18/2021

Technical Project Lead Review of MRTPA 

Recommendation

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

Technical Project Lead (TPL): /S/

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

Associate Director

Division of Population Health Science, Office of Science

Signatory Decision: Concur with TPL recommendation and basis of recommendation

/S/

Matthew R. Holman, Ph.D.

Director

Office of Science

1 Product details, amendments, and dates provided in the Appendix. MRTPA means modified risk tobacco product application. 

2 Submission tracking number

Modified Risk Tobacco Product Subject of this Review1

STN2 MR0000192

Attributes

Submission date March 18, 2021

Receipt date March 18, 2021

Applicant Philip Morris Products S.A.

Product manufacturer Philip Morris Products S.A. 

Product category Heated Tobacco Product (HTP)

Product subcategory Open HTP

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

☒ Exposure Modification 911(g)(2) order

Proposed Claims AVAILABLE EVIDENCE TO DATE:

• The IQOS system heats tobacco but does not burn it.

• This significantly reduces the production of harmful and 

 potentially harmful chemicals.

• Scientific studies have shown that switching completely from 

 conventional cigarettes to the IQOS system significantly reduces

 your body’s exposure to harmful or potentially harmful chemicals.

Cross-Referenced Submissions

MR0000192 , MR000059-61, 

MR0000133, PM0000634, PM0000479

(b) (4)
MR0000192 Page 2 of 16 

TABLE OF CONTENTS

1. EXECUTIVE SUMMARY....................................................................................................................3

2. BACKGROUND................................................................................................................................4

2.1. MODIFIED RISK TOBACCO PRODUCT ............................................................................................. 4 

2.2. PROPOSED CLAIMS ......................................................................................................................... 4 

2.3. REGULATORY ACTIVITY .................................................................................................................. 4 

2.4. SCOPE OF REVIEW........................................................................................................................... 4 

2.5. TOBACCO PRODUCTS SCIENTIFIC ADVISORY COMMITTEE (TPSAC) ............................................. 4 

2.6. PUBLIC AVAILABILITY OF MRTPAS ................................................................................................. 5 

3. SCIENTIFIC REVIEW.........................................................................................................................5

3.1. RELATIVE HEALTH RISKS OF THE PROPOSED MRTPS TO INDIVIDUAL TOBACCO USERS.............. 5 

Discipline key finding...................................................................................................... 5 

Synthesis......................................................................................................................... 5 

3.2. CONSUMER UNDERSTANDING AND PERCEPTIONS....................................................................... 6 

Discipline key findings.................................................................................................... 6 

Synthesis......................................................................................................................... 6 

3.3. TOBACCO USE BEHAVIOR AND IMPACTS TO THE POPULATION AS A WHOLE............................. 6 

Discipline key findings.................................................................................................... 6 

Synthesis......................................................................................................................... 7 

3.4. STATUTORY REQUIREMENTS ......................................................................................................... 8 

Public health conclusion................................................................................................. 8 

4. ENVIRONMENTAL DECISION...........................................................................................................9

5. CONCLUSION AND RECOMMENDATION..........................................................................................9

6. APPENDIX ...................................................................................................................................11

A. MODIFIED RISK TOBACCO PRODUCT .......................................................................................11

B. AMENDMENTS RECEIVED...................................................ERROR! BOOKMARK NOT DEFINED.

C. MODIFIED RISK GRANTED ORDER APPENDICES ......................................................................12

LIST OF TABLES

Table 1. Disciplines reviewed........................................................................................................................ 4 

Table 2. Consultations................................................................................................................................... 4 
MR0000192 Page 3 of 16 

1. EXECUTIVE SUMMARY

This modified risk tobacco product application (MRTPA) is a request for authorization to market the 

IQOS 3 System Holder and Charger3 (IQOS 3 device) under a Section 911(g)(2) (exposure modification) 

order, which was granted a Marketing Granted Order (MGO) under Section 910 of the FD&C Act on 

December 07, 2020 (PM0000634). The IQOS 3 device is an update to their previous device, the IQOS 2.4 

Holder and Charger (IQOS 2.4 device, PM0000479), that was granted a MGO on April 30, 2019 and a 

Modified Risk Granted Order under Section 911(g)(2) as an MRTP on July 07, 2020 (MR0000133). 

The table below summarizes the regulatory history of these two products. 

IQOS 2.4 System Holder and Charger IQOS 3 System Holder and Charger

PMTA Authorized for marketing in PM0000479 Authorized for marketing in sPMTA4 PM0000634

MRTPA Authorized as a MRTP5 in MR0000133 Subject of this TPL review

This MRTPA utilizes the same claims as in the MRTPA for the IQOS 2.4 System Holder and Charger (i.e., 

MR0000133), requests the same order that was requested and issued for MR0000133 (i.e., a reduced 

exposure order under Section 911(g)(2)) of the FD&C Act), and plans to utilize the same postmarket 

surveillance studies. In addition, the IQOS 2.4 device and IQOS 3 device are comparable products as the 

IQOS 3 device is similar in design to IQOS 2.4 device (with mainly aesthetic physical modifications) and 

uses the same tobacco source (Marlboro Heatsticks). As such, this review relies on the TPL review for 

the IQOS 3 device (PM0000634) and the TPL review for the MRTPA for the IQOS 2.4 device (MR000059-

61, MR0000133) to examine the relative health risks of the proposed MRTP to individual tobacco users, 

consumer understanding and perceptions of the proposed modified risk claim, and tobacco use behavior 

and impacts to the population as a whole. 

