Case 1:20-cv-00393-LO-TCB Document 1002-7 Filed 02/11/22 Page 1 of 9 PageID# 27968
`Case 1:20-cv-00393-LO-TCB Document 1002-7 Filed 02/11/22 Page 1 of 9 PagelD# 27968
`
`EXHIBIT G
`EXHIBIT G
`
`

`

`Case 1:20-cv-00393-LO-TCB Document 1002-7 Filed 02/11/22 Page 2 of 9 PageID# 27969
`
`PMTA
`
`over
`
`et
`
`hni
`
`roje
`
`Revew TPL
`
`11 99_RESP0001 0301
`
`

`

`Case 1:20-cv-00393-LO-TCB Document 1002-7 Filed 02/11/22 Page 3 of 9 PageID# 27970
`
`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY
`
`II REVIEW OF PMTA
`
`Regulatory History
`
`Product Description Engineering
`
`Chemistry Stability and Manufacturing
`
`General
`
`Heatsticks
`
`Tobacco
`
`Ingredients
`
`Non-tobacco
`
`Ingredients
`
`Manufacturing
`
`Process
`
`and Controls
`
`Quality Assurance/Sample
`
`Testing
`
`Product Stability
`
`Heating System
`
`Holder
`
`Charger
`
`Manufacturing
`
`Process
`
`and Controls
`
`Quality Assurance/Sample
`
`Testing
`
`Inspections
`
`of Manufacturing
`
`Facilities
`
`Summary
`
`of Engineering Chemistry Product Stability and Manufacturing
`
`Findings
`
`Toxicological
`
`Risk Assessment
`
`Harmful
`
`10
`
`14
`
`14
`
`14
`
`14
`
`16
`
`16
`
`17
`
`19
`
`19
`
`22
`
`25
`
`25
`
`25
`
`25
`
`26
`
`27
`
`29
`
`30
`
`30
`
`and Potentially
`
`Harmful Constituents HPHC5
`
`General Overview
`
`Constituents Unique to IQOS
`
`Comparison
`
`to Cigarette
`
`Smoke
`
`Environmental
`
`Exposure from Heatstick
`
`Aerosol
`
`In Vitro Studies
`
`Neutral
`
`Red Uptake NRU Assays
`Bacterial Reverse Mutation Ames test
`Mouse Lymphoma Assay MLA
`
`Summary
`
`of
`
`In Vitro Studies
`
`In Vivo Studies
`
`90-day Nose-only
`
`Inhalation
`
`Studies
`
`18-month Carcinogenicity
`Study with A/i mice
`Pharmacokinetic PK Study with Rats
`
`Nicotine
`
`Summary
`
`Systems Toxicology Studies
`
`Acute and Repeated
`
`Exposure Studies with Human Organotypic
`
`Tissues
`
`ApoE1 Mouse Switching Study
`
`Nonclinical
`
`Evaluation
`
`of Carbon Monoxide
`
`from Heatstick
`
`Aerosol
`
`Summary
`
`of Toxicological
`
`Findings
`
`30
`
`32
`
`33
`
`35
`
`35
`
`35
`
`36
`
`36
`
`37
`
`37
`
`37
`
`38
`
`38
`
`38
`
`39
`
`39
`
`39
`
`40
`
`41
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`11 99_RESP0001 0306
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`

