2012 JUN -5 A II : 10

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1 Ho an ovells Hogan Lovells US LLP Columbia Square 555 Thirteenth Street, NW Washington, DC T F JUN -5 A II : 10 June 4, 2012 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, room 1061 Rockville, Maryland Re: Docket No. FDA-2012-D-0071 Dear Sir/Madam: In response to the April 3, 2012, Federal Register notice (77 Fed. Reg ), attached are comments of Philip Morris International Management S.A. on the agency's Draft Guidance for Industry: Modified Risk Tobacco Product Applications. Also attached are comments regarding the types and levels of evidence that should be required to substantiate a modified risk tobacco product, which were previously submitted to Docket No. FDA-2011-N-0443, regarding the scientific evaluation of modified risk tobacco product applications. Philip Morris International Management S.A. requests that these documents both be filed in Docket No. FDA-2012-D Partner philip.katz@hoganlovells.com D Enclosures F12,- Hogan Loveils US LLP is a limited liability partnership registered in the District of Columbia. "Hogan Lovells" is an intemational legal practice that includes Hogan Lovells.US LLP and Hogan Lovells International LLP, with offices in: Abu Dhabi Alicante Amsterdam Baltimore Beijing Berlin Brussels Caracas Colorado Springs Denver Dubai Dusseldorf Frankfurt Hamburg Hanoi Ho Chi Minh City Hong Kong Houston London Los Angeles Madrid Miami Milan Moscow Munich New York Northern Virginia Paris Philadelphia Prague Rome San Francisco Shanghai Silicon Valley Singapore Tokyo Ulaanbaatar Warsaw Washington DC Associated offices: Budapest Jakarta Jeddah Riyadh Zagreb. For more information see 6

2 COMMENTS OF PHILIP MORRIS INTERNATIONAL ON DRAFT GUIDANCE FOR INDUSTRY: MODIFIED RISK TOBACCO PRODUCT APPLICATIONS DOCKET NO. FDA-2012-D-0071 INTRODUCTION AND GENERAL COMMENTS Philip Morris International Management S.A. 1 offers these comments on the Draft Guidance for Industry: Modified Risk Tobacco Product Applications, Docket No. FDA-2012-D-0071 (the "Draft Guidance") 2 as well as on specific recommendations in the report of the Institute of Medicine, Scientific Standards for Studies on Modified Risk Tobacco Products.3 PMI's goal is to develop, assess, and eventually commercialize the sort of products contemplated by the Draft Guidance: "bold, innovative product[s]...that substantially reduce, or even eliminate altogether, either the toxicity or addictiveness of tobacco products, or both" (pp. 1-2, ) 4 Guidance and regulations that clarify the evidentiary standards for successful Modified Risk Tobacco Product (MRTP) applications facilitate and encourage the achievement of that ambitious goal. PMI welcomes FDA's publication of this draft Guidance and appreciates FDA's commitment to work with stakeholders in the implementation of the Family Smoking Prevention and Tobacco Control Act. As the Draft Guidance explains, an MRTP applicant must demonstrate that its product will or is expected to benefit the health of individuals and the population as a whole by addressing five key areas: (1) the health risks of the tobacco product; Philip Morris International Management S.A., a Swiss company, provides administrative support to Philip Morris International Inc. and its affiliated companies worldwide (collectively, "PMI"). Although PMI does not currently sell products in the United States, and is still deciding where and how to study and market its potential MRTPs, we provide these comments because a clear understanding of FDA's views on how to study potential MRTPs and what type of data will be required to commercialize them will help PMI make informed decisions about research and commercialization plans. 2 Unless otherwise specified, all references are to page and line numbers in the Draft Guidance, available online at fault.htm [accessed 23 May 2012]. 3 Institute of Medicine (TOM), 2012, Scientific Standards for studies on modified risk tobacco products, Washington, DC, The National Academies Press (hereafter "IOM Report"). 4 PMI described its approaches to product development and assessment in a submission following the Public Workshop on Modified Risk Tobacco Products, Docket No. FDA-2011-N , attached as Appendix 1. As described there, we are working to develop products that are substantiated to reduce risk compared to conventional cigarettes that adult smokers will accept as substitutes for conventional cigarettes. Accordingly, although we recognize that a wide range of products and approaches can be used to develop, assess and substantiate tobacco products as MRTPs, our discussion in this submission focuses primarily on products designed to replicate the smoking experience as much as possible and their comparator product, conventional cigarettes.

3 (2) the effect the tobacco product and its marketing may have on tobacco use behavior among current tobacco users; (3) the effect the product and its marketing may have on tobacco use initiation among nonusers (both never users and former users); (4) the effect of the tobacco product's marketing on consumer understanding and perceptions; and (5) the effect the tobacco product and its marketing may have on the population as a whole. (pp , ). The Draft Guidance contains recommendations on the types of studies and other evidence that could substantiate these points. We provide a few general observations on those five elements here, and provide specific suggestions in correspondingly numbered subsequent sections. In general, both the Federal Food, Drug, and Cosmetic Act ("FD&C Act") and the Draft Guidance provide clear requirements and recommendations for conducting studies to demonstrate Point (1), the health risks of the tobacco product in individuals. Points (2), (3), and (4) relate to a product's potential effect on consumer behavior and, by extension, its potential impact on the population as a whole, Point (5). We agree that these are all important elements of an application. The Draft Guidance "acknowledges the difficulties inherent in making premarket assessments of the effect that the introduction of a modified risk product would have on the population as a whole..." (p. 27, ), and anticipates that MRTP applicants would only be able to provide "[q]uantitative estimates" (p. 21, ) prior to marketing the product. We agree with that observation, as do a number of public health authorities. In light of those inherent uncertainties, we would suggest that the Guidance clarify that all elements (1) through (5) are to be considered conjointly. Finally, we believe that those uncertainties need not be an obstacle to approval so long as there is adequate substantiation. For example, as the IOM described in its 2011 Report, "the closer risks and exposures from the MRTP are to cessation products, the more confident a regulator can be in the chances for net public health benefit."6 SPECIFIC COMMENTS AND SUGGESTIONS ON THE DRAFT GUIDANCE 1. The Draft Guidance should provide greater clarity on the evidence required to evaluate the health risks of the MRTP Section 911 of the FD&C Act requires MRTP applicants to provide scientific evidence regarding the effect of the product on the health of individuals. The Draft Guidance provides a number of 5 See, e.g., D.K. Hatsukami, G.A. Giovino, T. Eissenberg, P.I. Clark, D. Lawrence, and S. Leischow, Methods to assess potential reduced exposure products, 7 NICOTINE TOB RES 827, 833 (2005) (stating that "[The population effects of [MRTPs] after they enter into the market need to be assessed...post-marketing evaluation is conducted to ensure that [MRTPs] do not result in increased initiation of tobacco use, maintenance of use in those who were interested in quitting, or relapse to tobacco use in former tobacco users."). 6 IOM Report, p

4 clear, sound recommendations on the types of nonclinical and clinical studies and other evidence which could be used to substantiate the performance and impact of candidate MRTPs. In a few areas, additional clarity is needed. a. The Draft Guidance should clarify seeming inconsistencies related to the potential for product component material variability and provide recommendations on how to account for that in MRTP applications Tobacco, a main component of any tobacco product, is an inherently variable agricultural crop. As such, there is variability in physical and chemical properties of the processed tobacco, and hence of the resulting aerosol, which must be accommodated within the 1 TRTP design. MRTP applicants must be able to account for that variability and demonstrate that they have controls in place to ensure that the commercial product performs as intended. The Draft Guidance's recommendation that MRTP applicants include "a description of tobacco blending..., a description of manufacturing steps...and quality control measures in place" and provide "sufficient detail to assure FDA that the product meets manufacturing specifications and that it may be manufactured in a consistent manner that minimizes the variability in levels of exposures and/or risk" (pp , ) is helpful in that regard. Further guidance, however, should clarify or reconcile some potential inconsistencies. For example, Section 910(a)(1) of the FD&C Act establishes that "any modification" in a tobacco product, "including a change in...any component, any part, or any constituent, including a smoke constituent...or any other additive or ingredient" renders a tobacco product a "new tobacco product." In order to maintain consistent product performance (including nicotine delivery, constituent levels, and so on), it is necessary to make regular small changes to the tobacco blend. The Draft Guidance should clarify that changes that are necessary to maintain consistent product performance, and that do not adversely or materially alter aerosol chemistry or physics, do not render a product "new" for the purposes of Sections 910 and 911. Similarly, given the requirement of Section 911(g)(2)(B) of the FD&C Act that MRTP applicants demonstrate that "the product as actually used exposes consumers to the specified level of the substance or substances" (emphasis added), the Draft Guidance should recommend that manufacturers provide a mean and standard deviation for such values, in line with the approach taken in the Draft Guidance on Reporting Harmful and Potentially Harmful Constituents.7 The Agency should consider the use of an approved "design-space" or acceptable range of values for tobacco blends in this regard, or may consider following the principles in the FDA Guidance on Demonstrating Substantial Equivalence for Tobacco Products.8 7 Draft Guidance: Reporting Harmful and Potentially Harmful smoke Constituents, March 2012, P. 9, See Guidance for Industry and FDA Staff: Section 905(j) Reports: Demonstrating Substantial Equivalence for Tobacco Products, Jan 2011, p. 4 ("At this time, FDA does not intend to enforce the requirements of sections 910 and 905(j) for tobacco blending changes required to address the natural variation of tobacco (e.g., blending changes due to variation in growing conditions) in order to maintain a consistent product. Blending changes that are intended to alter the chemical or perception properties of the new product (e.g., nicotine level, ph, smoothness, harshness, etc.) compared to the predicate should be reported under 910 or 905(j).") 3

