U.S. Food & Drug Administration 

10903 New Hampshire Avenue 

Silver Spring, MD 20993

www.fda.gov

PMTA Scientific Review: Technical Project Lead (TPL)

New Tobacco Products Subject of this Review1

STN PM0000470-PM0000473

Common Attributes

Submission Date July 23, 2018

Receipt Date July 23, 2018

Applicant U.S. Smokeless Tobacco Company LLC

Product manufacturer U.S. Smokeless Tobacco Company LLC

Application type Standard

Product category Other

Product subcategory Other

Cross-Referenced Submission

All new tobacco products (b) (4)

Supporting FDA Memoranda Relied Upon in this Review

All new tobacco products None

Recommendation

Issue Marketing Order Letters

DISCIPLINES REVIEWED Primary Reviewers DATE OF REVIEW

Behavioral and Clinical Pharmacology Babita Das, Kia Jackson June 26, 2020

Chemistry Lida Oum July 14, 2020

Environmental Science Ronald Edwards June 25, 2020

Engineering Rashele Moore June 26, 2020

Epidemiology Carol Christensen June 25, 2020

Medical Theresa Watkins-Bryant June 29, 2020

Microbiology David Craft June 26, 2020

OCE – DEM (BIMO) Rachel Mohseni June 26, 2020

OCE – DEM (Laboratory) Ronald Yi June 29, 2020

OCE – DEM (Manufacturing) Ronald Yi June 29, 2020

OCE – DPAL Victoria Grabhorn June 29, 2020

OHCE Emily Talbert October 8, 2021

Social Science Jen Bernat June 25, 2020

Statistics Christopher Ellison June 29, 2020

Toxicology Erica Clark July 1, 2020

1. 1 Product details, amendments, and dates provided in Appendix B. STN = submission tracking number(s).
PM0000470 – PM0000473 Page 2 of 104

Digitally signed by Sheila M. Healy -S 

Date: 2021.10.08 15:56:57 -04'00'

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)

Technical Project Lead (TPL):

Sheila Healy, Ph.D.

Supervisory Toxicologist

Division of Nonclinical Science, Office of Science

Signatory:

Matthew R. Holman, Ph.D.

Director, Office of Science
PM0000470 – PM0000473 Page 3 of 104

TABLE OF CONTENTS

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

2. REVIEW OF PMTAS ............................................................................................................. 8

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

2.2. Product Composition, Design, and Manufacturing ......................................................................... 9

2.2.1. Tobacco Ingredients...................................................................................................................................10

2.2.2. Non-Tobacco Ingredients ...........................................................................................................................10

2.2.3. Product Design ...........................................................................................................................................11

2.2.4. Manufacturing, Process, and Controls .......................................................................................................13

2.2.5. FDA Sample Testing ....................................................................................................................................15

2.2.6. Product Stability .........................................................................................................................................20

2.2.7. Inspections of Manufacturing Facilities......................................................................................................23

2.2.8. Summary of Composition, Design, and Manufacturing Findings................................................................23

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

2.3.1. Harmful and Potentially Harmful Constituents ..........................................................................................26

2.3.2 Non-Nicotine Ingredients...........................................................................................................................31

2.3.3 Summary of Toxicological Findings.............................................................................................................34

2.4. Individual Health Impact ..............................................................................................................35

Overview of Behavioral and Clinical Pharmacology (BCP) Studies.............................................................35

2.4.2. Nicotine Pharmacokinetics .........................................................................................................................41

2.4.3 Behavioral Pharmacology...........................................................................................................................43

2.4.3.1. Abuse Liability...............................................................................................................................43

2.4.3.2. Use Behavior and Topography......................................................................................................45

2.4.3.3. Product Use/Consumption ...........................................................................................................46

2.4.3.4. Craving, Withdrawal, and Dependence ....................................................................................... 47

2.4.3.5. Cessation ......................................................................................................................................48

2.4.4 Summary of Overall Behavioral and Clinical Pharmacology Findings.........................................................50

2.4.5 Biomarkers of Exposure (BOE)....................................................................................................................51

2.4.5.1 Effect of Switching to Oral Tobacco Products on BOE ................................................................. 52

2.4.5.2 Dual Use and Non-compliance......................................................................................................54

2.4.5.3 Summary of BOE Findings.............................................................................................................54

2.4.6 Adverse Health Effects ...............................................................................................................................55

2.4.6.1. Health Risks to Non-Users ............................................................................................................57

2.4.6.2. Consumer Use and Potential Misuse............................................................................................57

2.4.6.3. Health Risks Associated with Poly-use..........................................................................................57

2.4.6.4. Health Risks Associated with Switching to these Products Compared to Continued Smoking ....58

2.4.6.5. Health Risks Associated with Switching to this Product Compared to Tobacco Cessation...........58

2.4.6.6. Health Risks Associated with Switching to Product Compared to Cessation Medication ............59

2.4.6.7. Summary of Adverse Health Effects .............................................................................................59

2.4.7. Likelihood of Product Misuse or Malfunction ............................................................................................59

2.4.8. Bioresearch Monitoring (BIMO) Inspection................................................................................................59

2.4.1.
PM0000470 – PM0000473 Page 4 of 104

2.4.9. Summary of Individual Health Findings......................................................................................................60

2.5. Population Health ........................................................................................................................61

2.5.1. Likelihood of Use by Current Cigarette Smokers........................................................................................62

Summary of Likelihood of Use by Current Cigarette Smokers...................................................................63

Poly Use of VERVE® and Cigarettes or Other Tobacco Products................................................................63

Summary of Poly Use..................................................................................................................................64

2.5.5 Use by Former or Never Smokers...............................................................................................................65

2.5.6 Summary of Use by Former or Never Smokers..........................................................................................66

2.5.7 Use by Vulnerable Populations ...................................................................................................................66

2.5.7.1. Youth ............................................................................................................................................66

2.5.8. Summary of Use by Vulnerable Populations ..............................................................................................67

2.5.9. Population Modeling ..................................................................................................................................67

2.5.10. Summary of Population Modeling..............................................................................................................68

2.5.11. Summary of Population Health Findings....................................................................................................69

2.6. Product Labeling, Consumer Comprehension, and Marketing Plan................................................70

2.6.1. Proposed PMTA Labeling............................................................................................................................70

2.6.2. Consumer Perception and Understanding of Risk......................................................................................71

2.6.3. Marketing Plan ...........................................................................................................................................73

3.ENVIRONMENTAL DECISION............................................................................................... 73

4.CONCLUSIONS AND RECOMMENDATIONS.......................................................................... 73

5.ACRONYMS ........................................................................................................................ 77

6.REFERENCES ....................................................................................................................... 79

7.APPENDIX A ........................................................................................................................ 82

8.APPENDIX B........................................................................................................................ 93

2.5.2.

2.5.4.

2.5.3.
PM0000470 – PM0000473 Page 5 of 104

Table of Tables

Table 1: Amendments submitted by applicant .....................................................................................9

Table 2: Product components and subcomponents............................................................................ 11

Table 3: Design parameters for product dimensions (from application) .............................................. 12

Table 4. Dimensional characterization based on inspection documents.............................................. 13

Table 5: Physical parameters required for product release of the new products................................. 13

Table 6: Chemistry-relevant parameters required for product release of the new products................ 14

Table 7: Samples submitted by USSTC to STL...................................................................................... 15

Table 8: Testing requested of STL by FDA ........................................................................................... 16

Table 9: Comparison of HPHC levels in the PMTAs to the STL testing results....................................... 17

Table 10: Product stability: Water activity initial sampling compared to STL results ........................... 17

Table 11: FDA sample product testing ................................................................................................ 19

Table 12. Product stability: Water activity over storage time.............................................................. 22

Table 13: Ingredients other than tobacco for cross-referenced PMTA submissions ............................. 82

Table 14: Total ingredients for cross-referenced PMTA submissions ................................................... 86

Table 15: Comparison of HPHC levels in the new products to Nicorette gum, General Snus, and

cigarettes (per portion basis) .............................................................................................................88

Table 16: Comparison of HPHC levels in the VERVE® products compared to Nicorette Gum, General

Snus, and Cigarette (wet weight basis) ............................................................................................... 89

Table 17: HPHCs of VERVE® products and other smokeless tobacco products..................................... 90

Table 18. Constituents of VERVE® Chews and Discs products over a 12-month period ........................ 91
PM0000470 – PM0000473 Page 6 of 104

1. EXECUTIVE SUMMARY

On July 23, 2018, the Food and Drug Administration (FDA) received four PMTAs from Altria Client

Services LLC (ALCS), submitted on behalf of U.S. Smokeless Tobacco Company LLC (USSTC). The applicant

is seeking market authorizations for four oral tobacco products under the brand name of VERVE®. The

four products are mint products, two disc and two chew products, with the names VERVE® Discs Blue

Mint, VERVE® Discs Green Mint, VERVE® Chews Blue Mint, and VERVE® Chews Green Mint. FDA issued

acknowledgement letters to the applicant on August 22, 2018. These products are categorized as

“other.”

On September 19, 2018, FDA received the applicant’s response (PM0000477) to information requested

during a teleconference held on September 5, 2018. FDA issued a Filing letter on February 8, 2019. On

February 14, 2019, FDA received an unsolicited amendment containing updates to the PMTAs

(PM0000500). FDA issued an Information Request letter on February 20, 2019, detailing the number of

samples requested to conduct independent testing of the new tobacco products that are the subject of

the PMTAs. FDA issued an Inspection Request letter on February 21, 2019. On February 27, 2019, FDA

received the applicant’s response to the Information Request letter (PM0000504). On March 7, 2019,

FDA received the applicant’s response to the Inspection Request letter (PM0000505). On May 8, 2019,

FDA received an unsolicited amendment containing corrections to validation reports previously

submitted to FDA (PM0000512).

The VERVE® products are novel oral tobacco products that do not contain cut, ground, powdered, or leaf

tobacco. All four products are used by the consumer by placing them in the mouth and chewing them,

with the product being discarded, rather than swallowed, once the user is finished with the product. The

Discs and Chews differ in part by the texture of the products. While both the Discs and the Chews are

flexible, the Discs have a firm texture and the Chews have a soft texture. The applicant claims the

products are intended for adult tobacco consumers interested in an oral tobacco product. They also

note that the products have significantly lower levels of harmful and potentially harmful constituents

(HPHCs) than smokeless tobacco products as well as cigarette smoke; the applicant states that, should

an adult smoker switch totally to a VERVE® product, the consumer would be exposed to substantially

lower HPHC levels, or even eliminate exposure to some HPHCs. The applicant also claims that the

VERVE® products are not appealing to nonusers.

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

any component, any part, or any constituent, including a smoke constituent, or in the content, delivery,

or form of nicotine, or any other additive or ingredient”), that was not commercially marketed in the

United States as of February 15, 2007 (section 910(a)(1)(B) of the Federal Food, Drug, and Cosmetics Act

(FD&C Act) generally requires premarket authorization from FDA (section910(a)(2)(A) of the FD&C Act).

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

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

product, unless FDA has found that the new tobacco product is substantially equivalent to a tobacco

product commercially marketed in the U.S. as of February 15, 2007 (see section 910(a)(2)(A)(i) of the

FD&C Act) or is exempt from a substantial equivalence determination pursuant to regulation (see

section 910(a)(2)(A)(ii) of the FD&C Act).
PM0000470 – PM0000473 Page 7 of 104

FDA will deny a PMTA and issue a no marketing authorization order stating that the product may not be

introduced or delivered for introduction into interstate commerce under section 910(c)(1)(A)(ii) where

FDA finds that:

• there is a lack of a showing that permitting such tobacco product to be marketed would be

appropriate for the protection of the public health;

• the methods used in, or the facilities or controls used for, the manufacture, processing, or

packing of such tobacco product do not conform to the manufacturing requirements of section

906(e) (21 U.S.C. 387f(e));

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

any particular; or

• such tobacco product is not shown to conform in all respects to a tobacco product standard in

effect under section 907 (21 U.S.C. 387g), and there is a lack of adequate information to justify

the deviation from such standard.

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

submitted would be appropriate for the protection of the public health shall be determined with respect 

to the risks and benefits to the population as a whole, including users and nonusers of the tobacco

product, and taking into account:

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

using such products; and

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

start using such products.

Scientific review of these applications has demonstrated the following:

• The PMTAs reference a tobacco product master file (TPMF) for information on the ingredients in the

VERVE® products. The TPMF includes Chemical Abstract Service (CAS) Registry numbers, percent

composition, and target weights expressed in milligrams per unit of product (mg/piece) for each of the

ingredients but does not include information on the grade, purity and function of each single

ingredient. However, the toxicology review found that none of the single ingredients found in the

VERVE® products were present in amounts that raise toxicological concerns, and that no hazards are

associated with, or expected from, the ingredients. In addition, the TPMF does not include

information on the name, grade, purity, functions, or quantities of the single ingredients for(b) (4)

(b) (4), which is found in Verve® Disc products. However, the toxicology review found that the

amount of(b) (4) present in the Disc products does not raise toxicological concerns.

• There are adequate process controls and quality assurance procedures to help ensure that the

VERVE® products are manufactured consistently to meet the applicant’s specifications.

• Based on the ingredients and the HPHCs in the VERVE® products, the toxicological potential is

reduced in comparison to cigarettes and smokeless tobacco. Information provided by the applicant

showed that the following HPHCs were higher in the VERVE® products than in the comparator

products:

o Arsenic: ↑114% (12.86 ng/portion) in the VERVE® Chews products compared to Marlboro

100’s Box cigarettes

o Free nicotine: ↑1486% (1.04 mg/g) in the VERVE® Discs products compared to

chewing tobacco products

o Total nicotine: ↑36% (0.73 mg/g) in the VERVE® Discs compared to Nicorette gum
PM0000470 – PM0000473 Page 8 of 104

However, arsenic levels are not of toxicological concern and the free and total nicotine levels are not

expected to impact abuse liability (see, respectively, sections 2.3 and 2.4).

• There were no studies conducted with the VERVE® products to investigate short-term health effects

of the products. However, adverse events (AEs) reported in the five clinical studies and reported to

the ALCS Consumers Call Center did not identify any serious adverse events (SAEs).

• The pharmacokinetic (PK) profile of the VERVE® products is supportive of a lower abuse liability than

consumers’ usual brand (UB) cigarettes, as well as supportive of a low risk of initiation or reinitiation of tobacco use by youth, nonusers, and former users.

• In terms of youth risk, the information extrapolating dissolvable tobacco products to VERVE® from

the literature and from national survey data support that there is low likelihood of youth initiating

tobacco use with the new products. Nonetheless, given the strong evidence regarding the impact of

youth marketing exposure to youth appeal and initiation of tobacco use, a marketing authorization

should include postmarket requirements to help ensure that youth exposure to tobacco marketing is 

limited.

• Current smokers who also use one or more other tobacco products are the consumer population

most likely to try VERVE® products. Polytobacco use was common in the VERVE® clinical studies

submitted in the PMTAs. Given the levels of HPHCs in the products, use of VERVE® products alone

would likely lower several biomarkers of exposure (BOE) and biomarkers of potential harm (BOPH)

in comparison to smoking cigarettes. Additionally, while smokers who dual use VERVE® products

with cigarettes, and do not substantially reduce their cigarettes per day (CPD) (i.e., by 50% or

greater), do not reduce their exposure to nicotine or non-nicotine BOE, even a modest reduction in

daily cigarette consumption may reduce the risk of tobacco related disease due to decreased

exposure to HPHCs.

• Use of VERVE® Chews and Discs products is not associated with significant second-hand exposure

which, in this respect, decreases risk for both users and nonusers.

As discussed in more detail in Sections 2.2 through 2.6 of this review, I recommend the PMTAs be

authorized.

2. REVIEW OF PMTAS

2.1. Regulatory History

On July 23, 2018, the FDA received four PMTAs from ALCS, submitted on behalf of USSTC. FDA issued

Acknowledgement letters to the applicant on August 22, 2018. On September 19, 2018, FDA received 

the applicant’s response (PM0000477) to information requested during a teleconference held on

September 5, 2018. FDA issued a Filing letter on February 8, 2019. On February 14, 2019, FDA received

an unsolicited amendment containing updates to the PMTAs (PM0000500). FDA issued an Information

Request letter on February 20, 2019, detailing the number of samples requested to conduct

independent testing of the new tobacco products that are the subject of the PMTAs. FDA issued an

Inspection Request letter on February 21, 2019. On February 27, 2019, FDA received the applicant’s

response to the Information Request letter (PM0000504). On March 7, 2019, FDA received the

applicant’s response to the Inspection Request letter (PM0000505). On May 8, 2019, FDA received an

unsolicited amendment containing corrections to validation reports previously submitted to FDA

(PM0000512). This TPL review focuses on whether the data provided by the applicant support marketing
PM0000470 – PM0000473 Page 9 of 104

(b) (4)

(b) (4)

orders for the four VERVE® products

Table 1: Amendments submitted by applicant

STN Date Received Amendment Type Content

PM0000477 September 19, 2018 Minor Response to FDA’s September 5,

2018, teleconference request for

information.

PM0000500 February 14, 2019 Minor Unsolicited amendment to notify

FDA of change in manufacturing

facility

PM0000504 February 27, 2019 Minor Response to FDA’s February 20,

2019, Information Request letter

PM0000505 March 7, 2019 Minor Response to FDA/OCE’s February

21, 2019, Inspection Request letter

PM0000512 May 8, 2019 Minor Unsolicited amendment to correct

validation reports previously

submitted to FDA on September

19, 2018

2.2. Product Composition, Design, and Manufacturing

The subject of the four PMTAs (PM0000470-PM0000473) are oral tobacco products containing United

States Pharmacopeia (USP)-grade tobacco-derived nicotine and other ingredients in a chewable form

with approximately 1.5 milligrams per piece (mg/piece) of nicotine. The applicant notes that versions of

the VERVE® Discs Blue Mint products were marketed in Virginia only. A version identified as Generation

(Gen) 1 was a VERVE® Discs Blue Mint first available in May 2012 in a small market in Virginia. Gen 1A

had an addition of an(b) (4) . Later in 2013 the texture was modified (Gen 2) and then in 2014 a flavor coating (Gen 3) was

added and the new product (VERVE® Discs Blue Mint) was created. The VERVE® Discs Green Mint

version was added in 2014, along with other flavors. The VERVE® Chews products were introduced, also

in Virginia, in 2015. The applicant states that the current VERVE® Chews products that are the subject of

the PMTAs are similar to the original version, with substitution of some flavor ingredients from an

alternate supplier and addition of a processing aid to improve machinability.

The ingredient information is cross-referenced to a TPMF ((b) (4) ) and includes polymer, nontobacco cellulose fiber, flavorings, texture modifier, binder, and colorant. These ingredients are

commonly used in food products. However, VERVE® Discs products contain a (b) (4) ), while the VERVE® Chews products contain

(b) (4) , an artificial sweetener. While all new products contain menthol characterizing flavor, the

VERVE® Discs Blue Mint product contains higher levels of menthol compared to the levels reported in

mentholated cigarettes (↑27%) and smokeless tobacco (↑302%) products (Section 2.3).

As to the design of the new products, both the VERVE® Discs and Chews are thick, teardrop-shaped, and

have a soft and flexible texture (VERVE® Chews) or a firm and flexible texture (VERVE® Discs). All four

new products are placed in the mouth, chewed, removed, and discarded after use. The new products do

not contain a heat source.
PM0000470 – PM0000473 Page 10 of 104

The applicant provided, either in the PMTAs or during the facility inspection, details regarding the

manufacturing processes for all four VERVE® products. This information supports the determination that

the product can be manufactured consistently.

2.2.1. Tobacco Ingredients

The four new VERVE® products are oral tobacco products that do not contain ground, cut, powdered or

leaf tobacco. The products do, however, contain tobacco-derived USP-grade nicotine (1.5 mg/piece).

2.2.2. Non-Tobacco Ingredients

As noted in the chemistry review, the applicant provided the ingredient information in a TPMF

(b)(4) which was cross-referenced in the PMTAs. These ingredients include polymer, nontobacco cellulose fiber, flavorings, texture modifier, binder, and colorant. The VERVE® Discs products

contain a (b)(4) while

the VERVE® Chews products contain(b)(4) an artificial sweetener. While all new products contain

menthol characterizing flavor, the VERVE® Discs Blue Mint product (PM0000470) contains higher levels

of menthol compared to the levels reported in mentholated cigarettes (↑27%) and smokeless tobacco

(↑302%) products. Appendix Tables 13 and 14 include all the non-tobacco ingredients in the four new

VERVE® products. Though the referenced TPMF (b)(4) did not demonstrate that food quality of

ingredients was used to manufacture the new tobacco products, the applicant notes in the PMTAs that

the non-tobacco ingredients are food- or biocompatible medical grade ingredients. As noted in the

chemistry review, the regulations that apply to food-grade and biocompatible medical-grade chemicals

are not applicable to tobacco products and have not been adopted for tobacco products. The data that

informs those designations can, however, be informative to an analysis of the risk of use in oral tobacco

products. These will be discussed further in the toxicology section of this review (Section 2.3).

2.2.2.1 Container Closure System Ingredients

The applicant provided container closure system information for the VERVE® Chews and the VERVE®

Discs products. According to the applicant, the VERVE® Discs products are packaged in a child-resistant

container with a lug finish closure comprising a cap, vial, and label. The vial and cap closure of the Discs

products is made of polypropylene resin and colorant. The resin and colorant are pre-mixed and injected 

into a molding process to achieve the desired color. The label is pre-perforated with a pull tab (tear 

strip) at the cap and attached to the vial with adhesive. The applicant did not provide the composition of

the colorant used in the vial and cap closure resins or composition of the label, adhesive, or ink printed

on the label. However, these missing ingredients do not come in direct contact with the new products

and therefore do not cause public health concerns.

The VERVE® Chews products are also packaged in a child-resistant container, composed of a button,

tube structure, label, and tamper-evident shrink band. The button and tube structure are made from

polypropylene resin and colorant that are pre-mixed prior to the injection molding process to achieve

the desired color. The label is attached to the tube structure with adhesive. The shrink band is made

from polyethylene terephthalate (PET) film and a seaming solution. It is perforated, cut to size for the

tube, and individually placed over the closure’s opening and button. The tube travels through a heat

tunnel to shrink the band in place. The applicant did not provide the composition of the colorant used in

the resin molded into button and tube structures or composition of the label, adhesive, or ink printed on

the label. However, these missing ingredients do not come in contact with the new products and

therefore do not cause public health concerns.
PM0000470 – PM0000473 Page 11 of 104

2.2.3. Product Design

The product design, based on chemistry and engineering reviews of the applications, note that the

VERVE® Discs and VERVE® Chews are oral products that are thick and teardrop-shaped and have a

flexible texture, with the Discs firm and the Chews soft. Both product types are placed in the mouth and

chewed; once chewed to satisfaction, the products are removed and discarded. The new products do

not contain a heat source. The product components and subcomponents are listed in Table 2 from the

engineering review. Figure 1 shows a diagram of the two types (disc and chew) of VERVE® products, as

presented in the PMTAs.

Table 2: Product components and subcomponents

Component Subcomponent Function and Purpose

Chews (Blue and Green Mint) N/A Consumption

Packaging (Chews)

Button Opens the tube structure

Tube Structure Houses the product

Label Provides information about the product

Shrink Band Tamper evidence for the product

Discs (Blue and Green Mint) N/A Consumption

Packaging (Discs)

Cap Opens the vial

Vial Houses the product

Label Tamper evidence and information about the

product

Figure 1. Product Diagrams (adapted from submission)

According to the engineering review, the target specifications and range limits are used to characterize

the products and test data are used to assess whether the products are being made according to the

manufacturer’s specifications. The applicant provided sufficient information concerning the range limits

for design parameters including product height, width, thickness, and piece weight. The VERVE® Chews

products have identical range limits for width, height, thickness, and weight, while the VERVE® Discs

products have identical physical dimensions but differences in weight. The engineering review

presented the applicant’s table with design parameters and product dimensions (Table 3).
(b) (4)

Table 3: Design parameters for product dimensions (from application)2 Pieces per Container

Height (Length) Width Thickness Container Weight3 4

Target Value

Range Limit

Test Data Range5

Within Range 

Limit?

Target Value

Range Limit

Test Data Range

Within Range 

Limit?

Target Value

Range Limit

Test Data Range

Within Range 

Limit?

Target Value

Range Limit

Test Data Range

Within Range 

Limit?

Count mm mm mm Yes/No mm mm mm Yes/No mm mm mm Yes/No g g g Yes/No

PM0000470

VERVE® Discs

Blue Mint

16

PM0000471

VERVE® Chews 

Blue Mint 12

PM0000472

VERVE® Discs

Green Mint 6 16

PM0000473

VERVE® Chews 

Green Mint 12

(b) (4) 

N/A = not applicable as indicated by the applicant

2. 2 The applicant stated that the “product’s test results are verified to be in conformance with the requirements for product release as defined” in the table.

3. 3 The 16-piece target weights are (b) grams (Discs Blue Mint) and grams (Discs Green Mint), which corresponds to individual piece weights of approximately 0.532 grams

(Discs Blue Mint) and 0.523 grams (Discs Green Mint).

4. 4 The 12-piece target weight is(b) (4) grams, which corresponds to an individual piece weight of approximately 2.1 grams, for all Chews products.

5. 5 The applicant gave a graphical representation of the test data. Based on this graphic, test data values were interpreted. Thus, the symbol (~) was used in the table.

6. 6 Test data were not provided for VERVE® Discs Green Mint. The applicant provided test data that were used to verify that the facility could manufacture the products to meet

specifications and states that because the Discs products are manufactured identically, only one Discs product was manufactured and tested. No additional test data are needed for

the VERVE® Discs Green Mint.
PM0000470 – PM0000473 Page 13 of 104

The blank cells of Table 3 represent information that the applicant did not provide in the applications.

While the lack of this information inhibits the ability to fully characterize the products, the information

attained during the manufacturing inspection sufficiently addressed the missing information. Table 4

indicates this inspection information. Additional details regarding these data are discussed in the

manufacturing section of this review (Section 2.2.4).

Table 4. Dimensional characterization based on inspection documents

Length Width Thickness

VERVE® Discs (b) (4) mm (b) (4) Not provided

) mm (b) (4) ) mm

VERVE® Chews Not provided (b) (4)mm

2.2.4. Manufacturing, Process, and Controls

The new VERVE® products are manufactured by U.S. Smokeless Tobacco Products LLC at the USSTP DPilot Plant, which is located at 4201 Commerce Road, Building D, Richmond, VA 23234. According to the

chemistry and engineering reviews, the PMTAs included information regarding the manufacturing

processes for both the VERVE® Discs and the VERVE® Chews; however, some information was missing

from the PMTAs. The applicant described manufacturing steps and controls but did not provide standard

operating procedures (SOPs) or quality documents, in-process parameters, details for the order of

addition of ingredients, quality (e.g., grade, purity) of ingredients, and quantity of some ingredients used

during manufacturing. The applicant provided specification requirements for nicotine and nicotinerelated impurities in the finished products and the results obtained from the performance qualification

(PQ) test records were within specifications. During the inspection of the manufacturing facility, this

additional information, along with the batch records, was obtained. The batch records (Exhibits #13,

#15-16, #19, and #21-22) and documentations (Exhibit #25 through #74) are included in the

Establishment Inspection Report (EIR). They contain SOPs, quality documents, in-process parameters,

the order of addition of ingredients, and information about other ingredients used during

manufacturing. Tables 5 and 6, from the chemistry review, show the parameters required prior to

process release of the new VERVE® products.

Table 5: Physical parameters required for product release of the new products

N/A = not applicable as indicated by the applicant

Design Feature

PM0000470

VERVE® Discs Blue Mint

PM0000472

VERVE® Discs Green Mint

PM0000471 and

PM0000473

VERVE® Chews Products

Low Target Upper Low Target Upper Low Target Upper

Piece per Container (b) (4) Weight per Container (g)

Piece Height (mm)

Piece Width (mm)

Piece Thickness (mm)
PM0000470 – PM0000473 Page 14 of 104

PMTA Product

Name

Nicotine 

Nicotine Degradant (weight % of nicotine)

(mg/g)

For the Chews products(b) (4)

width,(b) (4) . As for the VERVE® Chews length and

, but no specifications on the machine

were provided in the application or during the inspection (b) (4)

Table 6: Chemistry-relevant parameters required for product release of the new products

PM0000470 VERVE® (b)(4)

Discs Blue )

Mint

PM0000471 VERVE® (b)(4)

Chews

Blue Mint )

PM0000472 VERVE®

Discs

(b)(4)

)

Green

Mint

PM0000473 VERVE® (b)(4)

Chews

Green )

Mint

Additional manufacturing information was obtained by FDA during the inspection, during which both the

chemistry and engineering reviewers were present. According to the engineering review, during the

facility inspection, the applicant provided production records for VERVE® Blue Mint Chews and VERVE®

Green Mint Discs, as well as explained in detail the manufacturing process for all VERVE® Chews and

Discs products.

Inspection documents also showed that the VERVE® Discs products have target specifications for width

and length. However, unlike the VERVE® Chews, the VERVE® Discs products do have a target thickness

(b) mm with a range of(b)(4) mm). The facility records range limit is tighter than what was

provided in the application, demonstrating greater control of the product during manufacturing. Like the 

VERVE® Discs thickness, the range limits discovered during the inspections are tighter than those

submitted in the application, demonstrating a greater control of the product during manufacturing. See 

EIR Exhibit #19 for more details on the target specifications and range limits for the product dimensions.

Quality control, performance criteria, and test data are interrelated. Quality control establishes the 

overall monitoring program and identifies testing to be executed; performance criteria describe the

methods and pre-specified limits the product must meet; and test data are the result of the testing.

Both the Chews and the Discs products are manufactured at the same facility, the D Pilot Plant in

(b) (4)
PM0000470 – PM0000473 Page 15 of 104

Richmond, Virginia. The Chews and Discs products are produced under identical manufacturing steps.

Process controls were described, and process control parameters were quantified by USSTC. USSTC

provided a list of quality control documents detailing the names and numbers of the quality control

documents. During the facility inspection, USSTC provided the actual quality control documents that

describe the manufacturing steps, process controls, and process control parameters.

The applicant provided test data for both Chews products, but only one of the Discs products (VERVE®

Discs Blue Mint). All the provided test data demonstrate that the D Pilot Plant can manufacture the

VERVE® products consistently. The applicant states that Discs products are manufactured similarly, and

it did not find it was necessary to manufacture and test the VERVE® Discs Green Mint product. Because

the applicant stated that both Discs products were produced under identical manufacturing steps and

with similar degrees of consistency, test data for both Chews products and Discs Blue Mint was

considered sufficient by the engineering reviewer.

After the manufacturing inspection, the engineering review concluded that no additional information

was needed regarding the dimensional characterization of the VERVE® Chews and Discs products.