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`Case 1:20-cv-00393-LO-TCB Document 1002-7 Filed 02/11/22 Page 4 of 9 PageID# 27971
`
`Behavioral and Clinical Pharmacological
`
`Assessment
`
`Pharmacokinetics
`
`Exposure/Response
`
`and Clinical Pharmacology
`
`Pharmacokinetic/Pharmacodynamic
`
`PK/PD Studies
`
`Intrinsic and Extrinsic Factors
`NEQ in Urine
`
`Nicotine
`
`Equivalents
`
`Affecting
`
`Nicotine
`
`Pharmacokinetics
`
`Summary
`
`Behavioral
`
`Pharmacology
`
`Use Behaviorandlopography
`
`Product Use/Consumption
`
`Product Acceptability
`
`Abuse
`
`Liability
`
`Summary
`
`Summary
`
`of Behavioral
`
`and Clinical Pharmacology
`
`Findings
`
`Individual
`
`Health Impact
`of Exposure BOE
`
`Biomarkers
`
`COHb
`
`BOE for Carbon Monoxide
`
`Monohydroxybutenyl-mercapturic
`
`3-Hydroxypropylmercapturic
`
`acid MHBMA
`BOE for Acrolein
`acid 3-HPMA
`
`BOE for 13-Butadiene
`
`5-phenylmercapturic acid S-PMA
`
`BOE for Benzene
`
`Total NNAL- BOE for NNK
`
`CYP1A2 Activity
`
`Urine Mutagenicity
`
`Summary
`
`Biomarkers
`
`of Potential Harm BOPH
`of Inflammation
`
`42
`
`42
`
`42
`
`44
`
`44
`
`45
`
`45
`
`45
`
`45
`
`47
`
`47
`
`49
`
`49
`
`50
`
`50
`
`53
`
`53
`
`54
`
`54
`
`54
`
`55
`
`55
`
`55
`
`56
`
`57
`
`Assessment
`
`Assessment
`
`of Oxidative Stress
`
`Assessment
`
`Assessment
`
`of Cardiovascular CV Risks
`of Lung Function
`
`Assessment
`
`of Genotoxicity and Mutagenicity
`
`Summary
`
`Clinical Effects
`
`of
`
`IQOS
`
`Analysis
`
`of Adverse Events in Clinical Studies
`
`Review of Published Clinical Literature
`
`Summary
`
`Likelihood
`
`of Product Misuse or Malfunction
`
`Bioresearch Monitoring BIMO Inspection
`2017 Safety
`
`Report
`
`Update
`
`Summary
`
`of
`
`Individual Health Findings
`
`from Clinical Studies Literature
`
`Adverse Experience Reports
`
`and
`
`Safety
`
`Updates
`
`Population Health
`
`Likelihood
`
`of
`
`IQOS Use by Current Cigarette
`
`Smokers
`
`Poly-use
`
`of
`
`IQOS and cigarettes
`
`or other tobacco
`
`products
`
`Use of
`
`IQOS by Former or Never Smokers
`
`and Youth
`
`Likelihood
`
`of
`
`IQOS leading
`
`to Conventional
`
`Cigarette
`
`Smoking
`
`Cessation
`
`57
`
`57
`
`57
`
`58
`
`58
`
`59
`
`59
`
`60
`
`60
`
`61
`
`62
`
`62
`
`64
`
`65
`
`68
`
`72
`
`73
`
`76
`
`11 99_RESP0001 0307
`
`

`

`Case 1:20-cv-00393-LO-TCB Document 1002-7 Filed 02/11/22 Page 5 of 9 PageID# 27972
`
`Population Modeling
`
`Amendment MR0000117
`
`Study ZRHR-ERS-09-US
`
`Summary
`
`of Population Health Findings
`
`Ill PRODUCT LABELING CONSUMER COMPREHENSION
`
`AND MARKETING PLAN
`
`85
`
`Proposed PMTA Labeling
`
`Consumer Comprehension
`
`Marketing
`
`Plan
`
`Nicotine is Addictive Labeling
`
`Carbon Monoxide CO Warning
`
`IV CONCLUSIONS
`
`AND RECOMMENDATIONS
`
`90
`
`Recommendation for Marketing
`
`Postmarketing
`
`Recommendations
`
`Postmarketing
`
`Recordkeeping
`
`Retention
`
`Reporting
`
`and Marketing
`
`Requirements
`
`Record Retention
`
`Serious
`
`and Unexpected
`
`Adverse Experiences Reporting
`
`Manufacturing
`
`Deviations
`
`Periodic
`
`Reporting
`
`Marketing Requirements
`
`APPENDIX THE PUBLIC HEALTH RATIONALE FOR RECOMMENDED RESTRICTIONS ON NEW
`TOBACCO PRODUCT LABELING ADVERTISING MARKETING AND PROMOTION
`
`111
`
`.77
`
`79
`
`83
`
`85
`
`85
`
`86
`
`87
`
`89
`
`98
`
`99
`
`99
`
`100
`
`102
`
`103
`
`103
`
`107
`
`11 99_RESP0001 0308
`
`

