Substantiation of Modified Risk Information 08082018

R. J. REYNOLDS TOBACCO COMPANY (RJRT) MODIFIED RISK TOBACCO PRODUCT APPLICATIONS

Presented by: Deirdre Lawrence Kittner, PhD, MPH Deputy Director, Division of Population Health Science Office of Science Center for Tobacco Products U.S. Food and Drug Administration

Disclaimer: This is not a formal dissemination of information by FDA and does not represent Agency position or policy.

September 13-14, 2018 CENTER FOR TOBACCO PRODUCTS DISCLAIMER

The information in these materials does not represent agency position or policy. The information is being provided to TPSAC to aid in its evaluation of the issues and questions referred to the committee.

This presentation contains information prepared by the FDA for the members of the TPSAC. The presentation describes assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. This presentation may not include all issues relevant to FDA’s decision on the applications and instead is intended to focus on issues identified by FDA for discussion by TPSAC. The FDA will not make its determination on the issues at hand until input from TPSAC and from the public comments has been considered and all FDA reviews have been finalized. FDA’s determination may be affected by issues not discussed at the TPSAC meeting.

1 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS AGENDA

• Statutory framework for modified risk tobacco products and review process

• Summary of RJRT applications under review

• Questions for the committee

2 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS MRTP STATUTORY FRAMEWORK AND REVIEW PROCESS

3 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS MODIFIED RISK TOBACCO PRODUCTS (MRTPS) DEFINED

• Tobacco products sold or distributed for use to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products; this includes tobacco products whose – Label, labeling or advertising represents, implicitly or explicitly, that: • The product is less harmful or presents a lower risk of tobacco-related disease than one or more commercially marketed tobacco products • The product or its smoke contains a reduced level of, presents a reduced exposure to, or does not contain/is free of a substance

4 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS MRTP CONTEXT

• Before an MRTP can be marketed in the United States, an order from FDA under section 911(g) of the FD&C Act must be in effect with respect to the tobacco product

• To legally sell an MRTP that is also a new tobacco product, a company must have authorization from FDA under section 911 (i.e., an MRTP order) and also comply with the premarket requirements of section 910 – RJRT submitted premarket tobacco product applications (PMTAs) and SE reports for Camel Snus

5 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RISK MODIFICATION ORDER STANDARD - 911(G)(1)

The FD&C Act requires FDA to determine if a proposed MRTP, as it is actually used by consumers, will:

(1) significantly reduce harm and the risk of tobacco-related disease to individual tobacco users and

(2) 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

6 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EXPOSURE MODIFICATION ORDER STANDARD - 911(G)(2)

For products that • it is appropriate to promote the public health; • the label, labeling, and advertising is limited to a claim that the cannot receive an product does not contain or is free of a substance or contains a order under 911(g)(1), reduced level or presents a reduced exposure; FDA may issue an • scientific evidence is not available, and cannot be made available without conducting long-term epidemiological studies, order under 911(g)(2) for an application to meet the standard for a 911(g)(1) order; if it determines that • scientific evidence that is available demonstrates that a the applicant has reduction in morbidity or mortality is reasonably likely; and • testing shows that consumers will not be misled into believing demonstrated that, that the product has been demonstrated to be less harmful or among other things: present less risk.

7 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS RELEVANT TO THE MRTP EVALUATION

These questions are relevant to the evaluation of whether the applicant has met the applicable 911 standard: 1. Is there adequate scientific substantiation of the proposed modified risk information? 2. What are the health risks of the MRTP to individual tobacco users? 3. How do consumers perceive and understand the modified risk information? 4. What are the potential benefits and harms to the health of the population as a whole?

8 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS MRTPA REVIEW PROCESS

9 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RJRT MRTP APPLICATIONS

10 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RJRT CAMEL SNUS MRTPA PRODUCTS

The applicant is seeking an order under Section 911(g)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for each of its six Camel Snus products – Camel Snus Frost – Camel Snus Frost Large – Camel Snus Winterchill – Camel Snus Robust – Camel Snus Mellow – Camel Snus Mint

(Source: Section 3.1.3 of MRTPAs)

11 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RJRT REQUESTS MODIFIED RISK ORDERS TO MARKET THESE PRODUCTS WITH THE FOLLOWING “KEY” MODIFIED RISK CLAIMS

Smokers who switch completely from cigarettes to Camel SNUS can significantly reduce their risk of lung cancer, oral cancer, respiratory disease, and heart disease.

Smokers who SWITCH COMPLETELY from cigarettes to Camel SNUS can greatly reduce their risk of lung cancer, oral cancer, respiratory disease, and heart disease.

Smokers who SWITCH COMPLETELY from cigarettes to Camel SNUS can greatly reduce their risk of lung cancer and respiratory disease.

12 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS ADDITIONAL MODIFIED RISK INFORMATION IN ADS

Smokers who use Camel SNUS instead of No smoke means... cigarettes can significantly reduce their health No hassle risks from smoking. No lingering smoke smell More freedom Fewer carcinogens Less risk for you and those around you Scientific studies have shown that Camel SNUS contains fewer carcinogens than cigarette smoke. Switching to SNUS means ... Less of the harmful chemicals found in cigarette smoke Scientific studies have shown that Camel SNUS Less risk for you and those around you contains less of the harmful chemicals than No lingering smoke smell cigarette smoke. Hassle-free tobacco

Swap the smoke for more freedom and less risk.

No smoke. Less risk. Choose SNUS.

NO SMOKE = LESS RISK

*Modified risk information is bolded

13 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS LINES OF EVIDENCE

Evidence Related Consumer Likelihood of Use to Substantiation perception and of the Proposed of the Modified understanding MRTPAs Risk Information

Product chemistry Observational Studies Toxicological assessments

Pharmacokinetic Consumer Likelihood of use studies perception studies study

Clinical trials

Epidemiological Clinical trials studies

14 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS FOCUS OF TPSAC DISCUSSION & RECOMMENDATIONS

FDA will present the product chemistry, nonclinical and clinical studies, and epidemiological evidence used to assess the scientific accuracy of EVIDENCE RELATED TO the statements. HEALTH RISKS AND SUBSTANTIATION TPSAC will be asked to discuss the evidence and scientific accuracy of these statements.

15 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS FOCUS OF FDA TPSAC DISCUSSION & RECOMMENDATIONS

CONSUMER FDA will present the ads submitted by the applicant and the result of the consumer perception studies. PERCEPTIONS AND TPSAC will be asked to discuss consumer perceptions and understanding of the modified risk UNDERSTANDING information.

FDA will present data from observational studies to describe characteristics of Camel Snus users, patterns of use, and transitions from cigarette smoking to snus, as well as RJRT’s clinical studies and LIKELIHOOD OF USE OF likelihood of use studies. PROPOSED MRTPS TPSAC will be asked to discuss the potential use behaviors with respect to the proposed modified risk tobacco products, including the likelihood that cigarette smokers will switch completely to the six Camel Snus products.

16 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS FOR THE COMMITTEE

17 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SECTION 911(G)(1) OF THE FD&C ACT FOR SIX CAMEL SNUS PRODUCTS

The applicant submitted modified risk tobacco product applications (MRTPAs) seeking orders under section 911(g)(1) of the FD&C Act for six Camel Snus products.

To authorize a product under section 911(g)(1), the agency must find that the product, as actually used by consumers, will:

(1) significantly reduce harm and the risk of tobacco-related disease to individual tobacco users; and (2) benefit the health of the population as a whole taking into account both users of tobacco products and those who do not currently use tobacco products.

18 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS FOR TPSAC: SUBSTANTIATION OF MODIFIED RISK INFORMATION

Q1. The proposed modified risk claims that the applicant identifies as its “key” claims describe the reduction in risk for specific diseases as a result of completely switching to the six Camel Snus products from cigarettes.

DISCUSS the available scientific evidence and VOTE on the extent to which the available scientific evidence substantiates the following modified risk information in the applicant’s advertising: “Smokers who switch completely from cigarettes to Camel SNUS can significantly reduce their risk of…” a. lung cancer? (yes/no/abstain) b. oral cancer? (yes/no/abstain) c. respiratory disease? (yes/no/abstain) d. heart disease? (yes/no/abstain)

19 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS FOR TPSAC: SUBSTANTIATION OF MODIFIED RISK INFORMATION

Q2. The applicant’s advertising also contains modified risk statements that describe a reduction in harmful chemicals in Camel Snus vs. cigarettes, or that are not as specific as those presented in Question 1 (e.g., do not reference reduction in specific diseases or the need for complete switching). All of these statements are being evaluated as part of the MRTPAs.

DISCUSS the available scientific evidence and VOTE on the extent to which the available scientific evidence substantiates the following modified risk information in the advertising: a. “…Camel SNUS contains less of the harmful chemicals than cigarettes”? (yes/no/abstain) b. “Smokers who use Camel SNUS instead of cigarettes can significantly reduce their health risks from smoking.” (yes/no/abstain) c. “Switching to snus means less risk for you.” (yes/no/abstain) d. “NO SMOKE = LESS RISK” (yes/no/abstain)

20 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS FOR TPSAC: CONSUMER PERCEPTIONS & UNDERSTANDING

Q3. In addition to evaluating the proposed modified risk for scientific accuracy, FDA is also evaluating consumer understanding and perception of the modified risk information in the advertising. The applicant plans to communicate all of the modified risk information together, i.e., the first page has less specific modified risk information, while the second and third pages have more specific modified risk information and additional information the applicant refers to as “balancing information” (e.g., that Camel Snus and other tobacco products contain nicotine and are addictive; the recommendation that smokers concerned about the health risks of smoking should quit and talk to a healthcare provider).