5 b. The Draft Guidance should clarify the requirement for applicants to submit "all documents...relating to research findings...relating to the effect of the product..." Section 911(d)(5) of the FD&C Act requires MRTP applicants to submit "all documents (including underlying scientific information) relating to research findings conducted, supported, or possessed, by the tobacco product manufacturer relating to the effect of the product on tobacco-related diseases...including information both favorable and unfavorable..." We fully support the requirement that all of an applicant's research findings and underlying scientific information should be disclosed or available to disclose on request. More specific guidance on the extent to which included documents and underlying scientific information must be "relat[ed] to research findings" would avoid applications including marginally relevant data, and prevent them becoming so voluminous as to hinder effective decisions. Similarly, the FD&C Act's requirement to provide "underlying scientific information" on all studies, combined with the Guidance's view that those studies include all that an applicant "has received...or has reviewed to inform the development of the modified risk tobacco product" (p. 13, note 9), may prove needlessly burdensome or infeasible if the authors or sponsors of independent work are unwilling to release their underlying data. The Draft Guidance could be revised to recommend that applicants: Provide a thorough bibliography of the published, peer-reviewed literature in the field; Make reasonable efforts to obtain the underlying data for those studies; and Provide those upon FDA's request. c. The Draft Guidance should not recommend that applicants conduct new studies to prove the harmfulness of smoke constituents which are already well understood Section 911(g)(2) of the FD&C Act establishes the requirements for obtaining an exposure modification order. The Draft Guidance recommends that such applicants submit "nonclinical and/or human studies that demonstrate that the substance(s) or exposure(s) that have been reduced are harmful." (p. 18, ). We suggest that the Guidance distinguish between novel substances and substances which are well-known to be harmful. For the former, applicants could be required to provide evidence as described in the Draft Guidance, although conducting human studies to establish that a substance is harmful (as opposed to human studies supporting the proposition that reducing exposure to a substance is beneficial) raises a number of ethical challenges and should be clarified in the final Guidance. For substances already known to be harmful or potentially harmful, based on regulatory requirements or recommendations or published scientific studies, 9 the Guidance should not recommend conducting human studies to re-establish that fact. Because the FD&C Act requires that reductions be reasonably likely to lead to reductions in risk and harm, instead of recommending separate evidence of a substance's harmfulness, the Draft Guidance should be 9 For example, the presence of a substance on the FDA list of Harmful or Potentially Harmful Constituents could serve as prima facie evidence that a substance is harmful in this context. 4

6 revised to require that applicants submit "nonclinical and/or human studies that demonstrate that the reduction in the substances(s) or exposure(s) are reasonably likely to lead to reductions in risk and harm." d. The Draft Guidance should clarify its recommendation on assessing the health risks of the MRTP in individuals who do not use tobacco products The Draft Guidance recommends that MRTP applicants submit "scientific studies" using "clinical risk endpoints" which enable FDA to fully assess "[t]he health risks associated with initiating use of the product as compared to never using tobacco products." (pp , ). We are cognizant of the FD&C Act's requirement that MRTP applicants provide evidence of the impact of the product on never-users, but do not believe it is feasible, desirable or necessary to do clinical research in people who have never used tobacco products. We do not believe that the Draft Guidance intends to suggest otherwise. It may, for example, have been an oversight to exclude non-clinical evidence from the types of studies listed on p. 18, of the Draft Guidance, or that list could have been intended to provide examples of types of studies rather than being exhaustive. If that is the case, the Draft Guidance could be clarified by recommending that applicants submit "non-clinical, clinical, and other evidence" that would enable FDA to assess the risks listed in pp , of the Draft Guidance. On the other hand, if FDA believes that clinical studies in non-smokers are necessary, the Draft Guidance should be revised to provide clear recommendations on how to conduct such studies and suggest appropriate third party governance for conducting them. 2. The Draft Guidance should clarify evidentiary requirements on the effect an MRTP may have on "tobacco use behavior among current tobacco users" An MRTP application should contain "scientific evidence about the effect the product may have on tobacco use behavior among current tobacco users" (p. 19, ). The Draft Guidance recommends that applicants submit scientific studies which evaluate the following: "The likelihood that current tobacco users will start using the product; The likelihood that tobacco users who adopt the product will switch to or switch back to other tobacco products that present higher levels of individual health risk; The likelihood that consumers will use the product in conjunction with other tobacco products; The likelihood that users who may have otherwise quit using tobacco products will instead use the product; and The likelihood that consumers will use the product as intended or designed." (pp , ). a. The Draft Guidance should recognize inherent methodological limitations in assessing consumer behavior Although it will be difficult to precisely quantify the potential impact of a new product' s availability on consumer behavior before that product is marketed, pre-market clinical and behavioral studies can provide relevant evidence of that impact. For example, clinical studies 5

7 can allow applicants to compare (a) tobacco use behaviors (including correct use of the product, frequency of use, and dual use) as well as (b) cessation rates among subjects who switch from a conventional cigarette to a candidate MRTP and those who continue to smoke conventional cigarettes for the duration of the study. Similarly, behavioral studies which emulate conditions of actual use may allow applicants to compare tobacco use behaviors and cessation rates between study participants who use the candidate MRTP and study participants who do not and, potentially, against those behaviors observed in the marketplace prior to the product's introduction. Those data can provide "estimates," as the Draft Guidance recognizes. (p. 21, ). We agree with the Draft Guidance's recommendation that secondary data analyses and computational modeling can assist in the premarket assessment of post-market consumer behavior (p. 27, ). For example, because the long-term success rate in smoking cessation is generally well understood, and secondary, historical data on switching and dual use are available, the Draft Guidance could recommend that those data (and models based on them) be used as benchmarks against which clinical and behavioral data on MRTP use (and cessation following MRTP use) are compared. We also agree that consumer perception studies (discussed on pp , ) can be used to assess consumer understanding of health risks, packaging and labeling, and instructions for product use. Such studies can also provide evidence of the likelihood that current users of tobacco products would try a candidate MRTP, although in some areas, particularly in areas involving multiple hypothetical future choices, there can be significant discrepancies between what people say they would like to do (or what they would have done) and what they actually do (or will do). Guidance should draw on experience from other areas subject to FDA oversight, including food, over-the-counter medications, and cosmetics, and seek to establish, over time, criteria for assessing the validity, reliability, and relevance of various types of evidence on consumer behavior resulting from MRTP availability and associated communications. b. The Draft Guidance should clarify the definition and comparator products of "abuse liability" The Draft Guidance recommends that applicants submit "nonclinical and/or human studies to assess the abuse liability...of the product as compared to other tobacco products on the market..." (p. 19, ) as an indicator of the product's impact on consumer behavior and, by extension, on the population as a whole. The Draft Guidance defines "abuse liability" as "the likelihood that individuals will develop physical and/or psychological dependence on the tobacco product." (p. 19, note 11). That multivariate inquiry is not susceptible to a single test, methodology, or discipline, but is clearly relevant to assessments of consumer behavior. The likelihood of creating dependence alone is insufficient, however, for assessing the product's potential health impact on individuals or the population as a whole. Assessments of abuse liability should clearly consider the risks and/or harm resulting from dependence, compared to the risks / harm resulting from dependence on conventional tobacco products. 1 We therefore recommend expanding the definition of abuse 10 See, e.g., Henningfield et al., 2011, Conference on abuse liability and appeal of tobacco products: conclusions and recommendations. Drug and Alcohol Dependence 116:1-7 ("The term 'abuse liability assessment' is used to 6

8 liability in the Draft Guidance to include (a) the potential of the product to cause dependence and (b) the potential harm resulting from that dependence compared to other tobacco products. We also recommend that, consistent with the FD&C Act, the Guidance clarify that the primary comparator should be a conventional tobacco product for example, a conventional cigarette versus a candidate MRTP intended to replicate the smoking experience. 3. The Draft Guidance should clarify evidentiary requirements on the effect an MRTP may have on people who do not currently use tobacco products An MRTP application "must contain scientific evidence regarding the effect the product and its marketing will have on increasing the likelihood that persons who do not use tobacco products will start using the tobacco product that is the subject of the application." (p. 20, ). The Draft Guidance recommends that applicants provide evidence on: "The likelihood that consumers who have never used tobacco products, particularly youth and young adults, will initiate use of the tobacco product; The likelihood that non-users who adopt the tobacco product will switch to other tobacco products that present higher levels of individual health risk; and The likelihood that former users of tobacco products will re-initiate use with the tobacco product." (p. 20, ). a. The Draft Guidance should give explicit recommendations on whether or how MRTP applicants should conduct studies with minors The Draft Guidance recommends that applicants submit "[h]uman studies that evaluate consumer perception of the product," including evidence on "Mlle likelihood that consumers who have never used tobacco products, particularly youth and young adults, will initiate use of the tobacco product." (emphasis added). PMI does not conduct studies involving minors, and we question the feasibility, desirability, and necessity of MRTP applicants conducting research with minors as subjects. If FDA believes that such studies are necessary, the Draft Guidance should provide explicit instructions for how to conduct such studies and suggest appropriate third-party governance for conducting them. We believe that conducting consumer behavior research among young adults could provide sufficient evidence for FDA to evaluate the likelihood of youth initiating MRTP use. Similarly, secondary literature can provide relevant evidence on youth behavior, including risk preferences and tobacco use initiation rates. We suggest that the Draft Guidance recommend encouraging applicants to provide such data where relevant. describe the pharmacologically determined risk of abuse as well as the risk of harm resulting from abuse.") (emphasis added); see also U.S. FDA, Draft Guidelines for Abuse Liability Assessment, 1990 ("As the concept of abuse liability has two parts, the severity of abuse liability may be reflected by variations in either the likelihood/severity of self-administration or the likelihood/severity of undesirable consequences."). 7

