Tobacco Documents Online

Tab III (Continued) 282207215 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44657 INTRODUCTION On August 11, 1995, the Food and Drug Administration (hereinafter FDA or the Agency) announced the results of its extensive investigation and comprehensive legal analysis regarding the Agency's jurisdiction over ciga~ues and smokeless tobacco in a document entitled, "Nicotine in Ciga~ttes and Smokeless Tobacco Products Is a Drug and These Products Are Nicotine Delivery Devices Under the Federal Food, Drug, and Cosme~ Act" (he~ referred to as the "Jmisdictional Analysis"). 00 FR 41453- 41787 (Aug. 11,199~). The Agency reported that its investigation and analysis supported a finding at that time that nicotine in cigarettes and smokeless totmc, o is a drug and that these products are drug delivery devices within the meaning of the Federal Food, Drug, and Cosmetic Act (hereinafter the Act). Because of the unique importance of the jurisdictional issue, the Agency invited commem on this finding. The public comment period closed on January 2, 1996. 60 FR 53620 (Oct. 16, 1995). On March 20, 1996, the Agency publish~l in the Federal Register notice of an additional 30 day.comment period, until April 19, 1996. fimited to specific documents the Agency added to the docket in support of the Agency's analysis of jurisdiction. 61 FR 11419 (Mar. 20, 199~). The Agency rec~iv¢d over 700,000 comments on its Jurisdictional Analysis and ~ Propmed Rule restricting the tnde and di~'ibution of cigarettes and smokeless tobacco to protect children and adolescents. The Agency has carefully considered these comments. This final jurisdictional determination responds to the public comments and reports the Agency's conclusion that the nicotine in cigarettes and smokeless tobacco is a drug and that cigarettes and smokeless tobacco ate drug delivery devices whose purpose is to 1 282207216 PRODUCED FROM B&W WEB SITE 44658 Federal l~e~ister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Rc~,ulstions deliver nicotine to the body in a manner in which it can be readily absorbed. These product.s, therefore, are subject to FDA regulation under the Act. The legal question of whether cig~rcucs and smokeless tobacco are drugs and devices subject to FDA regulation is one that "'FDA has jurisdiction to decide with administrative finality." Weinberger v. Bemex Pharmaceuticals, Inc., 412 U.S. 645, 653 (1973). The Act defines a "drug" as (1) an article "intended for use in the diagnosis, cure, mitigation, treatment, or ~revention of disease in man or other animals," or (2) an article (other than food) ;'intended to affect the structure or any function of the body of man or other an/ma/s." Section 201(gX 1XB) and (C), 21 U.S.C. 32 l(gX 1XB) and (C) (emphasis added). The Act's device definition parallels the drug definition and provides that an instrument, apparatus, or other similar article is a "device" if it is (1) "intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals," or (2) "'intended to affect the structure or any function of the body of man or other ammals." Section 201(hX2) and (3), 21 U.S.C. 321(hX2) and (3) (emphasis added). These definitions are intended to be broad in scope and to encompass prtxiucts that are not within the ordinary medical def'mitions of drugs and devices. See United States v. An Article of Drug... Bacta.Unidisk, 394 U.S. 784, 793 (1969) ("we think it plain that Congress intended to define 'drug' far morn broadly than does the medical profession"). In applying these legal standards to cigarettes and smokeless tobacco, the Agency " has focused on the second prong of the definition of drug and device: whether cigarettes and smokeless tobacco are "'intended to affect the structure or any function of the body." Historically, the Agency has r~gulamd tobacco products whenever the. evidence heroin the 2 282207217 PRODUCED FROM B&W WEB SITE Federal Regisler / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44659 Agency was sufficient to establish that the products were intended to affect the structur~ or function of the body. FDA last considered whether cigarettes were drugs or devices in the late 1970's, determining that the Limited evidence then before the Agency was insufficient to demonsuate that these products were intended to affect the structure or function of the body. See Action on Smo~dng and Health v. Harris, 655 F.2d 236 (D.C. Cir. 1980). Since that time, substantial new evidence has become available to FDA. This evidence includes the emergence of a scientific consensus that cigaxetms and smokeless tobacco cause addiction to nicotine and the disclosure of thousands of pages of internal tobacco company documents detailing that the manufacturers intend to affect the structure and function of the human body. The determination whether a product is subject to FDA jurisdiction often requires the Agency to make difficult factual judgnmnts, including judgments regarding the imended use of the product. The Agency must have enough evidence to show that these factual judgments arc rational and not "arbitrary, capricious, an abuse of discretion, or othcrxvise not in accordance with law." 5 U.S.C. 706(2)(A); see National Nutritional Foods Ass'n v. Weinberger, 512 F.2d 688, 700-701 (2d Cir. 1975), cert. denied, 423 U.S. 827 (1975). The Agency must provide some evidentiaty support for i~s factual judgments, and there must be a rational connection betw~n these judgments and the conclusions reached..Motor Vehicle Mfrs. Ass'n o.f the United States. Inc. v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29, 42-43 (1983). The Agency should also have co~idered all the relevant data and the relevant aspects of the issue, ld.: Citizens to Preserve Overton Park. Inc. v. Volpe, 401 U.S. 402, 416 {1971). An agency's factual judgments made in the context of an informal ~gency action ordinarily need only be supported by a record that 282207218 PRODUCED FROH B&W WEB SITE 44660 Fmteral Reg/ster / Vol. 61, No. 168 / Wednesday. August 28. 1996 / Rules and Regulations shows a "'rational basis" for the agency's decision, Natural Resources Defense Council, Inc. r. EPA, 16 F.3d 1395, 1401 (4th Cir. 1993). or by a record consisting of "'some evidence" in support of the agency's decision. Aman ~'. FAA, 856 F.2d 946. 950 n.3 C/th Cir. 1988) fwhile an agency determination need only have "some evidentiary basis to avoid being he|d 'arbitrary and capricious,' [t]he difference between 'some' and "substamial' probably cannot be precisely stated except in the context of particular cases .... "). Several courts, however, have held that an agency's factual judgments must always be supported by "substantial evidence." even though that standard is intended to be applied only to formal "on the renard" agency actions, see 5 U.S.C. 706(2XE).' In this case, the Agency's evidentiary record exceeds these standards. That is, FDA has concluded that the evidence now before the Agency supports a finding of jurisdiction over these products. In assessing the new evidence, FDA has used a two-step approach, evaluating first whether the nicotine in these products "affects the structure or ~ See, e.g.. Ass'n of Data Peocessing Ser,~ce Organi:mions. Inc. v. Board of Governors, 745 F.~ 677, ~3-~4 (D.C. Cir. 1~) ($~ J) ('W~n ~e ~ ~ ~ici~ s~ ~ ~ff~n~ ~1 f~Uon of ~s~g fa~l su~ ~ ~ no sub.five dfffe~ ~t~n w~ i~ ~q~ ~ w~ w~ ~ ~ui~ by ~ su~ ¢v~ ~ ~ it ~ im~ib~ ~ ~ive of a 'u~i~' fact~ judg~nt su~cd only by evid~ ~t ~ not su~g m $c ~A s~ .... "). Costa Corrosion Pr~fFinings r. ~A, ~7 F.~ I~I, 1213-121d ~ n.l~ (5~ Cir. I~I) (~lining m fi~ s~c"): Am. Pa~r/nsL ~'. ~ ~¢c. Power 5~.. Co~., ~ I U.S. ~ ~I 2 n.7 (I ~3) (in ~e a~n~ of a s~fic com~d m ~c smmm m ¢mpMy a ~ s~ ~ review. ~ C~ of A~ have a~li~ ~e n~ Icnicm ~i~ ~ ~p~cio~ s~d in cvalua~g ~ fa~l ~is su~mng an age~y's i~o~l mlen~g). The difference in the case law. however, is of no consequence here because FDA's evidentiary recon:l exceeds the "'substantial evidence" smndard---~e more stringent of the two standards. Substantial ev~denc~ is "such relevant evidence as a reasonable mind n~ght accept as adequate *o suplxm a conclusion," Consolo v, Federal Marilime Conmusswn. 383 U.S. 607, 619-620 (1966) (quo~ing Consolidated Edason Co. v. NLRB. 305 U.S, 197, 229 (1938)), even il two inconsis~nt conclusions mi[hl be inferred front the same evidence. $e¢ Consolo. 383 U.S. at 620: NLRB v. Ne*~la Consolidated Copper Corp.. 316 U.S. 105, 106 (1942). Under the substantial evidence sumdard, an agency's factual detem~mation.,~ are conclusive even if supported by "something I¢~ than ~he weight of the evidence .... "" Consolo, 383 U.$. at 620 (emphasis added). 282207219 PRODUCED FROM B&W WEB SITE Federal Regi~er / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations ~4661 an)' function of the body" and second whether these effects are "intended." FDA has determined that the evidence overwhelmingly demonstrates that (l) nicotine in cigarettes and smokeless tobacco has sigmficant effects on the structure and function of the body and (2) these effects are intended by the manufacturers of these products. The Agency's determination that nicotine in cigarettes and smokeless tobacco "affect[s] the structure or any function of the body" is based on throe central findings: I. Nicotine in cigamues and smokeless tobacco causes and sustains addiction. 2. Nicotine in cigarcucs and smokeless tobacco causes other psychoactive (mood-altering) effects, including tmnquiltzation and sRmulation. 3. Nicotine in cigarenes and smokeless tobacco conu'ols weight. These findings demonstrate that nicotine in cigamues and smokeless u)bacco has the sarnc pharmacological effects as other drugs that FDA has Iraditionally regulated, including u'anquilizcrs, stimulants, appetim suppressants, and produc~s used in the maintenance of addiction such as methadone. Thus, the effects of mcotinc in cigareRcs and smokeless tobacco on the su'~cture and function of the body am within FDA's jurisdiction. FDA's determination that the rnanufaclurers of cigarcucs and smokeless tobacco "imcnd" the effects of nicotine on the structure and function of the body is based on five central findings: I. The addictive and other pharmacological effects of nicotine arc so widely known and accepted that i~ is foreseeable ~o a reasonable manufacturer tba[ cigamtms and smokeless ~ tobacco will cause addiction to nicotine and other significam pharmacological effects and will be used by 282207220 PRODUCED FROH B&W WEB SITE 44662 F~der~l Register / Vol. 61, No. 16S / Wednesday, August 28, 1996 / Rules and Regulations consumers for pbam-mcolog~cal purposes, includin~ sustaining their addiction Io nico~ne. 2. Cons~ers use cig~es and smokeless ~obac~ predominantly for p~a~logi~l p~s, including s~mining [he~ addiction to ni~tine, m~ al~m~on, and weigh~ loss. 3. M~ufaaure~ of cigars md ~o~l~ ~b~ ~ow ~a~ nico~e in t~g p~u~ ~es p~logi~l eff~ in ~nsu~, mclu~g ~i~on ~ m~e ~ m~ al~m~om and ~t ~~ ~e ~e~ p~ucu p~ly to ob~n ~e p~lo~ eff~ of ni~e. 4. Manufa~ of ~s and smo~less (~ design ~e~ p~uc~ to pmvi~ ~e~ wi~ a p~lo~ly a~ve d~ of m~, 5. ~ inevi~ble ~ue~ of ~e d~i~ of ~ ~ smo~less toba~ ~o pmv~ p~lo~y a~v~ doses of m~ne ~ m ~p ~ns~e~ ~mg clones ~d smokeless ~ by sus~in~g the~ ad~on ~o m~e. ~ch of t~ findings provides an insentient ~ for es~blis~ng ~ ~e ~nufa~ of cigare~s and smo~]ess to~o "in~n~ to affe~ ~e ~aure ~d run.ion of the ~y. T~n ~oge~en ~ cumu~tive weight of ~e eviden~ ~nvincingiy sup~ns ~e dete~ination that the eff~ of nicotine on ~e s~e and f~on of ~e ~A's ~on ofj~sdi~on over ~s ~d s~less toba~o ~ ~tent with ~e Agency's ~on ofju~ic~on over o~er s~i~ ~u~. ~A ~gulat~ a divene ~nge of p~u~ under t~ Act. ~e~ p~u~f~, ~gs, devils, cosme~cs, and ndia6on-emi~ng e]~nic pr~u~l] "~ ~ h~l~ ~d ~ll- ~ing of the public." Um~edStme~ ~ ~ar~ 421 U.S. 658, 672 (1975). ~e ~on f~m~ ~at d~tinguishes ~ese p~u~ is ~e~ in~te ~d ~n~lly ~ ~n~ 6 282207221 PRODUCED FROM B&W WEB SITE Federsl R~er / Vol. 61, No. 168 / Wednesday. Aus, ust 28, 1996 / Rules and Regulations 44663 with the human body. See id, at 668. FDA-regulated produc/s include those that are intended to be ingested, inhaled, applied to the skin, implanted, or otherwise used m close contact with the body. Cigarerms, which deliver a pharmacologically active dose of nicotine to the body through inhalation, and smokeless tobacco, which delivers a pharmacologically active dose of nicotine thn:)ugh buccai absorption, share this distinguishing feature and thus are properly subject to FDA jurisdiction. The determinations that (1) the nicotine in cig-~etms and smokeless tobacco "affects the structure or any function of the body" ~! (2) t~e effe~ m-~ "!intendS" by the manufacturers satisfy the legal requi~mems undm" th~ Act for FDA jurisdiction. FDA has also determined that cigarettes and smokeless tobacco contain both a "drug" and a "device" and are thus combination products within the rtmaning of the Act. Accordingly, the Agency has concluded that the nicotine in cigar~tms and smokeless ~ is a drug and that cigarettes and smokeless tobacco a~c drug delivery devices uadcr the Federal Food, Drug, and Cosmetic Act. 7 282207222 PRODUCED FROH B&W WEB SITE ~ Fsdt, raJ .ltsgistm" / VoL 61~ No..168-/ Wednesday,. August 28, 1996 '/ Rules anti'Reguletions L CIGARETTES AND SMOKELESS TOBACCO "AFFECT THE STRUCTURE OR ANY FUNCTION OF THE BODY" WITHIN THE MEANING OF THE ACT In the Jurisdictional Analysis, FDA found, based on the evidence available to it at the time, that nicotine in cigarettes and smokeless tobacco is "highly addictive, causes other psychoactive effects, such as relaxation arc] stimulation, and affects weight regulation." See Jurisdictional Analysis, 60 FR 41~164 (Aug. 11, 1995). The Agency found that the nicotine in these products "has pharmacological effects on both the structure and functio~ of the central nervous system, particularly the brain," and that "[a]ddiction is a direct result of nicotine's effects on the structare and function of the body." Id. at 41470. Based on these findings of pharmacologica!effects, the Agency found that cigarettes and smokeless tobacco "a/fect the structure or any function of the body. ~ ld. (emphasis added). As described more fully below, the Agency received comments that agreed and disagreed with the Agency's position.~ After considering the evidence in the administrative record,~ including the public comments, the Agency finds that cigarettes and 2 The Ageacy t'eceived • consolidated commem of the cigarette induslt~ (Brown & Williamson Tobacco Co~., Liggell Group Inc, Lotillard Tobacco Co., Philip Morris Inc., R.J. Reyuolds Tobacco Co., Tobacco lastiutte htc.) (Jan 2, 1996) (hereimfm Joint Comments of the Cigal~tte Mtllufacture~s). See AR (Vol. 535 Ref. 96). The At~mcy al~ n:ceived a coesolidat~d cornmeal ~ the smotr.k~ ~ac~o indus.7 (Smokeless Tobacco Cotmcfil. lac., Brown & Williamson Tobacco Coq~., Co~. wood Co., L.P., National Tobacco Co., LP., the Pinkerton Tobacco Co., R.C. Owm Co., Swisher latemational, Inc., Uni~d St~t~ Tobacco Co.) (Jim. 2, 1996) (he~mafl~ Joint Commenls of the Smokeless Tobacco Malmfacture~). See AR (Vol. 526 Ref. 95). ~ In the footnotes of this document, ciles to ~e adminis~ative record (AR) specify both the number of the re~erence and the volume of the AR ie which the t~e~nce is fotmd. The ~fe~nce may contain the full document or a partial documenL Where the ~eference contains a partial documenL the full document may be found elsewhere m the AR. Ina small number of cases, a reference will occupy several volumes of~he AK, fo~ example, the Joint Comments of the Cigarette Manufacttuzrs. In these cases, the cite will specify the volume of the AR in which the ~fetence begins. 8 282207223 PRODUCED FROH B&W WEB SITE F~deral Register / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations 44665 smokeless tobacc~ do indeed "affe~n the su-ucture or any function of the body" within the meaning of sections 201 (gX l XC) and 201(hX3) of the Act, 21 U.S.C. 321 (gX 1XC), 321(h)(3). To interpret the Federal Food, Drug, and Cosmetic Act in a manner that excludes the effects of these products from the scope of the struaure-function prong of the drug and device defmitions would be inconsistent with the plain meaning of the Act, its le~iative history, case law interpreting the structure-function prong, and ~ Agency's past applications of that provision. The Agency's conclusions are summamed in section I.A., followed by a detailed discussion of the comments and the Agency's responses them m seaion LB. A. THE PHARMACOLOGICAL EFFECTS OF THE NICOTINE IN CIGARETTES AND SMOKELESS TOBACCO ON THE BODY ARE SIGNIFICANT Cigaretw.s and smokele~ss tobacco contain nicotine., an addictive and pharmacologically active drug. See section ILA., b~low. Nioo~ine i~ the active ing~dicnt in sev~'al produ~s r~gula~l as ~ by ~he Agency, including nicotine tmnsdcrmal pathos, nicotine chewing gums, nicotin~ na~al spray, and Fav¢~, a hollow pape~mb¢ wi~h aicotme imprvgna~ m the mouthpiece. ~ee Jurigti~onal Amly~i~,i60 FR 41482, ~1549- ~1550. The effeas of the nicotine in cigar~a~ and snmk~less those exerted by the ni " " ' g produ~s already ~gula~i by ~he Agency," Nicotine in ¢igarvt~ and smokvle~ ~obaccv produ¢~ si~ant phammcoiogical effects on the human body. FL~St, nicvfin~ causes and susmin~ addiction. ~ Nicoune-use cessation pmduc~s a~ discussed in section II.A.5., below. 282207224 PRODUCED FROH B&W WEB SITE 44~66 Federal ge~/ster / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations that lea.d to addiction to nicotine in cigarettes and smoke]ess tobacco are similar Io those that lead to addiction to products such as morphine and opium. See section ILA.2., below. Like other addictive substances, nicotine in cigarettes and smokeless tobacco achieves its addictive effects by exerting psychoactive, or mood-altering, effects on the brain and by producing chemical reactions in the brain that motivate repeated, compulsive use of the substance. See section II.A.3., below. These pharmacological effects create dependence in the user. Id. In addition to creating and sustaining addiction, ci~ and smokeless tobacco produce other significant pharmacological effects. For example, under some circumstances, nicotine in cigarettes and smokeless tobacco has a sedating or tranquilizing effect on mood and brain activity. See section II.A.4., below. Under other circumstances, nicotine in cigarettes and smokeless tobacco has a stimulant or arousal-increasing effect on the body. ld. Nicotine in cigarettes and smokeless tobacco also controls body weight, ld. Clinical and animal studies indicate that nicotine adminiswation causes weight loss and that cessation of nicotine administration results in weight gain. ld. These effects on the structure tad function of the body are significant and quintessentially drug-like. They pnxluce immediate pharmacological changes in the function of the brain (depressing or slimulating arousal); they change the physical structure of the body (increased growth of nicotine receptors in the brain, weight loss); and they cause drug dependence (addiction). id. 10 282207225 PRODUCED FROM B&W WEB SITE FederRl Register / Vol. 61. No. 168 / Wednesday. August 28, 1996 1 Rules and Regulations 446b'7 I.A. The tobacco industry comments argue that "r~mote" or "insignificant" pharmacological effects are not subject to FDA jurisdiction. Although "¢tcnmt¢ physical effect[s] upon the body" may not be covered by the structure-function provision, see E.R. Squibb & Son.s, Inc. v. Bowen, 870 F.2d 678, 682 (D.C. Cix. 1989), the pharmacological effects of cigarettes.and smokeless tobacco are not "'remote" or insignificant. Indeed, they arc powerful and intmediate pharmacological effects that are not qualitatively or quantitatively different from the effects of other drugs subject to FDA jurisdiction. In fac~, the effects of cigarettes and smokeless tobacr.~addiction" sedation, stimulation, and weight loss---are precisely the types of effects the Agency traditionally .rcguhtcs. It is well established that the Agency has the authority to regulate, ~nd has regulated, products that sedate, tranquilize, or reduce anxiety (e.g., Valium and other benzcxiiazcpines); products that stimulate or restore menutl alermess (e.g., caffeine- contaimng pills such as NoDoz, see Stimulant Drug Products for Over-the-Counter Human Use, Final Monograph, 53 FR 6100 (February 29, 1988); 21 CFR Pan 3#,0);2 produc~s that cause weight loss (see Weight Control Products for Over-the-Counter Human Use, Certain Active Ingredients, 56 FR 37792 (August 8, 1991); 21 CFR 3 I0.545(a)(20); see also United S~aces v. 35,# Bulk Cartons... Trim Reducing-Aid Cigarettes, 178 F. Supp. 847, 851 (D.N.J. 1959)); and products that are used for maintenance treatment of addiction (e.g., methadone and other "namotic drugs [used] in the medical treatmcnt of narcotic addiction," 21 CFR 291.501). The approved uses of these products include uses to "affect the structure or any function of the body" under ~ A more detailed discussion of ~hc Agency's regulation of caffeil~c alld caffeine.conttinmg products is contained in secti~ I.B., below. ll 282207226 PRODUCED FROH B&W WEB SITE 44668 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and R~tations I.A. section 201(g)(IXC) of the Act. Thus, cigarettes and smokeless tobacco have the same effects as products that are undeniably within FDA's jurisdiction. IndcecL internal tobacco comlmny docunmnts reveal ttmt totmcco scientists understand that the nicotine in tobacco produces pharmacological cf[e~s no different fi'om those produced by approved drugs, These indus~y scientists viewed prescription drugs as competing products3 Over throe decades ago, the British American Tobacco Company (BATCO), the parent of Brown & Wiiliamson Tobacco Cot~poration. commissioned a study to compare the effects of nicotine with those of mmquilizers, "which might supersede tobacco habits in the near future3'~ The study concluded that nicotine was "more beneficial or less noxio~ the new tranquilizers" because it reduced stress and regulated weight_* Philip Morris and R.J. Reynolds Tobacco Company (ILIR) also have repeatedly compared the effects of nicotine from tobacco to the effects of drugs regulated by FDA. For example, Philip Morris researchers and officials have conoluded that smokers use cigarettes as "a narcotic., tranquilizer, o¢ sedative''¢ and that "[nicotine] is a physiologically active, nitrogen containing subsmnoe. $'unf/ar organic chemicals include ... quinine, * These docummts, and the cotdmiom the Agency has drawn from the~ ate deucribed in detail in sm II.C. and ll.D., below. ~ Har, elb~.h CH, Liben O. Final Repo~ on Proje:~ HIPPO II (Genev." Battelle Memmial Imtilme, Intenmfional Division. Mar. 1963), at 1. See AR (VoL 64 R~. 