21 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS FOR TPSAC: CONSUMER PERCEPTIONS & UNDERSTANDING

Q3. DISCUSS potential implications of the proposed modified risk information, including the non-specific modified risk language, as described in Question 2, on consumer understanding and perceptions and tobacco use behavior: a. Can the non-specific modified risk information be misinterpreted? b. Is there sufficient evidence that consumers would understand the non-specific modified risk information? c. Is there sufficient evidence about the impact of the non-specific modified risk information on the likelihood of use? d. Is there sufficient evidence about the impact of the non-specific modified risk information on poly tobacco use or partial switching?

22 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS FOR TPSAC: LIKELIHOOD OF USE OF PROPOSED MRTPS

Q4. DISCUSS the potential users of the proposed MRTPs. a. What is the likelihood that cigarette smokers will switch completely to the six Camel Snus products? b. Are there other groups of potential users, particularly unintended users (e.g., youth, former cigarette smokers), of concern?

23 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CLARIFYING QUESTIONS? EVIDENCE RELATED TO SUBSTANTIATION OF THE MODIFIED RISK INFORMATION

Presented by: Mimy Young, PhD Catherine Corey, MSPH Chemist Epidemiologist Division of Product Science Division of Population Health Science Office of Science, CTP, FDA Office of Science, CTP, FDA

Additional Contributors: Kausar Riaz Ahmed, PhD, Susan Rudy, MSN, CRNP, Theresa Carbonaro, PhD Colin Cunningham, PhD, Christopher Ellison, MA Office of Science, CTP, FDA

Disclaimer: This is not a formal dissemination of information by FDA and does not represent Agency position or policy.

September 13-14, 2018 CENTER FOR TOBACCO PRODUCTS DISCLAIMER

26 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS AGENDA

• Product chemistry

• Toxicological evidence

• Clinical evidence

• Epidemiological evidence

27 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS PRODUCT CHEMISTRY

28 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS DESCRIPTION OF THE SIX CAMEL SNUS PRODUCTS

Camel Snus products are portioned snus smokeless tobacco products.

Differences in product design: 600 mg pouch width, tobacco weight, fleece weight, pouches package weight

Frost Mint Mellow Similarities in product design: pH, moisture, tobacco particle size, pouch quantity per package, pouch length

1000 mg pouches Similarities in formulation: tobacco, salts, pH adjusters, sweeteners, flavorings, humectants, pouch materials Frost Large Robust Winterchill

29 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS DIFFERENCES OF KEY COMPONENTS AND INGREDIENTS IN THE SIX CAMEL SNUS PRODUCTS AND CIGARETTES

• Fleece pouch materials • Cigarette • Plug COMPONENTS paper • Wrap • Filter • Glues

• Different tobacco blend • Flue cured, burley, and oriental compared to cigarettes TOBACCO tobacco leaf; expanded tobacco and reconstituted tobacco

• Flavor ingredients • Flavor ingredients • pH adjusters INGREDIENTS • Menthol • Humectants • pH adjusters ADDED TO • Humectants TOBACCO

30 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS HPHCS IN SMOKELESS TOBACCO PRODUCTS AND CIGARETTE SMOKE

Abbreviated HPHC List2, 3 Scientific literature Cigarette Smoke Smokeless Tobacco Acetaldehyde Acetaldehyde • Over 7,000 chemical constituents reported in mainstream Acrolein cigarette smoke1 Acrylonitrile 4-Aminobiphenyl • Approximately 4,000 chemical constituents reported in 1-Aminonaphthalene 1 smokeless tobacco 2-Aminonaphthalene Ammonia 93 HPHCs in the established HPHC list Arsenic Benzene • 91 reported in mainstream cigarette smoke, 77 Benzo[a]pyrene (B[a]P) B[a]P carcinogens 1,3-Butadiene • 65 reported in smokeless tobacco, 51 carcinogens Cadmium Carbon monoxide Crotonaldehyde Crotonaldehyde “Abbreviated” HPHC list Formaldehyde Formaldehyde • 18 reported in cigarette smoke, 13 carcinogens Isoprene • 9 reported in smokeless tobacco, 8 carcinogens Nicotine (total) Nicotine (total and free) 4-(methylnitrosamino)-1-(3- NNK 1 Rodgman & Perfetti, 2009 pyridyl)-1-butanone (NNK) 2 Food and Drug Administration, 2102a Food and Drug Administration, 2012b N-nitrosonornicotine (NNN) NNN Toluene 31 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS COMPARISON OF HPHCS IN SIX CAMEL SNUS PRODUCTS AND CIGARETTE SMOKE

Mean of the Six Camel Snus Mean in Mainstream Cigarette Mean Difference (%) by (unit/pouch) Smoke Unit of Use Constituent (unit) 600 mg* 1000 mg** ISO, unit/cig CI, unit/cig ISO CI

Acetaldehyde (µg) 0.94 1.54 615 1673 ↓ 99 ↓ 99 Arsenic (ng) 46.6 76.0 3.0 9.0 ↑ 1904 ↑ 579 B(a)P (ng) 0.6 1.1 9.0 19.7 ↓ 91 ↓ 96 Indeno(1,2,3-c,d)Pyrene 2.8 5.1 4.5 9.8 ↓ 6 ↓ 56 (I[1,2,3-cd]P) (ng) Cadmium (ng) 241 402 42 116 ↑ 659 ↑ 177 Crotonaldehyde (µg) 0.41 < LOQ*** 13.0 49.0 ↓ 97 ↓ 99 Formaldehyde (µg) 0.76 0.97 23.8 92.2 ↓ 97 ↓ 99 NNK (ng) 200 330 68 152 ↑ 286 ↑ 73 NNN (ng) 698 1108 90 197 ↑ 895 ↑ 354 Total Nicotine (mg) 5.95 9.61 0.91 2.16 ↑ 746 ↑ 256 Data source: Section 7.1 of MRTPAs (RDM JMR 2016 235 [Analytical Testing of Camel Snus Products] for Camel Snus products; RDM JAB 2016 306 [Summary of 2014 and 2015 Cigarette Market Surveys] for cigarette tobacco products. * Mean of 600 mg pouch products in unit/pouch (i.e., MR0000068, MR0000070, and MR0000071) ** Mean of 1000 mg pouch products in unit/pouch (i.e., MR0000069, MR0000072, and MR0000073) *** < LOQ: Below limit of quantification

32 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SCIENTIFIC STUDIES OF CAMEL SNUS NNN AND OTHER HPHC LEVELS

NNN LEVEL (ng/g) PRODUCTS | LEAD AUTHOR (YEAR) 1136 All six Camel Snus products Bodnar (2016)

Camel Snus Frost, Mellow, Robust, Stepanov (2008; 2010; 829-1790* Winterchill 2012, 2013; 2014)

Camel Snus Frost, Mellow, Robust, Hatsukami (2007; 2015) 830-1570* Winterchill

684-703 Camel Snus Frost from 2006 and 2007 Borgerding (2012) 1197 Camel Snus Frost Ammann et al. (2016) 893-1113 All six Camel Snus products Labstat Report (2014) COMPARED TO CIGARETTE SMOKE, THE SIX CAMEL SNUS PRODUCTS CONTAIN:

• Higher levels of nicotine (total), NNN, NNK, cadmium and arsenic Note: Per pouch as-is basis or per cigarette basis. • Lower levels of B[a]P, formaldehyde, acetaldehyde, and crotonaldehyde (Source: Labstat report, Section 7.1.1 of MRTPAs) * Quantities reported in dry-weight basis (DWB) were converted to wet-weight basis (WWB) using the following equation: WWB = DWB x (1 – average moisture %) 33 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS DIFFERENCES BETWEEN CAMEL SNUS AND OTHER SMOKELESS TOBACCO PRODUCTS

Camel Snus does not contain fermented tobacco but undergoes a heat treatment process.

ALL SIX NNN levels in Camel Snus are similar to Compared to GOTHIATEK CAMEL GothiaTek CONSTITUENT STANDARD those in moist snuff (Unit, as-is basis) SNUS LIMIT* 10000 Voluntary Quality 95% CI 9000 Standard Limits, Nitrite (µg/g) 3.5 NP 8000 Camel Snus was: NNN+NNK (µg/g) 0.95 1.44 - 1.48 7000 NDMA (ng/g) 2.5 NP 6000 • Below the limit B(a)P (ng/g) 1.25 1.03 - 1.07 5000 for 6/15 NP 4000 AflatoxinB1+B2+G1+G2 (ng/g) 2.5 constituents NP 3000 Ochratoxin (ng/g) 10 MRTPAs (ng/g) MRTPAs 2000 Formaldehyde (µg/g) 7.5 1.1 - 1.3 • Above the limit 1000 Crotonaldehyde (µg/g) 0.75 0.64 - 0.74 NNN Levels Reported in Reported Levels NNN 0 for 1/15 Cadmium (µg/g) 0.5 0.4 - 0.4 Moist Camel Swedish Cig Cig constituents Lead (µg/g) 1 NP snuff Snus snus Smoke Smoke (NNN) Arsenic (µg/g) 0.25 0.08 - 0.08 (ISO) (CI) Nickel (µg/g) 2.25 NP • Not provided NP Data source: Section 7.1 of MRTPAs (RDM JMR 2016 235, RDM JAB 2016 281, LSI 2014 Chromium (µg/g) 1.5 113 [Determination of Smokeless Tobacco HPHC Values for Camel Snus and Other Tobacco for 8/15 Mercury (µg/g) 0.02 NP Products – M195-GLP]). Swedish snus levels converted as: Wet weight (‘as-is’) basis (WWB) = dry weight basis x (1 – average Moisture %) constituents Acetaldehyde (µg/g) 25 1.5 - 1.6 *Swedish Match, 2018. NP= Not provided. 34 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CHEMISTRY SUMMARY

• 4,000 chemical compounds are shown to be found in smokeless tobacco, compared to over 7,000 chemical compounds in mainstream cigarette smoke • HPHCs* measured in cigarette smoke were also present in the six Camel Snus products: – Lower levels of acetaldehyde (>99%), crotonaldehyde (97-99%), formaldehyde (97-99%), B[a]P (91-96%), indeno(1,2,3-c,d)pyrene (6-56%) compared to cigarette smoke – Higher levels of arsenic (579-1904%), cadmium (177-659%), NNK (73-286%), NNN (354-895%), and total nicotine (256- 746%) compared to cigarette smoke • HPHCs measured in the six Camel Snus products compared to other smokeless tobacco products: – The six Camel Snus products contain comparable median levels of NNN compared to moist snuff tobacco products and higher median levels of NNN compared to Swedish snus

* PAHs below limit of quantification (i.e., benzo[a]anthracene; benzo[b/j]fluoranthene; benzo[k]fluoranthene; dibenzo[a,h]anthracene; and naphthalene) are not included in the evaluation.