2.2.5. FDA Sample Testing

The testing methods for the VERVE® products were provided to FDA in amendment PM0000477,

following a teleconference with the company after identifying missing information in the PMTAs. This

information was needed for the analysis of the products by the FDA’s Southeast Tobacco Laboratory

(STL). In accordance with section 910(b)(1)(E) of the FD&C Act, samples of the four new VERVE®

products were received by STL on March 5, 2019, in support of these PMTAs. Table 7 shows the

quantities of the samples that were submitted to STL. Table 8 shows the test requests made by FDA for

each of the four VERVE® products and control samples.

Table 7: Samples submitted by USSTC to STL

Tobacco Product Samples

PMTA STN Tobacco Product Name

Total Quantity

Per Lot

Number

of Lots

Total Quantity

Needed

PM0000470 VERVE® Discs Blue Mint 20 vials

3

60 vials

PM0000471 VERVE® Chews Blue Mint 20 containers 60 containers

PM0000472 VERVE® Discs Green Mint 28 vials 84 vials

PM0000473 VERVE® Chews Green Mint 18 containers 54 containers

Control Samples

Control Sample Name

Total Quantity

Per Lot

Number of

Lots Total Quantity Needed

VERVE® Discs monitor sample

N/A

15 pieces

VERVE® Discs Placebo 39 pieces

VERVE® Chews Placebo 25 pieces

Monitor sample 129 grams
PM0000470 – PM0000473 Page 16 of 104

Table 8: Testing requested of STL by FDA

Test Requested VERVE® Discs

Blue Mint

VERVE® Chews

Blue Mint

VERVE® Discs

Green Mint

VERVE® Chews

Green Mint

Chemistry Test Requests

Nicotine (total & free)    

pH    

Cadmium 

NNN 

NNK 

Formaldehyde  

Acetaldehyde  

Arsenic 

Microbiology Test Requests

Water activity (aw)    

Physical Test Requests

Portion mass    

Portion height, width, and thickness    

Pieces per container    

The results of the STL testing show that the testing data are lower compared to the data included in the

PMTAs except for arsenic in the VERVE® Chews products and pH and free nicotine in the VERVE® Discs

products. The level of arsenic determined by STL in the VERVE® Chews products is 14% or 1.58 ng/g

higher compared to the PMTAs. The pH measured in the VERVE® Discs products by STL is 9% or 0.67

higher compared to the PMTAs. Subsequently, for free nicotine, the level calculated by STL in the

VERVE® Discs products is 110% or 0.9 mg/g higher compared to the level noted in the PMTAs. However,

compared to the measured data in Nicorette Gum, published data for General Snus smokeless tobacco,

and FDA internal data (n=3 to 242) for other smokeless tobacco products, the levels of arsenic in the

VERVE® Chews products and pH and free nicotine in the VERVE® Discs products are comparable or

lower. These data are presented in Table 9.
PM0000470 – PM0000473 Page 17 of 104

Table 9: Comparison of HPHC levels in the PMTAs to the STL testing results

Constituent

VERVE® Discs (PM0000470, PM0000472) VERVE® Chews (PM0000471, PM0000473)

PMTA Mean

(SD)

STL

Mean (SD) % Changea PMTAMean (SD)

STL

Mean (SD) % Changea

Nicotine (total), mg/g 2.62 (0.09) 2.51 (0.01) ↓4 0.67 (0.01) 0.57 (0.03)* ↓15

Nicotine (free), mg/g 0.82 (0.06) 1.72 (0.03) ↑110 0.02 (0.00) 0.01 (0.00) ↓50

pH 7.67 (0.03) 8.34 (0.00) ↑9 6.35 (0.10) 6.21 (0.02) ↓2

Cadmium, ng/g 14.67 (3.31) BLOQ§ N/D

Arsenic, ng/g N/D 11.04 (0.30) 12.62

(0.53)+ ↑14

NNN, ng/g 2.05 (0.80) N/D ↓100 BLOQ

NNK, ng/g 0.70 (0.03) 0.63 (0.17)§§ ↓10 BLOQ

Formaldehyde, μg/g 1.00 (0.00) 0.12 (0.008)

§§ ↓88 0.22 (0.04) 0.054

(0.002)++ ↓75

Acetaldehyde, μg/g 0.53 (0.08)

0.063

(0.003) §§ ↓88

0.20

(0.00)0.27

0.078

(0.006)++ ↓61

BLOQ = below limit of quantitation; N/D = not detected a % Change = ([STL mean constituent (all batches, unit/g of product)] – [PMTA mean constituent (unit/g of product)])/[PMTA

mean (unit/g of product)] * Not within the nicotine specification limits of(b) (4) ) mg/g for VERVE® Chews products (PM0000471,

PM0000473)

+ Arsenic was only tested in VERVE® Chews Green Mint ++Formaldehyde and acetaldehyde were only tested in VERVE® Chews Blue Mint

§Cadmium was only tested in VERVE® Discs Blue Mint

§§NNN, NNK, formaldehyde, and acetaldehyde were only tested in VERVE® Discs Green Mint

An independent analysis of the finished new tobacco products’ water activity (aw) was conducted by the

FDA’s Office of Regulatory Affairs (ORA) Southeast Food and Feed Laboratory (SFFL); results are

presented in Table 10. The average results (VERVE® Discs Blue Mint: 0.266, VERVE® Chews Blue Mint:

0.540, VERVE® Discs Green Mint: 0.266, VERVE® Chews Green Mint: 0.541), while analytically variable

(14 to 21%) from the applicant-provided data, are similar to the values provided by the applicant for

each new tobacco product at the initial storage time point (VERVE® Discs Blue Mint:(b) (4) , VERVE®

Chews Blue Mint:(b) (4) , VERVE® Discs Green Mint:(b) (4) , VERVE® Chews Green Mint: (b) (4) ). In

addition, the aw values for all new tobacco products, tested by SFFL, are below what has been reported

to support microbial proliferation ((b) (4)).

Table 10: Product stability: Water activity initial sampling compared to STL results

PMTA

Water Activity

(aw)

PMTA Dataa SFFL Testing

PM0000470

(VERVE® Discs Blue Mint) (b) (4) 0.266

PM0000471 (VERVE® Chews Blue Mint) 0.540

PM0000472

(VERVE® Discs Green Mint) 0.266

PM0000473 (VERVE® Chews Green Mint) 0.541

a Initial sampling from PMTA data
PM0000470 – PM0000473 Page 18 of 104

STL also measured the portion length, portion width, portion thickness, portion mass, and the number

of pieces per container for the new products. Table11 conveys the results from STL physical parameter

testing.
PM0000470 – PM0000473 Page 19 of 104

Table 11: FDA sample product testing

PM# Parameter Replicates

STL Results Applicant’s Range Limits

Tube (from application) 1 Tube 2 Tube 3

PM0000470 VERVE® Discs Blue Mint

Length (mm) 1 13.91 14.50 14.86 (b)(4)

2 14.38 14.56 14.43

3 14.58 14.67 14.68

Width (mm) 1 12.46 12.18 12.49

2 12.85 12.14 12.33

3 12.90 12.18 12.28

Thickness (mm) 1 3.22 3.00 3.24

2 3.18 3.15 3.19

3 3.24 3.24 3.18

Portion Mass (g) 1 0.50469 0.51514 0.54127

2 0.53892 0.54337 0.51247

3 0.55834 0.53677 0.51546

Container Weight (g) 8.42698 8.35991 8.30632

Pieces per Container (#) 16 16 16 16

PM0000471 VERVE® Chews Blue Mint

Length (mm) 1 20.60 20.13 N/A (b)(4)

2 20.77 20.12 N/A

3 20.68 20.47 N/A

Width (mm) 1 17.33 16.35 N/A

2 17.12 16.41 N/A

3 16.99 16.55 N/A

Thickness (mm) 1 8.12 9.19 N/A

2 7.82 9.36 N/A

3 8.37 9.00 N/A

Portion Mass (g) 1 2.13048 2.11467 N/A

2 2.13036 2.12807 N/A

3 2.09368 2.15748 N/A

Container Weight (g) 25.03287 25.26524 N/A

Pieces per Container (#) 12 12 N/A 12

PM0000472 VERVE® Discs Green Mint

Length (mm) 1 14.49 14.34 15.05 (b)(4)

2 15.02 14.60 15.06

3 15.02 14.66 14.79

Width (mm) 1 11.96 12.12 12.52

2 12.04 11.95 12.63

3 11.97 12.38 12.36

Thickness (mm) 1 3.18 3.25 3.13

2 3.30 3.24 3.23

3 3.28 3.17 3.18

Portion Mass (g) 1 0.49669 0.51468 0.51259

2 0.53205 0.51327 0.53645

3 0.53460 0.52036 0.51142

Container Weight (g) 8.39159 8.31329 8.23770

Pieces per Container (#) 16 16 16 16
PM0000470 – PM0000473 Page 20 of 104

(b) (4)

20.32

All the STL data points fall within the applicant’s established parameter range limits, which typically

illustrate parameters that meet the product attributes. Range limits are used to characterize the product

based on the target specifications and product attributes. Therefore, product test data should meet

these range limits; if not, the product should be discarded or reprocessed to resolve the deviation. The

test data show that the applicant can consistently manufacture the VERVE® products per their

specifications. No further information is needed regarding the sample test data.

The chemistry, microbiology, and engineering reviews each concluded that the independent FDA testing

of the products was consistent with the data submitted by the applicant.

2.2.6. Product Stability

The microbiology review noted that the applicant provided data from stability studies carried out under

two conditions: a long-term condition(b) (4)) measured over a (b) (4) period and an accelerated

condition ((b) (4)) measured over a (b) (4) period. The studies assess the changes in nicotine, nicotine

impurities (myosmine, nornicotine, cotinine, anatabine, nicotine-N’-oxide, β-nicotyrine, and anabasine),

water activity, and pH. Overall, the levels of nicotine and nicotine-related impurities increased with the

increase of storage times and temperatures. However, these increases are within the specification limits

of nicotine and nicotine-related impurities. Both the microbiology and chemistry reviews determined

that the submitted stability data support a proposed(b) (4) shelf life.

According to the microbiology review, the applicant indicated that the shelf-life of the new tobacco

products was determined by the levels of nicotine degradants and impurities over a (b) (4) period. The

levels of these degradants were within established limits during this storage time. In addition, a

microbiological examination for microbial content was conducted during this period and no increases in

microbial content were observed. Therefore, the shelf-life for the new tobacco products was set at

(b) (4) ). To assess microbiological stability during this shelf-life period, the applicant

provided adequate stability data. The parameters analyzed in this review to determine microbial

stability were water activity (aw), tobacco-specific nitrosamine (TSNA) content, and microbial count data.

In addition, comparisons of the applicant-provided stability data with known available tobacco product

(smokeless tobacco products, cigarettes) data (published literature or applicant-provided) were

conducted.

PM# Parameter Replicates

STL Results Applicant’s Range Limits

Tube (from application) 1 Tube 2 Tube 3

PM0000473 VERVE® Chews Green Mint

Length (mm) 1 19.77 19.99 (b) (4) 2 19.98 20.43 20.22

3 20.10 18.99 20.08

Width (mm) 1 16.95 16.27 16.68

2 16.66 16.32 16.28

3 16.65 16.28 16.34

Thickness (mm) 1 9.43 9.33 9.24

2 9.41 9.15 9.16

3 8.55 8.87 9.18

Portion Mass (g) 1 2.17920 2.03758 2.15118

2 2.14744 2.13103 2.06575

3 2.06498 1.98820 2.08724

Container Weight (g) 25.36221 25.23216 25.29342

Pieces per Container (#) 12 12 12 12
PM0000470 – PM0000473 Page 21 of 104

w

(

(b) (4)

b) (4) (b)(4)

The data provided by the applicant were collected from either long-term [

(b) (4) (aw and TSNAs)] or accelerated [

e

(aw only)] conditions.

The applicant provided aw data for the new tobacco products over a (b) (4) storage period. These

data are presented in Table 12. Analysis of the long-term data for the new tobacco products indicated

increases in aw of the new tobacco products during storage (VERVE® Discs Blue Mint: 17%, VERVE

Chews Blue Mint: 11%, VERVE® Discs Green Mint: 42%, VERVE® Chews Green Mint: 13%). Analysis of the

accelerated data for the new tobacco products indicated increases in aw of the new tobacco products

during storage (VERVE® Discs Blue Mint: 61%, VERVE® Chews Blue Mint: 17%, VERVE® Discs Green Mint:

52%, VERVE® Chews Green Mint: 15%). While increases in aw over storage raise concerns about

microbial stability, the value of the highest reported aw data (b) (4) associated with any of the new

tobacco products is less than the minimum a (b) (4) necessary to support microbial activity.
PM0000470 – PM0000473 Page 22 of 104

(b) (4)

↑17 % Change over time ↑61

(b) (4) 

(b) (4) 

Table 12. Product stability: Water activity over storage time

PMTA

PM0000470

(VERVE® Discs

Blue Mint)

Long-Term

Time (Months) Water Activity

(aw)

Accelerated

Time (Months) Water Activity

(aw)

PM0000471

(VERVE® Chews

Blue Mint)

% Change over time

% Change over time ↑11 % Change over time ↑17

PM0000472

(VERVE® Discs

Green Mint)

PM0000473

(VERVE® Chews

Green Mint)

(b) (4) 

% Change over time ↑42 % Change over time ↑52

% Change over time ↑13 % Change over time ↑15

The applicant provided microbial count data for the new tobacco products over a(b) (4) storage

period. The applicant evaluated aerobic plate counts (APC), coliforms, Escherichia coli, yeast and mold

counts, and the presence of Salmonella spp. or Listeria spp. The level of microbial content at each point

tested was either below the limit of detection or was slightly above detectable levels (b) (4) colony

forming units (cfu)/g). These microbial levels of the new tobacco products are not of concern from a

microbiology perspective.

The applicant provided TSNA data including N-nitrosanabasine (NAB), N-nitrosoanatabine (NAT), Nnitrosonornicotine (NNN), and 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) over a (b) (4)

storage period. The new tobacco products showed increases in NNN for VERVE® Discs Blue Mint (14%)

and VERVE® Discs Green Mint (4%) and NNK for VERVE® Discs Blue Mint (41%) and VERVE® Discs Green

Mint.7

 For VERVE® Chews Blue Mint and VERVE® Chews Green Mint, no changes in NNN and NNK were

7. 7 A percentage increase could not be determined because the one-month time point was Below Limit of Quantitation

(BLOQ).
PM0000470 – PM0000473 Page 23 of 104

indicated because the target constituents were not detected or were below the limit of quantitation

(BLOQ). For all new tobacco products, no changes in NAB and NAT were indicated because the target

constituents were not detected or were BLOQ. However, any increase in TSNA content over the storage

duration of a product containing tobacco-derived material is a potential concern. Because the water

activity (aw) of the new tobacco products does not support microbial activity, and there is a

demonstrated absence of microbial content of the new tobacco products, changes in TSNA levels are

not likely due to microbial-mediated TSNA formation during storage. For these reasons, including the

manufacturing quality controls (see section 3.4), the overall microbial stability, product quality, and

manufacture of the new tobacco products, TSNAs are not of concern from a microbiology perspective.

The applicant-provided microbial count data of the new tobacco products were compared to microbial

data of smokeless tobacco products (loose or portioned moist snuff, dry snuff, snus or chewing

tobacco). Comparison of the new tobacco products’ microbial content with smokeless tobacco products’

microbial content yielded differences in the microbial load of the products, with lower microbial load in

the new tobacco products. While high microbial content in the smokeless tobacco products could lead

to the formation of microbial-mediated TSNAs, the likelihood of this process in the new tobacco

products is not expected because the microbial content is at or below detectable limits.

The applicant also provided comparator TSNA data for an oral nicotine product, Nicorette®, a smokeless

tobacco product, General® snus, and cigarettes. However, because of the low aw ((b) (4)) and microbial

content of the new tobacco products (the microbial content is near the lower limit of detection), the

increases in NNN and NNK content as compared to Nicorette® are not of concern from a microbiology

perspective. When the maximum NNN and NNK content at any test point of the new tobacco products

was compared to those of either General® snus or cigarettes, decreases in NNN and NNK content were

observed in the new tobacco products.

The chemistry and microbiology reviews conclude that the available microbiological data provide

support that the new tobacco products are stable for at least (b) (4) .

2.2.7. Inspections of Manufacturing Facilities

FDA conducted an inspection of the applicant’s manufacturing facility on June 18-20, 2019 to confirm

the manufacturing information submitted in the PMTAs and determine whether the products can be

consistently produced. No inspectional observations (Form FDA 483) were issued at the conclusion of

the visit. The EIR documents a “No Action Indicated” classification for this visit.

2.2.8. Summary of Composition, Design, and Manufacturing Findings

The engineering review concluded that, given the totality of the evidence provided regarding the design

specifications, test data, manufacturing process, quality control, and quality control parameters, the

PMTAs contain adequate information regarding the following:

• A description of the principles of operation of the products

• An adequate description of the products

• Sufficient quality control test data

• Sufficient information in the description of product manufacturing processes, including

process controls and quality assurance procedures, in addition to the information

provided in amendments and inspection documents, to ensure that the product is

manufactured in a consistent manner
PM0000470 – PM0000473 Page 24 of 104

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

characterize the product design and adequate processes and controls to help ensure that the products

meet the manufacturer’s specifications.

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

following:

• Data on chemical stability of the new products stored under long-term(b) (4)) and accelerated 

(

(b) (4)) conditions

• Data on HPHC measurements of the new products over a(b) (4) period compared to

cigarettes

• Data on HPHC measurements of Nicorette Fresh Mint Gum

The chemistry review does discuss the increase of the level of arsenic reported by STL in the VERVE®

Chews products. This is addressed in Section 2.3.

The chemistry PMTA and TPMF reviews note two issues that the reviewer identified as requiring

clarification:

• The applicant did not provide bioanalytical testing information used in the biomarkers of

exposure (BOE) study or scientific evidence and rationale for how the BOE of the Generation 2

(Gen 2) product of the VERVE® Discs Blue Mint is appropriate to extrapolate to the new

products. The review concludes that the following deficiency should be conveyed to the

applicant:

1. Your PMTAs include BOE data in humans, but not bioanalytical methods used in the

study. In addition, you did not provide an explanation or scientific evidence and

rationale for using the Gen 2 product in place of the VERVE® Discs Blue Mint and for

how the use of the Gen 2 product can be extrapolated to represent BOE to the VERVE®

Discs Blue Mint and other three VERVE® products (VERVE® Discs Green Mint, VERVE®

Chews Blue Mint, and VERVE® Chews Green Mint). In order to evaluate the suitability

and acceptability of the BOE study and the impact of this study on public health, provide

the following information:

a. An explanation or scientific evidence and rationale for using the Gen 2 product

in place of the VERVE® Discs Blue Mint and on how the BOE of the Gen 2 

product can be extrapolated to the VERVE® Discs Blue Mint, VERVE® Discs Green

Mint, VERVE® Chews Blue Mint, and VERVE® Chews Green Mint products.

b. Testing information used to analyze urine BOE, creatinine, and blood

carboxyhemoglobin (COHb) including but not limited to bioanalytical test

protocols and methods, validation reports, testing laboratory information, and

relevant laboratory accreditation or certification.

• The TPMF did not provide the grade, purity, and function for each ingredient. In addition, the

applicant did not provide the name, grade, purity, functions, or quantities of the single

ingredients in (b) (4) . The chemistry TPMF review concludes that the following deficiency

should be conveyed to the TPMF owner:

1. Your TPMF provided the CAS numbers, percent composition, and target weights

expressed in milligrams per unit of product (mg/piece) for each of the non-tobacco

ingredients in support of the referenced submissions. However, your TPMF did not provide

the grade, purity, and function for each ingredient. In addition, you did not provide the

name, grade, purity, functions, or quantities of the single ingredients in(b) (4) 
PM0000470 – PM0000473 Page 25 of 104

Because the PMTA products are uniquely composed of single and complex ingredients and

manufacturing processes and controls that are not commonly used in tobacco products, the

grade, purity, and function of these ingredients are necessary to ensure appropriate quality

(e.g., food grade, generally recognized as safe [GRAS8

]); and for FDA to understand how

each ingredient is used in the manufacturing of the PMTA products. Provide the grade,

purity, function, for each of the listed ingredients and the complete listing of single

ingredients for(b) (4) . Without this information, we cannot assess the overall impact

of the PMTA products on the public health.

The chemistry review states that the TPMF lacks information on the grade, purity, and function of each

ingredient and single ingredients in(b) (4) However, scientific review of the single ingredients

and individual components of(b) (4) indicate that none of the ingredients in the new tobacco

products are present in amounts that raise toxicological concerns (Section 2.3). Further, sufficient

information regarding the manufacturing processes and controls that can affect the product

composition, chemical stability, and HPHC levels was provided to demonstrate the products meet the

manufacturer’s specifications. Therefore, the deficiency of information on grade, purity, and function of

ingredients need not be conveyed to the applicant.

Regarding the bioanalytical testing methods for the BOE measurements, the Behavioral and Clinical

Pharmacology (BCP) reviewer was not concerned with the lack of information regarding the methods.

There was limited BOE information, primarily showing nicotine content in similar prototype and

precursor products that was able to be bridged to the candidate PMTA products. In addition, the

reviewer felt there was sufficient information from the literature for other oral nicotine products and

reference data regarding HPHCs from the chemistry review to provide confidence in the BOE and use

behavior for VERVE® and similar products (section 2.4). While it is beneficial for an applicant to supply

the bioanalytical testing methods for biomarkers studied with PMTA products for FDA to review, as TPL,

I agree that it is not necessary that a deficiency for this issue be conveyed.

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

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

The OCE manufacturing review identified no significant compliance issues during the manufacturing

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

2.3. Toxicological Risk Assessment

No original toxicology studies were submitted by the applicant for any of the VERVE® products. The

applicant provided toxicological assessments, which included hazard and exposure assessments of the

ingredients associated with VERVE® Discs and Chews. The exposure assessments relied on toxicity values

intended for foods as derived by regulatory and industrial trade associations; as such, these values are

not intended for tobacco products. Nonetheless, based on the data from oral exposure studies and the

estimated exposures to ingredients made by the applicant from the use of VERVE®, the information

supported the determination that the added ingredients were not of toxicological concern given the

margins of exposure in relation to oral toxicity studies derived from published reference values. A

literature review based on published best practices for systematic reviews (Institute of Medicine [IOM],

Cochrane, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA]) was also

provided by the applicant, including chemical and nonclinical endpoints related to potential health

8. 8 GRAS designation does not apply to tobacco products.
PM0000470 – PM0000473 Page 26 of 104

effects. No novel health or toxicological concerns for VERVE® were identified as a result of this

systematic literature review conducted by the applicant.

2.3.1. Harmful and Potentially Harmful Constituents

The applicant also measured nine analytes included on the abbreviated HPHC list for smokeless tobacco

products A toxicological assessment of the VERVE® products can be greatly informed by the

measurement of HPHCs in the products and comparison of those values with other tobacco products,

primarily cigarettes and snus. The chemistry review provided evaluation of the applicant’s HPHC

measurements; comparisons across tobacco products are presented in Appendix Tables 16 and 17.

Evaluation of HPHCs in the New Products

The applicant claimed that because the new products do not meet the definition of a “smokeless

tobacco product” and in the absence of specific guidance, the applicant only evaluated constituents in

the new products that are listed in the abbreviated list of HPHCs for smokeless tobacco from the 2012

Draft Guidance.9 This is a reasonable approach as HPHCs listed for combustible cigarettes are not

expected in the VERVE® products. The applicant provided complete datasets for nine HPHCs from the

FDA abbreviated HPHC list for smokeless tobacco products that includes nicotine (total and free),

cadmium, arsenic, benzo[a]pyrene (B[a]P), formaldehyde, acetaldehyde, crotonaldehyde, NNN, and

NNK. The applicant also provided measurements for pH, portion weight, NAT, and NAB. The applicant

stated that the portion weight was used to convert the measured per-gram quantity to the reported

per-portion quantity in cases where a single piece is not used for analysis.

HPHC Experimental Design

The applicant also provided HPHC measurements using the same three production lots of the new

products employed in the stability studies. Each production lot was stored in the respective packaging at

(b) (4) (namely long-term conditions) and tested in seven 

replicates (n=7) at three different time points. The first time point was conducted once the samples

were received by the testing laboratory, between 7 and 30 days (termed 1 month or T=1M), postmanufacturing. Samples were stored in an environmental chamber at(b) (4)

(b) (4) and tested at(b) (4) and (b) (4) post-manufacturing. This

information is presented in Appendix Table 18.

HPHC Test Methods

The applicant stated that(b) (4) ), an ISO

17025:2005 accredited laboratory, conducted chemical and physical testing at Altria’s Center for

Research and Technology (CRT) in Richmond, VA, using the following analytical methods:

•

•

•

•

9. 9 Draft Guidance for Industry (2012).

https://www.fda.gov/downloads/TobaccoProducts/Labeling/RulesRegulationsGuidance/ucm297828.pdf

(b) (4)

(b) (4)

(b) (4)

(b) (4)
PM0000470 – PM0000473 Page 27 of 104

•

•

•

The PMTAs included quantitative protocols, validation summaries, validation reports, and relevant work

instructions necessary to evaluate the analytical methods used. The applicant implemented a

retrospective data verification of the raw data and identified incorrect entries in the validation reports

for TSNAs, cadmium and arsenic (supplemental). On May 8, 2019, the applicant submitted an

unsolicited amendment, PM0000512, correcting the information in the validation reports. From a

chemistry perspective, the information provided about the analytical testing methods is acceptable.

Evaluation of HPHC Test Data for the New Products 

The PMTAs included the summaries of measured HPHCs, individual HPHC measurements, and the limits 

of quantitation (LOQs) for each analytical method and product type.

The mean average and standard deviation across the three production lots of the new products for each

of the measured HPHCs at each time point are presented in Appendix Table 18. In the chemistry review,

the mean average and standard deviation across the three production lots of the new products are

calculated based on measured HPHC values that are at least equal to or above the method LOQ. For

measured values below the method LOQ, the data are omitted in determining the mean average and

standard deviation. If only one data point is detected at or above LOQ, no standard deviation is

reported. The quantity of each HPHC is expressed in milligrams per portion (piece) of product

(mg/portion) and % RSD (across lots and replicates) above 20% are in bold text in Appendix Table 18.

The relative change (%) in HPHC levels at time points T=6M and T=12M compared to T=1M is also

included.

Each HPHC is discussed below. This discussion includes the measured levels in the VERVE® products,

both those presented by the applicant (at 1M, 6M and 12M) and those measured by STL. The HPHC

levels in comparison to cigarette smoke, smokeless tobacco, and NRT are also presented in each section,

when applicable. The applicant provided data for three comparator products (Nicorette Fresh Mint

Gum, General Snus, and Marlboro 100’s Box cigarettes) expressed in amount per portion (Appendix

Tables 15 and 16). The chemistry review also used internal FDA data for other smokeless tobacco

products as a comparator for the new products (Appendix Table 17). The product stability of nicotine

and nicotine degradation and impurity is also discussed here, as well as previously in section 2.2.6 of this

review. The toxicological potential of these HPHCs in the VERVE® products, especially in comparison to

cigarettes, is discussed below.

Acetaldehyde - A decrease in acetaldehyde over time was seen in the VERVE® Discs products at both 6M

and 12M compared to 1M (0.06-0.51 mg/portion below 1M levels). However, an increase in

acetaldehyde was seen in the VERVE® Chews products at both 6M and 12 M, 30-90% (0.1-0.27

mg/portion). The amount of acetaldehyde measured in VERVE® Discs and Chews products is 94% less

than acetaldehyde measured in General Snus and > 99% less than acetaldehyde measured in cigarettes

(Appendix Table 16).

Arsenic - Over the 12-month testing period, arsenic was not detected in the VERVE® Discs products.

Arsenic is one of only two HPHCs for which the applicant’s comparator data show higher levels in the

VERVE® Chews; the arsenic level is higher in the VERVE® Chews by 114% (12.86 ng/portion) compared to

Marlboro 100’s Box cigarettes on a per-portion basis. However, when normalized to ng/g of product

(b) (4)

(b) (4)

(b) (4) t
PM0000470 – PM0000473 Page 28 of 104

(wet weight basis [WWB]), the level of arsenic detected is close to the level of arsenic measured in the

comparator cigarettes (↑2% or 0.21 ng/g). The mean arsenic level in the VERVE® Chews measurement

from STL was 14% higher than the mean level in the PMTAs. This equates to a 12% or 1.32 ng/g higher

arsenic level in the VERVE® Chews products reported by STL compared to Marlboro 100’s Box cigarettes.

However, the arsenic level reported by STL in the VERVE® Chews products is lower than the measured

levels in Nicorette Gum, General Snus (Appendix Table 16) and FDA internal data for chewing tobacco,

dissolvables, moist snuff, and snus tobacco products with similar daily usage patterns.

The toxicology review addressed the potential for toxicological concern from the increased arsenic in 

the VERVE® Chews products as compared to Marlboro 100’s Box cigarettes. Arsenic is a constituent with

both non-cancer toxicity and carcinogenic potential, including for oral cancer (1, 2).

Non-cancer toxicity

Arsenic exposure is evaluated in terms of reference dose (RfD) and daily exposure to arsenic through

diet and water consumption. U.S. EPA set the arsenic standard for drinking water at 10 ppb (0.01 mg/L

(3)). FDA CFSAN set an action level of 10 ppb, or 10 ug/kg, for arsenic in apple juice (1). This level was set

based on chronic exposure to the toxicant (0-50 years) and urinary tract and lung cancer disease rates.

The previous action level of 23 ppb was determined based on short-term exposure and non-cancer

endpoints.

The oral toxicity RfD for arsenic estimated by US EPA is 3.0x10-4 mg/kg/day. This RfD is based upon

possible cardiovascular and dermal toxicities (2). Conservatively assuming consumption of one tube of

VERVE® Chews per day (12 pieces; 1 piece = 1 portion) with the upper bound of reported arsenic as

24.16 ng/portion, or 290 ng arsenic per tube, the estimated daily exposure level is 4.0x10-7 mg/kg/day

for a 60 kg individual (750 times lower than the RfD), per the following formula:

Daily exposure on a per kg body weight basis [mg/(kg/day)] =

[Daily exposure to ingredient/60 kg]

Mean daily intake of arsenic through diet in adults has been estimated to range between 0.0167 and

0.129 mg/day (WHO, 2015). For an individual who weighs 60 kg, this indicates an exposure rate of

2.8x10-4 to 2.2x10-3 mg/kg/day. In contrast, the arsenic exposure level in VERVE® Chews based on the

upper bound of arsenic measurement is 4.0x10-7 mg/kg/day. Therefore, despite the increase compared

to Marlboro 100’s Box cigarettes, arsenic levels in VERVE® Chews compared to cigarettes do not raise

non-cancer toxicological concerns.