After conducting a thorough scientific review of the information contained in the MRTPA, comments, 

data, and information submitted to FDA by interested persons and other scientific information, I 

conclude that the proposed MRTP, as actually used, reduces a user’s exposure to harmful and 

potentially harmful constituents (HPHCs) if they switch completely from combusted cigarettes to the 

IQOS 3 System Holder and Charger when using Marlboro Heatsticks. A measurable and substantial 

reduction in morbidity or mortality among individual tobacco users is reasonably likely in subsequent 

studies. Further, the applicant has demonstrated that the modified risk labeling and advertising enable 

the public to understand the proposed MRTP to be a product with likely moderate risks of a range of 

tobacco-related diseases and a considerably greater risk than quitting smoking or using nicotine 

replacement therapies (NRT). As the two devices have similar operating procedures, use the same 

tobacco sources, and produce comparable aerosols, FDA has no reason to believe the IQOS 3 device will 

result in different nicotine exposure, use patterns, user populations, or abuse liability. 

As such, the IQOS 3 device has been found to be appropriate to promote public health and is expected 

to benefit the health of the population as a whole taking into account both users of tobacco products 

and persons who do not currently use tobacco products. I conclude that the current application meets 

the statutory requirements for an exposure modification order under Section 911(g)(2) of the FD&C Act. 

A finding of no significant impact (FONSI) has been established for the proposed MRTP. I recommend 

that the order be issued through July 07, 2024.

3 The MRTPA does not contain any modifications to the previously authorized Heatsticks (MR0000059-MR0000061). 

4 Supplemental premarket tobacco product application. 

5 Modified risk tobacco product.
MR0000192 Page 4 of 16 

2. BACKGROUND

2.1. MODIFIED RISK TOBACCO PRODUCT 

The applicant submitted information for the proposed modified risk tobacco product listed on 

the cover page and with more detail in Appendix A. 

2.2. PROPOSED CLAIMS

AVAILABLE EVIDENCE TO DATE: 

• The IQOS system heats tobacco but does not burn it. 

• This significantly reduces the production of harmful and potentially harmful chemicals. 

• Scientific studies have shown that switching completely from conventional cigarettes to 

the IQOS system significantly reduces your body’s exposure to harmful or potentially 

harmful chemicals

2.3. REGULATORY ACTIVITY 

On March 18, 2021, FDA received an MRTPA from Philip Morris Products S.A. FDA issued an 

Acceptance letter to the applicant on April 15, 2021. FDA issued a Filing letter to the applicant 

on May 13, 2021.

Refer to the Appendix B for a complete list of amendments received by FDA. 

2.4. SCOPE OF REVIEW

This review captures all compliance and scientific reviews completed for the modified risk 

tobacco product subject of this review. 

Table 1. Disciplines reviewed 

Discipline Cycle 1

Reviewers Review Date

Regulatory Donna Cheung 4/15/2021

Environmental Science Carla Figueroa 11/8/2021

Table 2. Consultations 

Discipline or Office Cycle 1

Reviewers Review Date

Chemistry/Engineering Yuan-Wei Nei/ 

Nashaat Rasheed March 8, 2022

2.5. TOBACCO PRODUCTS SCIENTIFIC ADVISORY COMMITTEE (TPSAC)

The MRTPAs for the IQOS 2.4 System Holder and Charger, Marlboro Heatsticks, Marlboro Smooth 

Menthol Heatsticks, and Marlboro Fresh Menthol Heatsticks (MR0000059-61, MR0000133) were 

referred to TPSAC and TPSAC reported its recommendations on the applications during an open 

public committee meeting held on January 24-25, 2018. The current MRTPA is for the IQOS 3 

device, which contains mainly aesthetic physical modifications to the Holder and Charger. FDA 

authorized the marketing of the IQOS 3 device without modified risk claims on December 07, 2020 

(PM0000634). The MRTPA largely cross-references the previously submitted and authorized

MRTPAs for the IQOS 2.4 System (MR0000059-61, MR0000133) and does not involve any new 

modified risk claims. FDA obtained TPSAC’s recommendations during the January 24-25, 2018 

meeting on the modified risk claims that accompany IQOS 2.4 and which would not change on IQOS 

3; therefore, the current application did not raise any new scientific matters that would require an 
MR0000192 Page 5 of 16 

additional TPSAC meeting. 

2.6. PUBLIC AVAILABILITY OF MRTPAS

Pursuant to Section 911(e) of the FD&C Act, FDA made the subject MRTPA available to the public 

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

information). The docket for public comment of the current MRTPA was opened May 14, 2021, 

extended on July 20, 2021 due to missing cross-referenced files in PM0000634 and closed on 

December 10, 2021. FDA received 33 public comments from individuals, academia, and other 

organizations. The comments included advocacy concerns and clinical concerns. FDA considered all 

significant comments when making our final determination on this MRTPA. 

