNN, and NNK was associated with lung cancer. However, the applicant did not provide 

any information that would allow calculation of user exposure and did not discuss the concerns raised 

by the nonclinical evidence showing that HPHCs associated with the proposed MRTP cause lung cancer. 

In addition to these HPHCs, the applicant provided information regarding the ingredients used in the 

proposed MRTP. Many of these ingredients were complex ingredients that were mixtures that went 

undefined by the applicant, limiting the ability to interpret the toxicity of such complex ingredients as 

described in the Chemistry review. This missing information was addressed in a deficiency. 

The applicant also submitted information regarding potential permeation enhancers, which are nontobacco ingredients not found in cigarette smoke. Though permeation enhancers may increase the 

absorption of HPHCs, and therefore, alter the potential toxicity of this product, the applicant did not 

provide information on such interactions, as noted by Chemistry. Furthermore, the inclusion of such 

chemicals may confound the calculation of user exposure, and ultimately, comparative disease risk. 

deficiency was conveyed at this time. 

In assessing the provided literature, the discipline noted 59 non-clinical studies related to the claim of 

decreased risk of lung cancer relative to cigarettes. There were five studies that included the 

Copenhagen brand. While these articles did show dysplasia of the oral mucosa and promotion of viralHowever, at this time, there is no conclusive evidence about any negative effects of these particular 

potential permeation enhancers (i.e., ) via the buccal route. Therefore, while 

these potential permeation enhancers are present and may influence the overall exposure to HPHCs, no 

(b) (4)
 

 

 

 

 

 

 

 

MR0000108 Page 27 of 75 

mediated carcinogenesis, they did not contain a comparison of ST products to cigarettes, limiting their 

utility. Furthermore, because other studies submitted to examine the effects of ST use on oral 

carcinogenesis did not examine the lungs of the animals, the reviewers determined the studies were 

irrelevant to the proposed modified risk claim. Thus, Toxicology did not have enough information to 

substantiate the claim based on the evidence they reviewed alone and recommended that this missing 

information be addressed in a deficiency. 

Comparison to other ST Products: Toxicology referenced Chemistry’s preliminary review of the HPHC 

information provided by the applicant, contingent upon the findings of missing information regarding 

the analytical test methods requested in the deficiencies and compared it to the mean values available 

in published literature for other ST products in the marketplace, including moist snuff, dry snuff, loose 

leaf, and Swedish snus products. Comparing quantities of measured HPHCs from the proposed MRTP to 

the mean values in published literature for other ST products showed relatively similar quantities for 

some HPHCs and lower quantities for some others; however, there were notably higher quantities of 

acetaldehyde (85% compared to dry snuff), arsenic (9-122% compared to dry snuff, moist snuff, and 

loose leaf), BaP (90-3243% compared to moist snuff, dry snuff, and loose leaf), cadmium (46-165% 

compared to moist snuff, dry snuff, loose leaf, and Swedish snus); NNN (113-427% compared to loose 

leaf and Swedish snus), and NNK (98-349% compared to loose leaf and Swedish snus). These higher 

quantities could potentially increase health risks (e.g., variety of cancers, cardiotoxicity, 

reproductive/developmental toxicities) associated with exposure to these HPHCs if users of some other 

ST products dual used or switched to the proposed MRTP. The implications of these findings were not 

discussed. This missing information was addressed in a deficiency. 

Comparison to Never Use: In addition, the proposed MRTP was compared to never use. ST, in general, is 

carcinogenic through a mutagenic mode of action, capable of modulating carcinogenicity, and 

associated with cardiovascular endpoints (e.g., vasodilation, increased heart rate), periodontal disease, 

and reproductive/developmental toxicities. Numerous studies have shown that ST use can cause 

addiction, precancerous oral lesions, oral cancer, esophageal cancer, pancreatic cancer, and 

reproductive and developmental toxicities. In terms of involuntary exposure, Toxicology notes that 

because the proposed MRTP is not combusted, it is unlikely that adult non-users would be involuntarily 

exposed. However, nicotine poisoning is a possibility in children who are inadvertently exposed to the 

proposed MRTP. 

In summary, the initial Toxicology review concluded the following: 

• The toxicology information reviewed was not sufficient to substantiate the claim on its own; 

the review noted higher quantities of certain carcinogenic HPHCs relative to cigarette 

smoke, but also acknowledged that differences in routes of exposure would be expected to 

affect the overall toxicity of the HPHCs present in the proposed MRTP. Toxicology concluded 

that without additional information to quantify the differences in routes of exposure, the 

HPHC data may have limited utility for assessing potential differences in specific health 

effects when comparing the proposed MRTP to cigarettes. 

• In a preliminary assessment, the proposed MRTP has lower quantities of some HPHCs, and 

higher quantities of others compared to other ST products, which could potentially increase 

health risk relative to other ST products.7 

7 These data are preliminary because they are contingent upon the findings of missing information regarding the analytical test 

methods as requested in a deficiency. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 28 of 75 

• The proposed MRTP also contains potential permeation enhancers, which could increase 

health risk. At this time, the literature is inconclusive regarding any negative effects of these 

specific potential permeation enhancers. 

• The published literature the applicant provided was limited in its utility because it only 

included five studies that potentially used the candidate product. 

• The scientific literature has established that ST use causes health risks: precancerous oral 

lesions, oral cancer, esophageal cancer, pancreatic cancer, and cardiovascular, reproductive, 

and developmental toxicities. 

Toxicology listed three deficiencies, which are listed in Section 6. This included one deficiency jointly 

submitted with Chemistry. 

As TPL, I largely concurred with these preliminary substantive conclusions. As noted in Section 3.1.4, I 

recommended conveying the joint deficiency with Chemistry. Toxicology also noted a deficiency in the 

data provided regarding the implications of HPHC quantities in the product, especially where these 

quantities appear higher than other marketed ST products. As this information is related to our overall 

understanding of the relative risks of the product, I agreed with the request for the applicant to discuss 

the implications of these data for potential MRTP users and recommended conveying this deficiency to 

the applicant. 

With respect to claim substantiation, the toxicologic evidence is informative but not determinative to 

make this finding. In determining claim substantiation and individual health risks relative to cigarettes, 

there is a large body of longitudinal epidemiologic studies submitted by the applicant and in the extant 

literature that can be relied on to determine long-term health effects including the risk for lung cancer. 

Because of this, I did not recommend conveying a Toxicology deficiency that requests additional 

information related to claim substantiation. 

In response to the deficiency letter, the applicant provided responses to each of the deficiencies. 

As described in section 3.1.2, Deficiency #6 was joint with Chemistry and requested clarification of 

complex ingredients made to the applicant’s specifications and those not, and for those made to the 

applicant’s specifications, to provide complete information. For those not made to the applicant’s 

specifications, specific information was requested. This information was requested in order to fully 

characterize the composition and evaluate the risks of the proposed MRTP. The applicant provided 

single chemical ingredients for all the complex flavors listed in the deficiency, including target values and 

ranges (in units of mg/g of product). The information provided on complex flavor did not raise concerns 

from Chemistry’s perspective. Likewise, evaluation of the information provided by the applicant 

regarding these ingredients did not identify any concerns from a Toxicological perspective. As the TPL, I 

agree that this deficiency was adequately addressed. 

Deficiency #8 requested that the applicant provide scientific evidence and rationale about how exposure 

to HPHCs in ST may impact the population of tobacco users that may completely switch to or begin to 

dual use their current product(s) with the proposed MRTP, particularly in comparison to other ST 

products. As described in Section 3.1.2., the applicant stated that because the vast majority of the 

marketplace was MST, the appropriate comparison for HPHCs was other MST products. Epidemiology 

confirmed this assertion and therefore, Chemistry and Toxicology determined this comparison was a 

reasonable approach, and therefore, compared HPHCs to levels in other MST products. Therefore, the 

portion of the deficiency related to dry snuff, loose leaf, and Swedish snus is resolved. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 29 of 75 

As analyzed by the applicant, comparison to the means of the MST product category indicated that 

arsenic, BaP, and cadmium were higher in the proposed MRTP. However, as described in 3.1.2, Statistics 

did not find the methods used by the applicant to be statistically appropriate because a range may 

indicate much more variability in the data than the true variability. Instead, Statistics recommended 

non-parametric tests and the use of medians. When Chemistry conducted those analyses, only BaP and 

Cadmium were higher while NNK and free nicotine were lower. Because the analyses in the first 

Chemistry and Toxicology reviews utilized means and not medians and because they both initially listed 

arsenic as higher, to be thorough, Toxicology examined both means and medians. Thus, though 

Chemistry did not find that arsenic was higher for the proposed MRTP compared to the MST 

subcategory, Toxicology analyzed arsenic using the means methodology to ensure the original deficiency 

was fully addressed. However, in terms of analyses that weighed into my decision making, arsenic was 

not considered because there were no differences once the more statistically appropriate analyses were 

conducted. 

To look at the totality of exposures from HPHCs, Toxicology used FDA/CTP’s scientific approach to 

evaluation of HPHC comparisons between tobacco products, which has evolved as documented in the 

memorandum “Harmful and potentially harmful constituent (HPHC) comparison and evaluation 

procedure for comparing two tobacco products in application review”, signed February 25, 2022. Briefly, 

this approach focuses on HPHC increases and decreases that are analytically non-equivalent between 

two tobacco products. The toxicity endpoints of the analytically non-equivalent HPHCs are central to the 

toxicological comparison between two tobacco products. An HPHC decrease that has a toxicity endpoint 

different from that of an HPHC that is increased cannot offset the HPHC increase. At this time, 

carcinogenic endpoints are considered equivalent. For example, an HPHC increase that evidence 

indicates increases liver cancer risk can be offset by a decrease in an HPHC that evidence indicates 

increases lung cancer risk. The analysis of non-cancer endpoints is more complicated than that of cancer 

endpoints. For example, the respiratory irritation of formaldehyde cannot be offset by a decrease in an 

HPHC that is not a respiratory toxicant (e.g., benzene might offset formaldehyde in terms of 

carcinogenicity, but cannot offset the respiratory effects of formaldehyde, because it is not a respiratory 

toxicant). HPHC measurements that are analytically equivalent are considered unchanged between the 

two compared products. The equivalence testing is determined by Chemistry using the “two one-sided 

t-test” procedure or TOST (Memo: Equivalence Testing for SE Evaluations, signed February 24, 2017). 

Through this offsetting analysis and using the more statistically appropriate medians that Chemistry did, 

Toxicology determined by, that the higher levels of some HPHCs relative to the MST category were 

offset by the lower levels of other HPHCs. Specifically, utilizing medians, lower levels of NNK and free 

nicotine offset the higher levels of BaP and cadmium from a carcinogenic perspective. Further, 

Toxicology determined that non-cancer toxicities resulting from potential exposure to higher levels of 

BaP and cadmium as compared to other MST products were not a concern due to values remaining 

below the reference doses established by the Environmental Protection Agency (EPA). 

In summary, from a Toxicological perspective, the carcinogenic and non-carcinogenic concerns 

associated with higher mean levels of HPHCs (i.e., arsenic, BaP, cadmium) are offset by reductions in 

other HPHCs in Copenhagen Classic Snuff compared to other MST products in the marketplace. When 

comparing the median levels of the HPHCs as recommended by Statistics and utilized in the Chemistry 

review, the higher levels of BaP and cadmium were then offset by lower levels of NNK and free nicotine. 
 

 

 

 

MR0000108 Page 30 of 75 

Therefore, at this time, Toxicology reports that both deficiencies have been addressed and there are no 

further toxicological concerns. 

As TPL, I concur with Toxicology’s assessment to utilize the MST sub-category as the comparison for this 

analysis. While Toxicology opted to assess both the means and median comparisons, per Statistics and 

Chemistry, the more appropriate comparison is through the medians. Because NNK and free nicotine 

were lower than the median levels of MST products, this offset the higher levels of BaP and cadmium. In 

totality, the higher levels of BaP and cadmium are not of concern with respect to both the carcinogenic 

and non-carcinogenic endpoints. 

3.2.2 Clinical 

3.2.2.1 Medical 

To assess the clinical aspects of the individual health effects, the Medical review examined adverse 

events (AEs) and biomarkers of potential harm (BOPH). 

The application referenced cross-sectional studies in the literature that examine BOPH in ST users 

compared to cigarette smokers and non-tobacco users. Compared to cigarette smokers, ST users 

showed significantly lower levels of markers associated with inflammation (i.e., IL-12(p70), sICAM-1, IL8) (Nordskog et al., 2015). BOPH are associated with lipid metabolism pathways (Prasad et al., 2016). In 

addition, measurement of other BOPH yielded significantly lower levels of lipid metabolism pathways, 

high-sensitivity-C reactive protein (CRP), and blood constituents (i.e., white blood cells, monocytes, 

lymphocytes, fibrinogen and hemoglobin, hematocrit) in ST users compared to cigarette smokers 

(Marano et al., 2015; Prasad et al., 2016). Across BOPH, the levels of markers were comparable between 

ST users and non-tobacco users (Nordskog et al., 2015; Prasad et al., 2016). No studies were discussed 

comparing BOPH between users of different ST products underscoring the need for the information 

requested in the deficiencies put forth by other disciplines. 

The Medical review also examined AEs reported in the application. The applicant provided a summary of 

AEs from the clinical study; however, these AE data are limited because this was a small, short-term 

pharmacokinetic study. The applicant notes there were 22 AEs that were primarily mild in severity and 

either unlikely or not related to the test product. No deaths, Serious Adverse Events (SAEs) or 

discontinuation of subjects secondary to AEs were reported. The applicant also submitted AE 

information from the ALCS Consumer Call Center on USSTC’s MST products sold in the marketplace 

including Copenhagen Classic Snuff. Thus, the utility of this information is limited given that the 

applicant did not disaggregate the AEs specific to Copenhagen Classic Snuff. The applicant did note that 

USSTC sold over 4.4 billion cans of MST products and received 1,353 calls from consumers with 2,546 

associated AEs during January 2012-June 2017. The majority (84.3%) of these cases were coded as mild 

in severity and the system organ class with the highest incidence of AEs was the gastrointestinal system. 

There were 203 moderate cases, seven severe cases, and three SAEs. 

In summary, the Medical review concluded that the scope of its review was constrained in that, aside 

from the one clinical (pharmacokinetics) study, the application did not include clinical evidence specific 

to the proposed MRTP to inform an assessment of individual health risk. Although the applicant cited 

several cross-sectional studies examining BOPH between ST and cigarette users, the applicant relies 

most heavily on the epidemiologic evidence to support its application. Finally, Medical concluded the AE 

data compiled from both the clinical study and the ALCS Consumer Call Center do not provide 

information sufficient to assess claim substantiation. 
 

 

MR0000108 Page 31 of 75 

As TPL, I agree that the scope of the Medical review did not include sufficient evidence to inform 

conclusions about individual health risk or claim substantiation, and that this information was instead 

within the scope of the Epidemiology review. The epidemiological evidence and how it informs 

conclusions about individual health risk and claim substantiation are discussed below in Section 3.2.3. 

Based on the availability of this evidence and other data, I concurred with Medical’s recommendation to 

not convey a deficiency. 

3.2.2.2 Behavioral and Clinical Pharmacology (BCP) 

The BCP review utilized the peer-reviewed scientific literature to examine biomarkers of tobacco 

exposure. BCP’s review of the applicant’s clinical (pharmacokinetics) study is discussed below in Section 

3.4.1. 

In comparing ST HPHC exposure with cigarette HPHC exposure, evidence suggests that exclusive use of 

ST leads to greater exposure to nicotine and NNK than cigarettes. In particular, studies that examined 

the longer-term effects of tobacco use and exposure have shown that exclusive ST users (includes users 

of “chewing tobacco and snuff”) have higher levels of serum cotinine (a metabolite of nicotine) and 

NNAL (a metabolite of NNK) than exclusive smokers (e.g., Campbell, Brown, Jones, Marano, & 

Borgerding, 2015; Rostron, Chang, van Bemmel, Xia, & Blount, 2015). On the other hand, exposure to 

some other tobacco-related HPHCs and their biomarkers (e.g., S-PMA, 3-HPMA) tends to be lower in ST 

users than cigarette smokers and similar in ST users and non-tobacco users (e.g., Campbell et al., 2015); 

however, concentrations of plasma lead may be higher in ST users than non-tobacco users (e.g., Rostron 

et al., 2015). 