Carcinogenicity

Higher levels of arsenic were measured in the VERVE® Chews products when compared to combusted

cigarettes. However, exposure to cigarette smoke and oral nicotine or smokeless tobacco products is

through different routes (oral vs. inhalation). There may be differences in HPHC bioavailability and

target tissues for carcinogenic effects associated with user exposures to carcinogens from cigarettes

versus the VERVE® Chews products, and therefore it is likely that users would exhibit different biological

responses to exposure to a given constituent from the VERVE® products or cigarettes. This aspect does

introduce some uncertainty of the risk from exposure to arsenic in inhaled versus oral tobacco products.

Furthermore, the applicant notes that an average use of VERVE® Chews is 6 per day versus 12, which

comprises a whole tube. Thus, the overall daily usage of the product may be less than an entire tube

over the time a user consumes the product. Daily variation in product use can also contribute

uncertainty regarding the exposure to arsenic, as can the form of the oral tobacco product or NRT (e.g.,

chew, disc, gum), which can impact arsenic levels and hazards presented by each product.
PM0000470 – PM0000473 Page 29 of 104

U.S. EPA IRIS gives an oral slope factor of 1.5 mg/kg/day for arsenic (2). The estimated daily exposure

level of arsenic from the highest level of arsenic measured in an entire tube of VERVE® Chews is 4.0x10-7

mg/kg/day for a 60 kg individual. Multiplying the oral slope factor by the estimated daily exposure level

of arsenic in VERVE® Chews results in a lifetime cancer risk of 6.0x10-7. Conversely, if a tobacco user

consumed the same number of Nicorette® Fresh Gum (756.8 ng arsenic, so 1.26x10-5 mg/kg/day for a 60

kg individual), the lifetime cancer risk is 1.9x10-5. Thus, according to this calculation, the lifetime cancer

risk from Nicorette® Fresh Gum is 32 times higher than that of VERVE® Chews.

The HPHC data submitted by the applicant also demonstrates potential for reduced toxicant exposure

from the VERVE® products compared to the comparator products (Nicorette® Gum, General Snus, and

Marlboro 100’s Box cigarettes), given the low levels or absence of some constituents (Appendix Table

15). Additionally, when the applicant compared arsenic levels in VERVE® Chews to those in General Snus

and Nicorette® Gum (which are through oral exposure), the levels of arsenic in VERVE® Chews were

lower on a per-product basis by 51% and 68%, respectively. When compared to internal FDA data

(Appendix Table 17), the levels of arsenic were lower (as calculated by the chemistry reviewer) in

VERVE® Chews than in smokeless tobacco products as follows (Appendix Table 17):

• Chewing Tobacco: VERVE® Chews ↓97% in arsenic

• Dissolvables: VERVE® Chews ↓94% in arsenic

• Moist Snuff: VERVE® Chews ↓ 95% arsenic

• Snus: VERVE® Chews ↓91% arsenic

In spite of the differences in exposure routes between the new products and cigarettes and considering

the available epidemiological data on risks of lung cancer and respiratory disease from smokeless

tobacco products compared to combusted cigarettes (4), it is reasonably likely that users are not subject

to excess risk from the levels of arsenic present in the new VERVE® products. Therefore, despite the

higher arsenic levels compared to Marlboro 100’s Box cigarettes, arsenic levels in VERVE® Chews do not

raise toxicological concerns.

Benzo[a]pyrene – Over the 12-month testing period, B[a]p was not detected in any of the VERVE®

products. Benzo[a]pyrene is measured to be 21 ng/g in cigarettes (Appendix Table 16)

Cadmium – Over the 12-month testing period, cadmium was not detected in the VERVE® Chews

products. In the VERVE® Discs Blue Mint there was an increase of 42% (3.6 ng/portion) at 12M. In the

VERVE® Discs Blue Mint at 6M and the VERVE® Discs Green Mint at both 6M and 12M, there was a

decrease in cadmium over time of 26-29% (2.11-2.17 ng/portion). From a chemistry perspective, the

42% increase in cadmium (12M, VERVE® Discs Blue Mint) may be due to the variability in the analytical

measurements, where the %RSD is 57% (see bolded text in Appendix Table 18). The amount of

cadmium measured in VERVE® Discs and Chews products is 87% less than cadmium measured in General

Snus and 80% less than cadmium measured in cigarettes (Appendix Table 16).

Crotonaldehyde – Over the 12-month testing period, crotonaldehyde was not detected in any of the

VERVE® products. Crotonaldehyde is measured in General Snus and Marlboro 100’ Box at

concentrations of 0.69 μg/g and 59 μg/g, respectively (Appendix Table 16).

Formaldehyde – A decrease in formaldehyde was seen in the VERVE® Discs products at both 6M and

12M ranging from 35-81% (0.3-0.7 mg/portion) below 1M levels. A reduction of 16% (0.07 mg/portion)

at 6M was seen in the VERVE® Chews Blue Mint, and a reduction of 17-18% (0.1-0.11 mg/portion) was

seen in VERVE® Chews Green Mint at 6M and 12M. These changes over time do not cause concern for

public health because formaldehyde is decreased. Moreover, the amount of formaldehyde measured in
PM0000470 – PM0000473 Page 30 of 104

VERVE® Discs and Chews products is 70% less than formaldehyde measured in General Snus and 98%

less than formaldehyde measured in cigarettes (Appendix Table 16).

Nicotine – When comparing 12M or 6M to 1M, free nicotine decreased over time in the VERVE® Discs by

24-44% (0.14-0.25 mg/portion). Free nicotine in the VERVE® Chews also decreased over time, by 40-80%

(0.02-0.06 mg/portion). Nicotine is the other HPHC for which levels are higher according to the

applicant’s comparator information; total nicotine higher by 36% (0.73 ng/g) in the VERVE® Discs

products compared to Nicorette gum. However, free nicotine is lower by 45% in the VERVE® products

compared to Nicorette gum, along with 22% lower pH in the VERVE® products compared to Nicorette

gum. When compared to smokeless tobacco, the free nicotine is higher by 1486% (1.04 mg/g) in the

VERVE® Discs compared to chewing tobacco, along with 29% (1.76) higher in pH in the VERVE® Discs in

comparison with chewing tobacco.

For the VERVE® Discs products, the pH and free nicotine are higher by 9% (0.67) and 110% (0.9 mg/g),

respectively, as measured by STL compared to the levels determined by the applicant. This equates to

36% (2.24) higher pH and 2357% (1.65 mg/g) higher free nicotine in the VERVE® Discs products tested 

by STL compared to FDA internal data for chewing tobacco products. However, the estimated free 

nicotine based on STL’s test data is comparable to or lower compared to the levels for General Snus and 

FDA internal data for dissolvables, moist snuff, and snus Error! Reference source not found.tobacco

products. Free nicotine is a calculated value and depends on pH and total nicotine. A slight change in pH

can significantly impact the amount of free nicotine, which is seen these cases. While pH in smokeless

tobacco products is generally controlled, pH is not controlled in VERVE® products. The estimated free

nicotine in the VERVE® Discs products is already higher by 1486% compared to chewing tobacco. With

the measured pH in VERVE® Discs higher in STL measurements (8.34) than in the applicant submitted

measurements ( ), this made the difference in STL’s free nicotine even higher (2357%) compared to

chewing tobacco. However, this increase in free nicotine does not translate into an increase in addiction

liability. The abuse liability aspect of the nicotine levels in the VERVE® products is addressed in section

2.4 of this review.

The toxicology review addressed the potential for nicotine poisoning with the VERVE® products. The

applicant contracted studies to assess that the packaging of VERVE® Chews and Discs complied with

child-resistant packaging to avoid potential accidental ingestion. The packaging was found to be

compliant with the current Consumer Product Safety Commission (CPSC) standards and protocols for

poison prevention packaging set forth in the Code of Federal Regulations Title 16, Part 1700. McGuigan

(2003) has reported that the pediatric lower limit of lethality is 1 mg/kg nicotine by oral ingestion (5, 6).

Mayer et al. (2014) provided an estimate of the fatal dose in adults as 0.5-1 g of ingested nicotine, or a

weight-based oral dosage (LD50) of 6.5-13 mg/kg (8, 9) (rounded upward to 7-14 mg/kg; 7, 9). To

include children <6 years old in this range, the range was extended to the lower limit of 1 mg/kg, or a

final range of 1-14 mg/kg. Ingestion of an entire tube of VERVE® Chews or Discs could result in nicotine

intakes of 18 and 24 mg of nicotine, respectively. In a 60 kg adult, ingestion of entire tube of VERVE®

Chews and Discs could result in nicotine exposures of 0.3 and 0.4 mg/kg body weight, respectively. Using

an estimated child weight for ages 3 to <6 years as 18.6 kg, this could result in exposures of 0.97-1.29

mg/kg body weight (8), assuming 100% absorption of the entire tube of chews or discs which could

result in a lethal dose of nicotine to children. However, because nausea and vomiting are early and

frequent symptom of nicotine poisoning, it is unlikely that 100% of the nicotine would be extracted

through accidental ingestion (10); If a child did ingest an entire tube, the nicotine that would enter the

system would likely cause the child to vomit before the entire nicotine dose could be absorbed (10,11).

If a child were to consume two VERVE® Chews or Discs, a more likely scenario than ingestion of an entire 

tube due to the products’ child-resistant packaging, this could result in exposure of 3 mg of nicotine or

0.16 mg/kg body weight of nicotine. Given the presence of the child-resistant packaging and the amount
PM0000470 – PM0000473 Page 31 of 104

(b) (4)

of nicotine available in an entire tube of discs or chews, death from accidental ingestion would be

unlikely. In conclusion, it is unlikely that a lethal dose of nicotine would be consumed with VERVE®

products by either the intended adult user population or in accidental ingestion in children.

NNK - Over the 12-month testing period, NNK was not detected in the VERVE® Chews products. In

VERVE® Discs Green Mint, NNK decreased at 12M by 11% (0.04 ng/portion). Compared to cigarettes

(145 ng/g) and General Snus (304 ng/g), NNK measured in VERVE® Discs is greatly reduced (0.74 ng/g;

Appendix Table 16)

NNN - Over the 12-month testing period, NNN was not detected in the VERVE® Chews products. In

VERVE® Discs Blue Mint there was an increase in NNN of 12-44% (0.05-0.29 ng/portion) at 6M and 12M;

in VERVE® Discs Green Mint, there was an increase of 17% (0.21 ng/portion) at 6M. From a chemistry

perspective, the 17% increase in NNN (12M, VERVE® Discs Green Mint) also may be due to the variability

in the analytical measurements, where the %RSD is 40-55% for NNN (see bolded text in Appendix Table

18). Compared to cigarettes (284 ng/g) and General Snus (1080 ng/g), NNN measured in VERVE® Discs is

greatly reduced (0.74 ng/g; Appendix Table 16)

The chemistry review showed (Appendix Tables 15 and 16) that HPHC exposure in the new products can

be reduced by 25-100% compared to Nicorette gum, General Snus, and cigarettes (Marlboro 100’s Box),

except for the arsenic and free and total nicotine, as discussed above. Because the use of the VERVE®

products is similar to other smokeless tobacco products, a comparison is also made of the measured

HPHC levels in the new products to HPHC levels found in chewing tobacco, dissolvables, moist snuff, and

snus (Appendix Table 17). The results indicate that HPHC levels in the new products can be reduced by

2-100% compared to other smokeless tobacco products, except for free nicotine as discussed above.

Based on the measured HPHCs in the VERVE® Discs and Chews and the comparator products, nicotine

and arsenic are the only HPHCs that increase over time in the Discs or Chews and are higher in

comparison to at least one product. Neither the toxicology nor the BCP review identified these increases

as a toxicological or abuse liability concern.

2.3.2 Non-Nicotine Ingredients

The applicant submitted information on the non-nicotine ingredients in a TPMF (b) (4) which

was reviewed by both the chemistry and the toxicology reviewers. The ingredients are presented in

Appendix Table 13. Literature reviews were included to address potential toxicity of the non-nicotine

ingredients.

The applicant references the TPMF for the quantitative formulations of all four products. The applicant

states that the primary ingredients in all the new products are tobacco-derived nicotine, polymer, nontobacco cellulose fiber, flavorings, texture modifier, binder, and colorant. These ingredients are

composed of materials commonly used in and generally recognized as safe (GRAS) in food products.

Although GRAS is not applicable to tobacco products, a consideration of the underlying data used in the

assessments for oral exposures to these ingredients can be informative for the toxicological evaluation

of ingredients in oral tobacco products, such as in these PMTA Reports. Additionally, the VERVE® Discs

products contain a (b) (4) ),

while the VERVE® Chews products contain an artificial sweetener, (b) (4) .

, is the primary component of

the VERVE® Discs products base material and is used for(b) (4) for the Discs pieces. Based

on Table 6.1-12 in Section 6.1.3.6.2 of the PMTAs, the VERVE® Discs products contain approximately(b) (4)

mg/piece of(b) (4) or 55% by weight relative to the weight of each Disc. Over time,(b) (4) 
PM0000470 – PM0000473 Page 32 of 104

(b) (4)

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

(b) (4)

materials may hydrolyze at excessive temperatures to the corresponding precursor diamines (i.e., 2,4- 

toluene diisocyanate, 2,4-diamino toluene), which have been reported in animal studies to significantly 

increase the incidence of tumors in the liver and mammary glands (12-14). Precursor diamines are not

expected to be present when this(b) (4) is chewed. The applicant provided gas

chromatography/massspectrometry (GC/MS) analyses of the(b) (4) (see Appendix

7.5.1-125 of the PMTAs) to determine the presence of the precursor diamines and the results show no

detectable levels of 2,4-toluene diisocyanate and 2,4-diamino toluene. In medicated chewing gum

formulations, elastomers and rubbers are generally present at a range of 15-45% (15). In addition, the

safety data sheet indicates that(b) (4) is not carcinogenic as defined by the International Agency

for Research on Cancer, the National Toxicology Program, and the Occupational Safety and Health

Administration (OSHA); and is also not hazardous under the criteria of the OSHA HaxCom 2012 (see

Appendix 7.4.1-129 of the PMTAs; 16). Thus, from a chemistry perspective, the level of(b) (4) in 

the VERVE® Discs products at 55% by weight ((b) (4) mg/piece) does not raise concerns.

The manufacturer of(b) (4) , indicates that this material meets the

requirements of the FDA-modified ISO 10993, Part 1 “Biological Evaluation of Medical Devices” tests

with human tissue contact time of 30 days or less (17). For example, aromatic polyurethanes based on

diphenylmethane diisocyanate (MDI) may hydrolyze and produce methylene dianiline (MDA) and, as

such, this needs to be considered in any end-use application. Per the U.S. Agency for Toxic Substances

and Disease Registry (18), no data on the oral absorption of MDI are available. However, 84 cases of

jaundice occurred following accidental ingestion of MDA in contaminated whole-meal bread in 1965 ,

but no MDA exposure levels were reported therein (19). WHO reports that the health endpoints of most

concern for MDA are occupationally induced respiratory diseases (20). The corresponding precursor

diamines (i.e., 2,4-toluene diisocyanate, 2,4-diamino toluene) have been reported in animal studies to

significantly increase the incidence of tumors in the liver and mammary glands (21, 14). However, given

that precursor diamines are not detectable in VERVE® products,(b) (4) ® as a thermostable base material

in the new products is therefore not of toxicological concern.

is commonly used as a binder, emulsion stabilizer, and fixative, and is a homopolymer

of (b)(4) (23).(b) (4) is listed as a Group 3 chemical (not classifiable) based on findings

of inadequate evidence of carcinogenicity in animals and no available human data (24). FDA permits use

of (b)(4) homopolymers and copolymers as components of adhesives, resinous and

polymeric coatings, and paper or paperboard when intended for contact with food (21 CFR 172.615).

Notably, 21 CFR 172.615 is not applicable to tobacco products. However, consideration of the

underlying data used to determine safety for oral exposures to ingredients listed in 21 CFR 172.615 can

be informative for the toxicological evaluation of ingredients in oral tobacco products, such as in these

PMTA Reports. Further, the ingredients literature review provided by the applicant (Section 7.5.1 of the

PMTAs) indicates that a dose of 0.2 ml of 1.25% (b) (4) in ethanol saline did not alter the

intact oral epithelium of hamsters in a 6-week study (25). No irritation was reported in human

volunteers exposed to a 50% concentration of aqueous polyvinyl solution in an occlusive skin 

irritation test (26). If the new products were to be accidentally ingested, this would not be of 

toxicological concern as the (b) (4) ®, and cellulose would not be absorbed in the gastrointestinal

tract and would be eliminated via defecation (16, 24).

Together, this evidence indicates that(b) (4) is not of toxicological concern as a base material

in the VERVE® products.

is a high-intensity sweetener that is 200-300 times sweeter than sucrose (table sugar).

Miao et al. (27) reported 0.13% of(b) (4) in chewing gum, 0.0076-0.013% in snus, and 0.27-0.82% in
PM0000470 – PM0000473 Page 33 of 104

(b) (4)

a candy mint lozenge. According to 21 CFR 172.804, the recommended limit for(b)(4) used as an

additive is no more than 0.5% by weight of ready-to-bake products or finished formulations, prior to

baking. In chewing gum, the level of artificial sweeteners range is 0.05-0.5% by weight. Based on Table

6.1-12 in Section 6.1.3.6.2 of the PMTAs,(b)(4) is present in the VERVE® Chews products at (b) (4)

mg/piece (0.15%), which is less than the recommended limit for a food additive in ready-to-bake

products or finished formulations, and within the range used in chewing gum and a candy mint lozenge.

The highest potential(b)(4) exposure per tube of the new products is (b) (4) mg/person/day or (b) (4)

mg/kg bw/day. The estimated potential exposure to(b)(4) from the new products is approximately

62 times lower than the acceptable daily intake (ADI; 40 mg/kg) established by Joint FAO/WHO Expert

Committee on Food Additives (JECFA) and 78 times lower than the FDA ADI of 50 mg/kg. Thus, from

chemistry and toxicology perspectives, the amount of(b)(4) used in the VERVE® Chews products

does not raise a concern.

All of the new products contain menthol characterization flavor in a form of or

in combination with either or

of the PMTAs, small amounts of

or both. Based on Table 6.1-12 in Section 6.1.3.6.2

mg/piece) are used in the VERVE® Chews Blue Mint

and VERVE® Chews Green Mint products. According to the TPMF, the total quantity of menthol

discussed in this review is the total amount of and menthol weight fraction present in other

menthol-containing ingredients. Chen et al., 2010 evaluated 25 sub-brands of mentholated and

nonmentholated smokeless tobacco products and the reported menthol levels range from 0.85 to 5.25

mg/g (28). Moreover, Ai et al., 2016 evaluated 45 cigarette products (23 mentholated and 22

nonmentholated) available in the U.S. market and the menthol content in mentholated cigarettes

ranges from 3.6 to 16.61 mg/g (2.9 to 19.6 mg/cig; 29). The menthol levels present in the VERVE® Chews

Blue Mint, VERVE® Chews Green Mint, and VERVE® Discs Green Mint products are comparable to those

reported in all smokeless tobacco products and mentholated cigarettes. However, the VERVE® Discs

Blue Mint product contains higher amount of menthol compared to the levels reported in mentholated

cigarettes (27%) and smokeless tobacco products (302%). Menthol has the potential to be a permeation

enhancer and could increase the uptake of HPHCs. However, as the HPHCs in the VERVE® products are

generally lower than selected comparators to represent the current U.S. tobacco market, it is unlikely

that the addition of menthol in the VERVE® products presents a toxicological concern.

Ingredients for generation products of the VERVE® Discs Blue Mint

The PMTAs included studies conducted using prototypes or previous-generation products of VERVE®

Discs Blue Mint. The applicant provided the CAS number, quantities, and functions for each generation

(b) (4) , Gen 1, Gen 1A, Gen 2 (VBM-FG2), and Gen 3) of VERVE® Discs

Blue Mint in Exhibit #85 of the EIR. As noted in the “additional information” section of the EIR,(b) (4)

The Gen 3 product is the current new product referenced as VERVE®

Discs Blue Mint in the PMTAs. The EIR also indicated that the difference between(b) (4)

and the current VERVE® Discs Blue Mint product is that(b) (4)

.
PM0000470 – PM0000473 Page 34 of 104

The chemistry review identified a deficiency in the information on the ingredients as presented in the

TPMF. The deficiency is presented in Section 2.2.8 of this review. As TPL, I do not recommend that this

deficiency be communicated to the TPMF owner or applicant. Scientific review of the single ingredients

and individual components of(b) (4) indicate that none of the ingredients in the new tobacco

products are present in amounts that raise toxicological concerns.

2.3.3 Summary of Toxicological Findings

The applicant states that an assessment of the toxicological risks of the non-tobacco ingredients used to

manufacture the new products suggest no substantial health risks. USP-grade tobacco-derived nicotine

in the new products conveys health risks that are likely comparable to those of NRT gum. The toxicology

review provides this summary of key findings:

• The data provided by the applicant for the four VERVE® products do not raise toxicological

concerns because of overall reduction of exposure to HPHCs compared to information available

for other tobacco products that comprise the current U.S. tobacco market.

• This determination was made in the absence of original toxicology study data; extensive

literature reviews, health assessments, and ingredient assessments provided by the applicant

support that the VERVE® products will not raise concern from the toxicological perspective.

• Arsenic levels in VERVE® Chews were lower by 51% and 68% than those of comparator

smokeless tobacco products with similar daily usage patterns (General Snus and NRT product

Nicorette® Gum, respectively).

• Arsenic levels in VERVE® Chews were lower than those of other smokeless tobacco products

(chewing tobacco (↓97), dissolvables (↓94), moist snuff (↓95), snus (↓91%)) based on 

FDA internal data and as calculated in the chemistry review.

• While there was a higher level of arsenic in VERVE® Chews compared to Marlboro 100’s Box

cigarettes, the highest arsenic exposure level in VERVE® Chews was estimated to be lower

(4.0x10-7 mg/kg/day) than USEPA RfD (3.0x10-4 mg/kg/day).

• The non-tobacco ingredients are identified by the applicant as food grade, GRAS, or

biocompatible medical grade. Although these designations are not applicable to ingredients

used in tobacco products, we note that exposure to these ingredients from use of the new

tobacco products is tens to thousands of times lower than the toxicity reference values for these

ingredients.

• Based on the underlying toxicity data that support the reference values for these ingredients,

there is no toxicological concern.

• Due to minimal HPHC exposure, the new products likely present lower public health concern for

tobacco-related diseases than cigarette smoking or other smokeless tobacco products, and the

(b) (4) 
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health effects of the candidate products would likely be similar to those of current NRT

products, including nicotine gum.

• If used exclusively instead of smokeless tobacco products, VERVE® products offer the potential

for reduction in oral cancer risk. TSNAs, potent tobacco carcinogens, are reduced greater than

100-fold in the new tobacco products compared to cigarettes and smokeless tobacco.

• From a toxicological perspective, the VERVE® Chews and VERVE® Discs PMTAs do not raise

concerns with respect to issuing marketing orders for these products.

As TPL, I agree with the toxicology review conclusion. Based on the ingredients and the measured HPHCs

in the VERVE® products, if a smoker were to significantly decrease or eliminate their CPD and replace

that with the VERVE® products, this would likely present lower public health concern for tobacco-related 

diseases than cigarette smoking. If a polytobacco user were to switch to the VERVE® products from a

smokeless tobacco product, this too has the potential of lower HPHC exposure and lower potential for

some tobacco-related diseases. Based on the ingredients and HPHCs, the health effects of the VERVE®

products would likely be very similar to those of current NRT products, including nicotine gum.

2.4. Individual Health Impact

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

The applicant submitted two abuse liability studies:

1. Characterization of nicotine exposure profiles and subjective measures of VERVE® Discs

products for abuse liability determination in adult smokers relative to combustible cigarettes

and nicotine gum

2. Characterization of nicotine exposure profiles and subjective measures of products currently

marketed as VERVE® Chews for abuse liability determination in adult smokers relative to

combustible cigarettes and nicotine gum

The PMTAs also included a study providing analysis of the subjective measures of withdrawal and direct

effects of the product that were obtained from the two studies above:

3. Comparisons of subjective measures on tobacco/nicotine withdrawal and direct effects of

product from two clinical studies

The BCP review also evaluated three studies that looked at use patterns of VERVE® products:

4. Six-week actual use study of oral tobacco-derived nicotine products currently marketed as

VERVE® Discs and VERVE® Chews

5. VERVE® Discs 12-Week extended home use test Final Report —PowerPoint presentation

6. ALCS In-Market Adult Consumer Study (MACS): Oral tobacco-derived nicotine products currently

marketed as VERVE® products

Finally, the BCP review also looked at the applicant’s literature review and the applicant’s studies of

other oral products that were prototypes for the products that are the subject of the PMTAs:

7. A randomized, controlled, parallel group pilot clinical study to determine changes in biomarkers

of exposure (BOE) in adult smokers allowed ad libitum VBM-FG2 disc use relative to adult

smokers not allowed VBM-FG2 disc use

8. Characterization of plasma nicotine profile from a single-use of two prototype oral tobacco test
PM0000470 – PM0000473 Page 36 of 104

products(b) (4) in adult smokers

The general design of the studies reviewed by BCP are provided below. The two abuse liability studies

were similar in design, with one evaluating VERVE® Discs and the other evaluating VERVE® Chews.

Characterization of nicotine exposure profiles and subjective measures of VERVE® Discs products for

abuse liability determination in adult smokers relative to combustible cigarettes and nicotine gum

Study Products: VERVE® Discs Green Mint, VERVE® Discs Blue Mint (GEN 3; 1.5 mg nicotine); Nicorette

Fresh Mint gum nicotine polacrilex gum (2 mg nicotine) and the participant’s UB cigarette were

reference products.

Study Population: Participants were 28 healthy male (n=19) and female (n=9) adult self-reported 

exclusive smokers of combusted cigarettes who reported consumption of 10-20 CPD for at least 1 year.

Participants were aged 21-65 years and provided a positive urine cotinine test at screening.

Study Design: This study used an open-label, randomized, four-way crossover design to evaluate PK

measures, subjective measures, and product use behaviors in response to use of VERVE® Discs Green

Mint, VERVE® Discs Blue Mint, subjects’ UB cigarettes, and Nicorette gum. The study characterized use

behavior of VERVE® Discs and compared nicotine PK profiles and subjective effects of VERVE® Discs with

UB cigarettes and Nicorette gum. The study lasted 10 days. Participants were asked to use the nicotine

disc products at home on Study Days -6, -5, -4, -3, and -2 as a trial period during which they reported the

number of VERVE® Discs and UB cigarettes used per day. They then used the VERVE® Discs, UB

cigarettes, and Nicorette gum under controlled conditions in the laboratory on Study Days 1-4, during

which PK and subjective measures were collected. Participants used each of the VERVE® products and

comparators once, and product order (Study Day) was randomized. In the laboratory, participants

smoked one of their UB cigarettes with 10 inhalations at 30-sec intervals, used one VERVE® Disc for 30

min, or "chewed and parked" one piece of nicotine gum for 30 min according to the product's

instructions for use. FDA’s statistics review included an evaluation of this study and concluded that the

linear mixed model used in the analyses was appropriate for the study objectives. The statistics review

found that despite differences in the sample size for the study groups, the study was sufficiently

powered to detect a range of clinical differences for the PK outcomes at the indicated significance level.

The secondary endpoints on subjective measures were analyzed using summary descriptive statistics

without statistical comparisons.

Relevant Study Outcomes: Primary endpoints included nicotine Cmax from blood plasma samples,

maximum reduction in subjective Urge to Smoke, and maximum subjective ratings of how pleasant the

product was. Secondary endpoints included nicotine Tmax and AUC from start of product use to 180 min

or last measurable concentration (AUC0-180), subjective measures of tobacco/nicotine withdrawal during

product use using a visual analogue scale (VAS), maximum reduction in withdrawal from pre- to postproduct use, subjective responses to the Direct Product Effects Questionnaire during product use

measured using a VAS, maximum responses of Direct Product Effects, subjective responses to the Use

the Product Again Questionnaire using a VAS both immediately after product use and 180 min after

product use, number of test products used during the trial period, time product was in mouth during the

trial period, number of CPD during the trial period, and subjective responses to the modified Cigarette

Evaluation Scale (mCEQ) one day before product use.

Characterization of nicotine exposure profiles and subjective measures of products currently marketed as

VERVE® Chews for abuse liability determination in adult smokers relative to combustible cigarettes and

nicotine gum
PM0000470 – PM0000473 Page 37 of 104

Study Products: VERVE® Chews Green Mint, VERVE® Chews Blue Mint (1.5 mg nicotine); Nicorette Fresh

Mint gum nicotine polacrilex gum (2 mg nicotine) and the participant’s UB cigarette were reference

products.

Study Population: Participants were 28 healthy male (n=18) and female (n=10) adult self-reported 

exclusive smokers of combusted cigarettes who reported consumption of 10-20 CPD for at least 1 year.

Participants were aged 21-65 years and provided a positive urine cotinine test at screening.

Study Design: This study used an open-label, randomized, four-way crossover design to evaluate PK

measures, subjective measures, and product use behaviors in response to use of VERVE® Chews Green

Mint, VERVE® Chews Blue Mint, subjects’ UB cigarettes, and Nicorette gum. The study characterized use

behavior of VERVE® Chews and compared nicotine PK profiles, nicotine delivery, and subjective effects 

of VERVE® Chews with UB cigarettes and Nicorette gum. The study lasted 10 days. Participants used the

nicotine chewable products at home on Study Days -6, -5, -4, -3, and -2 as a trial period during which

they reported the number of VERVE® Chews and UB cigarettes used per day. They then used the VERVE®

Chews, UB cigarettes, and Nicorette gum under controlled conditions in the laboratory on Study Days 1- 

4, during which nicotine PK and subjective measures were collected. Participants used each of the

VERVE® products and comparators once, and product order (Study Day) was randomized. In the

laboratory, participants smoked one of their UB cigarettes with 10 inhalations at 30-sec intervals, used

one VERVE® Chews for 30 min, or "chewed and parked" one piece of nicotine gum for 30 min according

to the product's instructions for use. FDA’s statistics review concluded that the linear mixed model used

in the analyses was appropriate for the study objectives and, despite differences in the sample size for

the study groups, the study was sufficiently powered to detect a range of clinical differences for the PK

outcomes at the indicated significance level. The secondary endpoints for subjective measures were

analyzed using summary descriptive statistics without statistical comparisons.

Relevant Study Outcomes: Primary endpoints included nicotine Cmax from blood plasma samples,

maximum reduction in subjective Urge to Smoke, and maximum subjective ratings of how pleasant the

product was. Secondary endpoints included nicotine Tmax and AUC0-180, subjective measures of

tobacco/nicotine withdrawal during product use using VAS, maximum reduction in withdrawal from preto post-product use, subjective responses to the Direct Product Effects Questionnaire during product

use measured using a VAS, maximum responses of Direct Product Effects, subjective responses to the

Use the Product Again Questionnaire using a VAS both immediately after product use and 180 min after

product use, number of test products used during the trial period, time product was in mouth during the

trial period, number of CPD during the trial period, and subjective responses to the mCEQ one day

before product use.