3. SCIENTIFIC REVIEW 

3.1. RELATIVE HEALTH RISKS OF THE PROPOSED MRTPs TO INDIVIDUAL TOBACCO USERS 

Discipline key finding

There are no new data specifically related to relative health risks to individual tobacco users 

in this MRTPA. I relied on the TPL review for the sPMTA (PM0000634) to examine the 

toxicant exposure and health effects of the IQOS 3 device. That TPL review found that “the

aerosol generated with the IQOS 3 device when using Marlboro Heatsticks is comparable to 

that generated with the IQOS 2.4 device using the same Heatsticks” and the “overall health 

risks appear to be similar for IQOS 2.4 and 3.” Further, to ensure that the changes to the 

device itself and the aerosols and related harmful and potentially harmful constituents 

(HPHCs) emitted would not alter claim substantiation (and thus, whether the proposed 

MRTP is appropriate to promote the public health and is expected to benefit the health of 

the population as a whole), Chemistry and Engineering provided a combined consultation. 

The consultation concluded, “This consultation has not identified any issues from a 

chemistry and engineering perspective in this MRTPA submission (MR0000192) that would 

alter our conclusions on the currently authorized MRTPA (MR0000133).” There was a public 

comment that disputed the substantiation of the claims noting that their concerns about 

individual health risks related to IQOS 2.4 still stood. However, because those risks have not 

changed since the original MRTPA, these comments do not impact the current assessment. 

I relied on the TPL review for the original MRTPA (MR000059-61, MR0000133) for the 

scientific basis for claim substantiation. That review found that all three claims submitted

for 911(g)(2) exposure modification, the same claims submitted in this MRTPA under review, 

were substantiated.

Synthesis

Based on the key findings in the cross-referenced sPMTA, original MRTPA and the 

consultation with Engineering and Chemistry, I conclude that all claims proposed are 

supported from the perspective of relative health risks to individual users. Further, the 

proposed MRTP, as actually used, reduces a user’s exposure to harmful and potentially 

harmful constituents (HPHCs) if they switch completely from combusted cigarettes to the 

IQOS 3 System Holder and Charger when using Marlboro Heatsticks. A measurable and 

substantial reduction in morbidity or mortality among individual tobacco users is reasonably 

likely in subsequent studies.
MR0000192 Page 6 of 16 

3.2. CONSUMER UNDERSTANDING AND PERCEPTIONS 

Discipline key findings

There are no new data specifically related to consumer understanding and perceptions in 

this MRTPA. The MRTPA noted that labeling used will be the same as authorized in 

PM0000634 and will be nominally different from that used in MR0000133 such that the 

proposed MRTP will note updated user instructions and safety warnings “to reflect learnings 

from the global in-market experience with IQOS.” Differences included additional 

information on battery risk, a new hot aerosol risk section, formatting for enhanced 

consumer comprehension, and clarified instructions for safe use as relates to Marlboro 

Heatsticks. After reviewing these changes, I conclude that they provide greater clarity 

regarding instructions for use and safety than prior versions, and thus, do not change my 

assessment. Due to these similarities with the labels authorized in PM0000634 and in 

MR0000133, I relied on the TPL review for MR000059-61 and MR0000133 on consumer 

understanding and perceptions. That review found sufficient consumer understanding of (a) 

the exposure reduction described in the proposed claims, (b) the health risks relative to 

non-use, cessation or nicotine replacement therapies (NRT), and (c) the conditions of use to 

reduce exposure (i.e., switching completely from combustible cigarettes). 

Synthesis

Based on the key findings in the reviews for the cross-referenced sPMTA, original MRTPA

and my review of the differences in labeling as noted above, I find that the applicant has 

demonstrated that the modified risk labeling and advertising enable the public to 

understand the proposed MRTP to be a product with likely moderate risks of a range of 

tobacco-related diseases and a considerably greater risk than quitting smoking or using NRT. 

This supports comprehension of the proposed modified risk claims in the context of total 

health.

3.3. TOBACCO USE BEHAVIOR AND IMPACTS TO THE POPULATION AS A WHOLE

Discipline key findings

There are no new data specifically related to tobacco use behavior and impacts to the 

population as a whole in this MRTPA. 

3.3.1.1. Impacts to Tobacco Users 

• Abuse Liability 

The applicant did not provide new data specific to abuse liability for this application or 

in the sPMTA. Because the product designs and operating procedures are similar 

between IQOS 2.4 and IQOS 3 and use the same Heatsticks, FDA has no reason to 

believe that the abuse liability will change. This is coupled with the findings from the 

original MRTPA, which concluded that “the data support the conclusion that IQOS will 

likely have an addictive potential and abuse liability similar to combusted cigarettes.” In 

addition, the TPL review also noted that due to the abuse liability, youth might also be 

interested in trying the product and noted the “importance of preventing youth access 

and exposure to the product and its marketing.”