9 b. The Draft Guidance should provide greater clarity on how applicants should evaluate "the likelihood that non-users who adopt the tobacco product will switch to other tobacco products that present higher levels of individual health risk" We discussed the challenges of reliably and precisely quantifying future behavior in Section 2(a). The requirement to assess the likelihood that people who currently do not use tobacco products will begin using the candidate MRTP and will then switch to another, higher-risk tobacco product, compounds those challenges. It is difficult to conceive of a means of scientifically establishing, prior to product launch, the number of nonsmokers who would use an applicant's product and who would then later switch to a conventional cigarette. The Draft Guidance should give greater clarity to methods of assessing this likelihood for example, by means of modeling based on known rates of initiation. c. The Draft Guidance should provide further clarity on assessing "relapse" rates The rate of relapse is widely recognized to be high among former smokers, and is higher still in people who have only recently quit." The Guidance should recommend that applicants distinguish between those two groups, if possible. Similarly, the Guidance should recommend distinguishing between (a) former users of tobacco products (whether conventional or an MRTP) who relapse to the candidate MRTP and who, but for the availability of the candidate MRTP, would not have used any tobacco product and (b) former users who would have relapsed to a tobacco product regardless of the availability of MRTPs. 4. The Draft Guidance should clarify evidentiary requirements on the effect of marketing on consumer understanding and perceptions The FD&C Act requires applicants to provide evidence of how the proposed MRTP is actually used in uncontrolled, real-world settings. The Draft Guidance accordingly recommends "actual use studies" which allow consumers to interact freely with the product in real-world conditions, and would allow FDA to assess: "How the product is consumed in early stages of use; How the product is consumed during continued use; The frequency and intensity (e.g., depth of inhalation) of product use; The amount of the product typically used per occasion; The duration of use per occasion; The use of the product with other tobacco products (i.e., the use of multiple tobacco products); The possible ways that a user may consume the product; specifically those that may differ from that intended by the applicant; The likelihood that a user may consume the product in a manner that may differ from that intended by the applicant; 11 Hawkins, J., W. Hollingworth, and R. Campbell Long-term smoking relapse: A study using the British household panel survey. Nicotine & Tobacco Research 12(12): Hughes, J.R., E.N. Peters, and S. Naud Relapse to smoking after 1 year of abstinence: A meta-analysis. Addictive Behaviors 33(12):

10 The potential impact to individual and public health from the failure to use the product as intended; and The elements of the product's design and manufacture that may lend themselves to product misuse by users." (p. 25, ). Although all of those conditions can be replicated in a test environment, doing so may introduce a number of elements which could reduce their relevance to "real world" conditions. We suggest that studies of "actual use" would be even more relevant if subjects had access to the candidate MRTP: In the packaging in which it would be sold; In the types of venues in which they would potentially be sold; and In the types of environments in which it would normally be used. Conducting large-scale tests under realistic, uncontrolled conditions of actual use (including purchase, packaging, marketing communications, and so on) could be difficult to execute absent clear guidance and/or prior authorization. Further guidance on how to conduct such "actual use" studies would be helpful. Current FDA Guidance on label comprehension studies and selfselection studies for non-prescription drugs could be a useful starting point. 5. The Draft Guidance should clarify evidentiary requirements on the effect that marketing the MRTP will have on the population as a whole, and establish robust, feasible requirements for post-market surveillance and studies to validate that effect As discussed above, the Draft Guidance anticipates that applicants would, by defmition, only be able to provide "[q]uantitative estimates" of post-market behaviors before they introduce the candidate MRTP; post-market surveillance and studies, however, can validate those estimates. The FD&C Act requires applicants to submit protocols for post-market studies and surveillance, and the Draft Guidance contains both general and specific recommendations on how such studies and surveillance could be conducted (pp ). We agree with the approaches outlined there. We recommend that the Guidance clarify two points. First, it should recognize that mechanisms for monitoring post-market events do not currently exist (at least with the same level of robustness as, for example, methods that the pharmaceutical industry uses to monitor adverse events. Second, requirements for post-market surveillance and/or studies should be feasible, and serve to substantially confirm premarket clinical and behavioral data. Completing long-term controlled investigations (e.g., multi-year cohort studies, as the IOM Report seems to suggest) should not be a prerequisite for granting a marketing order under Section 911(g)(1). RESPONSES TO QUESTIONS IN NOTICE The FDA Notice requesting comments on the Draft Guidance (Federal Register, vol. 77. No. 64, Tuesday, April 3, 2012, pp ) ("F.R.") also requested comments on specific recommendations in the IOM Report. 9

11 1. IOM's Recommendation 2 The IOM Report suggests that FDA establish guidance on the sequencing of studies, "such that preclinical work is completed and submitted to the FDA before clinical (human subjects) work commences, and [FDA should establish] that there is a reasonable expectation based on preclinical work that a reduction or lack of harm will be seen in humans." (F.R. at ). FDA has requested comments on that recommendation: "Should FDA address expected sequencing of studies in its guidance? If the Agency should, what guidance should the Agency provide?" PMI believes it is appropriate for FDA to address sequencing of studies in its Guidance. Specifically, the Guidance should recommend that sufficiently robust pre-clinical data demonstrate that the products proposed for clinical testing do not present greater hazards than conventional cigarettes, and that preclinical data demonstrate a potential for exposure and risk reductions in adult smokers compared to conventional cigarettes. Such data should also be shared with FDA as prospective MRTP applicants discuss proposed protocols for clinical trials. We do not think it necessary, however, for guidance or regulation to establish a new requirement, beyond those in the FD&C Act, requiring FDA to review and approve a separate application before clinical work can begin. 2. IOM's Recommendation 10 The IOM Report suggests that MRTP sponsors "should consider use of independent third parties to undertake one or more key functions, including the design and conduct of research, the oversight of specific studies, and the distribution of sponsor funds for research. Such independent third parties should be approved by the FDA in advance of the research." (F.R. at 20030). FDA has requested comments on that recommendation: "Should FDA recommend such an approach in its guidance? If the Agency should, what guidance should the Agency provide?" FDA's Guidance should recommend that all research be conducted in line with Good Clinical Practice principles; should follow established methodologies and protocols; should, where possible, be based on input and advice from noted experts in the relevant field; and should be registered on ClinicalTrials.gov or similar systems. Other than research involving minors, in which explicit guidance and third-party oversight would be beneficial, FDA's Guidance should not assume that potential MRTP applicants are incapable of conducting or sponsoring such research on their own, as the IOM Report seems to suggest. PMI can and is conducting reliable, valid research. FDA should continue to provide guidance to applicants as they develop their research protocols, and should assess applications on the quality of such research. Philip Morris International Management S.A. June 4,

12 PHILIP MORRIS PRODUCTS S.A. PM! RESEARCH & DEVELOPMENT February 13th, 2012 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Rm Rockville, MD Re: Philip Morris International's Comments on the Scientific Evaluation of Modified Risk Tobacco Product Applications, Docket No. FDA-2011-N Dear Sir or Madam: Attached please find Philip Morris International's suggestions on the types and levels of evidence that should be required to substantiate a modified risk tobacco product. Although comments were requested by September 23, 2011, Philip Morris International requests that this submission be accepted as a public comment to Docket No. FDA-2011-N Respectfully submitted, Bertrand Bonvin Senior Vice President Research & Development Philip Morris Products S.A. Bertrand.bonvinammi.com f QUA1 JEANRENAUD 5 CH-2000 NEUCHATEL SWITZERLAND TELEPHONE (41-58) TELEFAX (41-58) 24/28.11

13 Philip Morris International's Suggestions On The Types and Levels of Evidence That Should Be Required to Substantiate a Modified Risk Tobacco Product

14 Executive Summary The United States Food and Drug Administration (FDA) is developing guidance on the types and levels of evidence necessary to determine whether use of a "Modified Risk Tobacco Product" (MRTP) instead of conventional cigarettes would benefit individuals and public health. In this undertaking, FDA is charting a course for the United States and for regulators and public health officials around the world. Although Philip Morris International (PMI) currently does not sell products in the United States,' we are submitting this paper because FDA's guidance will have global significance, not only because the regulatory scheme under development will be the first in the world that is tailored to MRTPs, but also because of FDA's leading role and significant experience in the field of tobacco regulation and public health. In this paper, we discuss novel products that differ significantly from tobacco products currently available and the types and quality of evidence that we believe should be required to substantiate such products as reduced-risk MRTPs. The paper has four sections: Section I (pp. 3-4): MRTPs Are Important Tools For Reducing Tobacco-Related Mortality And Morbidity. Section 911 of the Family Smoking Prevention and Tobacco Control Act (FSPTCA) provides a distinct pathway for assessing and commercializing products that can provide adult smokers, for the first time, with acceptable, safer alternatives to cigarettes. Consistent with the views of many public-health experts, MRTPs that are marketed with validated reduced-risk claims pursuant to Section 911 and viewed by consumers as acceptable substitutes for conventional cigarettes can become a crucial component of tobacco-harm reduction. Section II (pp. 4-6): PMI's Potential MRTPs Are Designed To Be Acceptable Substitutes For Conventional Cigarettes. PMI's focus has been the development of products that do not combust tobacco but which replicate the "smoking experience" as much as possible. Our approach eliminates combustion and limits pyrolysis, either by heating tobacco at significantly lower temperatures than conventional cigarettes or by using a chemical reaction to produce an aerosol of nicotine salt. We believe such products present the best opportunity for reducing harm because they produce vastly lower levels of harmful smoke constituents and are more likely to be accepted by smokers as substitutes for cigarettes. Innovative products like these should be encouraged by guidance and regulations, not prevented by them. Further, communication with the consumer is critical to the acceptance and use of such novel products, as recognized by Section 911. Section III (pp. 6-17): Robust Evidence Is Necessary To Support MRTP Applications. We describe the types of evidence that we believe should be required in order to support an MRTP application, and provide examples of research PMI has conducted or contemplates conducting. An MRTP application should include the following: Documented quality systems (Section III.A); 1 PMI is the world's leading international tobacco company, with products sold in approximately 180 countries. In 2011, we held an estimated 16.0 percent share of the international cigarette market outside of the United States.