Within the ST category, there is also evidence of variability in HPHC exposure between product types, as 

one might expect based on differences in HPHC quantities as described in preliminary results by 

Chemistry, pending data requested in the deficiencies. Evidence suggests that exposure to NNK may also 

be greater from the proposed MRTP and other MST products relative to snus. In particular, Hatsukami 

and colleagues (2004) showed that NNAL levels decreased in participants of a clinical study who 

switched from brands of ST marketed in the U.S. to Swedish snus. 

In addition, biomarker studies discussed above (i.e., Campbell et al., 2015) showed no evidence of 

substantially reduced exposure to nicotine or other HPHCs in dual users compared to exclusive users of 

ST or cigarettes. Thus, the available evidence discussed here suggests any reductions in exposure to 

HPHCs the proposed MRTP could confer would come only with completely switching from combustible 

tobacco products to the proposed MRTP. 

Finally, no studies compared the risks of HPHC exposure associated with complete switching to the 

proposed MRTP with the risks associated with continued smoking, quitting altogether, or using an FDAapproved cessation aid. However, the evidence reviewed above suggests that the risks associated with 

complete switching to the proposed MRTP are likely greater than those associated with complete 

switching to an FDA-approved cessation aid and quitting altogether and likely less than those associated 

with continued smoking. Finally, the evidence suggests that many biomarkers of exposure are similar in 

ST users and non-tobacco users. 

In summary, the BCP review concluded that the MRTPA had adequate information to conclude the 

following: 

• ST use, in general, is associated with higher levels of exposure to some HPHCs and lower 

levels of others compared to cigarette smokers. 

• ST use, in general, exposes users to greater HPHCs than cessation aids and no tobacco use 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 32 of 75 

• There is some variation in exposure to HPHCs within the ST category – preliminary data 

suggest Copenhagen has higher HPHCs than some other ST products (i.e., snus); however, 

product characterization issues must be resolved to be confident in these findings, as laid 

out in the deficiencies. 

As TPL, I concur with BCP’s findings, but as noted in the Toxicology section, it is challenging to directly 

compare HPHC exposure between ST and cigarettes due to their different routes of exposure (i.e., 

buccal vs. inhalation). Because there is an abundance of literature on long-term epidemiologic health 

outcomes, I am relying on the Epidemiology review to compare ST use to cigarette smoking. 

3.2.3 Epidemiology 

The Epidemiology review is based on the applicant’s analysis of national survey data, including its linked 

mortality analyses and published long-term observational epidemiological evidence of mortality risks 

according to tobacco use status. 

ST products, including those referred to as chew, snuff, dip and spit, have been used in the U.S. for over 

a century. Thus, epidemiological evidence is available through peer-reviewed, published, cohort, casecontrol, and cross-sectional studies of the health risks of ST. No long-term epidemiological data are 

available pertaining specifically to the use of Copenhagen Snuff Fine Cut. Instead, the applicant 

summarized evidence from the published literature and conducted analyses of federal datasets of the 

health risks associated with ST use to draw inferences regarding the risk for tobacco-related diseases 

related to the proposed MRTP. The applicant states this published data is relevant because: (1) MST was 

the primary form of ST used in the U.S. at the time of these studies; (2) USSTC products generally, and 

specifically Copenhagen Snuff Fine Cut, held large market shares at the time of the studies; and (3) 

(according to the applicant) the product has not changed substantially since the time of the studies, with 

the exception of a decrease in TSNAs. Indeed, market data indicate that Copenhagen Snuff Fine Cut 

accounted for nearly 19-44% of the MST market in the time periods studied (1985-2005). Furthermore, 

the applicant provided literature demonstrating the decrease in TSNA over time and states that by the 

late 1990s, USSTC had reduced TSNA levels in its products by almost 90% (compared to the 1970s), and 

there is some evidence to suggest that harmful TSNA levels may have been higher in the time period of 

the published studies than in the proposed MRTP (Fischer et al., 2012). 

Substantiation of the Claim: 

ST is not combusted, and it is not inhaled; thus, it does not trigger the physiological processes that lead 

to lung cancer among cigarette smokers (International Agency for Research on Cancer 2007b). However, 

ST products contain NNK, a potent carcinogen that targets the lung (Yuan et al., 2012). 

Using never users as a common referent, the applicant’s National Longitudinal Mortality Study (NLMS) 

linked mortality analysis found similar point estimates for lung cancer mortality in complete switchers 

(i.e., those who switched from cigarettes to exclusive ST use: hazard ratio [HR]=5.34, 95% confidence 

interval [CI] 2.04-14.02) and cigarette quitters (HR=5.65, 95% CI=4.33-7.38), which was lower than the 

HR for continued smokers compared to never users (HR=11.52, 95% CI=8.74-15.19). 

Compared to never use, cigarette smoking poses substantial risks of lung cancer (US DHHS, 2014), 

whereas meta-analyses found that U.S. ST products have not been consistently associated with 

increased lung cancer risk (Boffetta et al., 2008; Lee & Hamling, 2009; Henley et al., 2005). Furthermore, 

in individual studies that have found associations between ST use and lung cancer mortality, risk is 

substantially lower than what is seen in cigarette smokers compared to never users. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 33 of 75 

To FDA’s knowledge, Henley et al. (2007) is the only published study that examined disease risk 

associated with sequential product use. In addition to users and quitters, they examined switchers, or 

those who exclusively smoked cigarettes and then switched to exclusive use of ST at the time of or after 

quitting smoking. In this U.S. study, “... relative risks for lung cancer were elevated in switchers vs. never 

tobacco users (HR=5.61)”. After twenty years of follow-up, switchers still had higher rates of lung cancer 

mortality than quitters (HR=1.46, 95% CI=1.24-1.73) (Henley et al., 2007). 

To examine that finding in the context of risk of complete switching relative to continued smoking, FDA 

conducted analyses of the findings from Thun et al. (2013) using former cigarette smokers (i.e., quitters) 

rather than never tobacco users as the common referent. FDA then examined the rate of death from 

lung cancer comparing continued smokers to quitters and found that the HR was 5.0. This is much 

higher than the HR from the Henley analyses comparing the rates of death from lung cancer between 

switchers and quitters (HR=1.46). In total, the epidemiological evidence assessed suggests that the 

relative risks for lung cancer are lower for switchers than for continued smokers. 

Based on the lack of combustion and magnitude of the reductions in relative risks between continuing 

smokers and switchers, as well as on mechanistic evidence, Epidemiology determined that the proposed 

modified risk statement “IF YOU SMOKE, CONSIDER THIS: Switching completely to this product from 

cigarettes reduces risk of lung cancer” is scientifically accurate. 

Relative Health Risks to Individuals: 

To examine whether the proposed MRTP would significantly reduce the harm and risk of tobaccorelated disease to individual tobacco users, the Epidemiology review examined the health risks of 

diseases other than lung cancer, and how these risks compared to smoking, other ST product use, 

complete switching (i.e., from cigarettes to exclusive ST use), or quitting cigarettes, and to never use. 

The 2012 IARC monograph “Personal Habits and Indoor Combustions” concluded that there was 

sufficient evidence to indicate the carcinogenicity of ST in humans and further stated that ST causes oral 

cancer, esophageal cancer, and pancreatic cancer (International Agency for Research on Cancer, 2012). 

One U.S. meta-analysis also reported an association between ST and fatal myocardial infarction and 

stroke (Boffetta & Straif, 2009). Data on all-cause mortality from individual studies are mixed (Henley et 

al., 2005; Accortt et al., 2002; Timberlake et al., 2017). Lastly, while there is relatively little information 

on ST use among U.S. women, several studies from Sweden have found an association between ST use 

and adverse pregnancy outcomes (Wikstrom et al., 2010; Baba et al., 2012; England et al., 2003). 

The applicant’s linked mortality analysis showed no significant differences in HRs between current 

exclusive ST users and non-users for lung cancer, all-cause mortality, all-cancer mortality, or mortality 

from diseases of the heart. In general, the HRs were lower for ST users than cigarette smokers. The point 

estimates for switchers and quitters generally fell between the point estimates for ST users who never 

used cigarettes and cigarette users. It should be noted that the number of deaths among ST users in the 

sample is small. For all cause-mortality, there were fewer than 50 deaths among current ST users who 

never smoked, so the sample may be underpowered to detect a difference. 

In the literature, Henley et al. (2007) reported similar findings for the risks for heart disease, oral cancer, 

stroke, and all causes as they did for lung cancer, where switchers had higher rates of death compared 

to quitters, but generally lower mortality rates than those of current smokers. 

Compared to other ST products, two studies that examined specific types of ST found no evidence of 

differences in disease risk in snuff users compared to chew users (Henley et al., 2005, Timberlake et al., 

2017). Epidemiological studies have observed differences in risks associated with U.S. ST product use 

compared with Swedish snus product use (Lee & Hamling, 2009; Boffetta &Straif, 2009; Rostron et al., 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 34 of 75 

2018). This difference may be due to generally lower levels of HPHCs, such as TSNAs, found in Swedish 

snus products. These data allow us to specifically conclude that exposure to Copenhagen Classic Snuff is 

riskier than exposure to Swedish snus. 

In summary, the Epidemiology review found that the MRTPA provided sufficient evidence to conclude 

the following: 

• The epidemiological literature regarding health risks associated with ST is relevant to the 

MRTPA given the market share of the proposed MRTP during the time period covered by 

these studies. 

• The claim was found to be scientifically accurate – complete switching from cigarettes to ST 

products, including the proposed MRTP, reduces the risks of lung cancer compared to 

continued smoking when both are compared to never users. 

• ST, including the proposed MRTP, causes oral cancer, esophageal cancer, pancreatic cancer, 

fatal myocardial infarction, stroke, and possibly mortality from any illness or injury; 

individual health risks for exclusive ST use are higher than for never users, but lower than 

those of cigarette users. 

• Individual health risks are higher for people who completely switch from cigarettes to ST 

than those who quit tobacco, but lower than continued smoking for lung cancer, heart 

disease, oral cancer, and stroke. 

As TPL, I agree with Epidemiology’s findings that the claim is supported by the available long-term 

epidemiological evidence. In addition, the data support the conclusion that relative to cigarette 

smoking, the proposed MRTP is associated with reductions in overall morbidity and mortality. 

3.2.4 Conclusions: Claim Substantiation and Individual Health Risks 

To evaluate individual health risks of the product, Toxicology, Medical, BCP, and Epidemiology reviewed 

evidence about HPHCs, biomarkers of exposure and potential harm, and health outcomes, respectively. 

Because of the substantial market share of Copenhagen Snuff Fine Cut, Epidemiology concluded it was 

appropriate to draw inferences about the health risks of the proposed MRTP, Copenhagen Classic Snuff, 

based on the available evidence. Given the availability of long-term epidemiological data providing 

direct evidence on health outcomes associated with ST use, biomarker evidence is of relatively less value 

to assess claim substantiation and individual health risks. Accordingly, long-term epidemiological 

evidence is the focus of the conclusions that followed. 

In comparison to never use of tobacco, use of ST exposes users to HPHCs and poses health risks. In 

comparison to cigarette smoking, ST use poses lower risks of certain health outcomes, including lung 

cancer. Indeed, TPSAC voted 8 to 0 (with one abstention) that the claim was supported by the scientific 

evidence, and particularly the epidemiologic evidence. In addition to a lower risk of lung cancer, the 

literature and the applicant’s own analysis suggest lower HPHC exposure as well as reduced risk of 

morbidity and mortality for other diseases relative to smoking, supporting the conclusion that this 

product would significantly reduce the risk and harm of disease among those who completely switched 

to it from cigarette smoking. 

There is relatively limited information that can be used to evaluate the health risks of the proposed 

MRTP compared to other ST products. Although the proposed MRTP poses lower risk relative to 

cigarettes, it is nevertheless a harmful tobacco product, posing greater health risks relative to no 

tobacco use, NRT, and Swedish snus. Due to the aforementioned incomplete manufacturing and product 
 

 

MR0000108 Page 35 of 75 

characterization, initial Toxicological assessments of the proposed MRTP relative to ST were preliminary. 

The comparisons did find that the proposed MRTP had higher levels of some HPHCs relative to other ST 

so a deficiency requested that the applicant provide scientific evidence and rationale about how 

exposure to HPHCs in other ST products may impact the population of tobacco users that may 

completely switch to or begin to dual use their current ST product(s) with the proposed MRTP. The 

applicant responded that due to MST comprising most of the ST market, MST was the appropriate 

comparator rather than the universe of ST products. Toxicology concurred as do I as TPL. Therefore, the 

portion of the deficiency related to dry snuff, loose leaf, and Swedish snus was resolved. Toxicology 

analyzed the proposed MRTP’s HPHC data compared to MST using a methodology that examines the 

risks of HPHCs collectively for a product. They determined that the lower levels of NNK and free nicotine 

in the proposed MRTP offset the higher levels of BaP and Cadmium from a carcinogenic perspective, 

rectifying concerns in the preliminary analysis. 

Overall, therefore, I maintain that the evidence supports claim substantiation: switching completely to 

the proposed MRTP from cigarettes will confer a lower risk of lung cancer. In addition, because other ST 

users could switch to the MRTP, it was critical to determine the relative risks of this product to other ST 

products. Knowing that the vast majority of ST users are MST users and that the higher level of some 

HPHCs in the proposed MRTP are offset by lower levels as compared to other MST products, I find that 

even if some ST users were to switch brands, the proposed MRTP, as actually used by consumers, will 

significantly reduce the risk to individual tobacco users and benefit population health. 

3.3 Consumer Understanding and Perceptions 

This section of the review discusses information related to consumer understanding and perceptions of 

the MRTP. Consumer understanding and perceptions are psychological constructs considered precursors 

to intentions to use the product. Understanding—or comprehension of the claim content—is relevant to 

the potential population health impact of the marketing of the proposed MRTP to the extent that it 

affects who uses the product and how they use it. Relatedly, Section 911(h)(1) of the FD&C Act requires 

that advertising and labeling concerning the proposed MRTP enable the public to understand the 

modified risk information and the relative significance of such information in the context of total health 

and in relation to all diseases and health-related conditions associated with the use of tobacco products. 

3.3.1 Social Science 

Labels, Labeling, and Advertising (LLA) with Proposed Modified Risk Information 

The applicant proposes a single modified risk claim: “IF YOU SMOKE, CONSIDER THIS: Switching 

completely to this product from cigarettes reduces risk of lung cancer.” The applicant provided the 

following sample label, labeling, and advertising (LLA) materials that contain this modified risk claim: 

print advertisement, direct mail advertisement, email advertisement, website pop-up screen, 

promotional card, bottom can label, and point of sale materials. USSTC stated that its marketing and 

advertising plans have features that will reduce the risk of youth uptake, including advertising in 

periodicals with predominantly adult readership, maintaining age-restricted brand websites, and using 

an age-verified consumer database for marketing communications, among other strategies. The Social 

Science review observes that the applicant’s planned advertising and promotions include non-targeted 

marketing techniques, such as a display in the parking lot or on the outside door of a retail outlet, that 

may expose youth to advertisements containing modified risk information. 

The applicant conducted one quantitative study, the Claim Comprehension and Intentions (CCI) study, to 

examine the effects of the modified risk claim on perceptions and behavioral intentions. The study used 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 36 of 75 

a quasi-experimental, pre-test-post-test, mixed design. Participants were assigned to one of two study 

conditions: viewing an advertisement either with the modified risk claim (test condition) or without the 

claim (control condition). Outcomes included behavioral intentions (discussed below in Section 3.4), 

claim recognition, and risk perceptions. The study examined a number of different risk perceptions, as 

discussed in the Social Science review. Here, I focus on those most relevant to determining whether the 

claim enables consumers to understand the risks of the product in the context of total health: 

perceptions of lung cancer risk, overall perceptions of health risks, and perceptions of health risks 

compared with smoking cessation and NRT use. Other relevant risk perceptions and how they affect the 

overall consumer understanding assessment, including perceptions of overall health risk relative to 

cigarettes and risk perceptions relative to other smokeless tobacco products, are discussed in the Social 

Science review. Note that risk perception measures assessed absolute risk perceptions; the applicant 

compared absolute risk perceptions in order to indirectly measure relative risk perceptions. 