35 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS TOXICOLOGICAL EVIDENCE

36 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS HPHCS AND ASSOCIATED ADVERSE EFFECTS

• RJRT measured HPHCs in the six Camel Snus products and cigarette smoke; the following nine HPHCs* were found in both cigarette smoke and the six Camel Snus products: – Acetaldehyde: carcinogen, respiratory toxicant, addictive – Nicotine: reproductive or developmental toxicant, addictive – Arsenic: carcinogen, cardiovascular toxicant, reproductive or developmental toxicant – Cadmium: carcinogen, reproductive or developmental toxicant, respiratory toxicant – Formaldehyde: carcinogen, respiratory toxicant – Crotonaldehyde, B[a]P (representative PAH), NNN & NNK: carcinogens

• Differences in portal of entry effects, differences in toxicant absorption and distribution through the body, and differences in metabolism can affect the toxicity of HPHCs introduced through different routes of exposure

• RJRT conducted in vitro genotoxicity studies using extracts from the six Camel Snus products and other smokeless tobacco products, as well as extracts from total particulate matter collected from cigarette smoke; all test articles were positive for genotoxicity

• RJRT conducted in vivo studies Camel Snus native tobacco blend and tobacco blend extract; these studies have several limitations and lack parallel studies with the comparator arm of conventional cigarettes, making their use for comparative conclusions on health effects difficult

* PAHs below limit of quantification (i.e., benzo[a]anthracene; benzo[b/j]fluoranthene; benzo[k]fluoranthene; dibenzo[a,h]anthracene; and naphthalene) are not included in the evaluation. 37 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CLINICAL EVIDENCE

38 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CLINICAL STUDIES: BACKGROUND

• Clinical studies are found in Section 7.4; Appendix B – 2 nicotine pharmacokinetic studies, 5 repeated use studies (range: 5-days confined to 52-weeks ambulatory), and 1 natural product adopters study • Camel Snus products assessed: – 600 mg pouches: Frost and Mellow flavors – 1000 mg pouches: Winterchill flavor (n=2-5) – 400 mg pouches: Frost, Spice and Original flavors (not the subject of the MRTPAs) • Over 150 biomarkers studied: – Biomarkers of exposure (BOE) were assessed in 3 studies . 01_HSD0702_QOL1, 03_CSD0901_SSSO2, and 04_CSD0904_PMS3 – Biomarkers of potential harm (BOPH) were assessed in 2 studies . 01_HSD0702_QOL1, 04_CSD0904_PMS3

. Inflammation, oxidative stress and other physiologic processes 1 HSD0702: 400 mg pouches 2 CSD0901: 600 mg Frost and Mellow 3 CSD0904: 600 mg Frost and Mellow,1000 mg Winterchill 39 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RJRT EVIDENCE SUGGESTS EXCLUSIVE CAMEL SNUS USE (BUT NOT DUAL USE) LOWERS SOME BOE • 24 weeks of 400 mg Camel Snus use lowered 18/21 BOE1 • 5-day confined Camel Snus use2 lowered most BOE – At Day 5: Exclusive and dual use of Camel Snus products lowered 26/28 and 23/28 BOEs, respectively – At Day 5: Exclusive Camel Snus users lowered 22/28 BOE compared to dual users • Among natural product adopters,3 exclusive Camel Snus users (but not dual users) had lower BOE – Exclusive smokers and dual users had higher levels of 18/26 and 16/26 BOE, respectively, compared to exclusive Camel Snus users – BOE were generally not different between exclusive smokers and dual users (1 decreased) – TSNAs were not lowered in exclusive Camel Snus or dual users; however, smokers, Camel Snus users, and dual users had lower TSNAs than other moist snuff users

• Similar to the natural product adopter study, TSNAs (NNN and NNAL) were generally not lower in 4,5,6 three independent, peer-reviewed publications 1 HSD0702: 400 mg pouches 2 CSD0901: 600 mg Frost and Mellow 3 CSD0904: 600 mg Frost and Mellow,1000 mg Winterchill 4Blank & Eissenberg, 2010 5Kotlyar et al., 2011 6Hatsukami et al., 2016 40 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS LIMITATIONS OF CLINICAL STUDIES & BIOMARKER DATA

• No bridging data from 400 mg products to 600 mg or 1000 mg products

• Clinical study design, conduct and analyses limitations – Statistical differences are not indicative of whether outcomes are clinically meaningful and would result in lower health risks as the proposed claims suggest – Results from 7 studies represent pooled data from more than one Camel Snus product – Data did not always reflect actual use or inclusion criteria

• Additional limitations for study 04_CSD0904_PMS include: – Product self-selection may bias results – No statistical adjustments for multiplicity - may result in false positives

41 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EPIDEMIOLOGICAL EVIDENCE

Catherine Corey, MSPH Epidemiologist Division of Population Health Science Office of Science, CTP, FDA

4242 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EPIDEMIOLOGICAL EVIDENCE FOR DISEASE RISKS ASSOCIATED WITH ST USE

• Evidence on disease risks associated with smokeless tobacco (ST) use from U.S. studies . HPHC yields indicate certain harmful constituents, including TSNA levels for NNN, in the six Camel Snus products exceed those of Swedish snus and are comparable to levels for U.S. moist snuff comparator products . Magnitude of relative risks associated with U.S. ST use and with Swedish snus use are generally more similar to each other as compared to relative risks for cigarette smoking • Studies provide disease risks for ST products generally • Focus on exclusive current or ever ST users (never cigarette smokers) • Relative risks for exclusive ST users based primarily on three U.S. cohort studies assessing fatal events • Relative risks produced from published meta-analyses

43 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EVIDENCE PERTAINING TO DISEASE RISKS FOR CONTINUING SMOKING VERSUS SWITCHING TO ST USE

• RJRT did not submit, nor is FDA aware of, evidence directly comparing disease risks for continuing smokers to risks for former smokers who switched to exclusive ST use • For lung cancer, oral cancer, respiratory disease and heart disease, relative risks (RRs) were evaluated for the following tobacco user groups:

Tobacco Use Status RRs Exclusive ST users compared to never tobacco users* Exclusive former smokers who switched to exclusive ST use at time of or after quitting smoking (i.e. “switchers”) compared to: • Never tobacco users • Former smokers who quit all tobacco use^ Exclusive smokers compared to never smokers**

* Sources for RRs are Boffetta et al., 2008; Lee & Hamling, 2009; Boffetta & Straif, 2009; Lee, 2007; and CPS-II from Henley et al., 2005. ^ Source for RRs is CPS-II from Henley et al., 2007. ** Source for RRs is US DHHS, 2014; Table 12-1 for current male cigarette smokers for CPS-II.

44 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS PRIMARY U.S. COHORT STUDIES OF EXCLUSIVE ST USE AND DISEASE RISK

Nutrition Health & Nutrition Examination Cancer Prevention Study Cancer Prevention Study Survey/Epidemiologic Followup Study (CPS)-I (CPS)-II (NHANES-I/NHEFS) Characteristics (Accortt et al. 2002) (Henley et al. 2005) (Henley et al. 2005) Study population Participants of NHANES-I completing >1 Recruited by American Cancer Society Recruited by ACS volunteers followup cycle of NHEFS (ACS) volunteers Males & females Males only Males only Study period 1971-75 to 1992 1959 to 1971 1982 to 2000

Study size 500 exclusive ever ST users 7,700 exclusive current ST users 2,400 exclusive current ST users (approximate) 900 ever ST and cigarette users 70,000 never tobacco users 800 former exclusive ST users 5,000 never users of ST or cigarettes 111,000 never tobacco users Smokeless ST, chewing tobacco, snuff chewing tobacco, snuff, “spit” tobacco chewing tobacco, snuff, “spit” tobacco tobacco (ST) type Exposure Baseline or first follow up interview Baseline interview Baseline interview ascertainment Outcome measure Hazard ratio (HR) Hazard ratio Hazard ratio

Mortality Lung cancer, ischemic heart disease Lung cancer, oral cancer, IHD, Lung cancer, oral cancer, IHD, outcomes (IHD), respiratory disease, stroke, all respiratory diseases, stroke, all cause respiratory diseases, stroke, all cause (selected) cause

45 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CPS-II: SWITCHING COMPLETELY FROM CIGARETTE SMOKING TO ST USE AND DISEASE RISK

Cancer Prevention Study (CPS)-II Characteristics (Henley et al., 2007) Study population Male participants of the Cancer Prevention Study (CPS)-II; recruited through American Cancer Society volunteers Study period 1982 to 2002 Study size (approximate) 112,000 former exclusive cigarette smokers (i.e. quit all tobacco use) 4,000 current exclusive ST users who began using ST at the time of or after quitting exclusive cigarette smoking (i.e. switchers) 112,000 never tobacco users Smokeless tobacco (ST) type ST, chewing tobacco, snuff

Exposure ascertainment Baseline interview; full cohort not re-interviewed Outcome measure Hazard ratio (HR) Mortality outcomes Switch to ST use vs. quit all tobacco: lung cancer, coronary heart disease, COPD, stroke, oral cancer, all causes Switch to ST use vs. never tobacco users: lung cancer, coronary heart disease, COPD, stroke Adjustment factors Number of cigarettes smoked per day (prior to quitting), number of years smoked cigarettes, age at quitting smoking, current age, race, education, BMI, exercise level, consumption of: alcohol, fat, fruit/vegetables, aspirin intake, employment type and status