15 Non-clinical evidence, including both chemical analysis and toxicological assessment (Section III.B); Clinical evidence, including both short- and long-term clinical studies (Section III.C); Evidence on consumer communication and understanding (Section III.D); Evidence on abuse liability (Section III.E); Evidence of the impact of the proposed MRTP on the population (Section III.F); and Plans for post-marketing surveillance and studies (Section III.G). Section IV (pp ): Conclusion: Coherent Evidence Can Substantiate Reduced Risk MRTPs In The Near Term. Section 911 requires MRTPs to establish that they reduce risk (or are likely to reduce risk) in comparison to conventional cigarettes. Fundamental to our proposed approach to Section 911 is our view that applicants should compare markers of exposure and biological responses among smokers who have switched to MRTPs with smokers who have stopped using tobacco products. We agree with the recent observation by the Institute of Medicine (I0M) that cessation is the "gold standard" for assessing risk reduction, and that "the closer risks and exposures from the MRTP are to cessation products, the more confident a regulator can be [of achieving a] net public health benefit." 2 Such an approach builds upon regulatory experiences with tobacco and drugs, while remaining true to the unique and separate regulatory arena created for MRTPs. With this approach, we believe that coherent non-clinical and clinical evidence can be gathered in the near term to substantiate the determination that a novel MRTP reduces risk. In the paper that follows, PMI offers more detailed information and perspectives on the evidence that we believe should support an MRTP application. We do not claim to have all the answers, but we have relevant expertise and experience that we hope can assist FDA as it begins to address this important topic. 2 INSTITUTE OF MEDICINE (I0M), SCIENTIFIC STANDARDS FOR STUDIES ON MODIFIED RISK TOBACCO PRODUCTS 204 (The National Academies Press 2011) (hereafter "lom Report 2011"). 2

16 I. MRTPs Are Important Tools For Reducing Tobacco-Related Mortality And Morbidity Although smoking prevalence has declined in the United States over the last forty years, almost one in five American adults continue to smoke cigarettes. 3 Current smoking cessation therapies have proven effective for some people, but the rates of long-term smoking cessation are very low. For example, according to the Surgeon General, although about 45% of smokers quit for a day, only approximately 5% succeed in obtaining long-term abstinence of one year or more. 4 Nicotine replacement therapies, used with or without counseling, may not improve smokers' long-term chances of successfully quitting smoking.5 Recognizing this, a growing number of public health experts advocate a strong public health need for less harmful substitutes for conventional cigarettes. For example, the Tobacco Advisory Group of the Royal College of Physicians opined in 2007 that "[i]f nicotine could be provided in a form that is acceptable and effective as a cigarette substitute, millions of lives could be saved."6 The Family Smoking Prevention and Tobacco Control Act embraces this concept. Section 911 of the FSPTCA establishes two distinct pathways for approving the marketing, sale, and distribution of MRTPs. Section 911(g)(1) permits approval of a "Reduced Risk" MRTP if the manufacturer demonstrates that the product, as actually used, significantly reduces the risk of tobacco-related disease in individual tobacco users as compared to conventional cigarettes and will benefit the health of the population as a whole. Section 911(g)(2) permits approval of a "Reduced Exposure" MRTP if the manufacturer demonstrates that the product reduces exposure to harmful smoke constituents and there is a reasonable likelihood that subsequent studies will demonstrate a measurable and substantial reduction in morbidity or mortality among individual tobacco users. 3 See Centers for Disease Control and Prevention, Cigatette Smoking Among Adults United States, , 60(44) MORBIDITY AND MORTALITY WEEKLY REPORT 1513, 1513 (2011) (stating that "From 1965 to 2010, the prevalence of cigarette smoking among adults in the United States decreased from 42.4% to 19.3%, in part because of an increase in the number who quit smoking.") (hereafter "CDC Report 2011"). 4 See OFFICE OF THE SURGEON GENERAL, How TOBACCO SMOKE CAUSES DISEASE: THE BIOLOGY AND BEHAVIORAL BASIS FOR SMOKING-ATTRIBUTABLE DISEASE 105, 170 (2010); see also D.K. Hatsukami, A.M. Joseph, M. Lesage, J. Jensen, S.E. Murphy, P.R. Pentel, M. Kotlyar, E. Borgida, C. Le, and S.S. Hecht, Developing the science base for 'educing tobacco harm, 9(4) NICOTINE & TOBACCO RESEARCH S537 (Dec. 2007). In its December 2011 report, the IOM noted that only 6% of smokers are able to quit successfully. See IOM Report 2011, at 22. Similarly, the CDC noted in November 2011 that 66.8% of current adult smokers reported that they were interested in quitting; 52.5% of all smokers reported that they had tried to quit in the last year; and only 6.2% reported that they had succeeded at quitting smoking in the last year. See CDC Report 2011, at See, e.g., H. Alpert, G. Connolly, and L. Biener, A Prospective Cohort Study Challenging the Effectiveness of Population-based Medical intervention for Smoking Cessation, TOBACCO CONTROL (Jan. 10, 2012, Epub ahead of print PMID: ) (finding that almost one-third of recent quitters reported to have relapsed, and that odds of relapse were unaffected by use of nicotine replacement therapies for more than six weeks, either with or without professional counseling.)., OBACCO ADVISORY GROUP OF THE ROYAL COLLEGE OF PHYSICIANS, HARM REDUCTION IN NICOTINE ADDICTION: HELPING PEOPLE WHO CAN'T QUIT, at Preface (October 2007) (emphasis added). 3

17 MRTPs can bring about harm reduction that has thus far not been achieved through smoking cessation, nicotine replacement therapies, and conventional cigarette modification, in two important ways. First, unlike nicotine replacement therapies, MRTPs can provide smokers with taste and behavioral experiences that more closely resemble cigarettes. Second, the regulatory framework established by Section 911 of the FSPTCA provides a means for consumers to receive validated claims that provide clear, non-misleading communications about product benefits.' This is crucial because, despite manufacturers' best efforts, there will likely be significant differences in ritual, taste, and convenience between cigarettes and MRTPs. Without clear and accurate communication about the benefits of using an MRTP instead of conventional cigarettes, MRTPs will fail to convince a large number of adult smokers to switch and consequently will fail to maximize their potential for harm reduction. We discuss both concepts in the next section. PMI's Potential MRTPs Are Designed To Be Acceptable Substitutes For Conventional Cigarettes Developing and commercializing MRTPs has been one of PMI's top priorities for many years. The two-fold challenge is to develop tobacco products that are shown to reduce risk and are acceptable to smokers as substitutes for conventional cigarettes. We believe that both objectives can be met by a next generation of tobacco products that replicate a "smoking experience" without combustion. Thousands of chemicals "smoke constituents" are formed when tobacco is burned or combusted. More than 5,300 smoke constituents have been identified, 8 and more than 100 of them have been categorized as harmful or potentially harmful constituents (HPHC). 8 There is no agreement, however, about which of these HPHCs are the cause of smoking-related diseases, nor is there any agreement as to which smoke constituent or constituents should be reduced (and by how much) in order to significantly reduce the risk of one or more diseases. In fact, most public health experts agree that selective reduction of smoke constituents is unlikely to significantly reduce the risk of tobacco related diseases.1 PMI agrees with this view and has focused on developing next generation products that provide an acceptable smoking experience without combustion. In this way, we can substantially reduce or eliminate the full spectrum of harmful smoke constituents. Our product development approaches achieve this either by heating tobacco at significantly 7 Section 911 provides that manufacturers of approved MRTPs can communicate about substantiated reductions of exposure and risk. In particular, manufacturers of approved "Reduced Risk" MRTPs may communicate the fact that the products reduce risk, subject to appropriate evidence that consumers correctly understand this. In contrast, communication about "Reduced Exposure" MRTPs is limited to statements that the product does not contain a substance, contains a reduced level of a substance, or presents a reduced exposure to a substance in tobacco smoke. 8 See, e.g., A. RODGMAN, AND T.A. PERFETTI THE CHEMICAL COMPONENTS OF TOBACCO AND TOBACCO SMOKE (Taylor & Francis Group 2009). 9 See, e.g., Food and Drug Administration, Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke; Request for Comments (76 FR 50226, Aug. 12, 2011). 10 D.K. Hatsukami, A.M. Joseph, M. Lesage, J. Jensen, S.E. Murphy, P.R. Pentel, M. Kotlyar, E. Borgida, C. Le, and S.S. Hecht, Developing the science base for reducing tobacco harm, 9(4) NICOTINE & TOBACCO RESEARCH S537 (Dec. 2007) (hereafter "Hatsukami 2007"). 4

18 lower temperatures than conventional cigarettes or by using a simple acid-base chemical reaction to produce an aerosol of nicotine salt. For example, as Figure 1 illustrates, the smoke from a conventional cigarette is significantly more complex than the aerosol generated by one of PMI's potential MRTPs that heats rather than burns tobacco.11 Figure 1: Comparison shows that conventional cigarette smoke constituents (top) is significantly more complex than aerosol from a potential MRTP (bottom). Chemicals identified in conventional ci arette smoke Chemicals identified in potential MRTP aerosol Total particulate matter from conventional cigarette and potential MRTP generated using the Health Canada smoking regime, analyzed using GCxGC MS-TOF. Source: PMI data. 11 Because PMI is focusing on developing products that replicate the smoking experience as much as possible, our discussion in this paper focuses on the aerosol generated by potential MRTPs compared to the smoke from conventional cigarettes. We recognize that other potential MRTPs may take different approaches, and may therefore require different terminologies, measurement methods, and evidentiary requirements. 5