`

`Case 1:20-cv-00393-LO-TCB Document 1002-7 Filed 02/11/22 Page 6 of 9 PageID# 27973
`
`Table
`
`Table
`
`Table
`
`Table
`
`Table
`
`Table
`
`Table
`
`Table
`
`Select HPHCs
`
`in Aerosol
`
`and Filler as Tested by Southeast Tobacco
`
`Laboratory STL
`of HPHC Yields from Heatstick Aerosols and Combusted Cigarettes
`Comparison
`HPHC5 Chemical Class Measured BOE and Toxicity Class
`
`Selected
`
`Summary of Device
`
`Issues in IQOS Clinical
`
`Trials
`
`Summary of Pre- and Post-Market Studies of IQOS Use Patterns Among Current Tobacco
`
`Users
`
`Intention
`
`to Try and Use IQOS among Current Smokers PBA-05-NOC
`
`Prevalence
`
`of Heatstick Trial and Switching
`IQOS and CC Use Over 6-Week Observational
`
`at Study End by Country
`
`Actual Use Study PBA-07
`
`Table
`
`Study Population
`
`ZRHR-ERS-09-US
`
`Table 10 Primary Analysis of CRE5 between THS Use and CC Use at Six Months for ZRHR-ERS-09-US
`
`Table 11 CO Acceptance Criteria for Heatsticks
`
`Figure
`
`The IQOS Charger Holder and Heatstick
`
`Figure
`
`Heatstick Components
`
`Figure
`
`Carboxyhemoglobin
`
`Plasma Carboxyhemoglobin
`
`Levels after Repeated Exposure to 3R4F
`Levels at Week
`
`for 90-day Rat
`
`Inhalation Study
`
`Product Consumption Number of Products Used During
`
`the REX Studies
`
`Arithmetic Mean and 95% Cl Total Scores
`
`for QSU-Brief Total
`
`Figure
`
`Figure
`
`Figure
`
`Figure
`
`Percent Change
`
`from Baseline of Geometric Mean Levels and 95% CIs at Day 90 in ZRHM-REXA
`
`08-US
`
`Figure
`
`Geometric Mean and 95% CIs of COHb Concentrations
`
`Figure
`
`Likelihood
`
`of Heatstick Purchase among Current Smokers who used at least
`PBA-07 Actual Use Study
`
`100 Heatsticks
`
`in
`
`Figure 10 THSCC light grey and Dual UseCC dark grey Ratios
`Month
`
`Figure 11 Perceived
`
`Addiction
`
`Risk for Heatsticks Pack Arm
`
`and Difference ppm and 95% Cl at
`
`20
`
`34
`
`51
`
`61
`
`66
`
`69
`
`70
`
`72
`
`80
`
`81
`
`90
`
`15
`
`16
`
`40
`
`41
`
`46
`
`48
`
`52
`
`53
`
`71
`
`81
`
`88
`
`11 99_RESP0001 0309
`
`