• Patterns of Use 

I relied on the TPL review for the sPMTA, which examined newly submitted use data 

from international markets (no new U.S. data were provided) that compared users of 

IQOS 2.4, IQOS 2.4P, and IQOS 3. That review found that data were limited and “may 
MR0000192 Page 7 of 16 

not reflect the way IQOS 3 would be used in the U.S.,” but “IQOS 3 seems to be 

accepted by tobacco users in other countries and some of the users report switching 

completely to IQOS (as opposed to dual use with cigarettes).” Because the proposed

MRTP will utilize the same marketing plans and the devices operate similarly, FDA has 

no reason to believe the use patterns in the U.S. for the proposed MRTP will be 

significantly different from those for the currently marketed version (IQOS 2.4). 

• Likelihood that Current Users will Start Using the Proposed MRTPs

I relied on the TPL review for the original MRTPA which concluded that “these findings 

are supportive that marketing IQOS with a reduced exposure claim could appeal to 

current smokers who are most likely to benefit from their use, and this supports a likely 

benefit to population health.” Because the MRTP will utilize the same claims and 

marketing plans, and the devices operate similarly, FDA has no reason to believe the 

impact on current users will be significantly different from those for the currently 

marketed version (IQOS 2.4).

3.3.1.2. Impacts to Non-Users of Tobacco

I relied on the TPL reviews for the authorized sPMTA and original MRPTA. The sPMTA 

concluded, “There is no evidence the user population for IQOS 3 will be different from 

the population who use IQOS 2.4. The survey data also show no evidence of increased 

youth and young adult initiation of IQOS 3 use in international markets. Given the 

product similarities, there is no evidence of increased risk for youth initiation and use 

for IQOS 3 as compared to IQOS 2.4.” The original MRTPA TPL review found that there 

was low interest in trying the product among adult and young adult never smokers with 

some interest in trying the product among former smokers, but the addition of the claim 

did not appear to increase interest among any of the non-user groups. Nonetheless, the 

same care to mitigate youth exposure taken with the original MRTP and the sPMTA also 

apply to this study, which will be monitored through required post-market surveillance 

studies.

3.3.1.3. Actions Proposed to Mitigate Risk of Unintended Use

As this application proposes to utilize the same marketing plans as outlined in the 

cross-referenced sPMTA and seeks to combine the data from the original MRTPA with 

data collected with the proposed MRTPA, I find the actions to mitigate risk of 

unintended use acceptable. 

3.3.1.4. Population Health Impact Model 

I relied on the TPL review for the original MRPTA as no new data were provided in this 

application that would change the population health impact model. The review found 

that the data were neither supportive nor unsupportive of a modified exposure order. A 

public comment to the MRTPA docket thought that the data provided by the applicant 

underestimated the health impacts and because this has not changed since the previous 

application, the current product and model assumptions carry the same flaws. Because 

these data did not change since the original MRTPA, this comment does not impact my 

assessment. 

Synthesis

I concur with the following TPL conclusion from the sPMTA that states, “As the two devices 

have similar operating procedures, use the same tobacco sources, and produce comparable 

aerosols, FDA has no reason to believe the IQOS 3 device will result in different nicotine 
MR0000192 Page 8 of 16 

exposure, use patterns, user populations, or abuse liability.” In addition, the applicant is 

proposing to market the product with the same claims that were authorized for IQOS 2.4. 

Thus, I find that the proposed MRTP would be expected to promote the public health and 

benefit the health of the population as a whole taking into account both users of tobacco 

products and persons who do not currently use tobacco products. 

3.4. STATUTORY REQUIREMENTS 

Public health conclusion 

The applicant has requested an exposure modification order under 911(g)(2) of the 

FD&C Act to market the product specified in Appendix A for the following claims: 

AVAILABLE EVIDENCE TO DATE: 

• The IQOS system heats tobacco but does not burn it. 

• This significantly reduces the production of harmful and potentially harmful chemicals. 

• Scientific studies have shown that switching completely from conventional cigarettes 

to the IQOS system significantly reduces your body’s exposure to harmful or 

potentially harmful chemicals

As discussed above, as TPL, I find that the MRTPA meets the following statutory 

requirements.

In making the determination under either section 911(g)(1) or 911(g)(2) of the FD&C Act, 

FDA must take into account: 

• The relative health risks the modified risk tobacco product presents to individuals; 

• The increased or decreased likelihood that existing tobacco product users who 

would otherwise stop using such products will switch to using the modified risk 

tobacco product; 

• The increased or decreased likelihood that persons who do not use tobacco 

products will start using the modified risk tobacco product; 

• The risks and benefits to persons from the use of the modified risk tobacco product 

compared to the use of smoking cessation drug or device products approved by FDA 

to treat nicotine dependence; and 

• Comments, data, and information submitted to FDA by interested persons 

(section 911(g)(4) of the FD&C Act). 