19 Consumers must accept an MRTP as a substitute for conventional cigarettes in order for the MRTP to benefit public health. Public health expert Ernst Wynder explained this in 1979: "...as a practical matter, it is important to appreciate that a virtually harmless cigarette smoked by only 1% of the population will have a lesser impact on the reduction of tobacco-related diseases than a somewhat more harmful product smoked by 80% of the total smoking population. Research on the less harmful cigarette should therefore be directed toward developing a cigarette containing the lowest possible amount of harmful elements for all tobacco-related diseases, but one that has sufficient acceptability for the largest segment of smokers."12 Eliminating or substantially reducing smoke constituents, however, reduces flavor and the appeal of the product, because the combustion of tobacco products provides cigarette smoke with much of its flavor. 13 A key component of PMI's work therefore has been to develop next generation tobacco products that replicate the smoking experience as much as possible. Important to this effort has been providing nicotine in a way that closely parallels conventional cigarettes. Despite PMI's efforts, our experience and research to date have shown that our potential MRTPs do not provide the exact same smoking experience as conventional cigarettes: the smoking ritual and taste are different. We believe it is unlikely that any MRTP will ever fully replicate the smoking experience of conventional cigarettes. Under these circumstances, risk/benefit communication must play a crucial role in helping adult smokers elect to use an MRTP. Ill. Robust Evidence Is Necessary To Support MRTP Applications In this section, we describe the types and quality of evidence that we believe should be required in an MRTP application. A. Documented Quality Systems Product design should take place within a structured quality management environment.14 Similarly, manufacturing processes should be well documented and include controls of critical quality attributes in order to consistently deliver a product with predefined characteristics. 12 E. Wynder, Banbury Conference on Safer Cigarettes (1979), cited in INSTITUTE OF MEDICINE, CLEARING THE SMOKE: ASSESSING THE SCIENCE BASE FOR TOBACCO HARM REDUCTION 21 (K. Stratton, P. Shetty, R. Wallace and S. Bondurant, eds., National Academies Press 2001) (emphasis added) (hereafter "IOM Clearing the Smoke"). 13 See, e.g., Hatsukami 2007 at S544 (observing that "[a]lthough conceptually a significant reduction in combustion products can occur when a product is not burned, the consumer acceptability of these products has been problematic."). 14 For example, ISO-9000, ISO-9001, and ISO-9004 collectively establish fundamental principles and standards for quality management systems (including a system-wide approach to quality management and continuous improvement). 6

20 B. Non-Clinical Evidence MRTP applicants should submit non-clinical evidence that demonstrates that the proposed MRTP does not present any new hazards by comparison to the known hazards of conventional cigarettes, that the proposed MRTP substantially reduces exposure to HPHCs, and that those reductions may be clinically relevant. Two main types of evidence can be used: (1) physical and chemical characterization of the aerosol, compared to the smoke from conventional cigarettes; and (2) comparative data from toxicological assays. 1. Physical and Chemical Comparison of the MRTP Aerosol to Smoke From Conventional Cigarettes All MRTP applications should include data reflecting a thorough physical and chemical assessment of the product's aerosol, including mainstream, sidestream, and environmental aerosol. In particular, applicants should quantify the levels of HPHCs in the MRTP aerosol in comparison to levels found in the smoke of conventional cigarettes. Applicants should also specify the method by which smoke from the comparator product and the aerosol from the proposed MRTP is generated. There is wide recognition in the literature that machine-smoking methods (such as the ISO method) do not replicate human smoking behavior and that machine-measured yields therefore may not correspond to a smoker's uptake of smoke constituents. A number of United States and foreign regulators have developed more "intense" machine-smoking regimes in order to enhance the value of machine measurements. PMI generates the smoke and aerosols used in its non-clinical assessments under both the ISO test method and the Health Canada "intense" smoking method.15 Applicants should conduct sufficient analyses of aerosol chemistry to determine whether new constituents are generated that may pose a new and meaningful risk. This requires a two stage approach: (1) screening for new chemical species that are not found in cigarette smoke, using state-of-the-art methods, such as gas and liquid chromatography coupled to mass spectrometry; and (2) assessment of any such chemical that occurs at a level that is toxicologically meaningful. 16 Applicants should also provide data that demonstrate that the proposed MRTP reduces the levels of HPHCs in comparison to those in cigarette smoke. Scientists, public health authorities, and governments have identified at least 100 HPHCs. 17 Although there has been a significant convergence in the chemicals thus identified, there is no single, 15 See, e.g., Tobacco Control Programme, Health Canada, TOBACCO REPORTING REGULATIONS, Determination of 'tar, nicotine and carbon monoxide in mainstream tobacco smoke official method. (Health Canada 2000); ISO, Routine analytical cigarette smoking machine definitions and standard conditions, ISO 3308, 4th ed. (International Organization for Standardization 1989). 16 In addition, MRTP applicants should provide detailed information on the physical properties of the product s aerosol, including its aerodynamic diameter (mass median aerodynamic diameter EMMADD and droplet size distribution (e.g. Geometric Standard Deviation [GSD]) and aerosol stability, as these factors affect the distribution of the products constituents in the respiratory tract. 17 See, e.g., S.S Hecht, Research Opportunities Related to Establishing Standards for Tobacco Products Under the Family Smoking Prevention and Tobacco Control Act, 14(1) NICOTINE TOB RES 18 (Jan. 2012). 7

21 standardized list of these smoke constituents. PMI uses standardized 18 and internally validated" methods to analyze 58 mainstream aerosol constituents, which include respiratory irritants and pulmonary or systemic toxicants. Some of these toxicants are precursors of biomarkers of exposure measured in clinical studies. PMI also analyzes the physical and chemical composition of the environmental aerosols generated by potential MRTPs. The FSPTCA requires that reductions in smoke constituents be "substantial." Our objective is to achieve such reductions in all HPHCs, on a per-unit and a per-unitnicotine basis, in comparison to conventional cigarettes. 2 Such reductions are more likely to indicate reduction of individual risk and population harm than would selective reductions of a few smoke constituents. 2. Toxicological Evidence MRTP applicants should also provide data from in vitro and in vivo toxicological assays. Such assays can serve to demonstrate that the proposed MRTP is less toxicologically hazardous than conventional cigarettes in a way that may have clinical relevance. First, if new chemicals are observed in the product's aerosol, toxicological assays can be used to verify that the product does not present a new hazard in comparison to conventional cigarettes. Second, toxicological assays can demonstrate that the product's aerosol is less biologically active than smoke from conventional cigarettes and can reveal a doseresponse relationship. A range of in vitro assays is available. They include, but are not limited to, the Neutral Red Uptake cytotoxicity assay; the Ames mutagenicity assay; the Mammalian Cell Micronucleus Assay; and the Mouse Lymphoma Assay. Similarly, a range of different in vivo assays of different durations may be used, including, for example, acute and repeated dose inhalation studies. The relevance of in vitro and in vivo toxicological test systems to humans represents a challenge in risk assessment. For a complex mixture such as tobacco smoke which causes complex diseases with long latencies there is a need to apply the latest approaches for data integration, analysis, and decision making. Recent research approaches have sought to deploy our growing understanding of the molecular pathways leading to diseases and the mechanisms of disease progression. These new methods can combine diverse data from in vitro and in vivo experiments in order to build an understanding of relevant biological networks and ultimately disease 18 See, e.g., ISO, Routine analytical cigarette-smoking machine definitions and standard conditions, /SO 3308 (International Organization for Standardization 2011); Health Canada PMI measures smoke constituents according to analytical methods that we have validated internally according to the guidelines of the International Conference on Harmonization that address investigations of accuracy, precision, quantification and detection limits. INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE, ICH HARMONISED TRIPARTITE GUIDELINE: VALIDATION OF ANALYTICAL PROCEDURES: METHODOLOGY Q2B (1996). 20 Applicants should specify the reference conventional tobacco product to which their proposed MRTP is compared. There are, of course, a wide range of conventional cigarette styles sold in the United States and in many other countries. Although "reference cigarettes" have utility, they do not capture the range of potential comparator products. 8

22 mechanisms in a way that has important, near-term utility in the comparative assessment of our MRTP candidates and conventional cigarettes. PMI is contributing to the developing science in this area. 21 We have gathered data that suggest switching from conventional cigarettes to a potential MRTP results in changes that are similar to those found following smoking cessation. For example, as Figure 2 illustrates, we found that atheromatic plaque in ApoE knockout mice grows faster in animals exposed to conventional cigarette smoke (CC) for six months than in those exposed to fresh air (Sham) for six months. Plaque growths were reduced significantly in animals exposed to conventional cigarette smoke for three months and subsequently exposed to air for three months (CC+Sham). Significantly, plaque growths were similarly reduced in animals exposed to conventional cigarette smoke for three months and subsequently exposed to aerosol from the potential MRTP (CC+MRTP). Figure 2: Switching from conventional cigarette smoke ("CC") to potential MRTP aerosol ("CC+MRTP") results in reductions in atheromatic plaque growth similar to reductions observed when switching to air ("CC+Sham"). 35 a) 30 cr 25 as a_ 20 -a (1) 15 0 o 10 "r= 5 0 n=10 n=10 n=10 n= 18 n=113 n=113 n= 10 Sham CC MRTP Sham CC CC+Sham CC+MRTP 3 month 6 m onth In the same experiment, changes in inflammatory markers measured in the bronchioalveolar fluid of the ApoE knockout mice and changes in gene expression associated with lung inflammation were also reduced by switching to a potential MRTP, following a trend similar to smoking cessation in this model. 21 See, e.g., J. Hoeng, R. Deehan, D. Pratt, F. Martin, A. Sewer, T.M. Thomson, D.A Drubin, C.A. Waters, D. de Graaf, and M.0 Peitsch, A Network-Based Approach to Quantify the Impact of Biologically Active Substances, DRUG DISCOVERY TODAY (Dec. 2, 2011, Epub ahead of print: PMID ). 9