46 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RISKS OF LUNG CANCER, ORAL CANCER, HEART DISEASE AND COPD ACCORDING TO TOBACCO USE STATUS

47 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS META-ANALYSES INDICATE U.S. ST USE ASSOCIATED WITH ELEVATED RISK OF ORAL CANCER, HEART DISEASE

Lung Cancer Oral Cancer Heart Disease Reference RR (95%CI) RR (95%CI) RR (95%CI) Boffetta et al., 2008 1.8 (0.9-3.5) 2.6 (1.3-5.2) n/a (n=3 estimates for meta-analysis) (n=9) Lee & Hamling, 2009 1.22 (0.82-1.83)* 2.16 (1.55-3.02)* n/a (n=6) (n=31) 1.38 (0.72-2.64)^ 1.65 (1.22-2.25)^ (n=4) (n=12) 1.79 (0.91-3.51)** 3.33 (1.76-6.32)** (n=3) (n=5) Lee, 2007^^ n/a n/a 1.14 (0.96-1.34) (n=3) Boffetta & Straif, 2009*** n/a n/a 1.11 (1.04-1.19) (n=3) * This estimate pertains to the “overall data” results for U.S. studies reported in Lee & Hamling, 2009. ^ This estimate pertains to the “smoking-adjusted” results for U.S. studies reported in Lee & Hamling, 2009. ** This estimate pertains to the “never smokers” results for U.S. studies reported in Lee & Hamling, 2009. ^^ Results reported are for the random-effects models for U.S. studies reported in Lee, 2007; disease endpoint is referred to as “IHD or AMI”. *** The disease endpoint is referred to as “fatal myocardial infarction” in Boffetta & Straif, 2009. Notes: the applicant did not provide, nor are we aware of, published meta-analysis results for smokeless tobacco use and respiratory disease. RR is relative risk produced as the summary estimate for the meta-analyses; 95%CI is the 95% confidence interval for summary estimate; n/a is not available. 48 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS DISEASE RISKS GENERALLY ELEVATED AMONG SWITCHERS COMPARED TO QUITTERS OR NEVER USERS

Disease Endpoint Switch vs Quit All Tobacco* Switch vs Never Tobacco Use* (fatal events) HR (95%CI) HR^ Lung cancer 1.46 (1.24-1.73) 5.61

COPD 1.31 (0.96-1.78) 3.24

Oral cancer 2.56 (1.15-5.69) **

Coronary heart disease 1.13 (1.00-1.29) 1.28

Stroke 1.24 (1.01-1.53) 1.34

All-cause mortality 1.08 (1.01-1.15) **

* As reported in Henley et al., 2007. Hazard ratios (HRs) compared mortality risks among exclusive former smokers who switched to exclusive ST use at the time of or after quitting smoking to risks for former exclusive cigarette smokers (i.e. quit all tobacco use) and to risks for never users of any tobacco product based on CPS-II. ^ Numerical values for 95% confidence intervals (CIs) were not reported for HRs for switchers versus never tobacco users; results were statistically significant for lung cancer, COPD, heart disease and stroke based on the 95%CI line corresponding to each HR in Henley et al. 2007 Figure 1 not including 1.0. ** HRs were not reported for fatal oral/pharyngeal cancers or for all-cause mortality among switchers compared to never tobacco users.

49 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CAUSE-SPECIFIC DISEASE RISKS ACCORDING TO TOBACCO USE STATUS

Lung cancer ***

COPD ***

Oral cancer*

Heart disease Relative Risk 0 5 10 15 20 25 Exclusive smoker vs never smoker^ Switcher to ST vs never user** Exclusive ST vs non-user^^ Source: Section 6.1.1.5 of the MRTPAs. * Oral cancer risks for former smokers who switched to ST products as compared to risks of never tobacco users were not reported by Henley et al., 2007. ^ Exclusive current cigarette smoker relative risks (RRs) as compared to never smokers obtained from CPS-II as reported in Table 12-1 (USDHHS 2014); heart disease RRs for male current cigarette smokers aged 35-64 years. ** RRs for former smokers who switched to smokeless tobacco products at the time of or after quitting exclusive cigarette smoking, as compared to never tobacco users (Henley et al. 2007). ^^ RRs for exclusive ST use compared to non-users of tobacco for lung cancer obtained from Boffetta et al., 2008; for COPD obtained from Henley et al. 2005 for CPS-II; for oral cancer obtained from Boffetta et al., 2008; for heart disease from Boffetta & Straif ,2009. *** Estimate is not statistically significant based on 95%CI for the RR including 1.0.

50 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EPIDEMIOLOGICAL EVIDENCE PERTAINING TO OTHER DISEASE RISKS AND TOBACCO USE BEHAVIORS

51 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RISKS FOR PREGNANCY OUTCOMES, DIABETES NOT CONSISTENTLY LOWER FOR EXCLUSIVE ST USERS THAN SMOKERS

Adverse pregnancy outcomes • Studies reviewed by Inamdar et al. (2015) found associations with ST use and stillbirth, preterm birth, low birth weight and small for gestational age (SGA) – Lee (2014) reported on four Swedish studies, which found increased relative risks among exclusive snus users compared to non-tobacco users including stillbirth, preterm birth, and neonatal apnea . For these conditions, risks among exclusive snus users were similar in size to risks among smokers* Type 2 diabetes • In a U.S. cohort, current ST users had higher measures of insulin resistance at baseline; an association was reported between former ST use and type 2 diabetes in partially-adjusted longitudinal analyses^ • A pooled meta-analysis of five Swedish cohort studies reported snus use was associated with increased risk of types 2 diabetes**

* Wikstrom et al. 2010a; Wikstrom et al. 2010b; Gunnerbeck et al. 2011 ^ Keith et al., 2016 ** Carlsson et al., 2017

52 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS DUAL USE, CUTTING BACK ON SMOKING DO NOT CONSISTENTLY REDUCE HEALTH RISKS

Dual use of smokeless tobacco and cigarettes • Relative risks for U.S. dual users are generally comparable to relative risks among exclusive smokers* • Risks among dual users of Swedish snus and cigarettes are generally comparable to risks among exclusive smokers^

Smoking reduction without complete smoking cessation • Evidence for lower lung cancer risk among smokers reducing >50% cigarettes per day** • Other evidence shows no change in disease or mortality risk by reducing smoking intensity^^

* Accortt et al,. 2002; Winn et al., 1981 ^ Lee, 2014 ** Song et al., 2008; Godtfredsen et al., 2005 ^^ Godtfredsen et al., 2002 , 2003; Hart et al., 2013; Tverdal et al., 2006

53 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CONSIDERATIONS RELATED TO EPIDEMIOLOGICAL EVIDENCE

• Disease risks associated with use of ST products generally – Relative risks for exclusive ST users based primarily on three U.S. cohort studies assessing fatal events – Magnitude of relative risks associated with U.S. ST use and with Swedish snus use are generally more similar to each other as compared to relative risks for cigarette smoking • In studies of U.S. ST use, exposure ascertainment at baseline only and extended follow-up time can lead to exposure misclassification and weaken associations between ST use and disease risk • Lack of direct evidence comparing disease risks among continuing smokers to switchers from smoking to ST use

54 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EPIDEMIOLOGY SUMMARY

Lung cancer and COPD – Relative risks are substantially elevated in smokers compared to never smokers – Relative risks are smaller but still elevated among switchers compared to never users – No conclusive evidence linking exclusive ST use with either condition Oral cancer – Relative risks are substantially elevated in smokers compared to never smokers – Relative risks are smaller but still elevated among switchers compared to former smokers – Relative risks are smaller but still elevated among exclusive U.S. ST users compared to non-users Heart disease – Relative risks are elevated in smokers compared to never smokers – Relative risks are smaller but still elevated among switchers compared to never users and to former smokers – Relative risks are smaller but still elevated among exclusive U.S. ST users compared to non-users

55 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EPIDEMIOLOGY SUMMARY (CONT.)

Other conditions – For adverse pregnancy outcomes, relative risks are generally similar for exclusive ST users and exclusive smokers – For type 2 diabetes, magnitude of differences in relative risks for exclusive ST users and smokers is unclear

Dual use of ST and cigarettes – Relative risk for dual users of ST and cigarettes are generally comparable to relative risks for exclusive smokers

56 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS USE AND CONSUMER PERCEPTIONS OF THE PROPOSED MRTPS

Presented by: Erin Keely O’Brien, PhD, MA Social Scientist, Division of Population Health Science Office of Science, Center for Tobacco Products U.S. Food and Drug Administration

Additional Contributors: Blair Coleman, PhD, MPH, Colin Cunningham, PhD, Office of Science, CTP, FDA

Disclaimer: This is not a formal dissemination of information by FDA and does not represent Agency position or policy.