321). sial. at2. v LMow A, Why People Start to Smoka (Jtm 2, 19"/6), in 141 Cong. Rec. H7664 (daily ed. Jul. 25, 1995). See AR (VoL 14 Ref. 175a). 12 282207227 PRODUCED FROH B&W WEB SITE Federa/_l~e~ister /, ,V°l' 61., No. 16,8 ~ Wedne~daT.. -Au, sust_ -28. 1996,/ Ru|es andRegulations',, 44669- I.A. cocalne, atropine and morphine. While each of these substances can be used to affect human physiology, nicotine has a particularly broad range of influence. Similarly, PUR scientists have reported that smokers who inhale lightly appear to use tobacco to achieve "mental activation and performance enhancement" whereas those who inhale more deeply show brain effects that "may reflect the anxiolytic properties of benzodiazepines,''11 prescription drugs used to alleviate anxiety. Another KIR researcher has stated: [I]n different situations and at different dos~ levels, nicotine appears to act as a stimulant, depressant, tranquilizer, psychic energizer, appetite reducer, an~i- fatigue agent, or energizer.... Therefore, in addition to competing withproducts of the tobacco induSt~, our products may, in a sense, compete with a variety of other products with certain types of drug action,s" Thus, the industry's own documents acknowledge that the pharmacological effects of their products are the same as the effects the Agency has considered to be sffuctute- function effects within the meaning of section 201(g)(1XC). Notwithstanding the views of their own scicmists, the tobacco indusu'y comments publicly assert that cigarettes and smokeless tobacco do not affect the structure or any function of the body within the meaning of the Act because their effects axe too "remote" or not therapeutic or beneficial. The ramifications of the tobacco industry's position are far-reaching. If the Agency were to determine that the pharmacological effects of cigarettes and smokeless t~o Philip Morris Inc., Draft Repoll Regarding a Proposal for a "Safer" Cigarette, Code-named Table (emphasi~ added). See AR (VoL 531 Ref. 122). ~ Pritchard WS, R.J. Reynolds Tobacco Co., Elecuoencephalographic effecls of cigaretle smoking, l~.sychopharnu~cology 1991;I04:485, at 488. See AR (Vol. 3 Ref. 23-2). 12 Tea~ue CK l~J. Reynolds Tobaoco Co., Research Planmng M~norandum on ~h~ Nat-re of the Tobacco B,~sin~ss and the Crucial Role of Nicotine Therein (Apr. 14, 1972), at I-2 (emphasis added). See AR (VoL 531 Ref. 125). 13 282207228 PRODUCED FROH B&W WEB SITE 44670 F~derM Ragi~er / Vok 61, No. 168 / Wednesday, August 28. 1995 / Rules and Regulations ].B. tobacco are not effects on the structure and function of the body, or are not significant effects, the Agency's authority to regulate other products with like phamaacological effects--sedation, stimulation, weight loss, and satisfaction of addiction--would be called into question. Under the industry's characterization of the effects of their products, even if the pharmacological effects of sedation, stimulation, weight loss, or satisfaction of addiction were expressly promoted or otherwise intended, products producing the same effects could not be regulated under section 201(g)(1)(C) or 201(h)(3) because, by the industry's definition, these products would not "affect the structure or any function of the body." This view, if accepted, could undermine the Agency's ability to regulate drugs and devices that are not used in the diagnosis or treatment of disease, but significantly affect the structure or any function of the body. Further, such an interpretation would be inconsistent with over 50 years of Agency practice since passage of the Act in 1938. In sum, cigarettes and smokeless tobacco do affect the structure and function of the body within the meaning of the Act. The pharmacological effects of nicotine- containing tobacco products are significant and the same as the effects of other products traditionally regulated by FDA. Because these effects are "'intended" within the meaning of the Act---the issue discussed in section IL, below.--ciprettes and smokeless tobacco fall within the jurisdiction of the Agency under the Act. B. RESPONSE TO COMMENTS I. As noted in section I.A., above, tobacco industry comments and others argue that the effects of nicotine delivered from cigarettes and smokeless tobacco am too remote or insignificant to be subject to the Act. These corrtments minimize nicotine's 14 ,.,,) 282207229 PRODUCED FROH B&W WEB SITE Federa] Re~ster / Vol. 61, No.. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44671 I.B. effects and argue that nicotine-containing • o~ of p~u~ ~ ~A's~on.~ ~e ~dus~ ~e~ ~e the ~ency to follow ~e hold~g of ~C v. ~gget~ • ~ver~ ~o~co Co., 1~ F. $upp. 573 (8.D~.Y. 1952), a~d, 203 F.2B 955 (1953), whe~ of ci~aes do not ~t ~e s~ct~ ~d fun~on of ~e ~y. ~A d~g~ ~ ~e ~en~. ~ ~ ~licr m ~ ~on, nicene's eff~ on ~e s~ ~d f~efion of ~ ~y ~ ~m~ble ~ in q~ty and q~ntity to ~e of ~nq~, s~uhnm, ~ight ~n~l p~u~ and p~u~ for long-te~ ~te~ of ~i~on. eff~ on the s~ or ~n of~e ~y ~t addition, the Aa's le~hve ~o~ ~d ~ ~w ~~g ~e ~ pm~e ~ple sup~n for ~e ~nelmion ~t ~e's eff~ ~ si~Wx~t md ~ ~e s~ of~e Act. While "remora ph~i~ eff~[s] on Act's j~sdiction, see Squibb, 870 F.~ at 682, ~e p~u~ si~ 9~1o~ ~ physiolo~ • ~e eff~ cl~ly f~l wi~ ~om ~I(~I~C) ~ ~l(h~3). ~e ~ ~ve held ~t eff~ on ~e s~ or fun~on of~e ~y and ~ wi~ ~A's j~i~on. t~ Joint Comments of the Smokeless Tolmoeo Mallufaclm, e~, Comazent (Jan. 2, 1996k at 241. 8e¢ AR (Vol. 526 R~. 95). Joint Comments of the Cisarette Manufacttwe~, Comment (Jan. 2, 1996), vol. II, at 65-66. See AR (Vol. 535 Ref. 96). 15 282207230 PRODUCED FROH B&W WEB SITE Federal Resider / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations I.g. Products whose effects have been found sufficient to fall within the scope of sections 201(g)(1)(c) and 201(hX3) include those for temtxa'ary smoothing of wrinkles, United States v ...."/~ne Away. Temporary Wrinkle Smoother," 284 F. Supp. 107 (D. Del. 1968), a~/'d, 415 F.2d 369 (3d Cir. 1969); United States ~. . . . "Sudden Change," 409 F.2d 734 (2d Cir. 1969); and produc~s that deliver low levels of oxygen for recreational use to enhance athletic performance, United States v.... "Sports Oxysen," Cir. No. 89- 2085 (D.N.J. Oct. 27, 1992), reprinted in Federal Food, Drug, and Cosmetic Act: A Judicial Record, 1991-92, 110-119. These effects are plainly less significant than the potent psychoactive, addictive, and weight-regulating effects of nicotine. Weight loss is one of the effects of cigarettes and smokeless tobacco. See section II.A.4., below. Courts have held that this type of effect alone is sufficient to make cigarettes a drug when the product is "intended to affect the structure and functions of the human body by... achieving a ~uction in the body's weight." United States ~. 354 Bulk Cartons... "Trim Reducing-Aid Cigarettes," 178 F. Supp. 84"/, 851 (D.NJ. 1959). Similarly, the legislative history of section 201(gX1XC) also demonstrates that weight loss alone is an effect on the suucture and function of the body within the meaning of the Act. Indeed, one of the principal t~asons cited by Congn:ss for broadening the definition of"druf"to include products that affect the structure or function of the body was to bring weight control products within FDA's jurisdiction. See 78 Cong. Rec. 8960, 7"3d Cong., 2d Sess. (May 16, 1934) (statement of Senator Copetand), reprinted in A Legislative History. of the Federal Food, Drag, and Cosmetic Act and Its Amendments (hereinlff~r Legislative History), vol. 2, at 831. 16 282207231 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 4467"3 ].B. The Agency disagrees that the effects of nicotine in cigarettes and smokeless tobacco are comparable to those produced by hammocks, gardening tools, or other similar articles. First. such articles do not introduce chemical ingredients into the body. By contrast, cigarettes and smokeless tobacco deliver a potent chemical ingredient, nicotine, whose significant pharmacological effects on the human body are widely recognized in the scientific community. Second, the powerful psychoactive effects produced by nicotine in cigarettes and smokeless tobacco are comparable to those produced by tranquilizers, stimulants, weight management agents, and drugs used for long-term maintenance of addiction, all of which are indisputably within FDA's jurisdiction. Third, as described in section I.A., above, tobacco industry officials have acknowledged that nicotine's effects are comparable to those of prescription drug products. FDA also disagrees that the 1952 decision, Liggett & Myers, 108 F. Supp. 573, represents a controllin~ determination that cigarettes do not affect the structure or function of the body within the Act's meaning. Much less was known about the addictive, psychoactive, and weight-regulating effoets of nicotine when the court decided Liggett in 1952 than is known today. The kinds of effects that were alleged in Liggett (lack of irritation to the respiratory system and "soothing" eff~s) are far diffe, mm from the addicting and other psychoactive and weight-regulating cffoets now known to be caused by nicotine in cigarettes. See sections II.A.1. and IV., below. Moreover, Liggett was decided before FDA regulated nicotine. The Agency now rogulates nicotine-containing products such as nicotine transdermal patches and nicotine nasal spray intended to treat nicotine addiction. If nicotine were not a powerful pharmacological agent with addictive 17 282207232 PRODUCED FROH B&W WEB SITE 44674 F~ler=l Register / Vol. 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations ].B. properties, nicotine cessation products would be unnecessary. Further, the Liggett opinion does not suggest that the definition of "drug" would preclude treating cigarettes as drugs if new evidence concerning cigarettes' effects became known. See section IV., below. Accordingly, FDA concludes that nicotine's significant pharmacological effects are effects on the structure or function of the body within the Act's meaning. 2. Tobacco industry comments contend that Congress intended to limit the drugs and devices covered by sections 201(g)(l)(C) and 201(hX3) (products "intended to affect the structure or any function of the body") to products with "therapeutic" or "'medical" uses. One industry comment further elaborates that the structure-function provision was added to the Federal Foo& Drug, and Cosmetic Act in 1938 only as a result of concern that certain "therapeutic" products used for weight management purposes had. escaped regulation under the 1906 Pure Food and Drug Act because obesity and leanness were not considered to be diseases. Consequently, this commem argues, the structure- function provision encompasses only products intended for "therapeutic" or "medical" use in "disease-treatment" conditions,j~ This industry comment also makes a related m'gttment that effects on the mucmre or function of the body must be "beneficial," or"drug-lil~" and not "destructive or toxic." According to this comment, "'FDA views 'addictivcness' as an undesirable characteristic, not as a beneficial ¢ffe~ and therefore more as a form of toxicity."~ This Joint Comments of ~e S mokeless Tobacco Manufacturers, Comment (Jan. 2, 1996), at 145-146. See AR (Vol. 526 Ref. 95). ~5 Id. at 151. 18 282207233 PRODUCED FROH B&W WEB SITE Federal ReSister / Vol. 61, No. 168 / Wednesday, August 28, 1906 / Rules and Resulations 44675 |.B. comment argues that the effects of cigarettes and smokeless tobacco are therefore outside the scope of the Act. Conversely, one public interest group comment argues that construing sections 201(g)(1)(C) and 201(hX3) as requiring a "therapeutic" effect would make these sections redundant of sections 201 (gXI)(B) and 201(h)(2), which clef-me drugs and devices as products "intended for use m the diagnosis, cure, mitigation, treatment, or pnevention of disease." According to this comment, such an imerpretation would violate basic rules of statutory construction. The Agency disagrees with the tobacco industry' s narrow reading of the structure- function provision. Neither the language of the statute, its legislative history, nor the case law supports the position that drugs and devices must have "therapeutic," "medicaL" or "'beneficial" effects .or purposes in order to "affect the structure or any function of the body." The plain language of the statute provides no support for the tobacco mdustry's position. The terms, "therapeutic," "medical," and "beneficial," or words of similar import, do not appear anywher~ in section 201(gX1XC) or 201(hX3). FDA agr~s wi~ the comments that assert that construing the "structure or any function" language to require a therapeutic or modical effect would make these provisions nsscntially identical in scope and meaning to sections 201(g)(1)(B) and 201(h)(2). To do so would violate the well-accepted principle that "a legislature is presumed to have used no superfluous words." Bailey v. United States, 116 S.Ct. 501,507 (1995). 19 282207234 PRODUCED FROH B&W WEB SITE 44676 Fsdsr~l Register / Vol. 61. No. 168 / Wednesday~ August 28, 1996 / Rules and Regulations The legislative history is also inconsistent with the tobacco industry's position. Congress added sections 201(gX 1XC) and 201(h)(3) to broaden the coverage of the Act to include a "comprehensive class of preparations which were intended to affect the structure or function of the body." "'L/he Away," 28~ F. Supp. at 110 (citations omitted). The Act's legislative history makes clear that Congress intended to expand the Act's jurisdiction, rather than merely "close a loop-hole" in subsection 201(gX1XB). See, e.g., H.R. Rep. No. 2139, 75th Cong., 3d Sess. 2 (1938), reprint~din 6 L~.slative History 301 ("Drugs intended.., for remedying underweight or overweight or for oth~rw/se affecting bodily structure or function are subject to regulation") (emphasis added); see also American Health Productx Co. v. Hayes, 57.4 F. Supp. 1498~ 1506 (S.D.N.Y. 1983) (The smacture-function provision was enacted to "reach those products.., which evaded regulation altogether because they were neither foods nor therapeutic agent~") (emphasis added). The inclusive nature of the strucuxre-function provision was raised several times during the heanngs that led to enactment of the 1938 Act. See Hearings on $. 1944, Serrate Subcomra. of th~ Comm. on Commerce, 73d Cong., 2d Sess. 1:5 (1933), reprinted in 1 Legislative History 107 ('~he definition of the ~ "drug' has been widened"); Hearing~ on S. 2800, Senme Comm. on Commerce, 73d Cong., 2d Sess. 516 (1934), reprinted in 2 Legislative History 519 ("This definition of 'drugs' is all-inclusive',); Hearings on 5. 5. Senate Comn~ on Commerce, 7*)th Cong., 1st Sess. 352 (1935). reprinted in 3 Legislative History 5~6 ("There is a unive~al recognition that the definition of the term 'drug' in the third subdivision is inclusive"). Congress consistently rejected 20 282207235 PRODUCED FROH B&W WEB SITE Federal Re~ister / VoL 61:~bio. 168 / Wednesday~,Aug~st 28, 1996 ./ Rules ~ ,Re~tlst~ons 44677- suggestions to limit the drug definition to products with medical or medicinal purposes. See, e.g., Hearings on S. 2800. Senate Comm. on Commerce, 73d Cong., 2d Sess. 515- 516 (193~,), reprinted in 2 Legislative History 518-519. Judicial decisions and Agency practice also conflict with the narrow interpretation urgedby the manufacturers. As the Supreme Court has stated: Viewing the structure, the legislative history, and the remedial nature of the Act .... it [is] plain that Congress intended to define "drug" far more broadly than does the medical profession .... •.. the word "drug" is a term of art for the purposes of the Act, encompassing far more than the strict medical definition of that word. If Congress had intended to limit the statutory definition to the medical one, it could have so stated explicitly. United States v. An Article of Drug... . Bacto-Unidist¢, 394 U.S. 784, 793 (1969). The gtructure-function provision has been applied since 1938 to a wide assortmem of products with a range of uses and effects, many of which cannot be considered "'therapeutic." For example, products that have been found to be within this provision include those with cosmetic, recreational, economic, or other nontherapeutic purlx)ses. These products include tanning booths; sunscreens; breast implants; injectable collagen; birth control pills; products purporting to remove wrinkles temporarily, e.g., "L/ne Away," "Sudden Change"; products intended to eliminate pet odors, e.g., United States v. Undetermined Quantities... "Pets Smellfree," 22 F.3d 235, 2dO (10th Cir. 1994); products intended to grow hair, e.g., United States v. Kasz Enterprises, Inc., 855 F. Supp. 534, 5,~O (D.R.I.), modifiedon other grounds, 862 F. Supp. 717 (D.R.I. 1994); products intended as aphrodisiacs, see 54 FR 28780 (July 7, 1989), 21 CFR 310.528; products intended to enhance athletic performance by delivering a low, non-therapeutic level of 21 282207236 PRODUCED FROH B&W WEB SITE 44678 Federal Register / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations |.B. oxygen, e.g.. "'Sports Oxygen"; and veterinary, products intended to increase milk production, e.g., United States v. Pro-Ag, inc.. 796 F, Supp. 1219 (D, Minn, 1991), aff'd, 968 F.2d 681 (8th Cir. 1992). In the case of tanning booths, the Agency considers the product to be a "device" intended to affect the structure or any function of the body despite the fact that the American Academy of Dermatology considers tanning booths to be a potcmi~l health hazard and discourages their use)6 FDA even regulates veterinary products intended to induce death in animals by humane means---an intended use that is indisputably not therapeutic. See United States v. Articles of Drug... . "Beuthanasia-D Regular," Cir. No. 77-0-39~ (D. Neb. August 1, 1979), reprinted in Federal Food, Drug, and Cosmetic Act." A Judicial Record, 1978-80, 83-89. The nature of a product's effect on the structure or function of the body-- therapeutic or non-therapeutic, beneficial or adverseDthus does not determine FDA's jurisdiction. The relevant inquiry is simply whether a product has an effect on the s~ucture or any function of the body. Cigarettes and smokeless tobacco do have such effects and, moreover, the effects ate achieved through pharmacological means. The tobacco industry comments admit that products with "drag-type characteristics" (i.e., pharmacological action) are within the Act's jurisdiction. ~ Photobioiogy Task Fo¢c¢ of the American Academy of Dermatology, ~ a~d l~me/'~Is from high- intensity ulh-aviolet A .stmrces used for cosmetic pro, poses: special report, Journal of the An~rican Academy of Dermatology 1985;12:380-381. See AR (VoL 711 ReL 17). 22 282207237 PRODUCED FROM B&W WEB SITE Federal Re~ister / Vol. 61. N~. 168 / Wednesday, August 28, 1996 / Rules and Regulations. 4.4679 The argument that a product's effects must be therapeutic or medical is also inconsistent with FDA's assertion of jurisdiction over products with cosmetic, recreational and economic uses. Notably, the comments that contend that effects on the structure or'function of the body must be therapeutic or medical and also beneficial do not claim that FDA incorrectly applied the structure-function provision to products with cosmetic, nxa'cational, or economic uses. Instead, these comments aue.mpt to avoid the inconsistency between their arguments and these precedents by expansively interpreting "therapeutic" and "medical" to encompass products with cosmetic, recreational, economic, and other apparently non-thexapeutic purposes or effects. Moreover, these comments do not provide any rationale to support the position that products regulating weight are subject to the Act, but that nicotine-containing cigarettes and smokeless tobacco, which also affect weight regulation, are not. Ins~.ad, the comments assert that the weight control effects of cigarettes and smokeless tobacco are too minor to be subject to the Act's jurisdiction. This argument is refuted in section H.A.4., below. The Agency rejects the legal premise that effeas on the structure or function of the body must be therapeutic or beneficial. However, even if the Agency we~ to accept the manufacturers' legal premise, this would nc¢ change the Agency's decision with respect to cigarettes and smokeless tobacco. As noted previously, cigarettes and smokeless tobacco produce pharmacological effects on the structure and function of th~ body that are indistinguishable from the effects of a wide range of products regulated by FDA, including sedation, stimulation, weight loss, and sustaining addiction. These pharmacological effects are as "therapeutic" or "beneficial" as many effects currently regulated under the 23 282207238 PRODUCED FROH B&W WEB SITE Federal Register / Vo|. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regu|ations Act, and would be sufficient to satisfy a requirement that produc~s regulated as drug delivery devices have beneficial or therapeutic effects. Tobacco iadustry scientists have themselves argued that tobacco products provide "ne~led psychological benefits (increcsed mental al~rmess; aaxiety t~luction,coping with strew)"~ and that "'nicotine is a very remarkable beneficent d~ug.''n Indeed, if a new product with the powerful phanmcological effects of ciga~ttes and smoimless tobacco---sedation, stimulation, weight loss, and suslaining addictio~m suddenly began to be distributed in the United States, there would be no question that the product would be subject ~o resulafion under the Act because it "affect{s] the stmctme or a~y function of the body" wid~ the Act's meaning. For example, the Agency has regulated ffamma hydroxybuu-a~e and gamma hydroxybut3¢ic acid (collectively, GI-[B), a product intended to affect the slracture or function of the body by promoting weight loss and muscle gain. The product is also used as a relaxant and sleep aid. GHB emerged as a steroid alternative after a~abolic s~'oids became conu'olled subs~ces. Very li~e was known about the produa when GI-[B first en~red the market because it was manufactured in clandestine laboratories (e.g, base, merits and kitchens), obtaimd f~om other black market sources, and usually dislriboted at health and sporting stores and clubs withom labeling. The use of GHB as a steroid alternative and body-building aid is not "therapeutic"; nonetheless, Lhe Agency successfully undertook regulawry ac~ons against 'v Robinson JH, Prichard WS, The role of eicotme i~ tobacco use, Po~imptum, u~otog,~ 1992:108:397- 40", at 398. See AR (VoL 66 Rcf. 31-1). Ellis C, Science Advisor ta the BATCO Board. The Smoking and Health Problem, preseated at the BATCO Research Cortfe~nce, Southampton, England (1962). at 15. See ,euR (VoL 15 Ref. |90). 24 282207239 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44681 GHB pursuant to the Act's drug authorities. See United States v. Wood, Nos. 92-50512, 92-50514 (9th .Cir. Oct. 21, 1993); 58 FR 33690, 33699 (Jun. 18, 1993); IDA Quarterly Activities Report, First Quarter, FY 1991 (Oct.-Dec. 1990). 3. One comment contends that the structure-function provision is limited to • products that "purport to change the physical structure of the body.m~ The Agency disagrees. Although the provision covers pr6ducts that change a structure or function of the body, it is not limited to such effects. Courts have rejected the view that section 201(g)(l)(C) requires an actual "change [m] the physical structure or function of the [ ] body." "'Pets Smellfree, "' 22 F.3d at 237. Moreover, cigarettes and smokeless tobacco do in fact change the physical structure of the body by, for example, affecting brain chemistry and electrical activity in the brain, reducing weight, and increasing the growth of nicotine receptors in the central nervous system. 4. One comment asserts that the structure-function provision "is not intended • to authorize the regulation of products solely because FDA believes their use is and undesirable.''~° The Agency agrees. However, if a particular product meets the statutory definition of drug or device, the fact that it is also associamd with harms to health is a reasonable consideration t~or the Agency in de~iding to regutate the product. The Act's legislative history supports this view. As noted, concern about weight loss products that escaped regulation m the 1906 Pure Food and Drug Act was an impetus for ~* Joint Comments of tl~ Cigarette Manufactm~s, Comn~t (Jan 2, 1996k voL I1, at 83 (~mphasis added). See AR (Vol. 535 Ref. 96). Joint Comments of the Smokeless Tobacco Manufacturers, Comment (Jan. 2, 1996), at 152. See AR (Vol. 526 Ref. 95). 25 282207240 PRODUCED FROH B&W WEB SITE 44682 Fmieral Register / Vol. 61, No, 168 / Wednesday, August 28. 1996 / Rules and Regulations I.B. broadening the definition of "'drug" to include products that affect the structur~ or function of the body. Congress was concerned not so much with the weight-reduction effects of weight loss products but with the serious and undesirable ~ to headth that resulted from their use. See, e.g., Hearing on H.R. 6906, H.R. 8805, H.R. 8941, and $. 5 Before a Subcomm. of the House Com~ on intersra~e and Foreign Commerce, 74th Cong., 1st Sess. 55 (1935) (statement of FDA Chief Walter CamlYoell), reprinted in 4 Legislative History 370. 5. Some comments s~ate that FDA's determination that cigarettes and smokeless tobacco are "drugs" and "devices" would obligate the Agency to regulate caffeine and caffeine-containing products as drugs or drug delivery devices. These comments assert that for this reason the Agency should not regulate tobacco products as drugs or devices. The Agency disagrees that a comparison to caffeine provides a reason not to regulate nicotine-containing cigarettes and smokeless tobacco. Caffeine is the active ingredient in several products ~egulated as drugs by the Agency. For instance,.caffeine is the active ingredient in NoDoz, an over-the-counter stimulant that is regulated for its effects on the sn'ucture and function of the body. Caffeine is also an ingredient in internal analgesics and menstrual discomfort relief products. Although these products are regulated as drugs, the effeas of these caffeine- containing products on the structure and function of the body are significantly less than those of nicotine. See section rl A.3.c.i., below. For instance, unlike nicotine, caffeine is not recognized at this time as an addictive drug by health organizations such as the 282207241 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44683 I.B. American Psychiatric Association or the World Health Organization. Indeed, even an internal Philip Morns report comparing smoking and caffeine found that nicotine has a stronger stimulant effect than caffeine and that the stimulant effects of caffeine are "more like those of... placebo" than of nicotine.21 The implication for nicotine-containing cigarettes and smokeless tobacco is clear:, if caffeine in products such as NoDoz "affect[s] the structure or any function of the body within the meaning of the Act," then afortiori mcotine-contaming cigarettes and smokeless tobacco "affect the structure or any function of the body" as well. Caffeine naturally occurs in coffee, tea, and other foods, and is used as an ingredient in soft drinks. The Act defines "food" as "articles used for food or drink for man or other animals." See section 201 (0(I) of the Act, 21 U.S.C. 321 (0( 1 ). The statutory definition "includes articles used by people in the ordinary way most people use food--primarily for taste, aroma, or nutritive value." Nutrilab v. Schweiker, 713 F.2d 335, 338 (Tth Cir. 1983). When caffeine is used in soft drink products in accordance with section z102 of the Act, 21 U.S.C. 342, and when it naturally occurs in other products that are foods, such as coffee, the product is a "food" under section 201(0(1) of the Act, 21 U.S.C. 321 (f)(1), and is explicitly excepted from the definition of drug in section 201(g)(I)(C), 21 U.S.C. 321(gXIXC) ("articles, other than food, intended to affect the structure or any function of the body") (emphasis added). The Agency's treatment of caffeine in beverages consequently has no bearing on how cigarettes and smokeless tobacco should be regulated. z~ Memons~'~um h'om Schon TR to Dunn WL, Smol6ng and Caffeine: A Comparison of Physiological Arousal Effects (May 17, 1972), at 1-2. See AR (Vol. 15 Ref. 189-7). 27 282207242 PRODUCED FROH B&W WEB SITE 44684 Fmleral Rt~ister / Vo|. 61. No. 168 / Wednesday, August 28, 1998 / Rules and Regulalions I.B. 6. Several comments assert that if FDA regulates nicotine-containing cigarettes and smokeless tobacco, it must also regulate the nicotine that occurs naturally in food products such as tomatoes, potatoes, eggplant, and cauliflower. The Agency. disagrees. As noted above in response 5, section 201(gXIXC) specifically excludes from its coverage products that arc "foods" under the Act. Tomatoes, potatoes, cggplanL and cauliflower are "foods" within the meaning of the Act because they are "articles used for food.., for man." See section 201(f)(1),.21 U.S.C. 321(f)(I). While these vegetables do contain trace amounts of nicotine, a person would have to consume 206 pounds of tomatoes, 309 pounds of potatoes, 22 pounds of eggplant, or 355 pounds of cauliflower to obtain the same amount of nicotine as in one cigarette.:2 Thus, these products are appropriately regulated as foods. 7. Some comments question whether applying the structure-function provision to nicotine-containing cigarettes and smokeless tobacco might provide precedent for applying the provision to a wide range of products that have effects on the structure or function of the bodymincluding guns and other weapons, products that prevent injury, such as airbags, and chemical sprays used for self-defense or law enforcement purposes. The Agency has never comtrued the su'ucture-function provision to include products such as guns, airbags, and chemical sprays, and applying the structure-function provision to nicotine-delivering tobacco products will not provide any precedent for doing :: Cttart Y. p~pared in conjunction with the t~stimony of David Kessler before the Subcommittee on Health and the Envimnmem, Committee on Eaergy and Commerce, U,S. House of Rclatsentatives (Mar. 25. 199g). See AR (Vol. 296 Ref. 4175)~ 282207243 PRODUCED FROM B&W WEB SITE Federal. Register / Vo]. 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44685 I.B. so. Moreover, there are fondamentat distinctions between these products and nicotine- delivering tobacco products. Cigarettes deliver a pharmacologically active dose of the drug nicotine to the body through inhalation. Smokeless tobacco delivers a pharmacologically active dose of the same drug through buccal absorption. Collectively, tobacco products achieve their effects on the structure and function of the body through nicotine's pharmacological effects. These include sedation, sth-nulation, weight control, and maintenance of addiction. Tobacco products are thus indistinguishable from products that the Agency has traditionally regulated as drugs and devices. In contrast, guns, aifoags, and chemical sprays are markedly different and distinguishable from such products. 29 282207244 PRODUCED FROM B&W WEB SITE 44688 F~der~d R~gister / Vol. 61. No. 168 / Wednesday, August 28. 1996 / Rules and Regulations II. I1. CIGARETTES AND SMOKELESS TOBACCO ARE "INTENDED" TO AFFECT THE STRUCTURE AND FUNCTION OF THE BODY WITHIN THE MEANING OF THE ACT . ~ Clgaxettes and smokeless tobacco clearly "affect the s~.ructure or any function of the body." The principal issue before the Food and Drug Administration (FT)A) is thus whether these effects are "intended" within the meaning of the Federal Food, Drug, and Cosmetic Act (the Act). The Aa's drug and device definitions provide in pertinem part that an article is a drug or device if it is "intended to affect the structure or any function of the body." Sections 201(gX 1 )(C) and 201(hX3), 21 U.S.C. 32 l(g)( l XC) and (hX3) (emphasis added). In determining whether an article is "'intended" to affect the structure or function of the body, "the FDA is not bound by the manufacturer's subjective claims of intent," but rather can fred actual intent "on the basis of objective evidence." National Nutritional Foods Ass'n (NNFA) v. Mathews, 557 F.2d 325,334 (2d Cir. 1977). That is, the Agency determines the intent of the manufacturers objectively by evaluating all of the relevant evidence in the record from the perspective of a reasonable fact finder. See 21 CFR 201.128, 801.4. In determining intended use, the Agency may "examine a wide range of evidence." United States v. Two Plastic Drums... Black Currant Oil, 761 F. Supp. 70, 72 (C. D. 111. 1991), aft'd, 994 F.2d 814 (7th Cir. 1993). In the Jurisdictional Analysis, 60 FR 41453-41797, the Agency determined, based on the evidence then available to it, that cigarettes and smokeless tobacco are "intended" to affect the structur~ and function of the body. This determination was based on thr~ grounds: 30 282207245 PRODUCED FROH B&W WEB SITE Federal Register / Vo|. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44687 II. ( 1 ) The addictive, psychoactive, and other significant pharmacological effects of cigarettes and smokeless tobacco are so widely known and foreseeable that these effects may be deemed to have been intended by the manufacturers, see Jurisdictional Analysis. 60 FR 41483-41490;, (2) Such a large percentage of consumers use cigarettes and smokeless tobacco to satisfy their addiction or to obtain other pharmacological effects that the manufacturers may be deemed to intend that their products will be used for such purpose, s, see Jurisdictional Analysis, 60 FR 41,190-41491; and (3) The statements, research, and actions of the tobacco manufacturers show that the manufacturers actually intend their products to affect thestructure or any function of the body, see Jurisdictional Analysis, 60 FR 41491- zH520. FDA received comments on its findings from the tobacco industry, public health organizations, and other interest groups and members of the public. In this section, the Agency considersl in light of the public comments, the objective evidence in the administrative record relevant to whether cigarette and smokeless tobacco manufacturers intend their products to affect the structure or any function of the body, including new evidence that has become available since the issuance of the Jurisdictional Analysis. The Agency also discusses the legal standa~l for establishing the intended use of cigarettes and smokeless tobacco, and responds to the substantive comments ~ived by the Agency on the evidence and the legal standard. Specifically: • Section II.A. discusses the evidence supporting FDA's finding that it is foreseeable to a reasonable tohaeco manufacturer that the nicotine in cigarettes and smokeless tobacco will cause pharmacological effects and will be used by consumers for those effects and responds to comments on this issue; 31 282207246 PRODUCED FROM B&W WEB SITE 446~8 Federal Register / Vot. 61. No. 168 / Wednesday. August 28, 1996 / Rules and Regulations II. • Section II.B. discusses the evidence supporting FDA's f'mding that consumers use cigarettes and smokeless tobacco predominantly to obtain the pharmacological effects of nicotine and responds to comments on this issue; • Section H.C. discusses the evidence supporting FDA's finding that cigarette manufacturers' statements, research, and actions show that they intend their products to be used for the pharmacological effects of nicotine and responds to comments on this issue; • Section II.D. discusses the evidence supporting FDA's trmding that smokeless tobacco manufacturers' statements, research" and actions show that they intend their products tO be used for the pharmacological effects of nicotine and responds to comments on this issue; • Sections II.E. and F. t~spond to comments, not already addressed in the foregoing se~tious, on the legal standard for evaluating intended use; and • Section II.G. discusses the cumulative evidence of intended use. Except as m~lified below, FDA confirms its prior findings and incorporates them by reference. FDA concludes that the evidence on the f~ility of nicotine's effects, actual consumer use of tobacco for those effects, and evidence of intended use based on indusu'y statements, research, and actions each provides an h~dependent basis for the determination that the manufacttLrers of cigarettes and smokeless tobacco intend their products to affect the stntcture of function of the body. Although the evidence thus provides several independent bases for establishing that cigarettes and smokeless tobacco are intended to affect the structure and function of the body, the Agency also looks at the objective evidence of intent as a whole. The 32 282207247 PRODUCED FROM B&W WEB SITE Federa] Re~ster / Vol. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations 44689 II. Agency finds that, both independently and cumulatively, the evidence of foreseeable pharmacological effects and useg, actual consumer use for pharrnacologieal putq~oses, and manufacturer intent as revealed through the statements, research, and actions of the manufacturers convincingly supports the Agency's determination that cigarettes and smokeless tobacco are intended to affect the structure and function of the body. 33 282207248 PRODUCED FROH B&W WEB SITE 44690 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A. A. A REASONABLE MANUFACTURER WOULD FORESEE THAT CIGARETTES AND SMOKELE&~ TOBACCO.WILL CAUSE ADDICTION AND OTHER PHARMACOLOGICAL EFFECTS AND WILL BE USED BY CONSUMERS FOR PHARMACOLOGICAL PURPOSES FDA may conclude that a product is intended to affect the structure or function of the body if a reasonable person in the position of the rnanufacture~ would foresee that the product will have pharmacological effects and that a substantial proportion of consumers will use the product for those effects. In the Jurisdictional Analysis, the Agency made extensive findings, based on the evidence then available, regarding the pharmacological effects of tobacco on the human body. See Jurisdictional Analysis, 60 FR 41534-41575. FDA received comments on these findings from the tobacco industry, many medical and public health organizations and medical practitioners, and from other members of the pubhc. The administrative record includes extensive, publicly disseminated evidence from scientific studies and expert panels on the subject of tobacco' s pharmacological effects on the human body. After considering the administrative record and reviewing public comments, the Agency finds that the evidence clearly demonstrates that a reasonable tobacco manufacturer would foresee that cigarettes and smokeless tobacco will cause and sustain addiction, produce other psychoactive effects, and control weight and be used by consumers for these effects. This finding provides an independent basis for the Agency' s conclusion that cigarettes and smokeless tobacco are intended to affect the structure and function of the body. 34 282207249 PRODUCED FROH B&W WEB SITE Federal Re~'t¢r / Vo[, 6L No. 168 1 Wednesday, August 28, 1996 1 Rules and Regulations II.A.1. In section U.A.I., below, FDA describes the legal basis for considering evidence of the foreseeabte effects and uses of a product. FDA presents its major findings and responds to significant comments in sections ILA.2. through II.A.6. In section II.A.7., FDA responds to the remaining relevant substantive comments. 1. "Intended Use" May Be Established on the Basks of Foreseeable Pharmacological Effects and Uses The Agency's legal authority to establish intended use based on the foreseeable effects and the foreseeable uses of a product comes from the plain language of the Act, as well as from FDA's regulations, case law, administrative precedent, and the public health purposes of the Act. The plain language of the Act provides that a drug or device is an a~ticle "'intended to affect the structare or any function of the body." Sections 201(g)(1Xc)and 201(h)(3) of the Act, 21 U.S.C. 321(g)(1)(C), 321(h)(3) (emphasis added). It is a widely accepted legal principle that persons can be held to "intend" the reasonably foreseeable consequences of their actions. In 1938, when Congress defined drugs and devices as articles "'intended" to affect the structure or any function of the body of man, it was well established that "[t]he law presumes that every man intends the legitimate consequences of his own acts." Agaew v. United Stales, 165 US. 36, 53 (1897); accord Fanning v. United States, 72 F.2d 929, 932 (4th Cir. 1934) ("the law imputes an intern to accomplish the natural results of one's own act") (citations omitted); Ea.~ra Drug Co. v. Bieriager- Hanauer Co., 8 F.2d 838, 839 (lst Cir. 1925) ("presumption that one intends the natural and probable consequences of his acts"); see also 4 Wigmore on Evidence 3388-3390 44691 35 282207250 PRODU£ED FROH B&W WEB SITE 44692 Federal Re~i~ter / Vo[. 6t. No, 168 / Wednesday, August 28, 1996 / Rules and R~gulations II.A.1. (I 904-1905) (intent is "a volition having consequences which ought reasonably to have been foreseen"), quoted in Rushmore v. Saxon, 158 F. 499, 506 (C.C.S.D.N.Y. 1908). In accordance with this well-accepted legal principle, FDA may establish that a manufacturer "intends" that its product affect the structure or function of the body when it is foreseeable that the product will in fact affect the structure or function of the body m a drug-like manner. The case for establishing intent through foreseeability is especially strong when a reasonable manufacturer would foresee that a product will both act like a drug and be commonly used like a drug. Where it is foreseeable that a product will have pharmacological effects on a significant proportion of consumers and will he used by these consumers to obtain these pharmacological effects, the statute allows FDA to recognize reality and find that the manufacturer "intends" its product to be used as a drug. Consistent with this well-established understanding of "intent," FDA's regulations defining "intended use" contemplate that foreseeability can be a basis for establishing the objective intent of the manufacturer. These regulations require product labeling to include adequate directions for all "intended uses." 21 CFR 201.5 (drugs); 21 CFR 801.5 (devices). The intended uses of a drug or device that must be included on the label are defined to include those that are, or that reasonablycan be, anticipated by the manufacturer. The definition of"intended uses" for drugs establishes an "objective intent" standard. Specifically, the regulations provides: The words "intended use" or words of similar import.., refer to the objec~i.