U.S. Food & Drug Administration

10903 New Hampshire Avenue

Silver Spring, MD 20993 

www.fda.gov 

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

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

SUBMISSION INFORMATION

Applicant Swedish Match USA, Inc.

Product Manufacturer Swedish Match USA, Inc.

Submission Date June 10, 2014 FDA Receipt Date June 10, 2014

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

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

Claims Using General Snus instead of cigarettes puts you at a lower risk of mouth

cancer, heart disease, lung cancer, stroke, emphysema, and chronic

bronchitis.

Primary STN(s) MR0000020 General Loose ☒Single ☐Co‐Packaged

Description N/A

MR0000021 General Dry Mint Portion

Original Mini

☒Single ☐ Co‐Packaged

Description: N/A

MR0000022 General Portion Original

Large

☒Single ☐ Co‐Packaged

Description: N/A

MR0000024 General Classic Blend

Portion White Large – 12 ct

☒Single ☐ Co‐Packaged

Description: N/A

MR0000025 General Mint Portion White

Large

☒Single ☐ Co‐Packaged

Description: N/A

MR0000027 General Nordic Mint

Portion White Large – 12 ct

☒Single ☐ Co‐Packaged

Description: N/A

MR0000028 General Portion White

Large

☒Single ☐ Co‐Packaged

Description N/A

MR0000029 General Wintergreen

Portion White Large

☒Single ☐ Co‐Packaged

Description: N/A

Amendments

Amendment STN Primary STN Description FDA Receipt Date

MR0000030 All Market Tracker raw data July 31, 2014

MR0000031 All HPHC raw data August 1, 2014

MR0000032 All Background information related to

cognitive testing for the

premarket consumer perception study

August 5, 2014

MR0000033 All Raw data for the consumer perception

study

August 15, 2014

MR0000035 All Response to November 12, 2014, FDA

Information Request

December 3, 2014
       

               

   

     

               

   

     

               

   

     

               

   

     

                     

                     

               

   

     

               

   

     

             

  

     

               

   

     

             

      

       

   

             

       

   

                      

              

       

    

       

       

   

                      

   

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 2 of 77

MR0000036 All Response to November 25, 2014, FDA

Information Request

December 9, 2014

MR0000038 All Response to January 9, 2015, FDA

Information Request

January 27, 2015

MR0000039 All Response to February 6, 2015, FDA

Information Request

February 20, 2015

MR0000041 All Response to March 6, 2015, FDA

Information Request

March 11, 2015

MR0000042 All Response to April 28, 2015, Information

Request

May 22, 2015

MR0000044 All Response to June 5, 2015, Information

Request

June 19, 2015

MR0000131 All Response to December 14, 2016, FDA

Information Request

September 17, 2018

MR0000138 All Response to October 24, 2018, FDA

Information Request

November 28, 2018

MR0000148 All Amended response of November 28,

2018 Amendment

January 30, 2019

MR0000158 All Response to April 18, 2019, FDA

Information Request

April 24, 2019

PROPOSED MODIFIED RISK TOBACCO PRODUCT (SINGLE PRODUCTS)

STN MR0000020

Product Name General Loose

Product Category Smokeless Tobacco

Product Sub‐Category Loose Snus

Package Type Cardboard Can with Plastic Lid

Package Quantity 45.0 g

Characterizing Flavor None

Product Use For Consumer Use For Further Manufacturing

STN MR0000021

Product Name General Dry Mint Portion Original Mini

Product Category Smokeless Tobacco

Product Sub‐Category Portioned Snus

Package Type Plastic Can

Package Quantity 6.0 g

Characterizing Flavor Mint

Product Use For Consumer Use For Further Manufacturing
STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page        3 of 77

STN MR0000022

Product Name   General Portion Original Large

Product Category Smokeless Tobacco

Product Sub‐Category Portioned Snus   

Package Type Plastic Can

Package Quantity 24.0 g

Characterizing Flavor None

Product Use For Consumer Use       For Further Manufacturing

STN MR0000024

Product Name   General Classic Blend Portion White Large – 12 ct

Product Category Smokeless Tobacco

Product Sub‐Category Portioned Snus   

Package Type Plastic Can

Package Quantity 10.8 g

Characterizing Flavor None

Product Use For Consumer Use       For Further Manufacturing

STN MR0000025

Product Name   General Mint Portion White Large

Product Category Smokeless Tobacco

Product Sub‐Category Portioned Snus   

Package Type Plastic Can

Package Quantity 24.0 g

Characterizing Flavor Mint

Product Use For Consumer Use       For Further Manufacturing

STN MR0000027

Product Name   General Nordic Mint Portion White Large – 12 ct

Product Category Smokeless Tobacco

Product Sub‐Category Portioned Snus    

Package Type Plastic Can

Package Quantity 10.8 g

Characterizing Flavor Mint

Product Use For Consumer Use       For Further Manufacturing

STN MR0000028

Product Name   General Portion White Large

Product Category Smokeless Tobacco

Product Sub‐Category Portioned Snus   

Package Type Plastic Can

Package Quantity 24.0 g

Characterizing Flavor None

Product Use For Consumer Use       For Further Manufacturing
       

  

    

      

   

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 4 of 77

STN MR0000029

Product Name General Wintergreen Portion White Large

Product Category Smokeless Tobacco

Product Sub‐Category Portioned Snus

Package Type Plastic Can

Package Quantity 24.0 g

Characterizing Flavor Wintergreen

Product Use For Consumer Use For Further Manufacturing
STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 5 of 77

DISCIPLINES REVIEWED DATE OF REVIEW

Engineering   September 14, 2016

Chemistry   September 15, 2016  

Microbiology   September 15, 2016

Toxicology   September 19, 2016

Social Science   October 27, 2016; October 11, 2019

Addiction Clinical Pharmacology   October 28, 2016

Behavioral Clinical Pharmacology   October 31, 2016

Medical   October 26, 2016

Epidemiology   November 2, 2016

Statistics   October 24, 2016; October 27, 2016

Environmental Science   October 3, 2019

OCE Review (DEM & DPAL)   November 12, 2014; September 16, 2016;

September 20, 2016; October 17, 2019

Recommended Action(s)

       

         

   

              

Issue a Denial letter

       

            

    

              

   

                

            

    

          

Issue a Modified Risk Granted letter

Technical Project Lead (TPL):

/S/ 

Benjamin J. Apelberg, Ph.D.

Director

Division of Population Health Science

Signatory Decision:

☒ Concur with TPL recommendation and basis of recommendation

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

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

/S/ 

Matthew R. Holman, Ph.D.

Director

Office of Science
       

   

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 6 of 77

Table	of	Contents	

I. Executive Summary............................................................................................................................... 7

II. Background .........................................................................................................................................13

A. FDA Evaluation of the Initial Submissions....................................................................................... 13

B. September 2018 Amendment ........................................................................................................ 17

C. Proposed Modified Risk Labels, Labeling, and Advertising (LLA).................................................... 17

D. Tobacco Products Scientific Advisory Committee .......................................................................... 18

E. Public Availability ............................................................................................................................ 19

III. Summary of Scientific Evidence...................................................................................................... 19

A. Relative Health Risks of the Proposed MRTPs to Individual Tobacco Users...................................19

1. Claim Substantiation and Health Risks of the Proposed MRTPs Compared to Cigarettes.........20

2. Health Risks of Proposed MRTP Use Compared to Other Use Behaviors...................................28

B. Effects of the Proposed MRTPs on Consumer Understanding and Perception..............................29

1. Perception and Behavioral Intentions (PBI) Study...................................................................... 29

C. Effects of the Proposed MRTPs on Tobacco Use Behavior among Current Tobacco Users...........39

D. Effects of the Proposed MRTPs on Tobacco Use Initiation among Non‐Users...............................42

E. Impact of the Proposed MRTPs to the Health of the Population as a Whole ................................43

IV. Conclusions and Recommendation................................................................................................. 45

1. Review Conclusions..................................................................................................................... 46

2. Environmental Impact................................................................................................................. 48

3. Postmarket Surveillance and Studies.......................................................................................... 48

4. Postmarket Advertising and Promotion Requirements, Recordkeeping and Retention, and

Manufacturing Information ................................................................................................................ 51

References ..................................................................................................................................................60

V. Appendix – The Public Health Rationale for Recommended Restrictions on Modified Risk Tobacco

Product Labeling, Advertising, Marketing, and Promotion ........................................................................ 64
       

                           

                           

                     

                             

                       

                      

                        

                  

                             

                           

  

                             

                             

                          

                             

                                  

                                  

                               

                                     

                              

   

  

                       

                         

                       

                               

                                                            

                                       

                                  

                                             

                           

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 7 of 77

I. Executive	Summary	

On June 10, 2014, FDA received applications from Swedish Match North America, Inc. (SMNA)1

1 The applicant changed its name from Swedish Match North America (SMNA) to Swedish Match USA, Inc. during the period

between submission of their initial applications and their September 2018 amendment described below. In this document we

will refer to the applicant as SMNA when describing events that took place during the time that was their name. We will refer

to the applicant as Swedish Match when describing events occurring subsequent to the name change.

requesting modified risk tobacco product (MRTP) orders under Section 911(g)(1) of the Federal Food,

Drug, and Cosmetic Act (FD&C Act) for eight General Snus products.

SMNA initially proposed marketing these products as modified risk through the removal and revision of

certain health warnings currently required by the Comprehensive Smokeless Tobacco Health Education

Act for smokeless tobacco products. In particular, the applicant proposed to:

1. Remove “WARNING: This product can cause gum disease and tooth loss.”

2. Remove “WARNING: This product can cause mouth cancer.”

3. Revise “WARNING: This product is not a safe alternative to cigarettes” to “WARNING: No

tobacco product is safe but this product presents substantially lower risks to health than

cigarettes.”

The applicant did not propose a change to the warning: “WARNING: Smokeless tobacco is addictive.”

The requests to remove warnings were evaluated as implied modified risk claims that the products

cannot cause the health outcomes named (gum disease and tooth loss; mouth cancer).

On December 14, 2016, FDA completed its review of the modified risk tobacco product applications

(MRTPAs) and issued a partial decision on the applications. The request to remove the gum disease and

tooth loss warning was denied, while FDA deferred final action on the other requests. In deferring final

action, FDA determined that the applications in their current form did not provide sufficient evidence to

meet the standard of 911(g)(1), but they could be amended in a way that would support the issuance of

a modified risk order. Accordingly, FDA issued a Response Letter, which included the following three

deficiencies:

1. You request to omit from the label and advertising “WARNING: This product can cause mouth

cancer.” This warning is currently required for smokeless tobacco products generally. Omission

of this warning from a subset of smokeless tobacco products indicates that unlike other

smokeless tobacco products, the eight General snus products cannot cause mouth cancer. Thus,

the request is to market the products with an implied modified risk claim that the products, as

compared to other smokeless tobacco products, cannot cause mouth cancer.

Although the eight General snus products contain significantly lower levels of harmful

carcinogens than other smokeless tobacco products currently in the U.S. market, the products

contain nitrosamines, including NNN and NNK, which have been demonstrated to cause cancer,

including cancers of the mouth. NNN in particular has been found to be a potent oral
       

                         

                           

                         

                                 

                                 

                       

                       

                         

                           

                             

                           

                         

                         

                                   

        

                           

                           

                             

                           

                           

                           

                         

                           

                             

                         

                         

                        

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 8 of 77

carcinogen, and since, according to the available toxicological evidence, there is no established

threshold level for NNN carcinogenicity, the products pose an increased risk of mouth cancer

compared to non‐use. In addition, the available epidemiological evidence on the products, as

actually used by consumers in Sweden and Norway, is not sufficient to conclude that the use of

the products themselves does not increase the risk of cancers of the mouth. In fact, the most

recent published epidemiological study found an association between snus use and mouth

cancer. Accordingly, the totality of the scientific evidence supports the statement that

smokeless tobacco products in general and these products in particular “can cause mouth

cancer” and the proposed modified risk claim is not substantiated. We therefore conclude that

the scientific evidence currently before the agency does not support the removal of the warning

related to mouth cancer. Additionally, you did not provide evidence regarding how the modified

risk information (i.e., the removal of the mouth cancer warning) would impact consumer

behavior or whether consumers would understand the modified risk information in the context

of total health. As a result, we are not issuing modified risk orders based on the proposed claim

in its current form.

Although your applications do not support the specific request related to removing the warning

related to mouth cancer, the evidence you provided may support applications that seek to

market the products with other claims about relatively lower risk of mouth cancer for these

products as compared to other tobacco products. Compared to the claim in your current

applications, any new claim should be more precisely tailored to the supporting science. For

example, you may consider pursuing explicit claims that appear outside of the health warning,

elsewhere on the label or in advertising, providing information to consumers concerning the

differences in mouth cancer risks between the eight General snus products and other tobacco

products. These claims will need to be carefully constructed and adequately tested so as to

ensure that the products meet the modified risk standards, including the requirement for

consumer comprehension. We recommend that you meet with the Office of Science in FDA’s

Center for Tobacco Products to discuss how your applications could be amended.

2. You request to revise the currently required “WARNING: This product is not a safe alternative to

cigarettes” on the label and advertising, by replacing it with an express modified risk claim

“WARNING: No tobacco product is safe, but this product presents substantially lower risks to

health than cigarettes.” Our review concluded that the claim that the eight General snus

products present substantially lower risks to health may be substantiated, but only in part. That

is, there is evidence to support that the eight General snus products, as actually used by

consumers in Sweden and Norway, as compared to smoking cigarettes may substantially reduce

the risks of some, but not all, tobacco‐related diseases to individual tobacco users. The scientific

evidence is insufficient to support that substantial reductions would be observed across the full

range of risks posed by tobacco products, as implied by a generalized statement about health

risks as compared to smoking (i.e., “substantially lower risks to health than cigarettes”). The

evidence is also insufficient that U.S. consumers would use the products in the same manner as

consumers in Sweden and Norway (e.g., frequency or intensity of usage; exclusive snus use

versus dual use with cigarettes); therefore, we cannot conclude that, as actually used by U.S.

consumers, the products would substantially reduce the risks to smokers. In addition, FDA

assessed the potential benefits and harms to the health of the population and concluded that

the evidence is insufficient to determine that the products will benefit the population as a

whole, taking into account, for example, smokers who switch completely to the General snus

products, non‐users who initiate use, and dual use by current tobacco users. Furthermore, the
       

                           

                             

                                 

                    

                           

                           

                             

                           

                           

                         

                         

                               

                       

                             

                  

  

                     

                         

                         

                       

                             

                         

                                   

     

                             

           

                                 

                          

                           

                               

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 9 of 77

scientific evidence is not sufficient to conclude that the modified risk information would be

comprehended by the public in the context of total health and in relation to all tobacco‐related

disease, particularly in the context of a warning. As a result, we are not issuing modified risk

orders based on the proposed claim in its current form.

Although your applications do not support the specific request to revise the warning, the

evidence you provided may support applications that seek to market the products with other

claims about relative health risks compared to cigarettes. Compared to the claim in your current

applications, any new claim should be more precisely tailored to the supporting science. For

example, you may consider pursuing explicit claims that appear outside of the health warning,

elsewhere on the label or in advertising, providing information to consumers concerning the

differences in specific health risks between the eight General snus products and cigarettes.

These claims will need to be carefully constructed and adequately tested so as to ensure that

the products meet the modified risk standards, including the requirement for consumer

comprehension. We recommend that you meet with the Office of Science in FDA’s Center for

Tobacco Products to discuss how your applications could be amended.

3. The Consumer Perception Study you conducted was deficient for purposes of providing insight

on potential behavioral impacts of the modified risk information or on consumer

comprehension because it did not use appropriate stimuli and the methods used to assess

comprehension, perceptions, and behavioral intentions were problematic. If you choose to

conduct a new consumer perception and comprehension study (e.g., as part of addressing the

deficiencies discussed in 1 and 2 above), you should address the deficiencies identified in our

review of the Consumer Perception Study. To best inform an evaluation of the effects of the

modified risk information, study stimuli should test the proposed modified risk information

verbatim. As noted above, consider providing modified risk information by some means other

than through the removal or revision of the warning statements. However, if modified risk

information remains in the warning statement itself, your study should also examine the impact

of the context of the modified risk information, i.e., how the context of the modified risk

information (e.g., whether presented within a warning or as a standalone claim) affects

consumer perception and comprehension.

Although a well‐designed study on consumer perception and comprehension will provide

indirect information on potential impacts on behavior, we recommend that you also consider

assessing consumer perception, comprehension, and intentions in the context of an actual use

study designed to address behavioral outcomes, particularly among current users of tobacco

products. Such data would provide direct evidence of the impact of the proposed claims on

consumer behavior, including evidence that U.S. consumers will use the proposed products as

intended, e.g., the products will be used by current tobacco users, in lieu of, and not in addition

to, smoking cigarettes.

On September 17, 2018, Swedish Match submitted an amendment to address the FDA Response Letter.

The applicant addressed the deficiencies accordingly:

 Deficiencies 1 and 2: The applicant has tested and proposed a revised modified risk claim that is

more precisely tailored to the scientific evidence. Specifically, the revised claim conveys specific

health risks that are reduced relative to cigarette smoking, describes how the products should

be used relative to cigarettes (i.e., “instead of”) and does not include a subjective qualifier of the
       

                         

                               

  

                           

                             

   

                         

                                  

                               

                

                                     

                            

                           

               

                         

                             

       

                         

                               

                   

                               

                      

                             

                             

                              

                             

        

                               

                                 

                                

                               

                                     

                           

                      

                         

                    

                             

      

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 10 of 77

risk reduction (e.g., “substantially”). The revised modified risk claim is explicit and appears

outside of the health warning label. The applicant no longer requests to change or remove any

warning labels.

 Deficiency 3: The applicant has conducted a new consumer perception study to evaluate the

revised modified risk claim and redress the initial study’s deficiencies in terms of study stimuli

and measures.

To communicate modified risk information to consumers, the applicant proposes to add the following

claim to the advertising of the eight General Snus products that are the subject of these applications:

“Using General Snus instead of cigarettes puts you at a lower risk of mouth cancer, heart

disease, lung cancer, stroke, emphysema, and chronic bronchitis.”

The applicant proposes to use the claim in advertisements but does not plan to add it to the products’

labels. The applicant submitted a new consumer study, the Perceptions and Behavioral Intentions (PBI)

study, to evaluate consumer reactions to the product with the proposed claim, including consumer

understanding, perceptions, and intentions to buy the products.

The applicant’s request was assessed, per Section 911(g)(1) to determine whether the applicant

demonstrated that, as actually used by consumers, the products sold or distributed with the proposed

modified risk information 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.

The assessment of whether the products meet the MRTP standard begins with an assessment of the

scientific substantiation of the proposed modified risk information. Under Section 911(g)(1), the

modified risk inquiry also involves an assessment of whether the proposed modified risk products, as

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

individual tobacco users. This assessment includes an evaluation of the relative health risks to individual

tobacco users, including a broad range of health risks beyond those specifically addressed in the

proposed modified risk claim.

The modified risk inquiry further includes an assessment of the potential benefits and harms to 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. This assessment considers the impact of the products with

the proposed modified risk information on tobacco use behaviors, such as the potential for adoption of

the products on the part of current tobacco users, dual or poly use of tobacco products by current users,

the likelihood of product uptake among current non‐tobacco users, and the ensuing health outcomes

resulting from those behaviors in the population. This evaluation includes assessments of:

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

stop using such products will switch to using the MRTPs;

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

using the MRTPs;
       

                                   

                        

                         

                           

                              

                             

                         

                                 

                

                           

                           

                             

                               

                      

                         

                     

                           

         

                           

  

                                   

                         

                       

                         

                                

                       

                           

                             

                               

                             

                          

                               

                             

                               

                                 

                             

                               

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 11 of 77

 The risks and benefits to persons from the use of the MRTPs compared to the use of smoking

cessation drug or device products approved by FDA to treat nicotine dependence.

The modified risk standard also involves an assessment of consumer perception, understanding, and

comprehension of the modified risk information, which may be an important precursor to consumer

behavior and could affect how consumers actually use the products. Relatedly, Section 911(h)(1) of the

FD&C Act requires that “any advertising or labeling concerning modified risk products 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.”

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

products and their potential effects on health and tobacco use behavior, including tobacco use

initiation, to determine both the net effect of the products on overall tobacco‐related morbidity and

mortality and the distribution of the benefits and harms across the population, e.g., harms to current

non‐users that result from significant increases in initiation of tobacco use.

In addition to the information contained in the MRTPAs, the assessment considered the

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

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

the Agency from other sources.

After conducting a thorough scientific review of all of these materials, I conclude that:

 The applicant has demonstrated that, as actually used by consumers, the eight General Snus

products sold or distributed with the proposed modified risk information, 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.

The claim “Using General Snus instead of cigarettes puts you at a lower risk of mouth cancer, heart

disease, lung cancer, stroke, emphysema, and chronic bronchitis" is scientifically accurate. The available

scientific evidence, in particular the long‐term epidemiological studies, reviewed under the original

submission and summarized again in this review, substantiates that relative to cigarette smoking,

exclusive use of the eight General Snus products poses lower risk of the above‐named health outcomes.

The applicant provided sufficient justification to determine that the epidemiological evidence from

Sweden and Norway, although not specific to the products that are subjects of these applications,

provides a reasonable characterization of the risks that would be expected to be observed among

General Snus users in the U.S. if they used the products in a similar manner.

The available scientific evidence demonstrates that exclusive use of the eight General Snus products will

significantly reduce harm and the risk of tobacco‐related disease to individual tobacco users. As

described above, exclusive use of these products poses lower risks than cigarette smoking for many of

the major causes of tobacco‐related disease. In addition to these lower risks relative to cigarette

smoking, FDA has previously determined that the levels of NNN and NNK, two potent carcinogens in

smokeless tobacco products, in these General Snus products are lower than those in the vast majority of

smokeless tobacco products on the U.S. market, and when used exclusively instead of other smokeless

tobacco products, the General Snus products offer the potential for reductions in oral cancer risk.
       

                           

                         

                                

                               

                         

                            

                   

                             

                                    

                           

                                     

                                

                             

                                

                                   

                          

                               

                            

                                 

                           

                                  

                               

                                 

                            

                               

                             

                            

                             

                   

                            

                              

                       

                             

                                  

                                  

                               

                                   

                               

                                

                               

                    

                             

                             

                                    

                             

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Although exposure to harmful and potentially harmful constituents (HPHCs) is lower than many other

smokeless tobacco products, exposure is still elevated compared with non‐use and, therefore, long‐term

use of General Snus is not without health risks. FDA’s 2016 Technical Project Lead (TPL) review

concluded that Swedish snus use (compared with no use of tobacco) has been associated with increased

risk of specific disease endpoints in individual epidemiological studies, including pancreatic cancer, fatal

MI and stroke, diabetes, and adverse pregnancy outcomes. In addition, there are potential negative

effects of nicotine exposure on the developing adolescent brain.

The additional evidence provided in the amendment also supports that, as actually used by consumers,

the eight General Snus MRTPs will benefit the health of the population as a whole. The PBI study

demonstrated that exposure to the claim positively impacted relative risk perceptions and intentions to

buy the product among smokers aged 25 years and older, a group who stands to benefit the most from

the marketing of the products. For instance, among adult smokers aged 25 years and older, participants

who were exposed to a marketing video with the modified risk claim reported significantly higher

intentions to buy the product compared to those who did not see the modified risk claim. Smokers

under age 25 years showed a similar pattern, although the impact of the claim on intentions was not

statistically significant for this group. Similarly, although not statistically significant, the pattern of

results also suggested the claim may have a positive impact on smokeless tobacco users’ intentions to

buy the product. In addition, smokeless tobacco users across conditions showed the highest mean

levels of intentions to buy the product, suggesting that the marketing of the products with the claim

could increase the likelihood of current smokeless users transitioning to the eight General Snus

products, which are likely to be a less toxic alternative. The applicant also provided evidence to show

that consumers can understand the claim and its significance in the context of total health, including

understanding that the risk reduction is not achieved via partial switching (i.e., dual use of General Snus

with continued use of cigarettes). In fact, the proposed claim improved consumers’ understanding of

the risks of General Snus relative to cigarettes and their understanding that dual use presents greater

health risks than exclusive General Snus use, thereby increasing the likelihood that consumers who use

the products will do so exclusively. Together, the demonstrated impact of the claim on understanding,

perceptions, and behavioral intentions, even in the context of a relatively brief exposure, supports that

the proposed MRTPs will benefit the population as a whole.