23 C. Clinical Evidence Clinical evidence should provide the primary support for any MRTP application. Evidence from both short- and long-term studies should demonstrate that the proposed MRTP reduces exposure and reduces the risk of smoking-related disease compared to conventional cigarettes. 1. Short-term Safety and Pharmacokinetic Studies MRTP applicants should provide data from short-term safety, pharmacokinetic, and pharmacodynamic (PK/PD) studies. Safety data should include data on vital signs, clinical biochemistry, hematology, spirometry, urine analysis, electrocardiogram, adverse events, etc. PK/PD studies should provide information on the relationship between nicotine plasma concentration and suppressing the urge to smoke/withdrawal symptoms in people who switch from conventional cigarettes to the potential MRTP, thereby indicating the extent to which adult smokers would find the product an acceptable substitute for conventional cigarettes.n Our PK/PD studies are designed to assess whether the kinetics and dynamics of our potential MRTPs parallel those of conventional cigarettes. We plan to conduct one or more single-use confinement studies of approximately 60 healthy male and female adult smokers in order to compare the kinetic profile of nicotine absorption in subjects who switch from a potential MRTP to conventional cigarettes or nicotine replacement therapy, and vice-versa. We will measure nicotine in plasma and monitor safety data. In addition, we will use validated tools to measure nicotine dependence, craving, and withdrawal symptoms. Data from the study will also support longer-term clinical studies by providing future researchers with an enhanced ability to monitor nicotine pharmacokinetics using a sparse sampling strategy. An initial nicotine pharmacokinetic study with one of our potential MRTPs has suggested that our product prototype had a nicotine pharmacokinetic profile similar to conventional cigarettes Exposure Reduction Studies MRTP applicants should provide clinical evidence that adult smokers who switch from conventional cigarettes to the proposed MRTP significantly reduce their exposure to HPHCs. Biomarkers of exposure provide direct, quantitative evidence of the presence of HPHCs or their metabolites in the body. 24 Although only a relatively small number of biomarkers 22 See, e.g., A.B. Breland, A.R. Buchhalter, S.E. Evans, and T. Eissenberg, Evaluating acute effects of potential reduced-exposure products for smokers: clinical laboratory methodology, 4(2) NICOTINE TOB RES S131 (2002); A.R. Vansickel, C.O. Cobb, M.R. Weaver, and T.E. Eissenberg, A clinical laboratory model for evaluating the acute effects of electronic "cigarettes": nicotine delivery profile and cardiovascular and subjective effects, 19(8) CANCER EPIDEMIOL BIOMARKERS PREV 1945 (2010); T. Eissenberg, Electronic nicotine delivery devices: ineffective nicotine delivery and craving suppression after acute administration, 19(1) TOBACCO CONTROL 87 (2010). 23 J.E. Rose, J.E. Turner, T. Murugesan, F.M. Behm, and M., Pulmonary delivery of nicotine pyruvate: sensory and pharmacokinetic characteristics, 18 EXP CLIN PSYCHOPHARMACOL 385 (2010). 24 D.K. Hatsukami, G.A. Giovino, T. Eissenberg, P.I. Clark, D. Lawrence, and S. Leischow, Methods to assess potential reduced exposure products, 7 NICOTINE TOB RES 827, 833 (2005) (stating that "measures of 10

24 of exposure can be reliably measured in smokers, 25 a number of them have been identified that: (a) are specific to the source of exposure, with other sources being minor or non-existent; (b) are easily detectable using reliable, reproducible, and precise analytical methods; and (c) either reflect a specific toxic exposure or serve as a reliable surrogate of exposure to HPHCs.26 Our objective in conducting short-term clinical exposure trials is to assess (1) whether subjects who switch to the potential MRTP have lower levels of all biomarkers of exposure other than nicotine metabolites than those who smoke conventional cigarettes and (2) how those exposure reductions compare with levels of biomarker reductions observed in subjects who cease using tobacco products altogether. For example, PMI has conducted and sponsored short-term clinical exposure studies on prior versions of a number of its developmental products in order to measure changes in HPHC exposure. A short-term clinical study found that an earlier version of one of our products reduced all observed biomarkers of HPHC exposures to levels similar to those found in subjects who quit smoking.27 We plan to conduct one or more 8-day confinement studies of approximately 150 healthy male and female adult smokers. The studies will compare the levels of biomarkers of exposure to HPHCs among three groups of subjects: (1) subjects who continue smoking conventional cigarettes; (2) subjects who switch from conventional cigarettes to a potential MRTP; and (3) subjects who cease using tobacco products altogether. Subjects who switch to the potential MRTP, and those who continue smoking conventional cigarettes, will use the products ad libitum. 3. Long-term Clinical Studies Applicants should be required to provide evidence from long-term, ambulatory clinical studies conducted under conditions of actual use. Beyond gathering further evidence of exposure reduction, these studies will measure molecular and functional changes in subjects who switch from conventional cigarettes to a potential MRTP. These studies will then compare the measurements to those taken with subjects who continue smoking conventional cigarettes and to those taken with subjects who cease using tobacco products altogether. actual toxin uptake, such as carbon monoxide, nicotine or cotinine, anatabine and carcinogens, are essential"). 25 For example, the World Health Organization Study Group on Tobacco Product Regulation has defined a "priority list" of 18 toxicants found in smoke. Of those 18, 9 were targeted for reduction. See D.M. Bums, E. Dybing, N. Gray, S. Hecht, C. Anderson, T. Sanner, R. O'Connor, M. Djordjevic, C. Dresler, P. Hainaut, M. Jarvis, A. Opperhuizen, and K. Straif, Mandated lowering of toxicants in cigarette smoke: a description of the World Health Organization TobReg proposal, 17 TOB CONTROL 132 (2008). Of those 9, 6 are measureable in humans with validated biomarkers. 26 PMI studies have used the following biomarkers of exposure to the following smoke constituents: 1,3- butadiene, acrolein, benzene, crotonaldehyde, o-toluidine, NNK, 4-aminobiphenyl, nicotine, pyrene, acrylamide, 2-naphthylamine, 4-aminobiphenyl, and crotonaldehyde. 27 Study YVD-CS01-EU, ClinicalTrials.gov, Identifier NCT

25 Such molecular and functional changes are relevant for two reasons. First, indicators of "exposure response" can include established risk factors for the diseases of interest.28 For example, it is known that increases in plasma HDL concentrations are strongly associated with a decreased risk of cardiovascular disease. 29 If switching from conventional cigarettes to a proposed MRTP were found to increase plasma HDL levels compared to subjects who continued smoking conventional cigarettes, that would provide evidence that the proposed MRTP may reduce risk. In this, we recognize that there are no accepted biomarkers of short-term health outcomes from which one can confidently extrapolate disease-specific risk reductions (i.e., "biomarkers of harm"). While a number of studies have been published on biomarkers of harm, 3 the science lags behind that for biomarkers of exposure.31 The second point of relevance for molecular and functional changes therefore is of particular importance. Comparing the totality of non-clinical data, exposure reductions, risk factor data, and molecular and functional changes in smokers who switch to the potential MRTP with the exposum reductions and functional changes observed in smokers who cease using tobacco products will provide strong evidence that the potential MRTP reduces risk. The molecular, functional, and clinical effects of smoking cessation are well-established. 32 As Figure 3 illustrates, some of those effects are 28 D.K. Hatsukami, G.A. Giovino, T. Eissenberg, P.I. Clark, D. Lawrence, and S. Leischow, Methods to assess potential reduced exposure products, 7 NICOTINE TOB RES 827, 833 (2005) (explaining that "Biomarkers of health effects include early chemical, biological, and functional effects that are or should be related mechanistically to disease outcome."). 28 See, e.g., D.J. Gordon, J.L. Probstfield, R.J. Garrison, J.D. Neaton, W.P. CasteIli, J.D. Knoke, D.R. Jacobs Jr., S. Bangdiwala, and H.A. Tyroler, High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies, 79(1) CIRCULATION 8 (1989); M.T. Cooney, A. Dudina, D. De Bacquer, L. Wilhelmsen, S. Sans, A. Menotti, G. De Backer, P. Jousilahti, U. Keil, T. Thomsen, P. Whincup, and I.M. Graham; SCORE investigators, HDL cholesterol protects against cardiovascular disease in both genders, at all ages and at all levels of tisk, 206(2) ATHEROSCLEROSIS 611 (2009); I.M. Singh, M.H. Shishehbor, and B.J. AnseII, High-Density Lipoprotein as a Therapeutic Target, 298(7) JAMA 786 (2007). 38 See, e.g., IOM Clearing the Smoke, at ; D.K. Hatsukami, S.S. Hecht, D.J. Hennrikus, A.M. Joseph, and P.R. Pentel, Biomarkers of tobacco exposure or harm: application to clinical and epidemiological studies, 5 NICOTINE & TOBACCO RESEARCH 387, 387 (2003) (identifying a number of potential biomarkers of potential harm, including "carcinogen-dna adducts, lipid peroxidation, chromosomal aberrations, mitochondrial mutation, lipids, F2 isoprostanes, white blood cell count, blood pressure of FEVI."); D.K. Hatsukami, G.A. Giovino, T. Eissenberg, P.I. Clark, D. Lawrence, and S. Leischow, Methods to assess potential reduced exposure products, 7 NICOTINE Toe RES 827, 833 (2005) (stating that "[i]ri addition to these types of biomarkers, directly observable measures such as visual inspection of airways or birth weight can be considered as biomarkers of health effect."). 31 See IOM Clearing the Smoke, at 145 ("It is recognized that today, biomarkers of exposure are better validated compared to biomarkers of potential harm, and that it is more feasible to consider exposure reduction in contrast to risk reduction."); see also Scientific Advisory Committee on Tobacco Product Regulation (SACTob), Statement of principles guiding the evaluation of new, or modified tobacco products, SACTob Fifth Meeting, Brisbane, Australia, at 7 (25-27 November 2002) (stating that "At present, the evidence linking existing biomarkers of injury to ultimate disease outcomes remains incomplete, and no biomarkers have been validated for use in distinguishing the relative injury caused by different levels of cigarette smoke uptake."). 32 In a seminal work, the International Agency for Research on Cancer (IARC) noted that "many studies have shown that males and females who stop smoking have substantially lower risk of developing or dying from lung cancer than people who continue to smoke." See International Agency for Research on Cancer (IARC), World Health Organization, Reversal of Risk after Quitting Smoking, 11 HANDBOOKS OF CANCER PREVENTION: TOBACCO CONTROL (2007). Similarly, smoking cessation lowers the risk for lung and other types of cancer, reduces the risk for coronary heart disease, stroke, and peripheral vascular disease; reduces respiratory symptoms, such as coughing, wheezing, and shortness of breath; and reduces the risk of 12