~ve intent of the persons legally responsible for the labeling of drugs. The intent is determined by such persons' expressiom or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, 36 282207251 PRODUCED FROH B&W WEB SITE Ft, dera] Register / Vol. 61. No. 168 / Wednesday, August 28. 1996 / Rules end Regulations 44693 be shown by labeling claims, advertising matler, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is heifer labeled nor advertised: ~ imended uses of an article may change after it has been introduced into interstate commerce by its manufacturer. If, for example, a packer, distributor, or seller intends an article for different uses than those intended by the person from whom he received the drug, such packer, distributor, or seller is required to supply adequate labeling in accordance with the new intended uses. But ira manufacturer knows, or has knowledge of facts that would give him notice, that a ~lrug introduced imo interstate commerce by him is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a drug which accords with such other uses to which the article is to be put. II.A.I. 21 CFR 201.128 (emphasis added). The definition of "intended uses" for devices is essentially identical. 21 CFR 801.4. Thus, under these regulatory provisions, objective intent can be established by evidence showing that the manufacturer "knows" or "has knowl~ge of facts that would give him notice," i.e., that a reasonable manufacturer would foresee that consumers will use a product for drug or device uses)3 Other parts of the regulations also provide that foreseeable pharmacological uses should be considered to be intended by the manufacturer. Section 201.128, for instance, ~STbe Agency disagrees wilh lhe tclacco indusuT's su~esdon ~at tlfis fot~eeabili~y lest m~st be int~pr~ted to apply only to producls lhat ar~ already classified as "drugs" or "devices." 'l'ne Agency regui~y us~ the rcgulalory de~'mitioll of "illte~l~ u~e~" to dell~mine whether products should be classi~ed as drugs or devices. S.e, e.g., United States v. A~icle~ of Dru~, 62~ F.2d 66~, 66~ ~.~ (~h Cir. 1980); United States v. Undetermined Qmantities of An Article or Drug Labeled a~ "IExachol," 716 F. Supp. 787, 791 ($,D.N.Y. 1989); tlnitad States v. 22... dev/ces... "The Ster-o.//zer MD-200." 714 Supp. 1159, 1165 (D. Utah 1989); United Stat~s v. Kas~ Enterprises, 855 W. Stlpp. 534, 539 (D.R.I. 1994), modified on other groonds, 862 E Supp. 717 (D.R.L 199~); UnitedStatex v. Articles of Foodand Drug Consisting of... Apricot~, ~l~ F. $lipp. 266, 27"3 (E.D. Wi$. 1977). Thti~ the ~ ~li~ on tile of objective intent tu the regulation (including the four, ee, tbi~ gtad~ degribed above) to e~ttbli~h: (1) in the case of products atrnady clastdfied as dm~ ~x devi¢~ the intended u$¢~ that mint appcm" on the product labeling; and (2) ia tbe case of products not yet classitr~i as drugs or devices, the int~nd~ uses that determit~ whether the product should be cla~ifted ~$ a drug o¢ device. The Agency's interpretation of its owll ~gulation is l'g~o~bl~ and elltitled to "¢mlurolling ~t~ight." Thomas Jefferson Univ. 114 $. CL 2381, 2386 (1994). 37 282207252 PRODUCED FROH B&W WEB SITE 44694 Federal Re~ister / Vol. 61, No. 168 / Wednesdey, August 28, 1996 / Rules end Regulatmns II.A.I. further provides that "'objective intent.., may be shown by the ci~zumstance that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neilher labeled nor advertised.''24 21 CFR 201.128 (entphasis added). The case law and administrative precedent interpreting the ~ recognize that the foreseeable pharmacological effe~ts and uses of a product are proper grounds for establishing intent. These precedents recogn~e that the Agency may consider evidence of • the likely oansumer use of a product in determining intended use. See, e.g., Two Plastic Drums, 761 F. Supp. at 72; Kasz, 855 F. Supp. at 539. They also recognize that a foreseeable drug effect is generally persuasive evidence that the product is intended to affect the structtu~ and function of the body. For example, the court in United States v. Undetermined Quantities... "Pets Smellfree" found that the presence of chlortetracy¢line, a drug ingredient, at doses sufficient to reduce thelevel of bacteria in animal intestines was evidence that the product was intended to affect the structure and function of the body. 22 F.3d 235, 240 (10th Cir. 1994). 25 Indeed, the court found this evidence to be relevent even though the dose of chlortetr~cycline in the product was "subtherapeutic"---that i~, the dose was suff~ient ta reduce bacteria levels, b~ not to cure promoting the me. The Agoncy does not so imeqget tbe regulation. The ordinary defmkion of the word "offe~" means simply "[t]O pt~ent for acceptance or t~jecfto~ " American Heritage Dictionary of the F.nglish l.zmguage (3d ed. 1992) at 1255. Moteove~ the tobac~ indu~u~'s interaction confli~ with the language in the regulation that provides that the me for which the product is oHe~ed is a use which it is neither labeled hog advert~ed.*' Ctl~i~tellt with the lmxgtlage of the geS~latio~ the interprets the t'equitement that the ptodu~ be "offered" to mean simply that the pt'odu~t be pteu~ted to t~e consume~ for purcha~. 25 See section II.E., below, for tn additional discussion of the t~ievlmt case law and administrative precedent 38 282207253 PRODUCED FROM B&W WEB SITE Federal Re~ister / Vol. 6~, No. 168 / Wednesday, August 28, ~99~ / Rules and Regulations 44695 II.A.1. or treat a disease. Id. Administratively, the Agency has asserted jurisdiction over products such as khat, imitation cocaine, hormone-containing skin ew~arns, and fluoride- containing toothpastes based primarily, if not exclusively, on evidence that these products have foreseeable drug effects and drug uses. See section II.E.l.e., below. Cases interpreting other public health statutes establish a test for determining intended use that is the same as the one used by FDA and that permits reliance on foreseeable uses. In N. Jonas & Co. v. EPA, 666 F.2d 829 (3d Cir. 1981), for example, the court held that a product was "intended for use" as a pesticide under the Federal Insecticide, Fungicide, attd Rodenticide Act (FIFRA) based on its foreseeable consumer use---even though the manufacturer did not promote the product as a pesticide (and even disclaimed use as a pesticide on the label). The court stated: The Act [and] the regulations. -. focus inquiry on the intended use, implicit or expressed. We take this to mean the use which a reasonable consumer would undertake .... In determining intern objectively, the inquiry cannot be restricted to a product's label and to the producer's representations. Industry claims and general public knowledge can make a product pesticidal notwithstanding the lack of express pesticidal claims by the producer itself. ld. at 833 (emphasis added). Similarly, in United States v. Focht, 882 F.2d 55, 60 (3d Cir. 1989), the court held that under the Federal Hazardous Substances Act (FHSA), "[i]ntended use .... objectively defined, necessarily encompasses foreseeability." In this case, the Consumer Product Safety Commission sought to take action against fireworks components that could be assembled to make banned fireworks. The court found that the testimony that 90% of consumers who order the components will use the components to make illegal fireworks "makes it foreseeable that the components in question will be used to build 39 282207254 PRODUCED FROH B&W WEB SITE 44696 FederM R~i~ter / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules ~nd R~zulations II.A.I. banned ftreworks. Such knowledge must be attributed to [the defendants]." ld.; accord United States v. Articles of Banned Hazardous Substances... Baby Rattles, 614 F. Supp. 226 (E.D.N.Y. 1985). The tobacco industry argues that the Agency may not rely on the interpretation of "intended use" in other statutes to interpret "'intended us~" under the Federal Food, Drug, and Cosmetic Act. The fact that FDA's interpretation of "intended use" under the Federal Food, Drug, and Cosmetic Act parallels the interpretation under other public health statutes, however, strongly supports the reasonableness of the Agency's analysis. Indeed, the court in Jonas relied in pan on eases interpreting intended use under the Fedexal Food, Drug, and Cosmetic Act in holding that intended uses encompass readily foreseeable consumer uses, specifically citing National Nutritional Foods Ass'n (NNFA ) v. Mathews, 557 F.2d 325, 334 (2d C~. 1977), for the proposition that "IDA [is] not bound by manufacturer's subjective claims of intent in assessing whether product is intended as a drug," and Bacto-Unidisk, 394 U.S. 784 (1969), for the proposition that "the definition of drug [is] to be given liberal interpretation in light of remedial purpose of Federal Fo~ Drug and Cosmetic Act." 666 F.2d at 833. z6 Moreover, contrary to the tobacco industry's contention, the FI-ISA and FIFRA cannot be distinguished from the Federal Food, Drug, and Cosmetic Act on the ground that foreseeability principles are alien to the Federal Food, Drug, and Cosmetic Act. Several other provisions of the Act contemplate foreseeability prigxiples. See, e.g., 21 2e Similarly, coum interpreting the Federtl F.(x~t, Drag, and Cosmetic Act rely ou interpre~efic~s of analogous consumer IX(lecfioa statics. See. e.8.."Su4~len C&mg,," 409 F.2d 734, 741 1.8 (2d Cir. 1~69) (citilg &cat, e interacting the Fedetl| Tmle Commission Act t~..Imse "the re.medial purpose of the Federal Trade Commissim Act is sulficiently analosou~"). 40 282207255 PRODUCED FROH B&W WEB SITE F~dera] Register / vo]. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44697 II.A.1. U.S.C. 32 l(a) (an article may be misbranded if its labeling and advertising fail to reveal "'consequences which may t~sul[ from.., such conditions of use as are customary or usual"); 21 U.S.C. 360h (FDA authorized to recall devices that "presen[[] an unreasonable risk of substantial harm"). Indeed, in United States v. Park, 421 U.S. 658 (1975), the Supreme Court concluded that the Federal Food, Drug, and Cosmetic Act imposes "requirements of foresight and vigilance" on manufacturers, stating: the Act imposes not only a positive duty to seek out and remedy violations when they occur but also, and primarily, a duty to implement measures that will insure that violations will not occur. The requirements of foresight and vigilance imposed on responsible corporate officials are beyond question demanding, and perhaps onerous, but they are no more stringent than the public has a right to expect of those who voluntarily assume positions of authority in business enterprises whose services and products affect the health and well-being of the public that supports them. ld. at 672 (emphasis added). Compelling policy reasons support the Agency's interpretation that it may establish that a product is intended to affect the structure or function of the body when it is foreseeable that a product will produce significant pharmacological effects in consumers and be widely used by consumers for these effects. The manufacturers' position is that they may ignore overwhelming scientific evidence that their product will have and be used for pharmacological effects so long as they avoid promoting their product for these pharmacological effects. Under this interpretation, however, the manufacturer of virtually any drug or device could avoid regulation under the Act--no matter how substantial and well-established the pharmacological effects and uses of the product--by simply avoiding making certain claims in the product's labeling and advertising. For example, it is not 41 282207256 PRODUCED FROM B&W WEB SITE 448~B Yedertl g.egi.,ler I Vo|. 61, No. lfi~ / Wedaesday, August 28, 1~8 / Rules ~nd Regulations II.A.2. difficult to imagine a manufacturer of a generic version of a drug like Prozac (fluoxetine hydrochloride), an antidepressant drug currently available only by prescription, seeking to avoid FE)A regulation by advertising its product as intended solely for the "pleasure" of its consumers. See section II.F.l.e., below. Accepting the manufacturers' position would leave the public vulnerable to the unregulated distribution of products with imown pharmacologically active ingredients. Moreover, it would reward manufacturers who deny the obvious pharmacological effects and uses of their products in their public statements, labeling, and advertising. Thus, the Agency concludes that the public health objcctivea of the Act require the Agency to regulate as "'drugs" or "devices" products that can be fore.seen to have widespread pharmacological effects and uses. 2. The Signltlcant Pharmacological Effects and Uses of Cigarettes and Smokeless Tobacco Are Foreseeable The evidence in the adrninisuative record e~tablishes that the pharmacological effects and uses of cigarettes and smokeless tobacco are so widespread and well-known that a reasonable manufactmer would foresee them. Since the Agency last considered the issue of whether cigarettes are drugs over 15 years ago, a scientific consensus has emerged that nicotine is addictive and has other significant phamzacological effect. Nicotine~J~e essential ingredient in cigarettes and smokeless tobacco~is a phamm~logical agent that substantially alters the structure and function of the brain and other systems of the body. After a single puff inhaled from a cigarette, nicotine enters the mouth, passes into the lungs, is absorbed from the lungs into the bloodstream, and diffuses 42 282207257 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 446~9 [I.A.2. from the blood into the brain. This process takes about I I seconds.~ When consumed in smokeless tobacco, nicotine is absorbed through the lining of the mouth into the .bloodstream and flows to the brain. Once inside the human brain, nicotine brads to unique receptors on the surfaces of brain cells. Thee nico~mc r~.eptors normally inte, mct with a natthral chemical messenger called acetylcholine, but can also be s~mula~d by ~ico~ine to al~er mood, alertness, and cognition. Exposure to ~coW~e causes the number of nicotinic receptors on the surfaces of brain cells to increase~ and significantly alters the brain's normal electrical and metabolic activity)9 Nicotine's actions on the central nervous sysw, m produce b(xh ~ Dcpamncnt of Health and Human Service, Office on Smoking ~ of Smoking: Nicotine Addiction, a Rel)ort of the Surgeon General OuL 29, 1~), DHHS P~bli(~iml No. (CDC) 88-8~10(5 (W~hingwn I~: GPO, 1988), at 13-14 (hc~inaf~ ciu)d as Surgeon General's Report, 1988). See AR (VoL 129 Bc~owitz NL, Climc~d Pharntaco~ogy of Inhaled Drugs of Ab~e: Implications in Under--rig Nicotia~ D~pen,/en¢e. NIDA Rese~.h Monograph 99 (Kockville MD: N~.ional Instituw ~ Dn~ Abuse, 199~), at 17. $¢e AR (VoL 3 Rcf. 18). 2m Bes~wcll lvflEM, Bailout DJg., Alldc~oo JM, Evick~ that fobacco smoking iocx~5~ ll~ dmsity of (-)-[~H]nicotin¢ binding sites in human bta~ Jo~rnol of Ncuroch~mixtry 1988;.~0:.12(~3-124"/. See AR (Vol. 136 Rcf. 1570). 29 Su~Bcon General's Report, 198g, at 79-123. See AR (Vol. 129 Rcf. 1 $92). 43 282207258 PRODUCED FROH B&W WSB SITE 44700 Federal Re~ister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.2. sedathng and stimulating effects, depending on dose and circumstances.3° Nicotine also plays a role in weight regulation.3' In addition to its sedating and stimulating effects, nicotine causes and sustains addiction. NicoUne dir~dy affects an intrinsic brain system, known as the rne~olimbic sysxem, that signals pleasure and r~ward and modulates emotions. When stimulated by an addictive subs~mce, the mesolimbic system responds by rewarding hhe repeated consumption of the subs~ce,s~ It is widely believed that amp~ine, cocaine, and nicotine all cause the compulsive flrug-s~king behavior of drug addiction through the same mechanism: increasing the activity of the neumtransmi~r dopamine within the mesoLimbic system.~3 s0 Pritghanl WS, C-ilben DG, Duke DW, Flexib~ effects of qu~nt~ed ciga~.~-smoke delivery o~ EEG dimcmsional complexity, Ps'ycl~p~'m~:olos~ 1993;113:95-102. See AR (VoI. 3 Reff. 23-1). Pritchard WS, Elcclroencephalographic effe~s of cigarette smoking, Psychopharmacology 199h 104:485- 490. See AR (VoL 105 Ref. 965). Norton R, Brown K, Howard I~. Smoking, nicotine do~e and the latera]isatio~ of electrocorticaJ activity, Psychopharnmcology 1992; 108:473-479. See AR (Vol 3 Ref. 22). Goldmg JF, Effects of cigagette smoking on resting EEG, ~ evoked pou~tials and photic driving, Pharmacology, Biochemistry and Behavior 1988;29:.23-32. See AR (VoL 3 Rgf. 23-3). Surgeon General's Report, 1988, at 431432. See AR (VoL 129 Ref. 1592). - Pomed~u OF, Pomerk~u CS, Neumt~-~l~,~s ~! ~ t~i~f~c~m~ of smok~g: ~ls a biobehavioral explanation, Ne~roacience and Biobehavioral Reviews 1984;8:503-513. See AR (VoL 3 Ref. 20-1 ). Wise R.A, Rompre PP, Brain 0opmni~ m~l ~ Ann~a/Review of Ps.yeSol~gy 1989;40:191-225. See AR (VOI. 3 Ref. 19-1). Clarke PBS, Mesolimbic dopamine activatioa---the key to nicotine retufofcemeat? CIBA Foundation Symposium 199~,152:153-168. See AR (Vol. 3 Ref. 19-2). Pomieri FF~ Tnnda G, Orzi F, er ~L, F.,ffec~ of nicotine on the nucleus accumbens and similarity to Ihose of addictive drugs, Na~are 199~;382:255-257. See AR (VoL 71 ! Ref. 51). ,./) 282207259 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No, 168 / Wednesday, August 28, 1996 / Rules and Regulations 44701 I1.A.3. • Extensive scientific evidence demonswating the significant effec~ of nicotine in tobacco products on the structure and function of the body is discussed in detail in the remainder of this section. The magnitude and wide dissemination of the scientific evidence demonstrates that it is foresee.able toa reasonable person in the position of tobacco manufacturer that many consumers will use tobacco products for these ptutrmacological Nicotine Is Widely Recognized as Addictive, and It ls Foreseeable That Consumers Will Use Cigarettes and Smokeless Tobacco To Satisfy an Addiction Nicotine's effects on the bntin am the biological basis of nicotine addiction---an addiction that has been proven by a wealth of laboratory and epidemiologieal evidence and recognized by every major independent medical organization .that has studied the question. Nicotine' s widely recognized addictive properties make it foreseeable to any reasonable ~rson that a substantial proportion of users of tobacco products will consume these products to satisfy their addiction.~ a. Scientific Consensus Overwhelming scientific evidence and broad recognition that nicotine is an Di Chiara G, lmpe~to A. Drugs abufa~d by huma~ pt~ereal~lly co~cenual.ions in the mesolimbic system of finely moving rats, Proceet6ngs ofth~ Nadon~ Academy of Sciences of ttte United States of America 1988;85:5274-$278. See AR (VoL 66 Ref. 26). Comgall W A, Franklin KBJ, Coen KM, et al., The meaofimbic dopaminergic system is implicated in the reinforcing effecls of nicotine, Pxychophatmacology 1992;107:285-289. See AR (VoL 8 Ref. 93-4). x FDA's conclusion dmt )hc phanuacolo~ e~ects mid use~ af Ilicotiae ia cigarettes ~ smokeless FDA's coaclmi(m lh~t the tol~cco 45 282207260 PRODUCED FROM B&W WEB SITE 447O2 Federal R~gister / Vol. 61, No. 168 t Wednesday, August 28, 1996 / Rules and Regulations addictive, dependence-producing substance emerged in the 1980's.3s All leading expert and public health organizations in the United States and the international community with expertise in tobacco or drug addiction now recognize that nicotine is addictive. The first major organization to do so was the American Psychiatric Association in 1980, when its Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-Ill), defined the Tobacco Dependence Disorder and the Tobacco Withdrawal Syndrome.3~ Since 1980, nicotine m tobacco products has also been recognized as addictive by the U.S. Surgeon General ( 1986 and 1988)37American Psychological Association (1988),a the Royal Society of Canada (1989),~9 the World Health Organization (WHO) (1992),`0 the II.A.3. u Americlm Psyehiamc Association, Diagnostic and Statistical Manual of Mental Disorders, 3d e¢~ (Washington DC: American Psychiatric Association. 1987), at 159-160. 176-178. See AR (VoL 535 Ref. 96~ voI III.A). 37 D~m~mt of H~:lth ~md Hum~ S~ Ollic~ ~m Smokiag t~! H~llh. "I~ H~tlth of Osi~ Smokeless Tolmc~ A Rq~xt of d~c Advisory ~ to ~1~ Sur~mm Gems! (AlX. NIH Publicatioll No. 86-2874 (Bcthe~lk MD:.Ig~6). See AR (VoL 1211Rcf. 1591) Surgeon Gene~l's Rep<~ 1988. Se~ AR(Voi: 129 P.~t'. 1592). 3, Hearing~ Before t~e 5~bcommin~ o¢, Heahh and ~ ~ro~ ~ ~ ~uee ~ ~r~ ~ ~rce, U.S. H~ ~ R~m~v~, I~ ~, l u S~ I (J~ ~, I ~)(s~t ~ ~ A~ ~y~l~i~ ~). See ~ (VoL 5 ~. 43-5). 3~ Royal Society of ~ Tobacco, Nicotine. and Addlc~ion.. A Commitl¢¢ Report, p~ at the request of lhe Royal $o¢iet7 of Caaada fo~ tlm Health Prolecl~m Branch, Heallh a~d Welfare Canada (Aug. 31, 1989), at v-vi See AR(VoL 621~. 