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`4,
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`The NEW ENGLAND
`JOURNAL of MEDICINE
`
`Perspective
`A Nicotine-Focused Frameworkfor Public Health
`
`Scott Gottlieb, M.D., and Mitchell Zeller, J.D.
`
`September21, 2017
`N Engl | Med 2017; 377:1111-1114
`DOI: 10.1056/NE)Mp1707409
`
`Article
`
`
`
`Metrics
`
`5 References
`
`198 Citing Articles
`4 Comments
`
`Article
`
`“
`
`ESPITE EXTRAORDINARY PROGRESS IN TOBACCO CONTROL AND PREVENTION,
`tobacco use remains the leading cause ofpreventable disease and deathin the United States.
`Combustible cigarettes cause the overwhelming majority of tobacco-related disease and are
`responsible for more than 480,000 U.S. deaths each year. Indeed, when used as intended, combustible
`cigarettes kill half of all long-term users.1
`
`Withthe tools provided to the Food and Drug Administration (FDA) under the Family Smoking Prevention
`and Tobacco Control Act of2009, the agency has taken consequential steps to prevent sales of tobacco
`products to children, expand the science base for understanding traditional and newer tobacco products,
`and conduct public education campaigns. But the agency needs to do more to protect Americans; in
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`particular, we must shape a regulatory framework that reduces their use of combustible cigarettes. The
`agency’s new tobacco strategy has two primary parts: reducing the addictiveness of combustible cigarettes
`while recognizing andclarifying the role that potentially less harmful tobacco products could play in
`improving public health. We must also work toward a greaterrole for medicinal nicotine and other
`therapeutic products in helping smokers to quit and remain nonsmokers.
`
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`
`
`Evidence shows that most cigarette smokers are concerned abouttheir health and are interested in quitting
`and that mosthave tried to quit.* Reducing cigarettes’ addictiveness could help addicted users quit more
`easily and help keep those who are experimenting — young people, in particular — from becoming regular
`smokers. And the availability of potentially less harmful tobacco products could reduce risk while delivering
`satisfying levels of nicotine for adults whostill need or wantit.
`
`The regulatory framework for reducing harm from tobacco mustinclude nicotine — the chemical
`responsible for addiction to tobacco products — as a centerpiece. Nicotine, though not benign, is not
`directly responsible for the tobacco-caused cancer, lung disease, and heart disease that kill hundreds of
`thousands ofAmericans each year. The FDA’s approach to reducing the devastating toll of tobacco use must
`be rooted in this foundational understanding: other chemical compoundsin tobacco, and in the smoke
`created by combustion, are primarily to blamefor such health harms.
`
`Nicotine is, however, responsible for getting smokers addicted to cigarette smoking in the first place —
`usually while they are children or young adults and their brainsare still developing — and keeping them
`addicted long-term. Combustible cigarettes’ efficient method ofnicotine delivery means that nicotine
`inhaled from a cigarette can travel through the lungs and to the brain in less than 10 seconds,? adding to the
`addictive potential.
`
`The Tobacco Control Act gave the FDA a regulatory tool called a tobacco product standard that can be used
`to alter the addictiveness of combustible cigarettes. Standards may be issued to set requirementsrelated to
`an ingredient or constituent in a tobacco product, or related to any other aspect ofproduct composition,
`construction, or other property. Establishing the right product standard could alter the addictiveness of
`combustible cigarettes by setting maximum nicotinelevels in these products.
`
`Section 907 of the Food, Drug, and Cosmetic Act authorizes the FDA to establish tobacco product standards
`that it has determined to be appropriate for the protection of the public health. The statute specifically
`notes that such a standard may address nicotine yields, among other characteristics. Althoughit prohibits
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`the FDA from “requiring the reduction of nicotine yields ofa tobacco productto zero,” the agency has clear
`authority to otherwise reduce nicotinelevels.
`
`A nicotine-limiting standard could make cigarettes minimally addictive or nonaddictive, helping current
`users of combustible cigarettes to quit and allowing mostfuture users to avoid becoming addicted and
`proceeding to regular use. Disrupting that progression —- from experimentationto regular use to tobacco-
`related disease and even death — could save millions of Americanlives.
`
`The FDA will consider peer-reviewed studies in proposing a maximumnicotine level. Rigorous studies of
`very-low-nicotine cigarettes have evaluated the potential effects ofvarious nicotine levels on smoking
`behaviors and biomarkers,* and findings from suchstudies could inform decision making on a possible
`maximum nicotine level in tobaccofiller. As on all matters ofpublic health policy, the FDA will be led by the
`science in this important area.