The PBI study provided sufficient evidence to support product authorization. However, the results were

not without limitations. In particular, although the evidence showed that exposure to the modified risk

claim significantly impacted perceptions of the absolute and relative risk of the products—shifting

perceptions in line with the claim, towards greater accuracy—this was true, on average, but not

necessarily for all participants. In fact, a proportion of participants was not affected by the claim and

continued to perceive the product as just as harmful as cigarettes, for instance. Likewise, just as some

participants did not perceive General Snus as less harmful compared to cigarettes, a proportion also did

not understand that exclusive use of General Snus would be less harmful than dual use of General Snus

with cigarettes. Considered in the context of the totality of the evidence, these results do not

undermine my conclusion that the product meets the standard in Section 911(g)(1) of the FD&C Act.

However, given their relevance to the population health impact of these MRTPs, these are areas that

need to be monitored through postmarket surveillance and studies (PMSS).

Finally, the new evidence supports that the population health benefits gained by cigarette smokers (and

potentially other smokeless tobacco users) switching to these products will not be outweighed by the

risks of initiating new tobacco use. The PBI study found low levels of intentions to buy the product

among non‐users of tobacco (including young adults) and, importantly, found that the inclusion of the
       

                                

                          

                               

                                  

                                  

                             

                          

                           

                            

                           

           

                                  

                             

                                

                                     

                              

                                 

                            

                                

                                 

                              

                             

                               

                  

                         

  

                  

            

                       

                    

                                                            

                               

                                 

                                   

                                 

                                 

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modified risk claim did not affect these intentions. Prevention of youth initiation of tobacco products is

a key consideration in FDA’s evaluation. Although the available evidence from epidemiological studies

does not demonstrate significant youth initiation of snus products at this time, it is possible that

marketing the product as a modified risk product could change this. In fact, some studies suggest that

risks perceptions predict tobacco product use among youth (e.g., Song et al. 2009; Strong et al. 2019).

Thus, it is essential that modified risk marketing be targeted to current tobacco users and disseminated

in ways to minimize exposure among youth. Based on these conclusions, the postmarket requirements

described below include measures to limit youth exposure to the products’ labeling, advertising, and

marketing. In addition, reporting requirements will enable FDA to monitor, among other things, the

degree to which the implementation of the marketing plans is effectively targeting the intended

audience and limiting exposure to youth.

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, given that these would be the first MRTP

authorizations issued by the Agency. Although this review has found that the products 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 eight General Snus products

that are the subject of these applications in terms of uptake, dual use, and complete switching is

required. As described below, postmarket surveillance and studies must include an assessment of MRTP

users’ behavior and understanding at multiple time points. 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.

II. Background	

A. FDA	Evaluation	of	the	Initial	Submissions	

On June 10, 2014, FDA received applications from SMNA seeking risk modification orders under Section

911(g)(1) of the Federal Food, Drug and Cosmetic Act (FD&C Act) for 10 smokeless snus tobacco

products2

2 Although ten applications were initially submitted, a request for withdrawal of two applications, MR0000023, General Classic

Blend Portion White Large‐15 count and MR0000026, General Nordic Mint Portion White Large‐15 count, was submitted on

October 7, 2015. On October 15, 2015, FDA issued withdrawal acknowledgement letters for these two products. Therefore, the

remaining eight products were considered for an order under Section 911(g)(1). FDA also issued premarket tobacco product

authorization (PMTA) marketing orders for these eight products but with no modified risk information in October 2015.

listed by the following FDA Submission Tracking Numbers:

 MR0000020: General Loose, smokeless tobacco, loose snus, 1.59 oz (45g), cardboard can (SKU

4852);

 MR0000021: General Dry Mint Portion Original Mini, smokeless tobacco, snus portions, 0.21 oz

(6g), 20 – 0.3g portions, plastic can (SKU 4800);

 MR0000022: General Portion Original Large, smokeless tobacco, snus portions, 0.9 oz (24g), 24 –

1g portions, plastic can (SKU 4880);

 MR0000023: General Classic Blend Portion White Large, smokeless tobacco, snus portions, 0.48

oz (13.5g), 15 – 0.9g portions, plastic can (SKU 4877);
       

                       

                    

                         

                

                       

                    

                       

                    

                           

              

                     

                    

                             

                       

                      

                        

                  

                             

                           

  

                             

                          

                                   

                                  

                           

                                   

                               

                           

                           

                      

                                 

                               

                                 

                            

   

  

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 14 of 77

 MR0000024: General Classic Blend Portion White Large, smokeless tobacco, snus portions, 0.38

oz (10.8g), 12 – 0.9g portions, plastic can (SKU 4878);

 MR0000025: General Mint Portion White Large, smokeless tobacco, snus portions, 0.9 oz (24g),

24 – 1g portions, plastic can (SKU 4352);

 MR0000026: General Nordic Mint Portion White Large, smokeless tobacco, snus portions, 0.48

oz (13.5g), 15 – 0.9g portions, plastic can (SKU 4876);

 MR0000027: General Nordic Mint Portion White Large, smokeless tobacco, snus portions, 0.38

oz (10.8g), 12 – 0.9g portions, plastic can (SKU 4875);

 MR0000028: General Portion White Large, smokeless tobacco, snus portions, 0.9 oz (24g), 24 –

1g portions, plastic can (SKU 4881); and

 MR0000029: General Wintergreen Portion White Large, smokeless tobacco, snus portions, 0.9

oz (24g), 24 – 1g portions, plastic can (SKU 4882).

SMNA initially proposed marketing these products as modified risk through the removal and revision of

certain health warnings currently required by the Comprehensive Smokeless Tobacco Health Education

Act for smokeless tobacco products. In particular, the applicant proposed to:

1. Remove “WARNING: This product can cause gum disease and tooth loss.”

2. Remove “WARNING: This product can cause mouth cancer.”

3. Revise “WARNING: This product is not a safe alternative to cigarettes” to “WARNING: No

tobacco product is safe but this product presents substantially lower risks to health than

cigarettes.”

The requests to remove warnings were evaluated as implied modified risk claims that the products

cannot cause the health outcomes named (gum disease and tooth loss; mouth cancer).

The MRTPAs were referred to TPSAC in April 2015. On December 14, 2016, FDA completed its review of

the MRTPAs and issued a partial decision on the applications. Based on its evaluation of the evidence,

the TPL Review (2016) reached several conclusions regarding the requested warning label changes.

In regard to the request to remove the gum disease and tooth loss warning, FDA issued a denial,

concluding that the claim was not substantiated and that the applicant had not demonstrated that as

actually used by consumers, the products sold or distributed with the proposed modified risk

information 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.

In regard to the request to remove the mouth cancer warning and revise the “safe alternative” warning,

FDA determined that the applications in their current form did not provide sufficient evidence to meet

the standard of Section 911(g)(1), but they could be amended in a way that would support the

authorization of a modified risk order. Accordingly, FDA issued a Response Letter, describing three

deficiencies:

1. You request to omit from the label and advertising “WARNING: This product can cause mouth

cancer.” This warning is currently required for smokeless tobacco products generally. Omission

of this warning from a subset of smokeless tobacco products indicates that unlike other

smokeless tobacco products, the eight General snus products cannot cause mouth cancer. Thus,

the request is to market the products with an implied modified risk claim that the products, as

compared to other smokeless tobacco products, cannot cause mouth cancer.
       

                       

                         

                       

                               

                         

                           

                         

                                 

                                 

                       

                       

                         

                           

                             

                           

                         

                         

                                   

        

                           

                           

                             

                           

                           

                           

                         

                           

                             

                         

                         

                        

                           

                             

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Although the eight General snus products contain significantly lower levels of harmful

carcinogens than other smokeless tobacco products currently in the U.S. market, the products

contain nitrosamines, including NNN and NNK, which have been demonstrated to cause cancer,

including cancers of the mouth. NNN in particular has been found to be a potent oral

carcinogen, and since, according to the available toxicological evidence, there is no established

threshold level for NNN carcinogenicity, the products pose an increased risk of mouth cancer

compared to non‐use. In addition, the available epidemiological evidence on the products, as

actually used by consumers in Sweden and Norway, is not sufficient to conclude that the use of

the products themselves does not increase the risk of cancers of the mouth. In fact, the most

recent published epidemiological study found an association between snus use and mouth

cancer. Accordingly, the totality of the scientific evidence supports the statement that

smokeless tobacco products in general and these products in particular “can cause mouth

cancer” and the proposed modified risk claim is not substantiated. We therefore conclude that

the scientific evidence currently before the agency does not support the removal of the warning

related to mouth cancer. Additionally, you did not provide evidence regarding how the modified

risk information (i.e., the removal of the mouth cancer warning) would impact consumer

behavior or whether consumers would understand the modified risk information in the context

of total health. As a result, we are not issuing modified risk orders based on the proposed claim

in its current form.

Although your applications do not support the specific request related to removing the warning

related to mouth cancer, the evidence you provided may support applications that seek to

market the products with other claims about relatively lower risk of mouth cancer for these

products as compared to other tobacco products. Compared to the claim in your current

applications, any new claim should be more precisely tailored to the supporting science. For

example, you may consider pursuing explicit claims that appear outside of the health warning,

elsewhere on the label or in advertising, providing information to consumers concerning the

differences in mouth cancer risks between the eight General snus products and other tobacco

products. These claims will need to be carefully constructed and adequately tested so as to

ensure that the products meet the modified risk standards, including the requirement for

consumer comprehension. We recommend that you meet with the Office of Science in FDA’s

Center for Tobacco Products to discuss how your applications could be amended.

2. You request to revise the currently required “WARNING: This product is not a safe alternative to

cigarettes” on the label and advertising, by replacing it with an express modified risk claim

“WARNING: No tobacco product is safe, but this product presents substantially lower risks to

health than cigarettes.” Our review concluded that the claim that the eight General snus

products present substantially lower risks to health may be substantiated, but only in part. That

is, there is evidence to support that the eight General snus products, as actually used by

consumers in Sweden and Norway, as compared to smoking cigarettes may substantially reduce

the risks of some, but not all, tobacco‐related diseases to individual tobacco users. The scientific

evidence is insufficient to support that substantial reductions would be observed across the full

range of risks posed by tobacco products, as implied by a generalized statement about health

risks as compared to smoking (i.e., “substantially lower risks to health than cigarettes”). The

evidence is also insufficient that U.S. consumers would use the products in the same manner as

consumers in Sweden and Norway (e.g., frequency or intensity of usage; exclusive snus use

versus dual use with cigarettes); therefore, we cannot conclude that, as actually used by U.S.
       

                         

                             

                             

                           

                           

                           

                             

                                 

                    

                           

                           

                             

                           

                           

                         

                         

                               

                       

                             

                  

  

                     

                         

                         

                       

                             

                         

                                   

   

                         

                           

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 16 of 77

consumers, the products would substantially reduce the risks to smokers. In addition, FDA

assessed the potential benefits and harms to the health of the population and concluded that

the evidence is insufficient to determine that the products will benefit the population as a

whole, taking into account, for example, smokers who switch completely to the General snus

products, non‐users who initiate use, and dual use by current tobacco users. Furthermore, the

scientific evidence is not sufficient to conclude that the modified risk information would be

comprehended by the public in the context of total health and in relation to all tobacco‐related

disease, particularly in the context of a warning. As a result, we are not issuing modified risk

orders based on the proposed claim in its current form.

Although your applications do not support the specific request to revise the warning, the

evidence you provided may support applications that seek to market the products with other

claims about relative health risks compared to cigarettes. Compared to the claim in your current

applications, any new claim should be more precisely tailored to the supporting science. For

example, you may consider pursuing explicit claims that appear outside of the health warning,

elsewhere on the label or in advertising, providing information to consumers concerning the

differences in specific health risks between the eight General snus products and cigarettes.

These claims will need to be carefully constructed and adequately tested so as to ensure that

the products meet the modified risk standards, including the requirement for consumer

comprehension. We recommend that you meet with the Office of Science in FDA’s Center for

Tobacco Products to discuss how your applications could be amended.

3. The Consumer Perception Study you conducted was deficient for purposes of providing insight

on potential behavioral impacts of the modified risk information or on consumer

comprehension because it did not use appropriate stimuli and the methods used to assess

comprehension, perceptions, and behavioral intentions were problematic. If you choose to

conduct a new consumer perception and comprehension study (e.g., as part of addressing the

deficiencies discussed in 1 and 2 above), you should address the deficiencies identified in our

review of the Consumer Perception Study. To best inform an evaluation of the effects of the

modified risk information, study stimuli should test the proposed modified risk information

verbatim. As noted above, consider providing modified risk information by some means other

than through the removal or revision of the warning statements. However, if modified risk

information remains in the warning statement itself, your study should also examine the impact

of the context of the modified risk information, i.e., how the context of the modified risk

information (e.g., whether presented within a warning or as a standalone claim) affects

consumer perception and comprehension.

Although a well‐designed study on consumer perception and comprehension will provide

indirect information on potential impacts on behavior, we recommend that you also consider

assessing consumer perception, comprehension, and intentions in the context of an actual use

study designed to address behavioral outcomes, particularly among current users of tobacco

products. Such data would provide direct evidence of the impact of the proposed claims on

consumer behavior, including evidence that U.S. consumers will use the proposed products as

intended, e.g., the products will be used by current tobacco users, in lieu of, and not in addition

to, smoking cigarettes.

Finally, in addition to the above deficiencies, the Response Letter included requests and

recommendations for any potential future submission, summarized as: (1) if a population model is
       

                             

                      

   

                           

           

                                 

                          

                             

                             

                          

                                

  

                           

                             

   

                       

                         

                           

                               

                          

                           

                         

               

                                 

                

                               

                

                                     

                              

           

                           

                               

                               

                              

                            

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 17 of 77

provided, a request for detailed information pertaining to its construction and inputs; and (2) a

recommendation to follow best practices for conducting systematic reviews and meta‐analyses.

B. September	2018	Amendment

On September 17, 2018, Swedish Match submitted an amendment to address the FDA Response Letter.

The applicant addressed the deficiencies accordingly:

 Deficiencies 1 and 2: The applicant has tested and proposed a revised modified risk claim that is

more precisely tailored to the scientific evidence. Specifically, the revised claim conveys specific

health risks that are reduced relative to cigarette smoking, describes how the product should be

used relative to cigarettes (i.e., “instead of”) and does not include a subjective qualifier of the

risk reduction (e.g., “substantially”). The revised modified risk claim is explicit and appears

outside of the health warning label. The applicant no longer requests to change or remove any

warning labels.

 Deficiency 3: The applicant has conducted a new consumer perception study to evaluate the

revised modified risk claim and redress the initial study’s deficiencies in terms of study stimuli

and measures.

In addition, the applicant acknowledged the request and recommendation provided by FDA.

With this amendment, the applicant requests marketing authorization under Section 911(g)(1) to market

the above mentioned eight modified risk General Snus products with the following explicit risk

modification claim in product advertising: “Using General Snus instead of cigarettes puts you at a lower

risk of mouth cancer, heart disease, lung cancer, stroke, emphysema, and chronic bronchitis.” The

applicant submitted a new consumer study, the Perceptions and Behavioral Intentions (PBI) study, to

evaluate consumer reactions to the product with the revised proposed claim, including consumer

understanding, perceptions, and intentions to buy the product.

C. Proposed	Modified	Risk	Labels,	Labeling,	and	Advertising	(LLA)	

The applicant seeks MRTP orders under Section 911(g)(1) of the FD&C Act for the eight General Snus

tobacco products with the following modified risk claim:

“Using General Snus instead of cigarettes puts you at a lower risk of mouth cancer, heart

disease, lung cancer, stroke, emphysema, and chronic bronchitis.”

The applicant proposes to use the claim in advertisements but does not plan to add it to the products’

labels. The applicant is no longer requesting any changes to the currently required smokeless tobacco

warning labels on its LLA materials.

The September 2018 amendment did not include a description of the marketing plan, sample

advertisements or other marketing materials, with the exception of the storyboard for the video used as

the PBI study stimulus. FDA requested this information on October 24, 2018, to which the applicant

responded on November 26, 2018. Upon review of this submission and the sample marketing materials

included, FDA identified possible additional modified risk claims. FDA contacted the applicant to clarify
       

                            

                           

                        

                              

                           

                                 

                       

                            

                         

                   

                                 

                       

                                

                             

                            

                               

                          

                             

                               

           

                             

                             

                               

                                

                         

                            

                          

                                    

                                 

                                

                 

                          

                        

                         

                             

                               

                                                            

                         

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 18 of 77

the applicant’s intentions. The applicant later submitted an amendment on January 30, 2019, which

replaced the information previously provided in the November 2018 amendment related to the general

marketing strategy and sample advertisements. This amendment also included a revised video

storyboard. In particular, after discussions with the Agency, the applicant revised the storyboard for the

proposed video by removing the text related to reducing impurities and the word “approved”.

As described in that amendment, the applicant proposes to include its claim in its advertising using the

following platforms: its branded website, print and online advertising, earned media/public relations,

direct mail, email, social media, and consumer activation selling events in adult only facilities. The

applicant submitted a video advertisement with the proposed modified risk claim, which consumers

would be able to view on the applicant’s branded website.

D. Tobacco	Products	Scientific	Advisory	Committee	

Pursuant to Section 911(f) of the FD&C Act, FDA referred the original MRTPAs to the Tobacco Products

Science Advisory Committee (TPSAC), and TPSAC reported its recommendations on the applications

during an open public committee meeting held on April 9‐10, 2015. At the meeting, TPSAC discussed

the ten submitted MRTPAs, including the adequacy of the scientific evidence to support the originally

proposed modified risk claims.3

3 Information about the meeting, including the complete transcript, is archived and available at: https://wayback.archive‐

it.org/7993/20170404143857/https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/TobaccoProductsScien

tificAdvisoryCommittee/ucm434209.htm.

The TPSAC discussion was summarized in the 2016 TPL Review.

The September 2018 amendment to the applications was also referred to TPSAC and TPSAC reported its

recommendations on February 6, 2019, during an open public meeting. TPSAC discussed FDA’s

preliminary assessment of the amendment and had the opportunity to raise any additional issues or

concerns raised by the revised claim. A brief summary is provided here. Meeting materials, including

complete meeting transcript, are available at: https://www.fda.gov/advisory‐committees/tobacco‐

products‐scientific‐advisory‐committee/2019‐tpsac‐meeting‐materials‐and‐information

FDA shared its preliminary assessment of the amendment with TPSAC, noting that the applicant has

addressed previous concerns by proposing an explicit modified risk claim that is more specific and

independent of the warning label, and by conducting a new consumer perception study that does not

suffer from the methodological flaws of its original study. TPSAC was asked to discuss FDA’s preliminary

assessment, including whether the revised modified risk claim raises new or additional concerns

regarding the potential impact on: (a) consumer understanding, and (b) population health. TPSAC did

not identify specific concerns about FDA’s preliminary assessment. The TPSAC discussion addressed a

number of topics. One topic of discussion was the issue of youth, including the lack of youth data

provided by the applicant and the potential risks to youth, suggesting that while snus use among youth

may currently be low, this could change. Another topic of interest was the claim wording. The

committee discussed the importance of communicating accurate information and acknowledged

challenges to ensuring universal interpretation among all subgroups. Some members felt that the

phrase “instead of” was vague and suggested alternative phrasing (e.g., “switching completely”). The

committee also discussed the level of misunderstanding among the U.S. population regarding the

relative harms of smokeless products in general, and some argued that the proposed modified risk

products may help benefit the health of the population as a whole by providing “corrective” information
       

                              

                          

                         

                                

                         

   

                                 

                       

                        

                          

                              

                                  

                            

                     

                             

                             

                          

                    

                           

                          

                                

                             

                             

                               

                                   

                        

                               

                            

                           

                       

                              

       

                           

               

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 19 of 77

in the context of widespread misinformation. In general, TPSAC felt that the applicant’s study was

reasonable, and its proposed modified risk claim seems to convey an accurate message. TPSAC

highlighted the importance of strategic post‐market surveillance for any product that obtains marketing

authorization as an MRTP. Concerns raised in TPSAC’s discussion related to (a) youth and (b) claim

interpretation are addressed elsewhere in this review and in the Social Science review.

E. Public	Availability	

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

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

information). The public comments on the original applications (including their amendments) are

discussed in the individual discipline and TPL reviews (2016). The September 2018 amendment

(including its subsequent amendments) was also made available to the public. The docket for public

comment on this amendment to the MRTPAs was open from October 29, 2018 to May 13, 2019. FDA

received 24 public comments from individuals, academia, and other organizations. In addition to legal

and advocacy issues, the comments included independent consumer perception information, critiques

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

The issues and concerns raised in the 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 are addressed in the Social Science review.

III. Summary	of	Scientific	Evidence	

The September 2018 amendment proposes a revised modified risk claim and includes a new consumer

perception study conducted to assess that claim. The evidence provided in the original submissions,

along with this amendment, is the basis for FDA’s assessment. This review integrates the new evidence

with our existing assessment and conclusions to evaluate (1) substantiation of the revised claim and

assessment of the relative health risks of the products to individual tobacco users, (2) consumer

understanding of the proposed revised modified risk claim, and (3) the potential impact of the products

with the proposed revised claim on tobacco use behavior and the health of the population as a whole.

Where appropriate, this review will quote or directly reference the 2016 TPL review.

A. Relative	Health	Risks of	the	Proposed	MRTPs	to	Individual	Tobacco	

Users

The 2016 TPL review provided a comprehensive review of the evidence related to the health risks to

individuals from the use of General Snus products. This included an assessment of the manufacturing

process, product ingredients, and levels of harmful and potentially harmful constituents (HPHCs) in the

finished products, clinical studies, toxicological evidence, and long‐term epidemiological evidence of the

health effects of Swedish snus. No additional information regarding health risks was included in the

September 2018 amendment.

The original evaluations from the perspective of engineering, chemistry, and microbiology led to the

following conclusion in the 2016 TPL review (p.31):
       

                       

                         

                           

                       

                   

                         

                            

                           

     

                       

                                 

                        

                                 

                                   

                                 

                             

                             

                             

                         

                             

       

                             

                           

                               

                           

                               

                                

                             

                                  

                       

                     

                                 

                               

                             

                                 

                             

                                  

                                   

                        

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 20 of 77

We conclude that sufficient information has been provided to characterize the product

composition in terms of ingredients and additives and ensure that manufacturing processes and

controls that can affect the product composition, chemical stability, [and] HPHC levels meet the

manufacturer’s specifications and ensure that the products do not contain microbial counts at

levels that would pose risks to users of the products.

The clinical pharmacology review concluded that the products were expected to produce reinforcing

effects and have an abuse potential. The underlying scientific findings from the toxicological review

“generally support[ed] the FDA’s conclusion regarding the lower risks to health presented by the

General Snus products.”

In the scientific review of the original applications, epidemiological studies provided the strongest

evidence for assessing the long‐term health risks of Swedish snus use as compared to the risks from

cigarette smoking. Although the epidemiological literature is not product‐specific, the body of literature

from Sweden and Norway is particularly relevant to the assessment of the long‐term health risks of the

General Snus products that are the subject of these MRTPAs, as noted in the 2016 TPL review (p.33):

Many, if not all, of the studies included in the modified risk applications for the General Snus

products did not include the specific products that are the subject of the applications. Rather,

the studies included products that were available in Sweden and Norway. SMNA justifies the use

of the studies by asserting that during the period of study, SMNA products dominated the

Scandinavian snus market; that the SMNA products in those studies conformed to the

GOTHIATEK® standard; and, any observed health effects are the result of use of products that

meet the GOTHIATEK® standard.

FDA’s review of the eight General Snus products confirms that the eight General snus products

also conform to the GOTHIATEK® standard. It is reasonable to expect that General Snus

products, when used in a manner similar to that observed in the submitted studies, would result

in similar exposures and potential health effects as those reported in those studies.

The applicant also argues that the products it manufactures today have lower HPHCs than the products

that were the basis of the long‐term epidemiological studies of Swedish snus. During the February 6

TSPAC meeting, the applicant described the GOTHIATEK® standard as one that has changed over time

with the inclusion of new HPHCs and the reduction of maximum allowable levels of HPHCs. In its

February 6 presentation, the applicant presented data showing substantial reductions in total tobacco‐

specific nitrosamines, NNN, NNK, and benzo(a)pyrene from the mid‐1980s until today.

In the section that follows, we review the epidemiological evidence on the health risks of Swedish snus

to assess whether the proposed revised modified risk claim is scientifically accurate and to describe the

health risks to individual tobacco users of Swedish snus relative to other use behaviors.