September 13-14, 2018 CENTER FOR TOBACCO PRODUCTS DISCLAIMER

58 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS AGENDA

• Camel Snus users: Observational Data

• Camel Snus users: Clinical Studies

• Current risk perceptions of smokeless tobacco (ST), including snus

• RJRT’s proposed Camel Snus advertising materials

• Understanding and perceptions of Camel Snus— With modified risk information

• Effect of modified risk information on likelihood of Camel Snus use

59 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CAMEL SNUS USERS: EVIDENCE FROM OBSERVATIONAL STUDIES

60 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS STUDIES ASSESSING CHARACTERISTICS AND BEHAVIORS OF CAMEL SNUS USERS

• The National Tobacco Behavior Monitor (NTBM)—Sponsored by RAI Services (RAIS) – National cross-sectional survey administered online monthly among U.S. adults of legal age to purchase tobacco – Approximately 2,000 surveys are completed each month – Reported on data collected from January, 2013 through March, 2016

• Additional observational evidence provided by the applicant – Consumer Brand Tracker (BT)—Sponsored by RJRT – Population Assessment of Tobacco and Health (PATH) Study

61 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CHARACTERISTICS OF CAMEL SNUS AND OTHER ST USERS IN THE U.S.—NTBM, 2013-2016

• 0.5% of U.S. adults used Camel Snus on one or more of the past 30 days (NTBM)1 – PATH Study data (Wave 1 - 2013-2014) found 0.4% of adults were current established users of pouched snus2 • Demographic characteristics among adult current users of Camel Snus are generally consistent with current users of other ST – Ages 25-49 (69.2-75.2%) – Male (80.8-85.7%) – Caucasian (52.3-65.2%) – More likely to report greater versus lesser educational attainment (63.8-69.4%) • Majority (92.8%) of Camel Snus users reported dual/poly use • ST literature suggests that snus use among U.S. youth is low

1Based on internal FDA analyses; NTBM defines current use of Camel Snus as any use in the past 30 days and identified Camel Snus as their usual brand. 2Chang et al. (2017) defines current established use as those who now use pouched snus every day or on some days, and has ever used the product “fairly regularly.” Includes adults who may or may not currently use other smokeless tobacco products.

62 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS LACK OF EVIDENCE ON COMPLETE SWITCHING FROM CIGARETTES TO CAMEL SNUS OR ST

• RJRT-sponsored RCT (CSD1010) compared smoking cessation rates among cigarette smokers receiving either Camel Snus or NRT to help them quit – No statistically significant difference in smoking cessation rates across groups – Cigarette smoking quit rates were low for all cessation endpoints (1-10%)

• Similar findings from studies in peer-reviewed literature – A published RCT found no statistically significant differences in switching from cigarettes to Camel Snus vs. NRT at Week 6 (37.6% vs. 36.6%) or Week 12 (26.8% vs. 28.4%), respectively1 – Evidence from observational studies suggests switching from exclusive cigarette smoking to exclusive ST use among adults is low (0%-1.4%), with transitions from exclusive smoking to dual use of cigarettes and ST being slightly more common (0.1%-3.2%)2

1Hatsukami et al., 2015. 2Tam et al., 2015.

63 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EVIDENCE ON REDUCTION IN CIGARETTE SMOKING AMONG DUAL USERS

RJRT used NTBM data to compare frequency of cigarette smoking (number of days in the past week) among past 30 day exclusive cigarette smokers vs. dual users of Camel Snus and cigarettes

Dual Users of Cigarettes and Exclusive Cigarette Smokers Camel Snus “Near daily” or “daily” use of 55.1% 76.5% cigarettes Cigarette smoking on 0-1 days of 19.6% 8.4% the past week Cigarette smoking on 2-5 days of 25.3% 15.1% the past week • In a linear regression looking at trends, frequency of cigarette use (i.e., number of days used in the past week) declined over time among dual users of cigarettes and Camel Snus; frequency of cigarette use among exclusive users remained unchanged

64 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SUMMARY: OBSERVATIONAL STUDIES

• Prevalence of pouched snus/Camel Snus among U.S. adults is low (<1%) • Characteristics of Camel Snus users are generally consistent with users of other ST products • Poly use of Camel Snus, other ST, and cigarettes is common • Evidence suggests few smokers would switch completely to Camel Snus or other smokeless tobacco

65 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CAMEL SNUS USE: EVIDENCE FROM CLINICAL STUDIES

66 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS BACKGROUND FOR CLINICAL STUDIES

• Clinical studies are found in Section 7.4; Summarized in Appendix B

• 8 clinical studies submitted: – 2 nicotine pharmacokinetic (PK) studies – 5 repeated exposure studies (from 5 days confined to 52 weeks ambulatory) – 1 natural product adopter study – Camel Snus Frost or Mellow 600mg or Camel Snus Frost, Spice, and Original 400mg used

• Clinical studies examined: – Nicotine exposure, PK, BOE, BOPH – Tobacco product use behaviors – Subjective effects (e.g. measures of dependence or withdrawal)

67 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EXCLUSIVE USE OF TESTED CAMEL SNUS PRODUCTS UNLIKELY

• Camel Snus appears to have lower abuse liability than cigarettes – Likelihood of complete substitution is low1 – Nicotine exposure/PK overall lower than cigarettes (CSD0914_SUL 2, CSD_1101_STM 3) – Produced similar or lesser subjective effects (e.g., liking) compared to cigarettes in submitted studies • Dual use of Camel Snus and cigarettes was common • Study compliance and completion rates were low – In one study, participants asked to reduce CPD by 75% while using Camel Snus only reduced by 59% at study completion (CSD0905_SL 2) – In another, the Camel Snus group was least likely to complete the study and be compliant (≥75% of total tobacco product use was the assigned product) . 55% of per-protocol subgroup were compliant (HSD0702_QOL 4) 1Popova & Ling, 2013 2 Study used Camel Snus 600 mg Frost or Mellow pooled 3 Study used Camel Snus 600 mg Frost 4 Study used Camel Snus 400 mg Frost, Original, or Spice 68 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RISK PERCEPTIONS OF SMOKELESS TOBACCO, INCLUDING SNUS

69 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS U.S. ADULTS BELIEVE ST AND SNUS ARE HARMFUL AND ADDICTIVE

Harmful & Addictive U.S. undergraduate students’ mean ratings Most U.S. Very dangerous 4 Most US adults Snus ST adults believe * * believe snus is 88% bothsnus harmful is both harmful and 3 and addictive U.S. Adults addictive Kaufman et al., 2014 Kaufman et al., 2014 2

Harmful & Addictive

Most U.S. adult Not very dangerous 1 smokers believe Nonusers Cigarette Cigarette Other only + other only snus is both Tobacco use group 82% harmful • Overall, young adults perceived snus and ST to be similarly high risk and addictive Smokers • Tobacco nonusers perceived the products to be higher risk than users

Kaufman et al., 2014 *p<.05 Latimer et al., 2014

70 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS MOST PEOPLE IN THE U.S. BELIEVE ST/SNUS ARE EQUALLY OR MORE HARMFUL THAN CIGARETTES

7-12% Less harmful Snus Wackowski 2016 48-59% Equally harmful Snus Richardson 2014 US Adults 22-38% More harmful ST Wackowski 2016 3-18% Don’t know ST Richardson 2014 Tobacco users are more likely to rate ST US Youth ST/snus as less harmful than cigarettes Persoskie 2017 compared to former and never users.

Borland et al., 2011; Capella et al., 2012; Kaufman et al, 2014; 0 20 40 60 80 100 Richardson et al., 2014

71 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RJRT’S PROPOSED ADVERTISING MATERIALS

72 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RJRT PROPOSED ADVERTISING

3 DIFFERENT AD VERSIONS MODIFIED RISK THE CHANNELS (“EXECUTIONS”) INFORMATION Each contains: Print material: ALL submitted ad •General product information •Print ads (magazines) materials contain modified risk •Modified risk information •Handouts information. •“Balancing information” •Direct mail NO modified risk information was •Execution 1: Developed first Online: contained in the •Execution 2: Developed to •Website submitted product simplify Execution 1 •Email labels. •Execution 3: Identical to Execution 2, with two health NO changes to the ST Ad materials for various effects removed (heart disease warnings were channels contained a subset and oral cancer) proposed. of information in the print ads.

73 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS MODIFIED RISK INFORMATION APPEARING IN AT LEAST ONE PRINT AD EXECUTION

EXECUTION 1 PRINT AD EXECUTION 2 PRINT AD EXECUTION 3 PRINT AD SWAP THE SMOKE FOR MORE FREEDOM & NO SMOKE LESS RISK CHOOSE SNUS NO SMOKE LESS RISK CHOOSE SNUS LESS RISK -Smokers who use Camel SNUS instead of cigarettes can significantly reduce their health risks from smoking. NO SMOKE = LESS RISK NO SMOKE = LESS RISK NO SMOKE = LESS RISK Smokers who switch completely from cigarettes to Smokers who SWITCH COMPLETELY Smokers who SWITCH COMPLETELY from Camel SNUS can significantly reduce their risk of from cigarettes to Camel SNUS can cigarettes to Camel SNUS can greatly lung cancer, oral cancer, respiratory disease, and greatly reduce their risk of lung cancer, reduce their risk of lung cancer and heart disease. oral cancer, respiratory disease, and heart respiratory disease. disease. Scientific studies have shown that Camel SNUS Scientific studies have shown that Camel Scientific studies have shown that Camel contains fewer carcinogens than cigarette smoke. SNUS contains less of the harmful SNUS contains less of the harmful chemicals than cigarette smoke. chemicals than cigarette smoke. -Fewer carcinogens -Less of the harmful chemicals found in -Less of the harmful chemicals found in cigarette smoke. cigarette smoke. -Less risk for you and those around you -Less risk for you and those around you -Less risk for you and those around you -However, smokers who use Camel SNUS instead of cigarettes can significantly reduce their health risks from smoking.