26 1 sufficiently sensitive to changes in smoking status that they can be used in clinical studies to determine the extent to which MRTPs approximate the effects of cessation. Figure 3: Functional, molecular, and clinical effects of smoking cessation.33 Clinical effects Functional and molecular changes, Within: 1 week 1 mo th 3 months 5 months i Year AbIty to smell and taste is enhanced Abstinence symptoms stait (craving, anxiety etc.) Ckculation knproves - walking becomes easier Cough or wheeze decreases, however in some smokers cough may be increased Phlegm production decreases Abstinence symptoms (e.g., craving, mood, hunger) peak Circulation improves - walking becomes easier Reduced presence and severity of respiratory symptoms Increased appetke, weiglt gain Improved bronchial hyper-responsiveness (BHR) and respiratory symptoms in asthmatics Increased appetite, weight gain +6 kg Improved respiratory symptoms in COPD CHD and MI risk -30 to 50%. Carboxyhaemoglobin (COHb) decreases to normal level Cypl A2 acthity (induced by cigarette smoke) is reduced Temperature in hands and feet increases Blood pressure and pulse rate decrease Platelet function improved, e.g. changes in clotting and in 11-dehydro-thromboxane-B, Oxidative stress reduced, e.g. changes in 8-epi-prodaglan di. n-f Some molecular cardiovascular markers improved, e.g. white blood cells counts (WBC), HDL-cholesterol Improved lung function (FEV,) Improved aiterial stiffness Improved endothelial function Improved inflammatory biomarkers. 2 years e' beyond Between 5 and 15 years. Risk for stroke = never-smoker After 10 years, LC risk drops, risk for other cancers decreases. Risk of ulcer also decreases After 15 years, Coronary Heart Disease (CHD) and myocardial infarction (MI) risk = never-smokers andl death risk = never-smoker 1 The M Report refers to cessation as the "gold standard", which "provides an aspirational goal for risk and exposure for MRTPs in principle, the closer risks and exposures from the MRTP are to cessation products, the more confident a regulator can be that the changes indicate a net public health benefit." 34 Thus, if observed changes in experimental subjects consistently and closely approximate the short- and long-term changes seen following cessation, and those changes are further supported by consistent findings from non-clinical and clinical research, it is reasonable to conclude that the proposed MRTP reduces risk compared to conventional cigarettes. developing chronic obstructive pulmonary disease (COPD), one of the leading causes of death in the United States. In addition, smoking cessation by women during their reproductive years reduces the risk for infertility, and women who stop smoking during pregnancy reduce their risk of having a low birth weight baby. See CENTERS FOR DISEASE CONTROL AND PREVENTION, THE HEALTH BENEFITS OF SMOKING CESSATION: A REPORT OF THE SURGEON GENERAL (1990). 33 See CENTERS FOR DISEASE CONTROL AND PREVENTION, THE HEALTH BENEFITS OF SMOKING CESSATION: A REPORT OF THE SURGEON GENERAL (1990); CENTERS FOR DISEASE CONTROL AND PREVENTION, THE HEALTH CONSEQUENCES OF SMOKING: A REPORT OF THE SURGEON GENERAL (2004); U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, TREATING TOBACCO USE AND DEPENDENCE: 2008 UPDATE: QUICK REFERENCE GUIDE FOR CLINICIANS (2008); C. Gratziou, Respiratory, cardiovascular and other physiological consequences of smoking cessation, 25(2) CURR MED RES OPIN 535 (2009). 34 IOM Report 2011, at

27 We plan to conduct long-term clinical studies, with the objective of assessing whether subjects who switch from conventional cigarettes to a potential MRTP show changes similar to those seen in people who cease using tobacco products altogether. For example, we intend to conduct a 1-year ambulatory study of approximately 900 healthy male and female adult smokers. In addition to measuring changes in biomarkers of exposure discussed in Section III.C.2 above, we plan to measure changes in lung function (forced expiratory volume, "FEV1"), inflammation (as indicated by white blood cell count (WBC)), cholesterol metabolism (indicated by high-density lipoprotein (HDL) levels), and blood coagulation (platelet aggregation). 4. Studies in Specific Populations It also may be possible to conduct carefully supervised and controlled studies in people who have an established tobacco-related disease (e.g., peripheral arterial disease) but who have been unsuccessful in quitting smoking or are unwilling to quit. Because disease progression frequently occurs in such people within a short period of time, studies of progression may be reasonably small in size and short in duration. Furthermore, unlike studies in healthy people, studies of progression in people with established tobacco-related disease could be conducted as randomized clinical studies rather than observational studies, thus minimizing the influence of confounding variables. Findings from studies of populations with established disease could also demonstrate other near term benefits to users of a potential MRTP. In designing these trials, a conventional approach would be to define two groups: those who use the modified-risk cigarette and (2) those who continue to use conventional cigarettes. An additional design might be to randomize people to engage in a serious effort of smoking cessation. If such a two-arm randomized trial were to show that use of a modified-risk cigarette achieved results comparable to smoking cessation, such findings could be readily translated into decisions about individual and public health. D. Consumer Communication And Understanding As stated earlier, communicating the benefit of risk-reduction is essential in order to achieve the full benefit of MRTPs. In particular, communications about the products' benefits are crucial to facilitate awareness, trial use, and continued use, especially in light of the likely sensory differences that adult smokers will perceive. At the same time, MRTP applications must demonstrate that adult consumers both understand the product's benefits and do not misinterpret or overestimate those benefits. This challenge is not unique to tobacco. As the 10M stated in 2001, "[t]he problem of conveying balance in communicating health benefits and risks is not unique to tobaccorelated [modified risk products], and the large body of experience in other areas of health and safety regulation may be applicable to these products as well."35 An MRTP applicant should test various messages in order to gather evidence about how consumers understand and interpret them, how the language used influences comprehension, and how additional health information may contribute to correct 35 10M Clearing the Smoke, at

28 understanding. Such tests ultimately should encompass consumer perceptions of the product itself, as well as their understanding of product labeling, packaging, instructions, prices, and any other form of communication used in marketing the product. Each message should be individually assessed and studies should be repeated as and when elements of the MRTP offer become available, in order to ensure that all components of the marketing package continue to be correctly understood. In order to generate statistically robust evidence, an MRTP applicant should run largescale studies that include a representative sample of adult smokers, as well as other audiences, including, for example, former smokers and individuals with low literacy. Such research may be conducted using individual, computer-assisted interviews. This method exposes consumers to both open-ended questions to obtain spontaneous reactions and message comprehension, as well as closed-ended questions to measure the degree of understanding of each message. E. Abuse Liability MRTP applicants should provide evidence regarding the proposed MRTP's potential for abuse. A 2009 article in the journal Cancer, Epidemiology, Biomarkers & Prevention described the challenges of translating the pharmaco-regulatory concept of "abuse liability" to the assessment of tobacco products which are known to be addictive and proposed: "[S]everal approaches [should] be used to gather information about abuse potential. The selection of approaches for tobacco products, as for drug products, will depend, in part, on the nature of the product, its state in development, and the questions of specific interest by the product sponsor and the FDA."36 As suggested by the 10M, studies in humans may be most relevant. 37 For example, MRTP applicants should be required to provide data from clinical studies on nicotine pharmacokinetics, as described in Section 111.C.1, above. They should also provide data from short- and long-term clinical studies showing how the products are used in controlled and uncontrolled settings, as described in Section 111.C.2 and 111.C.3, above. Finally, applicants should provide comparative, qualitative assessments of nicotine dependence among users of the proposed MRTP, users of conventional cigarettes, and users of conventional cigarettes who quit smoking for the study. 38 Collectively, these data should indicate that the proposed MRTP is an acceptable substitute for, but not more addictive than, conventional cigarettes. F. Impact on the Population A number of public health experts have expressed concerns that MRTPs may discourage quitting among smokers who would otherwise have quit using tobacco 38 L.P. Carter M.L. Stitzer, J.E. Henningfield, R.J. O'Connor, K.M. Cummings, and D.K. Hatsukami, Abuse liability assessment of tobacco products including potentially reduced exposure products, 18(12) CANCER EPIDEMIOL BIOMARKERS PREV 3241 (2009). As discussed in Section II, the nature of our potential MRTPs is significantly different from conventional cigarettes, and, in general, adult smokers find them less attractive than conventional cigarettes. 37 IOM Report 2011, at See, e.g., T.F. Heatherton, L.T. Kozlowski, R.C. Frecker, and K.O. FagerstrOm, The FagerstrOm Test for Nicotine Dependence: a revision of the FagerstrOm Tolerance Questionnaire, 86(9) BR J ADDICT 1119 (Sept. 1991). 15