A general summary of the subjective measures study is provided below:

Comparisons of subjective measures on tobacco/nicotine withdrawal and direct effects of product from

two clinical studies

Study Products: VERVE® Discs and Chews Green Mint, VERVE® Discs and Chews Blue Mint (1.5 mg

nicotine); Nicorette Fresh Mint gum nicotine polacrilex gum (2 mg nicotine) and the participant’s UB

cigarette were reference products.

Study Design: The secondary endpoints on subjective measures were analyzed using summary

descriptive statistics without statistical comparisons. Therefore, a linear mixed model for analysis of

variance was used to conduct post hoc analyses to compare responses to the subjective questionnaire
PM0000470 – PM0000473 Page 38 of 104

items from the Tobacco/Nicotine Withdrawal and Direct Effect of Product Questionnaires in Study 1 and

Study 2 (listed above).

Relevant Study Outcomes: The primary outcomes included maximum reduction in VAS scores (from

pre- to post-product use) for previously non-analyzed Tobacco/Nicotine Withdrawal and Direct Effect of

Product Questionnaire items. Change scores were compared between the four study products with

scores from UB cigarette and Nicorette gum use.

A general summary of the actual use and in-market survey studies are as follows:

Six-week actual use study of oral tobacco-derived nicotine products currently marketed as VERVE® Discs

and VERVE® Chews

Study Products: VERVE® Discs Green Mint, VERVE® Discs Blue Mint, VERVE® Chews Green Mint and

VERVE® Chews Blue Mint (collectively referred to as VERVE®, except where significant differences in

flavor or format are identified). All products contained approximately 1.5 mg nicotine/piece.

Study Population: Current adult cigarette smokers (n=517) of legal age to purchase tobacco10 up to age

64 years who were not planning to quit in the next 3 months. Participants reported having smoked at

least 100 cigarettes in their lifetime and smoking cigarettes “every day” or “some days” in the past 30

days. Participants who also reported current past 30-day use of other tobacco products (i.e., cigars,

pipe/hookah, dip/snuff, chewing tobacco, snus pouches, other oral tobacco-derived nicotine products,

electronic nicotine delivery systems [ENDS]) were included.

Study Design: A multisite 6-week ambulatory (i.e., at home) observational study of participants who

were randomly assigned to receive VERVE® Discs (n=256) or VERVE® Chews (n=261) in Blue Mint and

Green Mint varieties. Participants completed a two-day at-home product use trial (Phase 1) during

which participants were asked to sample both VERVE® flavor varieties (Blue Mint or Green Mint) for at

least 5 min. Participants were invited to participate in Phase 2 of the study if they used the product as

instructed during Phase 1, and if, in response to questions regarding whether they intended to use

VERVE®, stated they “strongly agree”, “agree”, “somewhat agree” or “somewhat disagree” with the

“Intent to Use” statements.11 Phase 2 of the study involved 6 weeks of ad libitum extended use of the

assigned VERVE® Discs or Chews products. The applicant noted that the data analyses for this

observational study were not hypothesis-driven. Therefore, a formal sample size calculation was not

conducted. No statistical testing of differences between groups was conducted. Instead, data were

analyzed and reported descriptively among the study groups and the total study sample using

proportions and frequency distributions.

Relevant Study Outcomes: The primary outcomes during Phase 1 included a) average ratings of liking

for each VERVE® product, b) average duration of VERVE® used per occasion (minutes), c) number of

VERVE® products used for each variety, d) types and amounts of other tobacco products used each day,

and e) CPD, if participants smoked cigarettes that day. During Phase 2, the primary outcomes described

participants’ use patterns of VERVE® over the 6-week study, including a) number of days per week using

VERVE®, cigarettes, and/or other tobacco products, b) amount of VERVE®, cigarettes, and/or other

10. 10 Applicant did not provide a specific age.

11. 11 Statements regarding Intentions to use VERVE®: I would consider using a VERVE® [DISC/CHEW] more than once. (6- 

point agreement scale); I expect to use a VERVE® [DISC/CHEW]. (6-point agreement scale); It is likely that I will

regularly use VERVE® [DISCS/CHEWS] in the next 6 months. (6-point agreement scale); VERVE® [DISCS/CHEWS] will be

my regular brand of oral tobacco in the next 30 days. (6-point agreement scale)
PM0000470 – PM0000473 Page 39 of 104

Study Population:(b) (4)

Study Design: (b) (4)

tobacco products used per week, and c) distribution change in CPD (e.g., decrease, same, increase) from

baseline to the end of study. The proportion of participants who a) started using VERVE®, b) used both

VERVE® flavor varieties, c) completely stopped using cigarettes and/or other tobacco products, d)

started using VERVE® and stopped using cigarettes and/or other tobacco products, or e) started using

VERVE® and continued using cigarettes and/or other tobacco products was also evaluated.

VERVE® Discs 12-week extended home use test Final Report—PowerPoint presentation

Study Products: Prior version of VERVE® Discs Blue Mint (Gen 1). The product is a non-dissolvable

tobacco-derived nicotine disc products, each piece containing 1.5 mg nicotine.

Study Population: 284 adult cigarette smokers aged 21-54 years. Participants reported “purchase

interest in VERVE® Discs.”

Study Design: This study measured extended at-home use of a prior version of VERVE® Discs Blue Mint

(Gen 1) products. This multi-site study lasted 12 weeks. Study objectives were to understand how adult

smokers used Gen 1 VERVE® Discs over time and to compare their product usage relative to cigarettes.

Participants initially conducted a trial “disc test” where they reported amount of cigarette and other

tobacco product use. For the next 8 weeks, they also reported VERVE® product use. They were given

Gen 1 VERVE® Discs to use at home during Weeks 1-8 but were also permitted to use cigarettes and

other tobacco products. Daily use of Gen 1 VERVE® Discs was compared to daily use of cigarettes and

changes in product acceptance to Gen 1 VERVE® Discs were measured.

Relevant Study Outcomes: Subjective measures of abuse liability were collected, including product

acceptance questionnaires with items that measured product acceptability, how the product was used,

product liking, and sensory experience from product use. The GEN1 VERVE® Discs contain the same

amount of nicotine (1.5 mg/piece) as the current VERVE® Discs Blue Mint product but they do not

contain flavor coating and have a modified texture. These changes could impact all the relevant study

outcomes (i.e., measured product acceptability, how the product was used, product liking, and sensory

experience from product use).

ALCS In-Market Adult Consumer Study (MACS): Oral Tobacco-Derived Nicotine Products Currently

Marketed as VERVE® Products

Study Products: VERVE® Discs, VERVE® Chews, VERVE® Melts, VERVE® Chewable Dissolvables.
PM0000470 – PM0000473 Page 40 of 104

(b) (4)

Relevant Study Outcomes:(b) (4)

(b) (4)

A Randomized, Controlled, Parallel Group Pilot Clinical Study to Determine Changes in Biomarkers of

Exposure (BOE) in Adult Smokers Allowed Ad Libitum VBM-FG2 Disc Use Relative to Adult Smokers Not

Allowed VBM-FG2 Disc Use

Study Products: Prior Version of VERVE® Discs Blue Mint (Gen 2), referred to as VBM-FG2 in this study.

The product is a non-dissolvable tobacco-derived nicotine disc product, each piece containing 1.5 mg

nicotine.

Study Population: Healthy male and female adult cigarette smokers aged 21-65 years. Of 154

participants enrolled and randomized in the study, 146 participants completed the study (n=89 test

group; n=57 control group). Data for the outcomes presented in all the application’s tables denote

sample size ranging from n=66-87 participants in the test group and n=43-55 participants in the control

group.

Study Design: Randomized, controlled, open-label, parallel group, multi-center, five-week pilot study to

determine changes in BOE in adult smokers allowed ad libitum (up to 24 discs per day) use of VBM-FG2

discs (test group) relative to adult smokers who were not permitted use of VBM-FG2 discs and

continued smoking their UB cigarettes (control group). The study consisted of a one-week baseline

period during which all participants smoked their UB cigarettes, followed by a four-week product use

period for participants randomized to the test group. Control participants continued smoking their UB

cigarettes during the four-week period.

Relevant Study Outcomes: The primary endpoint was the percent change in urinary total 4- 

(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNAL) from baseline to end of study. Secondary

endpoints included percent change in urinary nicotine equivalents (cotinine, trans-3'-hydroxycotinine,

trans-3'-hydroxycotinine-O-glucuronide, nicotine-N-glucuronide, and cotinine-N-glucuronide), Sphenylmecapturic acid (S-PMA), blood COHb, exhaled CO, CPD, and Fagerström Test for Cigarette

Dependence (FTCD) scores from baseline to end of study. Mean daily consumption of VBM-FG2 discs

was also reported.

Study Products:

(b) (4)
PM0000470 – PM0000473 Page 41 of 104

Study Design: (b) (4)

.

Relevant Study Outcomes:(b) (4)

(b) (4)

2.4.2. Nicotine Pharmacokinetics

Two Nicotine Exposure Studies

The BCP review of the applicant’s two nicotine exposure studies provides PK data for VERVE® Discs and

VERVE® Chews. In one study using the VERVE® Discs products, a mixed model analysis of variance

conducted by the applicant revealed that the nicotine Cmax means the VERVE® Discs Blue Mint and Green

Mint conditions were each statistically significantly lower than the Cmax mean for the UB cigarettes

condition and the Cmax mean for the nicotine gum condition. Median Tmax was 60 min for the VERVE®

Discs condition, which was equal to that of nicotine gum, but much longer than participants’ Tmax for the

UB cigarettes condition (10 min). Nicotine AUC0-180 for each of the VERVE® Discs Blue Mint and Green

Mint conditions was statistically significantly lower than the AUC0-180 mean for the UB cigarettes

condition and the AUC0-180 mean for the Nicorette gum condition. All participants used the two VERVE®

products and Nicorette gum for at least 30 min per product.

The mean values of nicotine Tmax were reported without statistical comparisons or significance levels. In

this study, nicotine PK data were collected only when participants used the VERVE® products and the

comparators one time each under controlled use (instructed) conditions, limiting the generalization of

the findings on nicotine exposure; real-world use of VERVE® Discs Green Mint and Blue Mint would not

involve controlled conditions.

Study Population (b) (4)
PM0000470 – PM0000473 Page 42 of 104

(b) (4)

(b) (4)

(b) (4)

Despite the limitations noted above, the BCP review concluded that based on findings from this study,

which compared nicotine PK of the VERVE® Discs products to those of UB cigarettes and Nicorette gum,

the VERVE® Discs products are associated with lower abuse liability than UB cigarettes. Although the

data collected in this study do not reflect real-world use of the products tested, the nicotine PK data

provide valid measures of abuse liability for those products.

A second study looked at the PK of the VERVE® Chews products. Nicotine Cmax for VERVE® Chews Blue

Mint and Green Mint was statistically significantly lower than Cmax for UB cigarettes, and slightly higher 

but not statistically significantly different than the Cmax for Nicorette gum. Tmax came much later for the

VERVE® Chews (at about 45 min) compared to the UB cigarettes (11 min), and somewhat earlier than

the Nicorette gum (54 min) (no statistical comparisons reported). Nicotine AUC for VERVE® Chews Blue

Mint and Green Mint was statistically significantly lower than that of UB cigarettes, and not statistically

significantly different than the AUC of Nicorette gum.

As with the study on the VERVE® Discs, the Tmax were reported without statistical comparisons or

significance levels. In this study, nicotine PK data were collected only when participants used the

VERVE® products and the comparators one time each under controlled use (instructed) conditions,

limiting the generalization of the findings on nicotine exposure; real-world use of VERVE® Chews Green

Mint and Blue Mint would not involve controlled conditions.

Despite the limitations, as stated above regarding the VERVE® Discs, the BCP review concluded that

based on findings from this study, which compared PK of the VERVE® Chews products to those of UB

cigarettes and Nicorette gum, the VERVE® Chews products are associated with lower abuse liability than

UB cigarettes. Similar to the study with the VERVE® Discs products, the data collected in this study do

not reflect real-world use of the products tested, but the nicotine PK data provide valid measures of

abuse liability for those products; there is lower likelihood of abuse associated with the slower speed of

nicotine delivery compared to UB cigarettes.

(b) (4)
PM0000470 – PM0000473 Page 43 of 104

2.4.3 Behavioral Pharmacology

2.4.3.1. Abuse Liability

Data on NRT gum from the literature were extrapolated to VERVE®, given that the applicant submitted

studies to support that abuse liability and nicotine PK are comparable between NRT gum and VERVE®

products (Section 3.1). The applicant also provided studies comparing NRT gum to NRT lozenges and

data on abuse liability of dissolvable tobacco products. Studies in cigarette smokers and smokeless

tobacco users were included.

Applicant’s Submitted Studies

The BCP review evaluated studies with data related to the abuse liability of VERVE® Discs and VERVE®

Chews in Blue Mint and Green Mint flavors and comparator products. Such data included, but were not

limited to: PK parameters measuring plasma nicotine levels during product use (i.e., Cmax, Tmax, and AUC),

measures of product use (i.e., number of products used per day, amount of use, frequency of use,

duration of product use, other product use topography parameters), subjective responses to product

use (i.e., self-reported questionnaire responses about urge to use a product, symptoms of nicotine

withdrawal, product liking, sensory effects from product use), and data related to BOE (e.g., nicotine and

metabolites, total NNAL).

The applicant-submitted studies on VERVE® products, as noted in Section 2.4.1 of this review, include

three abuse liability studies assessing VERVE® Discs and VERVE® Chews. As one study used expired

Nicorette gum, the applicant repeated the study. The BCP review only addresses the repeated study

with fresh Nicorette gum. The abuse liability studies were reviewed to evaluate the PK profiles of and

subjective responses after use of VERVE® Discs and/or Chews in smokers. The applicant submitted two

additional analyses to further evaluate outcomes from its VERVE® abuse liability studies. The applicant

states that the secondary endpoints on subjective measures in its two abuse liability studies using

VERVE® products were analyzed using summary descriptive statistics without statistical comparisons. To

make additional comparisons between products, the applicant conducted post hoc analyses on items

from the Tobacco/Nicotine Withdrawal and Direct Effect of Product Questionnaires. The BCP review also

includes an assessment of three studies, two actual use studies and the in-market survey study, to

evaluate patterns of actual use of VERVE® Discs and/or Chews among consumers.

The two studies that measured PK data from the VERVE® Discs and the VERVE® Chews also included

subjective measures of abuse liability. Maximum Reduction in Urge from pre- to post-product use was

smaller from use of VERVE® Discs Blue Mint and Green Mint, but not statistically significantly different,

than Maximum Reduction in Urge from use of UB cigarettes or Nicorette gum. In the VERVE® Discs Blue

Mint and Green Mint conditions, mean ratings for the “Is the product ‘pleasant’ right now?” item on the

Direct Effects of Product Questionnaire were each statistically significantly lower than mean ratings from

the same question in the UB cigarette condition, and were not statistically significantly different than

mean ratings from the same question in the Nicorette gum condition. All participants used the two

VERVE® Discs products and Nicorette gum for at least 30 min per product. Based on findings from this

study, which compared nicotine PK and subjective measures of abuse liability of the VERVE® Discs

products to those of UB cigarettes and Nicorette gum, this BCP review concluded that the VERVE® Discs

products are associated with lower abuse liability than UB cigarettes and Nicorette gum. Although the

data collected in this study do not reflect real-world use of the products tested, the nicotine PK data

from a controlled study design provides valid measures of abuse liability for these products.

(b) (4)
PM0000470 – PM0000473 Page 44 of 104

The study with the same design but using the VERVE® Chews products showed that Direct Product

Effects (“pleasantness” item) for the VERVE® Chews were statistically significantly lower than those of

UB cigarettes and not significantly different from those of Nicorette gum. Based on findings from this

study, which compared PK and subjective measures of abuse liability of the VERVE® Chews products to

those of UB cigarettes and Nicorette gum, we conclude that the VERVE® Chews products are associated

with lower abuse liability than UB cigarettes and a similar abuse liability to Nicorette gum. Although the

data collected in this study do not reflect real-world use of the products tested, the nicotine PK data

from a controlled study design provide valid measures of abuse liability for these products.

The applicant then conducted a post-hoc analysis of the secondary endpoints of subjective measures

from the two studies discussed above. The BCP review noted that UB cigarette smoking produced a

statistically significantly greater maximum reduction in VAS scores on the Tobacco/Nicotine Withdrawal

items than use of both flavors of VERVE® Chews. UB cigarette use produced a statistically significantly

greater maximum reduction in VAS scores for the “Difficulty Concentrating” item on the

Tobacco/Nicotine Withdrawal Questionnaire than use of VERVE® Discs Blue Mint. UB cigarette use

produced a statistically significantly greater maximum reduction in VAS scores for all but one item on

the Direct Effects of Product Questionnaire compared to use of both flavors of VERVE® Chews. UB

cigarette use produced a statistically significantly greater maximum reduction in VAS scores on multiple

items of the Direct Effects of Product Questionnaire compared to use of both flavors of VERVE® Discs.

UB cigarette use produced a statistically significantly greater maximum reduction in VAS scores for all

Direct Effect of Product Questionnaire items compared to Nicorette gum use. Use of Nicorette gum did

not statistically significantly reduce withdrawal or direct effects any better than use of VERVE® Discs or

Chews. The statistics review identified violations in the assumptions made while using a linear mixed

model to conduct this post hoc analysis. Plots of the subject measure residuals against the predicted

values exhibited increasing variability as the predicted means increased, which is an indication that the

constant error variance assumption may be invalid. Four subjective measures showed deviations from

the model assumptions: Emax-diffconc “Difficulty Concentrating”, Emax-anxious “Anxious,” Emax-sick “Is the product

making you feel ‘Sick’ right now?” and Emax-hunger “Is the product reducing your ‘Hunger’ for food right

now?” Taking these violations into consideration, the statistical review could not confirm the conclusion

provided in the post hoc statistical analysis report that the VERVE® products, as well as NRT, did not

statistically significantly reduce withdrawal or direct effects compared to UB cigarettes.

The subjective ratings assessed in this analysis reveal that participants' UB cigarettes reduce nicotine

withdrawal and improve direct effects of product use (such as satisfaction, calmness, and feeling sick) in

smokers better than VERVE® Discs and Chews. These findings suggest that the abuse liability of VERVE®

Discs and Chews is lower than the abuse liability of participants' UB cigarettes. Effects were comparable

between VERVE® Discs and Chews and Nicorette gum, suggesting that abuse liability for VERVE® Discs

and Chews is similar to Nicorette gum. However, based on the statistics review regarding the violations

in the assumptions made while using the linear mixed model, these conclusions cannot be confirmed. As

such, the BCP review relies on the descriptive statistics provided in the two nicotine PK and subjective

measures studies to support conclusions on subjective measures for VERVE® Discs and Chews compared

to UB cigarettes and Nicorette gum. As noted already, the results of these two studies support that the

VERVE® products have lower abuse liability than UB cigarettes and a similar abuse liability to Nicorette

gum.

Literature Review

Overall, findings from the applicant’s literature review support that, compared to UB cigarettes and high

nicotine content smokeless tobacco, abuse liability of oral tobacco products is low and comparable to

that of NRT products (gum or lozenge). These findings are based on nicotine PK profiles and subjective
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ratings (e.g., likeability, ability to relieve withdrawal and craving) of oral tobacco products compared to

UB cigarettes.

Early studies that assessed PK data in oral NRT products measured blood nicotine concentrations in

smokers who used 2 mg or 4 mg nicotine gum. Findings revealed that chewing 2 mg nicotine gum

(polacrilex) and 4 mg nicotine gum produced lower nicotine delivery and slower nicotine absorption

than cigarette smoking, with the 2 mg nicotine gum resulting in lower nicotine intake than the 4 mg

nicotine gum (30). Additional findings revealed that both the 2 and 4 mg nicotine gum produced higher

plasma nicotine concentrations at multiple time points during product use compared to a placebo, and a

decrease in plasma nicotine concentrations in smokers who switched to 2 mg, but not 4 mg, nicotine

gum (31). Further studies on nicotine gum show dose-related increases in serum cotinine levels; blood

cotinine concentrations rise with nicotine dose (32, 33). In addition, allowing nicotine lozenges to

dissolve produced higher nicotine exposures than immediately chewing and swallowing the lozenge, or

chewing the lozenge and then holding it in one’s mouth for 5 minutes before swallowing. Comparisons

between nicotine gum and lozenge (both 2 mg nicotine content) found that nicotine concentrations

associated with use were similar, but the gum’s nicotine absorption rate was slower (34). Additional

studies have shown that frequency of nicotine product use can also affect nicotine delivery (35), and

that nicotine from mouth spray is absorbed faster than a nicotine lozenge or gum (36).

PK findings from studies with non-NRT products similar to the VERVE® products reveal that smokers who

are non-oral tobacco users who chewed a 2012 version of VERVE® (1.5 mg/g nicotine) following 

cigarette abstinence showed smaller, though not significant, increases in plasma nicotine concentrations

than non-oral tobacco users who did not abstain (37). Additionally, in a study where several newer

smokeless tobacco products, including Ariva, Revel, Stonewall, and Copenhagen moist snuff, were

compared to a nicotine lozenge, the nicotine lozenge produced a higher nicotine Cmax compared to the

Stonewall, Ariva, and Revel products (38).

Therefore, PK studies on NRT products reveal that chewing nicotine gum produces lower blood nicotine

levels and a slower absorption rate of plasma nicotine than smoking cigarettes. PK studies comparing

nicotine lozenges with nicotine gum also find that these products produce comparable nicotine

exposure, although nicotine lozenges have a faster nicotine absorption rate. Studies report that moist

snuff delivers more nicotine than nicotine lozenges, and newer smokeless tobacco products deliver less

nicotine than lozenges.

Oral NRT products are associated with low ratings of pleasantness across products, including nicotine

gum and nicotine lozenges. Higher nicotine content gum and lozenges received decreased ratings of

acceptability and liking; never smokers and former smokers preferred lower doses of nicotine in gum. 

Young adults and never smokers appear to have a greater aversion to oral nicotine products and are less

likely to experience psychological reward (Section 2.4.3.4).

Studies comparing product acceptability as a measure of the abuse liability of oral tobacco products in

smokeless tobacco users show that snuff was rated highest in psychological reward and aversion

compared to VERVE® chewable discs, dissolvable tablets, and snus (Section 2.4.3.4). Findings from this

literature review conclude that VERVE® Discs have a low abuse liability.

2.4.3.2. Use Behavior and Topography

In the 6-week actual use study, the participants were asked how they used the VERVE® products during

a typical use session and where in the mouth they typically placed the product (topography). For

VERVE® Discs at Week 1, the majority of participants reported chewing the discs half the time and
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letting them rest in the mouth the other half. After Week 1, use patterns were equally divided, where an

approximately equal number of participants reported chewing the product most of the time, letting the

product rest in the mouth most of the time, or chewing the product half the time and allowing the

product to rest in the mouth the other half. Alternatively, for VERVE® Chews, throughout the 6-week 

use trial, the majority of participants reported chewing the product most of the time. Only 5-8% of

participants reported letting the product rest in the mouth most of the time. For both product varieties,

overall, an equal number of participants reported typically using the product in the same area of the

mouth or typically using the product in different areas of the mouth.

The in-market survey study also collected topography data (i.e., minutes in mouth, placement in mouth,

how typically used in mouth). Overall, 38% of current VERVE® product users report using VERVE® while

also using another tobacco product (e.g., smoking a cigarette with a VERVE® product in their mouth).

Among current VERVE® Discs users, 39% kept the product in their mouth for 10-19 minutes, and 32%

used the product for 5 minutes or less. The majority (54%) of participants chewed the discs half the time 

and let them rest in their mouth the other half, 19% chewed the disc most of the time, and 27%

reported letting the product rest in the mouth. Among users who did not chew the disc, 39% rested the

product between the lower lip and gum, and 36% kept the product somewhere else in their mouth.

Among VERVE® Chews users, 53% kept the product in their mouth for 10-19 minutes, and 22% used the

product for 5 minutes. Forty-four percent of participants chewed the VERVE® Chews most of the time,

while 34% chewed the product half the time and let them rest in their mouth the other half. Twentytwo percent let the product rest in the mouth most of the time.

2.4.3.3. Product Use/Consumption

The in-market survey study provided product use information. The BCP review noted that all current

VERVE® users reported past 30-day use of any VERVE® product plus two or more other tobacco

products. Current VERVE® users reported using VERVE® Discs and VERVE® Chews, on average, 13 and 11

days out of the past 30 days, respectively.

For current VERVE® Discs use in the past 30 days, the largest percentage of participants (37%) reported

using the product 10-14 days; 7% reported using the product 1-2 days, and 10% reported using the

product on all 30 days. Most participants (63%) reported using fewer than five discs per day, 25% used

5-9 discs per day, and 12% averaged 10 or more discs per day. Sixty-eight percent of current users

typically used one VERVE® Discs per use occasion and 29% used two VERVE® Discs per use occasion. Two

percent of participants reported using three or more discs at the same time.

For current VERVE® Chews use in the past 30 days, the largest percentage of participants (31%) reported

using the product 10-14 days, followed by 22% who reported using the product 3-5 days, and 3%

reported using the product either 1-2 days or all 30 days. Similar to VERVE® Discs, most (63%) current

past 30-day users of VERVE® Chews reported averaging fewer than five VERVE® Chews per day, 25% 

reported using 5-9 chews per day, and 13% averaged 10 or more chews per day. Fifty-six percent

reported typically putting one VERVE® Chews in their mouth during each use occasion, and 34% used

two chews during each use occasion. Nine percent reported using three or more chews at the same

time.

Almost all (92%) current VERVE® product users also reported currently smoking cigarettes. On average,

participants smoked on 24 of the past 30 days, and smoked an average 16 CPD. The frequency and

amount of cigarette smoking among VERVE® product current users was comparable to participants who

reported ever trying, but not currently using, VERVE products (80% smoked in the past 30 days,

average 26 days smoking out of 30 days, average 15 CPD), and among participants who currently
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smoked cigarettes, but had never tried an oral tobacco product (86% smoked in the past 30 days,

average 26 out of 30 days, average 15 CPD).

Fifty-one percent of current VERVE® product users reported smoking fewer CPD since starting VERVE®,

while 38% reported no change in smoking behavior. Eleven percent reported an increase in smoking

behavior since starting VERVE®.

Other past 30-day tobacco product use among current VERVE® product users also included cigars (82%),

pipe tobacco or hookah (60%), snus pouches (56%), chewing tobacco (42%), dip/snuff (56%), and

refillable END products (92%). The applicant notes that due to sample sizes of less than 20 participants

for use of some tobacco products among past VERVE® triers and the reference group (current tobacco

users who never tried oral tobacco products), the available sample limited the number of comparisons

that could be made to three tobacco products (cigars, dip/snuff, and refillable ENDS). Current VERVE®

product users who smoked cigars reported smoking on average 9 of the past 30 days, with 53%

reporting less than one or more cigars smoked per day on days smoked. Nineteen percent of current

VERVE® product users reported smoking five or more cigars per day on days smoked. Current VERVE®

product users who used dip/snuff reported using on average 13 of the past 30 days, with 55% reporting

using dip/snuff three or fewer times per day on days used. Current VERVE® product users who used

refillable ENDS reported using on average 13 of the past 30 days, with the average of amount of use

being less than one or 1-2 mL of e-liquid on days used.

Thirty-eight percent of current VERVE® users reduced their amount and frequency of other tobacco use

(aggregated for all non-cigarette tobacco products), while 47% reported no change in their use of other

tobacco products. Fifteen percent reported using greater amounts or more frequent use of other

tobacco products since initiating VERVE® product use.

2.4.3.4. Craving, Withdrawal, and Dependence

The applicant addressed craving, withdrawal, and dependence primarily with literature and the use of

oral NRT, smokeless tobacco, and other oral tobacco products.

The two studies that looked at nicotine PK and subjective measures included subjective measures of

tobacco or nicotine withdrawal during product use using a visual analogue scale (VAS) and maximum

reduction in withdrawal from pre- to post-product use. The BCP review concluded from these studies

that the subjective measures indicate lower abuse liability with the VERVE® products than UB cigarettes.

The post hoc analysis study also indicated that the VERVE® products, as well as NRT, did not statistically

significantly reduce withdrawal or direct effects compared to UB cigarettes. However, as noted earlier,

the statistics review noted violations in the assumptions made in this analysis.

Overall, findings from the applicant’s literature review support that, compared to UB cigarettes and high

nicotine content smokeless tobacco, the abuse liability of these oral tobacco products is low, and

comparable to that of NRT products (gum or lozenge). These findings are based on nicotine PK profiles

and subjective ratings (e.g., likeability, ability to relieve withdrawal and craving) of oral tobacco products

compared to UB cigarettes.

The abuse liability of nicotine gum has also been assessed using subjective measures. Withdrawal

symptoms during abstinence appear not to worsen as duration (1 vs. 3 months) of nicotine gum use

increases, implying low abuse liability (39). Additional evidence that nicotine gum possesses low abuse

liability comes from subjective reports of satisfaction and dependence, which were not higher in
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nicotine gum users compared to those who used nicotine patches, inhalers, or sprays (40). Furthermore,

ratings of liking from use of 2 mg and 4 mg nicotine gum did not differ (41).

Studies generally have found that for smokers, smokeless tobacco and oral tobacco products are not as

desirable as cigarettes and are less effective than cigarettes at reducing craving and withdrawal (42 - 

45). For example, Blank and Eissenberg (44) evaluated toxicant exposure and subjective effects in 21 

smokers who used potentially reduced exposure tobacco products. In this study, Camel Snus and Ariva

both had lower acceptability among smokers compared to UB cigarettes. Both of these smokeless

tobacco products were rated as significantly less pleasant and less satisfying than UB cigarettes and did

not taste as good. Camel Snus and Ariva were also less effective at relieving smoking urges across the

five-day study. Subjective ratings of VERVE® are lower for liking (37) and in ratings of psychological

reward and aversion compared to Skoal snuff (46).

The literature review included nicotine PK studies evaluating nicotine delivery from multiple oral

tobacco products from a number of clinical trials and population surveys that examine product use

behaviors and measures of dependence from oral NRT use. Long-term (greater than 3 months) use and

dependency on NRT gum is not common, and the risk of abuse or dependence on oral NRT products is

low. Few studies evaluate the abuse liability of VERVE® and dissolvable tobacco products; however,

studies support that subjective ratings of these products are low among smokers.

2.4.3.5. Cessation

The applicant's in-market survey and literature review indicate a low likelihood of former smokers

relapsing to tobacco use with VERVE® or other oral tobacco products. The in-market survey evaluated

the percentage of VERVE® product ever triers who had been former tobacco users and then relapsed to

using the tobacco product they had quit. No VERVE® product ever triers reported re-initiating cigarette

smoking after first trying a VERVE® product. Two percent of VERVE® product ever triers reported reinitiating to another tobacco product (other than cigarettes and VERVE®) after first trying a VERVE®

product.