1. Claim	Substantiation	and	Health	Risks	of	the	Proposed	MRTPs	Compared	to	

Cigarettes

This section provides a summary of and builds on FDA’s findings, as reported in the 2016 TPL and

Epidemiology reviews, regarding the risk of Swedish snus use compared to cigarette smoking, for each

of the health outcomes included in the revised modified risk claim. We focus on these outcomes both

because they are the subject of the revised modified risk claim and because they make up the vast

majority of the tobacco‐related disease burden. For detailed information on additional health
       

                         

                             

            

                                

                                 

                                   

                              

                                     

                          

                           

                                   

  

                           

                           

                                  

                               

                          

                             

                

                               

                             

                                

                               

                           

                             

                       

                             

        

                             

                        

                             

                          

                       

                                 

   

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 21 of 77

outcomes, including tooth loss and gum disease, esophageal cancer, stomach cancer, pancreatic cancer,

diabetes, and adverse pregnancy outcomes as well as all‐cause mortality, see FDA’s previous findings in

the 2016 TPL and Epidemiology reviews.

Note, the intended meaning of the claim may be subject to interpretation. In particular, the phrase

“instead of” might be interpreted as complete replacement of one product for another (i.e., use of snus

to the exclusion of cigarettes). Alternatively, it is possible that one might interpret the phrase to mean a

discrete instance of substitution – i.e., substituting snus for one cigarette. The assessment of scientific

accuracy in this section is based on a comparison of exclusive snus use to cigarette smoking (i.e., for the

former interpretation). The issue of consumer understanding of the claim is addressed separately, in

the context of the consumer perception study, including the degree to which consumers understand

that exclusive use of the General Snus products is the means by which the described risk modification is

achieved.

Table 1 presents summary relative risks from published meta‐analyses or pooled analyses of the

association between Swedish snus use and mouth cancer, heart disease, stroke and lung cancer

compared with non‐users of tobacco. The Roosaar et al. (2008) study, which is not a meta‐analysis, was

the only study FDA is aware of that assessed the relationship between Swedish snus use and

emphysema or chronic bronchitis. For comparison, Table 1 provides the cigarette smoking relative risks

based on the American Cancer Society’s Cancer Prevention (CPS) II study, which was used for

comparison in Appendix 6a of the original MRTPAs.

In characterizing the health risks of the products that are the subject of these MRTPAs, the applicant

relied on published epidemiologic studies of the health effects of Swedish snus conducted in Sweden

and Norway over the last several decades. The applicant presented this information on health risk in

various sections of the applications: Sections 6.1.1 “Health Risks Associated with the Use of Snus as

Compared to Using Cigarettes,” 6.1.2. “Health Risks Associated with Switching to Snus from Cigarettes

and Dual Use as Compared to Quitting Tobacco Entirely or Continued Smoking,” 6.1.3. “Health Risks

Associated with Switching from Cigarettes to Swedish Snus compared to Switching to FDA‐approved

Tobacco Cessation Products or Medication,” and Chapter 5 and the accompanying Appendix V of the

2013 ENVIRON Snus Monograph.

In assessing the scientific accuracy of the revised modified risk claim, we focus on the epidemiologic

evidence, drawing on the review conducted by the Epidemiology Branch in 2016. Epidemiology

reviewers conducted a full substantive review of the epidemiological evidence provided in the body of

the applications, along with supplemental material provided in the appendices. In addition, the review

incorporated findings from the independent systematic search for published epidemiologic studies of

Swedish snus use to identify any additional studies that pertain to the health risks of Swedish snus.
STN MR0000020‐22, MR0000024‐25, MR0000027‐29 

Table 1. Results from published studies11All but one study (Roosaar et al. 2008) are meta‐analyses

of health effects for oral cancers, heart disease, stroke, lung cancer, and emph

bronchitis associated with Swedish snus use or smoking compared to non‐users of tobacco (Data Source: MRTPAs, Appe

Snus Monograph; Rostron et al. 2018)

Reference Tobacco Product Used Mouth Cancer Heart Disease Stroke Lung Cancer Em

Bro

RR (95% CI), n RR (95% CI), n RR (95% CI), n RR (95% CI), n RR (

Boffetta et al. 2008 Swedish snus 1.0 (0.7‐1.3), n=4 n/a n/a 0.8 (0.6‐1.0), n=2 n/a

Lee & Hamling 2009;

Lee 2011 Swedish snus 1.01 (0.71‐ 1.45)†, n=4 n/a n/a 0.82 (0.52‐ 1.28)†, n=2 n/a

Rostron et al. 2018 Swedish snus n/a 1.04 (0.93‐1.16) §, n=3 † 1.04 (0.92‐1.17)†ǁ, n=1 n/a n/a

Boffetta & Straif 2009 Swedish snus n/a

Any MI: 0.87 (0.75‐1.02), n=6Fatal MI: 1.27 (1.07‐1.52), n=5

Any stroke: 1.02 (0.93‐1.13), n=3Fatal stroke: 1.25 (0.91‐1.70), n=2

n/a n/a

Lee 2011 Swedish snus n/a 0.99 (0.85‐1.14)†, n=9 1.06 (0.96‐1.17)†, n=6 n/a n/a

Roosaar et al. 2008 Swedish snus n/a n/a n/a n/a 0.8 

2.0 

CPS II Population 1982‐1988* Smoking 10.89 2.80 (35‐64 years old) 1.51 (64+ years old) 3.27 (35‐64 years old) 1.63 (64+ years old) 23.26 Bro

Chr

10.5

Abbreviations: RR=relative risk; CI=confidence interval; n=number of risk estimates for meta‐analysis; n/a=not applicable; MI=myocardial infarction*Male current smokers

†RR estimate is for never smokers

‡Nonmalignant respiratory disease death (which includes chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, pneumonia, and in§RR estimate includes a pooled study of 8 cohorts from Hansson et al. 2012

ǁRR estimate includes a pooled study of 8 cohorts from Hansson et al. 2014
       

                               

                                 

                                  

                                 

                              

                                   

                            

                               

                              

                           

                               

                               

                                 

                                 

             

                               

                               

          

                             

                           

                               

                       

                           

                       

                         

                      

                               

                               

                                

                                 

                                  

                                 

                              

                                 

                                    

                       

                             

                             

                               

                              

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 23 of 77

In its 2016 review, FDA considered the available evidence regarding the health risks of these snus

products in its evaluation of the scientific accuracy of the requested claims and to inform its assessment

of individual health risks of the product. The assessment of evidence pertaining to mouth cancer was in

response to the request to remove the mouth cancer warning, i.e., an implied modified risk claim that

the products, as compared to other smokeless tobacco products, cannot cause mouth cancer. In the

revised claim, the question is not whether snus can cause mouth cancer, but whether the risk of mouth

cancer among exclusive snus users is lower than among cigarette smokers. The remaining health

outcomes were originally assessed in regard to the applicant’s request to change the “not a safe

alternative” warning to “substantially lower risks to health than cigarettes” claim. For this claim, FDA

evaluated the evidence regarding how the risks among exclusive snus users compared to cigarette

smokers across a host of tobacco‐related diseases, to assess whether there was a reduction of risk

among the former group, and if so, whether it could be characterized as “substantial”. Because the

revised claim does not use the modifier “substantially”, the question here is limited to the first part:

whether the risk of the specific diseases listed in the proposed modified risk claim is lower among

exclusive snus users than among cigarette smokers.

Mouth    Cancer

FDA previously assessed the evidence related to mouth cancer to evaluate the request to remove the

mouth cancer warning and determined that the evidence did not support the implied claim that snus

use cannot cause mouth cancer.

The conclusions related to mouth cancer were summarized in the 2016 TPL review (p. 37):

Given the presence of nitrosamines in the products that are the subject of these applications,

the lack of a threshold dose for mouth cancer, the fact that the most recent published

epidemiological study (Roosaar et al. (2008)) found a statistically significant association between

snus use and mouth cancer, and the limitations related to the epidemiological evidence, the

totality of the available toxicological and epidemiological evidence demonstrates that the eight

General snus products can cause mouth cancer, and, correspondingly, does not support the

removal of the warning that these products can cause mouth cancer.

However, as noted in its Response Letter, FDA also concluded that the evidence the applicant provided

may support applications that seek to market the products with other claims about relatively lower risk

of mouth cancer for these products as compared to other tobacco products. The revised modified risk

claim from the applicant does not claim that the product cannot cause mouth cancer, but instead refers

to the General Snus products having lower risk for mouth cancer than cigarettes. In support of the

revised modified risk claim, the 2016 Epidemiology review concluded that the risk of oral cancer is lower

in exclusive Swedish snus users than in cigarette smokers. In particular, the review concluded that

“...based on the evidence presented by the applicant, the risk of oral cancer is lower in exclusive

Swedish snus users than in cigarette smokers” . This is clearly seen by comparing the relative risks for

Swedish snus and cigarette smoking compared to non‐users, shown in Table 1.

Heart    Disease

FDA previously assessed the evidence pertaining to heart disease and concluded that although the risk

of cardiovascular disease (CVD) in exclusive snus users may be lower than in cigarette smokers, there

was insufficient evidence to conclude that use of these products instead of smoking would result in

substantially lower risk of CVD. The revised modified risk claim no longer uses the phrase “substantially

lower.”
       

                           

                       

                       

                       

                         

                         

                           

                         

                       

              

                               

                 

                             

      

                                 

                           

                                 

                       

                               

                             

                               

                             

                             

                         

                

                             

                         

                       

                         

                           

                             

                       

                         

                               

                     

                               

                       

                         

                         

              

                           

                           

                                 

                               

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 24 of 77

The evidence related to CVD (ischemic heart disease, coronary heart disease, myocardial infarction (MI),

and overall CVD) was summarized in the 2016 TPL review (p. 51):

The applications contained studies evaluating the association between snus use and acute

cardiovascular effects as well as chronic effects. Acute effects evaluated included increased

heart rate and blood pressure. Longer term risk factors considered were hypertension, obesity,

and evidence of vascular disease (e.g., myocardial infarction, sudden cardiac death, and stroke).

Biochemical markers such as lipids or insulin resistance were also considered. The body of

published literature examining the relationship between use of snus and the various measures

of CVD risk and disease outcomes includes four experimental/clinical studies, two cohort

studies, two case‐control studies, and twelve cross‐sectional studies.

The physiologic effects of nicotine would not be expected to be different for snus compared to

other nicotine‐containing products. Cigarette smoke, however, has other cardiovascular toxins

not found in snus, e.g., carbon monoxide and fine particulate matter. Inhalation of these toxins

has significant cardiovascular effects.

Six cohort studies (Bolinder et al., 1994; Haglund et al., 2007; Hansson et al., 2009; Janzon and

Hedblad, 2009; Johansson et al., 2005; Roosaar et al., 2008), four case‐control studies (Hergens

et al., 2005; Huhtasaari et al., 1992; Huhtasaari et al., 1999; Wennberg et al., 2007), and one

cross‐sectional study (Bolinder et al., 1992) reported relative cardiovascular risk estimates for

both snus users and smokers in the same population. The study by Janzon and Hedblad (2009)

was excluded from the sponsor’s analysis because this study did not provide a smoking relative

risk estimate that was adjusted or controlled to exclude the potential effects of snus use. The

cross‐sectional study conducted by Bolinder et al. (1992) was not included in the sponsor’s plot

analysis because a later study by Bolinder et al. (1994), which was included, presented a

prospective analysis of the same cohort. Additional studies evaluating short‐term effects of snus

on biochemical markers were included in the monograph.

A number of studies suggest an association between Swedish snus and fatal MI and post‐MI

mortality. In the Swedish Construction worker cohort among never‐smoking men, there was a

positive association between Swedish snus use and fatal MI (RR= 1.32, 95% CI=1.08‐1.61)

(Hergens et al. 2007). Two different case‐control studies observed elevated but not statistically

significant associations between Swedish snus use and fatal MI (Huhtasaari et al., 1999; Hergens

et al., 2005). A recent pooled analysis of 8 prospective cohort studies observed a borderline

elevated 28‐day case‐fatality after an acute myocardial infarction (AMI) among current Swedish

snus users (RR=1.28, 95% CI=0.99‐1.68) (Hansson 2012). In a meta‐analysis, Boffetta and Straif

(2009) pooled six studies from Sweden and did not find an elevated risk of any myocardial

infarction (cardiovascular diseases, ischemic heart disease or myocardial infarction) (RR = 0.87,

95% CI = 0.75, 1.02). However, they did find a significant association between Swedish snus and

fatal myocardial infarction based on five Swedish studies (RR=1.27, 95% CI=1.07‐1.52). In

another meta‐analysis, Lee (2007) pooled five studies from Sweden and did not find an

association between Swedish snus and ischemic heart disease or acute myocardial infarction (RR

= 1.06, 95% CI = 0.83, 1.37).

In our independent systematic search of the literature, we identified an additional study that

examined Swedish snus use and mortality risk after myocardial infarction (Arefalk et al., 2014).

Among MI patients who were followed up for an average of 2 years, those quitting Swedish snus

had nearly half the risk of dying post‐MI compared with patients who continued to use Swedish
       

                 

  

                               

                                 

                         

                               

                               

                               

                         

                        

                           

                           

                             

                 

                                   

                             

         

                           

                           

                       

                                  

                           

                             

                                

                           

                     

                                 

                      

                                    

                                   

       

                             

                                 

                                  

                       

                           

                           

                                 

                           

                             

                       

                         

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 25 of 77

snus post‐MI (age and sex‐adjusted HR=0.51, 95% CI=0.29‐0.91; multivariable‐adjusted HR=0.57,

95% CI=0.32‐1.02).

The data clearly show acute cardiovascular effects related to use of snuff or snus. These effects,

which include increased heart rate and blood pressure, are likely due to nicotine. It is not clear

whether these acute effects lead to long‐term changes or chronic cardiovascular disease. Many

of the epidemiological studies are limited by the fact that a large percentage of the snuff/snus

users were current or former smokers. In the studies where ‘snus only’ users can be clearly

identified, the number of snus users is small. Additionally, in most of the studies that had long‐

term follow‐up, information about subjects’ tobacco usage was obtained at baseline so any

changes in behavior over the course of the study were not recorded.

In summary, while the negative effects of cigarette smoking on cardiovascular health are well

established, the data for SLT, including Swedish snus, are less so. Nevertheless, several studies

have found an association between snus use and CVD mortality, fatal MI, or post‐MI mortality,

including recent pooled and meta‐analyses. These findings deserve further investigation.

Although the risk of CVD in exclusive snus users may be lower than in cigarette smokers, there is

insufficient evidence to conclude that use of these products instead of smoking would result in

substantially lower risk of CVD.

Subsequent to the completion of FDA’s review, Rostron and colleagues (2018) conducted a systematic

review and meta‐analysis of studies pertaining to smokeless tobacco use and circulatory disease risk,

providing a more comprehensive examination of this relationship, including more recent data (e.g.,

Timberlake et al., 2017). Based on this review, risk of ischemic heart disease was not increased in

Swedish studies of current smokeless tobacco users who were never smokers (vs. non‐users) (RR=1.04,

0.93‐1.16, n=3), but was significantly increased in U.S. studies of smokeless tobacco users who were

never smokers (RR=1.17, 95% 1.08‐1.27, n=3). As described above and in the 2016 TPL review, the

evidence derived from studies of Swedish smokeless tobacco users is particularly relevant to this

assessment because products manufactured by Swedish Match dominated the Scandinavian market

during the period of these studies and the Swedish Match products in those studies conformed to the

company’s GOTHIATEK® standard. By comparison, as shown in Table 1, cigarette smoking has been

found to increase risk of CVD by a factor of about 1.5‐ to 3‐fold. This most recent review provides

additional clear evidence that the heart disease risks due to Swedish snus use are lower than the risks

from cigarette smoking.

Stroke

FDA previously assessed the evidence pertaining to stroke and concluded that although the risk of

stroke in exclusive snus users may be lower than in cigarette smokers, there was insufficient evidence to

conclude that use of these products instead of smoking would result in substantially lower risk of stroke.

The revised modified risk claim no longer uses the phrase “substantially lower.”

The evidence related to stroke was summarized in the 2016 TPL review (p. 53):

The applicant stated that two case‐control (Asplund et al., 2003; Koskinen and Blomstedt 2006)

and four cohort studies (Bolinder et al., 1994; Haglund et al., 2007; Hansson et al., 2009; Janzon

and Hedblad, 2009) reported relative risk estimates for stroke among both snus users and

smokers in the same population. The applicant also stated that, among snus users, stroke (CVA)

risk estimates from the individual studies and summary estimates from meta‐analyses (Boffetta

and Straif, 2009; Lee, 2007; Lee, 2011) were not statistically significantly increased. Among
       

                       

                             

                         

                           

                                 

                          

                         

                                 

                         

                             

                             

                  

                         

                             

                           

                             

                

                         

                                 

                         

                             

                             

                         

      

                       

                             

                             

                             

                       

                           

                             

                           

        

                                 

                             

                           

                                  

                             

                       

                                 

                      

                                    

                                     

   

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 26 of 77

smokers, risk estimates from most of the individual studies were statistically significantly

increased and where increased, generally ranged from 1.4 to 3.0. Meta analyses and large US

cohorts were generally consistent with the results from the individual studies. Overall, the

stroke risk is consistently at least 40% greater among smokers compared to non‐users of

tobacco. The analyses in three of the four studies (Asplund et al. 2003; Bolinder et al., 1994;

Hansson et al., 2009) controlled for hypertension, an important risk factor for stroke.

The findings for the association between Swedish snus and fatal stroke and post‐stroke

mortality have been mixed. In addition to the Hergens 2008 study as noted in the ENVIRON Snus

Monograph, in which current Swedish snus use was associated with fatal ischemic stroke

(RR=1.72, 95% CI=1.06‐2.78), the older study of the same cohort by Bolinder 1994 observed an

elevated, but non‐significant risk of death due to stroke among current Swedish snus users, in

younger men ages 35 to 54 (RR=1.9, 95% CI=0.6‐5.7).

Boffetta and Straif (2009) reviewed three studies of any stroke (cerebrovascular disease or

stroke) from Sweden and did not find a significant association between Swedish snus and stroke

(RR = 1.02, 95% CI=0.93‐1.13) or fatal stroke (RR‐1.25, 95% CI=0.91‐1.70). Lee (2007) reviewed

two studies from Sweden and did not find a significant association between Swedish snus and

stroke (RR = 1.17, 95% CI = 0.80‐1.70).

In our independent systematic search of the literature, we identified an additional pooled

analysis of 8 prospective cohort studies of Swedish snus and risk of stroke (Hansson et al., 2014).

The analysis was restricted to never smokers and included the Swedish Construction Worker

cohort. No association between Swedish snus and the overall risk of stroke or stroke subtypes

was observed, but an elevated risk of 28 day case fatality (OR=1.42, 95% CI=0.99‐2.04) and

stroke mortality (HR=1.32, 95% CI=1.08‐1.61) was observed, after adjusting for age, BMI, and

year of diagnosis.

SMNA acknowledges that nicotine has hemodynamic effects that may increase the risk of

vascular diseases – specifically elevations of heart rate and blood pressure. It is not clear

whether these effects lead to increased stroke risk among snus users. In summary, while the

negative effects of cigarette smoking on stroke risk are well established, the data for SLT,

including Swedish snus, are less so. Nevertheless, recent evidence suggests an association

between snus use and fatal stroke, which deserves further investigation. Although the risk of

stroke in exclusive snus users may be lower than in cigarette smokers, there is insufficient

evidence to conclude that use of these products instead of smoking would result in substantially

lower risk of stroke.

The updated systematic review discussed above (Rostron et al., 2018) also found that risk for stroke was

not increased in Swedish studies of current smokeless tobacco users who were never smokers (vs. non‐

users) (RR=1.04, 0.92‐1.17, n=1) but was significantly increased in U.S. studies of smokeless tobacco

users who were never smokers (RR=1.28, 95% 1.01‐1.62, n=3). As described above and in the 2016 TPL

review, the evidence derived from studies of Swedish smokeless tobacco users is particularly relevant to

this assessment because products manufactured by Swedish Match dominated the Scandinavian market

during the period of these studies and the Swedish Match products in those studies conformed to the

company’s GOTHIATEK® standard. By comparison, as shown in Table 1, cigarette smoking has been

found to increase risk of stroke by a factor of about 1.5‐ to 3‐fold. This most recent review provides

additional clear evidence that the risk of stroke due to Swedish snus use is lower than the risk from

cigarette smoking.
       

                                   

                                   

                                   

               

                             

                           

                               

                         

                           

                           

                         

                               

                             

                             

                             

                                   

                               

                               

                 

                         

                               

                                 

                          

                               

                         

                            

                               

                               

                   

                         

                         

                         

            

                             

                                 

                                   

                            

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 27 of 77

Lung    Cancer

In support of the revised modified risk claim, FDA’s review of the evidence pertaining to lung cancer risk

previously concluded that the use of Swedish snus does not have a significant effect on lung cancer risk

Therefore, and as clearly shown in Table 1, the risk of lung cancer is substantially lower in exclusive

Swedish snus users than in cigarette smokers.

The evidence related to lung cancer was summarized in the 2016 TPL review (p. 50):

The observed relative risks reported by the individual studies and the summary estimates from

the two meta‐analyses suggest that the use of Swedish snus that are the subject of these

applications does not have a significant effect on the risk of lung cancer.

The evidence related to lung cancer was summarized in the Epidemiology review (p. 24):

In section 6.1.1.3 of the applications, the applicant presented two Swedish studies that assessed

the association between Swedish snus and lung cancer and estimated the association between

smoking and lung cancer (Bolinder 1994; Luo 2007). A third study of Swedish snus and lung

cancer, not mentioned in section 6.1.1.3 of the applications, was described in section 5.3.5 of

Chapter 5 of the ENVIRON Monograph. The applicant concluded that “Swedish snus users are at

no greater risk of developing lung cancer than non‐ or never‐users of tobacco, while smokers are

7 to 30 times more likely to develop lung cancer.” (p 406 section 6.1.1.3 of the applications)

Based on the evidence presented by the applicant, we agree with the applicant that there does

not appear to be an elevated risk of lung cancer among exclusive Swedish snus users. Although

use of snus exposes individuals to 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK), a

potent lung carcinogen, the levels are lower than traditional smokeless tobacco products, which

have not been conclusively linked to increased lung cancer risks. On the contrary, smokers are at

greatly increased risk of lung cancer. Based on this evidence, we conclude that the risk of lung

cancer is substantially lower in exclusive Swedish snus users than in cigarette smokers.

Emphysema    and Chronic Bronchitis

In support of the revised modified risk claim, FDA’s Epidemiology review of the evidence pertaining to

respiratory disease, including emphysema and chronic bronchitis, previously concluded that the risk of

respiratory disease is substantially lower in exclusive Swedish snus users than in cigarette smokers.

The evidence related to respiratory disease was summarized in the 2016 TPL review (pp. 50‐51) :

Snus is an oral SLT product and therefore is unlikely to cause respiratory disease or chronic

obstructive lung disease (COPD), diseases commonly associated with cigarette smoking.

Although there are harmful and potentially harmful constituents (HPHCs) found in SLT products,

none have been linked to development of chronic lung disease unless inhaled. The pathobiology

of COPD involves multiple injurious processes which are triggered by inhaled toxicants and

modified by cellular senescence and infection.

The literature submitted by SMNA on the relationship between COPD and use of SLT products

such as Swedish snus (Schivo et al. 2014) and various types of NRTs (Jimenez‐Ruiz et al., 1998)

suggests that there is no relationship, which is believed to be due to the lack of inhaled irritants

being introduced directly into the lungs (Kirkham and Barnes, 2013; Stevenson et al., 2006).
       

                           

                             

                            

                           

                                 

                                 

                           

                         

                               

                                   

                          

                              

                               

                                

                           

                            

                           

                               

                               

                          

                        

                             

                           

    

                               

                                      

                       

                                

                                     

                          

                         

                                

                                 

                         

                            

                          

                                   

                           

                                        

                           

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 28 of 77

Nicotine concentrations do not appear to be relevant to the development of COPD. Age seems

to be the most important factor in the development of COPD in Swedish non‐smokers (Hagstad

et al., 2012) though SLT products were not analyzed as part of this study.

The primary risk factor for COPD and other chronic respiratory diseases is cigarette smoking.

Since the ‘tar’ of cigarette smoke is the primary source of toxins, snus (a smokeless product) is

much less likely to be a significant risk factor for COPD or other respiratory diseases. The large

review articles and population studies confirm minimal, if any, increase in risk of respiratory

disease related to use of the products which are the subject of these applications.