For 911(g)(2) specifically, FDA may issue an exposure modification order under 

section 911(g)(2) of the FD&C Act (the "special rule") if it determines that the applicant has 

demonstrated that:

• Such an order would be appropriate to promote the public health;

• Any aspect of the label, labeling, and advertising for the product that would cause 

the product to be a modified risk tobacco product is limited to an explicit or implicit 

representation that the tobacco product or its smoke does not contain or is free of a 

substance or contains a reduced level of a substance, or presents a reduced 

exposure to a substance in tobacco smoke;

• Scientific evidence is not available and, using the best available scientific methods, 

cannot be made available without conducting long-term epidemiological studies for 
MR0000192 Page 9 of 16 

an application to meet the standards for obtaining an order under section 911(g)(1); 

and

• The scientific evidence that is available without conducting long-term 

epidemiological studies demonstrates that a measurable and substantial reduction 

in morbidity or mortality among individual tobacco users is reasonably likely in 

subsequent studies (section 911(g)(2)(A) of the FD&C Act).

Furthermore, for FDA to issue an exposure modification order, FDA must find that the 

applicant has demonstrated that: 

• The magnitude of overall reductions in exposure to the substance or substances 

that are the subject of the application is substantial, such substance or substances 

are harmful, and the product as actually used exposes consumers to the specified 

reduced level of the substance or substances;

• The product as actually used by consumers will not expose them to higher levels of 

other harmful substances compared to the similar types of tobacco products then 

on the market unless such increases are minimal and the reasonably likely overall 

impact of use of the product remains a substantial and measurable reduction in 

overall morbidity and mortality among individual tobacco users;

• Testing of actual consumer perception shows that, as the applicant proposes to 

label and market the product, consumers will not be misled into believing that the 

product is or has been demonstrated to be less harmful, or presents or has been 

demonstrated to present less of a risk of disease than one or more other 

commercially marketed tobacco products; and

• Issuance of the exposure modification order is expected to benefit the health of the 

population as a whole taking into account both users of tobacco products and 

persons who do not currently use tobacco products (section 911(g)(2)(B) of the 

FD&C Act).

4. ENVIRONMENTAL DECISION 

A finding of no significant impact (FONSI) was signed by Luis G. Valerio on November 08, 2021. The 

FONSI was supported by an environmental assessment prepared by FDA on November 08, 2021. 

5. CONCLUSION AND RECOMMENDATION

After conducting a thorough scientific review of the information contained in the MRTPA, the TPL 

review for the cross-referenced sPMTA for the IQOS 3 device and the TPL review and 

recommendations from TPSAC for the original MRTPA, and comments, data, and information 

submitted to FDA by interested persons for the proposed MRTP, I conclude that the applicant has 

demonstrated that the proposed MRTP meets the statutory requirements for an exposure 

modification order as described in section 911(g)(2) of the FD&C Act. I recommend that a 

modified risk order be granted for a period to end on July 07, 2024. 

Section 911(g)(2)(C)(i) of the FD&C Act provides that an MRTP exposure modification order shall 

be limited for a term of not more than 5 years. I recommend authorization for a period to end on 

July 07, 2024, the date that the authorization ends for the original MRTP, MR0000133. Aligning 

the authorization period of this MRTPA with the original MRTPA allows for the applicant and the 

FDA to efficiently submit and review, respectively, renewal applications for all products at the 

same time. Although this review has found that an exposure modification order for the products 

would be appropriate to promote the public health and is expected to benefit the health of the 
MR0000192 Page 10 of 16 

population as a whole, that determination may change over time as a function of how the 

products are actually used by consumers. Therefore, monitoring use of the proposed MRTP in 

terms of uptake, dual use, and complete switching should be required, including the potential for 

initiation among youth. As described below, postmarket surveillance and studies must include an 

assessment of MRTP users’ behavior and understanding over time. The applicant is conducting 

studies for MR0000133 and can utilize those studies to also collect the required information for 

the product subject of this review once authorized. 

I recommend that the language in Appendix B be included in the marketing authorization for 

postmarket surveillance and studies (PMSS) and postmarket reporting. 

FDA has examined the environmental effects of authorizing the proposed MRTP and made a Finding 

of No Significant Impact (FONSI). 

A Modified Risk Granted Order should be issued for the modified risk product subject of this review, 

as identified on the cover page of this review.
MR0000192 Page 11 of 16 

6. APPENDIX 

A. MODIFIED RISK TOBACCO PRODUCT

 Attributes of MRTPA

Submission date March 18, 2021

Receipt date March 18, 2021

Applicant Philip Morris Products S.A.

Product manufacturer Philip Morris Products S.A.

Product category Heated Tobacco Product (HTP) 6,7

Product subcategory Open HTP

Order type 911(g)(2) Exposure Modification Order

Proposed Claims

AVAILABLE EVIDENCE TO DATE:

• The IQOS system heats tobacco but does not burn it.

• This significantly reduces the production of harmful and potentially 

harmful chemicals.

• Scientific studies have shown that switching completely from 

conventional cigarettes to the IQOS system significantly reduces 

your body’s exposure to harmful or potentially harmful chemicals.