The in-market survey also indicates that 4-5% of VERVE® ever triers quit using all tobacco products after

trying VERVE® products; however, it cannot be determined whether VERVE® was the catalyst for

tobacco product cessation. A study in the literature review indicates that 20-25% of smokers interested

in quitting smoking maintain use of oral tobacco products instead of quitting cigarettes (48); however,

12. 12 Percent change from baseline = study group + random error

13. 13 Change from baseline = study group + random error

(b) (4) 
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participants were instructed on how to use the oral tobacco products to assist with quitting smoking and

it is unclear whether consumers would normally initiate these non-NRT products with the intent of

quitting smoking. Given that the consumer population most likely to initiate VERVE® use is current

smokers who also use one or more other tobacco products and that VERVE® products will not be

marketed as cessation products, it is unlikely that smokers who are interested or motivated to quit

smoking would initiate VERVE® for this purpose. However, based on the BOE data provided and bridging

data on HPHCs present in VERVE® Discs and Chews compared to other tobacco products (Appendix

Tables 16 and 17), if consumers quit smoking but continue use of VERVE® products, exposure to many

HPHCs, including nicotine, CO, COHb, and other non-nicotine BOE, would be significantly reduced

compared to smoking cigarettes.

The literature review included studies of non-NRT oral nicotine tobacco products and the likelihood of

cessation among current smokers who try these products. Because the intended purpose of NRT

products is to assist with tobacco cessation, and the new PMTA products are not tobacco cessation

products, it is unclear how the information from NRT cessation studies can be extrapolated to likelihood

of cessation using non-NRT products; data for NRT products were not extrapolated to cessation

outcomes for VERVE®. While some studies included use of NRT products as comparators to oral tobacco

products, studies that focused solely on likelihood of cessation from use of NRT were not included in the

BCP review. The applicant states that the literature indicates the proportion of users who continued to

use non-NRT products instead of quitting was greater than what was observed for most NRT studies.

This finding is consistent with how non-NRT products are marketed. Given these differences in

marketing that contribute to differences in use behavior, studies of continued use of NRT products after

quitting smoking were not extrapolated to VERVE® products for this review.

The applicant provided summaries of studies that examined the effects of dissolvable tobacco and other

smokeless tobacco products on tobacco cessation. In a study of smokers not interested in quitting

(n=31), participants were randomized to groups receiving Ariva or Stonewall smokeless tobacco spit-free

tobacco lozenges for 2 weeks or a control group that continued to smoke for 2 weeks (47). Participants

who used Ariva or Stonewall reported 40% reductions in CPD over the two-week study; however, there

were no significant changes in exhaled CO during the two-week period. There were also no changes in

withdrawal or craving during the 2 weeks, an effect likely attributable to the fact that participants dualused cigarettes and oral tobacco products during the study (as opposed to switching completely).

Readiness to quit smoking in the next 30 days and within the next 6 months significantly increased

among participants who were using the dissolvable products compared to participants who continued to

smoke during the two-week study. Specifically, 53% of participants using dissolvable products reported 

being more motivated to quit, 37% did not change quit intentions, and 11% reported being less likely to

quit smoking (47).

Hatsukami et al. (48) evaluated preferences for five different oral tobacco products varying in nicotine

content (General Snus, Camel Snus, Marlboro Snus, Stonewall, Ariva) during a two-week cessation trial

among smokers interested in quitting (n=99). Participants were blinded to the snus brands but not oral

lozenges. During a two-week sampling phase, participants received instructions on how to use the

different types of oral tobacco products and instructions for which products to use on a specified day,

including time frames during the day for when they should use the oral tobacco products (i.e., use at

least three pouches/lozenges prior to 1 pm) and when they could smoke their UB cigarettes, if desired

(i.e., after 1 pm). At the end of the two-week sampling phase, participants were instructed to quit

smoking and use the oral tobacco product of their choice for an additional 2 weeks. Findings indicate

that Camel Snus users had higher cigarette abstinence rates than Ariva or Stonewall users. This effect

was likely due to the higher nicotine content in Camel Snus. At the end of the study, participants who

used Ariva were significantly more likely to relapse to smoking than participants who used Camel Snus.
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Four weeks after the study ended, 25% (Ariva), 20.8% (Stonewall), 48.2% (Camel Snus), and 17.4% 

(Marlboro Snus) of participants continued to use the oral tobacco products instead of quitting all

tobacco products. It was not reported whether these participants switched completely to oral tobacco

products or also continued to smoke cigarettes. Because participants were instructed on how to use the

oral tobacco products to assist with quitting smoking, the patterns of use in this study may not be

applicable to actual use. Given that these oral nicotine products are not smoking cessation therapies, it

is also unclear whether consumers would normally initiate these products with the intent of quitting

smoking.

Similarly, Borland et al. (43) completed two pilot studies in the United Kingdom (UK) (n=34) and in

Australia (n=29) designed to assess the feasibility of offering smokers alternative nicotine products to

consider for use in quitting smoking or as a long-term substitute for cigarettes. Participants who were

interested in alternatives to smoking cigarettes (UK) or who were respondents in a survey about the

harms of smoking (Australia) were provided with boxes of nicotine-containing products (in the UK:

NiQuitin CQ lozenge, Oliver Twist; in Australia: Nicobate lozenge, Catch Swedish Snus, Oliver Twist,

Stonewall and/or Ariva) and were told to use the products if they wanted to, and either to reduce their

smoking or try to quit smoking. Participants in Australia were contacted after one week for follow-up.

The length of time that participants sampled the product in the UK was not specified. In the UK, three

participants quit smoking during the study; none of the participants used non-NRT products to assist

with quitting. Forty-four percent of participants who used non-NRT oral tobacco products thought the

products were “possibly good enough” or “good enough” to replace smoking. Similarly, three

participants in Australia reported that they had quit smoking at the end of the week. Views of the

individual products varied significantly for acceptability as a smoking replacement, with non-NRT as a

smoking substitute being less favorable than the NRT lozenge.

The limited evidence suggests that some smokers (approximately 20-25%) who are interested in quitting

smoking may switch to and continue to use oral tobacco products instead of quitting all tobacco;

however, initiating non-NRT oral tobacco products to quit smoking is influenced by smoker perceptions

of whether non-NRT oral tobacco products are similar to NRT products, and the smoker population most

likely to initiate oral tobacco product use is unlikely to be current smokers who are interested in 

quitting. In general, smokers are unlikely to quit smoking or quit all tobacco products through use of

non-NRT oral tobacco products.

2.4.4 Summary of Overall Behavioral and Clinical Pharmacology Findings

The BCP review concluded that the PMTAs do not raise concerns about issuing marketing orders from

BCP’s perspective.

Based on the applicant’s submitted clinical studies, VERVE® Discs and Chews in Blue Mint and Green

Mint flavors are associated with lower plasma nicotine concentrations and lower positive subjective

ratings compared to UB cigarettes, reducing their abuse liability and likelihood of use for youth, nonsmokers, and former smokers.

• Current smokers who also use one or more other tobacco products are the consumer population

most likely to try VERVE® products. The data and literature review submitted by the applicant

suggest that smokers who completely switch to VERVE® products or reduce their CPD by 60% or

more upon initiating oral tobacco products may significantly reduce their exposure to nicotine and

other non-nicotine BOE. However, low subjective appeal and increased craving and withdrawal may

prevent current smokers from fully transitioning to VERVE® products. Data from the applicant’s

submitted studies suggest that few smokers (11%) switch completely to VERVE® or other oral
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tobacco products, but these data are based on one week of use and do not reflect the measured

decline in VERVE® acceptability among smokers that was captured in the applicant’s 12-week actual

use study. Therefore, the percentage of complete switching would likely be lower than the identified

percentage in the applicant’s study. Dual/poly use is the primary use behavior. Smokers who dual

use VERVE® products with cigarettes and do not substantially reduce their CPD (i.e., by 60% or

greater) do not reduce their exposure to nicotine or non-nicotine BOE. However, even a modest

reduction in daily cigarette consumption may reduce the risk of tobacco related disease due to a

decreased exposure to HPHCs.

As TPL, I agree with the BCP review conclusions that there is reduced abuse liability with the VERVE®

products compared to cigarettes and a similar abuse liability compared to nicotine gum. There is

evidence that a small number of cigarette users might transition to VERVE® products only. Data

evidence from a six-week pilot study demonstrate that some cigarette users might decrease their CPD,

with a small chance of some decreasing CPD by over 50%. Further, 12-week Extended Home Use data

show a consistent average CPD reduction of 32-44% (14.9 vs ≤ 10.2 CPD) concomitant with use of

VERVE® prototype products (5-6 discs/day) for the duration of the study. However, the design of the 6- 

and 12-week actual use study is not the same as real-world use and over time there is decreased appeal

of the products. I also agree with BCP conclusions that the low appeal of the VERVE® products over time

may impact any smokers transitioning away from cigarettes should the products be introduced into the

commercial U.S. tobacco market.

2.4.5 Biomarkers of Exposure (BOE)

The BCP review included an evaluation of BOE data, which was obtained from the applicant’s study with

VBM-FG2 (A Randomized, Controlled, Parallel Group Pilot Clinical Study to Determine Changes in

Biomarkers of Exposure (BOE) in Adult Smokers Allowed Ad Libitum VBM-FG2 Disc Use Relative to Adult

Smokers Not Allowed VBM-FG2 Disc Use). This study did not use the PMTA VERVE® products but instead

used a prior version of VERVE® Discs Blue Mint (Gen 2). The Gen 2 VERVE® Discs contain the same

amount of nicotine (1.5 mg/piece) as the current VERVE® Discs Blue Mint product but they do not

contain flavor coating. Based on the format (i.e., disc, chew, or prototype), nicotine content, and use

behaviors of VBM-FG2, BCP extrapolated these data to inform conclusions on VERVE® products. In this

study, the applicant measured BOE in adult smokers, with the test group allowed ad libitum VBM-FG2

and the control group not permitted to use VBM-FG2 but to continue smoking their UB cigarettes. The

primary endpoint was the percent change in urinary total NNAL from baseline to end of study.

Secondary endpoints included percent change in urinary nicotine equivalents (cotinine, trans-3'- 

hydroxycotinine, trans-3'-hydroxycotinine-O-glucuronide, nicotine-N-glucuronide, and cotinine-Nglucuronide), S-phenylmecapturic acid (S-PMA), blood COHb, and exhaled CO.

Cigarette smokers who used VBM-FG2 discs for 4 weeks smoked approximately 20% fewer CPD than UB

cigarette smokers and may have had significant reductions in COHb. Despite modest reductions in CPD,

total NNAL, TNE, S-PMA, and exhaled CO were not significantly different between study groups. Overall,

these findings indicate that the majority of smokers dual use VBM-FG2 discs, and do not substantially

reduce CPD or their exposure to nicotine or non-nicotine BOE.

The applicant-submitted literature relevant to BOE is summarized below.
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2.4.5.1 Effect of Switching to Oral Tobacco Products on BOE

Nicotine BOE

As previously noted, the applicant submitted one study with BOE, the study with VBM-FG2, - a prior

version of VERVE® Discs Blue Mint (Gen 2). The Gen 2 VERVE® Discs contain the same amount of

nicotine (1.5 mg/piece) as the current VERVE® Discs Blue Mint product but they do not contain flavor

coating. While this is not one of the PMTA VERVE® products, the BCP review noted that extrapolating

from VBM-FG2 to the VERVE® products was possible. While the non-nicotine BOE of NNAL was the

primary endpoint of this study, secondary endpoints included percent change in urinary nicotine

equivalents (cotinine, trans-3'-hydroxycotinine, trans-3'-hydroxycotinine-O-glucuronide, nicotine-Nglucuronide, and cotinine-N-glucuronide). For secondary outcomes, there was no significant difference

in percent change from baseline in mean nicotine equivalents between study groups. Similar results

were observed for analyses of absolute change. At Visit 6, there was a significant difference between

groups (p=0.035), with a greater increase from baseline in total nicotine equivalents (TNE) in the control

group compared to the test group. There was no significant difference between groups in nicotine

equivalents at any other time point.

The applicant-submitted literature review presented studies on nicotine and tobacco BOE from use of

NRT products (gum and lozenges) and oral tobacco products (e.g., snus, dissolvables).

Findings regarding the effects on BOE in cigarette smokers who switch to oral nicotine products suggest

that many BOE, including nicotine, are reduced in smokers who switch to oral tobacco products;

however, among smokers, dual or poly use is the predominant use pattern for oral tobacco products.

Compared to exclusive cigarette users, BOE are not significantly reduced in smokers who dual or poly

use oral tobacco products. Given the information regarding the VERVE® products indicating poly use, it

is not surprising that the nicotine BOE are not significantly different from the control group of smokers.

If consumers were to switch to only using VERVE® products, or significantly decrease their CPD (by 50- 

60%), the nicotine BOE would likely be reduced. One study found that, of smokers who switched to oral

nicotine products, total cotinine was significantly reduced compared to baseline UB cigarette smoking in

smokers (n=49) who switched to Exalt smokeless tobacco, Ariva dissolvables, or NRT lozenges for 2

weeks (45). Urinary cotinine levels were significantly reduced in smokers who used Ariva and Camel

Snus compared to smoking UB cigarettes.

The applicant-submitted literature review also presented studies that support the high prevalence of

dual use among smokers who use oral nicotine products. Allen et al. (49) evaluated gender differences

in response to use of snus or NRT gum in a group of cigarette smokers who were willing to substitute

snus or NRT gum for cigarettes over 12 weeks to reduce harm. The prevalence of dual use (i.e., using

study NRT gum or snus and smoking cigarettes) was high. Among women during Week 1, 85.9% and 

79.5% dual-used NRT gum or snus, respectively. Among men during Week 1, 70.7% and 74.0% dualused NRT gum or snus, respectively. By Week 12, prevalence of dual use was reduced among women 

(NRT gum=74.6%, snus=49.2%) and men (NRT gum=43.2%, snus=55.8%).

The applicant’s review also provided studies addressing the effects of dual use on BOE. Krauttner and

Borgerding (42) conducted a study evaluating consumption patterns and effects on BOE among smokers

who switched to Camel Orbs, dual-used, or quit tobacco products completely. Over 5 days in a clinic,

healthy smokers (n=133, aged 21-65 years) were assigned to either continue smoking their UB

cigarettes, switch completely to Camel Orbs (and use at least five Orbs/day), dual use (i.e., smoke UB

cigarettes and consume as many Orbs as desired at any time, but not while smoking), or quit use of all
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tobacco products. Plasma and urine samples were collected during the study to assess BOE. The dual

use group smoked on average two fewer CPD compared to baseline, and CPD in the dual use group were

significantly reduced compared to the UB cigarette-only group. There were no significant differences in

smoking topography between the UB cigarette and dual use groups. Smokers who switched to using

Orbs only consumed approximately 10 orbs/day and dual users consumed approximately 4 orbs/day.

Twenty biomarkers, including TNE, were quantified in 24-hr urine samples and the biomarkers nicotine

and cotinine were quantified in blood. Urinary TNE levels did not significantly differ between UB

cigarette or dual use groups or from baseline in either group; however, TNE levels were significantly

decreased in the Orb-only group compared to baseline and the UB cigarette group.

Overall, these studies suggest that TNE was significantly reduced in cigarette smokers who switch

completely to oral tobacco products. However, the majority of individuals who use oral tobacco

products are dual tobacco users, and very few smokers switch completely. Therefore, most smokers

who use oral tobacco products will likely dual use the products with their UB cigarettes. Dual users often

reduce their CPD when using oral nicotine products (42). Smokers interested in using oral nicotine

products to significantly reduce, but not quit, smoking may experience significant reductions in BOE,

including TNE, depending on the extent to which smoking is reduced. One study suggests that a 60%

reduction in CPD translates to significant reductions in TNE. However, in general, smokers who dual use

cigarettes and non-NRT oral tobacco products may not experience significant reductions in BOE

compared to smoking UB cigarettes, particularly if they do not substantially reduce their CPD upon

initiating use of oral tobacco products.

Non-Nicotine HPHC BOE

The applicant-submitted study with BOE -- the study with VBM-FG2, a prior version of VERVE® Discs Blue

Mint (Gen 2)-- included non-nicotine BOE as well. The Gen 2 VERVE® Discs contain the same amount of

nicotine (1.5 mg/piece) as the current VERVE® Discs Blue Mint product but they do not contain flavor

coating. This study indicates that there was no significant difference in percent change from baseline or

absolute change from baseline in urinary NNAL levels between the test (+ VBM-FG2) and control (-VBMFG2) groups. NNAL is a biomarker of TSNA exposure and was the primary endpoint of this study. The

applicant also conducted statistical analyses of the proportion of participants in subgroups based on

total NNAL. Participants were separated into subgroups of increases or decreases in total NNAL from

baseline to the end of study visit. There was no significant difference between groups in the proportion

of participants in these subgroups. The applicant notes that there was an increase in NNAL from

baseline in both study groups, with a smaller increase in the test group. Secondary endpoints of this

study included non-nicotine BOE S-phenylmecapturic acid (S-PMA), blood COHb, and exhaled CO. CPD

was also measured as a secondary endpoint.

There was a significant difference in percent change from baseline in S-PMA between groups at Visit 5,

with a greater increase from baseline observed for the control group (p=0.033); however, there was no

significant difference in percent change from baseline S-PMA at any other visit (including the end of

study visit) between study groups. There was no significant difference in absolute change from baseline 

in S-PMA between groups at any post-baseline visit.

The percent change from baseline in mean COHb was significantly different (p-values ranging from 0.003

to 0.045) between groups at all post-baseline visits; decreases in COHb were observed at most postbaseline visits for the test group while increases in COHb were observed at all post-baseline visits for the

control group. For absolute change in COHb, a significant between-group-difference from baseline was

only detected at Visit 5 (p=0.012) and at the end of study visit (p=0.024).
PM0000470 – PM0000473 Page 54 of 104

There was a statistically significant difference in percent change from baseline in mean exhaled CO at

Visit 5 (p=0.028), with a decrease from baseline mean CO observed for the test group and an increase

from baseline mean CO in the control group. Although these changes in mean CO were also observed at

other study visits (including the end of study visit), these changes were not significantly different

between groups. Decreases from baseline in mean CO were also observed in the test group at all postbaseline study visits in analyses of absolute change from baseline; however, there were no significant

differences in exhaled CO between study groups at any post-baseline visit.

The applicant’s literature review included information on BOE comparisons between cigarette use and

oral nicotine product use. One study found that, of smokers who switched to oral nicotine products,

total NNAL and exhaled CO were significantly reduced compared to baseline UB cigarette smoking in

smokers (n=49) who switched to Exalt smokeless tobacco, Ariva dissolvables, or NRT lozenges for 2

weeks (45). NNAL was significantly higher in smokers who switched to Exalt compared to using NRT

gum. There were no significant differences in NNAL between Ariva and NRT gum users. Blank and

Eissenberg (44) conducted a study where cigarette smokers (n=21) completed four 5-day conditions of

either smoking UB cigarettes, using Ariva dissolvables, using Camel Snus (various flavors), or abstaining

from all tobacco. Exhaled CO was significantly reduced in smokers who used Ariva and Camel Snus

compared to smoking UB cigarettes. Exhaled CO levels in Ariva and Camel Snus were comparable to the

tobacco-abstinent group. However, there were no significant differences in total NNAL levels for the

dissolvable or the tobacco-abstinent groups compared to UB cigarette smoking across the five-day study

period.

Overall, these studies summarized by the applicant suggest that TNE and some non-nicotine BOE are

significantly reduced in cigarette smokers who switch completely to oral tobacco products. However,

the majority of individuals who use oral tobacco products are dual tobacco users, and very few smokers

switch completely. Therefore, most smokers who use oral tobacco products will likely dual-use the

products with their UB cigarettes. Smokers interested in using oral nicotine products to significantly

reduce (i.e., 60% or greater), but not quit, smoking may experience reductions in BOE, primarily CO,

COHb, and TNE, depending on the extent to which smoking is reduced. One study suggests that a 60%

reduction in CPD translates to significant reductions in TNE and multiple non-nicotine BOE. However, in

general, smokers who dual-use cigarettes and non-NRT oral tobacco products may not experience

reductions in BOE compared to smoking UB cigarettes, particularly if they do not substantially reduce

their CPD upon initiating use of oral tobacco products.

2.4.5.2 Dual Use and Non-compliance

Dual use with oral tobacco products, as shown by both the applicant’s studies and the literature review

summarized in the PMTAs, is common. The one study that the applicant conducted to measure BOE did

not include a group that exclusively used the test product (a prior version of VERVE® Discs Blue Mint

(Gen 2; VBM-FG2)) but had two groups of smokers, one that also had ad libitum access to the test

product and the other that did not. In other words, both groups continued to smoke. The lack of a

difference in NNAL levels is confounded by the smoking. It is likely that a VERVE® product-only group

would show a decrease in NNAL, given the significantly lower levels of NNK in the VERVE® products, as

compared to cigarette smoke yields. This is true of comparison to smokeless tobacco as well.

2.4.5.3 Summary of BOE Findings

The applicant submitted one study that measured BOE in users and this was conducted with a prior

version of VERVE® Discs Blue Mint (Gen 2; VBM-FG2), not the products that are the subject of the

PMTAs. There was no test product-only group; therefore, no information on what might be expected if a
PM0000470 – PM0000473 Page 55 of 104

(b) (4)

(b) (4)

smoker were to switch to VERVE® products (or one similar to the PMTA products) is available. However,

the data that were submitted do not show an increase in BOE in the group that continued to smoke and

had ad libitum access to the test product compared to smoking alone. That is, using VERVE® products in

addition to smoking cigarettes, even if CPD does not change, does not result in higher BOEs. In addition,

the literature suggests that smokers who switch to from cigarettes to oral nicotine tobacco products will 

have reductions in BOE, including nicotine, CO, and COHb.

As noted in Section 2.2 of this review, the chemistry review identified a potential deficiency in the

bioanalytical testing information used in the biomarkers of exposure (BOE) study. However, the BCP

review described adequate reference HPHC data and other scientific evidence to provide confidence in 

the BOE and use behavior for the VERVE® PMTA products.

2.4.6 Adverse Health Effects

The medical review primarily focused on the analysis of AEs associated with the five clinical studies as

well as AEs reported to the ALCS Consumers Call Center, which included AEs on products similar to

VERVE®. In addition, the medical review evaluated AEs reported in the literature for oral nicotine

products similar to VERVE®. The medical reviewer noted that none of these studies evaluated

biomarkers of potential harm or were designed to evaluate health effects. The studies include one study

assessing associated BOE of a prior version of VERVE® Discs Blue Mint (VBM-FG2), one PK study of

VERVE® Discs Blue Mint prototype products, and three abuse liability studies including either VERVE®

Discs or Chews. Additionally, the medical review analyzed three different categories of scientific

literature submitted by the applicant: a review of the scientific literature on health effects associated

with nicotine and other ingredients in the new products; “authoritative statements” released by public

health agencies on nicotine-associated health effects organized by selected diseases (e.g., cardiovascular

disease, diabetes); and a compilation of diverse interventional and observational studies and case

reports on nicotine-related health effects.

The five studies evaluated in the medical review are as follows:

• Study COV-VER-01-13 / Covance Study No. 8290036

A Randomized, Controlled, Parallel Group Pilot Clinical Study to Determine Changes in

Biomarkers of Exposure (BOE) in Adult Smokers Allowed Ad Libitum VBM-FG2 Disc Use Relative

to Adult Smokers Not Allowed VBM-FG2 Disc Use

• Study ALCS-RA-16-19-VRV / CA201617

Characterization of Nicotine Exposure Profiles and Subjective Measures of VERVE® Discs

Products for Abuse Liability Determination in Adult Smokers Relative to Combustible Cigarettes

and Nicotine Gum (this was repeated due to expired Nicorette gum used in the original study)

• Study ALCS-RA-16-23-VRV / CA20655

Characterization of Nicotine Exposure Profiles and Subjective Measures of Products Currently

Marketed As VERVE® Chews for Abuse Liability Determination in Adult Smokers Relative to

Combustible Cigarettes and Nicotine Gum

• Study ALCS-RA-16-26-VRV / CA21469

Characterization of Nicotine Exposure Profiles and Subjective Measures of VERVE® Discs

Products for Abuse Liability Determination in Adult Smokers Relative to Combustible Cigarettes

and Nicotine Gum (this is the repeated study of ALCS-RA-16-19-VRV)

• Study
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Overall, there were no reports of either serious AEs or deaths in any of the five clinical studies. The

combined total of subjects from each of the studies was 253 participants. Of these, 79 participants

reported a total of 144 AEs. A majority (70.3%) of AEs were assessed by the principal investigators to be

not related or unlikely related to the use of VERVE® products. AEs assessed as likely or possibly related

to the use of VERVE® products comprised 29.7% of all reported AEs.

Additionally, all AEs were assessed by the principal investigators for severity (i.e., mild, moderate, severe

or serious). Of these, 94.5% of AEs reported among study participants using VERVE® products were

considered mild and 5.5% were assessed as moderate. All 27 AEs deemed likely or possibly related to

the use of VERVE® products were considered mild. There were no severe or serious AEs reported.

Respiratory, thoracic and mediastinal disorders comprised 34.1% of all AEs reported in the VERVE®

clinical studies and were the most prevalent system organ class (SOC) for AEs assessed likely or possibly

related to VERVE® products, followed by gastrointestinal (GI) disorders, nervous system disorders and

nutrition and metabolism disorders.

The top Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms identified for AEs likely

or possibly related to VERVE® products were headache, cough, throat irritation, nasal congestion,

oropharyngeal pain, dyspepsia and dizziness.

The medical review of the data from the ALCS Consumer Call Center AE data repository noted that the

information included data collected between May 2012 and December 2017. Four AEs were reported to

the ALCS Consumer Call Center. Three of the four consumers each reported one AE associated with the

use of VERVE® Blue Mint Discs and one consumer reported an AE associated with VERVE® Harvest Blend

discs. Although all four AEs were “mild in severity” and “unexpected,” the three AEs reported in

association with Blue Mint Discs included one incident of choking (2012) and two incidents of tooth

fracture (2013). Detailed background information on these AEs was not provided. The tooth fractures

would have been with a prior version of the current VERVE® product similar to VERVE® Discs Blue Mint.

The applicant notes a change in 2013 to the marketed prior version of the current VERVE® Discs Blue

Mint that included a change in the “product texture”.

In addition to the limited AE information from the applicant’s own data, the PMTAs also included a

summary of authoritative statements from public health agencies regarding generic nicotine health

effects by topic area including cardiovascular, reproductive and developmental, GI, diabetes and

carcinogenicity effects. Multiple references (many of which were foundational in the genesis of these

widely accepted public health statements) on generic nicotine health effects are also cited in this

application.

The applicant’s literature review provides the scientific framework for understanding nicotineassociated health effects; the medical reviewer noted that it does not address potential health risks

linked to VERVE® products. Only two of the numerous studies provided by the applicant were productspecific (37, 46). However, these studies were not designed to assess health effects and neither of the

publications reported AEs.

The applicant acknowledges the paucity of data on health risks associated with VERVE® products and

with oral NRT as a major limitation in predicting health effects specific to VERVE® products. While the

applicant acknowledges limitations and the applicant does not bridge existing data to VERVE® products,

no serious and unexpected AEs were reported. Additionally, the applicant submitted a compilation of

interventional and observational studies and case reports on generic nicotine-associated health effects.
PM0000470 – PM0000473 Page 57 of 104

2.4.6.1. Health Risks to Non-Users

The applicant stated that packaging for the VERVE® Chews and Discs products is child-resistant and

compliant with Consumer Product Safety Commission 16 CFR 1700.15(b)(1). There was no discussion or

specific information regarding accidental exposures or secondary exposures. Use of VERVE® Chews and

Discs products is not associated with significant second-hand exposure which, in this respect, decreases

risk for both users and nonusers.

2.4.6.2. Consumer Use and Potential Misuse

The applicant did not submit any information on consumer use and potential misuse for evaluation in

the medical review. However, the BCP review addressed potential misuse through the evaluation of the

applicant’s actual use studies of VERVE® Discs and Chews. These data indicate that the majority of

consumers use one disc or chew at a time, but approximately 30-43% use two or more discs or chews

simultaneously. Based on the plasma nicotine concentrations associated with VERVE® Discs and Chews

compared to cigarette smoking, it is unlikely that consumers who use 2-3 VERVE® Discs and Chews

simultaneously would be exposed to higher levels of nicotine or other BOE compared to cigarette

smoking. Thirty-eight percent reported using a VERVE® product while smoking a cigarette. There were

no specific data provided to determine how use of multiple VERVE® products during a single use session

or smoking while using VERVE® products may affect BOE. However, based on the plasma nicotine

concentrations associated with VERVE® Discs and Chews compared to cigarette smoking, it is unlikely

that consumers who use 2-3 VERVE® Discs and Chews simultaneously would be exposed to higher levels 

of nicotine or other BOE compared to cigarette smoking. FDA has also determined that there are no

relevant concerns with using NRT gum concurrent with smoking, which has a higher nicotine Cmax than

VERVE® Discs and VERVE® Chews. (52). Therefore, it is unlikely that consumers would be exposed to

greater levels of nicotine or other tobacco-related BOE following misuse of VERVE® Discs and Chews

(based on the incidences of misuse reported in the applicant’s actual use studies).

2.4.6.3. Health Risks Associated with Poly-use

The applicant did not submit any information on the health risks associated with polytobacco use and

VERVE® for evaluation in the medical review. However, the BCP review addressed the poly-use issue.

The applicant’s in-market survey, actual use survey, BOE study, and literature review indicate that most

tobacco users who use VERVE® dual or poly use with cigarettes. In particular, the applicant-submitted

in-market survey, which gives an indication of real-world VERVE® use, found that all current users of

VERVE® products also used one or more other tobacco products. Some smokers may replace one of

their non-cigarette tobacco products with VERVE®, although a small portion (22%) may progress to

polytobacco use with VERVE® products. Approximately half of smokers (51%) who used multiple tobacco 

products, including VERVE®, generally decreased their CPD while using VERVE®, while the other half of

smokers either maintained (38%) or increased (11%) their CPD. For other tobacco product use, the

majority of smokers reported either maintaining (47%) or increasing (15%) their non-cigarette tobacco

use when starting VERVE®. As VERVE® and oral tobacco products are actually used (i.e., dual or poly-use

while maintaining or modestly reducing CPD or other tobacco use), consumers are unlikely to

experience significant reductions in BOE compared to exclusive UB cigarette smoking. However, if

consumers were interested in using VERVE® to reduce CPD, studies suggest that a 60% reduction in CPD

while using oral tobacco products may lead to significant reductions in many BOE compared to exclusive

UB cigarette smoking. Even a modest reduction (< 50%) in daily cigarette consumption may reduce the

risk of tobacco related disease due to a decreased exposure to HPHCs.
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2.4.6.4. Health Risks Associated with Switching to these Products Compared to Continued

Smoking

The BCP review addressed the likelihood of and health effects associated with switching to use of

VERVE® products from cigarettes smoking. The applicant-submitted literature review indicates that

smokers who switch completely to oral nicotine tobacco products reduce exposure to several BOE

associated with cigarette smoking, including TNE, CO, and COHb. The applicant-submitted 6-week actual

use study indicates that a subset of smokers report switching completely to VERVE® products (11%).