Summary    and Conclusion

Swedish Match seeks MRTP orders for the eight General Snus products with the following claim: “Using

General Snus instead of cigarettes puts you at a lower risk of mouth cancer, heart disease, lung cancer,

stroke, emphysema, and chronic bronchitis.” This revised modified risk claim addresses the issues that

precluded a finding of scientific substantiation in FDA’s 2016 review of the applications. In particular,

the claim regarding mouth cancer risk is now in relative comparison with cigarette smoking, rather than

an implied claim that the products cannot cause mouth cancer. Second, rather than a generalized claim

about “lower risks to health than cigarettes”, the revised claim names specific diseases/endpoints for

which the evidence supports lower risks. Finally, whereas the original statement characterized the risk

reduction as “substantial”, the revised claim does not use this or any other modifier.

In sum, FDA’s assessment of the scientific evidence supports the conclusion that exclusive users of snus

have lower risk relative to cigarette smokers for each of the following health outcomes: mouth cancer,

heart disease, lung cancer, stroke, emphysema, and chronic bronchitis. This assessment supports the

revised modified risk claim as scientifically accurate. Overall, the available scientific evidence

demonstrates that the products that are the subject of these applications, as actually used by

consumers, will significantly reduce harm and the risk of tobacco‐related disease to individual tobacco

users.

2. Health	Risks	of	Proposed	MRTP	Use	Compared	to	Other	Use	Behaviors	

In the original review of SMNA’s applications, FDA evaluated the health risks of General Snus compared

with a range of other products and use behaviors. As described in the 2015 TPL review for the General

Snus premarket tobacco product applications (PMTAs) (FDA, 2015), General Snus products contain

significantly lower levels of NNN and NNK than other smokeless tobacco products in the U.S. market. As

a result, cancer risk is expected to be lower from the use of General Snus products compared to many

other smokeless tobacco products. Although exposure to HPHCs, including nitrosamines, is lower than

many other smokeless tobacco products, exposure is still elevated compared with non‐use and,

therefore, long‐term use of Swedish snus is not without health risks. The 2016 TPL review concluded

that Swedish snus use (compared with no use of tobacco) has been associated with increased risk of

specific disease endpoints in individual epidemiological studies, including pancreatic cancer, fatal MI and

stroke, diabetes, and adverse pregnancy outcomes. In addition, there are potential negative effects of

nicotine exposure on the developing adolescent brain. Similarly, FDA previously concluded that “the

health risks from the use of General Snus products that are the subject of the applications is greater

than those posed by cessation” and “greater than those posed by FDA‐approved cessation therapies.”

(FDA 2016, p. 58) In terms of dual use of General Snus and cigarettes, as opposed to exclusive use of

General Snus products, FDA has concluded that “there is insufficient information to conclude that
       

                             

         

                     

                  

                               

                                        

                                 

                                 

                      

                             

                                 

                     

                                

                        

                               

           

                                 

                                       

                                

                              

                               

                                   

                              

                               

                             

   

                           

                     

                            

                   

                       

                                 

                             

                                  

                         

                                  

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 29 of 77

smokers who use snus in conjunction with smoking will realize any reductions in risk of tobacco‐related

disease.” (FDA 2016, p. 59)

B. Effects	of	the	Proposed	MRTPs	on	Consumer	Understanding	and	

Perception	

Consumer understanding and perceptions of the MRTPs, including of the claim, 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

MRTPs to the extent that it affects who uses the products and how they use them. For instance, if an

MRTP is shown to reduce tobacco users’ risk via exclusive use of the product, then consumers should

understand they will not benefit from the risk reduction if they use the MRTP in conjunction with

another tobacco product. Relatedly, Section 911(h)(1) requires that the modified risk communication

enable consumers 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.

As discussed above, the applicant’s original consumer perception study suffered from methodological

flaws that limited the utility of those data. Accordingly, FDA concluded that there was not sufficient

information to conclude that participants comprehended the modified risk information. Because the

claim has since been revised, and a new study conducted, the present evidence and assessment replaces

the conclusions of the prior review.

As noted earlier, the revised proposed claim uses the phrase “instead of” – which could be interpreted

to mean one can reduce his/her risk by using the General Snus products as a replacement for and to the

exclusion of cigarettes. However, it is also possible that a consumer could interpret the phrase “instead

of” to imply a situational, rather than complete, pattern of product substitution. This is of consequence

because, if this latter interpretation of the claim led to users initiating the MRTPs while maintaining

some level of smoking, such users would not experience a reduction in their individual risk and, in turn,

the MRTPs would not benefit population health. Therefore, of particular interest in the assessment of

consumers’ understanding of the claim is the extent to which they understand that the risk reduction is

not achieved by partial switching (i.e., maintaining some level of cigarette smoking after initiating snus

use).

1. Perception	and	Behavioral	Intentions	(PBI)	Study	

The applicant conducted one quantitative study, the PBI Study, to assess the proposed modified risk

claim’s effects on consumer understanding, perceptions, and behavioral intentions related to tobacco

products. Prior to conducting this study, the applicant initiated its claim development process with

qualitative research, involving three phases of focus groups and triads.

The PBI Study was a between‐subjects experimental study administered via computer, smartphone, or

tablet. Characteristics of this study are presented in Table 2. Participants were randomized to view a

video advertisement for General Snus that included either the proposed modified risk claim, one of two

alternative test claims, or no test claim. The video is approximately one minute long and begins by

introducing General Snus and describing its product features (i.e., smokeless, spitless, chilled, upper‐lip

pouch). It states that General Snus is made with “only the best” air‐dried tobaccos; pure, clean water;
       

                                  

                             

                            

                                 

                               

               

                                 

                               

                   

                               

                           

                                    

                                    

                              

                           

                                    

                               

                                 

                               

                               

                                   

                             

                           

                             

                               

                           

                                     

                               

                               

                    

                                                            

                                     

                                       

                                 

                                           

                        

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 30 of 77

salt; and other natural and artificial flavors found in everyday food items. The video then describes the

production process for General Snus, stating that it reduces “impurities found in other tobaccos” and

that the product meets “strict Swedish food‐grade standards.” Concurrently, the video depicts an image

of an “APPROVED” stamp being applied. The video then provides the audio and text of the proposed

claim:

“Using General Snus instead of cigarettes puts you at a lower risk of mouth cancer, heart

disease, lung cancer, stroke, emphysema, and chronic bronchitis.”

This is followed by a web address (“Learn more at GeneralSnus.com”) and an audio and textual display

of one of the four currently required smokeless tobacco warning labels. The video in the control

condition included the same information but without the proposed claim.4

4 Note: As described above (pp. 17‐18), the video advertisement the applicant proposes to use in their marketing (January 30

amendment) varies slightly from the version used in the PBI Study. In particular, the revised version does not reference reduced

impurities; does not display the word “APPROVED”; and characterizes the Swedish food‐grade standards as “tough” rather than

“strict”. FDA does not expect these differences to affect the validity of the PBI Study’s results, given the findings and given that

the additional text was included in both the control and test conditions.

Note, the video ad featured one General Snus product style (a 24‐count portioned product) in two

flavors (mint and wintergreen), even though the MRTPAs include products with other flavors (including

unflavored) and styles (including a loose product). We do not consider this to be a major limitation of

the study. The aim of the PBI Study was to evaluate the effects of the proposed claim on consumer

understanding and intentions to use products. For these General Snus products, we do not expect that

consumer understanding of the claim would vary based on the products’ flavor or product style.

Intentions to use the product, on the other hand, may vary based on the flavor and product style. The

applicant’s rationale for using mint and wintergreen products in the study stimuli was that these are

popular variants, accounting for around 70% of General Snus sold in the U.S., which is a reasonable

justification. In contrast, if the study had included unpopular product flavors or styles – such as

unflavored products that most users do not initiate with – this could cause the study to underestimate

the claim’s effects on use intentions (e.g., because consumers may not intend to use a product that they

expect to dislike, even if the product confers reduced risk compared to other products).

After viewing the video, participants responded to items assessing the following key study outcomes:

comprehension of the proposed modified risk claim, perceptions of absolute and relative health risks of

using General Snus, intentions to buy General Snus, and intentions to quit smoking and using other

tobacco products. While answering these questions, participants were able to re‐watch the video by

clicking a link on the page, though very few did so (0.5%; November 26, 2018 amendment, p. 24). This

evaluation focuses on the condition in which participants viewed the ad with the proposed claim (i.e.,

Claim 1 in the PBI Study documentation) and the condition in which participants viewed the video

advertisement with no test claim, which serves as an experimental control.
       

                        

                       

                             

      

   

                

  

                      

                           

                  

       

                               

                             

                             

   

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Table 2: Characteristics of the applicant’s Perceptions and Behavioral Intentions (PBI) Study

Overview

Survey administered via computer, smartphone, or tablet. Participants viewed a General Snus video

advertisement with or without the proposed modified risk claim and then responded to measures of

perceptions and intentions.

Study Design

Between‐subjects experiment with stratified randomization across three factors:

 Modified risk test claim: one condition with the proposed modified risk claim; two conditions with

alternative test claims; one control condition without a test claim.‡

The three tested claims were: “Using General Snus instead of cigarettes puts you at a lower risk of mouth cancer, heart

disease, lung cancer, stroke, emphysema, and chronic bronchitis.”; “Using General Snus products instead of cigarettes would

significantly reduce harm and the risk of certain tobacco‐related diseases to individual tobacco users.”; “No tobacco is totally

safe, but using General Snus instead of cigarettes puts you at a lower risk of chronic lung diseases and other tobacco‐related

ailments.”

 Warning label: four currently required smokeless tobacco warning labels.

 Product flavors: mint and wintergreen.

Analyses collapsed across warning labels and product flavors, except where noted.

Sample

10,532 adults recruited from a mix of online panels to reflect demographic characteristics of online

U.S. adult population of legal age for tobacco use.

Tobacco user groups† included:

† Note: Young adult refers to participants of legal age to use tobacco products to age 24 years. Older adult refers to participants

over age 24 years. Adult refers to participants of legal age to use tobacco products or older.

 Young adult never tobacco users (n = 1,914)

 Older adult never tobacco users (n = 1,936)

 Young adult cigarette smokers (n = 1,828)

 Older adult cigarette smokers (n = 1,942)

 Adult former cigarette smokers (n = 1,942)

 Adult smokeless tobacco users (n = 970)

This review focuses on the 5,289 participants in the proposed modified risk claim condition and the

control condition, including 958 young adult never tobacco users, 977 older adult never tobacco users,

970 former smokers, 916 young adult smokers, 982 older adult smokers, and 486 smokeless users.

Key Outcomes

 Intentions to buy General Snus

 Intentions to use tobacco products

 Intentions to quit cigarettes and other tobacco products

 Perceptions of absolute and relative health risks

 Comprehension of the proposed modified risk claim

 Believability of the proposed modified risk claim

Comprehension  

Two items assessed recognition of information from the video advertisement, including claim text.

Results show that the majority of participants were able to correctly answer these items (>75%). In

particular, the item assessing participants’ processing of the claim’s message was a multiple‐choice

question about the effects of using General Snus instead of cigarettes on their risk of mouth cancer,

heart disease, lung cancer, stroke, emphysema, and chronic bronchitis. Response options included

“puts you at lower risk...”, “does not affect your risk...”, “puts you at higher risk...”, and “None of the

above.” The option defined as correct was the one that matched the proposed modified risk claim
       

                                

                              

                             

                                

                                 

                               

              

                               

                                  

                             

                                    

                             

                            

                           

             

                           

                                    

                                

                                 

                              

                         

                    

                                                            

                                   

                                 

                                 

                                

                                     

                   

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(“puts you at lower risk...”). Among participants who viewed the video with the proposed claim, most

selected the correct response (78‐88% across all tobacco user groups; PBI Study Report, pp. 155‐160). In

contrast, among participants who viewed the video without the proposed claim, few selected the “lower

risk” response option (9‐19% across all tobacco user groups; PBI Study Report, pp. 155‐160). As noted

above, participants were able to review the video as they answered questions if they wanted, but few

did so. These findings suggest that most consumers exposed to the proposed claim attended to the

study stimulus and processed the claim itself.

Perceptions        of Absolute Risks

Consumers’ perceptions of absolute risk are part of their overall assessment of risk and thus contribute

to our assessment of their understanding of the claim in the context of total health. Moreover, because

the proposed modified risk claim identifies specific disease endpoints, we would expect that the claim

might lower perceptions of risk of those diseases. At the same time, whereas the claim conveys a risk

reduction relative to cigarettes, this should not lead consumers to perceive the elimination of disease

risk. The PBI Study examined participants’ perceptions of absolute risks of General Snus including

whether, after viewing the video with the proposed modified risk claim, adult consumers understood

that using General Snus causes health risks.5

5 Note: In analyses of all risk perception items (PBI Study Report, pp. 87‐209), the applicant disregarded “Don’t know”

responses when calculating percentages. However, the Social Science review noted that visual inspection of the data tables

suggested that the proposed claim may have affected participants’ likelihood of responding “Don’t know” on some risk

perception items. Because “Don’t know” is a potentially meaningful response, the Social Science review included “Don’t know”

responses in the denominators of the percentages for risk perception items. As a result, the percentages presented in this

review differ slightly from those provided in the PBI Study Report.

Adding the proposed modified risk claim to the video advertisement reduced consumers’ perceptions of

the absolute health risks of using General Snus for all eight health effects assessed. This was true among

all tobacco user groups tested. However, though the absolute level of perceived risk was reduced after

exposure to the claim, relative to no claim, consumers still perceived daily use of General Snus as

causing substantial risks of the eight health effects assessed (Figure 1). Together these findings suggest

the claim improved participants’ understanding of the products’ risks and are consistent with an

appropriate understanding of the claim in the context of total health.
       

                                      

                                           

                                         

                             

                                   

                                   

                                 

                               

          

                           

                             

                                  

                               

                                

                              

                             

                                  

                               

                         

                           

                           

                             

                         

                   

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Figure 1. Percentages of participants in the PBI Study who perceived a “moderate,” “high,” or “very high” chance of health

effects from using General Snus, after viewing the video ad with the proposed claim. The item asked, “If a typical person uses

General Snus® every day and no other tobacco products, what is the chance that person would suffer from the following health

conditions during his/her lifetime?” Options included: “very low chance,” “low chance,” “moderate chance,” “high chance,”

“very high chance,” and “Don’t know.” Source: Based on data from the PBI Study Report. Error bars: 95% CIs.

Perceptions      of Health Risks      Compared to Cigarettes

The PBI Study also examined perceptions of the relative risk of the product as it compared to cigarettes.

Because the proposed modified risk claim conveys a message that users can reduce their disease risk by

using General Snus instead of smoking cigarettes, understanding of the claim would be reflected in their

perceptions of relative risk.

Adding the proposed claim to the video advertisement for General Snus substantially increased the

percentage of smokers who perceived General Snus as lower in specific health risks than cigarettes

(Figure 2). As shown in Figure 2, smokers who viewed the video with the proposed claim, compared to

without it, were statistically significantly more likely to perceive daily General Snus use as presenting a

lower chance of all eight health effects tested compared to daily smoking. Adding the proposed claim

had similar effects among smokeless tobacco users (not shown). This pattern of results suggests that

participants’ perceptions were affected in the expected direction based on the message of the claim

(i.e., General Snus poses lower risk of the diseases named compared to cigarettes). We note that this

pattern held across all health effects assessed—which includes the diseases named in the claim as well

as one that was not: gum disease. However, overall, the proposed claim brought participants’

perceptions into better alignment with current scientific evidence regarding the health risks of using

General Snus, as reflected in the applicant’s proposed claim that using General Snus instead of

cigarettes would put consumers at lower risk of mouth cancer, heart disease, lung cancer, stroke,

emphysema, and chronic bronchitis. These findings support the conclusion that participants had an

appropriate understanding of the claim in the context of total health.
       

                                    

                                       

                                   

                                         

                

                           

                          

                          

                                 

                                 

                              

                               

                                

                           

                               

        

                             

                               

                                    

                           

                                

                               

                            

                             

                             

                        

                             

                                  

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Figure 2. Percentages of cigarette smokers who perceived a “lower” or “much lower” chance of health effects from using

General Snus daily compared to smoking cigarettes daily. The item asked, “Compared to the daily use of only cigarettes, the

daily use of only General Snus® has...” Response options included “a much lower chance,” “a lower chance,” “the same

chance,” “a higher chance,” “a much higher chance,” and “Don’t know.” Source: Based on data from the PBI Study Report and

November 26, 2018 Amendment. Error bars: 95% CIs.

Understanding        that the Proposed Claim              Does Not Apply to Partial Switching

As discussed above, the applicant’s proposed claim states that using General Snus “instead of

cigarettes” reduces health risks, which could be subject to interpretation. Consumers could interpret

this as complete product substitution, or alternatively, as situational or partial product substitution. If

the latter is true, this suggests that consumers could interpret the claim to mean there are health

benefits of partial substitution—that is, using General Snus in place of some, but not all, of one’s

cigarettes. The applicant did not provide evidence that there are health benefits of partially switching

to General Snus. The health effects of partial switching may depend on a person’s smoking frequency,

the extent to which the person cuts down on smoking, and the health endpoint. If consumers

misunderstand the applicant’s proposed claim to mean that partially switching to General Snus reduces

their disease risk, this could result in smokers continuing to smoke, which could prevent them from

reducing their health risk.

The PBI Study examined whether, after viewing the video with the proposed claim, adult consumers

understood the need to switch completely to General Snus to achieve the claimed reductions in disease

risk. In particular, this can be assessed with consumer perceptions of how the risks of dual use of

General Snus and cigarettes compare with both (a) exclusive General Snus use, and (b) exclusive

smoking. With respect to the former, the results show that the proposed claim enabled consumers to

understand that dual use of General Snus with cigarettes is more harmful than exclusively using General

Snus. Among cigarette smokers who viewed the advertisement without the proposed claim, 41% of

young adult smokers and 32% of older adult smokers perceived exclusive daily General Snus use as

presenting a lower risk of “serious health problems” compared to daily use of both General Snus and

cigarettes (Figure 3). In contrast, when the advertisement contained the proposed claim, substantially

more smokers perceived exclusive use of General Snus as presenting lower health risks compared to

dual use (60% of young adult smokers and 55% of older adult smokers). Similar effects were also
       

                          

                   

                               

                                  

                           

                             

                       

                                     

                                   

                                     

                                     

                                     

                       

                                     

                        

                           

                               

                                     

                                

                           

                              

                             

                                 

                               

                             

                                 

                               

                          

                             

                                 

                                      

                                

                               

                                 

  

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observed among smokeless tobacco users. For example, adding the proposed claim to the

advertisement substantially increased the percentage of smokeless tobacco users who perceived

exclusive General Snus use as presenting the a “lower” or “much lower” risk of “serious health

problems” compared to dual use with cigarettes (from 49% to 66%) (Figure 3). These results show that

the proposed claim improved adult smokers’ (and smokeless users’) perceptions that dual using General

Snus with cigarettes presents greater risks of specific health effects than exclusively using General Snus.

In turn, these findings support the conclusion that participants understood the claim.

Figure 3. Percentages of cigarette smokers and smokeless tobacco users in the PBI Study who perceived a “lower” or “much

lower” chance of health effects from exclusive daily General Snus use compared to daily use of both General Snus and

cigarettes. The item asked, “Compared to the daily use of both cigarettes and General Snus®, the daily use of only General

Snus® has...” Response options included, “a much lower chance,” “a lower chance,” “the same chance,” “a higher chance,” “a

much higher chance,” and “Don’t know.” Source: Based on data from the PBI Study Report. Error bars: 95% CIs.

Whereas the study provided evidence suggesting the proposed claim led to consumers’ understanding

of the health risks of dual use compared to exclusive General Snus use, it did not assess perceptions of

risk from dual use (i.e., partial substitution) compared to exclusive cigarette smoking. However,

additional insight into whether participants perceived the risk reduction to be attainable via partial

substitution (vs. exclusive use) comes from an item that asked smokers about the number of cigarettes

one could smoke per day on a day when they also used General Snus, while still achieving the lower

disease risk. The results from this item showed that exposure to the claim increased the number of

participants correctly responding that “zero” cigarettes could be smoked in addition to using General

Snus while still reducing one’s risk (Figure 4). In particular, viewing the advertisement with the

proposed modified risk claim, rather than without it, increased the proportion of young adult smokers

who responded “zero” to 56% (with the claim) from 45% (without the claim); and among older adult

smokers, to 44% (with the claim) from 34% (without the claim) (PBI Study Report, pp. 158‐159).

Importantly, adding the claim did not increase the proportions of smokers who selected the response

options consistent with partial substitution (“Up to 5 cigarettes,” “Up to 20 cigarettes,” or “As many as

you want to smoke”), suggesting that the proposed claim did not lead smokers to believe partial

substitution would reduce their disease risk. Although “zero” was the most commonly reported

response, this is likely an underestimate because the question was asked among respondents who, even

after exposure to the modified risk claim, did not perceive that General Snus conveys lower risk of

disease. For those respondents, it would be unclear how to respond to the item and is likely why there

are sizeable proportions that selected “none of the above” and “don’t know.” In other words, the

proportion of correct responses would have likely been higher had the question been asked only among

those who indicated they perceived General Snus as lower risk compared to smoking (in line with the

claim).
       

                                             

                                           

      

                             

                               

                                

                         

                         

                    

                             

                                 

                                

                                 

                              

                                

                               

              

                           

                                 

                                       

                                

                                 

                               

                              

                                   

                                   

                                

                               

                          

                               

                                

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Figure 4. Smokers’ responses to a PBI Study item about the number of cigarettes one can smoke on a day when they also use

General Snus, for General Snus to put one at a lower risk of disease. Source: November 26, 2018 Amendment. Error bars: 95%

CIs. *p=.001; **p=.005.

Perceptions      of Risk Compared            to Cessation Aids and Quitting

The PBI Study also examined whether the proposed claim would enable adult smokers to understand

that using General Snus presents greater risks of specific health effects than using cessation aids and

quitting all tobacco use. Along with the results described above on perceptions of the absolute and

relative health risks of using General Snus, this provides information about overall consumer

understanding and could also be relevant to consumers’ expected use patterns, including whether

smokers would use General Snus instead of quitting all tobacco products.

After viewing the video without the proposed claim, the majority of participants perceived General Snus

as having greater health risks compared to cessation aids, but some perceived General Snus to be lower

in health risks. Specifically, across the eight health risks assessed, 16‐27% of young adult smokers and

15‐30% of older adult smokers perceived daily General Snus use as presenting a lower or much lower

chance of negative health effects compared to daily use of cessation aids. These proportions were

larger after smokers viewed the video with the proposed claim. After viewing the claim, 25‐33% of

young adult smokers and 32‐42% of older smokers perceived General Snus as lower in risks than

cessation aids across the eight health effects.

These findings are consistent with prior research finding that many U.S. smokers perceive nicotine

replacement therapies (NRTs) to be just as harmful as cigarettes (Shiffman et al., 2008; Czoli et al.,

2017), which may in part be due to beliefs that nicotine is the main cause of health harms from smoking

(e.g., Keely O’Brien et al., 2017). In other words, because the claim communicates that General Snus

reduces risks relative to cigarettes, for people who mistakenly believe the risks of NRT are similar to

cigarettes, the claim inadvertently shifted their perceptions of General Snus as lower risk relative to NRT

as well. Studies assessing perceptions of risk from smokeless tobacco compared to NRT are rare: a

review of the literature (Czoli et al., 2017) uncovered only one study, which found that around half of

U.S. adults who had heard of snus were “unsure” whether it was more harmful, less harmful, or as

harmful as NRTs or non‐nicotine medications (Regan et al., 2012). These results, along with the PBI

Study findings, suggest that many U.S. consumers do not understand the safety of NRT compared to

tobacco products. Indeed, such misunderstanding may partially explain why, in 2014‐2016, only one in

four adult cigarette smokers who tried to quit in the previous three months reported using nicotine

patches or nicotine gum during their most recent quit attempt (Caraballo et al., 2017). Regardless of
       

                             

                           

                             

                                  

                                 

                               

                             

                          

                        

                              

                               

                           

                               

                                

                                    

                               

                               

                               

                         

                              

                                 

                             

                         

               

                         

                                   

                                  

                              

                               

                                  

                                 

                                 

                             

                                  

                               

                             

                              

                                     

                             

                              

                                   

                                 

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these misperceptions related to NRT, there is no evidence that the MRTPs themselves are likely to

impact perceptions of NRT or affect consumers’ likelihood of initiating use of those products.