Attributes Tobacco Product

STN MR0000192

Product name IQOS 3 System Holder and Charger

Package type Box 

Package quantity 1 Holder, 1 Charger

Characterizing flavor None

Length 92.25 mm (Holder)

114.80 mm (Charger)

Diameter 14.40 mm (Holder) (smallest)

14.90 mm (Holder) (largest area with protruding button)

Wattage Not provided

Battery capacity > 110 milliAmpere hour (mAh) (Holder)

> 2600 mAh (Charger)

Additional property Ventilation: Not provided

Source of energy: Electric (rechargeable battery) 

Thickness: 23.00 mm (Charger) 

Width: 46.35 mm (Charger)

6 Upon scientific review, the product category and product subcategory were revised.

7 The IQOS products are also regulated as cigarettes and cigarette components and parts. Cigarettes and their components and 

parts must be in compliance with the FD&C Act and applicable regulations.
MR0000192 Page 12 of 16 

B. MODIFIED RISK GRANTED ORDER APPENDICES

Appendix B

Required Postmarket Surveillance and Studies (PMSS) 

Under section 911(g)(2)(C)(ii) of the FD&C Act, an order under 911(g)(2) is conditioned on the 

applicant’s agreement to conduct postmarket surveillance and studies in order to “determine the 

impact of the order on consumer perception, behavior, and health, and to enable the [FDA] to review 

the accuracy of the determinations upon which the order was based in accordance with a protocol 

approved by the [FDA].”

I. PMSS Content

MRTP Use Behavior and Consumer Understanding and Perception

After receiving authorization, the determination of whether the tobacco product that is the subject of 

this order continues to satisfy the requirements of section 911(g)(2)(A) and (B), is driven, in part, by use 

behavior. Therefore, monitoring use of the tobacco product that is the subject of this order in terms of 

uptake, dual use, and complete switching is required. In particular, your PMSS must assess the extent to 

which new MRTP users were never, former, or current smokers, or other tobacco product users before 

initiating the MRTP and the extent to which new users of the MRTP become exclusive IQOS users, dual 

users with combusted cigarettes or other tobacco products, or transition to combusted cigarette 

smoking over time. Relatedly, such surveillance must include an assessment of consumers’ 

understanding of the claim and perceptions of the product. These studies should be designed to observe 

behavior over a sufficient period of time to examine, for instance, the extent to which dual use of IQOS 

and combusted cigarettes is a transitional versus stable pattern of use.

Given the novelty of these products and the uncertainty related to the impact of modified risk 

information on youth, your studies must also be designed to monitor individuals under the age of 18 to 

assess: (a) youth awareness of IQOS, to evaluate how effectively your marketing is limiting unintended 

exposure to youth, and (b) youth use of the IQOS system, to help ensure that marketing of the MRTPs 

does not have unintended consequences for youth use. Your surveys must also monitor young adults 

below the legal age to purchase tobacco products (i.e., ages 18-20).

Your studies must also include an assessment of consumers’ understanding of the claim and perceptions 

of the products. In particular, your PMSS must assess the extent to which users of the product 

understand that reducing their exposure to harmful and potentially harmful chemicals is relative to 

smoking, as described in the modified risk information, and that current smokers must use the IQOS

system exclusively and stop smoking. Thus, current smokers who take up IQOS, must understand that 

they should switch completely to IQOS and stop smoking and that cutting down on combusted 

cigarettes per day while using IQOS is not sufficient. Other tobacco users who switch to IQOS must 

understand that the reduction in harmful and potentially harmful chemicals is relative to combusted 

cigarette smoking and not to other types of tobacco use.

Your studies must have clear research objectives, including assessing whether the modified risk tobacco 

product leads to changes in product use behaviors that are expected to benefit population health. Your 

protocol must include a statistical analysis plan describing, among other things, how you plan to conduct 

inferential statistical analyses to address these objectives.
MR0000192 Page 13 of 16 

In addition, FDA has determined that assessing the impact of your MRTP order on uptake of the product 

requires surveillance of MRTP sales and distribution, which provide information to assess tobacco 

consumption at the population level. Your PMSS protocols must describe procedures for monitoring and 

reporting MRTP sales and distribution in the U.S. by product, major metropolitan areas, and channels 

where the product is sold (e.g., IQOS stores and kiosks, convenience stores, food and drug stores, 

internet and digital retailers, tobacco specialty shops). Your annual PMSS report must include: 

• U.S. sales and distribution of the tobacco product by quarter since the date of issuance of your 

modified risk granted order (for the initial reporting period) or the previous reporting period (for 

all reports that follow), including total U.S. sales and distribution reported in dollars and units, 

and broken down by major metropolitan areas, and channels where the products were 

distributed and sold during the reporting period (e.g., IQOS stores, convenience stores, food and 

drug stores, internet and digital retailers, tobacco specialty shops). 

• A brief synthesis and summary of the sales and distribution data for the initial reporting period 

or the previous reporting period (for all reports that follow), including annual and quarterly 

growth rate (percent change) in total U.S. sales and distribution of the tobacco product, postMRTP authorization. 