Controlled trials (identified from the applicant-submitted literature review) found that smokers who

switched completely to oral nicotine tobacco products or who immediately reduced CPD by 60% or

more upon initiating use of oral nicotine tobacco products significantly reduced exposure to TNE, CO,

COHb, and other non-nicotine BOE. However, smokers who reduced CPD gradually over 3 weeks did not

significantly differ in BOE from UB cigarette smokers. Given the bridging information for VERVE® and

other oral dissolvable tobacco products (provided by the chemistry reviewer; see Appendix Tables 16

and 17), if smokers gradually reduce and ultimately maintain a 60% reduction in CPD while using

VERVE®, it is likely that nicotine and many other non-nicotine BOE would be reduced. Among smokers

who switch completely to oral tobacco products, CO levels are comparable to being tobacco abstinent

(i.e., comparable to smokers who abstained from all tobacco use for 5 days). However, given that these

outcomes in the actual use studies and the literature review were based on short-term assessments

(e.g., one week of use) and products were often provided free of charge, the generalizability of these

findings to real-world use is limited. The applicant’s in-market evaluations of VERVE®, which provided

real-world assessment of VERVE® products on the market, found that 13% of smokers replaced their

non-cigarette tobacco use with VERVE® (but continued smoking) and 2% of smokers switched from

cigarettes to VERVE® (but continued using other non-cigarette tobacco products). No current VERVE®

consumers switched completely from all tobacco products to exclusive VERVE® use. Furthermore, the

applicant’s abuse liability studies indicated that abuse liability and acceptability of VERVE® products is 

lower than for UB cigarettes and comparable to NRT gum. The 12-week actual use studies indicated that

VERVE® acceptability among smokers declines over time. Therefore, only a small percentage of smokers

are likely to switch to exclusive VERVE® product use.

2.4.6.5. Health Risks Associated with Switching to this Product Compared to Tobacco

Cessation

The applicant did not provide information comparing the short- and long-term health effects of

complete or incomplete VERVE® switching to abstinence. However, the BCP review addressed the health

effects associated with switching to use of VERVE® products from cigarettes smoking compared to

tobacco cessation. The applicant's in-market survey and literature review indicate a low likelihood of

former smokers relapsing to tobacco use with VERVE® or oral tobacco products. The in-market survey

evaluated the percentage of VERVE® product ever triers who had been former tobacco users and then

relapsed to using the tobacco product they had quit. No VERVE® product ever triers reported reinitiating cigarette smoking after first trying a VERVE® product. Two percent of VERVE® product ever

triers reported re-initiating to another tobacco product (other than cigarettes and VERVE®) after first

trying a VERVE® product.

The in-market survey also indicates that 4-5% of VERVE® ever triers quit using all tobacco products after

trying VERVE® products; however, it cannot be determined whether VERVE® was the catalyst for

tobacco product cessation. A study in the literature review indicates that 20-25% of smokers interested

in quitting smoking maintain use of oral tobacco products instead of quitting cigarettes; however,

participants were instructed on how to use the oral tobacco products to assist with quitting smoking and

it is unclear whether consumers would normally initiate these non-NRT products with the intent of
PM0000470 – PM0000473 Page 59 of 104

quitting smoking. Given that the consumer population most likely to initiate VERVE® use is current

smokers who also use one or more other tobacco products and that VERVE® products will not be

marketed as cessation products, it is unlikely that smokers who are interested or motivated to quit

smoking would initiate VERVE® for this purpose. However, based on the BOE data provided and bridging

data on HPHCs present in VERVE® Discs and Chews compared to other tobacco products (Appendix

Tables 16 and 17), if consumers quit smoking or substantially reduce their CPD (i.e., by 60% or greater)

but continue use of VERVE® products, exposure to many HPHCs, including nicotine, CO, COHb, and other

non-nicotine BOE, would be significantly reduced compared to smoking cigarettes.

2.4.6.6. Health Risks Associated with Switching to Product Compared to Cessation

Medication

The applicant did not provide clinical data to evaluate the relative health risks of switching to VERVE®

products compared to cessation medication. However, as the BCP review noted, based on the BOE data

provided and bridging data on HPHCs present in VERVE® Discs and Chews compared to other tobacco

products (Appendix Tables 16 and 17), if consumers quit smoking or substantially reduce their CPD (i.e.,

by 60% or greater) but continue use of VERVE® products, exposure to many HPHCs, including nicotine,

CO, COHb, and other non-nicotine BOE, would be reduced compared to smoking cigarettes.

2.4.6.7. Summary of Adverse Health Effects

The applicant submitted a dearth of health effects data specific to VERVE® products. The five short-term

clinical studies that were submitted with this application did not include clinical endpoints or BOPH. No

serious AEs were reported, and the majority of reported AEs were mild in severity. Additionally, data

from the ALCS Consumer Call Center were quite limited and did not inform an assessment of health

effects. In lieu of providing product-specific substantive evidence regarding the health impact of VERVE®

products, the applicant conducted an integrated nonclinical and clinical risk assessment. The applicant

stated that its approach assumes that “any health risks would be related to the individual ingredients...”

Health effects associated with individual ingredients are addressed in Section 2.3 of this review.

The applicant has demonstrated that, if smokers were to switch to the VERVE® Discs and Chews (i.e.,

quitting cigarettes), there would likely be health benefits. There would likely also be health benefits if 

smokers reduced their cigarette use due to use of the VERVE® products. As the review of the PMTAs

shows, dual or poly use is common with oral tobacco products, including the VERVE® products. The

HPHC information also indicates the potential for health benefits if a polytobacco user were to replace a 

smokeless tobacco product with a VERVE® product.

2.4.7. Likelihood of Product Misuse or Malfunction

The applicant did not submit information on potential misuse or malfunction of the VERVE® products.

However, as noted in section 2.4.6.2 of this review, it is unlikely that a user of VERVE® products would

be exposed to greater nicotine or other tobacco-related BOE following misuse of VERVE® Discs and

Chews. This is based on the applicant’s actual use studies.

2.4.8. Bioresearch Monitoring (BIMO) Inspection

OS reviewers did not identify any substantive concerns pertaining to the submitted clinical studies and

did not recommend BIMO inspection. FDA’s Office of Compliance (OCE) review of the submission did not

reveal any data integrity or human subject protection concerns and agreed with OS reviewers that BIMO

inspections for the protocols submitted and associated sites were not warranted.
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2.4.9. Summary of Individual Health Findings

The BCP review concluded that VERVE® Discs and Chews in Blue Mint and Green Mint flavors are

associated with lower plasma nicotine concentrations and lower positive subjective ratings compared to

UB cigarettes, reducing their abuse liability and likelihood of use for youth, non-smokers, and former

smokers. The abuse liability of VERVE® products was similar to that of nicotine gum.

Current smokers who also use one or more other tobacco products are the consumer population most

likely to try VERVE® products. The data and literature review submitted by the applicant suggest that

smokers who completely switch to VERVE® products or reduce their CPD by 60% or more upon initiating

oral tobacco products may reduce their exposure to nicotine and other non-nicotine BOE. However, low

subjective appeal and increased craving and withdrawal may prevent current smokers from fully

transitioning to VERVE® products. Data from the applicant’s submitted studies suggest that few smokers

(11%) switch completely to VERVE® or oral tobacco products, but these data are based on one week of 

use and do not reflect the measured decline in VERVE® acceptability among smokers that was captured

in the applicant’s 12-week actual use study. Therefore, the percentage of complete switching would

likely be lower than the identified percentage in the applicant’s study. Dual or poly use is the primary

use behavior expected of VERVE® product users. Smokers who dual use VERVE® products with cigarettes

and do not substantially reduce their CPD (i.e., by 60% or greater) do not reduce their exposure to

nicotine or non-nicotine BOE.

As TPL, I agree with the BCP review conclusions that if smokers switch to VERVE® or significantly reduce

CPD, they would see a reduction in BOE. Certainly, the likelihood of a larger number of smokers making

such changes is low, given the low appeal of the product and the polytobacco use with oral tobacco

products. However, data support the potential for a small percentage of smokers to make such changes.

Additionally, the reduced abuse liability and likelihood of use by youth, as well as non- and formersmokers, is small for the VERVE® products if marketed.

The medical review concluded the following:

• There was a dearth of health effects data associated with VERVE® products in this

application. Although five short-term clinical studies were submitted relating to VERVE®

products, prior versions, or prototypes, they were not designed to collect individual health 

data. Moreover, none of the studies included clinical endpoints or BOPH data.

• The AE findings for each of the five clinical studies did not provide additional clinical insight

on potential health risks related to VERVE® products. Consequently, these data were neither

substantive nor helpful in addressing short-term or long-term health effects associated with

the new products.

• The AE data culled from the ALCS Consumer Call Center represented events that occurred in

2012 and 2013 and may be linked to earlier versions of VERVE® Discs Blue Mint. Since the

applicant did not cite potential differences between the prior versions of VERVE® Discs Blue

Mint and the current VERVE® product, the applicability of these AE reports is unclear.

• Data compiled from the published literature on AEs associated with similar products do not

provide substantive clinical evidence to identify potential health risks associated with

VERVE® products.

• Although multiple authoritative statements on the effects of nicotine on organ systems

were referenced by the applicant, specific bridging of these findings to the VERVE® products

is absent from this application.

• The applicant does not bridge findings from generic nicotine studies to the use of nicotine in

the context of VERVE® products.
PM0000470 – PM0000473 Page 61 of 104

• The applicant attempts to extrapolate data from NRT studies to the new products; however,

the applicant did not present studies to corroborate these inferences.

The medical review concluded that there are limitations in demonstrating the potential health impact of

the new products on users and that the applicant did not bridge data from the published literature and

early VERVE® prototypes and prior versions of VERVE® Discs Blue Mint to the PMTA VERVE® products.

Overall, the medical review concluded that, from the medical perspective, the information presented in

the application has two limitations, described below.

First, although the applicant acknowledges the evolution of VERVE® products from earlier generations,

the applicant does not explain the similarities and differences between each of the earlier prototypes

and the current new products or the potential effects on user behavior, exposure and health risks.

Additionally, detailed information regarding composition and formulation changes during each

generation was not submitted. From the medical perspective, we are unable to bridge information from

the prototypes to the new products in the clinical studies, which limits the medical assessment.

Additional information is necessary for FDA assess the prototype differences with respect to user

behavior, exposure and health risks - specifically: identifying information (i.e., name(s) of the prototype

and reference number(s); years when the prototype was initially created, marketed, and removed from

the market (if applicable); and title and year of all industry and non-industry sponsored research studies

associated with each prototype.

Second, the applicant’s assessment of health risks is based on a clinical assessment of nicotine and a

non-clinical assessment for other ingredients. Although the applicant references multiple studies on

generic nicotine- and NRT-associated health effects, these findings are not bridged to the new products.

FDA needs detailed information from the scientific literature to assess potential differences in user

exposure and the health effects of these new products. Bridging information to justify extrapolating

findings from generic nicotine and NRT studies to substantiate health effects for the current new

tobacco products is necessary to adequately assess the applicant’s health risk assessment.

As TPL, I agree with the medical review in that insufficient clinical study data was submitted with this

PMTA. Clinical studies designed to delineate the health effects of new products, alone and in

combination with other tobacco products if there is evidence that the new products would be used in

conjunction with other tobacco products, can provide evidence of short-term, and possibly long-term,

health effects. However, the chemical composition of the new products, along with adequate toxicology

information on ingredients, provide sufficient information to support an overall determination that the

marketing of new products, from the standpoint of potential adverse health effects, are appropriate for

the protection of the public health. In addition, the limited information available on AEs, though not

designed to evaluate health effects, does not raise concerns about issuing marketing orders. There is

also information from the ALCS Consumers Call Center when the first- and second-generation (Gen 1

and 2) VERVE® Discs Blue Mint products, and then later the current four new products, were on the

market in Virginia. These sources of information do not indicate any SAEs.

2.5. Population Health

Several studies in the PMTAs provided information regarding the likelihood of use of the VERVE®

products. These include: (1) 6-week actual use study of oral tobacco-derived nicotine products currently

marketed as VERVE® Discs and VERVE® Chews, (2) VERVE® Discs 12-Week Extended Home Use Test Final

Report Final—PowerPoint Presentation, and (3) ALCS In-Market Adult Consumer Study (MACS): Oral

Tobacco-Derived Nicotine Products Currently Marketed as VERVE® Products. These studies were

evaluated in both the epidemiology and BCP reviews.
PM0000470 – PM0000473 Page 62 of 104

2.5.1. Likelihood of Use by Current Cigarette Smokers

The epidemiology review evaluated the applicant’s 6-week actual use study in which the applicant

presented evidence that smokers can adopt the use of VERVE® products within study conditions. The

review also evaluated the results of an in-market cross-sectional VERVE® use survey (MACS) to support

this finding. Studies indicate that 2-17% of current cigarette smokers can switch completely to VERVE®

under actual use study conditions and free product availability, and a modest proportion of other

tobacco product users and cigarette smokers (11%) can completely switch to VERVE®. However, most

current tobacco users co-use VERVE® and cigarettes or other tobacco products (77-84%). MACS data

indicated that 2% of current VERVE® users who reported daily or non-daily use in the past 30 days 

completely switched from cigarette smoking (retrospective exposure assessment). Because of free

product availability and retrospective self-report, the actual use study results likely represent an upperbound estimate of product use, and the results of the MACS are likely a more reasonable estimate.

Taken together, research submitted by the applicant demonstrates that there is limited evidence that

current cigarette smokers, including those intending to quit, would switch completely to the new

tobacco products as currently used by consumers.

The BCP review also evaluated the likelihood of use by current tobacco product users. The BCP review

noted that the applicant states that VERVE® products are designed to appeal to adult tobacco

consumers, particularly adult cigarette consumers, who are interested in an alternative to their current

tobacco product. The literature review and applicant-submitted studies support that current smokers

are the population most likely to try oral tobacco products, including dissolvable tobacco and VERVE®

products, often due to curiosity. Smokers interested in reducing cigarette smoking may also be

motivated to start using oral tobacco products. However, the applicant’s submitted abuse liability

studies indicate that VERVE® Discs and Chews do not deliver nicotine as well as cigarettes and are not

liked as much as UB cigarettes. The applicant’s 12-week actual use study for a prior version of VERVE®

Discs Blue Mint (Gen 1) also noted that product acceptability among smokers declined from Week 4 to

Week 12 during the study. Therefore, VERVE® products are unlikely to be a suitable substitute for

cigarettes, which reduces the likelihood of continued use for most smokers.

Current smokers who also use one or more other tobacco products are the consumer population most

likely to try VERVE® products. The data and literature review submitted by the applicant suggest that

smokers who completely switch to VERVE® products or reduce their CPD by 60% or more upon initiating

oral tobacco products may significantly reduce their exposure to nicotine and other non-nicotine BOE.

However, low subjective appeal and increased craving and withdrawal may prevent current smokers

from fully transitioning to VERVE® products. Data from the applicant’s 6-week actual use study suggest

that few smokers (11%) switch completely to VERVE® or other oral tobacco products, but these data are

based on a single week (Week 6) in the 6-week study and do not reflect the measured decline in VERVE®

acceptability among smokers that was captured in the applicant’s 12-week actual use study for a prior

version of VERVE® Discs Blue Mint (Gen 1). Therefore, the percentage of complete switching would likely

be lower than the identified percentage in the applicant’s study. Dual or poly use is the primary use

behavior expected of VERVE® product users.

The BCP review noted that the in-market survey also indicates that 4-5% of VERVE® ever triers quit using

all tobacco products after trying VERVE® products; however, it cannot be determined whether VERVE®

was the catalyst for tobacco product cessation. A study in the literature review indicates that 20-25% of

smokers interested in quitting smoking maintain use of oral tobacco products instead of quitting

cigarettes; however, participants were instructed on how to use the oral tobacco products to assist with

quitting smoking and it is unclear whether consumers would normally initiate these non-NRT products
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with the intent of quitting smoking. Given that the consumer population most likely to initiate VERVE®

use is current smokers who also use one or more other tobacco products and that VERVE® products will

not be marketed as cessation products, it is unlikely that smokers who are interested or motivated to

quit smoking would initiate VERVE® for this purpose. However, based on the BOE data provided and

bridging data on HPHCs present in VERVE® Discs and Chews compared to other tobacco products

(Appendix Tables 16 and 17), if consumers quit smoking but continue use of VERVE® products, exposure

to many HPHCs, including nicotine, CO, COHb, and other non-nicotine BOE, would be reduced compared

to smoking cigarettes.

2.5.2. Summary of Likelihood of Use by Current Cigarette Smokers

As TPL, I agree with the epidemiology and BCP reviews and the conclusion that there is limited evidence

that current smokers would switch completely to the VERVE® products. While 2-17% of smokers did

switch completely to VERVE® in the applicant’s studies, the actual use studies have limitations and 17%

is likely an upper-bound estimate; the in-market VERVE® use survey, which noted 2% of current VERVE®

users switched from cigarette use, is likely more accurate. However, results do not suggest that smokers

are likely to increase their overall tobacco product use when initiating VERVE® Discs or Chews; BOE were

not increased in study participants allowed cigarettes ad libitum.

2.5.3. Poly Use of VERVE® and Cigarettes or Other Tobacco Products

The epidemiology review noted that 52% (n=270) of the applicant’s actual use study participants, upon 

enrollment, reported also using other tobacco products in the past 30 days. Therefore, poly use was

common among participants (all were past 30-day smokers, and over half were also other tobacco

product users). Based on the MACS and the 6-week actual use study, the applicant confirmed that most

VERVE® users are dual or poly users of VERVE® products with other products; however, the applicant

also notes that a reduction in cigarette consumption accompanies co-use of tobacco products. At the

end of the 6-week actual use study, all participants (100%) reported "starting to use" a VERVE® product,

which was defined as using 20 or more VERVE® Discs or Chews during the 6-week study. The proportion

of participants that reported using VERVE® products only during the study increased from 7.35 % in 

Week 1 to 17.41% in Week 6, while the prevalence of dual or poly use of VERVE® with other tobacco

products including cigarettes decreased.

The epidemiology review noted that observational studies submitted in support of this application 

demonstrate that dual use of VERVE® with cigarettes is common among adult VERVE® product users. In 

the 6-week actual use study, among participants who completed the 6-week study and the end of study 

(EOS) survey, 17.4% reported using VERVE® only (complete switchers), 1.4% reported only cigarette 

smoking, 64.4% reported dual using VERVE® and cigarettes, 5.8% reported using VERVE® and other oral 

tobacco products, and 10.4% reported using VERVE® and other tobacco products and cigarettes. Among 

those who completed the study and who reported past 30-day use of other tobacco products at 

screening (137 of total n= 517), 20.4% reported dual use of VERVE® and other tobacco products at the 

EOS. The applicant noted that the proportion of participants who reported dual using at screening 

decreased over time in the actual use study. The applicant stated that although dual use with cigarettes 

is the predominant VERVE® tobacco user pattern, dual users report a reduction in CPD. In the actual use 

study, 58% of the total study sample (2-day pilot test and 6-week actual use test) reduced their 

screening-level daily cigarette consumption by 20% or more on days smoked, and of this group 77% 

were dual users. Screening to Week 1 CPD consumption decreased by 5 CPD (13 to 8 CPD), while Week 

1 to Week 6 CPD reduction was 2 CPD (8 CPD to 6 CPD). In the MACS, the applicant stated that 48 of 52

(92.3%) current VERVE® product users were dual users with cigarettes, and 50% of these users reported

using fewer cigarettes when using VERVE® than before starting to use VERVE®. The applicant further
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claimed that the amount of VERVE® use is related to the number of CPD in both the actual use study and

the MACS. In the actual use study, regression analyses suggested a statistically significant decrease in

CPD consumed by number of VERVE® products consumed (beta=-0.15 (95% Cl -0.17, -0.14)). Overall,

given the totality of tobacco use behavior data submitted by the applicant, it appears highly likely that

most VERVE® product users would also use other tobacco products including cigarettes, and among dual

users the reduction in smoking is modest (2-3 CPD). Epidemiological studies indicate that the health

benefit of smoking reduction (CPD) by less than 50% is unclear. However, some participants were able

to reduce CPD by 50% or more (n=8).

The BCP review noted that in the 6-week actual use study, the percentage of participants who reported

using only VERVE® and no other tobacco products increased from 7% to 17% across the 6-week study.

The percentage of participants who reported using VERVE®, cigarettes, and other tobacco products (i.e., 

polytobacco users) declined from 20% to 10% during the study. Alternatively, the percentage of dual

users (VERVE® and cigarettes or VERVE® and other tobacco products) did not substantially change over

the 6-week use period. Overall, the percentage of participants who reported using VERVE® with any

tobacco product (cigarettes and one or more other tobacco products) declined from 93% (Week 1) to

81% (Week 6). The findings in this study, according to the BCP review, suggest that the majority of

smokers who initiate use of VERVE® products may become dual users of cigarettes and VERVE®.

Smokers who dual use cigarettes and VERVE® decrease their CPD by a net 20% from prior to using

VERVE®. Of smokers who also currently use other tobacco products, the majority may replace their noncigarette tobacco product use with VERVE®. Twenty-two percent of participants may become poly users

of cigarettes, other tobacco products, and VERVE®. However, the decreases in prevalence of cigarette

smoking and other tobacco product use across 6 weeks when initiating use of VERVE® suggest that some

smokers may titrate their product use to maintain sufficient levels of nicotine. Results do not suggest

that smokers increase their overall tobacco product use when initiating VERVE® Discs or Chews.

The BCP review concluded that the MACS, actual use survey, BOE study, and literature review indicate 

that most tobacco users who use VERVE® dual or poly use with cigarettes. In particular, the applicantsubmitted in-market survey, which gives an indication of real-world VERVE® use, found that all current 

users of VERVE® products also used one or more other tobacco products. Some smokers may replace 

one of their non-cigarette tobacco products with VERVE®, although a portion (22%) may progress to 

polytobacco use with VERVE® products. Approximately half of smokers (51%) who used multiple tobacco 

products, including VERVE®, generally decreased their CPD while using VERVE®, while the other half 

either maintained (38%) or increased (11%) their CPD. For other tobacco product use, the majority of 

smokers reported either maintaining (47%) or increasing (15%) their non-cigarette tobacco use when 

starting VERVE®. As VERVE® and oral tobacco products are actually used (i.e., dual or poly use while 

maintaining or modestly reducing CPD or other tobacco use), consumers are unlikely to experience 

significant reductions in BOE compared to exclusive UB cigarette smoking. However, if consumers were 

interested in using VERVE® to reduce CPD, studies suggest that a 60% reduction in CPD while using oral 

tobacco products may lead to significant reductions in many BOE compared to exclusive UB cigarette 

smoking.

2.5.4. Summary of Poly Use

As TPL, I agree with the epidemiology and BCP reviews that there is evidence that smokers who use

VERVE® are likely to use other tobacco products including cigarettes; however, their total combusted

tobacco product consumption and toxicant exposure are not likely to increase and may be lower for the

small percentage of poly users who reduce overall CPDs compared to smokers who do not reduce

overall CPD. Further, the results of the clinical AUS suggests a substantial proportion of non-cigarette

tobacco users (46-68%) successfully switch to the new tobacco product. HPHC information submitted by
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the applicant indicates the potential for health benefits if a polytobacco user were to replace a 

smokeless tobacco product with a VERVE® product.

2.5.5 Use by Former or Never Smokers

The epidemiology review noted the applicant presented evidence using surrogate products to

demonstrate that initiation of tobacco use with VERVE® products is unlikely. Prevalence of use of

dissolvable tobacco products and NRT is low, and prevalence of dissolvables as the first tobacco product

used is <1%. ln the MACS, in which the applicant surveyed VERVE® product users in the test market

(Virginia), there were no adult participants who reported first tobacco use with VERVE® products.

Among adult users of VERVE® products, two MACS participants (1%) reported re-initiation of tobacco

products using VERVE® after successful smoking cessation for six months or more, and both reported couse of other tobacco products with VERVE®. Synthesizing data across diverse lines of evidence, the

applicant concluded that the likelihood that adult nonusers will initiate tobacco product use with

VERVE® is low. This conclusion is based upon results from the Perception and Behavioral Intention (PBI)

study, which indicate a low intention to try and to use the product among adults, including young adults

aged 18-24 years, and the observation that most VERVE® users in the MACS were current tobacco users

when they first started to use VERVE® (there was little evidence of tobacco use initiation with VERVE®

products from the cross-sectional survey). The applicant extrapolated results regarding youth initiation

of tobacco use with dissolvable tobacco products and NRT from national surveys to potential youth use

of VERVE® products and concluded that the prevalence of use of dissolvable tobacco products among

youth would be low. Furthermore, the applicant stated that given that the likelihood of nonusers

initiating tobacco use with VERVE® is low, the probability of transitioning to cigarettes is also low. The

applicant cited results of its own secondary data analysis, which illustrates that use of dissolvable

tobacco products is associated with lower probability of future cigarette smoking (PATH data). Overall,

the applicant concluded that the effect of marketing VERVE® products on nonusers is likely to be small.

Therefore, using both surrogate data and direct surveys, the applicant supports that the probability of

initiation or re-initiation of tobacco use with VERVE® products is low.

There are no longitudinal data to assess the probability of nonuser initiation of tobacco use with VERVE®

products. The applicant’s MACS reported that among VERVE® current and past product users who

enrolled in the survey, none reported that their first tobacco product ever tried or ever tried 

consistently was a VERVE® product. Results of the applicant’s literature review support that less than 2%

(1.2-1.6%) of adults report ever trying a dissolvable tobacco product. Furthermore, among college

students, the applicant cited studies in which 4.5% of participants reported using an “emerging tobacco

product” including a dissolvable, snus or e-cigarette as the first tobacco product ever tried, and most

reported use of e-cigarettes. ln the same study of college students, less than 1% (0.1%) of participants

reported initiation with a dissolvable tobacco product among current tobacco users. The applicant 

stated that in the PATH Wave 1 study data, the prevalence of current use of dissolvable tobacco

products was 0.2% among young adults and 0.1% among adults. Results of the applicant’s literature

review support that 1.2-1.6% of current tobacco users initiate tobacco use with a dissolvable, NRT, or

other oral tobacco product. Extending these results to the VERVE® products, the applicant concludes

that the likelihood that adult nonusers will initiate tobacco product use with the new products is low.

Regarding re-initiation of tobacco use with VERVE®, the MACS identified two VERVE® ever-triers (1%)

who reported smoking cessation for 6 months or longer before first trying a VERVE® product, and there

were no other tobacco product users who had quit for 6 months or longer prior to first trying VERVE®.

The BCP review also assessed the potential for use by former or never smokers and the potential to

progress to cigarette use. According to the BCP review, initiation among non-users for dissolvable
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tobacco products is low, and current smokers do not report that they first initiated using tobacco with

VERVE® products. These findings are supported by the applicant’s literature review, which discusses

initiation of oral tobacco products (e.g., dissolvable tobacco products) and the applicant’s actual use

studies on VERVE® products. Therefore, it is not anticipated that non-users will initiate tobacco use with

VERVE®, and for those who do, there is low likelihood that they will progress to regular use of VERVE®,

cigarettes, or other tobacco products after trying VERVE®. There is also low likelihood that former

smokers will relapse to smoking if they try VERVE®; however, a small subset (2%) of smokers who report

quitting other forms of tobacco may try VERVE® and relapse to non-cigarette tobacco product use.

Smokers who currently use one or more other tobacco products are the most likely tobacco users to

initiate and continue use of VERVE® or dissolvable tobacco products. The applicant-submitted actual use

studies suggest that among current smokers who ever tried VERVE® products, none reported that they

initiated tobacco product use with VERVE® products and later switched to cigarettes or other tobacco

products. Studies in the literature review and the applicant’s clinical studies support that nicotine

delivery and subjective ratings for VERVE® and dissolvable tobacco products are low compared to

cigarettes, indicating that these products have lower abuse liability compared to cigarettes. Given the

low prevalence of initiation with oral dissolvable tobacco products among never users and the low 

abuse liability of VERVE® and oral dissolvable tobacco products, it is not anticipated that never users

would initiate tobacco use with VERVE® and progress to regular use of VERVE®, cigarettes, or other

tobacco products.

Based on the applicant’s clinical studies, the BCP review concluded that the VERVE® products are

associated with lower plasma nicotine concentrations and lower positive subjective ratings compared to

UB cigarettes, reducing their abuse liability and likelihood of use for non-smokers and former smokers.

2.5.6 Summary of Use by Former or Never Smokers

As TPL, I agree with the epidemiology review that across the actual use study, MACS, literature reviews, 

and original data analyses presented to describe VERVE® product use and tobacco use behavior, the 

applicant demonstrated that: a large proportion of current tobacco users can start using VERVE® under 

actual use study conditions and free product availability; a modest proportion of current smokers switch 

completely to VERVE® product use (2% in the MACS, 17% in the actual use study); and 11% completely 

switch from all other tobacco product use. I agree with the BCP review that it is not anticipated that 

non-users will initiate tobacco use with VERVE®, and for those who do, there is low likelihood that they 

will progress to regular use of VERVE®, cigarettes, or other tobacco products after trying VERVE®. 

Submitted data suggest that there is also low likelihood that former smokers will relapse to smoking if 

they try VERVE®; however, a small subset (2%) of smokers who report quitting other forms of tobacco 

may try VERVE® and relapse to non-cigarette tobacco product use.

2.5.7 Use by Vulnerable Populations

2.5.7.1. Youth

The BCP review evaluated the applicant-submitted literature review to determine the likelihood that

individuals, particularly youth and young adults, who initiate with dissolvable tobacco products similar

to VERVE® would progress to regular tobacco product use. This assessment includes the likelihood of

progression to regular tobacco use among never smokers and the likelihood of increased, dual, and/or

polytobacco use among current smokers who start using dissolvable tobacco products.

Among youth, data also suggest that initiation and use of dissolvable products is low. A study using 2012

National Youth Tobacco Survey (NYTS) data of 11,667 middle school and 12,899 high school students
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found that ever use of dissolvables was 1.4% and 2.5% among middle and high school students,

respectively (50). Ever and current use of dissolvables was highest among youth who currently used

other tobacco products (50). We note that dissolvable use is no longer estimated separately in the NYTS;

Since 2013, the definition of smokeless tobacco use has broadened to include chewing tobacco, snuff,

dip, snus, or dissolvable products. The 2020 NYTS reports current use of smokeless tobacco among

surveyed to be 3.1% for high school students and 1.2% for middle school students (54). Data from

another study evaluated past and current use of tobacco products among university students in North

Carolina and Virginia. Among 1,656 students who reported current or former tobacco use, none had

tried dissolvables as their first product (52). Among 743 current cigarette smokers in the study, 0.1%

reported dissolvables as the first tobacco product tried, compared to 65% who reported cigarettes as

the first tobacco product ever tried (52). Overall, studies from the literature indicate that less than 1% of

non-users (youth and adults) initiate tobacco use with dissolvable tobacco products. Current tobacco

users are the most likely to try dissolvable products, and dual users are the most likely to continue use

of dissolvable tobacco products.