In addition, a minority of current cigarette smokers perceived that using General Snus would present

lower health risks than quitting the use of all tobacco and nicotine products. After viewing the video

with the proposed claim, 22‐26% of young adult smokers and 29‐38% of older adult smokers perceived a

lower or much lower chance of health effects (across the eight effects tested) for someone who

switches completely to General Snus than for someone who quits using all tobacco and nicotine

products. These percentages were significantly higher than among smokers who viewed the video

without the proposed claim (young adult smokers: 13‐20%; older adult smokers: 14‐26%). These

responses may reflect participants’ confusion about the survey item or response scale. According to the

applicant, cognitive testing of a prior version of the survey instrument found that some people were

confused about the comparison between switching to exclusive use of General Snus (i.e., quitting all

other tobacco and nicotine products and using General Snus only) vs. quitting all tobacco and nicotine

products. The applicant made changes to its survey items based on these cognitive testing results but

may not have completely solved the problems. It is useful to note that these findings are in direct

contrast to prior research on perceptions of health harm from using smokeless tobacco (e.g., in 2012‐13,

93% of U.S. smokeless tobacco users perceived smokeless tobacco as harmful to health; Agaku et al.,

2016) and findings from the PBI Study on Perceptions of Absolute Health Risks, which demonstrated that

these participants perceived considerable risks from using General Snus, including after viewing the

video with the proposed claim. Given the potential spurious nature of the above findings on

perceptions of General Snus compared to quitting the use of all tobacco and nicotine products, I believe

that these findings do not undermine the conclusion that consumers understood the claim, nor indicate

a significant likelihood that the proposed modified risk products would negatively affect consumers

quitting the use of all tobacco products.

Summary    and Conclusion

Overall, these results provide evidence that consumers generally understood the proposed modified risk

claim and the health risks of using the proposed modified risk General Snus products in the context of

total health. Exposure to the claim led to consumers understanding that the relative risk of snus is lower

compared to smoking with respect to the health outcomes described in the claim. This understanding is

an important precursor to tobacco use behaviors that will reduce harm to individual tobacco users and

benefit the health of the population as whole. In addition, the evidence (discussed in the Social Science

review) suggested that, though not the subject of the explicit modified risk claim, exposure to the claim

could lead smokeless tobacco users to accurately perceive General Snus to be lower in health risks than

other smokeless tobacco products, which in turn could lead to additional tobacco use behaviors that

would reduce harm to individual tobacco users and benefit the health of the population as a whole. In

terms of whether consumers understood how the product must be used to attain the purported risk

reduction (i.e., exclusively), these data provide evidence that the proposed claim did not lead smokers

to believe that partial substitution would reduce their disease risk. In particular, based on perceptions

of the relative risk of exclusive snus use compared to dual use with cigarettes, and an item about the

number of cigarettes one could smoke while using snus, the findings provide support that most

consumers do not infer that partial substitution is associated with a reduction in risk. These results allay

concerns that the phrase “instead of” will be interpreted by consumers to mean that one can dual use

the product with cigarettes and still reap the benefit of the risk reductions described in the claim.
       

                         

                         

                                

                               

                                  

                             

                             

                                

                               

                                 

                               

                                   

                           

                                

                                      

                                 

                                  

                               

                                    

                                

                           

                                   

                                

                             

                               

                             

                              

                                 

                               

                                  

                            

                                 

                                

                                  

                           

                             

                                

                                   

                               

                                   

                                   

                         

                                 

               

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Although the evidence showed that exposure to the modified risk claim significantly impacted

perceptions of the absolute and relative risk of the product—shifting perceptions towards greater

accuracy, in line with the claim—this was not true for all participants. Rather, there remained a

proportion of participants who were not affected by the claim and who continued to perceive the

product as just as harmful as cigarettes. For instance, whereas ~60% of young adult smokers who were

exposed to the claim correctly responded that General Snus presented lower risks of serious health

problems compared to smoking, the remaining ~40% either perceived General Snus as posing the same

or higher risk as cigarettes (or responded “don’t know”). Likewise, just as some participants did not

perceive General Snus to be less harmful compared to cigarettes, they also did not understand that

exclusive use of General Snus would be less harmful than dual use of General Snus plus cigarettes.

Accordingly, when asked how many cigarettes one could smoke while using General Snus and still get

the risk reduction, just over half (56%) of young adults exposed to the modified risk claim selected the

correct response (“zero cigarettes”), whereas a proportion responded “don’t know” or “none of the

above”. We evaluate these findings in the context of both the preexisting beliefs that participants bring

with them into the study as well as the “dose” of their exposure. It is well‐established in the literature

that the majority of U.S. consumers (up to 90%) perceive smokeless tobacco products to be just as

harmful as cigarettes (e.g., Song et al., 2009; Strong et al., 2019). This means that for most participants,

the modified risk claim for General Snus needs to overcome (and reverse) established beliefs about the

product category. In the course of a brief online study with a one‐time exposure to a marketing video, it

may be unsurprising that not all consumers will shift their perceptions to align with the claim. However,

a real‐world, appropriate marketing campaign would mean the intended audience would be exposed to

the information more than once and in more than one way, increasing the likelihood that more of these

users will shift their perceptions in line with the claim. Accordingly, it is important that postmarket

surveillance and studies assess the impact of the marketing on users’ understanding of the products’

risks relative to cigarettes and their understanding that to reduce their risk, they should use the

products exclusively, and not in conjunction with other tobacco products (e.g., dual use with cigarettes).

A few findings were contrary to expectations. For instance, addition of the claim reduced perceived

risks across all seven disease endpoints assessed, not just the six endpoints that were specified in the

claim, suggesting that the claim may have had a generalized effect of lowering perceptions of relative

risk. Likewise, the study revealed that a proportion of smokers believe that General Snus might be less

harmful than cessation aids—and exposure to the claim increased this proportion. As discussed above,

there may be a number of reasons for these misbeliefs, including confusion about the harms of nicotine

itself. Perhaps more unexpected is the finding suggesting that the claim increased the number of people

perceiving General Snus as less harmful than quitting all tobacco use. As noted, given what we know

about consumers’ perceptions of the harms of smokeless tobacco, including the PBI study results

showing that participants continued to perceive General Snus as presenting substantial health risks, it is

likely that this is a spurious finding. Finally, the concern about this misunderstanding of the relative

harm of General Snus vs. cessation is that it could present a reason for consumers who were considering

quitting all tobacco use to instead choose General Snus use. The results (discussed below) showing that

exposure to the modified risk claim did not affect intentions to quit do not bear this out.

Finally, the Social Science review also notes that there were a few gaps in the PBI study, including

measurement of perceived addiction risk and perceived risks of intermittent (i.e., non‐daily) product

use, which is a common use pattern among U.S. adult smokeless tobacco users generally and users of

snus pouches in particular (Cheng et al., 2017).
       

                         

                            

                             

                                 

                              

                             

                              

                          

                                   

                   

                             

                          

                               

                                

                           

                                 

                                

                             

                           

                              

                    

                       

                                  

                                       

                           

                       

                                 

                          

                            

                               

                              

                     

                                  

                              

             

                             

                         

                            

                             

                           

                         

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Consumers’ understanding of the modified risk claim, as reflected in their understanding of the

products’ risks in the context of total health, is a multifaceted construct. The assessment of

understanding can be complicated by the fact that, in many cases, consumers have preexisting beliefs

that are not aligned with scientific evidence (e.g., misconceptions related to the harms of NRT or the

risks of smokeless tobacco relative to smoking). To inform this assessment of the proposed modified

risk General Snus products, the PBI study assessed a number of different aspects of consumers’

perceptions and understanding. On the whole, the pattern of results shows an improvement in the

participants’ understanding of the risks of the product. Taken together, the evidence supports the

conclusion that the claim will be understood by consumers in the context of total health and in a

manner that could reduce individual risk and benefit population health.

C. Effects	of	the	Proposed	MRTPs	on	Tobacco	Use	Behavior	among	

Current	Tobacco	Users	

As described above, FDA has determined that exclusive use of the eight General Snus products would

pose lower risks to health than cigarette smoking for many smoking‐related diseases. Accordingly, the

primary behavioral impact of the MRTPs' marketing expected to result in a population health benefit is

smokers completely switching to snus use. In addition, though not a subject of the proposed modified

risk claim, evidence suggests that, compared to exclusive use of other smokeless tobacco products,

exclusive use of these snus products pose reduced exposure to some HPHCs and offer the potential for

reductions in oral cancer risk. FDA’s scientific review of PMTAs for the eight products concluded that

introducing the products to the market would give smokeless tobacco users “additional options for less

toxic smokeless tobacco products” compared to other smokeless tobacco products sold in the U.S.

market (FDA, 2015, p. 37). Thus, there could be additional population health benefits if current

smokeless tobacco users switched to exclusive use of these products.

The original applications were determined to contain insufficient evidence demonstrating that the

products would be used in a way that would result in a population health benefit. The applicant

proposed that, as MRTPs, its products could have a similar impact in the U.S. as snus has had in Sweden.

In particular, the applicant described a historical trend documented in Sweden, often called the

“Swedish Experience,” a grassroots movement wherein a large proportion of smokers transitioned to

exclusive snus use, bringing rates of smoking to historically low levels and resulting in a population with

a lower incidence of smoking‐related diseases than comparable countries. Thus, the applications relied

primarily on behavioral epidemiological data from Sweden and Norway. Ultimately, FDA’s review of this

evidence concluded that it had limited applicability to the potential impacts of marketing the MRTPs in

the U.S. FDA pointed to the range of social and cultural differences between the two marketing

contexts—including that snus is a traditional Swedish product—limiting the validity of extrapolating

from one to the other. Moreover, snus was not marketed as a reduced risk product in Sweden,

underscoring that adoption of the product was related to other factors. These limitations were also

identified by TSPAC in the 2015 meeting.

In addition, the applicant’s original consumer perception study was evaluated by FDA and found to

suffer from several serious methodological flaws, including that the proposed modified risk information

was not tested verbatim, as well as problematic measures. Although the original consumer perception

study could have provided support for the potential behavioral impact of the modified risk information

on the intended audience, ultimately the concerns with the study’s methodology rendered the findings

uninformative to the overall assessment. Thus, relying solely on the epidemiological evidence discussed
       

                           

                            

                             

                   

                          

                               

        

                                       

                                  

                              

                       

                          

                                  

                              

                           

                               

                                     

                                           

                                           

  

                               

                                  

                           

                                 

                           

                                 

                              

                                

                                 

          

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above, FDA concluded that the applicant had not demonstrated the likelihood that consumers would

use the product in a way that would benefit individual users and population health.

To assess the revised proposed claim, the applicant conducted a new consumer perception study, the

PBI study, which provides additional information on consumer perceptions, understanding, and

behavioral intentions. These findings replace those of the former study which evaluated the original

requests, and therefore are no longer relevant. The PBI study, and the findings relevant to behavioral

intentions, are presented next.

Participants were asked, “How likely are you to buy General Snus for yourself if sold in a store where you

usually shop?” The 11‐point response scale ranged from 0 (no chance, almost none [1 in 100]) to 10

(certain, practically certain [99+ in 100]). Results show that adding the proposed claim to the

advertisement statistically significantly increased older adult smokers’ intentions to buy General Snus

(MWITHOUT CLAIM = 1.49, MWITH CLAIM = 2.04) and non‐significantly increased young adult smokers’ (MWITHOUT

CLAIM = 1.85, MWITH CLAIM = 2.19) and adult smokeless tobacco users’ (MWITHOUT CLAIM = 3.41, MWITH CLAIM =

3.71) intentions to buy it (PBI Study Report)(Figure 5). These patterns support the conclusion that that

the proposed claim can positively impact intentions to buy among current tobacco users (cigarette

smokers and smokeless tobacco users) who stand to benefit from completely switching to the product.

Figure 5. PBI Study participants’ mean self‐reported likelihood of buying General Snus. The item asked, “How likely are you to

buy General Snus® for yourself if sold in a store where you usually shop?” Response options ranged from 0 = “No chance,

almost none [1 in 100]” to 10 = “Certain, practically certain [99+ in 100].” Source: PBI Study Report. Error bars: 95% CIs.

*p=.001.

The applicant did not submit evidence regarding how those who intended to buy the product expected

to use it: for instance, whether smokers would use General Snus as a complete substitute for smoking.

We acknowledge, however, that such future behaviors could be difficult for consumers to predict before

trying the product and thus challenging to assess in premarket research, which is one reason an actual

use study may have provided useful information about the claim’s effects on use patterns.

The study did assess smokers’ intentions to quit smoking and all tobacco users’ intentions to quit using

all tobacco products. Among current smokers and current tobacco users, adding the proposed claim to

the video advertisement did not affect intentions to quit smoking or quit using all tobacco products.

This is positive in that it appears the claim did not inadvertently depress smokers’ or smokeless tobacco

users’ interest in quitting.
       

      

                                   

                       

                              

                              

                           

               

                                   

                                   

                              

                             

                          

                            

                               

                           

                                

                               

                                

                        

                                   

                                  

                            

                                  

                                     

                              

                                

                                 

                           

                                  

                             

                             

                      

                                 

                                  

                                     

                                

                               

                         

      

                               

                                   

                                  

                                 

                         

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 41 of 77

Summary and Conclusion

The design and conduct of the PBI study addressed the flaws previously identified by FDA’s review of the

applicant’s previous consumer perception study, including testing the revised modified risk statement

verbatim. The soundness of the study method, in addition to FDA’s statistical replication (described in

Social Science Review), give us confidence to draw conclusions from this study. Accordingly, unlike the

original assessment, we can now draw conclusions based on the data provided about potential

behavioral effects of the proposed modified risk products.

In the 2016 TPL review, we noted that research had indicated that U.S. cigarette smokers may not find

snus an appealing alternative to cigarette smoking (Biener et al. 2014; Sami et al. 2012; Hatsukami et al.

2011; O’Connor 2011). However, PBI study results provide supportive evidence that the addition of the

proposed modified risk claim would positively impact intentions to use the product among older (25+)

adult smokers. In particular, the addition of the claim to the video advertisement statistically

significantly increased intentions to buy the product among adult smokers 25 years or older. Although

this difference was statistically significant, it should be noted that the absolute mean ratings on the

intentions scale were still relatively low (between 1 [“very slight possibility”] and 2 [“slight possibility”]).

When interpreting these values, it’s worth noting a few things. First, 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. Indeed, snus—as with other

smokeless tobacco products—does not universally appeal to users of other tobacco products.

Accordingly, just as snus currently has a very modest market share, it is likely that these MRTPs would

appeal to a minority of smokers. Appealing to that group of smokers and persuading them to switch

from cigarettes to a less harmful alternative presents an opportunity to benefit population health.

Second, these results reflect the impact of a one‐time exposure to an advertising video for a product.

This type of study is critical for assessing understanding of the claim in a premarket context and is also

informative of the potential effects on behavior. However, in the context of a single‐session online

study, it is hard to approximate the effects of a real‐world marketing campaign. Thus, as mentioned

above, it is reasonable to consider these study results as estimating a lower range of the potential

impact of the real‐world marketing of the products, where more frequent exposure to product

marketing would have the potential to have a greater impact on levels of interest. In addition, although

not statistically significant, the pattern of results for the other two user groups—young adult smokers

and smokeless tobacco users—suggested that the claim also had a positive impact on their product

interest. Moreover, perhaps unsurprisingly, smokeless users across conditions showed the highest

mean levels of intentions to buy the product, suggesting that the addition of the claim could increase

the likelihood of current smokeless users transitioning to a less toxic alternative (FDA, 2015). It is worth

noting that the sample of smokeless users was around half the size of the smoker groups, which may be

one reason why a significant effect was not detected for these users. Together, these findings provide

support that the proposed modified risk claim could increase the likelihood of use of General Snus

among adult tobacco consumers who could benefit from switching, including both smokers and

smokeless tobacco users.

The applicant did not submit direct evidence that the proposed claim would encourage smokers to use

General Snus as a complete substitute for smoking (e.g., the applicant did not submit an actual use study

testing the claim’s effects on frequency of General Snus use or dual use with cigarettes). FDA previously

noted relatively high rates of dual use among snus users (FDA, 2016); however, the findings described in

the section on consumer understanding suggest that the proposed claim enabled consumers to
       

                               

                 

                                     

                                  

                                   

                                  

                             

                             

  

                             

                               

                                  

                           

                      

                                

                              

                           

                                

                               

                                 

                                

                              

                                   

                                 

                         

                                 

                                   

                        

                                 

                             

               

                                 

                                  

                                 

                                   

                              

                               

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 42 of 77

understand that dual use presents greater health risks than exclusive General Snus use, and this would

provide users a reason to use the products exclusively.

The applicant elected to examine the effect of the claim in the format of a marketing video (e.g., rather

than another form of marketing such as a print advertisement). As this format is likely more engaging

than others (e.g., a print ad), these findings could reflect an upper bound of effectiveness in terms of

impact on consumers. On the other hand, as mentioned above, the study findings estimate the effect of

a one‐time exposure: it is expected that an appropriate marketing plan that effectively reaches the

intended audience (adult smokers) could have a larger impact than a single exposure (regardless of

format).

D. Effects	of	the	Proposed	MRTPs	on	Tobacco	Use	Initiation	among	Non‐

Users

The impact on tobacco use behavior among current users must be considered alongside the potential

effects on tobacco use initiation among non‐users, such that a positive impact on population health is

more likely when the benefits of the former are expected to outweigh the risk of the latter. Assessing

potential impacts on behavior in a premarket setting is difficult, especially for non‐users, particularly

youth. As discussed above, the applications originally relied on Scandinavian behavioral epidemiological

evidence to inform an assessment of the effect on non‐users. FDA again concluded these data had

limited applicability to the likely impact of the proposed MRTPs on non‐users in the U.S. Similarly,

though this question was addressed in the applicant’s original consumer perception study, those data

were determined to be uninformative due to flaws in the design and conduct of the study.

The PBI study was designed to address this issue by including adult non‐users and assessing their

interest in buying the product, including how the addition of a modified risk claim affected their interest

in buying the product. In particular, the PBI study included three groups of non‐users: adult former

cigarette smokers, young adult never tobacco users, and older adult never tobacco users. The study

found that mean levels of intentions to buy General Snus were low (<1) among all three groups of non‐

users, and the addition of the modified risk claim did not have a statistically significant effect: former

smokers (MWITHOUT CLAIM = 0.20; MWITH CLAIM = 0.31), older adult never tobacco users (MWITHOUT CLAIM = 0.29,

MWITH CLAIM = 0.23), and young adult never tobacco users (MWITHOUT CLAIM = 0.37, MWITH CLAIM = 0.34) (PBI

Study Report, pp. 71‐72) (Figure 5). These results are supportive of the conclusion that the claim will not

increase interest in the product among unintended groups, namely non‐users of tobacco.

Summary    and Conclusion  

The PBI findings show low levels of intentions to buy General Snus among non‐user groups (adult former

cigarette smokers; young adult never tobacco users; older adult never tobacco users), which were not

affected by the addition of the modified risk claim.

Although youth are, in general, at risk for tobacco use initiation, surveillance data on U.S. youth tobacco

use suggest snus is not a product category of particular interest among youth. Currently, snus use is

relatively low among U.S. youth (0.5% and 1.9% among middle school and high school students in 2014,

respectively; Arrazola et al., 2015; see Wang et al. [2018] for estimates of past‐30 day use of any

smokeless tobacco in 2017: 1.9% among middle school students and 5.5% among high school students).

As described above, in the PBI study, the applicant stratified its recruitment and analyses of never
       

                                   

                              

                               

                                    

                             

                              

                             

                                

                               

                               

                              

                                   

                

                               

                                       

                                       

                                        

                               

                               

                                   

                             

                     

                                     

                             

                                

                                   

                               

                              

                               

                           

             

                             

                                

                       

                         

                                 

                             

                                  

                               

                             

                        

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 43 of 77

tobacco users to separately examine young adults (i.e., legal age to 24 years) and older adults (i.e., 25

years or older), finding results that were generally comparable across age groups. Though data on

young adult non‐users is informative, there is no direct evidence that this claim would affect youth non‐

users in the same way. In the absence of research on how the proposed claim affects youth perceptions

and intentions, it is worth considering research on other modified risk statements, even though different

claims may affect youth differently. One available study suggests that a modified risk claim similarly

impacted risk perceptions among youth and adults and affected susceptibility to use the product only

among adults (El‐Toukhy et al., 2018). In particular, asking youth “Suppose the FDA approves a label

saying that Swedish snus is less harmful than cigarettes” caused youth to perceive Swedish snus as

exposing users to less harmful chemicals and as presenting a lower risk of serious health problems (El‐

Toukhy et al., 2018). Although generalizability may be limited, such research is the best available direct

evidence we currently have on youth and shows that, just as with adults, when youth are exposed to

modified risk information, it lowers their risk perceptions.

Studies suggest that perceptions of risk predict tobacco product use among youth (e.g., Song et al.,

2009; Strong et al., 2019) and adults (e.g., Brose et al., 2015). For example, in a national sample of U.S.

youth who had never used snus, youth who perceived snus as low or medium in risk were more likely to

try it during the next year compared to youth who perceived snus as high in risk (Strong et al., 2019).

Thus, even though the proposed claim did not increase never tobacco users’ intentions to use General

Snus in the applicant’s study, it is still possible that exposing youth and young adult non‐tobacco users

to the proposed claim could increase their risk of initiating use of General Snus by lowering their risk

perceptions. Accordingly, it is critical that an MRTP marketing plan target adult smokers and minimize

exposure to youth, as discussed further in the next section.

E. Impact	of	the	Proposed	MRTPs	to	the	Health	of	the	Population	as a	

Whole	

An assessment of the impact of an MRTP on the population as a whole is primarily a function of the

relative health risks of the proposed product and the likelihood of tobacco use behavior change,

including behavior change due to the modified risk marketing. As described in the section on individual

health risk, FDA has determined that exclusive use of the General Snus products that are the subject of

these MRTPAs poses lower risk for many diseases than cigarette smoking and the revised claim being

proposed by the applicant is scientifically substantiated. General Snus products also have been found to

have lower levels of HPHCs than many other smokeless tobacco products on the market (FDA PMTA

Review, 2015), suggesting that there would be a benefit to smokeless tobacco users switching

completely to these products as well.

In its original submission, the applicant presented findings from a population model to estimate the

potential impact of the proposed MRTPs on the population as a whole. In addition to concerns

regarding the scientific substantiation of the originally proposed claims, FDA’s initial assessment

determined that the applications contained insufficient information about the impacts of the proposed

modified risk products on the behavior of current users and non‐users of tobacco products and that the

uncertainty about the impacts on behavior among these groups precluded the ability to determine, with

any degree of certainty, that the products will benefit the health of the population as a whole. Although

the applicant modeled a number of different scenarios of the impact to users and non‐users, some

resulted in population health benefits and some resulted in population health harms, and the applicant

provided inadequate evidence as to which scenarios are more or less likely.
       

                               

                             

                        

                       

                                  

                         

                                  

                                 

                           

   

                          

                               

                               

                                  

                             

                            

                         

                            

                                 

                                  

                           

                               

                             

             

                               

                           

                                    

                               

                                

                                      

                                   

                             

                                 

          

                               

                                    

                                     

                                  

                           

                               

                        

                                 

              

                               

                               

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 44 of 77

FDA’s original assessment of the impact of the proposed MRTPs on likelihood of use among current

users and non‐users was based on evidence in the original applications from the applicant’s consumer

perception study and epidemiological behavioral evidence. In particular, the applications relied heavily

on observational data from Sweden and Norway to support its argument that the phenomenon

documented in Sweden could be replicated in the U.S. Ultimately, FDA and TPSAC did not find this

argument compelling, concluding that there was limited applicability of the behavioral evidence from

Sweden to the potential impact of the MRTPs on the U.S. population. The original applications did not

contain studies of “actual use”, and because of the flaws in the original consumer perception study, FDA

ultimately concluded the applicant had failed to demonstrate that the product will benefit population

health.

Swedish Match’s amended applications provide new information that addresses this gap. In particular,

the PBI study, designed in part to evaluate the revised proposed claim (and correct methodological flaws

of the original study), provides evidence of the impact of the proposed MRTPs on behavioral intentions

among users and non‐users. These data showed that the addition of the revised modified risk claim to

the marketing video had a positive, statistically significant effect on behavioral intentions to buy the

product among adult smokers aged 25+ years. Among younger adult smokers (18‐24 years), and

smokeless tobacco users, the claim also increased intentions, though these changes were not

statistically significant. On the other hand, among non‐users, intentions to buy the product were low

(<1 on the 0‐10 scale) and, importantly, were not statistically significantly affected by the addition of the

modified risk claim. FDA’s review finds that the study’s design was sound, and in sum, these findings

support the conclusion that these MRTPs will benefit population health, particularly by (a) increasing

interest and therefore likely uptake among those who could stand to benefit (adult smokers), and (b)

having no effect on the interest and therefore likely uptake among current non‐users, including young

adult never users and former users.