The study employed a non-probability sample of 5,871 adult participants: a main study sample of 4,927 

adult participants and a separate oversample of 944 young adult participants. Participants in the main 

sample were categorized as one of the following tobacco user subgroups: adult smokers planning to quit 

(ASPQ), adult smokers not planning to quit (ASNPQ), dual users, (i.e., people that concurrently use MST 

and cigarettes), MST users, former users (i.e., former users of any tobacco product who are currently 

not using any tobacco product), and never users (i.e., never users of any tobacco product). The sample 

of young adults were participants of the minimum legal age to purchase tobacco (at the time of the 

study) up to age 24 (LA-24) and were categorized as either tobacco users or tobacco nonusers. The 

applicant did not provide findings for the overall sample, but rather only by subgroup. 

Claim Recognition: At the end of the survey, a claim recognition item prompted participants in the test 

condition to look at the ad again and then identify the correct claim text from a list of answer options. 

The question read: “Please look at this ad again. Regardless of what you believe to be true, please 

answer the question based on the information shown in this ad. Based only on the information shown in 

this ad, smokers who switch completely from cigarettes to Copenhagen Snuff: Increase the risk of lung 

cancer, Reduce the risk of lung cancer [correct answer], Eliminate the risk of lung cancer, or Do not 

know.” 

Results show that, across all subgroups, a majority of participants (55-70%) correctly identified the claim 

text (Figure 1). These findings suggest that just over half of participants noticed and processed the claim 

text sufficiently to recognize and select it from the list of response options. For the remaining 

participants, it is unclear whether they noticed the claim but did not read it, they read the claim but did 

not understand or believe it, did not notice the claim, or something else. Accordingly, when interpreting 

study findings, bear in mind that they include responses from all participants—a sizeable proportion of 

whom may not have noticed or may not have read the claim. See also the Limitations section below 

regarding the lack of a manipulation check. 
 

 

 

 

 

 

 

 

 

 

MR0000108 Page 37 of 75 

Figure 1. Distribution of responses to the claim comprehension measure, test condition 

only. 

Perceptions of Lung Cancer Risk: 

First, in assessing whether consumers will understand the modified risk information in the context of 

total health, it is important that consumers understand the nature of the risk reduction purported by 

the proposed MRTP. As lung cancer is the subject of the modified risk claim, perceptions of lung cancer 

risk are informative to assessing the extent to which participants understand the risk of lung cancer from 

the proposed MRTP relative to cigarette smoking. Participants’ ratings of the absolute likelihood that a 

person who uses only Copenhagen Snuff daily would develop lung cancer were consistently lower than 

their ratings of the absolute likelihood that a person who only smokes cigarettes daily would develop 

lung cancer. This was true across all tobacco user groups. Among participants who viewed the modified 

risk advertisement, post-test ratings of the risk of lung cancer for someone using Copenhagen Snuff 

ranged from 39-70% (across user groups) and from 67%-86% (across user groups) for a person who 

smokes cigarettes daily. Note, the applicant did not conduct testing to establish whether these 

differences were statistically significant. Mean risk perception scores at post-test are shown below in 

Figure 2. I would have liked to have seen these findings aggregated across groups, which would have 

given the data more power and a more precise estimate as these ranges are large. While the 

aggregation would be helpful, the pattern of effects is similar across user groups, suggesting that were 

the data to be aggregated, the overall finding would likely remain the same (i.e., participants rated the 

absolute likelihood of developing lung cancer to be higher with cigarettes than the absolute likelihood of 

developing lung cancer from Copenhagen snuff). Taken together, these findings suggest that 

participants correctly understand that cigarettes are more likely to cause lung cancer than Copenhagen 

Snuff. 

Post-test ratings did not appear to differ from pre-test ratings, suggesting that the claim did not impact 

participants’ understanding of the relative risk of lung cancer. While ideally, I would have liked the 

experiment to have shown that participants’ beliefs around the claims are influenced by the claim, this is 
 

 

 

 

 

 

 

 

 

 

MR0000108 Page 38 of 75 

not a requisite for demonstrating an appropriate understanding of the proposed MRTP in three areas: 1) 

relative harm compared to NRT or quitting completely, 2) that the proposed MRTP is not harmless, and 

3) that consumers understand they need to switch completely to the proposed MRTP. As discussed

elsewhere, given the ingrained misperceptions around relative harms of different tobacco products and

the role of nicotine, it is understandable that participants’ beliefs were not changed by a brief one-time

exposure. Because the proposed MRTP is a smokeless product, a subset of consumers likely already

perceived the product to be lower than cigarettes in terms of lung cancer risk, potentially making it

more challenging to detect an effect of the claim about lung cancer, as compared to claims about other

health effects. For example, a latent profile analysis of smokers' perceptions of snus, another product

type in the ST category, found that a little over half perceived snus as posing lower risks for lung cancer

compared to cigarettes, with smaller subsets perceiving snus to pose lower risks than cigarettes for

heart disease or oral cancer (Wackowski, Ray & Stapleton, 2019).

Finally, the absolute levels of perceived risk suggest that consumers perhaps overestimated the absolute 

lung cancer risk in a person who uses only Copenhagen Snuff, perceiving the risk to be only modestly 

lower than in a person who only smokes cigarettes. As lung cancer risk perceptions were essentially 

unchanged from pre-test and did not statistically differ between the test and control conditions, this 

suggests that any overestimation of lung cancer risk was not a result of consumers’ misunderstanding 

the modified risk claim, but instead reflects what consumers already believed. This is consistent with the 

literature, which indicates that some U.S. consumers believe that ST use causes lung cancer, even 

though lung cancer has not been conclusively linked to exclusive ST use (Adkison, Bansal-Travers, Smith, 

O’Connor, & Hyland, 2014). 

As noted by TPSAC and consistent with the literature (Hornik, 2002), the success of a message relies on 

having adequate exposure. Because participants were only required to view the label once, it is not 

surprising that participants’ beliefs were not changed. Often an audience needs not only multiple 

exposures to a message, but multiple methods of exposure to effectively process message content. Even 

a well-designed message is subject to null effects if exposure is insufficient. 

Figure 2. Lung cancer risk: Mean absolute risk perception scores associated with using only 

Copenhagen Snuff daily and with only smoking cigarettes daily, at post-test, by tobacco 

user group, test condition only. 
 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 39 of 75 

In conclusion, although consumers may overestimate the absolute risk of lung cancer from using the 

product, these findings suggest that participants accurately understand that lung cancer risk is lower in a 

person who exclusively uses Copenhagen Snuff than in a person who exclusively smokes cigarettes. 

Given the salience of lung cancer as a smoking-related risk and the considerable portion of smokers who 

do not understand the different risk posed by the proposed MRTP compared to cigarettes, even for this 

particular health effect, provision of the modified risk information to consumers will enable consumer 

understanding and ultimately benefit population health, particularly as they will be exposed many more 

times to the message in real life. 

Overall Perceptions of Health Risks: Next, in assessing whether consumers will understand the modified 

risk information in the context of total health, an important consideration is that consumers do not 

perceive the proposed MRTP as having no risk. 

Participants were asked to rate the likelihood that a person who only uses Copenhagen Snuff daily 

would experience a negative impact to their health, using an 11-point scale with the endpoints 0% 

Extremely unlikely and 100% Extremely likely. Across tobacco user groups assigned to the test condition, 

mean ratings at post-test ranged from approximately 61% to 85%. (Ratings were very similar at pretest.) The applicant’s statistical analyses showed that the proposed modified risk claim had no significant 

effect on perceptions of overall risk except for one group: LA-24 (i.e., young adult) nonusers of tobacco 

had statistically significantly lower risk perceptions of Copenhagen Snuff at post-test (80.5%) compared 

to pre-test (81.6%) (t = -3.96, ρ < 0.001, d = 0.28), though perceived likelihood remained very high and 

the magnitude of change was quite small. 

In general, these findings suggest that, after seeing the advertisement with the modified risk claim 

participants accurately perceived that using the proposed MRTP daily is likely to negatively impact 

health. This finding supports the conclusion that consumers will understand that the proposed MRTP is 

not harmless. 

Perceptions of Health Risks Compared with Smoking Cessation and NRT Use: To assess whether 

consumers will adequately understand the modified risk information in the context of total health, I also 

considered whether the proposed claim may mislead people into thinking that using the product would 

present lower health risks compared to using NRT or compared to quitting all tobacco. 

At post-test, participants rated the risk of using half a can of Copenhagen Snuff daily as higher than the 

risk of using NRT (Figure 3). This was true across all tobacco user groups and both study conditions. 

Similarly, at post-test, all user groups rated using half a can of Copenhagen Snuff daily as riskier than 

quitting all tobacco, as well as never using tobacco products. Post-test ratings did not appear to differ 

from pre-test ratings, suggesting that the claim did not affect these perceptions. 

These data suggest that even with a modified risk claim, consumers have an appropriate understanding 

that using the proposed MRTP is more harmful to health than using NRT, completely quitting all tobacco 

use, or never using tobacco products. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 40 of 75 

Figure 3. Mean absolute risk perception scores associated with using Copenhagen Snuff and with 

using NRT, at post-test, by tobacco user group and study condition. 

Note: Perceived risk was rated on a scale from 1 (not at all risky) to 7 (very risky). 

Limitations: 

Our assessment of the individual health risks of the product, as described above, concludes that the 

reduction in lung cancer risk described in the claim is substantiated for those who switch completely 

from cigarettes and use the proposed MRTP exclusively, as proposed by the applicant. Therefore, a 

component of understanding the claim in the context of total health is understanding how to use the 

product. A limitation of the CCI study is that it did not evaluate participants’ understanding of how to 

use the proposed MRTP to attain the risk reduction purported in the claim; in other words, the CCI study 

did not directly assess the extent to which consumers understood that they must switch completely to 

the proposed MRTP. I would have liked the applicant to directly assess this given that this is critical to 

obtaining the full benefit of this proposed MRTP. However, the claim itself provides specific and clear 

language regarding who the product is for (with a call out to smokers) and directs potential users that 

they can reduce their lung cancer risk by “switching completely.” FDA has previously authorized the 

marketing of another MRTP with the same language and has required that consumer understanding of 

the need to switch completely be tested in PMSS for that MRTP as well as another. 

In examining this study overall, the Social Science review identified two limitations of the study method 

that could affect interpretation of the study results: the pre-post quasi-experimental design and the lack 

of a direct manipulation check. First, the review notes that pre-test-post-test designs, while scientifically 

appropriate in some situations, may have the disadvantage of potentially introducing testing effects 

and, in particular, make any potential effects of the claim harder to detect. On the other hand, another 

study used a similar design to examine the effects of reduced risk claims on consumer risk perceptions 

of tobacco that detected significant effects (Popova & Ling, 2014). It is difficult to know to what extent 

this particular study design element affected results. For instance, was this study a situation where 

individuals would have had such self-presentation concerns about consistency, and if so, is it likely they 

would be able to remain consistent in their answers given the large number of items, many of which had 

fairly wide response scales? However, because this methodology has been used in similar studies and is 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 41 of 75 

a common study design, we believe the findings are valid; if anything, the applicant may have found 

fewer null effects had they used a post-test only design. 

Second, a manipulation check could have been informative as it would have allowed the applicant to 

analyze results for only those participants who confirmed receipt of the manipulation. FDA recommends 

a manipulation check, which determines whether the manipulated factor (such as a modified risk claim) 

was noticed by the participants as intended. Such an assessment is important for evaluating internal 

validity of the study. For instance, if the manipulation check reveals that participants did not notice the 

modified risk claim, then this could account for a failure to find effects on the study outcomes. Although 

the study did not include a manipulation check administered directly following exposure to the ad, the 

claim recognition item does provide insight into the fact that there was a portion of participants who 

appeared not to attend to the claim. 

In summary, the Social Science review concluded that the CCI study evidence suggests consumers 

generally understood the modified risk claim and its significance in the context of total health. Although 

the claim did not significantly affect risk perceptions, participants accurately rated that lung cancer risk 

is lower in a person who exclusively uses Copenhagen Snuff than in a person who exclusively smokes 

cigarettes. Importantly, consumers were not misled by the claim to think that the product poses no risks 

or poses lower risks relative to NRTs or quitting all tobacco. However, the Social Science review also 

notes that the study findings are subject to limitations—namely with the pre-post design—and notes 

that the claim may have effects in the real world not reflected in the study findings. 

As TPL, I agree with the Social Science conclusion that the findings suggest consumers have an 

appropriate understanding of the proposed modified risk claim. As described in the Executive Summary, 

I concur with the Social Science review’s perspective on a number of limitations in the applicant’s CCI 

study and believe there were ways to have strengthened the study design. However, as noted earlier in 

this review, despite these limitations, I believe the applicant has met the statutory requirements for 

basic understanding of modified risk: participants understand that the proposed MRTP causes harm and 

that it is more harmful than quitting or NRT and the label directs users that they must switch completely 

to derive the benefits of the claim (in this case, a reduced risk of lung cancer relative to cigarettes). 

I also agree that, though I would have liked the applicant’s CCI study to provide more exposure to the 

claim at different time points, it is likely the findings from this study do not reflect the full real-world 

impact of the claim, which are likely to happen over a period of time as the idea gains more credibility 

and general awareness among the public. Thus, the findings likely underestimate the potential impact of 

the claim on consumers’ perceptions. In the CCI study, most participants’ perceptions of the risks of the 

product were unaffected by exposure to the claim, whereas with repeated exposure, it is likely more 

consumers would revise their beliefs regarding the relative risks of these products to bring them more in 

line with the scientific evidence. In turn, this increased believability of the claim, would allow a more 

informed choice of tobacco products and potentially lead to switching to this proposed MRTP. 

3.3.2 Social Science Support for TPL Deficiency 

At my request, Social Science examined the data submitted by the applicant in response to Deficiency #1 

to evaluate if the proposed MRTP, with its new name and advertising, still supports appropriate 

consumer understanding of the proposed modified risk claim and its significance in the context of total 

health. The applicant submitted a

(b) (4)

 that assessed whether 

(b) (4)
MR0000108 Page 42 of 75 

(b) (4)

(b) (4)

(b) (4)

(b) (4)

. 

(b) (4)
MR0000108 Page 43 of 75 

The

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

 

 

 

 findings suggest 

Taken together, Social Science concluded 

As TPL, I find that Deficiency #1 was adequately addressed 

postmarket surveillance studies (PMSS). 

(b) (4)

(b) (4)

(b) (4)

3.3.3 Conclusions: Consumer Understanding 

Overall, the CCI study 

(b) (4)

provided sufficient evidence to support appropriate 

consumer understanding of the proposed modified risk claim and its relative significance in the context 

of total health and in relation to all of the diseases and health-related conditions associated with the use 

of tobacco products. After seeing the advertisement with the modified risk claim, participants 

understood that the absolute risk of developing lung cancer is lower in a person who exclusively uses 

the proposed MRTP daily than in a person who smokes cigarettes daily. Participants also understood 

that using the proposed MRTP is risky to health, and that someone who only uses the proposed MRTP 

daily would likely experience a negative impact to their health. Finally, participants understood the risk 

of using the proposed MRTP is greater than that of using NRT, quitting all tobacco, and never using 

tobacco products. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 44 of 75 

Although the CCI 

(b) (4)

 support appropriate consumer understanding, the CCI study 

findings in general suggest that the modified risk claim had little or no impact on participants’ 

perceptions. However, it is possible these results underestimate the potential impact of the claim — 

even from a brief exposure — on consumers’ perceptions and intentions related to the MRTP. As the 

Social Science review noted, it’s possible the null findings are an artifact of the study design: biased 

responses resulting from the pre-post design, or a failure of the manipulation (i.e., a proportion of 

participants did not view or notice or read the claim). An alternate explanation, as discussed at length by 

TPSAC, is that a one-time exposure is simply limited in the impact it can have on perceptions— 

particularly when the message may not be consistent with pre-existing beliefs, as discussed in the Social 

Science review. It would have been ideal if the applicant had conducted a manipulation check and 

required multiple exposures. That said, as described earlier, even with multiple exposures in a study, it 

would be difficult to replicate the real-world impact of the claim, which is likely to happen over time as 

the idea gains more credibility and general awareness among the public. 