The BCP review also noted that in the applicant’s clinical studies, VERVE® Discs and Chews in Blue Mint

and Green Mint flavors are associated with lower plasma nicotine concentrations and lower positive

subjective ratings compared to UB cigarettes, reducing their abuse liability and likelihood of use for

youth, non-smokers, and former smokers.

In addition, the epidemiology review noted that the applicant reported that awareness of dissolvable

tobacco products among youth is very low and reported an 0.1% prevalence estimate of adolescents

who have ever used dissolvable tobacco products. In PATH, among the only 10 youth participants who

used a dissolvable tobacco product, they used no more than 10 occasions in their lifetime and most

(>70%) did not report use in the last 30 days. In the 2012 National Youth Tobacco Survey (NYTS), 2% of

middle and high school students reported ever use of dissolvable products, and 0.7% reported past 30- 

day use. In the Monitoring the Future (MTF) study, use among 12th graders was 1.4%. The applicant

extrapolated results regarding youth initiation of tobacco use with dissolvable tobacco products and

NRT from national surveys to potential youth use of VERVE® products and concluded the prevalence of

use of dissolvable tobacco products among youth would be low.

2.5.8. Summary of Use by Vulnerable Populations

As TPL, I agree with the epidemiology and BCP reviews that note that the information extrapolating

dissolvable tobacco products to VERVE® from the literature and from national survey data support that

there is little likelihood of youth initiating tobacco use with VERVE®. Also, the applicant’s clinical studies

show that the VERVE® products have lower plasma nicotine levels and lower subjective ratings

compared to the participants’ UB cigarettes, showing reduced abuse liability for the VERVE® products

and therefore reduced likelihood of use by youth.

2.5.9. Population Modeling

To investigate the impact of VERVE® on the population as a whole, taking into consideration users and

non-users of tobacco products, the applicant submitted the ALCS Agent-Based Model (ALCS ABM). The

model keeps track of tobacco product use prevalence and all-cause mortality in a hypothetical

population exposed to two tobacco product use behavior scenarios:

• Base Case Scenario: The prevalent behavior is the use of cigarettes together with a

combination of snus and dissolvable tobacco products. The combination of snus and
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dissolvable tobacco products is labelled as Novel Smokeless Tobacco (NST) products in the

applications.

• Modified Case Scenario: Similar behavior as in the base case scenario with the addition of

VERVE® (i.e., incorporating the VERVE® products into the NST products).

The statistics review noted two main limitations with the model. The model uses the year 2014 to

introduce the NST product in the Base Case scenario and year 2018 to introduce VERVE® in the Modified

Case scenario; this appears to be related to the availability of empirical data to inform input parameters

(initiation, cessation, relapse, and others). However, the transition probability of smokers switching to

VERVE® was derived from the applicant’s 6-week actual use study, which includes VERVE® only. Other

transition probabilities related to the VERVE® products were obtained in combination with the NST

products. Thus, comparing the results between the two scenarios may not be sufficient to isolate the

impact of VERVE® on the population based on all-cause mortality. That is, because the modified case

scenario includes VERVE® in combination with NST products, it might not be possible to isolate the

absolute impact of VERVE® on the U.S. population. Note also that because of the nature of the study

design of the actual use study, the results of that study are not representative of the U.S population.

Though these limitations could limit generalizability of the outputs from the model to the U.S.

population, the study informs our evaluation of actual use.

The statistics review also noted that the approach outlined in the PMTAs to estimate mortality rates has

several limitations. The approach was driven by the data sources the applicant selected to derive

mortality rates. Other data sources could have resulted in a more reliable approach to estimate

mortality rates. For example, a data source traditionally used to estimate mortality rates for the

development of population models in tobacco regulatory science is the CDC mortality-link file. The

statistics review concluded that, due to model limitations, the evidence generated from this model

cannot solely provide evidence on the impact of VERVE® on the U.S. population.

The epidemiology review evaluated the applicant’s public health impact (PHI) model. The model

estimated that the introduction of VERVE® into the U.S. tobacco marketplace would reduce smoking

prevalence by 0.07%, resulting in 19,000 smoking-related deaths averted over the 60-year modeling

period. Modelers utilized publicly available data sources and justifiable modeling assumptions to

produce this estimate. However, the estimate of prevalence of use of VERVE® use among smokers is

derived from the applicant’s actual use study and is likely overestimated due to elements of the study

design, i.e., recruitment of high proportion of smokers who were former oral tobacco product users. It is

pertinent to note that any AUS study will be performed under experiment conditions that cannot

perfectly represent real-world conditions. The applicant acknowledged that changing the prevalence of

VERVE® use greatly influences model estimates. The model estimated that a 0.56% reduction in smoking

prevalence due to switching completely to VERVE® results in 146,000 deaths prevented, as compared to

19,000 deaths prevented in the main analysis. Conversely, they stated a 300% increase in VERVE®

initiation among non-tobacco users (never and former smokers) would need to take place to obviate the

benefit of smokers switching to the product.

2.5.10. Summary of Population Modeling

The epidemiology review noted that the applicant’s model estimates 19,000 smoking-related deaths

averted over the 60-year period due to the introduction of VERVE® to the U.S. market. While the

statistics review noted limitations to the model, the epidemiology review concluded that the modelers

used reasonable assumptions in the model. The epidemiology review does assert that the model likely

overestimates the deaths averted due to the limitations in the actual use study design. While the

statistics review noted that the model cannot solely provide evidence of the public health impact of
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VERVE® on the U.S. population, the model is not the sole evidence of public health benefit provided in

the PMTAs.

As TPL, I agree with the epidemiology review that the model estimate is likely an overestimate based on

the actual use study data; however, the model does not predict an increase in smoking-related deaths

due to the introduction of VERVE® into the U.S. market. While I agree with the statistics review

regarding the limitations of the model (i.e., it might not be possible to isolate the absolute impact of

VERVE® on the U.S. population because the model scenario includes VERVE® in combination with NST

products) , the epidemiology review noted that the assumptions used are justifiable. The model,

therefore, can be viewed as one piece of evidence that the introduction of VERVE® has the potential to

avert some smoking-related deaths, despite the number presented being an overestimate. Therefore, 

while the findings from the model are likely overestimates, the model used justified assumptions and

predicts an overall reduction of smoking-related deaths with the introduction of VERVE® into the U.S.

tobacco marketplace.

2.5.11. Summary of Population Health Findings

The epidemiology and BCP reviews concluded that, evaluating the totality of the evidence including 

information available in published literature, the PMTAs do not raise concerns about issuing marketing 

orders. The epidemiology review noted that the PMTAs included several observational studies, literature 

reviews and secondary data analyses to demonstrate the that introduction of VERVE® products into the

U.S. would result in a public health benefit to the population as a whole. The applicant presented 

evidence that smokers can adopt the use of VERVE® products in study conditions and presented results 

of a 6-week actual use survey to support this finding. Studies indicate 2-17% of current cigarette 

smokers can switch completely to VERVE® under actual use study conditions and free product 

availability, and a modest proportion of other tobacco product users (11%) completely switch to 

VERVE®. However, most current tobacco users co-use VERVE® with cigarettes or other tobacco products 

(77-84%). For several reasons due to study design and methods, the results of the 6-week actual use 

study likely represent an upper-bound estimate of product use, and the results of the MACS are likely a 

more accurate estimate. For the small percentage of smokers who switch completely as reported in the 

MACS (2%), there is a clear health benefit.

Using surrogate products, the applicant presented evidence to demonstrate that initiation of tobacco

use with VERVE® products is unlikely. Based on the applicant’s submitted data, prevalence of use of

dissolvable tobacco products and NRT is low, and prevalence of first tobacco product used is <1% for

these products. In the cross-sectional MACS, there were no adult participants who reported first

tobacco use with VERVE® products. Among adult users of VERVE® products, two MACS participants

reported using VERVE® after successful tobacco cessation for 6 months or more, and of these two

participants, both reported co-use of other tobacco products with VERVE®.

The applicant’s PHI model suggests that the introduction of VERVE® into the U.S. tobacco marketplace

would reduce smoking prevalence by 0.07%, resulting in 19,000 smoking-related deaths averted over

the 60-year modeling period. Modelers utilized publicly available data sources and reasonable modeling

assumptions to produce this estimate. Though the estimate of prevalence of use of VERVE® and

transition probabilities between smoking and VERVE® use are likely overestimated, the model estimates

are reasonable given the inherent uncertainty of predicting future tobacco use behaviors.

As TPL, I agree that the PMTAs contain sufficient information to evaluate the potential population health

effects. While the studies of the VERVE® products are limited, the applicant also provided extrapolations

from literature and survey information on NRT and dissolvable tobacco products to the VERVE®

products. Based upon available data regarding tobacco use initiation among youth and young adults
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with oral nicotine products, it is unlikely that VERVE® will lead to increased initiation of tobacco 

products, as most VERVE® users are already tobacco users and dissolvable tobacco products are unlikely

to be a tobacco users first product.

The applicant’s studies show that most VERVE® users are polytobacco users and that they substitute

VERVE® for one of the other tobacco products. For some study participants, there is a reduction in

combusted tobacco use. While for most, the reduction in CPD is modest, there was a small number of 

participants who reported reducing CPD by 50% or more. The studies also showed a small number of 

smokers who completely stopped cigarette use. Again, these numbers are small, but the studies

themselves were of limited duration and there are limitations to actual use studies (e.g., participants

receive the product for free). The products were available to consumers in a limited market which

precludes the potential for epidemiological studies on nationally representative population data for the

products prior to the submission of the PMTAs; nation-wide survey data on tobacco use would not have

picked up this limited marketing and therefore would not provide information on VERVE® use. The

MACS provided real-world assessment through in-market survey evaluations. If the VERVE® products

were to be commercially available, then nationally representative population data may be obtainable

and would provide greater insight into the potential for smokers to either switch completely to VERVE® 

products or to significantly reduce the use of combusted tobacco products. The data supplied by the

applicant does not indicate that the availability of the VERVE® products would significantly increase

tobacco use, especially by non-users, former smokers, or youth. Therefore, the benefit to current

smokers or tobacco users of VERVE® in the marketplace, albeit small, is not likely to be outweighed by

risks that nonusers, including youth, would start using VERVE® and then possibly other more hazardous

tobacco products.

It is important to consider the relative strength and quality of data sources provided to support an

understanding of new tobacco product use among current tobacco users. The actual use study provides

direct evidence of new tobacco product use from a prospective clinical study. Results from the

applicant's AUS are comparable to clinical studies of smoking cessation with NRT (i.e., a comparable

proportion of dual users and non-users of VERVE® products report use of NRT to quit smoking,

indicating that VERVE® users are similarly likely to pursue smoking cessation measures (50)). The MAC

study is an observational, cross-sectional (data collected at one point in time only) study which utilized 

retrospective exposure assessment (i.e., participant recall of past tobacco use behaviors). Participants in

both studies were current tobacco users who either expressed interest in the new tobacco product

(AUS) or had already ever-used the new tobacco product (MACS) and who had no intention to quit

smoking. The AUS is likely an upper-bound estimate of actual product switching given free product

availability, daily/weekly diary completion requirement to continued participation, and high-interest in 

the product as an enrollment criterion. The MAC study provides information about observed tobacco

use behaviors in a limited test market area and may represent a lower-bound estimate given the

absence of a comprehensive, national marketing plan and non-probabilistic recruitment strategy (i.e.,

respondents to the applicant’s user survey).

2.6. Product Labeling, Consumer Comprehension, and Marketing Plan

2.6.1. Proposed PMTA Labeling

The applicant submitted specimens of proposed labeling for the four VERVE® products in section 4 of

the PMTAs. OCE DPAL reviewed these specimens of proposed labeling and concluded that there is no

evidence to suggest that the labeling is false or misleading at this time.
PM0000470 – PM0000473 Page 71 of 104

As TPL, I agree with OCE DPAL’s review that there is no concern regarding false or misleading statements

with the proposed labeling.

2.6.2. Consumer Perception and Understanding of Risk

The PMTAs included two consumer perception studies regarding the promotional materials and

consumer understanding, and a use study that examined consumer perception. The social science

review evaluated relevant information regarding consumer absolute and relative risk perceptions and

consumer understanding in the context of viewing VERVE® and their promotional materials (Risk

Perceptions Study and PBI Study) or using VERVE® (MACS).

Absolute Risk Perceptions. From the Risk Perception Study, the applicant reported absolute risk

perceptions before and after viewing VERVE® promotional materials. The social science review noted

that the Risk Perception Study is a qualitative study where the applicant provides frequency counts of

themes mentioned by the participants. The majority of participants, regardless of tobacco user status,

responded that there was a risk of negative impact to health (52% before, 61% after viewing VERVE®

promotional materials), nicotine addiction (81% before, 83% after), and harm to baby if pregnant or

nursing (60% before, 73% after). Approximately half of the participants believed there was a risk of

mouth cancer (49% before, 49% after) and discolored teeth or decay (47% before, 42% after). Fewer

participants believed there was a risk of lung cancer (23% before, 27% after), heart disease/heart attack

(34% before, 54% after), and harm to someone nearby (3% before, 3% after). The applicant assessed

these perceptions at the brand level; however, it also asked a question to assess whether risk

perceptions would change for other variations of the products. The applicant reported that 96.8% of all

participants said their response would be the same.

In the PBI Study, the applicant assessed absolute risk perceptions before and after full (viewed all

promotional materials (i.e., 30-second advertisement, compilation of print marketing materials) as well

as a picture of the four VERVE® products) and reduced (viewed a picture of the four VERVE® products)

exposure to promotional materials. Participants rated absolute risk of using VERVE® every day (0%

“extremely unlikely” to 100% “extremely likely”) for the following health effects: risk of harming health,

mouth cancer, lung cancer, heart disease/heart attack, nicotine addiction, discolored teeth or decay,

harm to baby if pregnant or nursing, worsens an existing illness, trouble catching breath, bad cough, and

harming someone nearby. The applicant also assessed absolute risk of smoking cigarettes every day for

the health effects and compared post-test mean scores using paired t-tests to see if risk perceptions

differed significantly. Nicotine addiction was the highest VERVE® absolute risk perception before and

after viewing promotional materials in both exposure conditions, and mean scores ranged from 56.84%

to 79.62%. Participants in all subgroups perceived the risks of harming health, mouth cancer, lung

cancer, heart disease/heart attack, nicotine addiction, discolored teeth or decay, harm to baby if

pregnant or nursing, worsens existing illness, trouble catching breath, bad cough, and harming someone

nearby associated with smoking cigarettes every day as statistically significantly greater than using

VERVE® every day (p < 0.001).

From the MACS, the plurality of current users rated VERVE® as “slightly harmful” (37%) or "not at all

harmful” (27%). ln contrast, the plurality of past triers and users responded "don't know" (43%).

Relative Risk Perceptions. From the Risk Perception Study, the applicant assessed VERVE® risk

perceptions relative to daily use of cigarettes, smokeless tobacco products, e-vapor/e-cigarettes 

products, FDA-approved over-the-counter smoking cessation medication, and completely quitting all

tobacco use. Risk perceptions were measured on a scale of 0 (no risk to health) to 7 (great risk to health)

both before and after viewing VERVE® promotional materials. Changes before and after viewing were
PM0000470 – PM0000473 Page 72 of 104

miniscule, so the social science review provided after-viewing scores only. The applicant also provided

scores for each user group separately in its report, but the social science review provided scores for the

whole sample. All participants rated VERVE® 4.4 (SD, 2.0), which is a bit higher than the midpoint,

indicating a perception of risk similar to that of e-vapor/e-cigarettes and less than smokeless tobacco.

Compared to VERVE®, participants rated smoking cigarettes as the greatest risk (6.7, SD 0.74), followed 

by smokeless tobacco (5.7, SD 1.51), e-vapor/e-cigarettes (4.5, SD 1.93), smoking cessation medication

(2.5, SD 1.84), and quitting all tobacco use (0.4, SD 1.02).

From the PBI Study, all tobacco user and non-user subgroups in both full and reduced exposure

conditions rated smoking cigarettes and using smokeless tobacco daily as higher risk than using VERVE®

and completely quitting all tobacco and never using tobacco as less risk than using VERVE®. The

applicant provided z-scores and all p values were significant at the p < 0.001 level. All tobacco user and

non-user subgroups in both conditions perceived that smoking cigarettes has higher risk of harming

one’s health, mouth cancer, lung cancer, heart disease/heart attack, nicotine addiction, discolored

teeth/decay, harm to baby if pregnant or nursing, worsens existing illness, trouble catching breath, bad

cough, and harming someone nearby compared to using VERVE® (p < 0.001). There were no significant

differences in perceived relative risk across all four varieties of VERVE® products in all subgroups in both

conditions.

From the MACS, the majority of current users and past triers/users perceived VERVE® as “less harmful” 

than smoking cigarettes (75% and 63%, respectively) and using smokeless tobacco products (63% and

68%, respectively). A little over a third of current users and past triers/users rated VERVE® as “less

harmful” than e-cigarettes (42% and 35%, respectively). The majority of current users and past

triers/users rated VERVE® as having "about the same" harm as smoking cessation aids (58% and 56%,

respectively). Lastly, relative risk perceptions were mixed regarding quitting and not using any other

tobacco products. Current users rated VERVE® as either "less harmful" (35%), "about the same" harm

(33%) or "more harmful" (23%) while the majority of past triers/users rated them as “more harmful”

(52%) or "don't know" (16%).

Understanding Risk Summary

Data from the Risk Perception Study, the PBI Study, and the MACS show that participants believe the

VERVE® products are not risk-free. The majority of participants from the Risk Perception Study and the

PBI Study also indicated that “nicotine addiction” was the highest health risk for using VERVE® every

day. Also, participants from all three studies rated cigarette smoking as higher risk than using VERVE®.

From the literature, there are mixed findings regarding risk perceptions of oral nicotine-containing

products; however, the studies all indicate that participants agree that these oral nicotine-containing

products are not risk-free.

The social science review noted that data from all three studies are at the brand level; however, some

format and flavor data are presented from the Risk Perception Study and PBI Study. First, the Risk

Perception Study included a question asking participants to indicate whether they would respond to

additional risk perceptions questions the same way regardless of VERVE® format and flavor. Though

they were not probed about each specific format and flavor, participants did respond that they would

answer the questions the same way. More specifically, relative risk data is presented for each format

and flavor subject to these PMTAs in the PBI Study. There were no significant differences across formats

and flavors. Based on the submitted data, this review identifies no concerns with the presented findings

and results regarding consumer understanding of risk.

The social science review concluded that based on the data submitted by the applicant, there are no

identified concerns with the findings of the Risk Perception Study, the PBI Study, and the MACS. And
PM0000470 – PM0000473 Page 73 of 104

therefore, there are no concerns with the results of these studies regarding consumer understanding of

risk.

As TPL, I agree with the social science review that there are no identified concerns regarding consumer

perception and understanding of risk for the four VERVE® products.

2.6.3. Marketing Plan

Per the OHCE consult, the applicant submitted marketing information as part of the subject applications

in Section 4. Specimens of Labeling (pp. 1-4). OHCE’s review notes that the information provided in the

applicant’s proposed marketing plan is broad and incomplete. The applicant states that it intends to

market its products to adult tobacco consumers (ATC), and specifically, to adult smokers (AS). However,

the applicant does not describe plans to target its audience by other demographic characteristics (e.g.,

race/ethnicity, geographic region), psychographic characteristics, or behaviors other than current

tobacco use, and the applicant does not specify how it intends to target and reach ATC/AS aged 21+.

Additionally, it is unclear if the marketing information provided by the applicant covers the full extent of

the applicant’s plan. For example, the applicant omits discussion of several marketing channels and

tactics (e.g., broadcast TV; digital radio; billboards and similar out-of-home media; sponsorships).

OHCE’s review raised concerns about the potential broad reach of the applicants marketing, absent

more robust targeting controls, to adults aged 18+ (instead of adults of the federal minimum legal age of

sale of tobacco products) and youth. OHCE concluded that if the products are authorized to be

marketed, FDA should place restrictions on digital marketing and TV and radio marketing to protect

youth. Additionally, OHCE recommends that any MGO letter encourage the applicant to take additional

steps to limit youth exposure to print and point-of-sale advertising, including, for example, limiting

advertising to print publications where 85% or more of the readership is 21 years of age or older and/or

selecting publications that do not over-index for youth. The applicant includes information about its

intended use of warnings, ingredients, and health information as part of its products’ labeling but does

not describe key message themes it intends to use in its labeling, advertising, marketing, or promotional

materials to target ATC/AS or the goals of such marketing materials. Understanding the key message

themes of the new products will enable better insight regarding the potential impact of the advertising

on youth appeal. OHCE recommends that if these applications will be the subject of MGOs then the

applicant should submit 30-day advance notifications of marketing materials for a period for time.

As TPL, I agree with the OHCE consult that the marketing granted order should include the

recommended marketing requirements and restrictions. In addition, I agree with OHCE to include

recommendations for the applicant to limit youth exposure to print and point-of-sale advertising.

3. ENVIRONMENTAL DECISION

A finding of no significant impact (FONSI) was signed by Dr. Luis Valerio on August 4, 2020. The FONSI

was supported by an environmental assessment prepared by FDA on August 4, 2020.

4. CONCLUSIONS ANDRECOMMENDATIONS

Based on the data received to date, the following U.S. Smokeless Tobacco Company LLC premarket

tobacco product applications do contain sufficient information to show that marketing of the new

products would be appropriate for the protection of the public health and support marketing orders

under section 910(c) of the FD&C Act:
PM0000470 – PM0000473 Page 74 of 104

As discussed in Sections 2.3 through 2.6 of this review, I recommend the PMTAs be authorized. None of

the grounds specified in Section 910(c)(2) of the FD&C Act apply. Specifically, I find the following:

1. Permitting the marketing of the new products in accordance with the requirements in the

marketing granted orders is appropriate for the protection of the public health, as described in 

Section 910(c)(4) of the FD&C Act;

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

packing of these products do not fail to conform to the requirements in 906(e);

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

particular; and

4. The products do not fail to conform to a tobacco product standard in effect under Section 907

of the FD&C Act.

I recommend FDA grant marketing authorization for the products described in the following STNs:

1. PM0000470 – VERVE® Discs Blue Mint 

2. PM0000471 – VERVE® Chews Blue Mint 

3. PM0000472 – VERVE® Discs Green Mint 

4. PM0000473 – VERVE® Chews Green Mint

The new products are authorized with a (b) (4) shelf life. The applicant may provide updated data on

production batches to propose an extension of shelf life as part of annual post market reporting.

4.1 Discussion

The PMTAs included inadequate information on the manufacturing processes (e.g., missing SOPs, detail

for the order of adding ingredients); however, during the inspection FDA received adequate information

to demonstrate that the four VERVE® products can be manufactured in a consistent manner. FDA

verified the levels of seven HPHCs (acetaldehyde, arsenic, cadmium, formaldehyde, nicotine, NNN, and

NNK) and the results were similar, with the exception of increased arsenic (14% higher) in the VERVE®

Chews and increased free nicotine (2357% higher) in the VERVE® Discs, both in comparison to the data

in the PMTAs. Both increases were determined to not be of concern based on the toxicology and BCP

reviews, respectively. Arsenic measured VERVE® Chews is less than or tantamount to arsenic measured

in all comparator products and well below the established reference (RfD) or acceptable oral dose for

arsenic. The increase in measured free nicotine in unlikely to result in increased abuse liability.

The results of the toxicology evaluation, along with the ingredient and HPHC information, demonstrate

that the toxicity potential of the VERVE® products is lower than cigarettes and smokeless tobacco, and

likely similar to that of NRT. If a smoker were to switch from cigarettes to VERVE® products, the

toxicological evaluation supports the assertion that the consumer would have much less HPHC exposure

compared to Marlboro 100’s cigarettes and General Snus (Appendix Table 16). The non-tobacco

ingredients do not present a toxicological concern because exposure to these ingredients from use of

the VERVE® tobacco products is tens to thousands of times lower than the respective toxicity reference

values. Together, this information indicates that the VERVE® products likely present a lower public

health concern for tobacco-related diseases. This is predicated based on switching from cigarettes to the

VERVE® products, which the limited data in the applications does not indicate is likely. This is supported

by the literature research on oral tobacco products. Further, a significant decrease in CPD (i.e., 50% or
PM0000470 – PM0000473 Page 75 of 104

greater), or substituting VERVE® products for a smokeless tobacco with polytobacco use could also have

the potential to decrease tobacco-related diseases.

Based on the applicant’s clinical studies, the VERVE® products have reduced abuse liability when

compared to the study subjects’ UB cigarettes, as indicated by the lower plasma nicotine concentrations

and lower positive subjective ratings. This also supports a reduction in the likelihood that youth, nonsmokers, or former smokers would initiate or reinitiate tobacco use with the VERVE® products. The

reduced subjective appeal, however, may prevent current smokers from switching completely to the

VERVE® products. The submitted studies suggest that few smokers (11%) switch completely to VERVE®

or other oral tobacco products, but these data are based on one week of VERVE® use and do not reflect

the measured decline in VERVE® acceptability among smokers that was captured in the applicant’s 12- 

week actual use study for a prior version of VERVE® Discs Blue Mint (Gen 1). Therefore, the percentage

of complete switching would likely be lower than the identified percentage in the applicant’s study.

However, this does not impact the finding that VERVE® products should be granted a marketing order

because the applicant has demonstrated a health benefit for the small percentage of smokers who

completely switch. Dual or poly use is the primary use behavior expected of VERVE® product users.

Smokers who dual use VERVE® products with cigarettes, and do not substantially reduce their CPD (i.e.,

by 60% or greater), do not reduce their exposure to nicotine or non-nicotine BOE. However, even a

modest reduction in daily cigarette consumption may reduce the risk of tobacco related disease due to

decreased exposure to HPHCs.

In terms of youth risk, the information extrapolating dissolvable tobacco products to VERVE® from the

literature and from national survey data support that there is low likelihood of youth initiating tobacco

use with the new products. Nonetheless, given the strong evidence regarding the impact of youth

marketing exposure to youth appeal and initiation of tobacco use, a marketing authorization should

include postmarket requirements to help ensure that youth exposure to tobacco marketing is limited.

While there were no clinical studies conducted specifically to evaluate the health effects of VERVE®

products, alone or in combination with other tobacco products, there were limited data on consumer or

study subject reports of any AEs. The five clinical studies had a combined total of 253 participants and

144 AEs reported. AEs assessed as likely or possibly related to the use of VERVE® products comprised

29.7% of all reported AEs. All 27 AEs deemed likely or possibly related to the use of VERVE® products

were considered mild. There were no severe or serious AEs reported. Although clinical studies designed

specifically to address the potential health effects of the VERVE® products would have strengthened the

PMTAs, the ingredients and ingredient levels in the products and HPHC measurements and comparisons

to cigarette smoke and smokeless tobacco support the determination that use of the VERVE® products

in place of smoking or combined with a significant (i.e., 50% or greater) decrease in CPD, would decrease

exposures to HPHCs and likely decrease the occurrence of tobacco-related disease. Though complete

substitution of cigarettes with VERVE® products or ≥ 50% decrease in CPD with poly use is unlikely, a

modest reduction in daily cigarette consumption may reduce the risk of tobacco related disease due to

decreased exposure to HPHCs.

The public health benefit of the VERVE® products is attributed to the ingredients and HPHC levels. This

benefit, however, is predicated on the use of the VERVE® products in place of cigarettes or in place of a

significant portion of a smoker’s CPD. The PMTAs indicate that VERVE® is only moderately appealing

among current tobacco users, and these users seem to have moderate intentions to try, to use, and to

switch to VERVE®. The PMTAs do indicate a small number of subjects who switched from cigarettes to

VERVE® and some tobacco users continued use even though self-reporting actual quitting after using

VERVE® during a 6-week study period. While the number of tobacco users who would alter their tobacco

use due to the use of VERVE® sufficiently to benefit from the decreased HPHC exposures is small, the
PM0000470 – PM0000473 Page 76 of 104

minimal HPHC exposure could positively impact health benefits for those tobacco users and for others

who are near them regularly (e.g., children); use of VERVE® products is not associated with significant

second-hand exposure which decreases disease risks for the general population.

4.2 Recommendation for Marketing

A marketing granted order should be issued for the new tobacco products subject of this review, as

identified on the cover page of this review.

The following language will be included in the marketing authorization:

Based on our review of your PMTAs, we determined that the new tobacco products, as described

in your applications and specified in Appendix A, are appropriate for the protection of public

health. It should be noted that our determination that the marketing of these products is APPH is

based on the submitted microbial stability data14. The issuance of these marketing granted

orders confirms that you have met the requirements of section 910(c) of the FD&C Act and

authorizes marketing of your new tobacco products. Under the provisions of section 910, you

may introduce or deliver for introduction into interstate commerce the tobacco products, in

accordance with the marketing order requirements outlined in these orders, including all

appendices.

14. 14 The data provided support microbial stability of the products over(b) (4) . The stability data for(b) (4) is

acceptable and there are no other stability concerns. If you would like FDA to evaluate additional microbial stability

data for a longer period, submit this information in a post-market report.
PM0000470 – PM0000473 Page 77 of 104

5. ACRONYMS

AE adverse events

ALCS Altria Client Services, LLC

APC aerobic plate counts

AUC0-t area under the nicotine concentration-time curve

aw water activity

BCP Behavioral and Clinical Pharmacology

BIMO Bioresearch Monitoring

(B)LOQ (below) limit of quantitation

BOE biomarkers of exposure

BOPH biomarkers of potential harm

CAS number Chemical Abstracts Service number

CDC Centers for Disease Control and Prevention

Cfu colony forming unit

Cmax maximum measured plasma nicotine concentration

CO carbon monoxide

COHb blood carboxyhemoglobin

CPD cigarettes per day

CPSC Consumer Product Safety Commission

CRT Center for Research and Technology

CTP Center for Tobacco Products

DPAL Division of Promotion, Advertising, and Labeling

EIR Establishment Inspection Report

ENDS electronic nicotine delivery systems

FD&C Act Federal Food Drug and Cosmetic Act

FDA Food and Drug Administration

FONSI finding of no significant impact

FTCD Fagerström Test for Cigarette Dependence

GRAS generally recognized as safe

HPHC Harmful and Potentially Harmful Constituents

ISO International Organization for Standardization

M Month

N/A not applicable

NAB N-nitrosoanabasine

NAT N-nitrosoanatabine

NNAL 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol

NNK 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

NNN n-nitrosonornicotine

NRT nicotine replacement therapy

NST novel smokeless tobacco

OCE Office of Compliance and Enforcement

ORA Office of Regulatory Affairs

OS Office of Science

OSHA Occupational Safety and Health Administration

PET polyethylene terephthalate

PK Pharmacokinetic

PMTA premarket tobacco application

RfD reference dose
PM0000470 – PM0000473 Page 78 of 104

RH relative humidity

RSD relative standard deviation

SAE serious adverse event

SD standard deviation

SFFL Southeast Food and Feed Laboratory

SOP standard operating procedure

S-PMA S-phenylmercapturic acid

STL Southeast Tobacco Laboratory

STN Submission Tracking Number

T1/2 apparent first-order terminal nicotine elimination half-life

Tmax time of the maximum measured plasma concentration

TNE total nicotine equivalent

TPL Technical Project Lead

TPMF Tobacco Product Master File

TSNA tobacco-specific nitrosamines

UB usual brand

UB-NCC usual brand-normal nicotine content

USSTC US Smokeless Tobacco Company

USSTP US Smokeless Tobacco Products, LLC

VAS visual analog scale

VLNC very low nicotine content
PM0000470 – PM0000473 Page 79 of 104

6. REFERENCES

1. U.S. Department of Health and Human Services, Food and Drug Administration (FDA). Draft Guidance for Industry

Arsenic in Apple Juice: Action Level Draft Guidance. Silver Spring, MD, USA: US Department of Health and Human

Services, Food and Drug Administration Center for Food Safety and Applied Nutrition; 2013.