The PBI study provided information about intentions to buy the products but did not examine how

consumers might use the products, including whether smokers who were interested in the products

would be interested in switching to exclusive use or would intend to dual use. These questions may be

less meaningfully addressed via self‐report (e.g., in the absence of any product trial) and better suited to

an actual use study that can examine patterns of product uptake/use. However, the applicant did not

conduct an actual use study. A key to the population health benefit of these MRTPs is not only that

smokers will adopt the products, but that they will switch to exclusive use of them and cease smoking.

Accordingly, confirming that the marketing of the MRTP has the intended effect on behavior (including

uptake and patterns of use) will be a priority question to be evaluated in postmarket surveillance and

studies (see Section IV).

A priority for the assessment of consumer understanding was to examine the extent to which smokers

will understand that they are to use the product exclusively and not in addition to cigarettes. As noted,

it is possible to interpret the phrase “instead of” in the revised modified risk claim in different ways, and

this concern was also raised by TPSAC members. The evidence provided in the PBI study found that,

overall, the addition of the modified risk claim to the marketing video improved consumers’

understanding of the relative risks of snus compared to cigarette smoking and that people had an

appropriate understanding of the claim. Moreover, addressing the potential ambiguity of the phrase

“instead of”, these data provided evidence that the proposed claim did not lead smokers to believe that

partial substitution would reduce their disease risk.

Finally, the assessment of the population impact must also consider the potential risks to youth, a

population vulnerable to initiating the use of tobacco products. The applicant assessed the impact of the
       

                               

                                  

                                

                                   

                               

                                    

                               

                             

                            

                               

                                

                                  

                             

                      

                     

                              

                                 

                           

                                  

                             

             

                                   

                 

                                     

                               

         

                       

  

                               

                   

                                 

                                     

                       

                           

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 45 of 77

modified risk products on non‐users, including young adult non‐users, but did not include youth in its

study. Snus products, including General Snus, are currently on the U.S. market and use by youth is

relatively low compared to other types of tobacco products. However, this is in the absence of

marketing a product as lower risk and although data on young adult non‐users (included in this study) is

helpful and informative, there is no direct evidence to determine whether this claim would affect youth

non‐users in the same way. 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 similarly impacted risk

perceptions among youth and adults, but affected susceptibility to use the product only among adults

(El‐Touhky et al., 2018). Nonetheless, given that lower risk perceptions can predict tobacco use

initiation, it is possible that exposing youth and young adult non‐tobacco users to the proposed claim

could increase their risk of initiating use of General Snus. In addition, it is well‐documented that

exposure to marketing impacts youth initiation. For this reason, it is critical that a marketing plan for

any products that receive MRTP orders be designed to target tobacco users and prioritize preventing

youth exposure. I recommend that postmarket restrictions include requirements focused on minimizing

youth exposure, including age‐ and identity‐verification and age‐restriction controls for digital marketing

and reporting metrics that will enable FDA to monitor the effectiveness of targeted marketing efforts.

Assessment of the marketing plan and the applicant’s adherence to it, along with metrics to ensure that

youth exposure to tobacco marketing is being minimized, are important elements to assessing the

degree to which the marketing of the MRTP continues to benefit the population as a whole.

IV. Conclusions	and Recommendation	

The applicant has requested risk modification orders under Section 911(g)(1) of the FD&C Act for eight

General Snus products with the following claim:

Modified Risk Claim: "Using General Snus instead of cigarettes puts you at a lower risk of mouth cancer,

heart disease, lung cancer, stroke, emphysema, and chronic bronchitis"

In order 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;
       

                           

             

                             

                               

   

                    

                               

                         

                                 

                           

                             

                             

                               

                 

                           

                       

                             

  

                                   

                         

                       

                         

                                

                       

                           

                             

                               

                             

                          

                               

                             

                               

                                 

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 46 of 77

 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 must require that the advertising and labeling of the MRTPs 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).

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

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

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

distribution of the benefits and harms across the population.

1. Review	Conclusions	

After conducting a thorough scientific review of the information contained in the MRTPAs; 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, I conclude that:

 The applicant has demonstrated that, as actually used by consumers, the eight General Snus

products sold or distributed with the proposed modified risk information 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.

The claim “Using General Snus instead of cigarettes puts you at a lower risk of mouth cancer, heart

disease, lung cancer, stroke, emphysema, and chronic bronchitis" is scientifically accurate. The available

scientific evidence, in particular the long‐term epidemiological studies, reviewed under the original

submission and summarized again in this review, substantiates that relative to cigarette smoking,

exclusive use of the eight General Snus products poses lower risk of the above‐named health outcomes.

The applicant provided sufficient justification to determine that the epidemiological evidence from

Sweden and Norway, although not specific to the products that are subjects of these applications,

provides a reasonable characterization of the risks that would be expected to be observed among

General Snus users in the U.S. if they used the products in a similar manner.

The available scientific evidence demonstrates that exclusive use of the eight General Snus products will

significantly reduce harm and the risk of tobacco‐related disease to individual tobacco users. As

described above, exclusive use of these products poses lower risks than cigarette smoking for many of

the major causes of tobacco‐related disease. In addition to these lower risks relative to cigarette

smoking, FDA has previously determined that the levels of NNN and NNK, two potent carcinogens in

smokeless tobacco products, in these General Snus products are lower than those in the vast majority of
       

                             

                               

                             

                             

                                  

                         

                        

                             

                             

                                    

                           

                                     

                                

                             

                                

                                   

                          

                               

                            

                                 

                           

                                  

                               

                                 

                            

                               

                             

                            

                             

                   

                            

                              

                       

                             

                                  

                                  

                               

                                   

                               

                                

                               

                    

                             

                             

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smokeless tobacco products on the U.S. market, and when used exclusively instead of other smokeless

tobacco products, the General Snus products offer the potential for reductions in oral cancer risk.

Although exposure to HPHCs is lower than many other smokeless tobacco products, exposure is still

elevated compared with non‐use and, therefore, long‐term use of General Snus is not without health

risks. FDA’s 2016 TPL review concluded that Swedish snus use (compared with no use of tobacco) has

been associated with increased risk of specific disease endpoints in individual epidemiological studies,

including pancreatic cancer, fatal MI and stroke, diabetes, and adverse pregnancy outcomes. In

addition, there are potential negative effects of nicotine exposure on the developing adolescent brain.

The additional evidence provided in the amendment also supports that, as actually used by consumers,

the eight General Snus MRTPs will benefit the health of the population as a whole. The PBI study

demonstrated that exposure to the claim positively impacted relative risk perceptions and intentions to

buy the product among smokers aged 25 years and older, a group who stands to benefit the most from

the marketing of the products. For instance, among adult smokers aged 25 years and older, participants

who were exposed to a marketing video with the modified risk claim reported significantly higher

intentions to buy the product compared to those who did not see the modified risk claim. Smokers

under age 25 years showed a similar pattern, although the impact of the claim on intentions was not

statistically significant for this group. Similarly, although not statistically significant, the pattern of

results also suggested the claim may have a positive impact on smokeless tobacco users’ intentions to

buy the product. In addition, smokeless tobacco users across conditions showed the highest mean

levels of intentions to buy the product, suggesting that the marketing of the products with the claim

could increase the likelihood of current smokeless users transitioning to the eight General Snus

products, which are likely to be a less toxic alternative. The applicant also provided evidence to show

that consumers can understand the claim and its significance in the context of total health, including

understanding that the risk reduction is not achieved via partial switching (i.e., dual use of General Snus

with continued use of cigarettes). In fact, the proposed claim improved consumers’ understanding of

the risks of General Snus relative to cigarettes and their understanding that dual use presents greater

health risks than exclusive General Snus use, thereby increasing the likelihood that consumers who use

the products will do so exclusively. Together, the demonstrated impact of the claim on understanding,

perceptions, and behavioral intentions, even in the context of a relatively brief exposure, supports that

the proposed MRTPs will benefit the population as a whole.

The PBI study provided sufficient evidence to support product authorization. However, the results were

not without limitations. In particular, although the evidence showed that exposure to the modified risk

claim significantly impacted perceptions of the absolute and relative risk of the products—shifting

perceptions in line with the claim, towards greater accuracy—this was true, on average, but not

necessarily for all participants. In fact, a proportion of participants was not affected by the claim and

continued to perceive the product as just as harmful as cigarettes, for instance. Likewise, just as some

participants did not perceive General Snus as less harmful compared to cigarettes, a proportion also did

not understand that exclusive use of General Snus would be less harmful than dual use of General Snus

with cigarettes. Considered in the context of the totality of the evidence, these results do not

undermine my conclusion that the product meets the standard in Section 911(g)(1) of the FD&C Act.

However, given their relevance to the population health impact of these MRTPs, these are areas that

need to be monitored through postmarket surveillance and studies (PMSS).

Finally, the new evidence supports that the population health benefits gained by cigarette smokers (and

potentially other smokeless tobacco users) switching to these products will not be outweighed by the
       

                                    

                             

                                

                          

                               

                                  

                                  

                             

                          

                           

                            

                           

           

                                  

                             

                                

                                     

                              

                                 

                            

                                

                                 

                            

                                   

                           

                     

                               

                                 

                               

                               

                           

  

                           

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risks of initiating new tobacco use. The PBI study found low levels of intentions to buy the product

among non‐users of tobacco (including young adults) and, importantly, found that the inclusion of the

modified risk claim did not affect these intentions. Prevention of youth initiation of tobacco products is

a key consideration in FDA’s evaluation. Although the available evidence from epidemiological studies

does not demonstrate significant youth initiation of snus products at this time, it is possible that

marketing the product as a modified risk product could change this. In fact, some studies suggest that

risks perceptions predict tobacco product use among youth (e.g., Song et al. 2009; Strong et al. 2019).

Thus, it is essential that modified risk marketing be targeted to current tobacco users and disseminated

in ways to minimize exposure among youth. Based on these conclusions, the postmarket requirements

described below include measures to limit youth exposure to the products’ labeling, advertising, and

marketing. In addition, reporting requirements will enable FDA to monitor, among other things, the

degree to which the implementation of the marketing plans is effectively targeting the intended

audience and limiting exposure to youth.

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, given that these would be the first MRTP

authorizations issued by the Agency. Although this review has found that the products 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 eight General Snus products

that are the subject of these applications in terms of uptake, dual use, and complete switching is

required. As described below, postmarket surveillance and studies must include an assessment of MRTP

users’ behavior and understanding at multiple time points. 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.

2. Environmental	Impact	

A finding of no significant impact (FONSI) was signed by Kimberly Benson, Ph.D. on October 3, 2019. The

FONSI was supported by an environmental assessment prepared by FDA on October 3, 2019.

3. Postmarket	Surveillance	and	Studies

I recommend that the following language be included in the marketing authorization:

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 eight General Snus products that are
       

                                 

                                    

                                 

                                

                             

                                   

                          

                                

                                   

                            

                           

           

                                 

                         

                        

                             

                               

                      

                             

                           

                             

                           

                       

                         

                               

                           

                             

          

                                   

                                 

                               

                           

                               

                                

                         

  

  

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 49 of 77

the subject of these applications, as actually used by consumers, continue to benefit the health of the

population as a whole is likely to be driven by use behavior. Therefore, monitoring use of the eight

General Snus products that are the subject of these applications in terms of uptake, dual use, and

complete switching is required. In particular, your PMSS must assess the extent to which new MRTP

users were non‐users, smokers, or other tobacco product users before initiating the MRTPs and the

extent to which new users of the MRTPs become exclusive users or dual users with cigarettes or other

tobacco products over time. Relatedly, such surveillance must include an assessment of consumers’

understanding of the claim and perceptions of the products. In particular, PMSS must assess the extent

to which users of these products understand that, to reduce their risk of disease relative to smoking as

described in the modified risk information, they must use General Snus 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 orders on uptake of the

products requires surveillance of MRTP sales and distribution, which provide information to assess

tobacco consumption at the population level. Your PMSS protocols must describe procedures for

monitoring and reporting MRTP sales and distribution in the U.S. by product, major metropolitan areas,

and channels where the products are sold (e.g., convenience stores, food and drug stores, internet and

digital retailers, tobacco specialty shops). Your annual PMSS report must include:

 U.S. sales and distribution of the tobacco products by quarter since the granting of your

modified risk granted orders (for the initial reporting period) or the previous reporting period

(for all reports that follow), including, for each MRTPA STN, total U.S. sales and distribution

reported in dollars and units, and broken down by major metropolitan areas, and channels

where the products were distributed and sold during the reporting period (e.g., convenience

stores, food and drug stores, internet and digital retailers, tobacco specialty shops).

 A brief synthesis and summary of the sales and distribution data for the initial reporting period

or the previous reporting period (for all reports that follow), including annual and quarterly

growth rate (percent change) in total U.S. sales and distribution of the tobacco products for

each MRTPA STN, post‐MRTP authorization.

MRTP          Use and Adverse Experiences

In order for FDA to determine whether the eight General Snus products that are the subject of these

applications, as actually used by consumers, continue 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

MRTPs. 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 products, 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

products including nature, frequency, and potential aggravating factors.
       

                                 

                                   

                             

                                

                             

                                  

                                

                                 

                  

        

                             

         

     

         

                           

   

         

                       

                                 

            

                           

                                   

                               

                           

                 

                         

                     

         

           

                                   

                                 

                             

                          

                                 

                           

                          

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In addition, the PMTA orders for your General snus products, issued on November 10, 2015, require you

to report to the FDA all adverse experiences that are both serious and unexpected and your analysis of

the association between the adverse experience and the tobacco product within 15 calendar days after

the report is received by you. These experiences may become known to you through any source,

including a customer complaint, request, or suggestion made as a result of an adverse experience,

tobacco product defect, or failure, reported to you, or identified in the literature or media. We request

that when submitting such reports, you reference both your PMTAs and you MRTPAs for these products.

Your information should be submitted with a cover letter that includes the following text in the subject

line: SERIOUS UNEXPECTED ADVERSE EXPERIENCE REPORT FOR STN(s) PM0000010‐PM0000017 and

MR0000020‐MR0000022, MR0000024‐MR0000025, and MR0000027‐MR0000029.

For purposes of this reporting, serious adverse experience means an adverse experience that results in

any of the following outcomes:

 Death;

 A life‐threatening adverse event;

 Inpatient hospitalization or prolongation of existing hospitalization;

 A persistent or significant incapacity or substantial disruption of the ability to conduct normal

life functions;

 A congenital anomaly/birth defect; or

 Any other adverse experience that, based upon appropriate medical judgment, may jeopardize

the health of a person and may require medical or surgical intervention to prevent one of the

other outcomes listed in this definition.

For purposes of this reporting, unexpected adverse experience means an adverse experience occurring in

one or more persons in which the nature, severity, or frequency of the experience is not consistent with:

 The known or foreseeable risks associated with the use or exposure to the tobacco product as

described in the PMTA (including the results of human subject investigations) and other relevant

sources of information, such as postmarket reports and studies;

 The expected natural progression of any underlying disease, disorder, or condition of the

person(s) experiencing the adverse experience and the person’s predisposing risk factor profile

for the adverse experience; or

 The results of nonclinical laboratory studies.

Surveillance                            of New Research Study Findings the MRTPs and Consumer Perception, Behavior, or Health

In order for FDA to determine whether the eight General Snus products that are the subject of these

applications, as actually used by consumers, continue to benefit the health of the population as a whole,

your PMSS must include surveillance of new research study information about the MRTPs and consumer

perception, behavior, or health. In particular, your PMSS protocol must include procedures for

monitoring and assessing findings both in your own studies (i.e., studies conducted by you or on your

behalf) and in publications including any new scientific data (published or otherwise) regarding the

MRTPs and consumer perception, behavior, or health. Your annual PMSS report must include:

 A summary of significant findings about the tobacco products from research studies conducted

by you or on your behalf, whether or not such studies were specifically required under this
       

                           

                                

           

                                 

                              

                            

                              

                         

                                    

                           

                               

                               

                                  

                                

                          

                               

                              

                       

             

                                 

                                

                                 

                              

                         

                             

                                    

                                    

                                

                                 

                        

                           

                            

                             

                             

                               

                            

       

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 51 of 77

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 MRTPs

and consumer perception, behavior, or health.

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 Numbers (STNs). If you have more than one protocol,

submit each protocol as 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

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) requires that the results of PMSS be submitted on an annual basis. These reports must be

identified as “PMSS Report”, and the MRTPA STNs should be referenced for each report. The PMSS

Report must indicate the beginning and ending date of the period covered by the report and must

include accomplishments since the last reporting period. For quantitative updates on studies in

progress (e.g., participant accrual), reports should describe both interim (since the last reporting period)

as well as cumulative (since study initiation) accomplishments. The PMSS Report describing studies in

progress must describe the status of PMSS, including, as applicable the status of recruitment, data

collection, and analysis; a summary of the study milestones achieved and any deviations from the

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.

4. Postmarket	Advertising	and	Promotion	Requirements,	Recordkeeping	and	

Retention,	and	Manufacturing	Information	
       

                     

                               

       

  

               

                 

                     

                         

                   

                   

                     

               

                       

               

                       

                         

                       

            

                         

                             

               

                     

                     

   

                     

                 

       

                     

          

                           

         

                       

            

                       

                     

                       

         

                           

                       

                   

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 52 of 77

I recommend that the following language be included in the marketing authorization:

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 products’ labeling, advertising, marketing, and/or promotion –

whether conducted by you, on your behalf, or at your direction – including:

o Specimens of all labeling, 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 products, 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 products, and including copies of the stimuli used in testing;

o Copies of any contractual agreements regarding the creation and/or dissemination of the

products’ labeling, advertising, marketing, and/or promotional materials;

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 18‐24, and other demographic and/or psychographic characteristics that reflect

your intended target audience;

 Actions taken to restrict youth‐access and limit youth‐exposure to the products’

labeling, advertising, marketing, and/or promotion;

 Use of owned, earned, 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 products;

 Consumer engagements – whether conducted by you, on your behalf, or at your

direction – including events at which the products were demonstrated; and/or

 Use of earned media and/or public‐relations outreach to create labeling for, advertise,

market, and/or promote the products

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
       

              

                       

                           

                   

   

                                 

                                   

                            

                                 

                           

                               

                                  

                            

                                   

                         

          

                       

                            

                                      

                                   

                                

                                   

                             

             

                           

                               

              

                     

                       

                               

                       

               

                         

                     

                 

      

                       

         

                     

            

                             

                     

                     

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 53 of 77

channel, by product, and by audience demographics; and

o Policies and procedures for real‐time digital media monitoring to identify, correct, and

prevent any delivery of advertising impressions to youth, ages 17 years and under, including

documentation of such monitoring activities and implementation of corrective and

preventive measures

II. Notifications

Under section 911(h)(5) of the FD&C Act these risk modification orders require that for the first six

months after the date of your modified risk order you provide FDA a 30‐day notification for all labeling,

advertising, marketing, and/or promotional materials for which you plan on disseminating to the public.

These notifications are not for pre‐approval, but are required so that FDA can have timely access to your

marketing plans and materials, and if needed, provide you advisory comments, including any concerns

about their possible impact on youth appeal and tobacco use initiation and on the finding that

continued marketing of your products will benefit the health of the population as a whole. You may

begin disseminating the materials 30 days after providing notification to FDA. This notification must be

received by FDA at least 30 days prior to dissemination, which includes but is not limited to the

publication, dissemination to consumers, or use in engaging or communicating with consumers of such

materials. The notification must include:

 Full‐color copies of all such labeling, advertising, marketing, and/or promotional materials for

the products. 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 advertisement 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 an media

buys;

o Target specific adult audiences by age‐range(s), including young adults, ages 18‐24, and

other demographic and psychographic characteristics that reflect your intended target

audience(s), including how the target audience(s) are defined and the insights used to

develop the target audience profile(s) and the source of such insights;

o Restrict youth‐access and limit youth‐exposure to the products’ labeling, advertising,

marketing, and/or promotion;

o Use owned, earned, shared/social, and/or paid media to create labeling for, advertise,

market, and/or promote the products;

o Use partners, influencers, bloggers, and/or brand ambassadors to create labeling for,

advertise, market, and/or promote the products;

o Conduct any consumer engagements – whether by you, on your behalf, or at your direction

– including events at which the products will be demonstrated; and/or

o Use public‐relations outreach to create labeling for, advertise, market, and/or promote the
       

                                 

                                       

                            

                              

        

                         

        

                         

                       

                             

                             

                               

                                 

                   

           

                 

                         

                         

                           

                             

                             

                                 

                                       

                                 

                             

                               

                                   

   

                               

                                  

               

                             

        

                         

     

                         

                                 

                                 

                  

                       

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 54 of 77

products.

III. Periodic    Reporting

Under sections 911(h)(5) of the FD&C Act, these orders require that you submit periodic reports every 6

months to FDA once during the month of June of each year and once during the month of December of

each year, beginning June 2020. For the six‐month reporting period, the report must include:

 A cover letter that includes the following text in your subject line: PERIODIC REPORT for

MR0000020‐MR0000022, MR0000024‐MR0000025, MR0000027‐MR0000029. The cover letter

should include the STN(s) and corresponding tobacco product name(s), applicant name, date of

report, and reporting period.

 All final printed labeling (including all variations, such as those reflecting different required

warnings) not previously submitted (e.g., if previously submitted under section 905(i) or

previously submitted at the last reporting period and no changes were made, please list the

date and manner of submission), including the date the labeling was first disseminated and the

date when the labeling was discontinued, and a description of all changes to the labeling. The

labeling must include all the panels and be presented in the actual size and color with legible

text. The labeling must include labels, inserts/onserts, instructions, and any other accompanying

information or materials for the products.

 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 may be provided separately and clearly

referenced. Digital media, such as videos must be submitted in a format that FDA is able to open

and review.

IV. Annual    Reporting

Under section 911(h)(5) of the FD&C Act, these risk modification orders require 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

MR0000020‐MR0000022, MR0000024‐MR0000025, MR0000027‐MR0000029. The cover letter

should include the STN(s) and corresponding tobacco product name(s), firm name, date of

report, reporting period.

 A description of the implementation of all advertising and marketing plans, including strategic

creative briefs and paid media plans – whether conducted by you, on your behalf, or at your

direction – by channel and by product, and the dollar amount(s) and flighting of such plans, by

channel and by product, including a description of any:

o Use of competent and reliable data sources, methodologies, and technologies to establish,
       

                       

                               

                       

                 

                         

                     

                       

        

                         

         

                       

            

                           

                 

                       

                               

                               

        

                             

                 

                             

                            

                 

                           

                     

                       

                             

              

                            

                         

         

                             

                   

                   

                                 

                           

                    

                         

                     

                     

                               

                     

                   

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 55 of 77

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 adult audiences by age‐range(s), including young adults, ages 18‐24,

and other demographic and/or psychographic characteristics that reflect the intended

target audience(s), how the target audience(s) were defined and the insights used to

develop the target audience profiles(s) and the source of such insights;

o Actions taken to restrict youth‐access and limit youth‐exposure to the products’ labeling,

advertising, marketing, and/or promotion;

o Use of owned, earned, shared/social, and/or paid media to create labeling for, advertise,

market, and/or promote the products;

o Use of partners, influencers, bloggers, and/or brand ambassadors to create labeling for,

advertise, market, and/or promote the products;

o Consumer engagements – whether conducted by you, on your behalf, or at your direction –

including events at which the products were demonstrated; and/or

o Use of public‐relations outreach to create labeling for, advertise, market, and/or promote

the products; including the original date such plans were first used and the date they were

discontinued, and a description of all changes to such plans since the last periodic report, by

channel and by product.

 An analysis of the actual delivery of advertising impressions, by channel, by product, and by

audience demographics (e.g., age, gender, race/ethnicity, geographic location), including a

breakout by age‐group (i.e., adults, ages 25+; young adults, ages 18‐24; and youth, ages 12‐17

and ages 11 and under), not previously submitted. This analysis should be verified against

post‐launch delivery‐verification reports submitted to you from an accredited source.

 A summary of media tracking and optimization, by channel, by product, and by audience

demographics (e.g., age, gender, race/ethnicity, geographic location), including a summary of

real‐time digital media monitoring to identify, correct, and prevent delivery of advertising

impressions to youth, ages 17 and under, and including a summary of implementation of any

corrective and preventive measures, not previously submitted.