814). • o WHO, The ICD-IO Cla:sif~mion of Mcmal and Beha~,ioural Disordtr~: Clinical Deseriptio~ and Diagnostic Guidelines (Geneva: World Health Organization, 1992), at 76. $,e AR (Vol. 43 Ref. 175). 282207261 PRODUCED FROH B&W WEB SITE Federal Reg/ster / Vo]. 61. No. 168 / Wednesday, August 28. 1996 / Rules and Regulations 44703 American Medical Association (1993),4' and the Medical Research Council in the United Kingdom (1994).'~ Every expert organization that has commented on whether nicotine is addictive has concluded that it is. Recognition of nicotine addiction is now so universal that even the vast majority of scientists who have received funding from the tobacco mdustsy believe that mcotme is addictive. In a survey of principal investigators of research projects funded by the tobacco industry in 1989, 83.3% agreed strongly and an additional 15.3% agreed somewhat that cigarette smoking is addictive.'3 Moreover, as demongmted in s~ction ILC., below, the tobacco industry itself, despite public pronouncemerl~s to the contrary, has long known nicotine to be addictive. Salient findings that reflect nicotine's addictiveness include the following: o Epidemiological Evidence. II.A.3. Persons who have smoked at least one cigarette arc about twice as likely to develop dependence as are persons who have ever meal cocaine or alcohol.~4 4~ Am~can MMical Association, Ethyl alcohol and nico~¢ as ~ ~ ~ 1~3 ~A Policy Com~um (~i~: ~ 1~3~ ~ 35. See ~ (VoL 37 ~. 2). '~ M~I R~ ~ ~ ~is of~ug ~~e, ~C F~ ~iew ~ M~ .R~ ~c~ l~k ~ 11. $ee ~ (VoL 41 ~. 1~). '~ C~gs ~, Sc~ ~ ~g~ ~ e~ ~., ~t ~ ~ by ~e ~ ~m~ ~e~ a~t ~e ~ of ci~ s~ A~J~ ofP~c H~g 1~1;81(7):8~. ~e ~ (Vol. 5 R~. ~). a~ Cli~col P~chopho~co~ 1~;2:2~. See ~ (VoL 37 ~. 4). 47 282207262 PRODUCED FROH B&W WEB SITE 447O4 Fmteral Register / Vol, 61. No. 168 / Wednesday. August 28. 1996 / Rules and Regulations II.A.3. • More than half of people presenting for treatment of alcohol or drug abuse who also smoke cigareues report that quitting smoking would be harder than giving up their other drug of abuse.'~ • Despite the interest of 70% of smokers in quitting smoking, fewer than 3% succeed per year.~6 • About two of every five users of smokeless tobacco have at~mpt~ to quR and failed,4~ and 68% of smokeless tobacco users who have attempted to quit report an average of four such attempts.'t * About 50% of smokers recovering from sm'gery for a smoking-related disease (e.g., lung cancer) and whose prognosis and symptoras would be improved by abstinence resume smoking.~9 Evidence from Animal and Human Laboratory_ Studies. • Nicotine ~ been determined to have significant potential to produce addiction in humafis on the basis of the same screening tests used to evaluate the addictive potential of any drug by the World Health Organization, the Drug Enforcement Administration, • s Koziowski LT, Wilki~oe ,g, Skixmcr W, et aL, Comparing tobacco cigarette dependence with ¢gher dmg dependet~es, Journal of the American Medical A.~socicaion 198~,261 (6):898-901. See AR (VoL 41 Re, f. 92). • s C.eau~ for Disease Control and Pre~ Cigare.u¢ smoking among adults~Unit~l Slates, 1993, Morbidity and Monality Weekly Report 199~ (Dec. 23):43:9"25-930. See AR (VoL 36 Ref. 616-1). '~ Novot~y "I'E. Pierc~ ~P, Fiore MC, et a/., Smokeless tobacco use in the 12nitt~d $tat~s: the adult use of tobacco surveys, MonographMNalioned Cancer in~ilule 1989;8:25-2g. ~ee AR (Vol 41 RP~. 109). ,s Seyez~ou HH, F.aough snuff: ST cessauotl from ~he behavioral, clinical, and ptlblic health pe~pectives, in Smokeless Tobacco or Health, An International Perspective, Smokiag ~ Tonic, co Control Monograph 2, NIH Publication No. 93-3461 (Washington DC: DHH$, 1993), at 281-282. $e¢ AR (Vol. 18 Ref. 5-1). Surgeon General's Report, 1988, at 150. See AR (VoL 129 Pet'. 1592). 282207263 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.3. the National Institute on Drug Abuse (NIDA), the College on Problems of Drug Dependence, pharmaceutical companies, and FDA's Drug Abuse Advisory Conumttee (the Committee).s° See section II.A.3.c.L, below. Nicotine's effects in the brain have been shown to be critical in the self-administration of nicotine by both animals and humans,s~ (The tendency of a substance to be self- administered demonstrates its ability to cause an animal or human to seek repeated doses of the substance.) This finding is a key element of addiction. The ability of nicotine to produce strong physiological and behavioral effects, including death at high doses, is no less than that of amphetamine or morphine,s2 Other Biological Evidence. Nicotine increases dopamine activity in the mesolimbic system of the bra~in. As with cocaine, amphetamine, and other drugs, this effect is believed to contribute to the compulsive drug-seeking behavior of addiction,s3 Chronic nicotine exposure causes the number of nicotinic receptors on the surfaces of brain cells to increase. This phenomenon is associated with tolerance to the effects of nicotine and has been well documented in animals and people.~ so ld. at 270. ~ ld. at 166, 173-175, 182-192. Comgall WA, Coen KM, Nicotine mammias robust selI-a~tr~ioa in rats o~ a limited access schedule, Psychopharmaeology 1989;99:473-478. $¢e AR (VoL 136 l~f. 1.561). sz Surgeon Gcnend'$ Report, 1988, at 272-274, 594. See AR (VoL 129 Ref. 1592). ~ Corrigall WA, Franklin KBJ, Coen KM, eta/., The mesolimbic dol~ninergic syztcm b implic~d in ~he reinforcing eHec.ls of nicoti~ Prychophaemaco/o~y 1992;107:295-289. See AR (VoL g l~f. 93-4). ~ Marl~ MJ, Butch |B, Collins AC, Effects of chr~c nicotine infmio~ c~ tole~ace devclopmeol ~ aicotia¢ rtc.epm~s, Journal of Pharmacolo~y and ~r~eri~n~ 7~eape~aics 1983;226:$I?-g25. See AR (Vol. 41 Ref. 103). 49 ~1705 282207264 PRODUCED FROM B&W WEB SITE 44706 Federal Register / Vol, 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations II.A.3. Commercial Evidence. • Non-nicotine-containing tobacco pr~lucts have never proved successful substitutes for tobacco despite the sophistication of some of them (e.g., Philip Moms' Next) in mimicking the non-tricotine-mediated effe.c'~ of conventioml cigareues. These data are just a few selections from the overwhelming evidence that has led the world's health authorities to classify nicotine as addictive. The following sections describe in detail the definition of addiction and how the widely known scientific evidence would lead any reasonable rnanu~acturer to foresee that a significant pn)portion of ~obacco consumers will become addicted to nicotine and will use tobacco products to satisfy their addiction. b. Definition of Addiction The tobacco industry is virtually alone in publicly contending tlmt nicotin~ is no~ addictive. Its primary argument for rejecting the massive body of research and the expert opinion of every authoritative medical organization that has comidered the issue is to claim that the entire scientific community is using the wrong definition of addiction/5 According to the tobacco industry, the "traditional criteria" of addiction are "meaningful Surseon Generars Report, 1988, at 53-5~. See Ag (VoL 129 Ref. 1592). Bcow~ll MF.~ Balfo~ DXK, And~oo ~M, Evidmcc ~ tobacco smoking incrmsm ~lm density of - (-)-[sH]nicorAue ~ sims in hunmu brab~ 3o,v~/e~fHe~roc/~.m/~,vy 1988;.~k.1243-1247. See AR (Vol. 136 Ref. 1570). Hwang SL, Otto Y, Tobacco dream temg exlx~s who insist nicoline isn' t addictive, WaLl Sweet Journal (Mar. 23, 1995). See AR (Vol. 711 Ref. 29). 50 282207265 PRODUCED FROH B&W WEB SITE F~ler~l Re~isler / Vol. 61, No. 1{18 / Wednesday, August 28, 199fi / Rules and Regu|ations 44707, II.A.3. intoxication, withdrawal, and tolerance." Although withdrawal and tolerance are still considered criteria for addiction, "intoxication" tins not been considered a necessary criterion for over thirty years. The industry cites no medical dictionary, expert panel, or scientific organization for this specific definition; the "criteria" a~ instead extracted from portions of a def'mition developed in the 1950's and used by the editors of the 1964 Surgeon General's Report on tobacco,s6 This definition was premised on the now- discarded, early twentieth-century conception of drag addiction as a personality disorder cha~cterized by weakness of will, immaturity of character development, and immorality,s7 Within months of publication of the Surgeon General's Report in 1964, its definition of addiction was cast aside by the scientific community. In a major report, the World Health Organization (WHO) recognized that intoxication was not a distinguishing characteristic of dependence for any drug under its purview,st Indeed, people dependent on stable daily doses of opiates may display no observable signs of intoxication,s9 Conversely, it is widely known that nonaddictin$ drugs such as antihistamines-and atropine and scopolamine preparations can produce intoxication.~° Moreover, under the s~ Department of Health. Educatitm. and We/fate, Public Health Service, Smoking and Health: Report of the Advisory Comminee to the Surgeon General of th~ Public Health $¢rvice (WashJllglon DC: GPO, 1964), at 349-352. See AR (Vol 43 Ref. 156). s~ Suxgeon General's Report, 1988, at 248. See AR (Voi. 129 ReL 1592). ~s WHO Expert Committee on Addiction-Producing Drags, WHO 1964, World Health Organization Technical Repor~ Series No. 273, Thirteenth Report (Geneva: World Health Org~zatiot~ 1964), at 3-20. See AR (Vol. 43 Ref. 169). 5~ Surgeon General's Report, 1988, at 251. See AR (VoL 129 Ref. 1592). 6~ Garrison JC., Histamine, bradykinia, 5-hydroxynvl~tmine, and their antagonisls, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 801 ed. (New Yoflc Pergalll~ Pless, 1990), chap. 23, at 584, 586. See AR (Vol. 711 Ref. 14). 51 282207266 PRODUCED FROM B&W WEB SITE 44708 Federal Register / Vol. 61, No. 168 / Wednesday. August 28. 1996 / Rules and Regulations II.A.3. old definition, cocaine and amphetamines would not clearly have begn considered addictive because of lack of evidence at the time demonstrating physical dependence.6' The scientific community thus rejected the old definition of addiction because of new scientific insights about the nature of addiction, more than 15 years before finding nicotine to be addictive. Today, drug addiction has been defined by scientific organizations from both laboratory and clinical perspectives. The laboratory perspective assesses experimentally whether a substance alters the central nervous system in a manner that can produce charaaeristic addictive behavior in humans. While the laboratory perspective focuses on the chemical substance, the clinical perspective on drug addiction assesses whether an individual in society consumes the, substance in a manner that demonstrates addiction. Consensus clinical criteria for diagnosing addiction have been developed by the American Psychiatric Association and were most recently published in the Diagnoytic and Statistical Manual of Mental Disorders (DSM-IV) in 1994: Criteria for Substance De~ndence A maladaptive pattern of substance use, leading to c "lmically $ignificam impairment or distress, as manifested by three (or more) of the following,. occurring at any time in the same 12-month period: ( 1 ) tolerance, as defined by either of the following: Brown JH, Atropine, scopalomin¢, and related anfimuscex~c drugs, in Goodman and Gilman's Pharmacological Basis of Therapeulies. 801 ed. (New York: PetgalItolx Press, 1990), chap. 8, at 157. See AR (Vol. 711 Ref. 14). 6~ WHO Expert Comafiuee on Addiction.Producing I>m~s, WHO 1964, Wotqd Health O~$aaization Teclmical Report Series No. 2"/3, Thirteenth Report (Geneva: World Health Organization, 1964), at 3.20. See AR (Vol. 43 Ref. 169). 52 282207267 PRODUCED FROM B&W WEB SITE Foder~l Register / Vol. 61. No. 168 / Wednesday. Augusl 28. 1996 / Rules and Regulations 44709 II.A.3. (a) a need for markedly increased amounts of the substance to achieve intoxication or desired effect (b) markedly diminished effect with continued use of the same amount of the substance (2) withdrawal, as manifested by either of the following (a) the characteristic withdrawal syndrome for the substance... (b) the same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms (3) the substance is often taken in larger amounts or over a longer period than was intended (4) there is a persistent desire or unsuccessful efforts to cut down or control substance use (5) a great deal of time is spent in activities necessary to obtain the substance (e.g., visiting multiple doctors or driving long distances), use the substance (e.g., chain-smoking), or recover fi'om its effects (6) important social, occupational, or recreational activities are given up or reduced because of substance use (7) the substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current cocaine use despite recognition of cocaine-induced depression, or continued drinking despite recognition that an ulcer was made wo~e by alcohol consumption)62 Clinicians rely on these criteria to identify addictive behavior in patients. In 1988, the U.S. Surgeon General used the most up-to-date laboratory tests and clinical criteria to develop the following consensus set of crit~ia for drug dependence: Criteria for Drug Dependence. Pmnary Critem • Highly controlled or compulsive use • Psychoactive effects • Drug-reinforced behavior Additional Criteria • Addictive behavior of~n involves: American P~ychiatric A~sociafion, Diagnostic and Statistical Manual of Men:al Disorders, 41h ed. 0Vashmgton DC: American Psychiatric Association, 1994), at 181. See AR(VoL 37 Ref. 8). 53 282207268 PRODUCED FROM B&W WEB SITE 44710 Federal Re~i~'ler / Vol. 61, No. 168 / Wednesday, August 28, 1995 / Rules and Regu|ations II.A.3. -stereotypic patterns of use - use despite harmful effects -relapse following abstinence -recurrent drug cravings o Dependence-producing drugs often produce: -tolerance -physical dependence -p:easant (euphoriant) effects63 The laboratory and clinical perspectives on drug addiction embodied in the criteria of the U.S. Surgeon General and the American Psychiatric Association are entirely consistent. Moreover, the definitions of addiction used by all other world scientific authorities, such as WHO6~ and the Royal Society of Canada,6s share the same principles, differing from each other only in wording and emphasis. To assess whether nicotine is addictive and whether consumer~ are addicted to nicotine, FDA utilized these modern laboratory and clinical pe~peetives on addiction supported in principle by every relevant medical authority in the world. The modern conception of addiction is not hazy. It do~s not--as the tobacco industry ~serts in its comments---encompass food ingredients, activities, or daily rituals. The scientifically accepted method of identifying addictive drugs emphasizes the pharmacological basis of addiction, rather than the simple ol~rvation of compuisive- appearing behavior. Addictive drugs are now known to exert. "psychoactive" or mood- 63 Surgeon General's Repo~ 1983, #17. See ~ (Vot 129 ~f. 1592). D~aic Gui~li~a (~ World H~ ~g~fi~ 1~2), tt 75-76. ~e ~ (VoL 43 ~. 175). ~t of ~e Ro~ S~ ~ f~ ~ H~ ~ B~ H~ ~ We~ ~ (~ug. 31, 1989), at v. See ~ (VoL 62 ~f. 814). 54 282207269 PRODUCED FROM B&W WEB SITE Federal R~ister / Vol. 61, No. 168 / Wednssday, August 28, 1996 / Rules and Regulations 44711 II.A.3. altering effects and to affect the structure and function of certai~ key pomons of the brain that motivate repeated, compulsive use of the substance. By activating, inhibiting, or mimicking normal centxal nervous system processes, dependence-producing drugs exert control over the behavior of users. Consumers are strongly compelled w consume these substances for the pharmacological effect of satisfying addiction. Metl~xis used to identify addictive drugs effectively exclude jogging, eating chocolate, playing computer games, or similar activities because these activities do not depend upon an exogenously administered drug. Contrayy to the suggestion of the tobacco industry, application of the criteria for identifying addictive dn~gs by the expert organizations responsible for this ~sk~ shows remarkable consistency across organizations and has resulted in the current identification .of a very small number of u'uly dependence-producing drugs and d~g types, These are cocaine, amphetamines, nicotine/tobacco, alcohol, hallucinogem, inhalants, cannabis, phencyclidine, opioids (including morphine and heroin), and the class of se~latives, hypnotics, and anxiolytics.~7 Application of the crimria has not led to the classification of ~ These organizations include the World Health Organization's Expert Commiuee ¢m Drug Dependence, the U.S. Drug Enforcement Admitmu'ati~, the Nttiottti Institute on Drug Abuse, and the Food and Drag A~traLion. e~American Psychiatric Association, Diagnostic and Stmistfcal Manual of Meraal Disorders. 4th ed. ,(Washington DC: American Psychia~c Associatioa, 1994). at 175-177. See AR (Vol. 37 Ref. 8). WHO, The ICD-I O Cta~sific~ion of Memal and Beh~ioural Disorders: Clinic~ Descriptions and Di~g~stic Guidelines (C.~mev=" World Health OrBaniza~on, 1992), a[ 75-76. See AR (Voi. 43 P~f. 175). Since no two ogthese substtnc~ are chemically or biologically identical, no two ~ddictio~¢ ~ exactly the same. The observation that dependence on nicotine can be distinguished in some rmpects from other addictions (as repeatedly asserted by tobacco industry comments) i~ thus irrelevant to whether nicotine should be classified &s addictive. 55 282207270 PRODUCED FROM B&W WEB SITE 44712 F,n/eral Regiater / Vol. 61, No. 168 / W~dnesday, August 28, ~99~ / Rules and Regulations II.A.3. carrots or jogging or any of the other activities claimed by the tobacco industry in its comments as "addictive drugs." A key reason for the reliability and validity of the modem definition of drug addiction is that scientific organizations rely upon the convergence of results from several different test procedures before determining that a substance is addictive. In assessing whether nicotine is addictive, FDA examined a wide range of such laboratory evidence, as well as epidemiological evidence of whether consumers are addicted to tobacco products. c. Data Establish That Nicotine Is Addictive and That Consumers Use Cigarettes and Smokeless Tobacco To Satisfy an Addiction Animal and human studies demonstrate that mcotine is a powerful psychoactive agent that can cause dependence by producing effects in the brain characteristic of other addictive substances. These findings have been widely published and presented and ~ at rmjor international scientific and medical meetings since the 1980's. Numerous laboratories throughout the worki have replicated the core findings using a variety of techniques and have produced convergent results, demonstrating that the findings are reliable and valid. A wealth of epklerniological studies complements these laboratory data by showing that smoke~ and users of smokeless tobacco display c lmical signs and symptoms of addiction. The evidence that has led to the nearly univer~l scientific conclusion that nicotine is addictive is discussed in the following sections. i. Laboratory_ Studies Establish That Nicotine Produces Pharmacolo_trical Effects Similar to Those of Other Addictive Substances. The tests used by the U.S. Surgeon General to develop its consensus definition of drug dependence are the following: 56 282207271 PRODUCED FROM B&W WEB SITE F~der~l Regi~er / Vol. B1. No. 168 / Wednesday, August 28, 199fi / Rules and Regulations 44713 II.A.3. . Animal and human "drug discrimination" tests, which assess a substance's ability to produce psychoactive effects that can be distinguished from those of other psychoactive substances; • Tests of human psychoactive or "sub_iective" effects, ~'hich assess a substance's ability to produce changes in perception, mood, and behavior, • Human and animal drug "self-administration" tests, which assess a substance's ability to induce repeated, compulsive use by functioning as a "positive reinforcer"; and • Tests for physiological de~ndence, which assess a substance's ability to produce tolerance and a withdrawal syndrome. These tests of an addictive drug are widely accepted for their validity,e* They are the screening tests for addictiveness used most commonly by pharmaceutical manufaaurers and regulatory agencies, as evidenced by their.prominence in reports by WHO, reviews by the National Institute on Drug Abuse (NIDA) and the College on Problems of Drug Dependence, and deliberations by the Drug Abuse Advisory Committee, which primarily serves FDA. ~9 Thus, these tests were not invented or selectively used to evaluate nicotine. Rather, they have been used to screen drugs of abuse for more than two decades before b'DA' s current deliberations concerning nicotine. Upon review of the evidence in the ss Surgeon General's Report. 1988, at 270-296. See AR (Vol. 129 Ref. 1592). Balster ILL, Drug alTt~e potelltial evaluatioll, ia anima~ BritiJh Journal of Atldieaon 1991;86:1549-1558. See AR (rot 8 lk~d. 89). 6, Surgeon C-eneml's Report, 1988, at 269-270. See AR (VoL 129 Ref. 1592). 