The study did not assess participants’ understanding that a user must completely switch to the product 

(from cigarettes) in order to reap the benefit, nor did the study assess perceptions of the risk of dual use 

or partial switching. These outcomes are relevant because, as described above in Section 3.2.2.2, risk 

reduction is expected for smokers who switch completely—but not for those who continue to use both 

products. While this is an important limitation in the consumer understanding data, it is mitigated by the 

fact that the claim itself directs potential users that they can reduce their risk by “switching completely”. 

Still, I agree with the Social Science review suggestion that the extent to which consumers understood 

that the proposed MRTP must be used exclusively and that dual users should switch completely should 

be monitored in postmarket surveillance as has been the case in previous MRTP authorizations. 

In addition, Social Science examined 

(b) (4)

. 

3.4 Likelihood of Use and Impacts to Population 

This section examines the potential benefits and harms of the proposed MRTP to the health of the 

population as a whole taking into account the impacts to users and non-users. This determination 

considers the increased or decreased likelihood that existing users of tobacco products who would 

otherwise stop using such products will switch to the MRTP and the increased or decreased likelihood 

that persons who do not use tobacco products will start using the MRTP. This section will review the 

evidence provided by BCP, Epidemiology, Social Science, and Statistics reviews. 

3.4.1 Impacts to Users 

3.4.1.1 Behavioral and Clinical Pharmacology 

The BCP review utilized the Altria Client Services LLC (ALCS) Clinical Study and the peer-reviewed 

scientific literature to examine use behaviors and topics associated with abuse liability such as 

topography, dependence, subjective effects, and the pharmacokinetics of the proposed MRTP. 

The ALCS Clinical Study was a within-subjects laboratory study that compared the nicotine 

pharmacokinetics and subjective effects of a test moist snuff tobacco product “produced to the identical 

specifications as for the Copenhagen Original Fine Cut Snuff product marketed on or before February 

2007” with participants’ usual brand of cigarettes and Nicorette Fresh Mint nicotine polacrilex gum (4 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 45 of 75 

mg). Participants in this study were 24 smokers (≥ 10 menthol or non-menthol cigarettes per day for at 

least 1 year), ages 21-65 who were non-daily users of “original,” “natural,” “regular,” or similarly 

flavored MST products (≥ 20 uses during lifetime, but not used every day in previous 30 days) with no

use of Nicorette Fresh Mint gum in the previous 3 months. 

The BCP review examined the pharmacokinetics associated with the proposed MRTP and focused on the 

rate of increase in plasma nicotine concentration because the rate affects abuse liability, such that a 

faster rate of increase results in greater abuse liability. In the ALCS Clinical Study, the rate of absorption 

suggests that the proposed MRTP may have lower abuse potential than usual brand cigarettes and 

similar or greater abuse potential than Nicorette gum. The literature related to nicotine and MST 

products corroborated the clinical study’s findings. The rate of nicotine absorption from MST is slower 

than cigarettes, and it is similar to that of nicotine gum and nicotine lozenges; however, more nicotine is 

typically delivered by MST than cessation aids (e.g., Benowitz et al., 1988; Kotlyar et al., 2007).

8 

Abuse liability is not determined based solely on plasma nicotine data, but also relies on subjective 

effects. In the ALCS clinical study, for items related to subjective effects such as craving and sensory 

impact, use of cigarettes was higher than use of Nicorette gum or the proposed MRTP. This suggests 

that the abuse potential of the test MST product may be lower than that for usual brand cigarettes and 

similar to or higher than the abuse potential of Nicorette gum among cigarette smokers under 

conditions of brief exposure. The scientific literature on positive subjective effects validated the study 

results. Subjective effects of ST products are similar to or greater than those associated with FDAapproved cessation aids and less than those associated with cigarettes. 

Another topic related to use of the proposed MRTP is topography, which refers to how a person uses a 

tobacco product in terms of quantity and duration of use. Topography data from multiple sources, 

including the ALCS Clinical study, show that the dip duration of “Copenhagen” and other moist snuff 

products is approximately 40 minutes, dip size is roughly 2 g, average dips per day is between six and 

nine, and MST products are typically used 22-28 out of 30 days among current users. No evidence of 

intentional or unintentional product misuse was reported in the ALCS Clinical Study, and limited reports 

of misuse were observed in the literature. 

While dependence was not assessed by the ALCS study, some evidence suggests tobacco cessation rates 

are higher among ST users than in cigarette smokers, indicating that ST users may be less dependent 

relative to cigarette smokers. For example, in a systematic review of tobacco cessation studies, higher 

rates of cessation were observed among ST users assigned to control conditions (19.1% – 33%) than 

cigarette smokers assigned to control conditions (9.8% - 11.2%; Fagerström & Eissenberg, 2012). 

Another study reported that the quit rate among exclusive ST users was three times higher than the quit 

rate among exclusive smokers (35% vs. 11.3%) in a sample of over 15,000 respondents who participated 

in a longitudinal survey in 2002 and 2003 (Zhu et al., 2009). Overall, evidence from the scientific 

literature suggests it may be less difficult for ST users to quit using their tobacco products than cigarette 

smokers. 

The BCP review notes several ALCS Clinical Study limitations. One limitation is that the study utilized a 

test product identical to Copenhagen Classic Snuff but did not add the proposed claim to the packaging, 

so it is unknown how the proposed MRTP would impact users relative to the study outcomes. 

Furthermore, study participants were regular cigarette smokers with previous experience using moist 

snuff tobacco products. Thus, the study provided no information about use patterns in daily ST users or 

8 One product in the studies was labeled “Copenhagen,” but the applicant did not specify that it was the proposed MRTP. 
 

 

 

 

MR0000108 Page 46 of 75 

smokers with no history of MST use. Third, no measures of dependence were assessed. All told, this 

reduces the generalizability of the study. 

In summary, the BCP review concluded that the MRTPA had adequate information to draw conclusions 

regarding clinical studies examining abuse liability: 

• The abuse liability associated with the proposed MRTP is equal to, or greater than, some 

FDA-approved cessation aids (e.g., nicotine gum) and no use of tobacco products 

• The risk of addiction associated with use of the proposed MRTP may be lower than the risk 

of addiction with cigarette smoking 

As TPL, I agree with BCP’s findings and interpret the evidence to suggest that the proposed MRTP may 

confer a lower risk of addiction than cigarettes, but a greater risk of addiction than cessation aids or 

quitting suggesting that the level of satisfaction may still be sufficient to encourage smokers to 

completely switch. While pharmacokinetics should not be affected by the claim, I note that all data 

evaluated in the BCP review were collected from participants who were not exposed to the modified risk 

claim. 

3.4.1.2 Epidemiology 

The Epidemiology review is based on the applicant’s secondary analysis of national survey data and 

internal, unpublished secondary analysis of national survey data both specifically regarding Copenhagen 

Snuff Fine Cut as well as published long-term observational epidemiological evidence. The published 

literature addresses ST use and health effects overall, which informs the current review given that the 

applicant was a market leader during the time the studies were conducted. 

In the current marketplace, ST use among adults in the National Health Interview Survey (NHIS) was 

2.4% with 5.9 million total estimated users (Creamer et al., 2018). This is consistent with Population 

Assessment of Tobacco and Health (PATH) Wave 5 (2018/19) data, which also found a prevalence of any 

ST product use among adults of 2.4%. Use of non-snus ST is more common among males, non-Hispanic 

whites, adults living in nonurban areas, and adults ages 25-49 (Cheng et al., 2017). Data from the 2021 

National Youth Tobacco Survey found that the prevalence of reported current ST use was 1.2% (95% CI: 

0.8-1.6) for high school students and 0.6% (95% CI: 0.4-0.9) for middle school students. NYTS results 

from 2021 cannot be directly compared to results from 2019 and 2020 due to differences in data 

collection methodology (Park-Lee, Ren et al. 2021, Gentzke, Wang et al. 2022). These data are 

concordant with the 2019 Youth Risk Behavior Survey, which found that 3.8% of high school students 

reported ST use (Creamer et al., 2020). However, rates vary by rurality, with rates of ST use among rural 

adults and youth twice as high as those in urban areas (Buettner-Schmidt et al., 2019). 

Epidemiology examined patterns of use of any Copenhagen product using data from PATH Wave 5. 

FDA’s analysis of past 30-day non-light ST users (i.e., those who reported using ST more than ten times 

in their lifetime and last used ST within the past 30 days) found that nearly four in ten youth (ages 12-17; 

38.3%), roughly half of young adults (ages 18-24; 52.7%), and nearly a third of adults 25 and older 

(30.6%) reported using a Copenhagen product as their brand usually or most recently used. 

Copenhagen users reported consuming the product on 26.3-28 days in the past month. Copenhagen 

users consumed, on average, 0.57 cans on those days compared to 0.56 cans, on average, among all 

MST users. Among Copenhagen Snuff Fine Cut users who were exclusive users, the average number of 

cans used on days used was 0.56, compared to 0.60 among exclusive total MST users overall. 
 

 

MR0000108 Page 47 of 75 

The Epidemiology review also examined patterns of transitions around dual use and complete switching 

in the current marketplace. Studies from the observational literature find that complete switching from 

exclusive cigarette smoking to exclusive ST use is low, in the range of 0.3% to 4.9% (Tam et al., 2015; 

Anic et al., 2018; Chang, Levy & Meza, 2018). Dual users are most likely to continue dual use of both 

products (44.3% in a 4-year period), but if they completely switch, more dual users move to exclusive 

cigarette use (27.0% in a 4-year period) than to exclusive ST use (17.4%). A recent 2021 report by 

Jackson et al. using data from PATH Study Waves 3 (2015/16), 4, and 5 indicates that very few people 

who smoke cigarettes transition to ST, either for dual use or exclusive use (Jackson, Ren et al. 2021). 

Among exclusive smokers at PATH Study Wave 3, only 1.6% (95% CI: 1.3-2.1) transitioned to dual use 

with an ST product and only 0.1% (95% CI: 0.1- 0.2) switched to exclusive ST use at PATH Study Wave 4. 

Of the dual users at Wave 3, 7.6% (95% CI: 4.4-10.6) transitioned to exclusive ST use at Wave 4. The 

majority of exclusive cigarette smokers who transitioned to dual use at Wave 4 continued smoking 

cigarettes at Wave 5, either as dual users or as exclusive cigarette smokers. The conclusions of this 

article align with previous research indicating that switching from cigarette smoking to ST is uncommon 

(Tam, Day et al. 2015, Chang, Levy et al. 2018). This recent study was also concordant with other studies 

including a systematic review and found that dual users were more likely than exclusive smokers to 

switch to exclusive ST use (Zhu et al., 2009; Tam et al., 2015), with estimates ranging from 4.9% to 

17.4%. 

Examining data on dual use specific to the applicant’s product but without modified risk information, 

Wave 4 of the PATH study found that approximately 16.7% of Copenhagen users also used cigarettes 

(i.e., dual use) in the past 30 days, which equates to about 67,000 U.S. dual users. These estimates for 

the percent of past 30-day cigarette use in Copenhagen users are lower than the 30% and 40% of overall 

MST dual users found in the ALCS and in PATH studies (at Wave 1 and Wave 4), respectively, suggesting 

that a much larger proportion of Copenhagen users do not use cigarettes relative to other brands of 

MST. In addition, PATH analyses showed dual Copenhagen users reported smoking fewer cigarettes on 

days they smoked (11.0) than did MST users overall (16.2), though tests of statistical significance were 

not conducted. Furthermore, among Copenhagen dual cigarette users the average number of cans used 

on days used was 0.59, compared to 0.44 among MST dual cigarette users overall. Taken together, while 

there is a smaller proportion of dual users of Copenhagen relative to other brands, they use more of 

their Copenhagen product and smoke fewer cigarettes relative to other brands, which may indicate a 

greater chance of success in complete switching to Copenhagen than with other MST brands. Therefore, 

among users who may benefit from the proposed MRTP, dual users of ST and cigarettes, and especially 

the 67,000 dual users of Copenhagen, might be likely to view and find the claim relevant and are a 

particularly important target population for the proposed MRTP were it to be authorized. 

In conclusion, Epidemiology found sufficient evidence to describe the current behavioral patterns of use 

for the proposed MRTP and found that while ST use is low, the proportion of ST users using Copenhagen 

products in the current marketplace is large and roughly one in six of those users also smokes cigarettes. 

As TPL, I agree with these conclusions and note that the dual users of the proposed MRTP are among 

the users most likely to benefit from the proposed MRTP were it to be authorized. 

3.4.1.3 Social Science 

The Social Science review examined the potential impact of the proposed MRTP on users by examining 

the applicant’s CCI study. In the study, the pre-test and post-test questionnaires assessed participants’ 

behavioral intentions to try, use, dual use, and switch to Copenhagen snuff. Each of these outcomes was 

assessed with multiple items using a response scale ranging from 1 (strongly disagree/definitely not) to 
 

 

 

 

 

 

 

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6 (strongly agree/definitely). In addition, participants were asked about intentions to quit smoking 

(yes/no) and intentions to quit all tobacco (yes/no). 

Overall, the results showed that levels of interest among current users is low to moderate (Table 4). In 

general, there were no significant differences9 between conditions (or from pre- to post-test) suggesting 

the claim did not influence intentions. On average, among smokers, ratings of intentions were low. 

When exposed to the claim, adult smokers (ages 25 and older) not planning to quit reported intentions 

below the scale midpoint for intentions to try (M = 2.48), use (M = 2.34), or switch (M = 2.09) to 

Copenhagen.

10 Similarly, for LA-24 (i.e., young adult) tobacco users, the means were a bit higher, but still 

below the midpoint for intentions to try (M = 3.24), use (M = 3.20), or switch (M = 2.73). Notably, dual 

users of any ST product and cigarettes had the highest levels of intentions to try (M = 4.54) and use (M = 

4.32) the product; however, among this group, intentions to dual use (M = 4.3) were higher than 

intentions completely switch (M = 3.5). 

Table 4. Unadjusted mean scores for intentions to try, use, switch, and dual use Copenhagen Snuff, at pre-test and post-test, 

among adult tobacco users. 

Group Condition Intentions to Try a Intentions to Use a Intentions to Switcha Intentions to Dual 

Use 

Pre Post Pre Post Pre Post Pre Post 

ASPQ 

Control 

Test 

2.43 

2.40 

2.30 

2.36 

2.31 

2.29 

2.20 

2.25 

2.19 

2.16 

2.11 

2.11 

2.19 

2.15 

2.06 

2.05 

ASNPQ 

Control 

Test 

2.54 

2.49 

2.46 

2.48 

2.41 

2.32 

2.31 

2.34* 

2.08 

2.02 

2.06 

2.09 

2.33 

2.24 

2.22 

2.23 

MST Users 

Control 

Test 

4.36b

4.49b

4.35b

4.37b

4.27 

4.22 

4.18 

4.16 

Not asked 

Dual Users 

Control 

4.51b 4.38b 4.22 4.13 3.33 3.27 4.19 3.97 

9 This analysis yielded only one statistically significant result: intentions to use Copenhagen Snuff were higher among ASNPQ 

who viewed the advertisement with the claim, compared to those who viewed the advertisement without the claim (F = 9.15, ρ

= 0.003, eta2 < 0.01). However, the magnitude of the change was so small that given the context of the other findings both for 

intentions to use across user groups as well as other metrics for the ASNPQ group, this finding was not seen as meaningful. 