V. Additional        Conditions for Marketing

Under section 911(h)(5) of the FD&C Act, these risk modification orders require you to:

 For any of the products’ labeling, advertising, marketing, and/or promotion appearing in your

owned digital properties (e.g., your company‐owned, consumer‐directed, product‐branded

website(s) and/or mobile applications) – whether conducted by you, on your behalf, or at your

direction – establish, maintain, and monitor use of independent age‐ and identity‐verification

service(s) that compare consumer information against independent, competent, and reliable

data sources, such as public records, at the first point of access to such properties, to restrict

access to such labeling, advertising, marketing, and/or promotion to only individuals who are at

least of federal minimum legal age to purchase tobacco products.

 For any of the products’ labeling, advertising, marketing, and/or promotion appearing in any

shared digital properties (e.g., your product‐branded social media accounts, pages and

associated content; content promoting your products on your behalf disseminated through

another entity’s social media accounts) – whether conducted by you, on your behalf, or at your

direction – establish, maintain, and monitor use of the available site‐, platform‐ and content‐

(e.g., post, video) specific age‐restriction controls (e.g., age‐restrict an entire product‐branded
       

                       

                           

                                 

                           

              

                         

                         

                         

                             

                       

                           

                     

             

                     

                     

                           

                     

                   

                   

                     

                         

               

                     

                         

                                   

                         

                     

                                

                       

                          

                      

                         

                             

                               

                   

                         

                     

                           

                                

                           

                            

                     

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 56 of 77

account and all associated content disseminated through such account; ensure age‐restriction of

a specific video disseminated by an influencer promoting the products on your behalf through

the influencer’s account), at the first point of access to such properties, to restrict access to such

labeling, advertising, marketing, and/or promotion to only individuals who are at least of federal

minimum legal age to purchase tobacco products.

 For any of the products’ labeling, advertising, marketing, and/or promotion appearing in paid

digital media (e.g., paid digital banner advertisements for the product(s) running on another

company’s website; paid advertising for the product(s) running in social media; paid distribution

of influencer content) – whether conducted by you, on your behalf, or at your direction:

o Establish, maintain, and monitor use of competent and reliable data sources,

methodologies, and technologies to precisely target delivery of such labeling, advertising,

marketing, and/or promotion to only individuals who are at least of federal minimum legal

age to purchase tobacco products. Such targeting must use only first‐ and/or second‐party

age‐verified data, where:

 “First‐party” age‐verified data is data owned by you (e.g., your customer registration

data collected via site traffic to your company‐owned website; data you use in direct

marketing to your adult smoking customers) that you have age‐verified through

independent, competent, and reliable data sources; and

 “Second‐party” age‐verified data is first‐party data owned and age‐verified by another

competent and reliable entity (e.g., another company’s first‐party user registration data)

to which you have access. Such data must be age‐verified by the second party.

 “First‐party” and “second‐party” data does not include data obtained from data

aggregators who categorize consumers based on trackable activities and inferred

interests (e.g., internet search terms, video interactions, browsing history, purchasing

behaviors) to create demographic and psychographic profiles marketers may use to

enhance audience targeting. Such data is not considered age‐verified and can only be

used in combination with first‐ and/or second‐party age‐verified data.

 Establish, maintain, and monitor use of competent and reliable data sources, methodologies,

and technologies (e.g., using an embedded tracking pixel in all digital advertising) – whether

conducted by you, on your behalf, or at your direction – to track and measure actual delivery of

all advertising impressions, by channel, by product, and by audience demographics (e.g., age,

gender, race/ethnicity, geographic location), including a breakout by age‐group (i.e., adults, ages

25+; young adults, ages 18‐24; and youth, ages 12‐17 and ages 11 and under). Such monitoring

requires real‐time digital media tracking, and identifying, correcting, and preventing delivery of

advertising impressions to youth, ages 17 and under. Such monitoring also requires post‐launch

delivery verification reports be submitted to you from an accredited source.

 For any use of partners, influencers, bloggers, and/or brand ambassadors to create labeling for,

advertise, market, and/or promote the products – whether conducted by you, on your behalf, or

at your direction – disclose to consumers or viewers, via the use of statements such as

“sponsored by [firm name]” in such labeling, advertising, marketing, and/or promotional

materials, any relationships between you and entities that create labeling for, advertise, market,

and/or promote the products, on your behalf, or at your direction.

The requirements above are intended to help ensure that your modified risk tobacco products, as

actually used by consumers, will continue to benefit the health of the population as a whole. Limiting

youth initiation of the products and, relatedly, youth exposure to advertising and marketing materials

for the products are important factors in the population health benefit analysis. Accordingly, FDA

also recommends limiting youth‐exposure to any of the tobacco products’ labeling, advertising,
       

                 

                         

                                 

                                      

                                

                                 

                               

                            

                           

  

                              

                       

                       

                       

               

                                 

                                 

                                

                                

                                     

                       

                                 

                                      

                                      

                               

                              

                                           

                                

                             

                                    

                      

                                   

                               

             

                       

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 57 of 77

marketing, and/or promotion appearing in print media publications.

After receiving authorization, the determination of whether the eight modified risk General Snus

products, as actually used by consumers, continue 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 products would

have a significant negative impact on the population health benefit analysis. To help ensure that your

products, as actually used by consumers, continue 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 products,

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 products:

 For any digital sales – whether conducted by you, on your behalf, or at your direction –

establish, maintain, and monitor use of independent age‐ and identity‐verification service(s)

that compare customer information against independent, competent, and reliable data

sources, such as public records, to prevent the sale of the products to individuals who are

under the federal minimum legal age to purchase tobacco products.

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 products.

 A summary of the implementation and effectiveness of any policies and procedures

regarding restrictions on youth access to the products.

Recordkeeping      and Retention

We remind you that if FDA can no longer make the determination that your products, as actually

used by consumers, will benefit the health of the population as a whole, FDA must withdraw the

modified risk orders, 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 products 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 orders.

The risk modification orders for your modified risk tobacco products are effective for 5 years from the

issue date of the orders. If you wish to renew your orders, we recommend you submit a request for

renewal 360 days prior to the end of your effective timeframe. In order to help ensure that your risk

modification orders meet the standard for renewal and to help expedite the review of any renewal

applications, we request that you establish and maintain the records listed below. The records should

be retained for a period of not less than four years from the date of distribution of the last batch of the

tobacco products listed in your orders under section 911(g)(1). The records should be legible, written in

English, and upon request, available for inspection and copying by officers or employees duly designated

by the Secretary. Please note that Appendices B and C require you to periodically submit some of these

records to FDA (e.g., in PMSS reports and/or advertising and promotion‐related reports). Additionally,

we remind you that the PMTA orders for your General snus products issued on November 10, 2015, also

require you to establish and maintain records, some of which overlap with the records listed below:

 The MRTPAs submitted prior to the orders

 Postmarket reports, as described in the Required PMSS Appendix, including adverse experience
       

                 

               

   

           

                   

                     

     

         

       

   

   

     

       

         

       

     

       

                       

                         

                   

                         

                         

                     

                   

                          

                           

  

                     

                   

                             

             

                                 

                          

                            

                         

                               

                   

                                                            

                                 

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 58 of 77

reports and all relevant documentation associated with the experience

 Records of all nonclinical or clinical studies, including:

o Source data;

o Study protocols (including statistical analysis plan);

o Amendments showing the dates and reasons for any protocol revisions;

o Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approvals or non‐

approvals;

o Informed consent forms;

o Correspondence with study monitors/investigators/contract research

organizations/sponsors/IRB/IEC;

o Investigator financial disclosure statements;

o Progress reports;

o Monitoring reports;

o Adverse experience reports;

o Case report forms/subject diaries/medical records/laboratory reports;

o Subject data line listings/observation records;

o Test article accountability records;

o Study results/protocol summaries/study reports; and

o Certifications and amendments to certifications

 Records pertaining to the manufacture, in process and release testing, production process

(including any changes to the process, facility, or controls), packaging, storage, and stability

monitoring and testing (including protocol and results) of the products

 Records pertaining to the sale, distribution, or other disposition of the products, specifically:

o A list of distributors and retailers of the products, including brick‐and‐mortar and digital6

6 For the purposes of this order, here and throughout the document, “digital” includes internet/online and mobile.

;

o Any available information (not to include personally identifiable information) about product

purchases, such as purchasers’ demographics (e.g., age, gender, race/ethnicity, geographic

region) and previous or current use of other tobacco products (i.e., dual use);

o Policies and procedures regarding verification of the age and identity of purchasers of the

products; and

o Policies and procedures regarding restrictions on youth access to the products

 Health hazard analyses, if performed voluntarily or directed by FDA

 Records pertaining to any and all complaints associated with any of the products that you

receive or of which you are aware

Manufacturing    Information

The PMTA orders for your General Snus products, issued on November 10, 2015, require you to report

to the FDA manufacturing information. We request that when submitting such reports, you reference

both your PMTAs and you MRTPAs for these products. When cross‐referencing, please provide the date

of submission and location in the submission where the information is covered. When cross‐referencing,

please provide the date of submission and location in the submission where the information is covered.

For each twelve‐month reporting period, the annual reports should include:

 A cover letter that includes the following text in your subject line: ANNUAL REPORT for
       

        

                         

     

                           

       

                       

              

                           

                             

                             

                       

                    

                     

                       

                         

                      

                       

                        

                               

                             

                                

               

                 

                             

                             

  

   

                                                            

                                             

                      

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 59 of 77

MR0000020‐MR0000022, MR0000024‐MR0000025, MR0000027‐MR0000029. The cover letter

should include the STN(s) and corresponding tobacco product name(s), firm name, date of

report, reporting period.

 A description of each change made to the manufacturing process, facilities, or controls during

the reporting period including:

o A comparison of each change to what was described in the MRTPAs;

o The rationale for making each change; and

o A certification that the reported change did not result in any modification (including a

change in design, any component, any part, or any constituent, including a smoke or aerosol

constituent, or in the content, delivery, or form of nicotine, or any other additive or

ingredient) of the tobacco products and the basis for concluding that each manufacturing

change did not result in any modification to the products.7

7 We note that any modifications made to a tobacco product would render it a new tobacco product that would be subject to

the premarket review requirements under section 910 of the FD&C Act.

 A summary of all manufacturing deviations, investigations, and corrective and preventive

actions, including, but not limited to, those deviations associated with processing, testing,

packing, labeling, storage, holding, and distribution and indicate any deviation(s) that may affect

the characteristics of the products. For additional information on manufacturing deviations, see

below.

Manufacturing    Deviations

You should promptly investigate all manufacturing deviations including, but not limited to, those

associated with processing, testing, packing, labeling, storage, holding, and distribution. The PMTA

orders for your General snus products, issued on November 10, 2015, require that, for products that

have been distributed, if the deviation may negatively impact public health, you promptly identify and

report that deviation to CTP. We request that when submitting such reports, you reference both your

PMTAs and you MRTPAs for these products.

Discontinuation    and Reintroduction

If you discontinue the manufacture, preparation, compounding, or processing for commercial

distribution of these modified risk tobacco products and later decide to reintroduce the modified risk

tobacco products into the market, please contact the Office of Compliance and Enforcement prior to

reintroduction.
       

                               

                     

                             

                 

                                         

                             

                                     

   

                                 

                 

                                   

                               

         

                           

               

                             

                     

                               

                             

     

                                 

                

                                       

       

                               

                       

                

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 60 of 77

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V. Appendix	–	The	Public	Health	Rationale	for	Recommended	

Restrictions	on	Modified Risk	Tobacco	Product	Labeling,	

Advertising,	Marketing,	and	Promotion	

I. Background

Most tobacco use is established in adolescence and age of initiation plays a significant role in the

progression from tobacco experimentation to regular use (HHS 2012). It is well established that industry

practices, such as tobacco product labeling, advertising, marketing and promotion, substantially impact

youth trial and uptake of tobacco product use. Part of FDA’s premarket review of a modified risk

tobacco product (MRTP) application is aimed at determining whether the applicant has demonstrated

that the modified risk tobacco product will or is expected to benefit the health of the population as a

whole, taking into account both users of tobacco products and persons who do not currently use

tobacco products.

Firms seeking a marketing order for an MRTP may not have robust data on the degree to which its

labeling, advertising, marketing, and promotion may influence youth perception or appeal to youth. This

memo describes FDA’s authorities under the Family Smoking and Tobacco Control Act (Tobacco Control

Act) to monitor and restrict tobacco product marketing and related activities in the context of MRTP

application review and authorization. The MRTP application review process includes an evaluation of

product labeling and advertising, as well as evidence concerning consumer comprehension of the

proposed modified risk information. Given FDA’s statutory mandate to protect young people from the

dangers of tobacco use and ensure that the marketing of an MRTP will or is expected to benefit the

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

who do not currently use tobacco products (e.g., youth or minors), the agency can request and review

any changes to labeling, advertising, marketing, and promotional materials and plans for MRTPs that

have received modified risk authorization to ensure that there are no grounds for withdrawing

authorization and restrict the marketing of such products as appropriate to continue satisfying the

requirements of Section 911 of the Federal Food Drug and Cosmetic Act. This will help FDA evaluate the

potential impact of such materials on the likelihood of initiation and use of the MRTPs by youth or

others who do not use tobacco products and provide the firm and/or the agency an opportunity to

prevent or mitigate any related potential harms to the public health.

II. The Food, Drug, and Cosmetic Act, as Amended by the Tobacco Control Act: Congressional

Findings and FDA Authorities Related to Tobacco Product Labeling, Advertising,

Marketing, and Promotion

The Tobacco Control Act makes clear the harmful influence of tobacco product labeling, advertising,

marketing and promotion on youth tobacco use, and the intent of Congress to give FDA the authority to

restrict these activities. In the Tobacco Control Act, Congress finds that, “[t]obacco advertising and

marketing contribute significantly to the use of nicotine‐containing tobacco products by adolescents,”

and “[b]ecause past efforts to restrict advertising and marketing of tobacco products have failed

adequately to curb tobacco use by adolescents, comprehensive restrictions on the sale, promotion, and

distribution of such products are needed.” TCA §2(5) and (6). Thus, Congress concludes,

“[c]omprehensive advertising restrictions will have a positive effect on the smoking rates of young

people,” and “[r]estrictions on advertising are necessary to prevent unrestricted tobacco advertising
       

                       

            

                                 

                             

                                 

                               

                               

                               

                                 

                               

                                 

                                 

                                   

           

                               

                                   

                             

                                 

                               

                                 

                           

                                 

                           

                                 

                                 

                                

                         

                                

                           

                           

                                 

                             

                               

                         

           

                                   

                                       

                               

                                     

                           

              

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 65 of 77

from undermining legislation prohibiting access to young people and providing for education about

tobacco use.” TCA §2(25) and (26).

These findings are underscored by section 906(d) of the FD&C Act, which grants FDA the authority to

“require restrictions on the sale and distribution of a tobacco product, including restrictions on the

access to, and the advertising and promotion of, the tobacco product, if [...] such regulation would be

appropriate for the protection of public health,” and section 910(a)(2) of the FD&C Act, which grants

FDA the authority to require premarket review and authorization of a new tobacco product before such

product may be legally marketed in the United States. Further, as part of premarket application review,

FDA may require “information relevant to the subject matter of the application” to assist the agency in

determining “whether the marketing of a tobacco product [...] is appropriate for the protection of public

health” (section 910(b)(1)(G) and 910(c)(4) of the FD&C Act). In an order authorizing the marketing of a

new tobacco product FDA may also restrict the sale and distribution of the tobacco product to the

extent that the sale and distribution of a tobacco product may be restricted under section 906(d) of the

FD&C Act. FD&C Act §910(c)(1)(B).

Similarly, with respect to MRTPs, Congress found that “[i]t is essential that the [FDA] review products

sold or distributed for use to reduce risks or exposures associated with tobacco products and that it be

empowered to review any advertising and labeling for such products.” TCA §2(36). Congress also found

that “[t]he [FDA] is a regulatory agency with the scientific expertise to... evaluate the impact of labels,

labeling, and advertising on consumer behavior in order to reduce the risk of harm and promote

understanding of the impact of the product on health.” Accordingly, under section 911 of the FD&C Act,

Congress gave FDA authority to require premarket review and authorization of MRTPs before such

products may be legally marketed in the United States. §911(a). As part of the MRTP application review

process, FDA reviews the proposed product labeling and advertising and may require any other

information to assist the agency in determining whether the MRTP will or is expected to “benefit the

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

persons who do not currently use tobacco products.” §911(d)(1), (4), (7) and § 911(g)(1)‐(2). In making

these determinations, the agency specifically evaluates the likelihood that persons who do not use

tobacco products, including youth, will start using the MRTP that is the subject of the application.

§911(g)(4)(C). In addition, under section 911(h)(1), FDA must require that any advertising or labeling

concerning MRTPs 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. Finally,

under section 911(h)(5), FDA has broad authority to require that the MRTP for which an applicant

obtained an order under section 911(g)(1) “comply with requirements related to advertising and

promotion of the tobacco product.”

III. Effects of Youth‐Exposure to Tobacco Product Labeling, Advertising, Marketing, and

Promotion on Youth‐Appeal, ‐Perception, and ‐Use of Tobacco Products  

A. Influence    of Tobacco Product                Marketing on Youth Tobacco Use, in General

As noted in the FD&C Act, as amended by the Tobacco Control Act, a key consideration in determining

whether the marketing of an MRTP will or is expected to benefit the health of the population as a whole

is the increased or decreased likelihood that persons who do not use tobacco products, especially youth,

will start using the MRTP. In addition to Congress’ findings in the Tobacco Control Act, there is a large

body of scientific evidence that documents the potential harm of tobacco product labeling, advertising,

marketing and promotion on youth tobacco use.
       

                             

                           

                         

                       

                               

                             

                                 

                         

                       

                           

                         

                           

                               

                             

                     

                             

                             

                         

              

                           

                           

                         

                     

                         

                           

                         

                           

                               

                               

                     

                               

                       

                            

                                   

                           

                     

                           

                             

                             

                               

                               

                                   

                 

                         

                         

                         

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In one of the first comprehensive reviews on the subject—the National Cancer Institute’s (NCI) 19th

monograph, The Role of the Media in Promoting and Reducing Tobacco Use—authors conclude that “the

total weight of evidence—from multiple types of studies, conducted by investigators from different

disciplines, and using data from many countries—demonstrates a causal relationship between tobacco

advertising and promotion and increased tobacco use” (NCI 1998). As such, the direct role of tobacco

product marketing and related activities in increasing tobacco use in the United States, especially among

youth, and the high rates of youth‐exposure to tobacco marketing due to its ubiquity, are two key

rationales cited by NCI for restricting tobacco product marketing and related activities.

The 2012 Surgeon General’s report, Preventing Tobacco Use Among Youth and Young Adults,

synthesizes more than 30 years of research on the topic. This report outlines similar findings—tobacco

product labeling, advertising, marketing, and promotion influence a wide range of established risk

factors for youth tobacco use by shaping attitudes, beliefs, and risk perceptions, and promoting pro‐

tobacco social and cultural norms. The report states, “there is strong empirical evidence, along with the

tobacco industry’s own internal documents and trial testimony, as well as widely accepted principles of

advertising and marketing that support the conclusion that tobacco manufacturers’ advertising,

marketing, and promotions recruit new users as youth and continue to reinforce use among young

adults” (HHS 2012). This evidence is sufficient to conclude that “marketing efforts and promotion by

tobacco companies show a consistent dose‐response relationship in the initiation and progression of

tobacco use among young people” (HHS 2012).

To illustrate these points, the report cites findings of studies that demonstrate “advertising and

promotion by the tobacco industry are effective in raising awareness of smoking, increasing brand

recognition, and creating favorable beliefs regarding tobacco use. There is strong and consistent

evidence that marketing influences adolescent smoking behavior, including selection of brands,

initiation of smoking, and overall consumption of cigarettes” (HHS 2012). Further, “research conducted

by the tobacco industry consistently demonstrates that the brand imagery portrayed on packages is

particularly influential during youth and young adulthood—the period in which smoking behavior and

brand preferences develop,” and “displays of packages in retail outlets, commonly referred to as

‘powerwalls,’ have high visibility among youth and help to establish brand imagery and social norms at

an early age” (HHS 2012). “Young people who are more familiar with tobacco advertising can identify

specific advertisements, have a favorite tobacco advertisement, or possess cigarette promotional items

are more likely to begin smoking than their peers who do not have these characteristics,” and

“adolescents who both owned cigarette promotional items and had a favorite cigarette advertisement”

were more likely to progress from initiation of smoking to established smoking (HHS 2012).

Research has found that a key tactic of tobacco companies seeking to attract and recruit youth users is

to use advertising with aspirational imagery and themes known to resonate with younger audiences,

such as independence, popularity, rebelliousness, attractiveness, and being “cool” (HHS 2012). Even

tobacco advertising that purportedly targets adult users can have a profound influence on adolescent

tobacco use behaviors if it creates positive feelings in youth toward the product; pleasant feelings

motivate actions that consumers anticipate will reproduce those feelings (Slovic & Peters 2006). As such,

youth are more likely to mimic behavior portrayed as favorable in advertising, such as tobacco use.

Furthermore, youth often misjudge the risks and benefits of advertised products based on how they feel

about them (Slovic & Peters 2006). If youth feel positively toward a product, they are more likely to

perceive it as having lower risks and higher benefits.

In addition, adolescents are “uniquely susceptible to social and environmental influences to use

tobacco” given their developmental stage and are heavily influenced by peers, family members,

prominent members of their community, celebrities, and other cultural icons and adult role models—
       

                               

                               

                               

                             

                                   

                           

                               

                             

                       

                       

      

                                 

                           

                         

                       

                             

                         

                           

                  

                       

                               

                                   

                             

                         

                       

                             

                               

                               

          

                             

                               

                           

                                       

                           

                                 

                           

                             

                             

                           

                           

                           

                                 

                                   

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especially those they perceive to be popular, attractive, and “cool” (HHS 2012). As such, images of

tobacco use in various types of media are “a potentially powerful socializing force among adolescents, in

part because they are communicated by people who are identified by youth as media stars,” and

“adolescents actively rely on external information as they seek to shape their own identities, often

looking to media stars as models of what to wear and what to do” (HHS 2012). These marketing

campaigns may be misleading in that they imply positive, pervasive and/or pro‐tobacco social norms

that are inaccurate or overstated. The misleading impression can be enhanced by failing to disclose a

sponsor’s relationship with a company or failing to reveal that the content was not organically

generated independently of the sponsoring company. Because youth have a heightened sensitivity to

normative influences, sponsored tobacco marketing content may encourage youth uptake of tobacco

use (HHS 2012).

B. Influence of Tobacco Product Marketing on Youth Tobacco Use in the Context of Tobacco

Products Other Than Cigarettes

Much of the research spanning the past few decades has focused on the influence of tobacco product

marketing on cigarette smoking in particular; however, companies that sell other types of tobacco

products engage in the same labeling, advertising, marketing, and promotional practices used by

cigarette companies. “[T]he traditional division of products, brand identities, and marketing between

cigarette and smokeless tobacco companies has all but become nonexistent in recent years as major

U.S. cigarette companies, including RJR and Altria, have acquired smokeless tobacco companies and

have developed new smokeless tobacco products” (HHS 2012). Some of these products are even

marketed with popular cigarette brand names (e.g., Camel Snus).

Beyond cigarette‐specific marketing, research has found that youth exposed to in‐store marketing of e‐

cigarettes, hookah, cigars, smokeless tobacco, and pipe tobacco were two to three times more likely to

use those products as well as to initiate cigarette use (Cruz et al. 2018). Further, research exploring the

influence of tobacco marketing on youth use of novel tobacco products, such as e‐cigarettes, confirms

that exposure and receptivity to tobacco advertising is significantly associated with tobacco initiation

among adolescents. The 2016 Surgeon General’s report, E‐cigarette Use Among Youth and Young Adults,

concluded “e‐cigarette products are marketed in a wide variety of channels that have broad reach

among youth and young adults,” and themes in e‐cigarette marketing are “parallel to the themes and

techniques that have been found to be appealing to youth and young adults in conventional cigarette

advertising and promotion” (HHS 2016).

The report also summarizes the results of several studies looking at the relationship between e‐cigarette

marketing and youth tobacco use. For example, an analysis of the 2011 National Youth Tobacco Survey

(NYTS) found that “adolescents who reported frequent exposure to protobacco advertising at the point

of sale and on the Internet (e.g., seeing ads most of the time or always) had significantly higher odds of

ever using e‐cigarettes, and there was a dose‐response association between the number of marketing

channels to which they were exposed and ever use” (HHS 2016; Agaku & Ayo‐Yusuf 2014). Two analyses

of 2014 NYTS data assessing exposure to e‐cigarette advertising in different channels (i.e., internet,

print, television and movies, retail stores) found that “exposure to each type of e‐cigarette marketing

was significantly associated with increased likelihood of ever having used and current use of e‐cigarettes

among middle and high school students. Exposure was also associated with susceptibility to use e‐

cigarettes among current nonusers. In multivariate models, as the number of channels of e‐cigarette

marketing exposure increased, the likelihood of use and susceptibility also increased” (HHS 2016; CDC

2016; Mantey et al. 2016). These findings are particularly relevant in the context of more recent NYTS

data showing a substantial increase in youth use of e‐cigarettes from 2017 to 2018 (Gentzke et al. 2019).
       