57 282207272 PRODUCED FROH B&W WEB SITE 44714 Federal Register / Vol. 51, No. 168 / Wednesday. Augus~ 28, 199ti ! Rules and Regulalions II.A.3. administrative record. FDA concludes that nicotine tests positive in all relevant laboratory tests for addictive potential. Testing_ for .osychoaetivity. Psyehoactivity is a hallmark characteristic of all dependence-producing drugs. Psychoactive etIects (sometimes also refened to as "subjective effects") are changes in mo~ or feelings that result from the pharmacological etIects of the sube~mce on d¢ cenwal rmrvous system. Changes in mood or f~elings d~a a~ no~ produced pharmacologically are no~ considered psyc~active effects. The ps~:hoacdv~y of a drug is Drug discrimination s~udi~, Drug discrim~tion s~udics evaluale fl~e ps)choactivi~y of a drug by t~ing whedmr animal or hun'~m subjects can r~liably ~miau: tt¢ drug ~m tes~ allow dire~ comparisons of a drug's effects m lmown dependenc~-pmducing drugs.~° Tt¢ drug discrimm~ion paradigm is rourJnely used in prectinicalassessmcm of the abuse po~emial of a drug and is considered ~o be an animal model for human subjea~ reactions to drugs.~ ~ appendix.~z Using a vari~ of drug discrimina~n pazadign~ researchm~ have shown fl~ To Balster RL, Drug abuse potential evaluatim in animal~ British Journal of Addiction 1991;86:1549- 1558 See AR (VoL 8 Ref. 89). ~ Surgeon General's Report, 1988, at 274-275. $¢e AR (Voi. 129 fief. 1~92), ~ See appendix 1 to Jurisdictional Analysis at 23-25. See AR (Vol 1 Appendix 1). 58 282207273 PRODUCED FROH B&W WEB SITE Federa] P.~ister / Vol. 61, No. 168 / Wednesday, August 2/3, 1996 / Rules and Re,relations 44715 II.A.3. nicotine can serve as a dLscrimim~ve stimulus in rats~ and squin~l monkeys.TM Comparative stuciie, s have demonstrated that, akhough mcotine's stimulus effcx~s are unique, they more • ~losely resemble the stimulus effects elicited by amplg'tamine~ than those of opioids, sedatives, or hallucinogens.~ Nicotine's posizive resu~ in these drug discriammion tests are a consequence of ~ action in the central nervous system. M~;~u~:, a nicotine antagonis~ that acts in the bra~ attenuates nicotine's abi~y to serve as a disa-imi~ve stimulus, whemu the peripheral amagonist hexan'ethonium~which does not enter the brain---does not affect nicotine ~e Rmea'ans JA, MeR~ LT, CenR'ai si~es and mech~ism ~ ~ ¢[ ~ Nearo~cience and Biobehavioral gevk, ws 1981;5(4):497-50L ,~¢e AR (Vd. 42 P.,ef- 12"/). pma JA, S ida-man 11~, Gatdm HS, ¢ta/., Disa, iminafiv¢ stimulus propexties of nic~in¢: fm'thez ¢videm~ fox modiation at a cholinergic x,~cep~r, P~chopharnmcology 1983;81:5~b60. See AR (VoL 8 Re£ ~0-2). 59 282207274 PRODUCED FROM B&W WEB SITE ~4716 FederaJ Re~ister / VoL 61. No. 168 / Wednesday, August 26. 1996 / Rules and Regulations II.A.3. discrimination.~ Thcsc studies demonstrate that mcotine's psychoactive effects are the direct results of its actions m the brain. Hurrah drug discrimination ~ for nicotine a~ also positive. Using a chug discrimination procedure analogous to those eng~loyed with animals, Kallman and colkagues originally demonstrated that nicotine., as delivered by the inl,.ala~n of totmco smoke, acts as a ~scrin~ve s~nulus in hurmas]* R~sc~ndy, Pe.rldns et al. den~nstrated that immmmlly res~ from a product that produces no sensory effects from smoke confirms that the phammcological action of nicotine--ra~her ~ha~ the taste or flavor of tobacco smokem produces these hallmark psychoactive effect.79 psychoactive effects. Psychoactive or subjective effects produced by addictive chugs may range from very mild relaxation to imense intoxication or impaired cognitive abilities,s° Assessment in humans of the subjective effects of addictive drugs involves giving either drug or placebo to volunteers and then asking them r~ report what they feel. "Rmecraas JA, Oance WT, Cholinergic and nm.dtolinergic aspem o~ the discrimia~ve stimalus tael~'~es o~ Kmcfme, in Discnminative ,Stimulus Prol~rties of Drug~, ed. Lal H (New York: Plenum Press, 1977), at 155-185. See AR (VoL 42 l~ 126). R~ecnms JA, Mellz~ LT, Ce~lraJ ~s m~d ~ani~m ~ aaim ¢g ~ Neuroscience and Biobehavioral Reviews 1981",5(4):49%501. See AR (Vol. 42 P,~ 127). Melo.er LT, Rasccram JA, Acem MD, eta/., Discrimi~ttive slimulus l~ or'the optical is0mms ~" nicotin~ Psycho/,kamawo/oD, 1980;68:283-286. ,gee AR (VoL 41ReL 106). ~* Kaliman WM, Kallman M.l, Harry GJ, et a2., Nicotine as a discriminative stimulus in human subjects, in Dru8 Discrim~ncaion: Applications in CN$ Pharmaco/ogy, eds. Colpaert F.C, Slangml JL (Amsterdam" Elsevier Biomedical Press, 1982), at 211-218. See AR (VoL 41 Ref. 89), ~ "Perkins IL Grobc J, 5cicrka A, e~ a/., Discriminative stimulus effects of nicotine in smokers, in lntern~ionai Symposium on Nicotine: The Eff#cls of Nicotine on Biological :Systems ll, eds. Cial~e Quik M, Thma-u IL Adlkofer F (Basel: Bixkhauser Vertag, 1994), at l I 1. See AR (VoL 42 Ref. | l | ). s0 Surgeon General's Report, 1988, at 270. ,fee AR (Vol. 129 Re, f. 1592). 6O 282207275 PRODUCED FROM B&W WEB SITE Federal Register / Vo]. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44717 lI.A.3. Individuals with histories of addictive drag use report what drug, if any, the test drug feels like. This testing helps determine whether the test drug produces any effects on mood and feeling that resemble those of previously studied drugs. Individuals with histories of using a variety of addictive drugs and who report "liking" the effects of several types of drugs help assess the addietiveness of the test drug. These individuals are asked to evaluate the ability to feel a drug effect, to rate how much they "like" the drug effect, and to attempt to identify the drug that was given from a list of widely used and abused drugs. Results that show consistem kinds of effects across drugs confirm that these drugs are appropriately categorized together as addicting drugs,si Nicotine produces significant psychological semationswhether inha~ or injected. In or~ study, smokers with histoms of abuse of other drugs idcntif~ intravenous or inhaled nicotine as being a euphoriant s'm~ilar to cocaine or amp~..2 W'lh a common treasure of the subjective effects of addieu've drugs (the Addiction ResearchCenter Inventory), nicotine produced dose-related increases in the "euphoria" seal~ (also known as the Morphine- Be~ Group Scale or MBG) and the "hT~ing" scale, showing that nicotine produces subjective effects sim~ to those of other addictive drugs. This study essentially ex~nded the original finding of Johnston in 1942, who had argued from the premise that "smoking tobacco is essentially a means of administering nicotine, just as smoking opium is a means of administering morphine."s3 In his study, Johnston administenxl intravenous injections ,1 Id. at 271-272. '~ Hemangfield JE, Miyasato K, Jasimki DR, Abuse liability tad l~mmacody~nic ¢imac~-istics of inlravcnous and inhnled nicotine., Journal of Pharmacology and Experimental 7herapemies 198~;234:1- 12. See AR (VoL 39 Ref. 69). Johnston LM, Tobacco smoking and nicotine., lancet 1942;9"742. See AR (Vol. 278 Ref. 3947). 61 282207276 PRODUCED FROM B&W WEB SITE 44718 Federal Register / VoL 61. No. 168 / Wednesday, August 28. 1996 / Rules and Regulations II.A.3. of nicotine, in doses comparable to those that people obtain from cigarettes or smokeless tobacco, to cigarette smokers to de~ermine both nicotine's effects and its potential usefulness in helping people abstain from tobacco. He found that the nicotine injections produced "'psychic" effe~.s that "closely resembled" those of cigarette smoke inhalation, were, plea.sam for smokers, and left the smokers "disinclined to smoke." See also section II,C.6.b. (comment 1). Similar findings were also obtained m a study by Jones et al., who found that intravenous nicotine injections in doses comparable to those that people obtain from cigarettes or smokeless tobacco produced "a pleasurable stimulant-like sensation that many of them termed a 'rush.'" Half of the subjects tested requested substantially higher doses,s' More recently, these early results have been confirmed by Pomerleau and Pomerleau, Perkins et a~., and Sutherland et al., who have found that nicotine delivered from cigarettes, inwavcnous injection, and inWanasal spray produces psychoactive and mood-altering effects consistent with those of other addictive drugs.'s =~ 1ones RT, Fan'c0 TR rlL Hemmg ILL Tobacco smoking ~ nicotine toleJaac¢, in 3¢lf.Admini=~razion of Abused Sub=maces: Me,hods.for Study, ed. Kras~go MD: National Institute on Drug Abuse, 1978), at 202-208. See AR (VoL 41 Ref. 88). .s Pomerleau C$, Pomcrleau OF, Eut~:maat effecls of ~icod~ in smoicem, P~'ychopharmacology 1992;108:460-465. $e¢ AR(Vol. 87 Re, f. 426). Perkins KA. Grobe/E, Epstein LI-L et aL, Effects of nicoan¢ on s~bjective arousal may be dependmt on baseline subjective stat~ .Im=rnal of Substance Aloe 1992;4:131-141. See AR (VoL 348 Ref. 5516). Perkins KA, C-robe JE, Epstein LH. eta/, Ommic and acute tolerance m subjective effects of nicotine, Pharmacology, Biochemi~ry and Begavior 1993;45:375-3gl. See AR (VoL 271 Ref. 3"728). Satherland G, SUtl~leton JA, Rugse, ll MAIL et smoking cessation,/.~cet 1992;340:.324-329. $e¢ AR (Vol. 91 Ref. 527). Sutherland G, Russell MA, Slapletlm J, et a/., Nasal nicOtille spray:, a rapid nicotii~ delivery system, Ps'ychopharnuurology 1992; 108:512-518. See AR (VoL 91 Ref. 526). 62 282207277 PRODUCED FROM B&W WEB SITE F~deral Register / Vol. 61. No. 168 / Wednasday. August 28, 1996 / Rules and Regulations 44719 II.A.3. The tobacco industry contends that tobacco is used for pleasure. So, too, is cocaine used for pleasure. These data establish, however, that receiving nicotine through a , route that does not provide any sensory qualities of tobacco use (e.g., through the venous system) also is pleasurable. Thus, the pharmacological effects of nicotine administered • through non-inhahuion routes are able to produce the characteristic psychoactive effects of tobacco use. Self-administration testing. In self-administration testing, human or animal subjects are given access to a drug and then evaluated for their tendency to seek repeated doses of the drug. The self-a&mmstmtion test determines the ability of a chug to sustain drug-seeking behavior--one of the key distinguishing features of drug dependence. The seif-adminisumion test is widely used to detemme whether a drug can control behavior, a drug whose inta~ leads to more consumption is called a "positive reinforcer." It is generally acoepted in the scientific coramunity that the ~3ility of addictive drugs to serve as positive reinforcers is the core propeny that promotes the development and rmintenanee of addiction,s6 Setf-administ.,a~n procedures using primates and rats have been shown robe valid and reliable predictors of the potential for a compound to result in drug dependence. There is a associated with addiction in humans.~7 Flennmgfield JE, Miyaxato K, Jasin~kl DR. Abuse liability a~d l~mrmacodynamic ~c~ of intravenous and inhaled nicotine, $ournal of Pharmacology and Experimental Therapeutics, 1985;234(1): 1-12. See AR (VoL 39 Ref. 69). ,6 Balster RL, Drug abuse potential evaluation in animals, British Journal afAddictioa 1991;86:1549- 1558. See ARCVoL 8 R¢t~ 89). s7 Gri~ths R1L Bigelow GE, l-im~gfiekl JE, Similarities in animal and human druB-taking behavi~, Advances in Substance Abuse ! 981~, 1:1-90. See AR (Vol. $ R~ 91-2). 63 282207278 PRODUCED FROH B&W WEB SITE 44720 Register / Vol. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations II.A.3. Animal s~lf-adminisuation studi~ using a var~y of administm~n ~h~cluk~ and controls, have shown that nieotim funcaions as a positive maforcm ac~ss s~v~l spools.'~ Nicotir~ is more avidly s~lf-admini~t~ when availabk~ on an ~ ~zl~lul~ than wl~n ~ly avai]abk~.~ Since ~obacco users ~lf-admin~r ira~mitt~ do~s of rd~otine p~r cigam~ or pinch of smo~i~a tolzacco, tb~ sch~lub of nieotim adminima~n that is most reinfo~tg in animals con~sponds to tl~ ~ of actual tolzcco coraumption. laboratory con~Aons?° Su~cts ~elf-~ iraravenous ~ in a ~mlar and Wcmlveram WL, Nader Iv{A, ~~ evalua~ ~ the remf~ciag effec~ of dru~ in Mo&rrn Me~hod.~ in Phann~otoSy, e~. Ad~ MW, Co~a A (New Yct~k: W'dey-Li~ 1990), 6:165-192. ~ AR (VoL 535 u O:klberg SIL Spealman PJ3, ~ DM, Pmisamt behavior at hi~b t't~s maintained by inuavmous sdf- adminismu~ c~ nicotine, $~ence 1981;214:573-575. See AR (VoL 5 Re~ 35-2). C.,dd~g $1L Spealman RD, Maimemmoe and suppression d bdmvi~ by iauavmous nkxxiae iajeaims in sq~reJ nx~g~ Federmion Procecdinfs 1982;41(2):21@220. See AR (VoL 391~ 52). See AR (VoL 42 R~. 146). Therapem/es 1983:22a,(2):319-326. S~e AR(Vct 42Re£ !19). Cox BM. ~ A. ~ WT, lqicmine self-adminisa-at~ in ra~ Br/~h Journa/oJ'~ 1984;83:49-55. See AR O/oL 8 Rift. 93-1). S]ffe~ EL, Balsm. RL baravmom self-admiaisuat~ c~ nicotia~ with aad wi~out schedule-~ P/tarmaco/ogy, B/o~m/ary msd Be/tmgor 1985;22:61-69. See AR(VoL 81~ 93-3). Corrisall WA, Coen KM, Nicotine maJmnins robust self-adminlqrttion in mls ¢m a limited access schedule, Psychopharmacology 198~99:473-478..See AR (VoL 34"/Ref. 5495). *~ Surgeon Generars Report, 1988, at 182-189. See AR (Vol. 129 Ref. 1592). Pharmacology, Biochemiarry and Beha~or 1983;19:887-890. See AR ('VoL 8 Re£ ~/). 282207279 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, AugUst 28, 1996 / Rules and Regulations 44721 II.A.3. orcterly pattern giving then-~lves amoums of nicotine comparable to those they were accustomed ~o receiving f~um their ~. These studies demonstrate that the • :: pharmacological effects of nicotine can explain why people engage in compulsive consumption - of tobacco. At a molecular level, nicotine's reinforcing effects a~ widely belie~:l to Uc a , consequence of ~ actions on specific areas in the central nervous system. Within the scientific amphetami~ and morphine, muses addictm" n by increasing the activ~y of the neumtramminer dopamine within the mesolimbic system of the brain.~ A ve~ recem s~udy, which expands on ~system by selectively inc~as~ dopamine ~n and energy metal~olism in a speci~ ~gion of the nucleus accumbem previously shown to be impormm in mediating the addictive effects of these ¢lrugs.~: ~ Clarke PBS, Mesolimbic dopsmine acfivaticm--lhe key to nicotine teinfmeemeat? CILIA Found~on Sympo~am 1990:152~153-168. See AR (VoL 3 Ref. 19-2). reinforcing effects of nicotine, P~ychopharmacology 1992:107:285-2~9. See AR (VoL 8 R~ 9~4). Iverson LL, ... harmful to the brain, Nature 1996;382:206-207. ~e AR (Voi. 711 Ref. $1). ~2 Pontieri FE, Tanda G, Orzi F, et al., Elfects of nicotine oa the nucleus accumbem and similarity to those of addictive drugs, Nasure 1996;382:255-257. See AR (VoL 711 Ref. 51). 65 282207280 PRODUCED FROH B&W WEB SITE 447ZZ Fsderal ~gister / Vol. 61, No, 168 / Wednesday, August 28, 1996 / Rul~s and I~gulations II.A.3. Ob-~cr~ing ~t food, water, and salt also increase doparnine activity in the mesolimbi¢ system, the tobacco industry comments that nicotine's action is no~ unique. FDA's f'mding, however, is not that nicotine's role in this system is unique, but that it is significant. Indeed, the tobacco industry's own observation on food, water, and salt reflects the significance of nicotine's action, As researchers have noted, the mesolimbic "reward" system of the brain natuntlly reinforces the intake of essential substances (such as food, water, and salt) because these substanc~ are necessary for human existence. Without an intrinsic reward for eating and drinking, humans would perish. Researchers believe that addictive substances such as nicotine, amphetamine, cocaine, and morphine are so powerful precisely because they activate and even control this natural system of reward. Indeed, the same scientists quoted by the tobacco industry state that "nicotine could substitute for food or other reinforcers" in the mesolimbic system..3 That nicotine can mimic life-sustaining substances and alter such a pivotal neurological system demonstrates its substantial effect on the structure and function of the human body. Wnlxt~wal and tolerance. Documentation of a drug withdrawal syndrome is the primary metl~ of establishing that a substance causes physical dependence. According to the Surgeon General. "~m]easurement of drug withd~wal phenomena entails ~conJing mmimtecL"~ Numerous studies document a characteristic withdrawal syndrome, e3 Mffsud JC.. Hemnndez L, Hoebel BG, Nicotine infused into O~e uudeus acx:umbcns incx~eases syuaiMic dopamine as measured by in vivo microdialysi& Bra~n Research 1989;478(2):365-367, at 367. See AR (Vol. 535 Ref. 96, voL lllJ). u Surgeon General's Report, 1988, at 291. See AR (Vol. 129 Ref..1592). 282207281 PRODUCED FROH B&W WEB SITE Federal ReSister / Vol. 61, No. 168 / Wednesday, Ausust 28, 1996 / Rules and Regulations 44723 II.A.3. including both physiological and psychological symptoms, associate~ with nicotine abstinence..5 Widely used criteria for diagnosing withdrawal come from the American Psychiatric Association's DSM-IV, which defines Nicotine Withdrawal Syndrome as four (or more) of the following symptoms within 24 hours after cessation of use: dysphoric or depressed mood; msomma; imtability, frusuation, or anSer, anxiety, difficulty concentrating; r~stlessness; decreased heart rate; increased appetite or weight gain.~ Although nicotine withdt-awal is not as Iife-t.hreatening as withdrawal from alcohol or some barbiturates, it is comparable to or stronger than withdrawal from such other stimulants as cocaine and can be lfighly disn~ptive to pe~onal life.9~ After several weeks of nicotine exposure, users who are deprived of nicotine for mo~ than a few hours can develop withdrawal symptoms.9s Withdrawal symptoms after quitting tobacco use can persist for months.9~ The tobacco industry contends that nicotine withdrawal is associated only with psychological changes; the evidence, however, demonstrates that tobacco abstinence also causes significant physiological effects on the body. These effects include decrea~d bean g5 ld. at 19%207. (Washingmu DC: Americaa Psychiat~ Association, 1994), at 2A4-7.45. $ee AR (VoL 37 Ref. 8). ,7 eenowitz NL, Cigaxeue smoking tad mcofme 1992;76(2):415-437. See AR (Vol. 535 Ref. ,s Jaffe JFL Drug addiclio~l alld drag abuse, in Goodman and Gilman's The Pharmacological Ba.~is of Thera~eu:ics, 8,h ed. (New Yorl~ Pergamoa ~ 1990), ch~ 22 (522-573), at 548. ,See AR (VoL 535 Ref. 96, voL HI.G). ; ~ Ryan FJ, Cold turkey in On~nfieid, Iowa: a follow-up study, in Smoi~ing Behavior: Motives and Incentives, ¢d. Dunn WL (Washington DC: VIi Wim~m & Sore, 1973), at 231-234. $¢e AR Otot 8 gel. 105). 67 282207282 PRODUCED FROH B&W WEB SITE 447Z4 Federal Re~ister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and ReRulations II.A.3. rate at rest and after standing, alteration of the electroenc, phalogram (EEG, a me2~ure of brain electrical activity), skin te, mp~ratur~ changes, and disruptions in sl~p patmms)~° Studies have also demonstrated that tohacco withdrawal e,,&n cau~ an incre~e in weight. This weight increase nmy I~ attributed to increased caloric intak~ dec~ metabolism, and decreased energy expenditur~ during nicotine withdrawal)°t The physiological signs of nicotine withdrawal am substimtially rcvers,d when mcotin~ i.~ given in a form other than tobacco.t°2 Sigrfificant behavioral and subjectiv~ symptoms common to nicotine withdrawal include depression, anger, irritability, anxiety, poor conc~ntrition, and r~tl~sn~s,t°3 too ~v~t R,I. Jarvis M J, R~,,~ll MAH, a al., Effect of nicotine r~pla~ment o~ the cigarette withdrawal s~ British lo, rmal of Addiction 1994;79(2):215-219. Se~ A~ (Vol. g Rtf. 102-1). 1996;43:299-294. See AR (Vol. g Ref. 102-2). Hugh~/l~ Higgim ST, Ha~ukami D, Eff~:ts of al~tinen~ from tobacco: a critical review, Re,earth Advancesin Alcohol dmf Drug Problems 1990:10:3 ! 7-398, at 382. See AR (Vol 535 Ref. 9~, voL IILG). ~ 05 Wack IT, RoOm J. Smok~g ~,ud it~ effect on body weight ~nd t~ syste, l~ of ciilodc regl,tlabot~. Amtric~t Jour~d ofC~ini~al Nmritio~ 1~82;35(2):3(~-380. See AR (VOl. 8 l~f. 10~-1). Ghm~" SC~ Gl~mer EIvL Reidelthedg MM. et aL, Metabolic cl~lgm ~ with tim ~atio~ of ¢igamtm slmokitag. Amhive$ ofEwtvirormtem~l Hea~,th 197~,~D:.37"/-38|. See AR (Vok 8 P-~. 103-~). ~o~ Surgt~ Gttmtal's R~ 1~, m~. Se~ ~(Vok 1~ ~. 1592), t o~ see, e.g.. H~ ~ ~ D, S~ ~ sy~ a ~ ~~ A~ive, of Ge~r~ P~ 1~:43:~. See ~(V~ g ~ I~-2). wi~waI ~g ~nt ~ y~g a~t ~M~ m-Um~ Sm !~3, Morb~ ~ MonM~ WeeMy Rein 1~;43(41):745-7~. See ~ (VoL 7 ~f. ~). 535 R~. ~ vol. III.F). 68 282207283 PRODUCED FROM B&W WEB SITE Federal Register / Vo]. 61, No. 168 / Wednesday, August 28, ~996 / Rules and Regulations 44725 II.A.3. Dependent smokers also show substantial withdrawal symptoms within a day of nicotine absr~nenceJ~ These psychological symptoms are substantially reversible or preventable .by providing income m the form of convcnt~oml cigarettes or by providing equivalent or lower doses of nicotine in other forms (e.g., nicotine gum) including forms without the taste of nicotine (e.g., nicotine patches).I°~ Withd~wa] from smokeless tobacco also causes physiological changes attributable to nicotine abstinence. I-latsukami and colleagues showed the following changes in users deprived of chewing tobacco: (1) decreased heart r~e at rest and after standing; (2) increasvd craving for tobacco; (3) increased confusion score on the Profile of Mood Sta~es (POMS) (this measures temion/anxiety, depression/dejec~on, confusion, anger/hostility, vigor, and fatigue); (4) incw, ased eating; (5) increased number of sleep interruptiom; and (6) increased total scores on a withdrawal symptom checklist for both self-rated and obser~er-rmed measuresJ°~ ~o, Jaffe JH. Drug ad~cfi~l ~ dttlg ab~$¢., in Goodman and Gilman's The Ptmrn~wolo~c~ Basis of Therapeutics, Sth ed. (New YoOc Pergam~ Pn~, 1990), chap. 22 (~22.Yr3), at Ref. 96, voL Ill.G). ,o~ Surgeon Gcmcg~'s Report. 1988, az 470-485. See AR (VoL 129 l~. 1.