MRTP Use and Health Risk – Toxicology

Although your applications demonstrated that switching completely from combusted cigarettes to the 

IQOS system would, in general, significantly reduce exposure to harmful or potentially harmful 

chemicals, there were some chemicals that were higher in Heatstick aerosol than in combusted cigarette 

smoke. Additional research must be conducted to better characterize the potential impact of these 

exposures. In your applications, you reported computational toxicology predictions on chemicals found 

in higher levels in Heatstick aerosols than in reference combusted cigarette smoke. However, your 

applications lacked details of the quantitative structure-activity relationship (QSAR) modeling prediction 

results including, information to judge reliability of the modeling results, information on how you made 

interpretations of the model predictions, and a description of the training sets used in the models and 

why they are appropriate for tobacco constituents to predict adverse effects at the endpoints that were 

tested. An adequate computational toxicology assessment of Heatstick aerosols must be conducted in 

order to predict potential adverse effects in users before toxicity may be evident. 

Given that the chemicals analyzed by QSAR are found in higher levels in Heatstick aerosols than in 

reference combusted cigarette smoke and that Heatsticks are novel tobacco products for which long 

term health consequences have not been established, you must conduct a rigorous computational 

toxicology study using a battery of genotoxicity and carcinogenicity models (modeled endpoints: in vitro 

bacterial mutagenicity, mammalian cell mutagenicity, clastogenicity, rodent carcinogenicity) that have 

been validated in the published literature. A well-designed computational toxicology study must use 

both structure-activity-relationship (SAR), as well as QSAR models, and provide a full explanation of the 

computational basis for each prediction from the models. This includes probabilistic information of the 

prediction from a statistical model (i.e., probability of being positive), how the predictions were 

interpreted, model training set information including structurally similar compounds in the training set 

to the query compound, information on external validation testing and applicability domain of the 

models to understand reliability of the results for assessing the tobacco compounds.

MRTP Use and Health Risk – Serious and Unexpected Adverse Experiences

In order for FDA to determine whether the modified risk product that is the subject of this order, as 

actually used by consumers, continues to be appropriate to promote the public health and continues to 
MR0000192 Page 14 of 16 

be expected to benefit the health of the population as a whole taking into account both users of tobacco 

products and persons who do not currently use tobacco products (section 911(g)(2)(A-B)), your PMSS 

must include ongoing surveillance of all adverse experiences including those that are both serious and 

unexpected associated with the use of the MRTP. These experiences may become known to you through 

any source, including a customer complaint, request, or suggestion made as a result of an adverse 

experience; or tobacco product defect, or failure, reported to you, or identified in the literature or 

media. Your PMSS protocols must include procedures for monitoring and analyzing adverse experiences 

and your annual PMSS report must include: 

• A summary of reported serious and unexpected adverse experiences for the tobacco product, 

which includes a listing of all serious and unexpected adverse experiences during the reporting 

period and a cumulative list, including all serious and unexpected adverse experiences 

previously reported. The summary must be accompanied by an analysis of the reports and a 

statement of any changes to risk information related to the products including nature, 

frequency, and potential aggravating factors. 

In addition, the PMTA order for your tobacco product, issued on December 07, 2020, requires you to 

report to the FDA all adverse experiences that are both serious and unexpected and your analysis of the 

association between the adverse experience and the tobacco product within 15 calendar days after the 

report is received by you. These experiences may become known to you through any source, including a 

customer complaint, request, or suggestion made as a result of an adverse experience, tobacco product 

defect, or failure, reported to you, or identified in the literature or media. We request that when 

submitting such reports, you reference both your PMTAs and your MRTPAs for this product. Your 

information should be submitted with a cover letter that includes the following text in the subject line: 

SERIOUS UNEXPECTED ADVERSE EXPERIENCE REPORT FOR STNs PM0000424-PM0000426, PM0000419, 

PM0000634, MR0000059-MR0000061, MR0000133 and MR0000192.

For purposes of this reporting, serious adverse experience means an adverse experience that results in 

any of the following outcomes: 

• Death; 

• A life-threatening adverse event; 

• Inpatient hospitalization or prolongation of existing hospitalization; 

• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 

life functions; 

• A congenital anomaly/birth defect; or 

• Any other adverse experience that, based upon appropriate medical judgment, may jeopardize 

the health of a person and may require medical or surgical intervention to prevent one of the 

other outcomes listed in this definition. 

For purposes of this reporting, unexpected adverse experience means an adverse experience occurring in 

one or more persons in which the nature, severity, or frequency of the experience is not consistent with: 

• The known or foreseeable risks associated with the use or exposure to the tobacco product as 

described in the PMTA (including the results of human subject investigations) and other relevant 

sources of information, such as postmarket reports and studies; 

• The expected natural progression of any underlying disease, disorder, or condition of the 

person(s) experiencing the adverse experience and the person’s predisposing risk factor profile 

for the adverse experience; or 

• The results of nonclinical laboratory studies. 
MR0000192 Page 15 of 16 

Surveillance of New Research Study Findings on the MRTP and Consumer Perception, Behavior, or

Health

In order for FDA to determine whether the tobacco product that is the subject of this order, as actually 

used by consumers, continues to be appropriate to promote the public health and continues to be 

expected to benefit the health of the population as a whole, your PMSS must include surveillance of 

new research study information about the MRTP and consumer perception, behavior, or health. In 

particular, your PMSS protocol must include procedures for monitoring and assessing previously 

unreported (new) findings both in published or unpublished studies conducted by you or on your behalf 

and in published or otherwise available studies regarding the MRTP and consumer perception, behavior, 

or health. Your annual PMSS report must include:

• A summary of significant findings about the tobacco product from research studies conducted 

by you or on your behalf, whether or not such studies were specifically required under this 

order. 