10 These smokers represent adult smokers who reported planning to quit. Scores were within a 0.2 difference relative to 

smokers who were not planning to quit. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Test 

4.59b 4.54b 4.43 4.32 3.51 3.51 4.32 4.15 

Control 

3.19b 3.13b 3.15 3.10 2.63 2.62 2.91 2.82 

Tobacco Users 

LA-24 Test 

3.31b 3.24b 3.23 3.20 2.73 2.73 3.02 2.96 

aComposite measure 

bRepresents only those MST Users (43%), dual users (42%), and tobacco users LA-24 (70%) who were not current Copenhagen Snuff users. 

*Denotes statistical significance. After Bonferroni adjustment, ρ-values < 0.008 were considered to be statistically significant. 

Note. Response scale ranging from 1 (strongly disagree) to 6 (strongly agree). 

Finally, the results showed that viewing the advertisement with the claim versus without the claim did 

not significantly impact intentions to quit smoking. Therefore, there is no indication that the marketing 

of the proposed MRTP would adversely impact the likelihood of quitting tobacco among those who 

planned to do so. 

Social Science concluded that these findings show that exclusive smokers are unlikely to completely 

switch to Copenhagen Snuff, and that while dual users are more likely than exclusive smokers to 

completely switch to the proposed MRTP, they are more likely to continue to dual use rather than 

switch completely. These findings are consistent with the use patterns currently observed in the U.S. 

population, described by Epidemiology: complete switching from exclusive cigarette smoking to 

exclusive ST use is low among U.S. consumers, and dual users of MST and cigarettes tend to continue 

dual using, with transitions from dual use to exclusive smokeless use being relatively uncommon. 

As TPL, I generally agree with the conclusions of Social Science. However, my interpretation of these 

findings also accounts for the limitations of the CCI study discussed in Section 3.3 with regard to 

consumer understanding. In particular, just as I interpreted the CCI study to underestimate the potential 

impact of the proposed MRTP on consumer understanding and product perceptions given the 

entrenched beliefs about the product category; here, too, I expect it may take time and multiple 

exposures to reach and influence users who could stand to benefit. Still, I expect that the ultimate 

proportion of smokers who are likely to completely switch to this proposed MRTP is small, yet, for those 

smokers who are open to ST, this proposed MRTP has the potential to significantly reduce their risk. The 

CCI study results support that the group most likely to adopt the proposed MRTP would be current ST 

users. Taken together, dual users of ST products and cigarettes are most likely to benefit from the 

proposed MRTP. In addition, a real-world, targeted marketing campaign is likely to repeatedly expose 

these users to the message, which over time further increases the likelihood they would switch 

completely. While intentions did not change substantially between pre- and post-test nor for those 

viewing the claim or not, given the one-time exposure to the claim, it is unlikely to have changed 

people’s beliefs or motivations. However, with repeated exposure to the claim that would be seen in 

real world circumstances, and particularly for dual users who showed more interest than other groups in 

trying, using, and switching, the proposed MRTP has the potential for population health benefit. Thus, 

while the universe of people who will benefit from this MRTP is modest, given that the claim has been 

substantiated and the risk for nonusers to initiate tobacco use due to the MRTPA is quite low (see 

Section 3.4.2), there will be a net benefit to population health, and the modified risk information will 

enable consumers to make a more informed choice about their tobacco use. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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3.4.2 Impacts to Non-users 

This section will address the potential impact of authorizing the proposed MRTP on non-users. Nonusers include youth, young adults, and adults older than age 25. The impact to youth was examined by 

Epidemiology using secondary analysis of national datasets as examined by the applicant and FDA. The 

impact to non-user young adults and adults over age 25 was examined by Social Science using the 

applicant’s CCI study. 

3.4.2.1 Epidemiology 

Youth are considered a vulnerable population of non-users because youth who initiate with Copenhagen 

Snuff Fine Cut and other ST products are at risk of developing sustained addiction to tobacco products. 

Epidemiology used the applicant’s analysis of national data as well as literature to examine the 

likelihood of use among youth. In 2021, data from NYTS showed that the prevalence of reported current 

ST use was 1.2% (95% CI: 0.8-1.6) for high school students and 0.6% (95% CI: 0.4-0.9) for middle school 

students. As noted above, NYTS data from 2021 cannot be directly compared to results from past years 

(2019 and 2020) (Park-Lee, Ren et al. 2021, Gentzke, Wang et al. 2022). NYTS 2021 data also showed 

that past 30-day use of any ST product was lower than use of electronic cigarettes, cigars, or cigarettes, 

equal to hookah, but higher than traditional pipe (Gentzke et al., 2022). Recent analyses of the 2020 

NYTS report a linear decrease in ST product use among high school students from 7.9% in 2011 to 3.1% 

in 2020 and among middle school students from 2.7% to 1.2% (Gentzke et al., 2020). These rates vary 

substantially by rurality with rural youth, who view ST use as normative and as a personal choice with 

social benefits, using ST at roughly twice the rate of urban youth (Buettner-Schmidt et al., 2019). 

Looking specifically at Copenhagen products, in the ALCS analysis of data from the National Survey on 

Drug Use and Health (NSDUH), Copenhagen (no sub-brand specified) was commonly used (no 

proportion provided) among youth ST users during 2002-2014. Contrarily, the applicant’s analysis of 

PATH Wave 1 Study data found that only 1.5% of youth ages 12-17 who reported using ST more than ten 

times in their lifetime and last used ST within the past 30 days used “Copenhagen Snuff” as the type of 

Copenhagen product usually or most recently used. However, when expanding the analysis to any 

Copenhagen product, consistent with NSDUH, FDA found that 40.8% reported Copenhagen as their 

usual or most recent brand used in Wave 1. This estimate was similar in Wave 5 with 38.3% of youth 

citing Copenhagen as their usual or most recently used brand. The discrepancy in the applicant’s analysis 

and FDA’s analysis is likely due to the way in which the applicant analyzed the data, specifically using 

only responses in which youth specified “Copenhagen Snuff” and excluding youth who responded that 

they used “Copenhagen” in general. In the context of PMSS, the applicant would need to ensure that 

the participants in their studies can reliably identify that they are using the proposed MRTP, which will 

have a new sub-brand name (i.e., Copenhagen Classic Snuff), as opposed to Copenhagen brand products 

overall. Moreover, the applicant will need to ensure that participants can distinguish between 

Copenhagen Classic Snuff and other sub-brands such as Copenhagen Snuff Fine Cut. This may be 

challenging in a national study such as PATH and may be more likely to occur in smaller, focused studies. 

Examining young adults, another vulnerable population, the applicant found that 1.9% of young adult 

(ages 18-24) current established ST users (defined as: “has ever used the product fairly regularly and 

now uses every day or some days”) used Copenhagen Snuff as their last brand used or usual brand, 

compared to 9.4% of adult established users ages 25 and older. However, when FDA ran internal 

analyses of PATH Wave 5 and examined all Copenhagen products, the trend was reversed; half of young 

adults (52.7%) reported Copenhagen as their most recent or usual brand as compared to a third of 

adults ages 25 and older (30.6%). This is notable in light of the new Tobacco 21 law because the 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 51 of 75 

Copenhagen brand now has a much larger market share among young adults not of legal age to 

purchase tobacco. 

While some studies have suggested that youth who use ST products may be more likely to subsequently 

initiate tobacco products that present higher levels of individual risk such as cigarettes (Haddock et al., 

2001; Severson, Forrester, & Biglan, 2007; Soneji et al., 2015; Tam et al., 2015; Tomar, 2003; Watkins, 

Glantz, & Chaffee, 2019), other studies in youth and young adults have found no association (O'Connor 

et al., 2005; Kozlowski et al., 2003; Timberlake, Huh, & Lakon, 2009). 

It is concerning that nearly 40% of youth and about half of young adults that used ST recently and have 

used more than 10 times in their life, reported Copenhagen as their usual or most recent brand in PATH 

Wave 5. Nevertheless, youth use of ST is quite low (1.3% in 2020) and has been decreasing for a decade 

(Gentzke et al., 2020) suggesting a likely low overall impact of an authorization on youth. As explained 

below, careful placement of advertising of the proposed MRTP to prevent exposure to youth and young 

adults under the age of 21 is warranted, as are stringent postmarket surveillance requirements of 

impacts to users under age 21 were the proposed MRTP to be authorized. 

3.4.2.2 Social Science 

The MRTPA did not contain any data for nonsmokers or former smokers regarding initiation. The 

applicant relied on evidence from its CCI, which was reviewed by Social Science. Results from the CCI 

study showed that non-users, including former users, never users, and young adult nonusers of tobacco 

products, had virtually no intentions to try nor use the proposed MRTP (Ms = 1.2-1.4; 1.2-1.4). The 

modified risk claim neither increased intentions to try nor use the proposed MRTP among these groups. 

In addition, evidence suggests youth initiation of ST is expected to be low (<2%) (Miech, 2016). However, 

these data are in the absence of marketing a product as lower risk. There is no direct evidence to 

determine how the proposed claim would affect youth non-users. FDA is aware of one published study 

evaluating the impact of a modified risk claim about snus on youth, which found that a modified risk 

claim impacted risk perceptions among youth and adults similarly but affected susceptibility to use the 

product only among adults (El-Touhky et al., 2018). Though this study did not examine the same 

modified risk claim nor MST, the ST sub-category of the proposed MRTP, it is still potentially informative. 

While the CCI data suggesting that non-users are unlikely to want to try the proposed MRTP are 

encouraging, given that lower risk perceptions can predict tobacco use initiation, and ST initiation, 

specifically (Chafee et al., 2019), it is possible that exposing youth and young adult non-tobacco users to 

the proposed MRTP could increase their risk of initiating use, especially if they are in an area with higher 

ST use in those groups (i.e., rural areas). 

In summary, the Epidemiology and Social Science reviews concluded that the MRTPA contained 

adequate information on the impact to non-users with respect to the following: 

• Epidemiologic literature showing relatively low use of ST amongst youth, though use is higher in 

rural youth, especially males 

• Intentions data suggesting very low intentions of use amongst non-users 

As TPL, I agree that in the current marketplace, there is not a large overall risk of non-users – including 

youth – initiating tobacco use using the proposed MRTP. Paired with the small group of smokers and 

dual users that may switch to the MRTP, there stands to be a modest population health benefit. 

However, given the association between risk perceptions and initiation there is a potential risk of any 

MRTP to youth and young adults. In addition, there is a larger risk of initiation for rural youth, especially 

males. In addition, the large (and increasing for youth) market share of Copenhagen products among 

youth and young adults supports a greater measure of caution. Accordingly, if authorized, the proposed 
 

MR0000108 Page 52 of 75 

MRTP marketing must be targeted to maximize exposure to intended users, and prevent exposure 

among unintended users, particularly youth and young adults under the age of 21. 

3.4.3 Population Modeling 

The applicant developed its own model, the ALCS Cohort Model, for population modeling to examine 

the total difference in all-cause mortality of a hypothetical cohort comparing a base scenario (i.e., 

current market conditions where there is no authorized MRTP) and a modified scenario (i.e., the 

proposed MRTP receives a modified risk granted order). Though validated for both sexes, the current 

MRTPA’s model only includes males, due to the historically low prevalence of ST use among women. 

3.4.3.1 Statistics 

Overall, the Statistics review assessed the modeling approach as a reasonable tool to determine the 

potential effect that authorization of the proposed MRTP would have on the population. No statistical 

concerns were identified regarding the step-by-step model development approach, nor the validation 

and programming code associated with the model. Inputs were calculated based on results of the CCI 

study. However, some limitations were identified. First, transition probabilities (e.g., initiation, 

switching, cessation, relapse) for both cigarettes and the proposed MRTP and their association with 

mortality rates are kept constant over the five-year modeling period. This likely obscures some changes 

that could occur in shorter periods, such as quitting and relapsing within a two-year period. Second, the 

Linked Mortality Analysis is based on a small number of deaths among ST users, which could lead to 

greater variability and bias in the estimates. Third, estimates of differences in tobacco use behaviors 

with the proposed MRTP from CCI study data were generally not statistically significant with very small 

differences, even though these estimates are used as model inputs. Fourth, the model did not account 

for users of other STs completely switching to or dual using with the proposed MRTP, which further 

underscored the need to receive additional information from the applicant regarding product 

characterization. Thus, while Statistics was comfortable with the modeling approach, there were 

concerns about the inputs used for the model. As with other population models, the outputs vary based 

on the inputs, and this application contained considerable uncertainty around the inputs. 

3.4.3.2 Epidemiology 

For a cohort of one million males, the applicant’s model determined that, by age 73, there would be 

1,120 more survivors with the proposed MRTP in the marketplace. The model found that the transition 

producing the greatest benefit was cigarette smokers switching to exclusive ST use, which led to 425 

more survivors. The model also found that non-smokers who initiate tobacco use using the proposed 

MRTP instead of smoking led to 393 additional survivors. The transition producing a significant 

detriment was cigarette smokers who would have otherwise quit smoking switching to ST use (63 fewer 

survivors). Based on CCI findings, the applicant estimated that initiation of MST use by never tobacco 

users would actually decrease by 5% with authorization of the product with the proposed modified risk 

claim because intentions to use and try the proposed MRTP decreased from pre- to post-test (nonsignificantly). This input led to a very small population health benefit (10 additional survivors). 

Epidemiology also noted that estimates of differences in tobacco use behaviors were derived from the 

CCI study, and data were generally not statistically significant, even though these estimates are used as 

model inputs. Given the small number of additional survivors relative to the uncertainty in the 

parameters used as inputs, it is possible that with more robust and certain parameters, the number of 

survivors could shift in either direction. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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With that caveat in mind, overall, Epidemiology noted an expected population health benefit from 

current cigarette smokers who would otherwise continue smoking switching to exclusive use of the 

proposed MRTP and from adult non-tobacco users who would otherwise initiate cigarette smoking 

instead initiating use of the proposed MRTP. Though there would be some harm from non-users who 

would not have initiated now using the proposed MRTP and smokers who would have quit switching to 

the proposed MRTP, the applicant estimated that authorization of the product with the proposed 

modified risk claim would result in 7,500 additional survivors in the U.S. native-born male population 

after a follow-up period of 60 years. 

In summary, the Epidemiology and Statistics review concluded that the MRTPA contained adequate 

population modeling with respect to the following: 

• The step-by-step model development approach and the validation and programming code 

• The model itself 

• The finding that the proposed MRTP would result in modest population health benefit 

However, both disciplines noted the concerns around the inputs used and recognize that a model is only 

as good as the inputs. 

As TPL, I agree with the conclusion that the population modeling tools and approach were appropriate. 

However, a significant limitation is that many behavioral inputs into the model were derived from nonstatistically significant findings in the CCI study, which led to considerable uncertainty regarding the 

model and its findings. While the applicant’s population health model indicates that the proposed MRTP 

would yield modest health benefits for the population, the results of the population model are 

dependent on the behavioral inputs and would therefore differ (and could even show a net negative 

impact) if the behavioral inputs were different. Because of this, I assigned minimal weight to the 

population model, and instead relied on other findings such as consumer understanding of the claim in 

the CCI study and the broader literature on tobacco use behavior to reach conclusions about the 

population health impact. 

3.4.4 Conclusions: Impact to the Population 

Currently, ST use in the U.S. is low, but dual use with cigarettes among the product class is substantial. 

Patterns of switching indicate that the likelihood of completely switching from either exclusive cigarette 

or dual use to exclusive ST remains quite low. Though the applicant’s CCI study corroborated the current 

patterns by demonstrating low to moderate levels of interest in using the proposed MRTP among those 

who stand to benefit (i.e., smokers and dual users), this must be examined in the context of 

misperceptions about the relative harms of ST relative to cigarettes also shown in the CCI study. In 

addition, although it is unlikely that a one-time exposure would significantly change perceptions and 

then intentions in general, a real-world, targeted marketing campaign is likely to repeatedly expose 

these users to the message, which over time, further increases the likelihood they would switch 

completely. 