`

`Case 1:20-cv-00393-LO-TCB Document 1002-7 Filed 02/11/22 Page 7 of 9 PageID# 27974
`
`The statute provides that
`
`the finding as to whether
`
`the marketing
`
`of
`
`product
`
`for which
`
`PMTA is
`
`submitted would be appropriate
`
`the risks and benefits to the population
`
`of the public health shall be determined with respect
`for the protection
`as whole including users and nonusers of the tobacco product
`
`to
`
`and taking into account
`
`the increased
`
`or decreased likelihood that existing
`
`users of tobacco products will stop using
`
`such products and
`
`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
`
`controls and quality assurance
`There are adequate process
`1005 Charger Marlboro Heatsticks
`manufactured
`to meet
`
`Fresh Menthol Heatsticks
`
`and Smooth Menthol Heatstick are
`
`procedures to help ensure
`
`the 1005 Holder
`
`consistently
`
`the applicants
`
`specifications
`
`Marlboro Smooth Menthol
`
`found in combusted
`
`different
`
`from those
`
`or cytotoxic
`
`these
`
`substantial
`
`decrease
`
`and Fresh Menthol Heatstick aerosols contain some chemicals
`cigarettes CC.6 Although some of the chemicals
`and potential effects
`
`which are
`
`are genotoxic
`
`are outweighed
`
`by the
`
`chemicals
`
`in very low levels
`are present
`in the number and levels of HPHCs
`
`found in CC see below
`
`The toxicological
`
`profiles
`
`of Marlboro Smooth Menthol
`
`and Fresh Menthol Heatsticks are essentially
`
`identical
`
`relative
`
`data
`
`indicates the potential for
`
`to 1005
`
`of menthol The available toxicological
`for the quantity
`except
`benefit compared to CC for smokers who switch completely
`Smooth Menthol Heatsticks
`Fresh Menthol Heatsticks contain 13.23
`
`brands
`
`in the U.S
`
`contain 6.98 mg menthol/Heatstick
`The applicant
`compared this to 23 mentholated cigarette
`mg menthol/Heatstick
`which had 2.9-19.5 mg menthol/cigarette
`PK studies show Marlboro Smooth Menthol
`and abuse liability similar
`
`addiction potential
`
`and Fresh Menthol Heatsticks have nicotine delivery
`to CC This is potentially beneficial
`for smokers trying to
`switch to 1005 as they are more likely to have satisfactory results
`and not resume CC smoking
`The
`users who initiate use of these products
`nicotine levels do pose an addiction
`and initiation is
`tobacco products
`however
`the risk is no higher
`than for other currently available
`
`risk for non-tobacco
`
`expected to be low generally See also
`warning below
`
`the discussion regarding the inclusion of
`
`nicotine addiction
`
`improvement
`
`of exposure BOE which indicates reduced HPHC
`studies despite reduced compliance and
`trends persisted in the 90-day
`
`biomarkers
`
`The 5-day studies demonstrate improved
`exposures These
`data from six-month
`tobacco products Additionally the applicant
`recently submitted
`in eight BOE as well as NNAL and COHb for self-reported
`
`use of other
`
`clinical
`
`trial which demonstrated reduction
`
`users of 1005 compared to CC users
`do not demonstrate reduction
`Although the studies conducted by the applicant
`in long-term disease
`indicates CC smokers who switch completely
`
`risks the currently available evidence
`
`to 1005 will have
`
`and this is likely to lead to less risk of tobacco-related
`reduced toxic exposures
`smokers who use 1005 while continuing
`to smoke dual use is less clear but
`no increase in HPHC exposures for those who dual use
`shows
`There have been
`
`no specific
`
`short-term health-related
`
`or product
`
`quality issues unique
`
`diseases
`
`The data for CC
`
`the available evidence
`
`clinical studies
`
`the current world-wide markets or the published literature
`and the product
`design makes
`it unlikely users will have
`
`experience
`
`nicotine is delivered with reusing
`
`Heatstick
`
`Misuse of 1005 is uncommon
`e.g no significant
`Dual use of 1005 and CC was common in all countries
`users in the U.S actual use study who switched
`
`in the pre- and post-market
`
`studies though the CC
`
`to exclusive 1005 use during the study remained
`
`to 1005 in the
`
`satisfactory
`
`For
`
`the purposes
`
`of this review CCcombusted
`
`cigarettes
`
`or conventional
`
`cigarettes
`
`11
`
`11 99_RESP0001 0311
`
`