29 products altogether or may encourage non-smokers or youth to begin using tobacco products. 39 In order to assess these issues, the FSPTCA requires MRTP applicants to present evidence concerning the effect of a product's availability and marketing on tobacco product initiation, cessation, dual use, and relapse, in both individual smokers and in the population as a whole. Finally, the impact on population harm should take into account the potential benefit to the population that the MRTP can bring, and, as indicated by the FSPTCA, FDA should approve MRTP applications which demonstrate that individuals and the population as a whole would benefit from the introduction of an MRTP. Several authors have noted the challenge of quantifying such future behaviors. 49 We nevertheless believe that qualitative and quantitative evidence can provide reasonable pre-market evidence of post-market impact. For example, data from short- and longterm clinical studies can provide evidence that would assist regulators in assessing the impact of the availability of a proposed MRTP on switching, dual use, and cessation rates in adult smoker populations. Behavioral experiments can give a more concrete understanding of how such consumers would behave if a proposed MRTP were to be commercially available. PMI's own clinical and consumer use studies will focus on adults, primarily on adult smokers. In order to quantify the impact the availability of a proposed MRTP would have on the behavior of youth, further research would be required. Existing, publicly-available data may provide a basis for such assessments, or evidence could be developed by using econometric techniques and economic modeling to analyze prior experience with products perceived by consumers to be less-risky alternatives. Any studies that directly involve minors should be conducted by an independent third party, using pre-agreed, established protocols. Some public health advocates have suggested that "attractiveness" should be assessed for MRTP applications.'" We do not believe that "attractiveness" would make an effective criterion for considering an MRTP application. Although we do not believe that an MRTP will ever fully replicate the smoking experience of conventional cigarettes, we believe that restricting or prohibiting an MRTP on the basis of "attraction" would be counterproductive because the benefit of the product will be driven by its ability to persuade adult smokers to use them an MRTP must be more "attractive" to them than 39 See, e.g., Presentation of Karla Sneegas, M.P.H., Tobacco Prevention and Cessation Commission, Indiana State Department of Health, at Food and Drug Administration, Scientific Evaluation of Modified Risk Tobacco Product Applications: A Public Workshop (August 25, 2011), Transcript from the Workshop, at , available online at 4 See, e.g., D.K. Hatsukami, G.A. Giovino, T. Eissenberg, P.I. Clark, D. Lawrence, and S. Leischow, Methods to assess potential reduced exposure products, 7 NICOTINE TOB RES 827, 833 (2005) (stating that "[T]he population effects of [MRTPs] after they enter into the market need to be assessed. This assessment is accomplished through post-marketing surveillance and epidemiological studies. Post-marketing evaluation is conducted to ensure that [MRTPs] do not result in increased initiation of tobacco use, maintenance of use in those who were interested in quitting, or relapse to tobacco use in former tobacco users. Furthermore, the use of [MRTPs] should not result in an increase in morbidity and mortality."). Henningfield et al. grouped a number of similarly diverse covariates together under the general heading of "product appeal", while recognizing that further research is required to understand how these various factors may impact on abuse liability. J.E. Henningfield, D.K. Hatsukami, M. Zeller, and E. Peters, Conference on abuse liability and appeal of tobacco products: conclusions and recommendations, 116(1-3) DRUG ALCOHOL DEPEND. 1 (2011). 16

30 conventional cigarettes. At the same time, applicants should demonstrate that a proposed MRTP does not discourage cessation or encourage initiation among nonsmokers or youth in a way that would increase population harm. We believe that consumer research should focus on these more specific and functional endpoints. G. Plan for Post-marketing Surveillance And Studies MRTP applications should contain plans for post-market studies concerning the impact of the MRTP on consumer perception, behavior, and health. Based on our own experience with quantitative market research and common principles underlying postmarket surveillance designs, we have developed the following preliminary views on the elements of such plans. First, applicants should present a program for "market vigilance" in order to obtain and track reported experience with the product once it is on the market. Extensive market surveys already exist for tracking use of conventional cigarettes. They typically consist of monthly surveys conducted using a variety of techniques (e.g. face-to-face, telephone interview, and online research). This survey method could be adapted to assess patterns of tobacco product consumption, perception, and understanding among adult smokers, never smokers, MRTP users, and former smokers after an MRTP is marketed. Current sample sizes and survey frequency can be adjusted as necessary to ensure sufficient power to permit reliable conclusions to be drawn. In addition, applicants should also present a system for capturing product complaints or event reports originating from consumers. An appropriate mechanism and agreed methodology would need to be established before such a system could be implemented. Second, applicants should include any plans for conducting prospective longitudinal research. Such studies might be conducted with representative samples of current, ever, and never users of tobacco products in order to quantify trajectories of tobacco use and MRTP-specific perceptions and behaviors. IV. Conclusion: Coherent Evidence Can Substantiate Reduced Risk MRTPs In The Near Term The FSPTCA creates a regulatory pathway for MRTPs that is different from the approach for regulation of conventional tobacco products, and is likewise distinct from the regulation of pharmaceuticals and medical devices. Specifically, Section 911 requires proof of superiority over a known harmful alternative conventional cigarettes rather than the standards of safety and efficacy as they are used to assess drugs. Unlike the current regulatory regime for tobacco products, Section 911 recognizes the importance of consumers receiving meaningful information about the benefits of tobacco products that demonstrate substantially reduced exposure or significantly reduced risk compared to conventional tobacco products. FDA understandably may be reluctant to define precise standards for what reductions are "substantial" or "significant" enough to support such a determination at this time, given existing scientific and methodological uncertainties. We believe, however, that meaningful guidance can be provided in the short term, so that the public health aim of Section 911 can be advanced and necessary research and assessments can proceed. 17

31 Although MRTP regulation occupies a place that is distinct from conventional cigarettes and drug regulation, it can also draw upon both of those functions for crucial support. For example, the FSPTCA incorporates the science-based approach and specific research methods that are the hallmark of drug regulation. It also requires comparison to approved pharmaceutical nicotine replacement therapies. And the ultimate standards for MRTP approval apply scientific metrics exposure, risk, and public health impact that have a long history in medical research and pharmaceutical regulation. The new path charted by the FSPTCA should likewise draw upon science and public health experience with tobacco. An extensive body of consensus science provides a strong evidentiary basis for assessing in the short- and medium-term the reduced risk benefits of MRTPs: namely, decades of authoritative science on the health risks of smoking and the impact of cessation on long-term disease risk. 42 Development and regulatory approval of MRTPs therefore can advance by using two well-established goal posts: the risk of disease due to continued smoking, on the one hand, and the reduction in disease risk upon cessation, on the other hand. Determining how close a product comes to the latter requires a coherent approach to non-clinical and clinical assessment. The product-specific comparative data described in Section III above can demonstrate that an MRTP achieves outcomes that are more similar to cessation than they are to conventional cigarettes. To the extent that the comparison to cessation is determined, both product-specific data and the wealth of science on the benefits of cessation can support an assessment that the proposed MRTP in fact reduces and indeed, has reduced risk of disease in individuals.43 Evidentiary standards should permit MRTP assessments to build upon the accumulated science on smoking cessation rather than replicating it, a task that would undermine and most likely prevent for the foreseeable future a significant opportunity to benefit public health:" Guidance that defines disciplines and methodologies making those comparisons to those well-understood benchmarks should together with the language of the statute enable MRTP applicants to conduct research and present their products for approval in a realistic timeframe. In that spirit, PMI is pleased to offer its perspectives on the evidence that should support an MRTP application. We have relevant expertise, but we by no means have all the answers. By combining expertise and working together in good faith, we believe that FDA can lead the world in one of the most important public health initiatives in recent history, and save millions of lives in the process. We welcome the opportunity to participate in that dialogue. 42 see, e g International Agency for Research on Cancer (IARC), World Health Organization, Reversal of Risk after Quitting Smoking, 11 HANDBOOKS OF CANCER PREVENTION: TOBACCO CONTROL (2007); see generally, discussion at Section III.C.3, above. 43 Equivalence to cessation is not the standard set by the FSPTCA, nor do we suggest that it should be required by regulations or guidance. But comparing MRTPs to the effects of cessation can and should be a key benchmark for regulatory assessment, and guidance and regulations could require that the relationship between a proposed MRTP and the effects of cessation be coherently demonstrated. " By definition, developing long-term, product-specific epidemiologic data could take decades because of the lag time between introduction of a specific MRTP and the differentiation in the development of many tobacco-related diseases. Requiring such data before approving a Reduced Risk MRTP application would, in effect, prevent approval of any innovative MRTP for a significant period of time, and would miss significant opportunities to reduce the harm caused by smoking cigarettes for smokers who do not quit. 18

32 Philip Morris International, Inc. February

33 wip S S 4 0 fedex.com t800.gofedex Cri RECIPIENT: PEEL HERE -a c-b CI) CI) 0 Cr) "13 -As " *sas c) c.c:1 * CI nj E-1 in 5 6CEE x3p3j :axepai,