The CCI study demonstrated that the level of interest in using the proposed MRTP among those who 

stand to benefit most—current smokers—is relatively low, and the addition of the modified risk claim 

did not affect this. On the other hand, current dual users of an ST product and cigarettes expressed 

more interest in the product. As might be expected, these results suggest greater appeal to current 

users already using a product in the category of the proposed MRTP, rather than the average smoker. 

Certainly, ST products do not universally appeal to users of other tobacco products. Accordingly, it is 
 

MR0000108 Page 54 of 75 

likely that this proposed MRTP would appeal to a minority of smokers—those who are open to the 

category of ST. Appealing to that group of smokers and persuading them to completely switch to a less 

harmful alternative presents an opportunity to benefit population health. 

In examining whether the proposed MRTP provides a strong enough subjective effect and sensory 

experience to encourage complete switching, I found that the abuse liability for the proposed MRTP is 

greater than use of FDA-approved cessation aids, but lower than that associated with cigarette smoking. 

This suggests that for those tobacco users who wish to reduce their tobacco-related risks, but do not 

wish or are not able to quit altogether, the proposed MRTP is a viable alternative. 

The group that the proposed MRTP may be most likely to impact is current dual users who could reduce 

their individual risk by switching completely. It is notable that current dual-use Copenhagen users 

appear to consume more of their Copenhagen product daily and smoke fewer cigarettes daily than do 

dual users of other ST products, suggesting that dual users of the applicant’s products may have an 

easier time with switching to exclusive use of the proposed MRTP (since the balance of the use of the 

two products may be weighted more toward Copenhagen use) than dual users of other ST products. 

Overall, by enabling people who smoke to switch completely, the proposed MRTP would benefit 

population health. Taken together, these findings provide support that the proposed MRTP would 

increase exclusive use of Copenhagen Classic Snuff among adult tobacco consumers who would benefit 

from complete switching, including both smokers and dual users of cigarettes and ST. As noted earlier, 

likewise, the applicant’s population health model indicates modest health benefits for the population. 

However, due to behavioral inputs into the model from non-significant findings in the CCI study, I 

assigned minimal weight to this evidence in my decision making. 

Regarding the impact to non-users, national estimates suggest that use of ST among youth is low (1.3%) 

and is declining over time and that the likelihood of initiating on an ST product is low. However, this 

varies by rurality with rural youth use of ST at roughly twice the rate of urban youth (Buettner-Schmidt 

et al., 2019). While Copenhagen appears to be perhaps the most popular brand among youth who use 

ST, the applicant’s CCI study showed that non-users (including young adults) had virtually no intentions 

to try or use the proposed MRTP. Overall, this suggests a low risk for vulnerable groups in granting an 

MRTP marketing authorization. However, given the association between risk perceptions and initiation, 

and ST initiation, specifically (Chafee et al., 2019), there is a potential risk of any MRTP to youth. 

Accordingly, if authorized, MRTP marketing must be targeted to maximize exposure to intended users 

and prevent exposure among unintended users, particularly youth, especially given the popularity of the 

applicant’s brand among youth. 

Overall, as the TPL, I find that the evidence on likelihood of use suggests that the proposed MRTP will 

benefit population health. 

4. Environmental Impact 

A finding of no significant impact (FONSI) was signed by Luis Valerio, PhD, ATS, on October 25, 2022. The 

FONSI was supported by an environmental assessment prepared by FDA on October 24, 2022. 

5. Conclusions and Recommendation 

5.1 Statutory Requirements for Authorization 

On March 20, 2018, on behalf of USSTC, ALCS submitted an MRTPA for its Copenhagen Classic Snuff 

tobacco product (GF1200194). 
 

 

 

 

 

 

 

 

MR0000108 Page 55 of 75 

The application requested authorization under Section 911(g)(1) of the FD&C Act to market the product 

with the following risk modification claim: “IF YOU SMOKE, CONSIDER THIS: Switching completely to this 

product from cigarettes reduces risk of lung cancer.” 

For FDA to issue a risk modification order under Section 911(g)(1) of the FD&C Act, FDA must determine 

that the applicant has demonstrated that the proposed modified risk tobacco product, as it is 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 taking into account both users of tobacco 

products and persons who do not currently use tobacco products. 

In accordance with Section 911(g)(4) of the FD&C Act, in evaluating the benefit to health of individuals 

and of the population as a whole under Section 911(g)(1) of the FD&C Act, FDA must take into account: 

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

• 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. 

Furthermore, FDA requires that the advertising and labeling of an 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 diseases and health-related 

conditions associated with the use of tobacco products (section 911(h)(1) of the FD&C Act). 

5.2 Conclusions: Scientific Evidence 

My review of the scientific evidence integrated various threads regarding the proposed MRTP and its 

potential effects on health and tobacco use behavior. I undertook this assessment to determine whether 

the MRTPA met the statutory requirements listed above. 

Based on the original MRTPA (MR0000192), I recommended sending a deficiency letter to the applicant 

to address insufficient information across eight deficiencies identified by the disciplines of Engineering, 

Chemistry, Toxicology. This letter was sent on March 26, 2021. The deficiencies identified by 

Engineering, Chemistry, and Toxicology requested information needed to adequately characterize the 

product and determine whether it could be manufactured consistently in order to draw final conclusions 

about the individual health risks of the product (including risks relative to other ST products) and, 

ultimately, the benefit to the population as a whole. 

(b) (4)

(b) 

(4)

In response to the Deficiency Letter, in MR0000199, the applicant addressed all eight deficiencies. (b) (4)
MR0000108 Page 56 of 75 

Based on its review of this 

information, Social Science concluded that 

. As 

(b) (4)

(b) (4)

 

 

 

 

 

 

 

 

 

 

 

 

mentioned earlier, the extent to which consumers understand that the proposed MRTP must be used 

exclusively and that dual users must switch completely should be monitored in postmarket surveillance. 

Deficiencies #2-7 requested information to aid in FDA’s determination of whether the applicant can 

manufacture its product consistently and to allow full product characterization to be able to make 

definitive conclusions regarding our assessment of the risk from the proposed MRTP compared to the 

risk from other ST products. In response, the applicant provided the requested test data; manufacturing 

and processing components such as steps, controls, and SOPs; manufacturing and testing protocols; 

ingredient information; method validation summaries; and HPHC information. The applicant’s responses 

addressed the deficiencies in an acceptable manner to Engineering, Chemistry, and Toxicology. As TPL, I 

agree with the conclusions of Engineering, Chemistry, and Toxicology regarding the responses to these 

deficiencies, and find that the product can be manufactured consistently and can now be fully 

characterized. Therefore, the HPHC data initially submitted by the company is valid and can be analyzed 

as was submitted and a definitive assessment of risk of the proposed MRTP relative to other ST products 

could be undertaken. 

Deficiency #8 requested that the applicant provide scientific evidence and rationale about how exposure 

to HPHCs in ST may impact the population of tobacco users that may completely switch to or begin to 

dual use their current product(s) with the proposed MRTP, particularly in comparison to other ST 

products. In MR0000199, the applicant stated that because the vast majority of the marketplace was 

MST, the appropriate comparison for HPHCs was other MST products. Epidemiology confirmed this 

assertion and therefore, Chemistry and Toxicology determined this comparison was a reasonable 

approach and compared HPHCs to levels in other MST products. Therefore, the portion of the deficiency 

related to dry snuff, loose leaf, and Swedish snus is resolved. As TPL, I agree with this approach to 

compare the proposed MRTP to the MST category. 

Toxicology used an offsetting analysis that focuses on HPHC increases and decreases that are analytically 

non-equivalent between two tobacco products. Through this approach, Toxicology determined that 

higher levels of some HPHCs relative to the MST category were offset by the lower levels of other 

HPHCs. Specifically, utilizing median HPHC levels as recommended by Statistics, lower levels of NNK and 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 57 of 75 

free nicotine offset the higher levels of BaP and cadmium from a carcinogenic perspective. Further, 

Toxicology determined that non-cancer toxicities resulting from potential exposure to higher levels of 

BaP and cadmium as compared to other MST products were not a concern due to values remaining 

below the reference doses established by the Environmental Protection Agency (EPA). Therefore, 

Toxicology felt this deficiency was appropriately addressed and had no further toxicological concerns. 

As TPL, I concur that all deficiencies have been adequately addressed by the applicant. With these 

deficiencies addressed, I was able to fully assess the individual health risks, and therefore, the benefit to 

the population as a whole. 

In examining claim substantiation and the risks to individual health of the proposed MRTP, the applicant 

used data from the ST product category and bridged to the proposed MRTP, which is an acceptable 

approach given the robust body of longitudinal epidemiologic literature on STs and the applicant’s 

market share during the time period of these studies. When comparing ST use to cigarette smoking, ST 

use poses lower risks of certain health outcomes. Specifically, those who completely switched from 

cigarettes to ST had generally lower risks for lung cancer, heart disease, oral cancer, and stroke. 

FDA also examined the proposed MRTP compared to use of other tobacco products, including other ST 

products, and to never use. In comparison to never use of tobacco, use of ST exposes users to HPHCs 

and poses health risks. Based on authoritative reviews and meta-analyses, ST has been demonstrated to 

be a cause of oral, esophageal, and pancreatic cancer world-wide. In addition, numerous studies have 

shown that ST use can cause addiction as well as reproductive and developmental toxicities. 

Overall, I find that the claim has been substantiated: switching completely to the proposed MRTP from 

cigarettes will confer a lower risk of lung cancer. This is also consistent with TPSAC’s evaluation of the 

evidence. The evidence also suggests that switching completely to the proposed MRTP would lower 

HPHC exposure as well as reduce risk of morbidity and mortality for several other diseases relative to 

smoking. 

In examining consumer understanding, the CCI study, although limited in several ways, provided basic 

evidence to support appropriate consumer understanding of the proposed modified risk claim and its 

significance in the context of total health. After seeing the advertisement with the modified risk claim, 

participants understood that using the proposed MRTP is risky to health, and that someone who only 

uses the proposed MRTP daily would likely experience a negative impact to their health. Participants 

also understood that the absolute risk of developing lung cancer is lower, but not eliminated, in a person 

who exclusively uses the proposed MRTP daily than in a person who smokes cigarettes daily. Finally, 

participants understood that using the proposed MRTP is not less risky than using other MST products, 

and that the risk of using the proposed MRTP is greater than that of using NRT, quitting all tobacco, and 

never using tobacco products. Although the CCI study findings in general suggest that a one-time 

exposure to the claim did not significantly affect risk perceptions, and I would have liked to have seen 

multiple exposures in the study and an assessment of the dose-response relationship, it is likely the 

findings do not reflect the full real-world impact of the claim once consumers are exposed to the claim 

repeatedly and over time with credible and substantiated information; thus, these findings likely 

underestimate the potential impact of the claim on consumers’ perceptions. 

The limitation that the study did not assess participants’ understanding that a user must completely 

switch to the product (from cigarettes) in order to reap the benefit is mitigated by the fact that the claim 

itself directs potential users that they can reduce their risk by “switching completely.” Still, the extent to 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 58 of 75 

which consumers understand that the proposed MRTP must be used exclusively and that dual users 

must switch completely should be monitored in postmarket surveillance. 

In examining the likelihood of use and impacts to the population, Epidemiology examined current use 

behavior, patterns of use, intentions to use, and modeling. Currently, ST use in the U.S. is low, but dual 

use with cigarettes among the product class is substantial. Patterns of switching indicate that the 

likelihood of completely switching from either exclusive cigarette or dual use to exclusive ST remains 

quite low. Though the applicant’s CCI study corroborated the current patterns by demonstrating low to 

moderate levels of interest in using the proposed MRTP among those who stand to benefit (i.e., smokers 

and dual users), this must be examined in the context of misperceptions about the relative harms of ST 

relative to cigarettes also shown in the CCI study, as noted above. With the repeated exposure to the 

modified risk claim that would occur if the proposed MRTP were to be authorized, that may lead to the 

desired effect: moving users of combustible products to a product with modified risk. 

The CCI study demonstrated that the level of interest in using the proposed MRTP among those who 

stand to benefit most—current smokers—is relatively low, and the addition of a one-time exposure to 

the modified risk claim did not affect this. On the other hand, current dual users of an ST product and 

cigarettes expressed more interest in the product. As might be expected, these results suggest greater 

appeal to current users already using a product in the category of the proposed MRTP, rather than the 

average smoker. I note that because these are group means, they do not reflect variability within the 

group; this is particularly relevant when considering a consumer product about which people will 

naturally vary widely in terms of interest. Certainly, ST products do not universally appeal to users of 

other tobacco products. Accordingly, it is likely that the MRTP would appeal to a minority of smokers— 

those who are open to the category of ST. In examining whether the proposed MRTP provides a strong 

enough subjective effect and sensory experience to encourage complete switching, BCP found that the 

abuse liability for the proposed MRTP is greater than use of FDA-approved cessation aids, but lower 

than that associated with cigarette smoking. This suggests that for those tobacco users who wish to 

reduce their tobacco-related risks, but do not wish or are not able to quit altogether, the proposed 

MRTP is a viable alternative. With targeted marketing toward cigarette smokers of brands of the 

applicant’s parent company, there is a large segment of current smokers who may receive direct 

marketing materials regarding the proposed MRTP, which may present them with new information 

about the relative lung cancer risk. Appealing to that group of smokers and persuading them to 

completely switch to a less harmful alternative presents an opportunity to benefit population health. 

As mentioned previously, the group that the proposed MRTP may be most likely to impact is current 

dual users who could reduce their individual risk by quitting cigarettes but continuing to use the 

proposed MRTP, thereby switching completely. Perhaps unsurprisingly, current dual users of smokeless 

products reported the highest mean levels of intentions to use the product. I expect that the MRTP will 

influence some proportion of these users to stop smoking and use the product exclusively, which would 

significantly reduce their individual risk and help benefit the population health. 

(b) (4)

Given the brand’s 

market share and the over dual users of Copenhagen, this is a particularly ripe population who 

would benefit from the proposed MRTP. In addition, it is notable that dual-use Copenhagen users 

consume more of their Copenhagen product daily and smoke fewer cigarettes daily than do dual users 

of other ST products, suggesting that dual users of the applicant’s products may have an easier time 

switching to exclusive use of the proposed MRTP as the balance of the use of the two products may be 

weighted more toward Copenhagen use than dual users of other ST products. 

Regarding the impact to non-users, specifically to youth, national estimates suggest that use of ST 

among youth is low (2.3%) and is declining over time and that the likelihood of youth initiating tobacco 
 

 

MR0000108 Page 59 of 75 

use with an ST product is low. However, this varies by rurality with rural youth use of ST at roughly twice 

the rate of urban youth (Buettner-Schmidt et al., 2019), a concern substantial enough that the FDA’s 

Real Cost Campaign has a series of ads targeted at rural youth use of ST with the tag line “smokeless 

doesn’t mean harmless.” While Copenhagen appears to be perhaps the most popular brand among 

youth who use ST, the applicant’s CCI study, though it did not include youth, showed that non-users 

(including young adults) had virtually no intentions to try or use the proposed MRTP. However, given the 

association between risk perceptions and initiation, there is a potential risk of any MRTP to youth. 

Accordingly, if authorized, MRTP marketing should be targeted to maximize exposure to intended users, 

and prevent exposure among youth, especially given the popularity of the applicant’s brand among 

youth ST users. 