`
`As we pursue a product standard, the FDA will explore possible adverse effects of such measures, so that any
`final standard may anticipate and address potential unintended consequences. For instance, compensatory
`smoking — altering smoking behavior to continue obtaining enoughnicotine to satisfy addiction — is a
`possible countervailing effect of setting a nicotine product standard. Several recent studies have assessed
`this potential, and some evidence suggests that compensation may be minimal; studies have shown
`reductions in cigarettes smoked per day and in exposure to harmful constituents.* A recent 6-weekstudy by
`Donnyet al. showed that cigarettes with lower nicotine content reduced nicotine exposure and dependence,
`as well as the numberofcigarettes smoked, as compared with cigarettes with standard nicotine levels.°
`These results are encouraging, but the FDA will scrutinize all relevant science as part of a transparent,
`public rulemaking process.
`
`Our assessment of expected population health benefits will also consider the potential for migration —
`smokers turning to tobacco products other than cigarettes, in combinationor as replacements, to maintain
`their nicotine dependence. Finally, we intend to explore the possibility that regulation might giverise to an
`illicit market for higher-nicotine products; the FDA will seek input onthis issue from experts as we develop
`our regulatory policy.
`
`With these considerations in mind, and led by the best available evidence, the FDA will pursue a regulatory
`frameworkthat focuses on nicotine and supports innovation to promote harm reduction. This framework
`will recognize that the core problem ofnicotinelies not in the drug itself but in the risk associated with the
`delivery mechanism. In contrast to combustible cigarettes, nicotine delivery mechanisms such as medicinal
`gums, skin patches, or lozenges can be so safe and effective in helping smokers quit that they maybe sold
`without a prescription.
`
`To truly protect the public, the FDA’s approach must take into account the continuumofriskfor nicotine-
`containing products. We are examining possible steps the agency could take to address the
`pharmacokinetic performance ofFDA-approved medicinal nicotine products to help more smokers quit.
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`Factors for consideration may include the speed with whichnicotine is delivered and other possible
`innovations.
`
`There are already products, such as electronic nicotine delivery systems, that could conceivably deliver
`nicotine without posing the dangers associated with tobacco combustion. Experts on bothsides ofthe
`“harmreduction” debate have expressed strongly held views about the potential benefits andrisks of e-
`cigarettes. We must continue to build on our understanding of the potential benefits for addicted cigarette
`smokers, in a properly regulated marketplace, of products capable of delivering nicotine without having to
`set tobacco onfire. The FDA’s ongoing investmentin regulatory science will contribute to this
`understanding.
`
`Rendering cigarettes minimally addictive or nonaddictive, within a landscape including other,
`noncombustible products suchas e-cigarettes, represents a promising foundation for a comprehensive
`approachto tobacco harm reduction. In working toward this vision, the FDA is committed to striking an
`appropriate balance between protecting the public and fostering innovationin less harmful nicotine
`delivery.
`
`Weare at a crossroads in efforts to reduce tobacco use, withthelives of tens of millions of currently
`addicted cigarette smokers and future generations hanging in the balance. Even as we evaluate the
`characteristics ofvarious nicotine-delivery products — and watch the sometimes-divisive debate over these
`products’ pros and cons — the FDAis focusing squarely on nicotine as the centerpiece of a comprehensive,
`lifesaving tobacco regulatory strategy. In developing this strategy, we will rigorously assess the best
`available evidence and provide extensive opportunities for stakeholder input. Asafirst step, the agencyIs
`working on an advance notice of proposed rulemaking to obtain informationrelevant to reducing the
`nicotine levels in combustible cigarettes and to ask key questions related to the benefits and potential
`unintended consequences of sucha policy.
`
`The public health benefits ofimplementing a nicotine-reduction policy for combustible cigarettes could be
`enormous: we would expect smoking-related morbidity and premature mortality to decrease considerably.
`Ultimately, we may be able to transform the tobacco marketplace and the delivery of nicotine to protect
`future generations ofyoung people and save many millionsoflives.
`
`Funding and Disclosures
`
`Disclosure forms provided by the authors are available at NEJM.org.
`
`This article was published on August 16, 2017, at NEJM.org.
`
`Author Affiliations
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`v
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`Vv
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`Fromthe Office of the Commissioner(S.G.) and the Center for Tobacco Products (M.Z.), Food and Drug
`Administration, Silver Spring, MD.
`
`Supplementary Material
`Disclosure Forms
`
`PDF
`
`92KB
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`References(5)
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`v
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`v
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`1.
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`2.
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`3.
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`4
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`53.
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`The health consequences of smoking —- 50 years of progress: a report of the Surgeon General. Atlanta:
`Department of Health and HumanServices, Centers for Disease Control and Prevention, National Centerfor
`Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014.
`Google Scholar
`
`Babb S, Malarcher A, Schauer G, AsmanK,Jamal A. Quitting smoking among adults — UnitedStates,
`2000-2015. MMWRMorb Mortal Wkly Rep 2017;65:1457-1464
`Crossref WebofScience Medline Google Scholar
`
`The health consequences of smoking:a report of the Surgeon General. Atlanta: Departmentof Health and
`HumanServices, Centers for Disease Control and Prevention, National Center for Chronic Disease
`Prevention and Health Promotion, Office on Smoking and Health, 2004.