~)2). Robinson IH, Pritchard W$. Davis RA, Psyc~C~mmmo~o~ ~ c~ smc~i~ • ciganme with typical "l~r" and c~Ixm ma~oxide yields but ~ mcotine~ Psydwpharnmco/ogy 1992;I0~:466-4T2. 5¢~ AR (VoL 59 gel 236). Fage~trom KO, Sawe U, Tom~en P, "I]temlamfic use o~ ~ofme patches: efficacy and safety, Journal of Drug Development 1993;5:191-205. $¢¢ AR (VoL 76 Ref. I~6). l~icxe MC., Joeenby D~ Bake~ TB, ¢t al., Tobaovo dependem~ and tim ~ ~ Jom, aal of the American Medical Association 1992;268:2687-2694. $¢¢ AR (VoL 351 Rift. 5609). ,~s Hatsukami DK, Cn~t SW, Kecnaa ILM, l~ygiologic aml mbjecliv¢ cimuge$ f~nn $moke.ie~ totmooo withdrawal, Clinical Pharmacology and Therapeutics 1987;41:103-107. $¢e AR (VoL 7 Rcf. 73). 69 282207284 PRODUCED FROH B&W WEB SITE 44~26 Federal Register / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations II.A.3. A second key test of a substanoe's ability to produce physical dependence is whether it promotes tolerance.1°7 Tolerance occurs when responses produced by an initial dose are diminished with repeated doses, so that increasing doses are necessa~ to reproduce the initial effects. Tolerance to some effects of a substance can be acute, occurring within hours to days, while tolerance to other effects develops chronically as a result of long-term substance exposure. Tobacco users become tolerant to nicotine both acutely and chronically,le~ After a single night of abstinence, the nervous systemt°9 and the cardiovascular system~ ~o are highly responsive to small doses of nicotine. But after the administration of the equivalent of a few cigarettes, the responsiveness of the human body to mcotine declines markedly. Thus, a cigarette smoked in the middle of the day may not elicit the same psychological or physiological response in a cigarette smoker as one smoked earlier in the morning. This severe degree of acute tolerance seems to greatly exceed that produced by cocaine and to be more comparable to that produced by morphine.TM Tolerance to other effects of nicotine develops over weeks and months. For example, new smokers often experience nicotine-related effects such as dizziness, nausea, intoxication, vomiting, and headac~ymptoms that disappear eventually as the ~o~ Sur~etm General's Rel~rt, 198S, at 50-54. See hit (Vol. 129 Ref. 1592). ~o~ Perkins KA, Grobe/E, Epstein Ll-t. e~ al., Clm~u~c and seute tolet-ance to subjective eltects of nicotine, Pharmacology, Biochemistry and Behavior 1993;45:375-38 !. See AR (Vol. 271 Ref. 3728). t~0 Surgeon General's Report, 1988, at 47-48. See AR (Vol. 129 Ref. 1592). ' J ~ Jaffe JH, Drug ackliction tud drug abuse, in Goodman and Oibnan's The Pharmacological Basis of Therapeuncs, 8th ed. (New Yottc Pergame~ Pros, 1990), cha~. 22 (522-573), at 533, 543, .5~8. See AR (Vol. 535 Ref. 96, vol. Ill.G). 70 282207285 PRODUCED FROH B&W WEB SITE Federal Re~ister / Vo]. 61, No. 168 / Wednesday, Au~tst 28, 1996 / Rules and Regulations 447~7 I1.A.3. smokers' bodies adapt to nicotine and tolerance to these effects develops.": These and other examples of chronic tolerance (such as faster nicotine metabolism among exp~ricncecl smokers) are consistent with laboratory evidence of long-term structural changes in the brain and other pans of the body from nicotine use."3 There is also epidemiological evidence that the vast majority of smokers and smokeless tobacco users increase their consumption and usage of tobacco products over time. See section II.A3.c.ii., below. This escalation of dose is an additional demonstration of the development of tolerance. Like users of other addictive chugs, tobacco users eventually reach a stable level of consumption."4 Laboratory studies on drug discrimination, psychoactive/subjective effects, self- administration, and withdrawal and tolerance thus demonstrate that nicotine has the properties of an addictive drug. Nicogin¢ corn_mind to saccharin and caffeine. In its comments, the tobacco industry attempts to discount a muhitudc of laboratory studies of nicotine by selectively pointing to a single test used to screen for addictive substances and arguing that, in that test, nicotine's effect was similar to saccbarin's. From tt~ premise, the indusu'y concludes that nicotine is no more addictive than saccharin. This argument misrepresents the published data on saccbarin's and nicotine's properties and overlooks fundamental t12 Department of Health and Hunmn Services, Office on Smoki~ and Health, Pre~miag Tobac~ ~]se Among Young People: A Report of the Surgeon General (Washington DC: Govemngnt Pt~tiltg Offge, 1994), at 138. See AR (VoL 133 Ref. 1596). ~ See section II.A_3.i. and ii., below, for a more detailed disca~ion. ~,4 Jaffe JH, Drug addicticm and drug abuse, m Goodman and Gilman's The Pharmacological Bmis of Therapeutics, 8th ed. (New Yolk: Pergalno~ Press, 1990), chap. 22 (522-532). See AR (VoL 535 Ref. 96, voL III.G). 71 282207286 PRODUCED FROM B&W WEB SITE 44728 Federal Reg/s/er / Vo]. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.3. differences between saccharin and nicotine. Contrary to the tobacco industry's argument, saccharin has not been shown to meet the most fundamental ~ of an addictive drug, namely, psychoactive effects in the brain that account for its appeal to humans and artimals. Nicotine has been shown to have these effects. In contrast to nicotine, which can be pleasurable even when mjecaed intravenously, saccharin is liked primarily because of its taste. For example, rats can be uained to self- administer oral doses of saccharin m preference to water, demonstrating only that mrs prefer the taste of saccharin to that of water. FDA is unaware of any studies, and the tobacco industry cites none, in which rats have self-administered saccharin intravenously. Such a study would be an essential step in proving that saccharin's appeal lies m its effects on the brain. Moreover, there is no evidence that saccharin produces any psychoactive effects. In contrast, nicotine, which produces no such pleasant taste, demonstrates all of the properties of an addictive drug, including self-adminisl~tion and psychoactivity, through its actions on the centzal nervous system. The tobacco indusl~ also argues that nicotine is similar to caffeine in tests of addictive potential. FDA disagzee~ In eompaz~n to the more orderly txtttern of self- adminisnation observed with nicotine and stimulant clings, the pattern ofcaffeine self- ~ ~s Heislm~ SJ, 14mningf~!/E, S~ulus funaims ~'caffeine in hum~s: t~latim to aepmdmce pou~tial, Neuron's, rice and Biobehav~al Reviews 1992;16:273-2~7. See AR (3/ol. 79 P-,e£ 230). C,¢i~lhs RR, W~ PP, Reinfot'ci~g i~ ef caffein~ sl~dies in humans and la~ animals, Pharmacology. Biochemislry and Behavior 1988;29(2):419-427. See AR (VoL 535 Re£ 96, vol. HI.E). Jaffe JH, Drug addiction and drag tbu~ m Goodman and Gilman's 77~ Pharmacological Basis of Therapeutics. 8th ed. (New York: Pergamon Pt~,s, 1990), chap. 22 (522-573), at 524. $¢e AR (VoL 535 Ref. 96. vol. III.G). 72 282207287 PRODUCED FROH B&W WEB SITE Federal Re~ister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rulss and Regulations 447~9 II.A.3. drugs of dependence (e.g., cocaine, morphine, and nicotine), ea/teine has a lower relative dependence potential as well as a low risk of adved~ ¢t~s ill amoul~ etll~lltly ~ ill substance by the American Psychiatric .. ~7 • Association ~d tl~ World Health OIBanization.t~' patterns of sub~an~ consumption. Neal Beaowim, a I~omimm addiction rw, eareh~r, noted that, "[i]n contrast to coffee drinlw~ the vast majority of ei~n~tm smole~s exh~ addictive general abilizy to control intake and minimize undesimbi~ effects of catfeine. Moreover, while nicotine/tobacco addiction is e~mated to be one of the leading eat~ of pre~mur~ death the United Stat~'~° caffeine at customary doses poses f~w risk~ to ti~ individual or to :Is I-le~man SJ, Hetmingfieid JE, Stimulus functiclas ¢Kcaffeine in hmmm~ relatim to~ potml~al, Neuroscience andBiobehaviaral Reviews 1992;16:273-287. See AR (V~L 79 R~ 230). Benowitz NL, Cigarette smoking mad nicotine addiction, Medical Clit~ic$ ~fNorth Anwrica 1992;76(2):415437. See AR (VoL 535 Ref. 96, vol. III.A). ,7 America~ Psychittric Assoeimion" Diagnm~ic and $:a~s~cai Manual of Meraal (Washington DC: American Psychiatric Association, 1994), at 176. See AR (VoL 37 Ref. 8). . i WHO, The IC D- I O Classi.~cation of Mental and 8~havioural Di~r d~r:: Clinical Descripao~ and Diagnasge Guidelines (Geneva" World Health Ot~,anizafioa. 1992), at 75-76. See AR (VoL 43 Ref. 175). ~'~ Benowitz NL, Cigtretle smokiag and nicotine addiction. Medical Clinics of North America 1992;76(2):415-437, at 430. See AR (VoL 535 Ref. 96, voL IILA). ~0 McGinnis JlvL Foc~ WH, Actual tames of dealh in the United Stat~ Journa/o/the Amer/can Medical Association 1993;270(18):2207-2212. See AR (VoL 2 Ref. 15-1). Hearing on Preventiw Health: An O.,nce of Pr~ention Saves a Pound of Cure. Before the Special Comminee on Aging, U.$. Senate, 103d Co~, Ist Sess. 2 (May 6, 1993) ($1atement of Rose~ Herdman, Maria Hewitt. Mary l~tsc.hobet, o~ smoking-zelated deaths and financial costs: Office of Technology Assessment esti.mat~ for 1990). See AR (VoL 170 Ref. 2024). 73 282207288 PRODUCED FROH B&W WEB SITE 44730 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1998 / Rules and Regulations II.A.3. Thus. the average tobacco consur~r---but not the average coffee drinker---uses tobacco despite severe health risks, a c hnical s/gn of addiction.TM In summary, widely publL'ized laboratory studies show that tobacco use, ~ heroin and cocaine use, is a behavioral-pharmacological process in which the individual's continued consumption of tobacco is controlled by a psychoactive and reinforcing drug that exerts its contn31 through the central nervous system.. Thus, nicotine is similar to other addictive drugs in every relevant aspect. For this reason, every scientific authority that has reviewed the results of the laboratory evidence has concluded that nicotine is addictive. ii E~dermological Data Establish That Many Tobacco Users Are Addicted. Numerous well-publicized studies and health surveys have documented the characteristics of nicotine dependence among tobacco users. In the United States, clinical criteria to assess addiction come from the DSM-IV published by the American Psychiatric Association. Several large studies have eonf'trmed that most cigarette smokers qualify for a diagnosis of nicotine dependence. As d~eribed in depth in the appendix to the Jurisdictiohal Analysis, and discussed further in section ILB.2.a., below, as many as 92% of smokers are addicted to cigarettes,t" Smokers are more likely to become addicted than a~ ~ PSychiallic AssoC~,io~ D~gnosti¢ and Statistical Manual of Memal Disorders, 4th ed. (WMi~gtoa DC: Atwxict~ Ps,jcbittric Associttio~, 1994), tt lgl. Set AR (VoL 37 R~f. $). See appendix 1 tO Jurisdictiollal Analysis, at ~2-~7. 5¢¢ AR (VoL 1 Appendix 1). in the Jurisdictional Analysis (60 FR 41576), FDA ~ened to rme~ smokers" as being in the range of 7$% Io 90~. In this document, PDA does not ese'*fn~lue~t" but hither describes the definition of smokers used in each study. See section IIB.~_, below. 74 282207289 PRODUCED FROH B&W WEB SITE Federal Re~i~er / Vol. 61, No. 168 / wednesday, August 28, 1996 / Rules and Regulations 44731 II.A.3. users of other dependence-producing drugs, including cocaine, alcohol, marijuana, inhalants, and heminJ~ Consistent with the malts from these larBe studies, which assessed the prevalence of mcotinc dependence as dot-reed by meeting three or more of the seven criterm for addiction, are the f'mdings of other studies that assessed the proportion of tobacco users meeting individual criteria. Of the seven criteria listed in section II_A.3.b., above, DSM-IV observes that six are readily apparent among tobaoco users: desire to quit or unsuccessful efforts to cut down, use continued despite medical problems, a great deal of time spent using, use of substance m Ire'get amounts and longer than intended, withdrawal and tolerance,ta These results strongly support the conclusion that addiction to nicotine is widespread among smokers. Although there have been no population-based studies using criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM) to assess rates of addiction to smokeless tobacco, substantial evidence demonstrates that a high proportion of smokeless tobacco users meet individual DSM criteria for addiction. This evidence strongly supports the conclusion that a substantial proportion of such users are addicted. In 1992, the Inspector Oeneml of the Depamnemt of Health and Human Services estimated that approximately 75% of young mgulm" users of smokeless tobacco are addicted.~ '2~ Anthony JC, Wame~ LA, Kessler RC, Comparative epidemiology of depeade, m:e tm tobacco, alcohol, controlled subsumces and inlmlams: bmic findings from the National Conm~dity Survey, F-,W~rim,'nm/ and Clinical Psychopharmacology 1994;2:244-268. See AR ~ American Psychia~c Association. Diagnos~c and Statistical Manual of Mental Disorders, 4~h (Washington I~C: Ameti~.an Psychiatric Association, 1994), ~t 243. See AR (Vol. 37 Ref. 8). ~2~ Department of Health and Human Services, Office on Smoking and Healllk 5pit Tobacco and ¥omh (Washington DC: GPO, 1992), atS. See AR (Vol. 7 Ref. 76). 75 282207290 PRODUCED FROM B&W WEB SITE F~cleral R~/~t~r / Vol. 61. No. 16B / Wednesday. August 28. 1996 / Rules and R~gulations II.A.3. Dam demonstrating that a high proportion of smokers and users of smokeless tobacco mcct individual DSM criteria for addiction are now discussed. Desi~ to quit or unsuccessful efforts to cut down. Each year, more than 15 million people in the Umtcd Stams~almost one-third of all daily smokers--try to quit smoking. Fewer than 3% of smokers achieve 1 year of abstinence,t~ Quitting smokeless tobacco is also difficult. In one study, only 2.3~ of smol~l~ss tobacco users at a cessation clinic were able to remain abstinent for 6 months; the study concluded that using smokeless tobacco may be more addicling than ciga~Re smoking.127 The Centers for Disease Conu~ol and Prevention (CDC) found that the greater the ~vel of use of the tobacco pnxluct, the more likely young people were to report that"it's reaUy hard to quit." This increasein difficu~ quimng as the amount of tobacco consumed increases demonstntes a dose-response relationship, one of the characterist/c features of pharmacological effects. This dose-response relationship holds true for both cigarettes and smokeless tobacco used by 10- to 22-year-olds. For example, 74~ of young people who used smokeless tobacco every day reported that it was very difficnlt to quit, compared to only 11% who used smokeless tobacco 1 to 14 days a month,m i~ C.¢a~ for Disease C_.ont~ and Prevention. Smoking cessation during I~evious year amo~ adulm--- United Sates, 1990 and 1991, Morbidity and Mortality Weeidy Reporf 1993;42(26):504-50.7. See AR (VoL 66 Ref. 2). ~ 27 Glove~ ED, Glov~r PN, $molmless tobacco ct~aticm and nicotiae mdaclioa tla:rapy, in $mo~/¢~ Tobacco or Health. an lmernmi~nM Perspective. Sl:~:~king ~ Tobacco ControL NIDA Research Monograph 2, NIH PubLication NO. 93-3461 (Rock"ville MD: Govemmem Priming Offa:~ 1993), at 291- 295. See AR (Vol. "7 Reg. 79-1). t ~s C.eamts for Disease Control and l~vemion, P.t~som for toimcco us¢ and symptoms of nicotine withdrawal arming adolesceats anti young adult tobacco usets~bMimd Statm, 1993, Morbidity and Mortality Weeidy Report 1994;43(41):'~45-750. See AR (VoL 7 Rcf. 76 282207291 PRODUCED FROM B&W WEB SITE Federal R~er / Vol. 61. No. 168 / Wednesday, August 28. 1996 / Rules and Regulations 44733 I1.A.3. Additional studies on the common desire to quit and the failure of the vast majorit~ of attempts can be found in appendix 1 to Jurisdictional Analysis.12~ Use continued despite medical problems. As many as 90% of smokers know that tobacco products are harmful to their own health, 65% of current smokers believe that smoking "has already affected" their health, and 77% of smokers believe that they could "avoid or decrease serious health problems from smoking" if they quit.~30 Yet they keep smoking. Consumers of smokeless tobacco also recognize the health risks of their tobacco use, but do not stop. In one study, 96% of young men who regularly used smokeless tobacco agreed that chewing tobacco and snuff can cause cancer.TM Another study of users age 17 and over revealed that 77.4% believe that smokeless tobacco is a health hazard,t32 People even continue tobacco use in the face of life-threatening, tobacco-related illnesses. For example, studies have shown that about half of smokers who have had See appeadix 1 to Jltlri.qliedit3llal ~dilly~i~ at 52-55. See AR C¢oL 1 Appendix 1). ~ ~ C_mllup GI'L Smoking Prevalence. lleli~fs, and Ac~i~iti~ by Gender and O~her Demographic Indicators (Pmtceton NJ: G~lup Organization, 1993). See AR (VoL 38 Ret'. 43a). ~st Deptgtmettt of Health and Human Sex'vices, Office mt Smo~ ~ Health, Preventing Tobacco Use Among Young People: A Report of the S.rg, on General (WasKu~t~m DC.: Govemmz~ Phnfing Office, 1994), at 101. See AR OIoL 133 Rr~ 1596). ~2 Novomy TE, Piece JP, Fio~e MC, et aL, Smokeless tobacco use in the U~i~vd Slates: the adult use of t0baeco surveys, Monographg~at/ona/C.an~er In.~z/IuIe 1989;8:25-28. $,ee AR (Vol. 41 Red. 109). 77 282207292 PRODUCED FROH B&W WEB SITE 44734 F~derai Rt~ister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.3. surgery for lung cancer resume smoking'" and that almost ~ of smokers who have had their larynxes removed try smoking again.TM Additional data on the use of tobacco prt~lucts despite the health problems they have caused are presented in appendix I to the Jurisdictional Analysis)~s Great deal of time spent using. Studies have demonstrated that tobacco users consume tobacco regularly and compulsively. For example, 90% of smoke~ consume five or more cigarettes every day)~ Over two-thirds of smokers who consume five cigamtes a day smoke their fast Cigareue within the first half-hour after awakening;,137 according to many expem, this need is a key symptom indicating a very significant level of dependence.~ Among users of chewing tobacco and moist snuff over 18, half use the products every day, and the proportion of daily users rises with age."9 The Inspector General of 133 Davison G, Duffy M, Smoking habits of long ml'm survivors of suxgca'y for lung canc~, Thora~ 1982;37:331-333. See AR (Vol 6 l~ef. 58). '~ West R, Himbuty S, Smoking habits after laryngectomy, British Me&~cal Journal 1985;291:514-515. 5¢e AR (VoL 6 Ref. 59). '3~Seeappel~fix 1 tO Jurisdictio~ Analysis, at 56-58. See AR (VoL 1 Appendix 1). *~" BeaowRz N~ Cigm'e~ smoking and akx:~le addiction, Medical Clinics of North America 1992;76(2):415-437. See AR (VoL 535 Ref. 96, voL rnA). Henningfzld J~ Cohen C, Siade JD, Is aicodite mole ad~cbve th~ cocaine? British Jounud of Addiction 1991;86:565-569. $¢¢ AR (Vol. 277 Ref. 3904). ~ ~ Giovino GA. 21m eP. Tomar S, ¢~ d., Ep~em~o~y oyTobac¢o Use ~I Sympmm~ of Nicoti.~ Addiclion in the United Stcaca: A C~ o/Data from large National Surveys, pl~sentali~ of ~e Cemers for Disease Comml and P~evemion to d~e FDA's Drug Abuse Advisory Comm/me (Aug. 2, 1994), $Iid¢ 19 (from National Heal,h Imerview Survey 198"/). See AR (Vol. 459 Reg. "/820). ~ American Psy~c Associal/o~ Diagnostic and Statis~eal Manaal oj~Mental Disorders, 4#a ed. (Washington DC: American Psychiatric A.ssocia~ 1994), 245. See AR (VoL 37 Ref. 8). ~ ~t of Health and Human Services, National Center for Health Statistics, Vital and Health Sta~i~ics: Smoking and Other Tobacco Use: United Sta~es, 1987, Series I0: Data faom the National 78 282207293 PRODUCED FROH B&W WEB SITE Federal Re,g/ster / Vo|. 61, No. 168 / W~sdsy, August 28, 1996 / Rules and R~q.tlations 44735 II.A.3. the U.S. Department of Health and Human Services reported that "our 1986 and 1~2 users typically held their dip or chaw 25 to 30 minums, with most keeping it m over 30 minutes, and often up to one hour. Use of substance in larger amounts or longer than intended.. Few beginning smokers plan to becom~ daily smokers. Yet 90~ of current smokers consume at least five cigarettes a day)41 Smokers also smoke for longer periods than they intend. Among high school seniors from the Monitoring the Future Project (1976-86), almost half of the daily smokers reported that they would either probably or definitely not be smoking 5 years after graduation, t,2 In it follow-up study conducted ~ to 6 years after gxaduation, more ~ than two-thirds were smoking as frequently or more frequently than they had in high • school (26% were smoking at the same level, and 40% were smoking more).|43 Other evidence that users of cigarettes and smokeless tobacco consume more than they intend comes from surveys demonstrating that many people try to quit but faiL For Health Survey, No. 169, Sep. 1989, DI-IHS Publication No. (PHS) 89-1597 (Washington DC: Govcramcat Priming Oflic¢, 1989), at24, 26. £ee AR(VoL 711 Ref. 9). t~ Depanment of Heallh tud Human Setvic~ Ofi~ m Smakiag aed Hesllh, $Pit Tobacco amd Ymah (Washingum DC: Oovemmem Priming Offtce,, 1992), at 7. $~e AR(VoL 7Ref. 76). ~'t Benowir2 NL, Cigan~e smoking and nicotine addiction. Medical Climcs of North America 1992;76(2):415-437. See AR (VoL 535 Ref. 96. voL IILA). Hctmmgfmld JF.. C.o~m C, Sla~c SD. Is nicotine more a~ftctivr, than cocaine? Br~ Jou,'aal of Addiction 1991;86:56.5-.569. S,e AR (VoL 27? R~'. 3904). t,z Ekie~s MJ, Pen'~ CL, Eriksea MP, eta/., The ~ of the Surgeon General: pn:veutmg tobacco use among ymmg~ple, American Journal of Public Health 1994;84(4):543-.547, at 544. See AR (Voi. 38 Ref. 39). 