74 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EXAMPLE: PRINT AD EXECUTION 2

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p.2 p.3

75 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EXAMPLE: PRINT AD EXECUTION 2

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76 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EXAMPLE: PRINT AD EXECUTION 2

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77 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EXAMPLE: CONSUMER HANDOUT, EXECUTION 2

Outside Inside

78 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EXAMPLE: CONSUMER HANDOUT, EXECUTION 2

Outside Inside

79 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS PERCEPTIONS AND UNDERSTANDING OF CAMEL SNUS WITH MODIFIED RISK INFORMATION

80 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS THREE RJRT STUDIES: KEY FEATURES

OBJECTIVE Assess whether consumers understood key communication messages of the messaging and health risk perceptions of using Camel Snus DESIGN • 1 study per print ad execution • Non-experimental, post-test only, online surveys SAMPLES

• “Research Now” Online Panel AD EXPOSURE & • U.S. adults at least legal age UNDERSTANDING QUESTIONS

In each study: • All participants shown the same ad with modified risk information • Participants saw one understanding question per page along with the ad

• Ad was not on these pages RISK PERCEPTION QUESTIONS

• Descriptive statistics only ANALYSES • Data weighted to be nationally representative

81 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RJRT UNDERSTANDING AND PERCEPTION STUDIES: MAIN OUTCOME MEASURES

Rated Camel Snus, ST other than Camel Snus, cigarette risk of: • Lung cancer • Heart disease • Oral cancer • Generally poor health RISK PERCEPTIONS • Respiratory disease • Addictiveness Different products and diseases

1. “Is quitting the best choice for a smoker who is concerned about the health risks from smoking?” • Yes/ No/ Don’t Know 2. “Should adults who do not use or who have quit using tobacco products start using Camel Snus?” • Yes/ No/ Don’t Know UNDERSTANDING 3. “According to the ad, what do smokers need to do in order to receive a health benefit from using Camel Snus?” • Stop smoking completely and use Camel Snus instead • [Reduce smoking by half and use Camel Snus in addition, Ex 1 only] • Continue to smoke [Not change their smoking habits, Ex 1], but use Camel Snus as well • Don’t know

82 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS PARTICIPANTS PERCEIVE USING CAMEL SNUS AS POSING RISK OF MULTIPLE HEALTH PROBLEMS

Substantial 7 risk Ex 1 Ex 2 Ex 3 6

No risk 1 Lung cancer Oral cancer Respiratory disease Heart disease Generally poor Addiction health

Current tobacco users had lower risk perceptions compared to former and never users. (Data not shown)

Note: Error bars represent 95% CIs Source: Section 7.5 of the MRTPAs 83 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS PARTICIPANTS PERCEIVED CIGARETTES AS MOST HARMFUL, FOLLOWED BY OTHER ST AND CAMEL SNUS

7 7 7

4 4 4

1 1 1 Camel Snus ST Cigarettes Camel Snus ST Cigarettes Camel Snus ST Cigarettes Lung Cancer Oral Cancer Generally Poor Health

7 7 7

4 4 4

1 1 1 Diseases mentioned info Diseases in MR Camel Snus ST Cigarettes Camel Snus ST Cigarettes Camel Snus ST Cigarettes Respiratory disease Heart disease Addictive

Note. Error bars represent 95% CIs Source: Section 7.5 of the MRTPAs 84 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS MOST PARTICIPANTS RESPONDED CORRECTLY TO UNDERSTANDING ITEMS

1. Is quitting smoking the best choice for a smoker who is concerned about the health risks from smoking?

87-89% Yes 6-7% No 5-6% Don’t know

2. Should adults who do not use or who have quit using tobacco products start using Camel Snus?

83-84% No 5-6% Yes 10-11% Don’t know

3. According to the ad, what do smokers need to do in order to receive a health benefit from using Camel Snus?

3% 10% 15% 72% Use in addition Reduce smoking by Ex 1 Don’t know Switch completely to smoking half and use

4% [Response option removed] 18% 78% Use in addition Reduce smoking by Ex 2-3 Don’t know Switch completely to smoking half and use

Source: Section 7.5 of the MRTPAs 85 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SUBGROUP CAMEL SNUS RISK PERCEPTIONS: NO CLEAR DIFFERENCES FROM OVERALL SAMPLE

• RJRT provided results separately for: – Tobacco experimenters – Potential quitters – People with limited health literacy – White men – Racial and ethnic minorities – Young adults

• No clear patterns of differences by subgroup – Compared to overall sample, people with limited health literacy thought Camel Snus was: . Higher risk for lung cancer and respiratory disease . Lower risk for oral cancer, generally poorer health, and addiction.

Note: Error bars represent 95% CIs. Source: Results for Execution 2, Section 7.5 of the MRTPAs 86 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SOME SUBGROUP DIFFERENCES IN INCORRECT RESPONSES TO UNDERSTANDING ITEMS

1. Is quitting smoking the best choice for a smoker who is concerned about the health risks from smoking? OVERALL SAMPLE LIMITED HEALTH LITERACY POTENTIAL QUITTERS Yes: 87-89% Yes: 76-79% Yes: 91-93%

2. Should adults who do not use or who have quit using tobacco products start using Camel Snus?

OVERALL SAMPLE EXPERIMENTERS LIMITED HEALTH LITERACY No: 83-84% No: 71-73% 3. According to the ad, what do smokers need to do in order to receive a health benefit from using Camel Snus?

OVERALL SAMPLE EXPERIMENTERS LIMITED HEALTH LITERACY Ex 1 10% Reduce smoking by 19% Reduce smoking by POTENTIAL QUITTERS 15-16% Reduce smoking by half and use half and use half and use

YOUNG ADULTS OVERALL SAMPLE LIMITED HEALTH LITERACY Ex 2-3 WHITE MEN Switch completely: 72-78% Switch completely: 53-65% Switch completely: 81-85%

Note: Statistical tests of differences were not provided by RJRT. Source: Section 7.5 of the MRTPAs 87 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS LIMITATIONS OF RJRT STUDIES

• No assessments of risk perceptions of dual use. This is important, as it is the predominant use pattern

• The studies were not experiments and therefore did not assess the effect of the modified risk information on perceptions – Five peer-reviewed experiments1 find a causal effect: Exposure to modified risk information decreased the perception of product risk relative to cigarettes

1Callery et al., 2011; Capella et al., 2012; Mays et al., 2016; Wackowski et al., 2017.

88 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SUMMARY: UNDERSTANDING AND RISK PERCEPTIONS

Peer-Reviewed Studies (No MR Information): RJRT’S Ad Studies (With MR Information): • Most US adults and youth believe that snus is • Most people thought Camel Snus was moderately to harmful and addictive high risk for diseases, including addiction • Most people believe that snus is equally or more • People thought Camel Snus was lower risk than harmful than cigarettes cigarettes, and slightly less risky than other smokeless products

RJRT’S Proposal: RJRT Studies’ Limitations: • To use 3 advertising executions to market 6 Camel • Risk perceptions of dual use are unknown Snus products as MRTPs • Effect of MR information on perceptions and • Not to alter the current smokeless tobacco understanding not assessed warnings Peer-Reviewed Experimental Studies: • Modified risk claims reduce risk perceptions of ST/snus relative to cigarettes

89 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS EFFECT OF MODIFIED RISK INFORMATION ON LIKELIHOOD OF PURCHASING CAMEL SNUS FOR TRIAL

90 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RJRT’S THREE “LIKELIHOOD OF USE” STUDIES: PROCEDURE

RECRUITMENT Research Now Online Panel, U.S. adults, legal age to 75

RANDOM ASSIGNMENT Stratified by tobacco use group, to view 3-page ad:

MR Info Example Control Example (p.1/3) With modified risk information Without modified risk information (p.1/3)

MAIN OUTCOME: Likelihood of use rating “Assuming the product were available today, how likely would you be to purchase Camel SNUS in order to try it?”

ANALYSIS • Data were weighted to be nationally representative • Participant ratings converted into predicted percent likelihood they would purchase for trial

91 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CONVERTING SELF-REPORT RATING TO PURCHASE PROBABILITY: RJRT’S ALGORITHM DERIVATION

• RJRT created an algorithm to convert self-report purchase likelihood ratings into purchase probabilities

RJRT Algorithm Study Design RJRT Algorithm

D J F M A M J J A S O E A E A P A U U U E C C N B R R Y N L G P T

Online survey pre-test: Likelihood of purchasing any variety of Marlboro Special Blend X X

Marlboro Special Blend sold throughout U.S. X X X X X X X X X X

Online survey post-test: Purchase of any variety of Marlboro Special Blend in the past 9 months X X

• Algorithm validity was assessed in two studies: – One of specific varieties of Marlboro Special Blend (Blue and Black) – One of a specific size of a specific Camel Snus flavor (Frost Large) – Algorithm’s purchase rates were 1-2 percentage points higher than actual purchase rates

Source: Section 6 of the MRTPAs (Methodology report for likelihood of use algorithm). 92 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS OVERALL SAMPLE: MR INFORMATION CAUSES SMALL INCREASE IN 2 OF 3 STUDIES

10 10030 MR Info Control MR Info Control 9 25 8

7 20

6 15 5

4 10 3 * * 5 1.3 1.7 * 1.5 1.7 2.0 * 1.9 2.0 1.9 1.3 1.5 2 1.7 1.7

1 0 Ex 1 Ex 2 Ex 3 Ex 1 Ex 2 Ex 3

Mean likelihood of purchase rating (1-10) Transformed to… Predicted purchase probability (0-100%) 1= Definitely would not purchase it (to try) 10= Definitely would purchase it (to try) Considering: • Age group • Tobacco user group

Note. Error bars represent 95% confidence intervals. * p < .05. Source: Section 7.5 of the MRTPAs (likelihood of use study final reports). 93 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CURRENT SMOKERS: MR INFORMATION CAUSES SMALL INCREASE IN ALL 3 STUDIES

10 10030 MR Info Control MR Info Control 9 25 8

7 20

6 15 5 * 8.2 * 8.0 * 3.7 * 3.8 6.9 6.9 4 3.4 3.4 10 5.8 3.0 * 5.4 3 2.8 5 2

1 0 Ex 1 Ex 2 Ex 3 Ex 1 Ex 2 Ex 3

Note. Error bars represent 95% confidence intervals. * p < .05. Source: Section 7.5 of the MRTPAs (likelihood of use study final reports). 94 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS FORMER SMOKERS: MR INFORMATION DOES NOT CAUSE AN INCREASE

10 10030 MR Info Control MR Info Control 9 25 8 20 7

6 15 5 10 4

3 2.0 5 2.1 2.2 1.9 2.0 2.0 1.9 1.9 1.9 2 1.8 1.8 1.8 0 1 Ex 1 Ex 2 Ex 3 Ex 1 Ex 2 Ex 3