`

`Case 1:20-cv-00393-LO-TCB Document 1002-7 Filed 02/11/22 Page 8 of 9 PageID# 27975
`
`applications
`PM0000426
`
`the weight specifications arePI14
`in theI1
`
`In addition
`
`for PM0000425 and
`
`process the specification
`
`for weight
`
`three Heatsticks
`
`In the batch
`
`record for Marlboro Smooth Menthol Heatsticks
`for weight isPII
`the specification
`Heatsticks
`in the Japanese and the U.S markets
`mainly due to different cigarette paper used
`
`The applicant
`
`indicated that
`
`for
`
`for the
`
`.boro i-
`
`Menthol
`
`the differences are
`
`Summary of Engineering Chemistry Product Stability and Manufacturing
`
`Findings
`
`The engineering
`
`review concludes
`
`that
`
`the PMTAs
`
`contain adequate information with respect
`
`to the
`
`following
`
`complete characterization
`
`of the design parameters
`
`An adequate description
`
`of manufacturing steps and quality control measures
`
`Adequate process
`
`controls and quality assurance
`
`procedures to help ensure
`
`that
`
`the products meet
`
`manufacturing specifications
`
`for the 1005 Holder Charger and Marlboro Smooth Menthol
`
`and
`
`Fresh Menthol Heatsticks and that
`
`the products
`
`are manufacture
`
`in
`
`consistent manner
`
`that
`
`minimizes the variability
`
`in product
`
`quality
`
`Performance
`
`testing to verify
`
`The engineering
`
`review concludes
`
`that
`
`the product
`design
`these PMTAs
`
`contain sufficient
`
`information
`
`to characterize the
`
`product
`
`and adequate processes
`manufacturers specifications
`
`design
`
`and controls to help ensure
`
`that
`
`the products meet
`
`the
`
`In addition to the above
`As TPL
`the applicant
`agree with the engineering
`information
`made changes to the Holder
`and Charger which are likely to lead to more consistent manufacturing
`and improve product
`reliability The applicant
`and design
`process
`of the Heatstick filters The applicant
`The applicant
`
`control
`
`nicotine delivery
`
`has provided
`
`an adequate description
`
`of the firmware functionality
`
`as well as for function
`
`conclusions
`
`has
`
`has provided
`
`description
`
`of the function
`
`has no efficiency requirements
`
`for Heatstick filters as
`
`the filters do not
`
`for control of the heating blade temperature and cleaning function
`and Charger Additionally the applicant
`management of the Holder
`and reduce
`the vendors that will help to ensure
`
`consistency
`
`product
`
`and battery
`
`has described
`
`battery specifications
`
`for
`
`concerns
`
`of malfunction The battery
`
`testing performed at the Winchester
`
`Engineering
`
`and Analytical Center demonstrated consistent
`
`battery
`
`performance
`
`which reduces
`
`concerns
`
`of malfunction
`
`The chemistry
`
`review concludes
`
`these PMTAs contain adequate information
`
`as follows
`
`complete list of uniquely
`new tobacco product
`
`identified
`
`components
`
`ingredients
`
`and additives by quantity
`
`in each
`
`as well as the applicable specifications
`
`and
`
`description
`
`of the intended
`
`function
`
`for each
`
`An adequate description
`
`of manufacturing steps and quality control measures in place
`
`Sufficient
`
`information
`
`nicotine
`
`to assure
`
`FDA that
`
`the products meet manufacturing specifications
`phenol carbon monoxide acrylamide and menthol and that
`
`for
`
`the
`
`products
`
`are manufactured
`
`in
`
`consistent manner
`
`that minimizes
`
`the variability
`
`in product
`
`quality
`
`Data
`
`on chemical
`
`endpoints
`
`establishing the stability of the product
`
`through the stated shelf
`
`life
`
`Product
`
`analyses
`
`for verifying the product
`
`formulations
`
`Testing data to demonstrate that
`
`HPHCs
`
`including formaldehyde acrolein
`
`the new products
`lower
`levels of certain
`contain significantly
`carbon monoxide NNN NNK compared to major types of
`
`combusted cigarettes
`
`on the U.S market
`
`and the batch noted during the
`There were small weight differences between the application
`The difference was due to different cigarette paper used
`
`inspection of the Bologna
`
`Italy facility
`
`Japan vs the U.S and do not
`
`raise any concerns
`
`regarding product
`
`quality
`
`in
`
`29
`
`11 99_RESP0001 0329
`
`