• A summary of significant findings in publications not previously reported and full copies of the 

articles. This must include any new scientific data (published or otherwise) on the MRTP and 

consumer perception, behavior, or health.

Modeling the Impact of the MRTP on Population Health

In order for FDA to determine whether the tobacco products that are the subject of this order continue 

to be appropriate to promote the public health and continue to be expected to benefit the health of the 

population as a whole, your PMSS must include computational modeling of the impact of the MRTPs on 

population health. Such modeling must incorporate data and information collected through PMSS, 

including the percentage of former smokers who start using IQOS; the percentage of current smokers 

who start using IQOS and become dual users; the percentage of current smokers who switch completely 

to IQOS; the percentage of youth and young adults below the legal age of purchase who start using 

IQOS; and the percentage of individuals who start using IQOS and then initiate or re-initiate combusted 

cigarette smoking. Postmarket modeling must incorporate the latest information on acute and longterm health effects of using IQOS relative to combusted cigarette smoking in order to assess the short 

and long-term population health impacts of the marketing. Your annual PMSS report must include:

• A description of the methodological approach used in the model;

• A copy of the model or its underlying code, such that FDA can independently run and verify the 

model inputs and outputs;

• A description of all model inputs, including the justification for input values and how they were 

derived from postmarket data and information; and

• A summary of the modeling results and their implications for assessing whether the MRTPs 

continue to be appropriate to promote the public health and continue to be expected to benefit 

the health of the population as a whole.

II. Submitting PMSS Protocols and Reports

As required under section 911(g)(2)(C)(ii) of the FD&C Act, your modified risk order is conditioned on 

your agreement to conduct PMSS under an approved protocol, and to submit the results for FDA to 

determine the impact of the order and review the accuracy of determinations on which the order is 
MR0000192 Page 16 of 16 

based. Within 30 days of receiving this notice, you must submit your agreement to conduct PMSS and 

complete protocols for your PMSS. FDA expects that modifications of previously approved protocols 

for the original MRTPA (MR0000133) that incorporate the product subject of this order would be 

appropriate for the PMSS required under this order. Label your submission clearly as a “PMSS 

Protocol,” and reference your MRTPA Submission Tracking Numbers (STNs). If you have more than one 

protocol, submit each protocol as a separate submission. If applicable, each protocol should include the 

name(s) of the principal investigator(s) and materials that demonstrate the relevant professional 

credentials and training that qualify them to lead the study. Within 60 days of receipt of the protocol(s), 

FDA intends to review the protocol(s) and evaluate if the principal investigator proposed to be used in 

the surveillance has sufficient qualifications and experience to conduct the surveillance and if the 

protocol(s) will result in collection of data or other information that has the potential to enable FDA to 

accurately determine the impact of the order on consumer perception, behavior and health and to 

review of accuracy of the determinations upon which the order was based, pursuant to section 

911(g)(2)(C)(ii) of the FD&C Act. FDA will notify you of, and provide opportunities to address, any 

deficiency in the submission. If the PMSS protocol is amended subsequent to FDA approval, FDA must 

receive the amended protocol promptly. For protocol amendments that are administrative in nature 

(e.g., corrections in punctuation or titles), the amended protocol must be received by FDA within 30 

days of the update. For protocol amendments that seek to modify the study design (including endpoints, 

sites, questionnaires, methodology, etc.) or other scientific parameters, you may not initiate the change 

until you receive FDA approval.

As part of the requirement to conduct PMSS, you must initiate and conduct your PMSS per the 

timeframes established in your protocols and approved by FDA. Note that for PMSS that involve human 

subjects, the anticipated start date for each study must account for the time required for securing IRB 

approval, as needed. In addition to specifying the start date, your protocols must contain timelines for 

completion of major study milestones including, as applicable, the start and completion of participant 

recruitment, initiation of data collection (per wave, if applicable), completion of data collection, analysis, 

and report writing. If you deviate from these timelines, we request that you report the deviation within 

30 days to FDA.

Section 911(g)(2)(C)(iii) requires that the results of the PMSS be submitted on an annual basis. As this 

product will be modifying the previously approved protocol for MR0000133, it should be submitted 

when the PMSS report is submitted for MR0000133. These reports must be identified as “PMSS Report”, 

and the MRTPA STNs should be referenced for each report. The PMSS Report must indicate the 

beginning and ending date of the period covered by the report and must include accomplishments since 

the last reporting period. For quantitative updates on studies in progress (e.g., participant accrual), 

reports should describe both interim (since the last reporting period) as well as cumulative (since study 

initiation) accomplishments. The PMSS Report describing studies in progress must describe the status of 

PMSS, including, as applicable, the status of recruitment, data collection, and analysis; a summary of the 

study milestones achieved and any deviations from the approved timelines in the protocol; a summary 

of protocol amendments; and a summary of any preliminary analyses conducted. Once a study is 

completed, the PMSS Report should include the complete final study report.