Note. Error bars represent 95% confidence intervals. * p < .05. Source: Section 7.5 of the MRTPAs (likelihood of use study final reports). 95 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS NEVER SMOKERS: MR INFORMATION DOES NOT CAUSE AN INCREASE

10 10030 MR Info Control MR Info Control 9 25 8

7 20

6 15 5

4 10

3 5 2 1.7 1.7 1.7 1.7 1.4 1.4 0.4 0.4 0.5 0.4 0.4 0.4 1 0 Ex 1 Ex 2 Ex 3 Ex 1 Ex 2 Ex 3

Note. Error bars represent 95% confidence intervals. * p < .05. Source: Section 7.5 of the MRTPAs (likelihood of use study final reports). 96 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RJRT’S FINDINGS GENERALLY CONSISTENT WITH SIMILAR PUBLISHED EXPERIMENTAL STUDIES ON EFFECTS OF MR AND RR* INFORMATION

vs Control, p-value by Smoking Status Author Stimuli MR/RR info example Self-reported outcome Current Former Never RJRT Camel Snus ads Multiple MR statements Likelihood, purchase <0.05 ns ns (for 2/3) Purchase probability <0.05 ns ns Callery, Packages of Marlboro Snus, “Using ST is less harmful than smoking cigarettes.” Likelihood of trying <0.05 - - 2011 deMaurier snus, Copenhagen snuff Capella, Camel Snus ads “Using this product is 90% less dangerous than cigarettes.” Intention to switch 0.10 - - 2012(Study 1) Capella, Camel Snus ads “SLT is less risky to your health than cigarettes.” Intention to try - ns ns 2012(Study 2) Mays, 2016 General Snus ads “Switching completely from cigarettes to snus may Intentions to use ns nsa nsa substantially lower health risks.” Rodu, 2016 General Snus packages “No tobacco product is safe, but this product presents Likely to use <0.05 nsb nsb,c substantially lower risks to health than cigarettes.” Motivation to buy <0.05 Wackowski, Imitation news story on research Brief description of Swedish construction worker study Interest in trying <0.0001 - - 2017 finding using snus and SLT to be finding snus users had lower cancer risks than smokers safer than cigarettes. and no increased oral cancer risk. Likelihood, buying <0.0001 - - Likelihood, complete switching <0.0001 - - a Analysis were for nonsmokers overall (not for former and never smokers separately). *RR: relative risk b Former and never tobacco users rather than former and never smokers. Note. ns = not statistically significant, exact p-value not reported. Statistically significant results at p < .05 are bolded. c Not significantly different than control for MR info that said “lower risk,” but was (p<.05) for MR info that said “substantially lower risk.” 97 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SUMMARY: LIKELIHOOD OF PURCHASE FOR TRIAL

• The presence of the proposed modified risk information on Camel Snus ads: – Increases the proportion of smokers who are likely to purchase Camel Snus for trial by about 1% – Does not affect likelihood of purchase for trial for former and never smokers • When shown a Camel Snus advertisement with the proposed modified risk information: – 5.8-8.2% of smokers are likely to purchase for trial – About 2% of former smokers and 0.4% of never smokers are likely to purchase for trial • Findings are generally consistent with similar peer-reviewed studies

98 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SUMMARY OF FDA PRESENTATION

99 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SUMMARY OF CHEMISTRY, NONCLINICAL, AND CLINICAL EVIDENCE RELATED TO SUBSTANTIATION OF MODIFIED RISK INFORMATION

• ST has 4,000 chemical compounds, compared to over 7,000 chemical compounds found in mainstream cigarette smoke • All HPHCs RJRT tested were present in both cigarette smoke and in the six Camel Snus products • Differences in portal of entry effects, differences in toxicant absorption and distribution through the body, and differences in metabolism can affect the toxicity of HPHCs introduced through different routes of exposure • Extracts from the six Camel Snus products and other ST products, as well as extracts from total particulate matter collected from cigarette smoke, tested positive for genotoxicity • In a 5-day confined study, exclusive and dual users of the proposed Camel Snus MRTPs (600mg Frost and Mellow) had lower levels of several BOE compared to baseline smoking • Among natural adopters, exclusive, but not dual users, of the proposed Camel Snus MRPTs had lower levels of several BOE; – Exclusive use of Camel Snus or dual tobacco use did not lower TSNAs; – Smokers, Camel Snus users, and dual users had lower TSNAs than other moist snuff users.

100 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SUMMARY OF EPIDEMIOLOGICAL EVIDENCE RELATED TO SUBSTANTIATION OF MODIFIED RISK INFORMATION

• Relative risks (RRs) for lung cancer, COPD, oral cancer and heart disease are elevated in smokers compared to never smokers • Though smaller in magnitude compared to smokers, RRs for oral cancer and heart disease are elevated in exclusive U.S. ST users compared to non-users – Lack of consistent associations between exclusive U.S. ST use and lung cancer or COPD • RRs for lung cancer, COPD, and heart disease for former smokers who switched completely to exclusive ST use compared to never users are smaller than the RRs for exclusive smokers and generally larger than the RRs for exclusive ST users – RRs for oral cancer among switchers compared to never tobacco users are not available • RRs for adverse pregnancy outcomes are generally similar for exclusive ST users and for smokers, while for type 2 diabetes, the size of any differences in RRs for ST users and smokers is unclear • RRs for dual users of ST and cigarettes are generally comparable to RRs for exclusive smokers

101 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SUMMARY OF USE: OBSERVATIONAL & CLINICAL STUDIES

Observational Studies (current use without proposed modified risk information) • Prevalence of pouched snus/Camel Snus among U.S. adults is low • Poly use of Camel Snus, other ST, and cigarettes is common • Evidence suggests few smokers would switch completely to Camel Snus or other smokeless tobacco

Clinical Studies • Few smokers switch completely to Camel Snus – In RJRT’s clinical studies, dual use of Camel Snus and cigarettes was common – Camel Snus appears to have lower abuse liability than cigarettes

102 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SUMMARY OF UNDERSTANDING AND PERCEPTIONS AND LIKELIHOOD OF PURCHASE FOR TRIAL Understanding and Risk Perceptions • In the absence of modified risk information, most people believe that snus is equally or more harmful than cigarettes • After seeing RJRT’s 3-page ad with MR information, most people thought that Camel Snus was… – Moderate to high risk for diseases – Lower risk than cigarettes – Slightly lower risk than other smokeless tobacco products

Likelihood of Purchasing Camel Snus for Trial • Presence of modified risk information on Camel Snus ads increased the proportion of smokers who are likely to purchase Camel Snus by about 1% • Likelihood of purchase for trial was not affected for former or never smokers

103 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS REFERENCES

• Accortt, N. A., Waterbor, J. W., Beall, C., & Howard, G. (2002). Chronic disease mortality in a cohort of smokeless tobacco users. American Journal of Epidemiology, 156(8), 730-737. • Ammann, J. R., Lovejoy, K. S., Walters, M. J., Holman, M. R. (2016). A survey of N′-nitrosonornicotine (NNN) and total water content in select smokeless tobacco products purchased in the United States in 2015. Journal of Agricultural and Food Chemistry, 64(21):4400-4406. doi: 10.1021/acs.jafc.6b00922. • Blank, M. D., & Eissenberg, T. (2010). Evaluating oral noncombustible potential-reduced exposure products for smokers. Nicotine & Tobacco Research, 12(4), 336- 343. • Boffetta, P., Hecht, S., Gray, N., Gupta., P., & Straif, K. (2008). Smokeless tobacco and cancer. Lancet Oncology, 9(7), 667-675. • Boffetta, P., & Straif, K. (2009). Use of smokeless tobacco and risk of myocardial infarction and stroke: a systematic review with meta-analysis. British Medical Journal, 339, b3060. • Borgerding, M. F., Bodnar, J. A., Curtin, G. M., & Swauger, J. E. (2012). The chemical composition of smokeless tobacco: A survey of products sold in the United States in 2006 and 2007. Regulatory Toxicology and Pharmacology, 64(3), 367-387. • Borland, R., Cooper, J., McNeill, A., O'Connor, R., & Cummings, K. M. (2011). Trends in beliefs about the harmfulness and use of stop-smoking medications and smokeless tobacco products among cigarettes smokers: Findings from the ITC four-country survey. Harm Reduction Journal, 8, 21-32. • Callery, W. E., Hammond, D., O'Connor, R. J., & Fong, G. T. (2011). The appeal of smokeless tobacco products among young Canadian smokers: the impact of pictorial health warnings and relative risk messages. Nicotine & Tobacco Research, 13, 373-383. • Capella, M. L., Taylor, C. R., & Kees, J. (2012). Tobacco harm reduction advertising in the presence of a government‐mandated warning. Journal of Consumer Affairs, 4, 235-259 • Carlsson, S., Andersson, T., Araghi, M., Galanti, R., Lager, A., Lundberg, M., . . . Magnusson, C. (2017). Smokeless tobacco (snus) is associated with an increased risk of type 2 diabetes: Results from five pooled cohorts. Journal of Internal Medicine, 281(4), 398-406. • Chang, J. T., Levy, D. T. & Meza, R. (2017). Examining the transitions between cigarette and smokeless tobacco product use in the United States using the 2002-2003 and 2010-2011 longitudinal cohorts. Nicotine & Tobacco Research, [E-pub ahead of print]. • Food and Drug Administration (2012a). Draft Guidance for Industry: Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke Under Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act. 77 FR 20030. Federal Register: Washington, DC; April 3, 2012. https://www.fda.gov/tobaccoproducts/guidancecomplianceregulatoryinformation/ucm297752.htm

104 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS REFERENCES (CONT.)