`

`Case 1:20-cv-00393-LO-TCB Document 1002-7 Filed 02/11/22 Page 9 of 9 PageID# 27976
`
`showed
`
`no difference between THS 2.2 and CC Findings were similar
`THS 2.2 had significantly
`the REX studies
`ratings than CC on Day
`
`lower
`
`for Menthol
`
`and Regular products In
`
`end of confinement
`
`but no
`
`differences were found on Day 90 for the two extended REX studies This may reflect
`period to the new product
`
`adaptation
`
`learning or
`
`In the Actual Use study participants were asked
`
`at the end of the observational
`
`about
`
`their
`
`likelihood to purchase
`
`reported that
`
`period Week
`and
`pack of Marlboro
`the IQOS system if the iQOS device were available for $79.99
`pack of Marlboro cigarettes In the overall
`HeatSticks were available at
`price comparable to
`sample
`N987 nearly 20% of participants
`they probably or definitely would buy IQOS Findings
`age groups and across baseline smoking
`were similar based on menthol/non-menthol
`preference across
`N138 nearly 50%
`70% of the time Week
`subsample of participants who used
`THS 2.2
`rates In
`reported they probably or definitely would buy IQOS Although descriptive
`data were provided this was
`they had already owned the
`assumed
`listed as an outcome measure It
`the question was
`about buying Heatsticks only or if they assumed
`
`not
`
`is unclear
`
`if participants
`
`that
`
`IQOS system and were being asked
`
`referring to purchasing
`
`both the IQOS system and Heatsticks
`
`There are limitations to interpretation of questionnaire
`
`data including
`
`Recall
`
`bias
`
`and other
`
`inaccuracies associated
`
`with self-report
`No assessment of the relationship between subjective measures and behavior
`No data was provided
`not conducted
`in the U.S
`
`on the validation of translated versions of the questionnaires
`
`used
`
`in studies
`
`The QSU-Brief
`
`was not modified to replace references to cigarettes with Heatsticks/IQOS/THS
`
`2.2
`
`if participants were aware of which product
`so it
`is unclear
`Scoring of the MNWS differed between studies
`limited generalizability to participants who have quit intent of greater
`have
`criteria and are difficult
`to interpret because it was not clear whether
`
`Intent
`
`to quit
`
`results
`
`than
`
`six months inclusion
`
`was being
`
`asked
`
`about
`
`the
`
`intent to quit
`
`refers to quitting all tobacco vs switching
`
`completely
`
`from smoking CC to THS 2.2
`
`Summary
`
`As noted above
`
`there are limitations for self-reported
`
`obtaining
`
`information
`
`of this type These are validated
`
`data however this is an informative method for
`tobacco research
`and
`
`for outpatient
`
`questionnaires
`
`are commonly used
`and multiple uses of THS 2.2 and CC both Regular
`
`in studies of tobacco use behaviors Systemic
`
`appear sufficient
`
`to
`
`single
`
`nicotine exposure was similar after
`and Menthol Nicotine exposures
`provide user satisfaction which can facilitate
`partial or complete switching to THS 2.2 THS 2.2 use rates
`to CC use rates Self-report questionnaires
`found that THS 2.2 produces reinforcing
`or close to levels of CC reinforcement
`for THS 2.2 increased
`the 90-day
`reaching
`Likeability
`period for those who used
`it more consistently which may indicate the need for an adjustment
`transition phase from CC i.e dual use
`
`were similar
`
`scores
`
`over
`
`effects
`
`or
`
`The data indicate that THS 2.2 has addictive potential and abuse liability similar
`
`to CC This is important
`
`as it
`
`signifies
`
`users however there is also
`
`risk tobacco-na(cid:239)ve
`
`THS 2.2 can provide an adequate nicotine source
`for dependent
`populations
`new THS users will develop
`
`including current CC
`
`nicotine addiction
`
`The behavioral
`
`concludes
`
`that
`
`the similar systemic exposure to
`
`nicotine as well as similar use rates reinforcement
`
`reduction
`
`profiles
`
`between THS
`
`Summary of Behavioral and Clinical
`and clinical pharmacology BCP review
`and withdrawal/craving
`
`Pharmacology
`
`Findings
`
`2.2 and CC suggest
`
`similar abuse liability of these
`
`tobacco products Thus THS 2.2 use may sustain
`
`49
`
`11 99_RESP0001 0349
`
`