2. Integrated Risk Information System (IRIS). Arsenic, inorganic; CASRN 7440-38-2; 1991. Retrieved from

https://cfpub.epa.gov/ncea/iris/iris_documents/documents/subst/0278_summary.pdf#nameddest=canceroral.

3. U.S. Department of Health and Human Services, Food and Drug Administration (FDA). Beverages: bottled water. Final

rule. Federal Register 2005; 70(110):33694.

4. World Health Organization (WHO). WHO Study Group on Tobacco Product Regulation. Report on the Scientific Basis

of Tobacco Product Regulations: Fifth Report of a WHO Study Group. World Health Organization Technical Report

Series (989); 2015.

5. McGuigan, M. Nicotine. Medical Toxicology. 3rd ed. pp. 601-604. Philadelphia, PA: Lippincott Williams & Wilkins;

2003.

6. Connolly GN, Richter P, Aleguas A, Pechacek T, Stanfill SB, Alpert, HR. Unintentional child poisonings through

ingestion of conventional and novel tobacco products. Pediatrics 2010; 125(5):896-899.

7. Mayer B. How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious selfexperiments in the nineteenth century. Arch Toxicol 2014; 88(1):5-7.

8. United States Environmental Protection Agency (U.S. EPA). Child-specific exposure factors handbook. Washington,

DC: National Center for Environmental Assessment; 2008.

9. Matsushima D, Prevo ME, Gorsline, J. Absorption and adverse effects following topical and oral administration of

three transdermal nicotine products to dogs. J Pharm Sci 1995; 84(3):365-369.

10. Kamboj A, Spiller HA, Casavant MJ, Chounthirath T, Smith GA. Pediatric exposure to e-cigarettes, nicotine, and

tobacco products in the United States. Pediatrics 2016; 137(6):e20160041.

11. Smolinske S, Spoerke D, Spiller S, Wruk K, Kulig K, Rumackt B. Cigarette and nicotine chewing gum toxicity in children.

Hum Toxicol 1988; 7(1):27-31.

12. Kim MJ, Jang JC, Lee IM, Lee HS, Yoon JS. Toxicity and Biodegradation of Damines. J Environ Sci Health 2002; 

B37(1):53-64.

13.

14.

15. Chaudhary SA, Aliasgar FS. Medicated chewing gum - a potential drug delivery system. Expert Opin Drug Delivery

2010; 7(7):871-885.

16.

17. U.S. Department of Health and Human Services, Food and Drug Administration (FDA). Use of International Standard

ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management

process". Silver Spring, MD: Food and Drug Administration; 2018.

18.

19. Hall A, Harrington J, Waterhouse J. The Epping jaundice outbreak: a 24-year follow up. J Epidemiol Community Health

1992; 46(4):327-328.

(b) (4) 

(b) (4) 

(b) (4) 

(b) (4) 
PM0000470 – PM0000473 Page 80 of 104

20.

21.

22.

23. Food Chemical Codex. Food Chemicals Codex, 10th Edition (Tenth ed.): Baltimore, MD: United Book Press, Inc.; 2016.

24. International Agency for Research on Cancer (IARC). Working Group on the Evaluation of the Carcinogenic Risk of

Some Monomers, Plastics and Synthetic Elastomers, and Acrolein. Lyon, France: International Agency for Research on

Cancer; 1979.

25.

26. (b) (4) 

27. Miao S, Beach ES, Sommer, TJ, Zimmerman, JB, Jordt, SE. High-intensity sweeteners in alternative tobacco products.

Nicotine Tob Res 2016; 18(11):2169-2173.

28. Chen C, Isabelle LM, Pickworth WB, Pankow JF. Levels of mint and wintergreen flavorants: Smokeless tobacco

products vs. confectionery products. Food Chem Toxicol 2010; 48(2):755-763.

29. Ai J, Taylor KM, Lisko JG, Tran H, Watson CH, Holman MR. Menthol content in US marketed cigarettes. Nicotine Tob

Res 2016; 18(7):1575-1580.

30. Benowitz NL, Jacob P, Savanapridi C. Determinants of nicotine intake while chewing nicotine polacrilex gum. Clin

Pharmacol Ther 1987; 41(4):467-473.

31. Sherwood N, Kerr JS, Hindmarch I. The use of nicotine gum in psychopharmacological research. Med Sci Res 1989;

17(21):891–892.

32. Leischow SJ, Sachs DP, Hansen MD, Bostrom AG. Nicotine polacrilex dose effects: serum nicotine levels and sensory

characteristics. Psychopharmacol 1995; 117(2):125-129.

33. Hindmarch I, Kerr JS, Sherwood N. Effects of nicotine gum on psychomotor performance in smokers and non-smokers.

Psychopharmacol 1990; 100(4):535-541.

34. Choi JH, Dresler CM, Norton MR, Strahs KR. Pharmacokinetics of a nicotine polacrilex lozenge. Nicotine Tob Res 2003;

5(5):635-644.

35. Hansson A, Rasmussen T, Kraiczi H. Single-dose and multiple-dose pharmacokinetics of nicotine 6 mg gum. Nicotine

Tob Res 2017; 19(4):477-483.

36. Kraiczi H, Hansson A, Perfekt R. Single-dose pharmacokinetics of nicotine when given with a novel mouth spray for

nicotine replacement therapy. Nicotine Tob Res 2011; 13(12):1176-1182.

37. Koszowski B, Viray LC, Stanfill SB, Lisko JG, Rosenberry ZR, Potts JL, Pickworth WB. Nicotine delivery and

pharmacologic response from Verve, an oral nicotine delivery product. Pharmacol Biochem Behav 2015; 136:1-6.

38. Kotlyar M, Mendoza-Baumgart MI, Li ZZ, Pentel PR, Barnett BC, Feuer RM, Smith EA,.Hatsukami DK. Nicotine

pharmacokinetics and subjective effects of three potential reduced exposure products, moist snuff and nicotine

lozenge. Tob Control 2007; 16(2):138-142.

39. Hatsukami D, Huber M, Callies A, Skoog K. Physical dependence on nicotine gum: effect of duration of use.

Psychopharmacology 1993; 111(4):449-456.

40. West R, Hajek P, Foulds J, Nilsson F, May S, Meadows A. A comparison of the abuse liability and dependence potential

of nicotine patch, gum, spray and inhaler. Psychopharmacol 2000; 149(3):198-202.

(b) (4) 

f

(b) (4) 

.

(b) (4)

(b) (4) 
PM0000470 – PM0000473 Page 81 of 104

41. Heishman SJ, Snyder FR, Henningfield JE. (1993). Performance, subjective, and physiological effects of nicotine in nonsmokers. Drug and Alcohol Depend 1993; 34(1):11-18.

42. Krautter GR, Borgerding MF. Comparison of consumption patterns, biomarkers of exposure, and subjective effects in

cigarette smokers who switched to dissolvable tobacco (Camel Orbs), dual use, or tobacco abstinence. Nicotine Tob

Res 2014; 16(10):1336-1347.

43. Borland R, Li L, Mortimer K, McNeil A, King B, O'Connor RJ. The acceptability of nicotine containing products as

alternatives to cigarettes: Findings from two pilot studies. Harm Reduct J 2011; 8:27.

44. Blank MD, Eissenberg T. Evaluating oral noncombustible potential reduced exposure products for smokers. Nicotine

and Tob Res 2010; 12(4):336-343.

45. Mendoza-Baumgart MI, Tulunay OE, Hecht SS, Zhang Y, Murphy S, Le C, Jensen J, Hatsukami DK. Pilot study on lower

nitrosamine smokeless tobacco products compared with medicinal nicotine. Nicotine and Tob Res 2007; 9(12):1309- 

1323.

46. Buzzell GA, Das B, Cruz-Cano R, Nkongho L, Kidanu AW, Kim H, Clark PI, McDonald CG. Using electrophysiological

measures to assess the consumer acceptability of smokeless tobacco products. Nicotine Tob Res 2016; 18(9):1853- 

1860.

47. Carpenter MJ, Gray KM. A pilot randomized study of smokeless tobacco use among smokers not interested in

quitting: Changes in smoking behavior and readiness to quit. Nicotine Tob Res 2010; 12(2):136-143.

48. Hatsukami DK, Jensen J, Anderson A, Broadbent B, Allen S, Zhang Y, Severson H. Oraltobacco products: preference

and effects among smokers. Drug Alcohol Depend 2011;118(2-3):230-236.

49. Allen A, Vogel RI, Meier E, Anderson A, Jensen J, Severson HH, Hatsukami D. Gender differences in snus versus

nicotine gum for cigarette avoidance among a sample of US smokers. Drug Alcohol Depend 2016; 168:8-12.

50. Wang B, King BA, Corey CG, Arrazola RA, Johnson SE. Awareness and use of non-conventional tobacco products

among U.S. students, 2012. Am J Prev Med 2014; 47(2 SUPPL.1):S36-S52.

51. Sutfin EL, Reboussin BA, Debinski B, Wagoner KG, Spangler J, Wolfson M. The impact of trying electronic cigarettes on

cigarette smoking by college students: a prospective analysis. Am J Public Health 2015; 105(8):e83-89.

52. Food and Drug Administration. Modifications to labeling of nicotine replacement therapy products for over-thecounter human use. Federal Register 2013; 78(63):19718. https://www.govinfo.gov/content/pkg/FR-2013-04- 

02/pdf/2013-07528.pdf. Accessed April 30, 2019.

53. Gentzke AS, Wang TW, Jamal A, Park-Lee E, Ren C, Cullen KA, Neff L. Tobacco product use among middle and high

school students – United States 2020. MMWR 2020; 69(5): 1881-1888
PM0000470 – PM0000473 Page 82 of 104

7. APPENDIX A

Table 13: Ingredients other than tobacco for cross-referenced PMTA submissions

Product

Name

Ingredients Breakout of Ingredient Target Weight

(mg/piece)

(b) (4) 

PM0000470

VERVE®

Discs Blue

Mint

Single and

complex+

ingredients

(b) (4)

+

PM0000471

VERVE®

Chews Blue

Mint

Single and

complex+

ingredients
PM0000470 – PM0000473 Page 83 of 104

(b) (4)

Product Ingredients Breakout of Ingredient Target Weight

Name (mg/piece)

(b) (4)

(b) (4)

(b) (4)

(b)(4)

(b)(4)

PM0000472

VERVE®

Discs Green

Mint

Single and

complex+

ingredients
PM0000470 – PM0000473 Page 84 of 104

+

) 

s

(b) (4)

Product

Name

Breakout of Ingredient Target Weight

(mg/piece)

(b)

PM0000473

VERVE®

Chews

Green Mint

(b) (4)

+

(b) (4)

Single and

complex+

ingredient

(4

Ingredients
PM0000470 – PM0000473 Page 85 of 104

+ Complex purchased ingredients

(b) (4

(mg/piece)

)

Product Ingredients Breakout of Ingredient Target Weight

Name
PM0000470 – PM0000473 Page 86 of 104

Table 14: Total ingredients for cross-referenced PMTA submissions

Product

Name

Ingredients Total Quantity

per Piece

(mg/piece)

Total Quantity

per Gram of

Each Piece

(mg/g)

Quantity as Percent

of Total Weight per

Piece (%)

PM0000470

VERVE® Discs

Blue Mint (b) (4) 

PM0000471

VERVE®

Chews Blue

Mint

PM0000472

VERVE® Discs

Green Mint

PM0000473

VERVE®

Chews Green
PM0000470 – PM0000473 Page 87 of 104

Product

Name

Ingredients Total Quantity

per Piece

(mg/piece)

Total Quantity

per Gram of

Each Piece

(mg/g)

Quantity as Percent

of Total Weight per

Piece (%)

Mint (b) (4) 
PM0000470 – PM0000473 Page 88 of 104

Table 15: Comparison of HPHC levels in the new products to Nicorette gum, General Snus, and cigarettes (per portion basis)

Constituent

New Products Comparator Products

% Changea

VERVE® Discs VERVE®

Chews

Nicorette® Fresh

MintTM Gum

General

Snus15,16

Cigarettes17

(Marlboro 

100’s Box)

Nicorette

Gum

General

Snus Cigarettes

Nicotine (total), mg/portion 1.33-1.45 1.33-1.54 2.02 (2.00-2.05) 10.915 2.59 ↓25 ↓86 ↓41

Nicotine (free), mg/portion 0.31-0.58 0.01-0.08 2.00 (1.98-2.03) 5.0315 N/A ↓71 ↓88

pH 7.50-7.86 5.95-6.79 10.03 (10.0-10.07) N/A ↓22

Cadmium, ng/portion 5.60-12.15 N/D 50.7 (45.0-55.2) 179.2216+ 114 ↓78 ↓93 ↓89

Arsenic, ng/portion N/D 22.88-24.16 47.3 (44.4-49.6) 74.6316+ 11.3 ↓51 ↓68 ↑114

Benzo[a]pyrene, ng/portion N/D N/D N/D 20.5

NNN, ng/portion 0.66-1.48 N/D N/D 108015 284 ↓100 ↓99

NNK, ng/portion 0.33-0.39 BLOQ N/D 30415 145 ↓100 ↓100

Formaldehyde, μg/portion 0.16-0.86 0.36-0.60 BLOQ 5.5515 91.2 ↓85 ↓99

Acetaldehyde, μg/portion 0.09-0.76 0.30-0.57 BLOQ 20.715 1690 ↓96 ↓100

Crotonaldehyde, μg/portion N/D N/D N/D 0.68515 59.2

Bold text denotes that the % change is higher than 10%.

N/D = not detected; BLOQ = below LOQ; N/A = not applicable

+ The reported values were obtained from Appendix C for General Original Portion of the Borgerding et al. publication16 and converted from ng/g of dry basis to ng/portion using the moisture

content reported as 50.9% and 1 g per portion. The dry basis weight = 1 g – 0.509 g = 0.491 g. For example, cadmium (ng/portion) = 365 ng/g dry basis x 0.491 g = 179.215 ng/portion.

a % Change = ([Maximum constituent limit in VERVE® product (all batches, mg/portion) – [Maximum constituent limit in comparator product (mg/portion)])/[Maximum constituent limit in

comparator product (mg/portion)]

15. 15 Stepanov I, J. J., Hatsukami D, Hecht SS, New and traditional smokeless tobacco: comparison of toxicant and carcinogen levels. Nicotine Tob Res. 2008, 10 (12), 1773-1782.

16. 16 Borgerding, M. F.; Bodnar, J. A.; Curtin, G. M.; Swauger, J. E., The chemical composition of smokeless tobacco: A survey of products sold in the United States in 2006 and 2007.

Regul. Toxicol. Pharmacol. 2012, 64 (3), 367-387.

17. 17 Oldham, M. J.; DeSoi, D. J.; Rimmer, L. T.; Wagner, K. A.; Morton, M. J., Insights from analysis for harmful and potentially harmful constituents (HPHCs) in tobacco products.

Ibid.2014, 70 (1), 138-148.
PM0000470 – PM0000473 Page 89 of 104 

Table 16: Comparison of HPHC levels in the VERVE® products compared to Nicorette Gum, General Snus, and Cigarette (wet weight basis) 

Constituent 

New Products Comparator Products 

Nicorette Gum 

% Change' 

General Snus Cigarettes

VERVE® Discs VERVE8 Chews Nicorette® Fresh MintTM Gum General Snus9

•

10 

Cigarettes11 

(Marlboro lD0's 

Box) 

Nicotine (total), mg/g 2.50-2,78 0.63-0.73 2.02 (2.00-2.05) 10.99 2.59 ↑36 ↓75 ↑7 

Nicotine (free), mg/g 0.58-1.11 0.01-0.04 2.00 (1.98-2.03) 5.039 N/A ↓45 ↓78 

pH 7,50-7,86 5,95-6.79 10,03 (10,0-10,07) N/A ↓22 

Cadmium, ng/g 10.77-22.92 N/D 50.7 (45,0-55.2) 179.2210+ 114 ↓58 ↓87 ↓80 

Arsenic, ng/g N/D 10.69-11.51 47.3 (44.4-49.6) 74.6310+ 11.3 ↓77 ↓85 ↑2 

Benzo[a]pyrene, ng/g N/D N/D N/D 20,5 

NNN, ng/g 1.25-2,85 BLOQ N/D 10809 284 ↓100 ↓99 

NNK, ng/g 0.63-0.74 BLOQ N/D 3049 145 ↓100 ↓99 

Formaldehyde, μg/g 0.30-1.66 0.17-0.29 BLOQ 5.559 91.2 ↓70 ↓98 

Acetaldehyde, μg/g 0.16-1.16 0.16-0,27 BLOQ 20.79 1690 ↓94 ↓100 

Crotonaldehyde, μg/g N/D N/D N/D 0.6859 59.2 

Table source: Internally generated based on applicant-submitted data 

N/D = not detected; BLOQ = below LOQ; N/A = not applicable 

+ The reported values were obtained from Appendix C for General Original Portion of the Borgerding et al. publication4 and converted from ng/g of dry basis to ng/g using the moisture

content reported as 50.9% and 1 g per portion. The dry basis weight = 1 g – 0.509 g = 0.491 g. For example, cadmium (ng/portion) = 365 ng/g dry basis x 0.491 g x 1 g/portion= 179.215

ng/g a % Change = ([Maximum constituent limit in VERVE® product (all batches, unit/g of product}] – [Maximum constituent limit in comparator product (unit/g of product)])/[Maximum

constituent limit in comparator product (unit/g of product)]
PM0000470 – PM0000473 Page 90 of 104 

Table 17: HPHCs of VERVE® products and other smokeless tobacco products 

Constituent 

New Products FDA Internal Data+ % Changea

VERVE® Discs VERVE® Chews Chewing Tobacco Dissolvables Moist Snuff Snus Chewing 

Tobacco 

Dissolvables Moist Snuff Snus 

Nicotine (total), mg/g 2.50-2.78 0.63-0.73 8-14 8-11 11-12 9-12 ↓80 ↓75 ↓77 ↓77 

Nicotine (free), mg/g 0.58-1.11 0.01-0.04 0.04-0.07 1-2 3-4 4-6 ↑1486 ↓45 ↓72 ↓82 

pH 7.50-7.86 5.95-6 .79 5.6 -6.1 6.9-8.1 7.6 -7.8 8· 8.5 ↑29 ↓3 ↑1 ↓8 

Cadmium, ng/g 10.77-22.92 N/D 400 - 500 300-600 500-560 200- 400 ↓99 ↓100 ↓99 ↓99 

Arsenic, ng/g N/D 10.69-11.51 10-420 120-200 180-230 90 -130 ↓97 ↓94 ↓95 ↓91 

Benzo[a]pyrene, ng/g N/D N/D 5-6 68-105 42 -58 1-1.7

NNN, ng/g 1. 25-2.85 BLOQ 590-667 1004 -6795 3025-3748 500-1053 ↓100 ↓100 ↓100 ↓100 

NNK, ng/g 0.63-0.74 BLOQ 120 -167 666-7577 953-1135 175 -325 ↓100 ↓100 ↓100 ↓100

Formaldehyde, μg/g 0.30-1.66 0.17 -0.29 4.08 -7.23 2.16 -6.94 0. 4-1.7 5.7-8.4 ↓77 ↓76 ↓2 ↓80 

Aceta ldehyde, μg/g 0.16-1.16 0.16-0.27 2-2.8 2.51-3.44 1-6 11-15 ↓59 ↓66 ↓81 ↓93 

Crotonaldehyde, μg/g N/D N/D - - 0.07 - 0.08 1.0-3.4 

+ FDA internal data obtained from Appendix B of the “FDA Testing for PMTA Norms and Triggers” memo (M:\PMTA Reviews\USSTC_PM0000470-PM0000473\STL consult memo\FDA Testing

for PMTA_Norms and Triggers_DPS.pdf) a % Change = ([Maximum constituent limit in VERVE® product (all batches, unit/g of product}] – [Maximum constituent limit in comparator product (unit/g of product)])/[Maximum

constituent limit in comparator product (unit/g of product)]
PM0000470 – PM0000473 Page 91 of 104

Table 18. Constituents of VERVE® Chews and Discs products over a 12-month period

PMTA Constituent

Mean Average Across 3 Lots with (Standard Deviation) % Change a

(T=6M from

T=1M)

% Change b

(T=12M

from T=1M) T = 1M T = 6M T = 12M N1

PM0000470

(VERVE® Discs Blue Mint)

Nicotine (total), mg/portion 1.37 (0.02) 1.38 (0.01) 1.33 (0.02) 21 ↑1 ↓3

Nicotine (free), mg/portion 0.55 (0.11) 0.38 (0.01) 0.31 (0.04) 21 ↓31 ↓44

pH 7.85 (0.16) 7.59 (0.03) 7.50 (0.06) 21 ↓3 ↓4

Cadmium, ng/portion 8.55 (0.28) 6.35 (1.13) 12.15 (6.90) 21 ↓26 ↑42

Arsenic, ng/portion N/D N/D N/D 21

Benzo[a]pyrene, ng/portion N/D N/D N/D 21

NNN+, ng/portion 0.66 (0.06) 0.95 (0.15) 0.74 (0.15) 21 ↑44 ↑12

NNK++, ng/portion 0.38 0.38 (0.05) 0.39 (0.09) 21 0 ↑3

NAB*, ng/portion N/D 0.47 N/D 21

NAT**, ng/portion N/D 0.33 (0.03) N/D 21

Formaldehyde, μg/portion 0.86 (0.51) 0.56 (0.08) 0.17 (0.05) 21 ↓35 ↓80

Acetaldehyde, μg/portion 0.35 (0.35) 0.29 (0.08) 0.12 (0.01) 21 ↓17 ↓66

Crotonaldehyde, μg/portion N/D N/D N/D 21

PM0000471

(VERVE® Chews Blue Mint)

Nicotine (total), mg/portion 1.35 (0.07) 1.47 (0.03) 1.33 (0.05) 21 ↑9 ↓1

Nicotine (free), mg/portion 0.05 (0.02) 0.03 (0.01) 0.01 (0.00) 21 ↓40 ↓80

pH 6.62 (0.2) 6.27 (0.14) 5.95 (0.06) 21 ↓5 ↓10

Cadmium, ng/portion N/D N/D N/D 21

Arsenic, ng/portion 23.35 (0.81) 22.43 (0.26) 22.44 (0.37) 21 ↓4 ↓4

Benzo[a]pyrene, ng/portion N/D N/D N/D 21

NNN+, ng/portion N/D N/D N/D 21

NNK++, ng/portion BLOQ BLOQ BLOQ 21

NAB*, ng/portion N/D N/D N/D 21

NAT**, ng/portion N/D 1.21 N/D 21

Formaldehyde, μg/portion 0.43 (0.01) 0.36 (0.02) 0.43 (0.03) 21 ↓16 0

Acetaldehyde, μg/portion 0.33 (0.06) 0.43 (0.02) 0.49 (0.09) 21 ↑30 ↑48

Crotonaldehyde, μg/portion BLOQ N/D N/D 21

PM0000472

(VERVE® Discs Green

Mint)

Nicotine (total), mg/portion 1.42 (0.04) 1.45 (0.03) 1.32 (0.03) 21 ↑2 ↓7

Nicotine (free), mg/portion 0.58 (0.06) 0.44 (0.03) 0.33 (0.01) 21 ↓24 ↓43

pH 7.86 (0.10) 7.65 (0.05) 7.54 (0.03) 21 ↓3 ↓4
PM0000470 – PM0000473 Page 92 of 104

PMTA Constituent

Mean Average Across 3 Lots with (Standard Deviation) % Change a

(T=6M from

T=1M)

% Change b

(T=12M

from T=1M) T = 1M T = 6M T = 12M N1

Cadmium, ng/portion 7.87 (1.78) 5.76 (0.20) 5.60 (1.15) 21 ↓27 ↓29

Arsenic, ng/portion N/D N/D N/D 21

Benzo[a]pyrene, ng/portion N/D N/D N/D 21

NNN+, ng/portion 1.27 (0.71) 1.48 (0.59) 1.32 (0.54) 21 ↑17 ↑4

NNK++, ng/portion 0.37 0.35 (0.10) 0.33 (0.07) 21 ↓5 ↓11

NAB*, ng/portion N/D N/D N/D 21

NAT**, ng/portion N/D 0.29 N/D 21

Formaldehyde, μg/portion 0.86 (0.39) 0.54 (0.08) 0.16 (0.02) 21 ↓37 ↓81

Acetaldehyde, μg/portion 0.60 (0.28) 0.22 (0.06) 0.09 (0.01) 21 ↓63 ↓8 

Crotonaldehyde, μg/portion N/D N/D N/D 21

PM0000473

(VERVE® Chews Green

Mint)

Nicotine (total), mg/portion 1.37 (0.05) 1.54 (0.05) 1.36 (0.05) 21 ↑12 ↓1

Nicotine (free), mg/portion 0.08 (0.03) 0.04 (0.01) 0.02 (0.00) 21 ↓50 ↓75

pH 6.79 (0.18) 6.38 (0.12) 6.09 (0.06) 21 ↓6 ↓10

Cadmium, ng/portion N/D N/D N/D 21

Arsenic, ng/portion 22.88 (0.12) 24.16 (1.43) 23.86 (1.17) 21 ↑6 ↑4

Benzo[a]pyrene, ng/portion N/D N/D N/D 21

NNN+, ng/portion N/D N/D N/D 21

NNK++, ng/portion BLOQ BLOQ N/D 21

NAB*, ng/portion N/D N/D N/D 21

NAT**, ng/portion N/D BLOQ N/D 21

Formaldehyde, μg/portion 0.60 (0.12) 0.49 (0.04) 0.50 (0.03) 21 ↓18 ↓17

Acetaldehyde, μg/portion 0.30 (0.03) 0.39 (0.01) 0.57 (0.1) 21 ↑30 ↑90

Crotonaldehyde, μg/portion BLOQ N/D N/D 21

Bold text denotes that the %RSD across lots and replicates was 20% or greater. + N-nitrosonornicotine; ++ 4-(N-methyl-N- nitrosoamino)-1-(3- pyridyl)-1-butanone; * N-nitrosoanabasine; ** N-nitrosoanatabine 1 Total number of replicates across three lots (n=7 per lot) of samples analyzed to determine mean quantity per time point

N/D = not detectable; BLOQ = below LOQ; N/A = not applicable a % Change = ([Constituent mean (all batches, mg/portion) at T = 6M – [Constituent mean (all batches, mg/portion) at t = 1M)])/[Constituent mean (all batches, mg/portion) at T = 1M]

b % Change = ([Constituent mean (all lots, mg/portion) at T = 12M] – [Constituent mean (all lots, mg/portion) at t = 1M)])/[Constituent mean (all lots, mg/portion) at T = 1M]
PM0000470 – PM0000473 Page 93 of 104

8. APPENDIX B

APPLICATION INFORMATION

Applicant U.S. Smokeless Tobacco Company LLC

Product Manufacturer U.S. Smokeless Tobacco Company LLC

Submission Date July 23, 2018 FDA Receipt Date July 23, 2018

Primary STN(s) PM0000470 VERVE® Discs Blue Mint ☒ Single ☐ Co-Packaged

Description: Other

PM0000471 VERVE® Chews Blue Mint ☒ Single ☐ Co-Packaged

Description: Other

PM0000472 VERVE® Discs Green Mint ☒ Single ☐ Co-Packaged

Description: Other

PM0000473 VERVE® Chews Green Mint ☒ Single ☐ Co-Packaged

Description: Other

Cross-referenced

Submission(s)18

Cross-referenced STN Primary STN(s)

(b)(4) Applies to all STNs above

Amendment(s) Amendment STN Primary STN FDA Receipt Date

PM0000477 Applies to all STNs above September 19, 2018

PM0000500 Applies to all STNs above February 14, 2019

PM0000504 Applies to all STNs above February 27, 2019

PM0000505 Applies to all STNs above March 7, 2019

PM0000512 Applies to all STNs above May 8, 2019

NEW TOBACCO PRODUCT (SINGLE PRODUCT(S))

STN PM0000470

Product Name VERVE® Discs Blue Mint

Product Category Other

Product Sub-Category Other

Package Type Plastic Vial and Cap

Package Quantity 8.51 g

Characterizing Flavor Mint

Nicotine Concentration 1.5 mg/piece

Portion Count 16 Pieces

Portion Mass 0.53 g

Portion Thickness 2.83 mm – 3.83 mm

Portion Length 13 mm – 16 mm

Portion Width 10.75 mm – 13.75 mm

STN PM0000471

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

reference the entire file or certain sections thereof.
PM0000470 – PM0000473 Page 104 of 104

Product Name VERVE® Chews Blue Mint

Product Category Other

Product Sub-Category Other

Package Type Plastic Button Container

Package Quantity 25.2 g

Characterizing Flavor Mint

Nicotine Concentration 1.5 mg/pieces

Portion Count 12 Pieces

Portion Mass 2.1 g

Portion Thickness 7.0 mm- 11.5 mm

Portion Length 18.5 mm – 21.5 mm

Portion Width 14.0 mm – 17.5 mm

STN PM0000472

Product Name VERVE® Discs Green Mint

Product Category Other

Product Sub-Category Other

Package Type Plastic Vial and Cap

Package Quantity 8.37 g

Characterizing Flavor Mint

Nicotine Concentration 1.5 mg/piece

Portion Count 16 Pieces

Portion Mass 0.52 g

Portion Thickness 2.83 mm – 3.83 mm

Portion Length 13 mm – 16 mm

Portion Width 10.75 mm – 13.75 mm

STN PM0000473

Product Name VERVE® Chews Green Mint

Product Category Other

Product Sub-Category Other

Package Type Plastic Button Container

Package Quantity 25.2 g

Characterizing Flavor Mint

Nicotine Concentration 1.5 mg/piece

Portion Count 12 Pieces

Portion Mass 2.1 g

Portion Thickness 7.0 mm – 11.5 mm

Portion Length 18.5 mm – 21.5 mm

Portion Width 14.0 mm – 17.5 mm