• Food and Drug Administration. (2012b). Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke: Established List. https://www.federalregister.gov/documents/2012/04/03/2012-7727/harmful-and-potentially-harmful-constituents-in-tobacco-products-and-tobacco-smoke-established- list • Godtfredsen, N. S., Prescott, E., & Osler, M. (2005). Effect of smoking reduction on lung cancer risk. Journal of American Medical Association, 294(12), 1505-1510. • Gunnerbeck, A., Wikstrom A.K., Edstedt Bonamy, A.K., Wickstrom, R., Cnattingius, S. (2011). Relationship of maternal snuff use and cigarette smoking with neonatal apnea. Pediatrics, 128(3): 503-509. • Hart, C., Gruer, L., & Bauld, L. (2013). Does smoking reduction in midlife reduce mortality risk? Results of 2 long-term prospective cohort studies of men and women in Scotland. American Journal of Epidemiology, 178(5), 770-779. • Hatsukami, D. K., Ebbert, J. O., Feuer, R. M., Stepanov, I., & Hecht, S. S. (2007). Changing smokeless tobacco products new tobacco-delivery systems. American Journal of Preventive Medicine, 33(6 Suppl), S368-378. • Hatsukami, D. K., Stepanov, I., Severson, H., . . . Hecht, S. S. (2015). Evidence supporting product standards for carcinogens in smokeless tobacco products. Cancer Prevention Research (Philadelphia), 8(1), 20-26. • Hatsukami, D. K., Vogel, R. I., Severson, H. H., Jensen, J. A., & O'Connor, R.J. (2016). Perceived health risks of snus and medicinal nicotine products. Nicotine & Tobacco Research, 18(5), 794-800. • Henley, S. J., Thun, M. J., Connell, C., & Calle, E. E. (2005). Two large prospective studies of mortality among men who use snuff or chewing tobacco (United States). Cancer Causes & Control, 16(4), 347-358. • Inamdar, A. S., Croucher, R. E., Chokhandre, M. K., & Marinho, V. C. C. (2015). Maternal smokeless tobacco use in pregnancy and adverse health outcomes in newborns: a systematic review. Nicotine and Tobacco Research, 17(9), 1058-1066. • Kaufman, A. R., Mays, D., Koblitz, A. R., & Portnoy, D. B. (2014). Judgments, awareness, and the use of snus among adults in the United States. Nicotine & Tobacco Research, 16, 1404-1408. • Keith, R. J., Al Rifai, M., Carruba, C., De Jarnett, N., McEvoy, J. W., Bhatnagar, A., & Defilippis, A.P. (2016). Tobacco use, insulin resistance, and risk of type 2 diabetes: results from the Multi-Ethnic Study of Atherosclerosis. PLOS One, 11(6): e0157592. • Kotlyar, M., Hertsgaard, L. A., Lindgren, B. R. . . . Hatsukami, D. K. (2011). Effect of oral snus and medicinal nicotine in smokers on toxicant exposure and withdrawal symptoms: a feasibility study. Cancer Epidemiology, Biomarkers, & Prevention, 20(1), 91-100.

105 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS REFERENCES (CONT.)

• Latimer, L. A., Batanova, M., & Loukas, A. (2013). Prevalence and harm perceptions of various tobacco products among college students. Nicotine & Tobacco Research, 16(5), 519-526. • Lee, P. N. (2007). Circulatory disease and smokeless tobacco in Western populations: a review of the evidence. International Journal of Epidemiology, 36(4): 789-804. • Lee, P. N. (2014). Health risks related to dual use of cigarettes and snus - a systematic review. Regulatory Toxicology and Phamacology, 69(1), 125-134. • Lee, P. N., & Hamling, J. (2009a). Systematic review of the relation between smokeless tobacco and cancer in Europe and North America. BMC Medicine, 7, 36. • Mays, D., Moran, M. B., Levy, D. T., & Niaura, R. S. (2016). The impact of health warning labels for Swedish snus advertisements on young adults’ snus perceptions and behavioral intentions. Nicotine & Tobacco Research, 18, 1371-1375. • Persoskie, A., O'Brien, E. K., Nguyen, A. B., & Tworek, C. (2017). Measuring youth beliefs about the harms of e-cigarettes and smokeless tobacco compared to cigarettes. Addictive Behaviors, 70, 7-13. • Popova, L., & Ling, P.M. (2013). Alternative Tobacco product use and smoking cessation: a national study. American Journal of Public Health,103(5), 923-930. • Richardson, A., Pearson, J., Xiao, H., Stalgaitis, C., & Vallone, D. (2014). Prevalence, harm perceptions, and reasons for using noncombustible tobacco products among current and former smokers. American Journal of Public Health, 104, 1437-1444. • Rodu, B., Plurphanswat, N., Hughes, J. R., & Fagerström, K. (2016). Associations of proposed relative-risk warning labels for snus with perceptions and behavioral intentions among tobacco users and nonusers. Nicotine & Tobacco Research, 18, 809-816. • Rodgman , A., & Perfetti, T. A. (2016). The Chemical Components of Tobacco and Tobacco Smoke, Second Edition. CRC Press. • Song, Y. M., Sung, J., & Cho, H. J. (2008). Reduction and cessation of cigarette smoking and risk of cancer: a cohort study of Korean men. Journal of Clinical Oncology, 26(31), 5101-5106. • Stepanov, I., Biener, L., Knezevich, A., Nyman, A. L., Bliss, R. Jensen, J., . . . Hatsukami, D. Kl. (2012). Monitoring tobacco-specific N-nitrosamines and nicotine in novel Marlboro and Camel smokeless tobacco products: findings from Round 1 of the New Product Watch. Nicotine & Tobacco Research, 14(3), 274-281. • Stepanov, I., Biener, L., Yershova, K., Nyman, A. L., Bliss, R., Parascandola, M., & Hatsukami, D. K. (2014). Monitoring tobacco-specific N-nitrosamines and nicotine in novel smokeless tobacco products: findings from round II of the new product watch. Nicotine & Tobacco Research, 16(8), 1070-1078.

106 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS REFERENCES (CONT.)

• Stepanov, I., Jensen, J., Hatsukami, D., & Hecht, S. S. (2008). New and traditional smokeless tobacco: comparison of toxicant and carcinogen levels. Nicotine & Tobacco Research, 10(12), 1773-1782. • Stepanov, I., Yershova, K., Carmella, S., Upadhyaya, P., & Hecht, S. S. (2013). Levels of (S)-N'-nitrosonornicotine in U.S. tobacco products. Nicotine & Tobacco Research, 15(7), 1305-1310. • Swedish Match. (2018). GOTHIATEK® limits for undesired components. https://www.swedishmatch.com/Snus-and-health/GOTHIATEK/GOTHIATEK-standard/. • Tam, J., Day, H.R., Rostron, B.L. & Apelberg, B.J. (2015). A systematic review of transitions between cigarette and smokeless tobacco product use in the United States. BMC Public Health, 15(258), 1-12. • Tverdal, A., & Bjartveit, K. (2006). Health consequences of reduced daily cigarette consumption. Tobacco Control, 15(6), 472-480. • U.S. Department of Health and Human Services (US DHHS). (2014). The health consequences of smoking—50 years of progress: A report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General. Retrieved from https://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf • Wackowski, O. A., & Delnevo, C. D. (2016). Young adults’ risk perceptions of various tobacco products relative to cigarettes: results from the National Young Adult Health Survey. Health Education & Behavior, 43, 328-336. • Wackowski, O. A., Manderski, M. T. B., Lewis, M. J., & Delnevo, C. D. (2017). The impact of smokeless tobacco risk information on smokers’ risk perceptions and use intentions: a news media experiment. Health Communication, 1-8. • Wikstrom, A.K., Cnattingius S., Galanti, M.R., Kieler, H., Stephansson O. (2010a). Effect of Sweidsh snuff (snus) on preterm birth. BJOG, 2010; 117;1005-1010. • Wikstrom, A.K., Cnatingius, S., Stephansson O. (2010b). Maternal use of Swedish snuff (snus) and risk of stillbirth. Epidemiology, 21(6), 772-778. • Winn, D. M., Blot, W. J., Shy, C. M., Pickle, L. W., Toledo, A., & Fraumeni, J. F. (1981). Snuff dipping and oral cancer among women in the southern United States. New England Journal of Medicine, 304(13), 745-749.

107 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS CLARIFYING QUESTIONS? FDA’S QUESTIONS TO TPSAC ON RJRT’S CAMEL SNUS MRTPAS

Presented by: Deirdre Lawrence Kittner, PhD, MPH Deputy Director, Division of Population Health Science Office of Science Center for Tobacco Products U.S. Food and Drug Administration

Disclaimer: This is not a formal dissemination of information by FDA and does not represent Agency position or policy.

September 13-14, 2018 CENTER FOR TOBACCO PRODUCTS DISCLAIMER

110 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS RISK MODIFICATION ORDER STANDARD - 911(G)(1)

The FD&C Act requires FDA to determine if a proposed MRTP, as it is actually used by consumers, will:

(1) significantly reduce harm and the risk of tobacco-related disease to individual tobacco users and

(2) 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

111 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS SECTION 911(G)(1) OF THE FD&C ACT FOR SIX CAMEL SNUS PRODUCTS

The applicant submitted modified risk tobacco product applications (MRTPAs) seeking orders under section 911(g)(1) of the FD&C Act for six Camel Snus products.

To authorize a product under section 911(g)(1), the agency must find that the product, as actually used by consumers, will:

112 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS FOR TPSAC: SUBSTANTIATION OF MODIFIED RISK INFORMATION

113 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS FOR TPSAC: SUBSTANTIATION OF MODIFIED RISK INFORMATION

114 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS FOR TPSAC: CONSUMER PERCEPTIONS & UNDERSTANDING

115 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS FOR TPSAC: CONSUMER PERCEPTIONS & UNDERSTANDING

116 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS QUESTIONS FOR TPSAC: LIKELIHOOD OF USE OF PROPOSED MRTPS

117 September 13-14, 2018 TPSAC Meeting | RJRT Modified Risk Tobacco Product Applications CENTER FOR TOBACCO PRODUCTS