Taken together, these findings provide support that the proposed MRTP would increase exclusive use of 

Copenhagen Classic Snuff among adult tobacco consumers who would benefit from complete switching, 

including both smokers and dual users of cigarette and ST products while posing a low risk of initiation 

to non-users of tobacco, including youth. Overall, by enabling people who smoke to switch completely, 

the proposed MRTP would benefit population health 

In conclusion, I conducted a thorough scientific review of the information contained in the MRTPA, and 

considered the recommendations from TPSAC, comments, data, and information submitted to FDA by 

interested persons, and other scientific information identified by the agency from other sources. After 

examining the totality of evidence across scientific reviews, I found that the proposed modified risk 

claim is scientifically accurate: smokers who switch completely to the proposed MRTP will have a lower 

risk of lung cancer. Furthermore, the data support a benefit to population health through reductions in 

overall morbidity and mortality associated with the use of the proposed MRTP, relative to cigarette 

smoking, that would not be offset by nonusers initiating with the product nor users of other ST products 

switching to the proposed MRTP. Although the CCI study findings suggest that a one-time exposure to 

the claim did not significantly affect risk perceptions, this is likely due to widespread and persistent 

misperceptions of the product as more harmful than it is relative to cigarettes and the several study 

design limitations. Importantly, the applicant did demonstrate that consumers have an appropriate 

understanding of the MRTP as not harmless and more harmful than NRT or quitting. An authorization of 

the proposed MRTP would allow for multiple exposures to credible and substantiated information over 

time in real-world settings. This will allow those tobacco users most likely to switch completely to 

receive information that will help combat those misperceptions and enable them to choose an MRTP. 

5.3 Recommendation for the Risk Modification Order Request 

With respect to the risk modification order request, I find that the proposed MRTP, 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, taking into account both users of tobacco 

products and persons who do not currently use tobacco products. Therefore, I recommend issuing a 

Modified Risk Granted Order (MRGO) to the applicant. 

Section 911(h)(4) of the FD&C Act requires an MRTP order to be for a specified time period. I 

recommend authorization for a period of five years. Although this review has found that the product will 

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

of how the product is actually used by consumers. Therefore, monitoring use of the product that is the 

subject of this application in terms of uptake, dual use, and complete switching is required. Postmarket 

surveillance and studies (PMSS) (refer to Appendix 1 for requirements to be conveyed to the applicant) 

must include an assessment of MRTP users’ behavior and understanding at multiple time points as well 

as a computational model using data from users’ behaviors as inputs to demonstrate a continued 
 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 60 of 75 

benefit to population health. A five-year period is a reasonable amount of time for trends in use 

behavior to emerge to evaluate in postmarket surveillance and studies and assess whether the standard 

continues to be met and whether the order should be renewed. 

Section 911(h)(5) of the FD&C Act enables the Secretary to require that an MRTP, for which an applicant 

obtained an order under subsection (g)(1), comply with requirements relating to the product’s 

advertising and promotion. Under this Section, I recommend that the MRGO include the advertising and 

promotion requirements listed in Appendix 2, including requirements related to (i) annual reporting of 

certain advertising and marketing information; (ii) notifications related to the product’s labeling, 

advertising, and marketing; and (iii) additional conditions for marketing. Based on my review and a 

consult by the Office of Health Communication and Education, these requirements are necessary to my 

conclusion that permitting the marketing of the proposed MRTP will benefit the population as a whole. 

Regarding the reporting of certain advertising and marketing information in point (i) above, I considered 

whether to recommend requiring the applicant to submit their reports to FDA annually vs. more 

frequently, such as every 6 months. Several factors led me to conclude that annual reports would be 

sufficient. The proposed MRTP is a pre-existing tobacco product that has been on the U.S. market for 

many decades, being granted pre-existing status by FDA in 2012. It is a traditional loose MST product 

with an established user base and brand, no characterizing flavor, and no evidence of novel features 

that appear likely to rapidly generate youth interest in the product. Based on my evaluation, annual 

reporting would be appropriate for the proposed MRTP. 
 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 61 of 75 

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32. Kotlyar M, Mendoza-Baumgart MI, Li Z, et al. Nicotine pharmacokinetics and subjective effects of 

three potential reduced exposure products, moist snuff and nicotine lozenge. Tob Control. 

2007;16(2),138-42. 

33. Kozlowski LT, O'Connor RJ, Edwards BQ, Flaherty BP. Most smokeless tobacco use is not a causal 

gateway to cigarettes: using order of product use to evaluate causation in a national US sample. 

Addiction. 2003;98:1077-85. 
 

 

 

 

 

 

 

 

 

 

 

 

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34. Lee PN, Hamling J. Systematic review of the relation between smokeless tobacco and cancer in 

Europe and North America. BMC Med. 2009;7:36. 

35. Marano KM, Kathman SJ, Jones BA, Nordskog BK, Brown BG, Borgerding MF. Study of cardiovascular 

disease biomarkers among tobacco consumers. Part 3: evaluation and comparison with the US 

National Health and Nutrition Examination Survey. Inhal Toxicol, 2015;27(3),167-73. 

36. Nordskog BK, Brown BG, Marano KM, Campell LR, Jones BA, Borgerding MF. Study of cardiovascular 

disease biomarkers among tobacco consumers, part 2: biomarkers of biological effect. Inhal Toxicol. 

2015;27(3),157-66. 

37. O'Connor RJ, Kozlowski LT, Flaherty BP, Edwards BQ. Most smokeless tobacco use does not cause 

cigarette smoking: results from the 2000 National Household Survey on Drug Abuse. Addict Behav. 

2005;30:325-36. 

38. Park-Lee, E., C. Ren, M. D. Sawdey, A. S. Gentzke, M. Cornelius, A. Jamal and K. A. Cullen (2021). 

"Notes from the Field: E-Cigarette Use Among Middle and High School Students - National Youth 

Tobacco Survey, United States, 2021." MMWR Morb Mortal Wkly Rep 70(39): 1387-1389. 

39. Popova L, Ling PM. Nonsmokers’ responses to new warning labels on smokeless tobacco and 

electronic cigarettes: an experimental study. BMC Public Health, 2014;14:997. 

40. Prasad GL, Jones BA, Chen P, Gregg EO. A cross-sectional study of biomarkers of exposure and effect 

in smokers and moist snuff consumers. Clin Chem Lab Med. 2016;54(4):633-42. 

41. Rostron BL, Chang CM, van Bemmel DM, Xia Y, Blount BC. Nicotine and toxicant exposure among US 

smokeless tobacco users: results from 1999 to 2012 National Health and Nutrition Examination 

Survey data. Cancer Epidemiol Biomarkers Prev. 2015;24(12):1829-37. 

42. Rostron BL, Chang JT, Anic GM, Tanwar M, Chang CM, Corey CG. Smokeless tobacco use and 

circulatory disease risk: a systematic review and meta-analysis. Open Heart. 2018;5(2):e000846. 

43. Severson HH, Forrester KK, Biglan A. Use of smokeless tobacco is a risk factor for cigarette smoking', 

Nicotine Tob Res. 2007;9:1331-7. 

44. Soneji S, Sargent JD, Tanski SE, Primack BA. Associations between initial water pipe tobacco smoking 

and snus use and subsequent cigarette smoking: results from a longitudinal study of US adolescents 

and young adults. JAMA Pediatr. 2015;169:129-36. 

45. Tam J, Day HR, Rostron BL, Apelberg BJ. A systematic review of transitions between cigarette and 

smokeless tobacco product use in the United States. BMC Public Health. 2015;15:258. 

46. Timberlake DS, Huh J, Lakon CM. Use of propensity score matching in evaluating smokeless tobacco 

as a gateway to smoking. Nicotine Tob Res. 2009;11:455-62. 

47. Timberlake DS, Nikitin D, Johnson NJ, Altekruse SF. A longitudinal study of smokeless tobacco use 

and mortality in the United States. Int J Cancer. 2017;141:264-70. 

48. Thun MJ, Carter BD, Feskanich D, Freedman ND, Prentice R, Lopez AD, Hartge P, Gapstur SM. 50-

year trends in smoking-related mortality in the United States. N Engl J Med. 2013;368:351-64. 

49. Tomar SL. Is use of smokeless tobacco a risk factor for cigarette smoking? The U.S. experience. 

Nicotine Tob Res. 2003;5:561-9. 

50. U.S. Department of Health and Human Services (US DHHS). The health consequences of smoking— 

50 years of progress: A report of the Surgeon General. Rockville, MD: US DHHS; 2014. 

51. U.S. Food and Drug Administration (US FDA). Evaluation and Definition of Potentially Hazardous 

Foods-Chapter 3: Factors that Influence Microbial Growth. Silver Spring, MD: US FDA; 2013. 

52. Vaddi HK, Ho PC, Chan SY. Terpenes in propylene glycol as skin-penetration enhancers: permeation 

and partition of haloperidol, Fourier transform infrared spectroscopy, and differential scanning 

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53. Wackowski OA, Ray AE, Stapleton JL. Smokers' perceptions of risks and harm from snus relative to 

cigarettes: A latent profile analysis study. Addict Behav. 2019;91:171-174. 

doi:10.1016/j.addbeh.2018.11.011 

54. Wang TW, Gentzke A, Sharapova S, Cullen KA, Ambrose BK, Jamal A. Tobacco product use among 

middle and high school students - United States, 2011-2017. MMWR Morb Mortal Wkly Rep. 

2018;67:629-33. 

55. Watkins SL, Glantz SA, Chaffee BW. Association of noncigarette tobacco product use with future 

cigarette smoking among youth in the Population Assessment of Tobacco and Health (PATH) Study, 

2013-2015. JAMA Pediatr, 2018;172:181-7. 

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preterm birth. BJOG. 2010;117:1005-10. 

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7. Appendices 

Appendix 1: Required Postmarket Surveillance and Studies (PMSS) 

Under Section 911(i)(1) of the FD&C Act, FDA must require postmarket surveillance and studies for any 

product for which an applicant received an order under 911(g)(1) in order to: “...determine the impact of 

the order issuance on consumer perception, behavior, and health, to enable the Secretary to review the 

accuracy of the determinations upon which the order was based, and to provide information that the 

Secretary determines is otherwise necessary regarding the use or health risks involving the tobacco 

product.” 

I. PMSS Content 

MRTP Use Behavior and Consumer Understanding and Perception 

After receiving authorization, the determination of whether the tobacco product that is the subject of 

this order (hereinafter, the MRTP), as actually used by consumers, continues to benefit the health of the 

population as a whole is likely to be driven by use behavior. Therefore, monitoring use of the MRTP in 

terms of uptake, dual use, and complete switching is required. In particular, your PMSS must assess the 

extent to which new users of the MRTP were non-users of tobacco products, smokers, or other tobacco 

product users before initiating the MRTP, and the extent to which such new users of the MRTP become 

exclusive users or dual users with cigarettes or other tobacco products, including other smokeless 

tobacco (ST) products, over time. Relatedly, such surveillance must include an ongoing assessment of 

consumers’ understanding of the claim and perceptions of the MRTP. In particular, PMSS must assess 

the extent to which users of the MRTP understand that, to reduce their risk of lung cancer as described 

in the modified risk claim, they must switch from smoking cigarettes to using the MRTP exclusively. To 

adequately assess these impacts, you must conduct PMSS that include assessing users’ behavior and 

consumer understanding at multiple time points. 

In addition, FDA has determined that assessing the impact of your MRTP order on uptake of the product 

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 major metropolitan areas and channels where the 

MRTP is 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 MRTP by quarter since the granting of your modified risk 

granted order (for the initial reporting period) or the previous reporting period (for all reports 

that follow), including, total U.S. sales and distribution reported in dollars and units, and broken 

down by major metropolitan areas and channels where the product was 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 

growth rate (percent change) in total U.S. sales and distribution of the MRTP since this Order 

was issued. 

• All Universal Product Codes (UPCs) used for the MRTP when selling or distributing it in the U.S. 
 

 

 

 

 

 

 

 

 

 

 

 

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MRTP Use and Health Risk – Adverse Experiences 

In order for FDA to determine whether the MRTP, as actually used by consumers, continues to benefit 

the health of the population as a whole, your PMSS must include ongoing surveillance of all adverse 

experiences associated with the use of the MRTP. 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. Your PMSS protocols must include procedures for monitoring and analyzing adverse experiences 

and your annual PMSS report must include: 

• A summary of reported adverse experiences for the tobacco product, which includes a listing of 

all 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 

product including nature, frequency, and potential aggravating factors. 

For purposes of this reporting under this order, serious adverse experience means an adverse experience 

that results in any of the following outcomes: 

• Death; 

• A life-threatening condition or illness; 

• 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 

• 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 under this order, 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 MRTPA (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. 

Surveillance of New Research Study Findings on the MRTP and Consumer Perception, Behavior, or Health 

In order for FDA to determine whether the MRTP, as actually used by consumers, continues to benefit 

the health of the population as a whole, your PMSS must include surveillance of new research study 

information about the MRTP and consumer perception, behavior, or health. In particular, your PMSS 

protocol must include procedures for monitoring and assessing findings both in your own studies (i.e., 
 

 

 

 

 

 

 

 

 

 

 

 

 

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studies conducted by you or on your behalf) and in publications including any new scientific data 

(published or otherwise) regarding the MRTP and consumer perception, behavior, or health. Your 

annual PMSS report must include: 

• A summary of significant findings about the tobacco product from research studies conducted 

by you or on your behalf, whether or not such studies were specifically required under this 

order. 

• A summary of significant findings in publications not previously reported and full copies of the 

articles. This must include any new scientific data (published or otherwise) on the MRTP and 

consumer perception, behavior, or health. 

Modeling the Impact of the MRTP on Population Health 

In order for FDA to determine whether the MRTP continues to benefit the health of the population as a 

whole, your PMSS must include computational modeling of the impact of the MRTP on population 

health. Such modeling must incorporate data and information collected through PMSS, including the 

percentage of former smokers who start using the MRTP; the percentage of current smokers who start 

using the MRTP and become dual users; the percentage of current smokers who switch completely to 

the MRTP; the percentage of youth and young adults below the federal minimum age of sale who start 

using the MRTP; the percentage of individuals who start using the MRTP and then initiate or re-initiate 

combusted cigarette smoking; the percentage of other tobacco product users, including a specific 

breakout for other ST products, who start using the MRTP and become dual users; and the percentage 

of other tobacco product users, including a specific breakout for other ST products, who switch 

completely to the MRTP. Postmarket modeling must incorporate the latest information on acute and 

long-term health effects of using the MRTP relative to 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 MRTP 

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

II. Submitting PMSS Protocols and Reports 

Within 30 days of receiving this notice, you must submit complete protocols for your PMSS as required 

under section 911(i)(2) of the FD&C Act. Label your submission clearly as a “PMSS Protocol,” and 

reference your MRTPA Submission Tracking Number (STN). 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 will 

determine 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 

the data or other information that FDA designates as necessary to protect public health, pursuant to 

section 911(i)(2) of the FD&C Act. FDA will notify you of and provide opportunities to address, any 
 

 

 

 

 

 

 

 

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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 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, and report 

writing. If you deviate from these timelines, we request that you report the deviation within 30 days to 

FDA. 