                               

                 

                           

                           

                           

                     

                           

                           

                           

                           

                           

         

                         

                       

                           

                                     

                             

                               

                         

                             

                       

                         

                                 

                             

                             

                           

                                     

                             

                           

   

                               

                         

                         

                               

                                 

                             

                           

                         

                         

                             

                               

           

                                                            

                                 

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This uptick in youth e‐cigarette use also contributed significantly to the first increase in overall youth

tobacco use in recent years (Gentzke et al. 2019).

Recent studies have also assessed the influence of e‐cigarette marketing on youth use of conventional

cigarettes. For example, an analysis of data collected between 2013‐2015 via the Population Assessment

of Tobacco and Health study found youth receptivity was highest for e‐cigarette advertising (compared

to conventional cigarette, cigar, and smokeless tobacco product advertising), and receptivity to e‐

cigarette advertising was also associated with initiation of conventional cigarette smoking (Pierce et al.

2018). Another study had similar findings concluding that exposure to any e‐cigarette advertising may

play a role in teens’ decision to initiate e‐cigarette and conventional cigarette use (Padon, Lochbuehler,

et al. 2017). These findings further underscore the powerful influence of tobacco product labeling,

advertising, marketing, and promotion within and between product types, and the need for marketing

restrictions for novel tobacco products.

C. Influence    of Digital Tobacco            Marketing on Youth Tobacco Use

While all tobacco product labeling, advertising, marketing, and promotion has the potential to

significantly influence youth tobacco use, digital8

8 For the purposes of this memo, here and throughout the document, “digital” includes internet/online and mobile.

labeling, advertising, marketing, and promotion is

particularly concerning given that it is transforming traditional marketing practices and is highly targeted

to young people. The Pew Research Center reports that a vast majority of teens have access to a home

computer or smartphone and nearly half of teens report using the internet “almost constantly” (2018),

which means that many youth are constantly being exposed to marketing of a variety of different

products, including tobacco products. While there is overwhelming evidence that children, teens, and

young adults are exposed to and influenced by marketing of unhealthy products in traditional media,

the internet provides marketers with new, relatively inexpensive channels and tools for disseminating

their messages (Dunlap et al. 2016). Research examining online engagement with tobacco marketing

among youth found a sizable increase of engagement over time (Soneji, Yang, Knutzen, et al. 2018) and

that the number of engagements is associated with tobacco use initiation, frequency of use, and

progression to poly‐product use (Soneji, Yang, Moran, et al. 2018). According to the 2012 Surgeon

General’s report, “the techniques of digital marketing are part of sophisticated behavioral targeting in

which the marketer collects data on the users’ every move (e.g., every click of the mouse, sign‐up for a

contest, forwarding to a friend) to enable ever more precisely targeted marketing” (HHS 2012). This

precision marketing also represents an opportunity to limit youth‐exposure to the digital marketing of

tobacco products.

Via social media applications, marketers gain access to detailed profiles of users and their friends. Social

media has fundamentally altered the marketing landscape by moving young audiences from passive

recipients of advertising to active participants in the co‐creation and dissemination of marketing

messages (Dunlap et al. 2016). Corporate brands leverage the use of social media by adolescents and

young adults to target and engage with young audiences (Dunlap et al. 2016). Unlike traditional forms of

advertising that target potential customers with ads, companies that join in the “complex network of

relations” of social media “befriend” their customers, which is a particularly appealing approach for

companies wanting their consumers to express their personality through brand association (Dunlap et

al. 2016). “Marketers seek to create ‘brand ambassadors,’ [i.e., social‐media influencers] who promote

the product in the context of their online communications, whether or not such promotions are

recognized by the users or receivers as marketing. The effect is to blur the distinction between

marketing communications and market research” (HHS 2012).
       

                             

                             

                               

                             

                               

                         

                         

                                 

                               

                             

                               

                           

          

                                   

                                 

                                 

                           

                               

                                     

                           

                               

                               

                             

                           

                         

                       

                               

                                  

                              

                               

                               

                                 

                             

                                     

                               

                                       

                                         

                                     

                                     

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 69 of 77

For example, a study examining message content on Twitter concluded that Twitter serves as an

important platform for e‐cigarette marketing (Chu et al. 2015). Whenever a message posted by an e‐

cigarette brand is “retweeted” by another user, the message has reached a new network of users.

Additional retweets can provide a cascading spread within and outside an original poster’s network and

cause the message to go viral. This exposure through a retweeting network allows rapid diffusion of

messages across groups (Chu et al. 2015). However, Twitter content often reaches unintended

audiences, including youth and other vulnerable populations, due to the platform’s exponential reach

and relatively limited control over what types of people are exposed to specific messages (Chu et al.

2015). With more than 30% of today’s youth reporting they use Twitter, marketing and promotion of

tobacco products through Twitter can influence youth (Pew Research Center 2018). In addition, a recent

study found that sales growth of JUUL was accompanied by a variety of innovative, engaging, and wide‐

reaching campaigns on social media platforms popular among youth, such as Twitter, Instagram, and

YouTube (Huang et al. 2018).

IV. The Public Health Rationale for Requiring Submission of Modified Risk Tobacco Product

Labeling, Advertising, Marketing, and Promotional Materials and Plans and for Placing

Restrictions on the Marketing of Modified Risk Tobacco Products to Limit Youth‐Exposure

to Such Marketing

A. Purpose    of Marketing Requirements and                Restrictions for Modified Risk Tobacco Products, in

General

As noted in the introduction, FDA has a statutory mandate to authorize the marketing of a modified risk

tobacco product only if the applicant has demonstrated that such tobacco product will or is expected to

benefit the health of the population as a whole, taking into account the relative health risks to

individuals, the increased or decreased likelihood that existing users of tobacco products who would

otherwise stop using such products will switch to the MRTP, the increased or decreased likelihood that

persons who do not use tobacco products will start using the MRTP, and the risks and benefits of the

MRTP as compared with using smoking cessation products. Thus, FDA’s premarket review under the

MRTP application pathway is aimed, in part, at determining if marketing an MRTP would increase or

decrease the likelihood that those who do not currently use tobacco products will start using them.

Among non‐users, youth are a significant population of concern as their current stage of brain

development makes them especially susceptible to nicotine addiction (HHS 2012). Prior sections of this

memo have illuminated the powerful impact of tobacco product labeling, advertising, marketing, and

promotion on youth‐perceptions of tobacco products, youth‐appeal of tobacco products, the likelihood

of youth initiation and use of tobacco products, even when said marketing is purportedly targeted or

designed to appeal to adults. In addition, MRTP marketing will likely include claims that are intended to

lower perceptions of risk. Indeed, recent studies have demonstrated that when youth are exposed to

modified risk statements about a product, they perceive it as less harmful. For instance, asking youth

“Suppose the FDA approves a label saying that Swedish snus is less harmful than cigarettes” caused

youth to perceive Swedish snus as exposing users to less harmful chemicals and as presenting a lower

risk of serious health problems (El‐Toukhy et al., 2018). Given that risk perceptions predict tobacco

product use among youth (e.g., Song et al., 2009; Strong et al., 2019), if youth are exposed to modified

risk advertising and labeling, this could increase their likelihood of initiation. For example, in a national

sample of U.S. youth who had never used snus, youth who perceived snus as low or medium in risk were

more likely to try it during the next year compared to youth who perceived snus as high in risk (Strong et

al., 2019). Thus, for FDA to help ensure that the continued marketing of an MRTP will benefit the health

of the population as a whole, it is critical for FDA to conduct ongoing review and evaluation of the
       

                         

                       

                             

            

                           

                             

                                   

                           

                                 

           

                         

                       

                               

                                 

                         

                   

                         

                         

                           

           

                         

                             

                               

                                 

                               

                                   

                             

                               

                       

        

                           

                               

                               

                           

                           

                               

                               

       

                                                            

                                   

                                       

             

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 70 of 77

product’s labeling, advertising, marketing, and promotional materials and plans to assess any possible

effects on perceptions, appeal, intentions, and behaviors among intended and unintended audiences,

and to place appropriate restrictions on the product’s marketing and related activities from the outset

to limit youth‐exposure to such marketing.

Additionally, requiring a firm that receives marketing authorization for its MRTPs to provide labeling,

advertising, marketing, and promotional materials and plans in advance of their use is not for pre‐

approval, but 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 likelihood that the marketing of the products will continue to benefit

the health of the population.

B. Reducing Youth‐Appeal    of Tobacco Product    Marketing

Generally, firms receiving marketing authorization for an MRTP should seek to reduce the youth‐appeal

of the tobacco product’s labeling, advertising, marketing, and promotional materials, including avoiding

the use of imagery and themes known to resonate with youth, such as aspirational content depicting

tobacco use as “cool,” attractive, rebellious, and/or risky, or as a means to make one more popular,

desirable, or independent (HHS 2012). Other potential strategies for limiting youth‐appeal of labeling,

advertising, marketing, and promotional materials include focusing marketing content on instructional

demonstrations and product comparisons and avoiding bright, bold, cheerful designs and colors, which

can influence youths’ product choices because these characteristics affect their perception of the

products, draw attention to them, and influence purchase decisions (Padon, Mahoney, et al. 2017;

Akcay 2012; Lempert & Glantz 2016).

Instead, labeling, advertising, marketing, and promotional materials should be clearly tailored to appeal

to adults by using personalization strategies that make the content relevant and meaningful to adult

recipients and should depict individuals who are similar to the target audience in terms of attributes,

beliefs, and interests, in relatable situations that make it easier for adult viewers to engage with and

connect to the advertising (Hawkins et al. 2008; Nielsen 2014). For example, advertising tailored to adult

tobacco users would likely use headline and body copy that is relevant only to adults who might be

considering switching products; would use models that are obviously older adults (ages 35‐54) who look

like and/or explicitly state they are tobacco users; and would portray people in realistic situations for

tobacco users without making them look highly appealing or aspirational to other non‐targeted

populations, such as youth.

C. Limiting Youth‐Exposure    to Tobacco Product Marketing  

Given the association between tobacco product marketing and youth initiation of tobacco use detailed

in Section III, to help ensure the marketing of the products receiving marketing authorization under the

MRTP application pathway continues to benefit the health of individuals and of the population as a

whole, it is critical to limit youth‐exposure to the products’ marketing, advertising, labeling, and

promotion. Placing certain marketing restrictions9

9 For the purposes of this memo, this section focuses on restrictions related to digital tobacco product marketing.

Considerations for other types of marketing restrictions may be addressed in the future, and the contents of this memo should

not be viewed as an exhaustive list.

on the newly authorized MRTPs from the outset, such

as the media channels through which the firm markets its products, are essential components of limiting

youth‐exposure, and are thus critical to ensuring the products will benefit the health of the population

as a whole.
       

1. Restrictions              on Paid Digital Tobacco Product Marketing

                               

                           

                         

                           

                           

                   

                               

                               

                     

                               

                       

                     

                     

                               

                         

                       

                       

                           

                               

                         

                               

                

                           

                           

                             

                           

                                   

                       

                               

                       

                         

                     

                 

                                                            

                                   

                               

                         

                                   

     

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 71 of 77

The rise of digital marketing has changed media consumption habits over the past decade and created

an increasingly complex media landscape where it is not yet possible to completely eliminate youth‐

exposure to tobacco marketing. However, the data sources, methodologies, and technologies used to

deliver and track digital media consumption have also evolved, enabling product marketers to create

sophisticated, highly targeted digital marketing plans and paid media buys designed to reach their

intended audiences based on specific demographics, psychographics, and media passion‐points while

also limiting reach or “spill” to unintended audiences. Thus, it is possible, efficient, and necessary for

firms to take advantage of these technologies to help ensure that tobacco product marketing is targeted

to adults and that “spill” to youth audiences is minimal.

For example, paid digital advertising targeting capabilities have evolved such that it is possible, if not

standard practice, to target paid advertising using sophisticated data management systems and

algorithms connecting individuals to a range of data points, including their demographic characteristics,

purchase behaviors, preferences, political opinions, internet search terms, browsing history, interactions

with digital content (e.g., liking a social media post, following a specific influencer, sharing a video),

digital accounts, connected devices, physical location, and information about other members of their

household. Consumers are also increasingly digitizing and sharing detailed information about their

personal beliefs, experiences, and behaviors, giving marketers ever‐growing capabilities to track and

target individuals who meet the exact demographic and psychographic profiles of their ideal consumers.

As a result, targeting advertising based on a “digital destination,” such as placing advertising on a

specific website, is becoming largely obsolete and economically inefficient in comparison to targeting

advertising based on specific digital profiles connected to actual consumers who can thus be reached in

almost any digital location and time (IAB 2018).

This is especially significant when considering the need to limit youth‐exposure to tobacco marketing

appearing in the digital environment, which is exponentially more vast, ever‐changing, and difficult to

categorize than more traditional media channels like broadcast television and radio and print, making it

difficult to accurately determine the audience composition of a specific digital property (i.e., what

percent of visitors to a specific website are within a certain age‐range), or even assess where one digital

property ends and another begins. Fortunately, paid digital advertising targeting capabilities offer

tobacco marketers the ability to target adults who meet specific age criteria through the use of first‐

and/or second‐party age‐verified data (see table) on any digital property accepting paid tobacco

advertising, while also restricting youth‐access to such advertising. Marketers can also layer on

additional demographic and psychographic data (e.g., tobacco product purchase behaviors) to further

enhance the efficiency of their paid digital media buys.10

10 In addition to first‐ and second‐party age‐verified data, firms can use 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 to enhance first‐ and second‐party age‐verified

audience targeting data. However, such data is not considered age‐verified and should only be used in combination with first‐

and/or second‐party age‐verified data.
       

                               

                           

                     

     

                       

                           

                     

                           

                                       

                                    

                                  

                             

                       

                               

               

                               

                                   

                                  

                             

                           

                       

                                 

                       

                             

                               

                             

                         

             

                             

                         

                             

                             

                                   

                                   

                   

                             

                           

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 72 of 77

Table. Definitions of first‐ and second‐party age‐verified data

First‐party

age‐verified

data

Data owned by a firm (e.g., a firm’s customer registration data collected via site traffic to

the firm’s company‐owned website; data the firm uses in direct marketing to its adult

smoking customers) that the firm has age‐verified through independent, competent, and

reliable data sources.

Second‐party

age‐verified

data

First‐party data owned and age‐verified by another competent and reliable entity (e.g.,

another company’s first‐party user registration data) to which a firm has access. This data

must be age‐verified by the second party and not through data aggregators.

Using targeting through the use of first‐ and/or second‐party age‐verified data (see table) does not

mean that a firm will not be able to advertise at all in certain digital platforms, for example on certain

websites that do not have age‐restriction measures in place. Rather, even if a website does not have its

own first‐party age‐verified data, tobacco advertising could still show up on that site. For example, if an

adult that a tobacco marketer has age‐ and identity‐verified as meeting the federal minimum legal age

to purchase tobacco products through independent, competent, and reliable data sources visits

TeenVogue.com, that adult could be delivered a tobacco ad on the site using the marketer’s first‐party

age‐verified targeting data (regardless of whether TeenVogue.com has its own first‐party age‐verified

data to share with the tobacco marketer), but an age‐verified teen on TeenVogue.com would not be

delivered the same tobacco ad as a result of this targeting. Therefore, through the use of targeting data,

different individuals can see different ads when visiting the same website at the same time. This allows

for a highly targeted approach to tobacco advertising delivery, which can help ensure that youth

exposure is minimized, while at the same time not restricting access to adults.

                         

   

2. Restrictions on Tobacco Product Social Media Marketing and the Use of Influencers, Bloggers,

Brand Ambassadors, etc.

Although paid digital advertising can be effectively targeted using first‐ and second‐party age‐verified

data to reach adults, there are other types of digital marketing that cannot be targeted using this

approach. For example, product‐branded social media accounts essentially operate as both mini

websites and “free” advertising channels offering a range of effective means of directly reaching and

engaging consumers. In fact, “the ability to influence a large number of individuals, the minimal effort

required to make influence attempts, and the flexibility to deploy a variety of influence strategies

through information technologies are a potent combination making influence in online social networks

considerably more compelling and pervasive than in conventional interpersonal interactions,”

highlighting the need for close scrutiny of these methods (Subramani & Rajagopalan 2003). Further, one

of the most effective digital marketing practices today—especially among youth who are particularly

susceptible to social influences—is the use of “organic” depictions of tobacco use and endorsements of

tobacco products by cultural icons and other influencers through their own social media accounts (HHS

2012).

Thus, as part of ensuring digital media plans and buys for tobacco products are highly targeted to adults

while limiting spill to youth, it is critical to mitigate against the incredible reach and influence of social

media, including “organic” influencer promotion. Currently, there are no universal age‐restriction

controls on social media platforms and some do not offer any age‐restriction options; however, many

social media platforms are beginning to offer branded‐account owners the option to age‐restrict some
       

                             

                             

                           

                           

                                   

                

                                     

                             

                           

                                 

                               

                               

         

  

                         

                         

                           

                             

                           

                           

                               

                     

                     

       

                           

                         

                           

                   

                       

                       

                         

               

                           

       

                       

        

                         

         

                       

            

                     

                         

                   

                     

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 73 of 77

or all of their account pages, followers, and content, including even specific posts, photos, videos,

events, etc. These options still face a few additional limitations; for example, most social media

platforms allow users to establish their own account profile settings, including self‐reported age, and

users are not age‐ or identity‐verified. However, users are increasingly prompted to “link” digital profiles

and accounts (e.g., option to sign‐up for a new account using an existing email account or social media

account), increasing the likelihood of more accurate self‐reporting.

As part of these restrictions, firms must ensure that their own social media accounts as well as those of

any influencers promoting a tobacco product on a firm’s behalf use the available age‐restriction controls

to restrict youth access to any product promotion disseminated through social media accounts. Firms

must also ensure the disclosure to consumers or viewers, via the use of statements such as “sponsored

by [firm name],” of any relationships between the firm and entities that creating labeling for, advertise,

market and/or promote the product on the firm’s behalf to help prevent misleading marketing, which is

especially likely to influence youth.

V. Proposed Marketing Restrictions in MRTP Authorization Orders   

In this context, FDA should consider including detailed marketing restrictions and requirements, in

addition to other requirements, for any MRTP receiving market authorization. FDA should determine

such marketing restrictions and requirements on a case‐by‐case basis when issuing a modified risk

order. Information that should be considered in these determinations includes, but is not limited to,

information submitted to FDA by a firm seeking authorization under the MRTP application pathway

regarding the firm’s intended labeling, advertising, marketing, and promotion of the product; use of

industry practices known to substantially impact youth trial and uptake of tobacco product use; new and

emerging technologies, media, and marketing practices; and existing applicable laws and legal

agreements affecting the sales, distribution, marketing, advertising, labeling, and/or promotion of

certain tobacco products.

Generally, firms seeking marketing authorization for MRTPs should seek to limit youth‐exposure to the

products’ labeling, advertising, marketing, and promotion. Restrictions in a marketing order should be

aimed at the following with respect to advertising and marketing plans, including strategic creative

briefs and paid media plans, by channel and by product:

 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 adults, ages 18‐24, and

other demographic and psychographic characteristics that reflect the intended target

audience(s), including how the target audience(s) are defined and the insights used to develop

the target audience profile(s);

 Actions taken to restrict youth‐access and limit youth‐exposure to the products’ labeling,

advertising, marketing, and/or promotion;

 Use of owned, earned, shared/social, and/or paid 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 products;

 Consumer engagements, including events at which the products will be demonstrated; and/or

 Use of public‐relations outreach to create labeling for, advertise, market, and/or promote the

products.

Firms should establish, maintain, and monitor use of independent age‐ and identity‐verification

service(s) that compare customer information against independent, competent, and reliable data
       

                                 

                

                   

                     

                                   

           

                           

                                 

  

                     

                         

                       

                           

                             

                           

                           

                       

                            

                         

                         

                         

                         

                             

                           

                         

                             

                         

                         

                           

                             

                     

                                 

                         

                             

                           

        

                           

                                 

                                 

       

                               

                         

                     

                               

STN MR0000020‐22, MR0000024‐25, MR0000027‐29 Page 74 of 77

sources, such as public records, to prevent digital sales of the products to individuals who are under the

federal minimum legal age to purchase tobacco products.

Firms should establish, maintain, and monitor use of independent age‐ and identity‐verification

service(s) that compare consumer information against independent, competent, and reliable data

sources, such as public records, at the first point of access to any owned digital properties (e.g., the

firm’s company‐owned, consumer‐directed, product‐branded website(s) and/or mobile applications), to

restrict access to any of the products’ labeling, advertising, marketing, and/or promotion appearing in

such properties to only individuals who are at least of federal minimum legal age to purchase tobacco

products.

Firms should establish, maintain, and monitor use of the available site‐, platform‐ and content‐ (e.g.,

post, video) specific age‐restriction controls (e.g., age‐restrict an entire product‐branded account and all

associated content disseminated through such account; ensure age‐restriction of a specific video

disseminated by an influencer promoting the products on the firm’s behalf through the influencer’s

account), at the first point of access to any shared digital properties (e.g., the firm’s product‐branded

social media accounts, pages and associated content; content promoting the products on the firm’s

behalf disseminated through another entity’s social media accounts), to restrict access to any of the

products’ labeling, advertising, marketing, and/or promotion appearing in such properties to only

individuals who are at least of federal minimum legal age to purchase tobacco products.

Firms should establish, maintain, and monitor use of competent and reliable data sources,

methodologies, and technologies to precisely target delivery of any of the products’ labeling,

advertising, marketing, and/or promotion appearing in paid digital media (e.g., paid digital banner

advertisements for the product(s) running on another company’s website; paid advertising for the

product(s) running in social media; paid distribution of influencer content), to restrict access to such

labeling, advertising, marketing, and/or promotion to only individuals who are at least of federal

minimum legal age to purchase tobacco products. Such targeting must use only first‐ and/or second‐

party age‐verified data (see table). Firms should restrict advertising practices that are not and/or cannot

be targeted using such data (e.g., tactics like “Run‐of‐Site,” “homepage takeovers,” “splashy buys”).

Firms should 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) to

track and measure actual delivery of all advertising impressions, by channel, by product, and by

audience demographics (e.g., age, gender, race/ethnicity, geographic location), including a breakout by

age‐group (i.e., adults, ages 25+; young adults, ages 18‐24; and youth, ages 12‐17 and ages 11 and

under). Such monitoring should require real‐time digital media tracking, and identifying, correcting, and

preventing delivery of advertising impressions to youth, ages 17 and under. Such monitoring also should

require post‐launch delivery verification reports be submitted to the firm from an accredited source

(e.g., Media Ratings Council).

Firms should disclose to consumers or viewers any relationships between the firm and entities that

create labeling for, advertise, market, and/or promote the products, on the firm’s behalf or at the firm’s

direction, via the use of statements such as “sponsored by [firm name]” in any such labeling, advertising,

marketing, and/or promotional materials.

It is vital to the continued protection of public health that FDA take these and other marketing‐related

considerations seriously when evaluating marketing plans to ensure they are sufficiently targeted to

limit youth‐exposure to tobacco product labeling, advertising, marketing, and promotion. The evaluation

of these marketing plans, including evaluation of their potential impact on youth tobacco use, will help
       

                               

           

                               

                                 

                           

                             

                               

                                 

  

                          

               

                             

       

                           

             

                               

   

                                   

                         

         

                                 

                         

                                   

                       

                               

                      

                         

       

                                   

               

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FDA determine whether the marketing, and continued marketing, of an MRTP will benefit the health of

the population as a whole.

VI. Conclusion

Given the level of evidence indicating the direct and powerful impact of tobacco marketing on youth

tobacco use, and FDA’s statutory mandate to protect young people from the dangers of tobacco use, it

is both reasonable and critical for firms to submit planned labeling, advertising, marketing, and

promotional materials and plans for MRTPs that have received authorization, and for FDA to place

restrictions on the marketing of such products. This important safeguard will help FDA ensure, on an

ongoing basis, that the continued marketing of MRTPs will benefit the health of the population as a

whole.

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