`Google Scholar
`
`Donny EC, Hatsukami DK, Benowitz NL, Sved AF, Tidey JW, Cassidy RN. Reduced nicotine product
`standards for combustible tobacco: building an empirical basis foreffective regulation. Prey Med 2014;68:17-
`22
`
`Crossref WebofScience Medline Google Scholar
`
`Donny EC, Denlinger RL, Tidey JW, et al. Randomizedtrial of reduced-nicotine standards forcigarettes. N
`Engl J Med 2015;373:1340-1349
`Free Full Text Web ofScience Medline Google Scholar
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`Citing Articles (198)
`
`Close References
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`v
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`Comments (4)
`
`Assoc ProfDarlene H Brunzell and colleagues ~»
`Sep 27, 2017
`
`Close Citing Articles
`
`v
`
`Nicotine, not just about the addiction
`Weagree with the overwhelming need to decrease cigarette consumption, but are concerned about labeling
`various nicotine products and alternative delivery systemsas ‘so safe.’ It is difficult, to fully disentangle the
`harm done by nicotine versus the othertoxic constituents in tobacco. Nicotine is a knowncarcinogen, toxin
`and teratogen, Preclinical studies show that nicotine promotes tumor growth and GWAS studies show that
`some nicotinic receptor variants increase cancer vulnerability. While e-cigarettes can help some smokers to
`quit, e-cigarette use encouraged by youth-targeted marketing is rapidly increasing in never-smoker
`adolescents who reportstarting e-cigarettes because they are viewed as “safer” than conventional cigarettes.
`There is growing evidencethat e-cigarettes encourage cigarette consumption in these youth and there are
`conflicting claims about the health concerns posed by e-cigarette vapors. As we work togetherto reduce
`tobacco’s toll, we should take great care in crafting messages about nicotine; otherwise we may inadvertently
`spur chronic use and perpetuate some of tobacco’s harms.
`DH Brunzell, PhD; P Gardner, PhD; SA Grando, MD, PhD, DSc: IM McIntosh, MD
`
`RAMAKRISHNAPINJALA
`Sep 21, 2017
`
`Is it possible to stop production of combustible cigarettes?
`Itis still a challenge, but I feel behavioural therapyis essential to overcome the addictions. Reduction of
`nicotine levels will help many, but there is concern about the possibility of smoking moreto get the same
`effect. Combustible cigarettes production should be stopped, this will help the non smokers. Alternatives can
`be provided for some time, such as e-cigarettes.
`
`AKI NILANGA BANDARA
`Sep 21, 2017
`
`Smoking cessation and harm reduction
`I read with interest a recent article by Gottlieb and Zeller(1). Even though the authors have explicitly stated
`that there is growing evidence to support e-cigarettes and it’s effectiveness and safety for smoking cessation
`and harmreduction, unfortunately this statement does notreflect the current best evidence. Best evidence
`includes empirical evidence from methodologically strong systematic reviews.
`
`There is currently little evidence on the long-term benefits or harms of e-cigarette. According to the FDA,
`there's no evidence any e-cigarette is safe and effective at helping smokers quit. E-cigarette contains nicotine,
`whichis addictive in itself and therefore, we should not promote these products until the evidenceis clear on
`their efficacy and safety. Therefore, clinicians and the public health community must direct their patients,
`those who wanted to quit tobacco to other proven and safe tobacco cessation products such as nicotine gum
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`and patches. E-cigarette is strictly regulated in many countries due to advice from the World Health
`Organization (WHO), exclusively based on currently available best evidence.
`
`BRIAN MCMILLEN
`Sep 21, 2017
`
`Nicotinesets the taste
`The authors seem to be unaware of the role of nicotine in setting the taste of a cigarette for the smoker. The
`"Tobacco Papers" revealed that the tobacco industry knew that a cigarette was a unit dose of nicotine and that
`the amountofnicotine set the taste. Before varenicline (Chantix) there was mecamylamine, a ganglionic
`blocker that entered the central nervous system. Smokers that received a dose of mecamylamine whothen
`inhaled fromtheir favorite brand of cigarette would complainthat the cigarette did not taste good. When
`Phillip-Morris came out with their Marlboro brand, it quickly knocked out the competition and the other
`companies were at aloss as to why. Turned out, the tobacco had been fumed with ammonia that allowed
`greaterrelease of nicotine when smoked: i.e. better taste.
`
`What we are observing in the 2015 reports from both the CDC's Youth Rusk BehaviorSurveillance system and
`Monitoring the Future is a large drop off in consumption ofcigarettes by youth with a compensatory increase
`in e-cigarettes and vaporizers. Instead of burnt plant products, they are getting a potpourri of flavorings.
`
`In sum, we need to address the behaviors.
`
`
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`PAGE 1
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