Section 911(i) of the FD&C Act requires that the results of PMSS be submitted on an annual basis. These 

reports must be identified as “PMSS Report” and reference the MRTPA STN 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 agreed upon 

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. 
MR0000108 Page 69 of 75 

Appendix 2: Advertising and Promotion Requirements 

I. Recordkeeping and Retention 

Under section 911(h)(5) of the FD&C Act, these risk modification orders require you to establish and 

maintain the following records: 

• Records pertaining to the product’s labeling, advertising, marketing, and/or promotion – 

whether conducted by you, on your behalf, or at your direction – including: 

o Specimens of all labeling (including all labeling variations, such as those reflecting different 

required warnings), labels, inserts/onserts, instructions, and other accompanying 

information; 

o Copies of all advertising, marketing, and/or promotional materials published, disseminated 

to consumers, or for use in engaging or communicating with consumers; 

o Copies of any formative research studies conducted among any audiences in the formation 

of the labeling, advertising, marketing, and/or promotional materials, including qualitative 

and quantitative research studies used to determine message effectiveness, consumer 

knowledge, attitudes, beliefs, intentions, and behaviors toward using the product, and 

including copies of the stimuli used in testing; 

o Copies of any consumer evaluation research studies conducted among any audiences to 

determine the effectiveness of labeling, advertising, marketing, and/or promotional 

materials and any shifts in consumer knowledge, attitudes, beliefs, intentions, and behaviors 

toward using the product, and including copies of the stimuli used in testing; 

o Copies of any contractual agreements regarding the creation and/or dissemination of the 

product’s labeling, advertising, marketing, and/or promotional materials, including for 

example, in print media, online or through digital platforms (e.g., social media and mobile 

applications), such as influencers, bloggers, and ambassadors, on your behalf, or at your 

direction; 

o Copies of all advertising and marketing plans, including strategic creative briefs and paid 

media plans, by channel and by product, and the dollar amount(s) and flighting of such 

plans, by channel and by product, including any: 

 Use of competent and reliable data sources, methodologies, and technologies to 

establish, maintain, and monitor highly targeted advertising and marketing plans and 

media buys; 

 Targeting of specific adult audiences by age-range(s), including young adult audiences, 

ages 21-24, and other demographic and/or psychographic characteristics that reflect 

your intended target audience; 

 With respect to individuals under the federal minimum age of sale of tobacco products, 

actions taken to restrict youth-access and limit youth-exposure to the product’s 

labeling, advertising, marketing, and/or promotion; 

 Use of owned, shared, and/or paid social media to create labeling for, advertise, market 

and/or promote the products; 

 Use of partners, influencers, bloggers, and/or brand ambassadors to create labeling for, 

advertise, market, and/or promote the product; 

 Consumer engagements – whether conducted by you, on your behalf, or at your 

direction – including events at which the product was demonstrated and how access will 

be restricted to individuals at or above the federal minimum age of sale of tobacco 

products; or 

 Use of public-relations or other communications outreach to create labeling for, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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advertise, market, and/or promote the product; 

o Copies of all records pertaining to media tracking and optimization, by channel, by product, 

and by audience demographics (e.g., age, gender, race/ethnicity, geographic region), and all 

post-launch delivery-verification reports submitted to you from an accredited source, by 

channel, by product, and by audience demographics; and 

o Policies and procedures for real-time digital media monitoring to identify, correct, and 

prevent delivery of advertising impressions to individuals under the federal minimum age of 

sale of tobacco products, including documentation of such monitoring activities and 

implementation of corrective and preventive measures. 

II. Annual Reporting 

Under section 911(h)(5) of the FD&C Act, this order requires that you submit the following reports to 

FDA on an annual basis, beginning twelve months from the date of this order. For each twelve-month 

reporting period, these annual reports must include: 

• A cover letter that includes the following text in your subject line: ANNUAL REPORT for 

MR0000108. The cover letter should include the STN, static product ID if applicable, and 

corresponding tobacco product name, applicant name, date of report, and reporting period. 

• Records pertaining to the product’s labeling, advertising, marketing, and/or promotion – 

whether conducted by you, on your behalf, or at your direction – including: 

o A summary of all formative research studies conducted among any audiences in the 

formation of new labeling, advertising, marketing, and/or promotional materials, not 

previously submitted, including qualitative and quantitative research studies used to 

determine message effectiveness, consumer knowledge, attitudes, beliefs, intentions, and 

behaviors toward using the product, and including the findings of these studies and copies 

of the stimuli used in testing; 

o A summary of all consumer evaluation research studies conducted among any audiences, 

not previously submitted, to determine the effectiveness of labeling, advertising, marketing, 

and/or promotional materials and shifts in consumer knowledge, attitudes, beliefs, 

intentions, and behaviors toward using the product, and including the findings of these 

studies and copies of the stimuli used in testing; and 

o A summary of the creation and dissemination of the product’s labeling, advertising, 

marketing, and/or promotional materials including a list of all entities involved and a 

description of their involvement, including a description of contractual agreements with 

such entities. 

• A description of the implementation of all advertising and marketing plans – whether conducted 

by you, on your behalf, or at your direction – not previously submitted, including strategic 

creative briefs and paid media plans, by channel, and the details, dollar amount(s) and flighting 

of such plans, by channel, including a description of any: 

o Use of competent and reliable data sources, methodologies, and technologies to establish, 

maintain, and monitor highly targeted advertising and marketing plans and media buys, 

including a list of all data sources used to target advertising and marketing plans and media 

buys; 

o Targeting of specific group(s) by age-range(s), including young adults, ages 21-24, and other 

demographic or psychographic characteristics that reflect the intended audience(s), 

including the source(s) of such data; 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 71 of 75 

o With respect to individuals under the federal minimum age of sale of tobacco products, 

actions taken to restrict access to the product and limit exposure to the product’s labeling, 

advertising, marketing, and/or promotion; 

o Use of owned, earned, shared, or paid media to create labeling for, advertise, market, 

and/or promote the product; 

o Use of partners, influencers, bloggers, or brand ambassadors to create labeling for, 

advertise, market, and/or promote the product; 

o Consumer engagements – whether conducted by you, on your behalf, or at your direction – 

including events at which the product was demonstrated and how access was restricted to 

individuals at or above the federal minimum age of sale of tobacco products; or 

o Use of public-relations or other communications outreach to create labeling for, advertise, 

market, and/or promote the product; including the original date such plans were first used 

and the date they were discontinued, and a description of all changes to such plans since 

the last periodic report, by channel; 

• An analysis of the actual delivery of advertising impressions, by channel, and by audience 

demographics (e.g., age, gender, race/ethnicity, geographic region), not previously submitted. 

This analysis must be verified against post-launch delivery-verification reports for paid media 

submitted to you or entities working on your behalf or at your direction from an accredited 

source; 

• A summary of media tracking and optimization, by channel and by audience demographics (e.g., 

age, gender, race/ethnicity, geographic region), including a summary of real-time digital media 

monitoring to identify, correct, and prevent delivery of advertising impressions to individuals 

under the federal minimum age of sale of tobacco products, and including a summary of 

implementation of any corrective and preventive measures, not previously submitted; 

• All final printed labeling (including all variations, such as those reflecting different required 

warnings) not previously submitted (e.g., if previously submitted under section 905(i) or 

previously submitted at the last reporting period and no changes were made, please list the 

date and manner of submission), including the date the labeling was first disseminated and the 

date when the labeling was discontinued, and a description of all changes to the labeling. The 

labeling must include all the panels and be presented in the actual size and color with legible 

text. The labeling must include labels, inserts/onserts, instructions, and any other accompanying 

information or materials for the product; and 

• All final full-color advertising, marketing, and/or promotional materials, published, disseminated 

to consumers, or for use in engaging or communicating with consumers not previously 

submitted (e.g., if previously submitted under 905(i) or previously submitted at the last 

reporting period and no changes were made, please list the date and manner of submission), 

along with the original date such materials were first disseminated and the date they were 

discontinued, and a description of all changes to the materials. The materials must be legible, 

include all panels where applicable (e.g., print ads, point of sale signs) and reflect the actual size 

and colors used. For any materials that would not fit on an 8.5” x 11” piece of paper, you may 

resize and submit electronic versions of such materials in a format that FDA can review and with 

sufficient resolution to allow FDA to read lettering clearly. If resizing the advertisement does not 

allow for text to be read easily, the complete text must be provided separately and clearly 

referenced. Digital media, such as videos and animations must be submitted in a format that 

FDA is able to open and review. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MR0000108 Page 72 of 75 

III. Notifications 

Under section 911(h)(5) of the FD&C Act, this order requires that as of the authorization date of your 

modified risk order, and for a period of six months starting with the initial dissemination of the 

marketing materials for the MRTP, you submit the following notifications of your marketing plans and 

materials to FDA and all other labeling, advertising, marketing, and promotion. This notification must be 

received by FDA at least 30 days prior to dissemination, which includes but is not limited to the 

publication, dissemination to consumers, or use in engaging or communicating with consumers of such 

materials. 

This 30-day notification requirement to submit the product’s labeling, advertising, marketing, and/or 

promotional materials and plans in advance of their use is not for pre-approval – that is, FDA is not 

requiring that it review and approve such materials or plans before they may be used. Rather, such 

advance notification will provide FDA timely access to such materials and plans and, if needed, allow 

FDA to provide advisory comments, including any concerns about their possible impact on youth appeal 

and tobacco use initiation and on the finding that continued marketing of your product will benefit the 

health of the population as a whole. You may begin disseminating the materials 30 days after the 

notification is received by FDA. 

Each 30-day notification must include: 

• A single submission with a cover letter that includes the following subject line: 30-DAY 

NOTIFICATION for MR0000108. The cover letter should include the STN and corresponding 

tobacco product name, applicant name, date of notification, and planned dissemination date; 

• Full-color copies of all such labeling, advertising, marketing, and/or promotional materials for 

the product, Copenhagen Classic Snuff. The materials must include all panels where applicable 

(e.g., print ads, point of sale signs) and reflect the actual size and colors used. For any materials 

that would not fit on an 8.5” x 11” piece of paper, you may resize and submit electronic versions 

of such materials in a format that FDA can review and with sufficient resolution to allow FDA to 

read lettering clearly. If resizing the material does not allow for text to be read easily, the text 

may be provided separately and referenced. Digital media, such as videos, must be submitted in 

a format that FDA is able to open and review. 

• All advertising and marketing plans, including strategic creative briefs and paid media plans, by 

channel and by product, and the details, dollar amount(s) and flighting of such plans, by channel 

and by product, including any plans to: 

o Use competent and reliable data sources, methodologies, and technologies to establish, 

maintain, and monitor highly targeted advertising and marketing plans and media buys, 

including a list of all data sources used to target advertising and marketing plans and media 

buys; 

o Target specific group(s) by age-range(s), including young adults, ages 21-24, and other 

demographic or psychographic characteristics that reflect your intended audience(s), 

including the sources of such data; 

o With respect to individuals below the federal minimum age of sale of tobacco products, 

actions taken to restrict access to the product and limit exposure to the product’s labeling, 

advertising, marketing, and/or promotion; 

o Use owned, earned, shared, or paid media to create labeling for, advertise, market, and/or 

promote the product; 
 

 

 

 

 

 

 

MR0000108 Page 73 of 75 

o Use partners, influencers, bloggers, or brand ambassadors to create labeling for, advertise, 

market, and/or promote the product; 

o Conduct consumer engagements – whether by you, on your behalf, or at your direction – 

including events at which the product will be demonstrated and how access will be 

restricted to individuals at or above the federal minimum age of sale of tobacco products; 

and/or 

o Use public-relations or other communications outreach to create labeling for, advertise, 

market, and/or promote the product. 

IV. Additional Conditions for Marketing 

Under section 911(h)(5) of the FD&C Act, this order requires you to: 

• For any of the product’s labeling, advertising, marketing, and/or promotion appearing in your 

owned digital properties (e.g., your company-owned, consumer-directed, product-branded 

website(s) and/or mobile applications)– whether conducted by you, on your behalf, or at your 

direction – establish, maintain, and monitor use of independent age- and identity-verification 

service(s) that compare customer information against independent, competent, and reliable 

data sources, such as public records, at the first point of access to such properties, to restrict 

access to such labeling, advertising, marketing, and/or promotion to only individuals who are at 

or above the federal minimum age of sale of tobacco products. 

• For any of the product’s labeling, advertising, marketing, and/or promotion appearing in any 

shared digital properties (e.g., your product-branded social media accounts, pages and 

associated content; content promoting your product on your behalf disseminated through 

another entity’s social media accounts) – whether conducted by you, on your behalf, or at your 

direction – establish, maintain, and monitor use of the available site-, platform- and content-

(e.g., post, video) specific age-restriction controls (e.g., age-restrict an entire product-branded 

account and all associated content disseminated through such account; ensure age-restriction of 

a specific video disseminated by an influencer promoting the product on your behalf through 

the influencer’s account), at the first point of access to such properties, to restrict access to such 

labeling, advertising, marketing, and/or promotion to only individuals who are at or above the 

federal minimum age of sale of tobacco products. 

• For any of the product’s labeling, advertising, marketing, and/or promotion appearing in paid 

digital media (e.g., paid digital banner advertisements for the product running on another 

company’s website; paid advertising for the product running in social media; paid distribution of 

influencer content; paid advertising in streaming/Over-The-Top video programming; paid 

advertising in streaming/internet radio content) – whether conducted by you, on your behalf, or 

at your direction: 

• Establish, maintain, and monitor use of competent and reliable data sources, 

methodologies, and technologies to precisely target delivery of such labeling, advertising, 

marketing, and/or promotion to only individuals who are at or above the federal minimum 

age of sale of tobacco products. Such targeting must use only first- and/or second-party ageverified data, where: 

 “First-party” age-verified data is data owned by you (e.g., your customer registration 

data collected via site traffic to your company-owned website; data you use in direct 

marketing to your adult smoking customers) that you have age-verified through 

independent, competent, and reliable data sources; and 

 “Second-party” age-verified data is first-party data owned and age-verified by another 

competent and reliable entity (e.g., another company’s first-party user registration data) 
 

 

 

 

 

 

 

 

 

 

 

 

 

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to which you have access. Such data must be age-verified by the second party. 

 “First-party” and “second-party” data does not include data obtained from data 

aggregators who categorize consumers based on trackable activities and inferred 

interests (e.g., internet search terms, video interactions, browsing history, purchasing 

behaviors) to create demographic and psychographic profiles marketers may use to 

enhance audience targeting. Such data is not considered age-verified and can only be 

used in combination with first- and/or second-party age-verified data. 

• Establish, maintain, and monitor use of competent and reliable data sources, methodologies, 

and technologies (e.g., using an embedded tracking pixel in all digital advertising) – whether 

conducted by you, on your behalf, or at your direction – to track and measure actual delivery of 

all advertising impressions, by channel, by product, and by audience demographics (e.g., age, 

gender, race/ethnicity, geographic region). Such monitoring requires real-time digital media 

tracking, and identifying, correcting, and preventing delivery of advertising impressions to 

individuals under the federal minimum age of sale of tobacco products. Such monitoring also 

requires post-launch delivery verification reports for paid media be submitted to you or entities 

working on your behalf or at your direction from an accredited source. 

• For any use of partners, influencers, bloggers, and/or brand ambassadors to create labeling for, 

advertise, market, and/or promote the product – whether conducted by you, on your behalf, or 

at your direction – disclose to consumers or viewers, via the use of statements such as 

“sponsored by [firm name]” in such labeling, advertising, marketing, and/or promotional 

materials, any relationships between you and entities that create labeling for, advertise, market, 

and/or promote the product, on your behalf, or at your direction. 

The requirements above are intended to help ensure that the MRTP, as actually used by consumers, will 

continue to benefit the health of the population as a whole. Limiting youth initiation of the product and, 

relatedly, youth exposure to advertising and marketing materials for the product are important factors 

in the population health benefit analysis. Accordingly, FDA also recommends limiting youth exposure to 

any of the tobacco product’s labeling, advertising, marketing, and/or promotion appearing in print 

media publications. 

After receiving authorization, the determination of whether the MRTP, as actually used by consumers, 

continues to benefit the health of the population as a whole is likely to be driven by use behavior. An 

uptake in youth initiation and use of the product would have a significant negative impact on the 

population health benefit analysis. To help ensure that your product, as actually used by consumers, 

continues to benefit the health of the population as a whole, we strongly recommend that you take 

measures to limit youth initiation and use of the product, beyond limiting advertising and promotion as 

required in this order. For example, we strongly recommend you adopt the following measures related 

to all digital sales of your product: 

• For any digital sales – whether conducted by you, on your behalf, or at your direction – 

establish, maintain, and monitor use of independent age- and identity-verification service(s) 

that compare customer information against independent, competent, and reliable data sources, 

such as public records, to prevent the sale of the product to individuals who are under the 

federal minimum age of sale of tobacco products. 
 

 

 

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Relatedly, we request that you submit the following information to CTP on an annual basis: 

• A summary of the implementation and effectiveness of any policies and procedures regarding 

verification of the age and identity of purchasers of the product. 

• A summary of the implementation and effectiveness of any policies and procedures regarding 

restrictions on youth access to the product. 

We remind you that if FDA can no longer make the determination that your product, as actually used by 

consumers, will benefit the health of the population as a whole, FDA must withdraw the modified risk 

order, after an opportunity for an informal hearing. See under section 911(j)(1) of the FD&C Act. 

Although adopting the measures above is not in itself a guarantee that the product will continue to 

benefit the health of the population as a whole, it is an important step in helping to ensure that there 

are no grounds for withdrawal of your order.