79 282207294 PRODUCED FROM B&W WEB SITE 44736 Federal ~,~/ster / Vol. 61, No. 166 / Wednesday, Aug~s~ 28, 1996 / Rules and Regulations II.A.3. example, two of every five adult users of smokeless tobacco have tried to quit.1~ Additional studies are discussed in detail in appendix I to the Jurisdictional Analysis,'45 Withdn~. In addition to experimental evidence of withdrawal from nicotine described in section ILA.3.c.L, above, persuasive data from epidemiological studies also demons~ate that the vast majority of consumers who abstain from tobacco products experience withdrawal symptoms.1~ Studies show that the symptoms of irritability, nervousness, restlessness, and increased appetite each affect over half of abstinent smokers; indeed, about halfof abstinent smokers q~mlify for a formal diagnosis of Nicotine Withdra'~al Syndrome under the Diagaostic and StmisticaI Manual of Mental Disorders, 3d ed., revised (DSM-ffl- R).''~ Withdrawal symptoms show a dose-response relationship; hea~ier smokers are more likely than light smokers to experience the symptoms of difficulty concentrating, hunger, irritability, restlessness, and sadness when they try to quit.'~* A similar dose- response relationship between the likelihood of withdrawal symptoms and the level of t~" Novomy TE, Pierce JP, Ftcxe MC, et ,d., Sm0keless tol~cco use in the 13ni~ Sm~: the aduh use of tci:mcco sm-vey~ Monogrcq~t~doe~ Cancer ln~g/l~e i¢~9;,8:2.~-28. See AR (Vol. 41 Re/'. 109). '~ Seeappeadix I to Jurisdictioeal Analysis, at 4g-5~. See ~ (Vol. 1Appeadix 1). ~ ~e ~ ! to J~ Anal~is. at 58-61. See AR (VoL 1 Alq~adix 1). ~ Bl~slsu N, Kilbcy MM, Aadmski MA, Nicotine withdrawal symptoms and psychiatric disordas: f'md~ from an cpidcmiologic stlsdy of young adults, American Journal of Prych~awy 1992;149(1):.464- 469. See AR (Vol. 3"; Ref. 18). *" G~ovino GA, 21ru BP, Tom~r S, e~ aL, F~d~m/o/oo of Tobacco Use and Sym~om~ of Ni¢otbse Add~c~oa in ~he Un~ed S~me~: a C.omp~s~on of Dam ~om i.~v~e N~oaa[ Sarv~y~, prescm~ioa of the Ce.mas for Disease Control and Pn;vcoliea m the FDA's Drag Abuse Advisory Committee (Au~ 2, 1994). slides 27-32. See AR (VoL ~59 P.cf. 7820). gO 282207295 PRODUCED FROH B&W WEB SITE F~ler~l .Re~i~ter / Vol. 61, No. 168 / Wednesday. August 28. 1996 / Rul~s and R~ulations 44737 I1.A.3. nicotine intake was found among British schoolgirls~(9 and other populations studied?~° .~ Most people who quit smoking relapse within 1 week,TM when withdrawal symptoms are • at or near their peak.ts2 Smokeless tobacco users typically experience withdrawal symptoms similar to those reported by smokers. In a study of young smokeless tobacco users, over 90% of daily users reported at least one symptom of nicotine withdrawal when trying to discontinue use. Restlessness and irritability were reported by half of daily users during abstinence.' ~3 Tolerance. In addition to laboratory measures of tolerance to nicotine described in section ~l.A.3.c.i., above, epidemiological studies show that users of tobacco products • require increasing amounts to maintain the same effects. The 1991 and 1992 National Household Survey on Drug Abuse found that 12% of smokers 25 years or older and 20% of smokers 12 to 24 years of age who smok~ 16 m 25 cigarettes per day report f~ling the nccd for an increased number of cigarettes over time to obtain the desired clIccts.~s t~9 McNeill AD, West P~, l~.vis NL et al., Cigm'~tm withdrawal symptoms in tdol~sctnt smol~rs, psychopharmacology 1986;9(X4):533-536. S~e AR (VoL 95 Ref. 693). t~* Sm-geon Generars Report. 1988, at 206-207.. See AR (VoL 129 Rel'. 1592). ~ Hughes JR, Gulliver SB, Feawick JW, ~t a/., Smoking cessaticm amcmg self-qeine~, Psychology 1992;I I-.331-33~I. 5~e AR (VoL 348 Ref. $~12). m Hughes JR, Gust SW, Slmog K, et aL, Symptoms of tobacx~ wirJadrawaI: a replication tad exmmicm, Arcbivea ofGenerat Psy~ 1991;48:52-59. See AR (Voi. 129 Ref. 1404). - witlxlmwtl among adole~ems and young ad~lt tobacco users. United States, 1993, Morb/d/ty and Mortality Weekly Repor~ 1994;43(41):745-750. See AR (Vol 7 Ref. I~i). is G-iovino O~ Zlm BP, Tomar $, ~n a/., Epidem/dogy of Tobacco Use and Symp~onts of Addiction in th~ Uniled States: A Compilation of Data J~rom l nv~¢ National Ssrveys, Centers for Disease Cotm~l and Prevention m ~e FDA's Dn~$ Almse Advisory Commitme (Aug. 1994), slide 24. See AR (Vol. 459 Rift. 71~20). $1 282207296 PRODUCED FROM B&W WEB SITE 447311 Federal Reg/sler / Vol. 61, No. 168 / Wednesday, Augusl 28, 1996 / Rules and Regulations II.A.3. Among those who have tried an addictive substance at least once, people who have tried cigarettes are more likely to report the need for larger doses to get the same effect than people who have tried cocaine, marijumm, and alcohol.I~ Most consumers of tobacco products escalate their doses over time. Whereasfew cigareue smokers initially plan robe re~lar daily users, approximately 90% of them consume more than five cig'atettes every day.~ Smokeless tobacco users also increme their dose of nicotine. One study showed a positive relationship among the number of years of smokeless tobacco use, the number of minutes per day of reported use, and urinary nicotine and cotinine Levels. ts7 (Cotinine is a major metabolite of nicotine and an mch'cator of nicotine absorption.) Other studies on dose escalation of tobacco products can be found in appendix 1 to the Jurisdictional The epidemiological data demonstrate that a large proportion of tobacco users are dependent on nicotine and that overwhelming numbers of use~ show signs of addiction. These data complement laboratory evidence proving that nicotine is an addictive substance and have led to the nearly universal scientific recognition of nicotine as a drug whose ~s~ Hem~ingfield/E, Clayton 17,, Pollin W, Involvement of tobacco in alcoholism and illicit drub use, British Journal of Addiction 199~85:279-292, See AR (Vol. 39 Ref. 66). i~ Be~owitz ~ Cib~tte smokinll m~d nicotine ldd/ctio~ Medical Clinics of North America 1992;76(2):415-437. See AR (VoL 535 Re/. 96, voL Ill.A). Hem~ngfield JE. Cohea C, Siade JD, Is ~co~ine more arkfictive than cocaine? BraSh Journal of Addiction 1991;86:565-569. See AR (Vol 277 Ref. '~ World Health ~ 5moh~ Tobacco C, muroL. Report of a WHO ~ Group, WHO Tedmic~ Repro Sines 1~o. 773 (Gema: WHO, 1988), 3~ S~¢ .Air (VoL 7 Ref. 83). ts' See appendix 1 to Jmisdieaomd Amlysis, at 48-51. S¢¢ AR (Vol. I Appendix !). 82 282207297 PRODUCED FROH B&W WEB SITE Federal ~e~ist~r / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Resula~ions 44739 II.A.4. pharmacological effects compel continued use. These widely disseminated public findings establish that a reasonable person in the position of a tobacco manufactu~r would foresee ,tbat tobacco products would be consumed to satisfy an addiction to nicotine)s~ 4. It is Foreseeable That Consumers Will Use CigarelZes and Smokeless Tobacco for Other Pharmacological Purposes In addition to its foreaeeable addictive effects, nicotine produces a range of other well-known and foreseeable significant pharmacological effects of importance to tobacco users. Evidence demonstrating that consumers actually use tobacco products for these effects is discussed in section II.B.2., below. Central Nervous S_vs'tem Effects: Sedation, Stimulation. Mood. and Co~ition. Nicotine significantly alters the structure and function of the brain. At the molecular level, nicotine acts by stimulating receptors on the surfaces of brain ceils intended for natural neurotransmitters such as acetylcholine and by stimulating the release of other key substances such as dopamine:~° Nicotine also changes the brain's molecular structure. Extensive animal research by both the tobacco industry and other researchers shows that nicotine exposure, ranging from a few days to a few weeks, within the range of doses equivalent to those received from smoking ciga~ues, increases the number and changes the functional activity of nicotine receptors in the brain:at In one study, dof, es of nicotine "~ddicting" propm~ of ciganmes is ~ widely dissemin~ed tlm it must be ctmsid~smd fonsraseable. In qu~ities of cigageue smoking are so well Imown that smoke~s nmst be held to have fot~eea them. See section ILC.2.b.iv., below. ~60 See the discussion of doptmiae in the mmolimbic system, section IL A.3.c,i., ~ve. ~ M~ks MI, Butch JB, Collins AC, Effects of d~onic nicotine infusion on tolemge development and nicofme receptors, .loumal oj'Pharma~ology and Experimemal Therapeutics 1983;226:817-82~. See AR (Vol. 41 Ref. 103). 83 282207298 PRODUCED FROH B&W WEB SITE 44740 F~Im'al Registvr / Vol. 61, No. lf~ / Wednesday, August Z8, 1996 / Rulss and Regulations II.A.4. considered equivalent to those received by a fetus of a smoking mother increase the number of nicotine receptors in the brains of newborn rats.te2 Consistent with animal data, cigarette smokers show clear evidence of inca~ased numbers of cerebral nicotine receptors as a consequence of their smoking.'s The result of these molecular actions is that nicotine clinically affects arousal, attention, moocL and, under certain conditions, cognition. Depending on the dose and the ci~umstanc~, nicotine delivered by cigarette smoking can have an arousal-increasing or arousal-reducing effect.J~ This is another respect in which nicotine is similar to such other addictive drugs as opiates, which can have both stimulating and sedating effects. Nicotine's effects on mood and arousal have been confwmed using electroencephalographic (EEG) analysis, a measurement of electrical activity in the brain,j~ When smokers are placed in a stressful situation, smoking can have a depressant Surgeon C, enentl'$ Report, 1988, at 53-54. See AR (VoL 129 Ref. 1592). ~t of Health and Human Services, Office on Sn~)king and Health, Preveming Tobacco Use Among Young People: A Repot: of the Surg#on General 0NashingtOll DC: 131)O, 1994), at 32-33. See AR (Vol. 133 Ref. 1596). ~62 $1otkin TA, Orbtnd-Mille~ L, Queen KL, Developmeut of (~H)nicotine binding sites in brain regioes of rats exposed to nicotine lmmamlly via material injectioes or i~fusiom, ./ourna~ of Pharmacology and F.werimental Therapeu~cs 1987;242:232-237. See AR (Vol. 140 Red. 1656). ~.s Beawell MEM, Balfoer DJK, Ande~oa JM. Evidence that ~ smoking incnmses ~e demity of (-)-[~l]aicotiae bim~R siles in human bmi~ $oumal ofNa~roche~n'y 198&5(k 1243-17A7. See AR (Vol. 136 Ref. 1570). ,e~ Nomm R. Brown K. Howard It. Smoking, nicotine dose and Ibe latexa//salion of electroco~ictl actiyity, Psychopharmacology 1992;108:473-479. $¢e AR (VoL 3 Ref. 22). ~ Priteha.rd WS, Gilbert 13<3, Duke DWo Flexible effec-m of quantified cigm~tte-smoke delivery oa EEG dillle~ional complexity, Psychopharmaeolofy 1993; 113:95-102. See AR (Vol 3 Ref. 23- i ). Ptitchard W$, Eieetroencephalographic effects of cisarelle smoking, Prychopharmacology 1991;104:485- 490. See AR (Vol. 105 Ref. 965), 84 282207299 PRODUCED FROH B&W WEB SITE Federal Re~ster / Vol. 61, 'No. 168 / Wednesday, August 28, 1996 / Ru|es and Regulations 44741 lI.A.4. effect on the EEG profde.~ When smokers are placed in conditions of low arousal induced by mild sensory isolation, cigareue smoking can have a stimulant effect.~6v In other words, smoking can have a relaxing effect m st_re~sful situations and a stimulating effect in otherwise nonstimulating cin:umstances. The tobacco indust~ conealy observes that many substances affect the EEG. But what is significant is not that nicotine affects the EELS, but how nicotine does so. Nicotine's impact on the EEG: (l) is reproducible, (2) is clinicagy significant, (3) corresponds to other physiological and psychological changes of smoking, and (4) is similar to certain EEG changes associated with other addictive drugs such as benzodiazepmes.== Altenxl elec~ical a~ivity of rig brain as dcmonsuated by EF.G is convincing evidence of nicotine's significant ptanzacological effects on rig structure and function of the body. Smokers perform better on some cognitive tests than do deprived smokers, but nicotine does not improve general learning or make smokers generally perform better than nonsmokersJs~ One leading researcher noted that, after a few hotu-s of abstinence, "[P]eople are repotting they can't concentrat~ as well, they can't get the tasks done as PharmacoLogy. Biocht.mLm-y mgf Be/un, tor 1988;29:23-32. See ~ (V~ 3 ~. ~-3). ~ ~ WS, E~ ~ ~ ~ s~ P~~~ 1~1; I ~:~. See ~ ~ 1~ ~. ~). s~ ~d ~ s~ ~ P~~ 1~1~4):~ ~e ~ (V~ ~ ~ 101). *~ ~ WS, E~c eff~ of ~ s~ 1~1; 1~:~54~ at ~, ~. &¢ ~ (VoL 1~ ~ ~). t~ S~ ~'s ~ 1~, at ~1. See ~ (Vo~ 1~ ~. 15~). 85 282207300 PRODUCED FROM B&W WEB SITE 44?47. Federal Register / Vol. 6L No. 168 / Wednesday, August 28, ~996 / Rules and RegulaUons II.A.4. well, and our objective performance battefies confm'n that. They're fight.., it's not just a psychological effect. They really aren't functioning as well"17° Evidence on nicotine's effects on mood and cognition is strongly supported by the work of tobacco industry researchers, who concur that p~ople us~ tobacco for the psychoactive effects of nicotine. These researchers contend that nicotine delivered by tobacco produces psychoactive effects comparable to the effects of prescription wanquilizers. For example, a researcher for the R.J. Reynolds Tobacco Company (PJR), W. S. Pritchard, reported that smoking cigarettes could produce "an EEG effect that in the benzodiazepme literatu~ is associated with anxiet7 relief," leading him to conclude that "'an important smoking motive for deep inhaling smokers might be anxiety reduction" and that his results were consistent with the theory that smoking provides beneficial psychological effects ("psychological tools" or "resources").TM In a significam extension of this work, Robinson et aL concluded that"the beneficial effects of smoking on cognitive performance are a function of nicotine absorbed from cigarette smoke upon inhalation.''l~ These PJR re, searchers performed their study because they thought that, although earlier work with various nicotine preparations was consistent with the hypothesis that people smoked for"psychophannacological effects," ]~o Henningfield J, TramcrilR. ~o the FDA 13vu~ Abuse Advisory Committee, Meeting 27, Concerning Nicofiae-Comaini~ Cigarettes and Other Tobacco Produc~s" (Aug. 2. 1994), at 309. See AR (VoL 255 R=f. ,-,t Pritchard WS, E~© effects of ¢iSatam smokia~ pOcko/,/tez,,mcoto~ 1991:104:485-490, at 485,488. See AR(VoL 105 Re,,f. 965), ~z Robinsoll JH, Pritchard WS, Davis P,A, Psychcohanmcolo~ical effects of smokia8 a ci~rette wilh typical "mr" and cJrbon mo~o~de yields trot ~ ~cofme, Prychopharmacology 1992;108:466-472. ,.fee'/x,,R (VoL 59 Ref. 236), 282207301 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44743 II+A.4. the role of nicotine in cigarettes was inconclusive. They therefore compared standard nicotine-delivering cigarettes to cigarettes that were similar in all other relevant characteristics (e.g., similar gases, tar, etc.) but that provided only "trace" or "minimal" levels of mcotme. The regular cigarettes provided psychopharmacological effects, while 'the minimal nicotine cigarettes did not. One of the leading tobacco industry-funded proponents of the contention that nicotine is not addictive, D. M. Warburton, is also one of the leading proponents of the view that people smoke because of the pharmacological actions of nicotine in the brain, rather than in the mouthJv3 Wafourton argues that nicotine is a "therapeutic agent" that is self-administered by smokers to "control their bodily state''~ 74 and that "the rapid absorption and rapid metabolism make this substance suitable for hour-by-hottr serf- medication because of the personal control [over dosage needs] that can be exercised. In this respect mcotme is superior to other compounds for medication.''i ~5 Thus, the conclusions of tobacco industry-funded researchers support FDA's finding that a reasonable manufacturer would foresee that nicotine in tobacco products produces significant pharmacological effects important to users. Other Effects: Wei_~_ht Regulation. Nicotine also plays a role in weight regulation. The 1988 Surgeon General's Report summarized the available data: In summary, there is substantial evidence of an inverse relationship between cigarette smoking and body weight. Of 71 studies reported since 1970, 62 (87%) collectively indicate that smokers ~3 warburton DM, Nicotine: an addictive substance or a therapeutic agent. Progress in Drug Research 1989:33:9-41. ,.~tt AR (VoL 140 Ref. 1657). ~7'/d. at 11. :75 Id. al 37. 87 282207302 PRODUCED FROH B&W WEB SITE 44744 F~deral l~gister / Vol. 61, No. 168 / Weduesdsy, August 28, t996 / Rul~s and R~ula~ions II.A.5. weigh less than nonsmokers and that people who quit smoking gain weight.... Animal studies indicate that nicotine administration results in weight loss or decreased weight gains and that cessation of nicotine results in body weight gains greater than those of controls [animals that did not receive nicotine] .... Recent research on nicotine polaerilex gum with humans corroborates the role of nicotine in body weiglat effects,m76 Numerous studies show that many tobacco cunsumers use tobacco to control their weight. For example, in two surveys, between one-third and one-half of young people reported that controlling weight was one of their reasons for smoking)77 An extensive discussion of the physiological and cenual nervous system effects of nicotine is available m the 1988 Surgeon General's ReportJTM Thus, aside from addiction, there are other foreseeable pharmacological effects of nicotine use that are important to users; that these effects are actual reasons for consumption is discussed in ~-tion II.B.3., below. $. Cigarettes and Smokeless Tobacco Deliver Pharmacologically Active Doses of Nicotine Currently marketed cigarettes and smokeless tobacco deliver sufficient doses of nicotine to cause addiction and lead to other significant pharmacological effects that cause continued use of the producm. This robust conclusion is supported by published research presented in section II.A., above, and thus is foreseeable to a reasonable tobacco manufacturer. For example, laboratory studies using comme~ia~ cigarenes demonsu~tte that the products contain pharmacologically active levels of nicotine; epidemiological data ~96 S~g~:m General's Report, 1988, at 431-432. See AR (VOl 129 l~f. 1592). 88 282207303 PRODUCED FROM B&W WEB SITE Federal R~i~ter / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44745 II.A.5. show that actual tobacco consumers do become addicted. Four additional types of evidence conclusively demonswate that tobacco products deliver sufficient doses of nicotine: (1) measurements of blood nicotine levels after consumption of tobacco products; (2) laboratory studies using doses of nicotine that are equivalent to those imparted by tobacco use; (3) studies demonstrating that nicotine levels control tobacco consumption behavior (known as "compensation"); and (,~) studies of nicotine replacement therapy. Measurement of Blood Nicotine Level~. Evidence demonstrates that tobacco users receive pharmacological doses of nicotine when they consume cigarettes and smokeless tobacco. A currentlymarketed cigarette typically delivers about 1 mg of nicotine to the bloodstream of a smoker,179 with individual intake ranging from 0.3 to 3.2 mg of nicotine per cigaretteJ~° Studies have also revealed that, with regular use throughout the day, the levels of nicotine in the blood of smokeless tobacco users are similar to those observed in eiga~tte smokers. Data demonstrating that these products deliver substantial, pharmacologically active doses of rti~tine are summarized in the Jurisdictional Analysis. See 60 FR 41571--~1575. Laboratory_ Studies. Long before evidence emerged that nicotine is addictive, studies demonstrated that the quantitative and even qualitative nature of the effects of ~ ~ Benowitz NL, Henninglield IF., Establishing a nicotine threshold for addictio~ Ne~, Eng/and./o,,rna/ of Medicine 199~;331:123-125. See AR(VoI. 12 Ref. 130). Got'i GB, Lynch C_l, Analytical cigarette yields as predictot~ of smoke bioavailability, Regulatory Toxicology and Pharmacology 1985;5:314-326. See ~ (VoL 12 Ref. 142). 1~o Benowitz NL, Henningfield JE, Establishing a mcotine Ila~shold for ~elio~ N~,w England lournal of Medicine 1994;331:123-125. See AR(VoL 12 Ref. 130). 89 282207304 PRODUCED FROM B&W WEB SITE 44746 F~deral Rt~--ter / Voi. 61, No. 168 / Wednesday, Augxtst 28. 1996 / Rules and Regulations II.A.5. nicotine were dependent on the doseJ*1 In the 1980's, particularly important discoveries provided indisputable proof that the mcotme dose levels produced by cigarette smoking affect the structure and function of the body, and that many of these effects are similar to those of prototypic addictive drugs. For example, mcotme, administered in doses considered biologically equivalent to those from tobacco use, was found to affect the brain's use of energy (cerebral glucose utilization),t*: Additionally, nicotine exposure at doses equivalent to those from tobacco use altered the brain so that excess nicotine receptors appeared on the surfaces of brain cells; this structural change was associated with altered responsiveness to nicotine,t~3 In addition, mcotme administered to animals in doses and at intervals compmable to those humans obtain from smoking produces one of the hallmark effects of addictive drugs: brain-mediated reinforcement of self-administration behavior. In the early 1980's, Goldberg and colleagues at Harvard and the National Institute on Drug Abuse provided unequivocal evidence that nicotine in doses comparable to those obtained in humans could See Surgeon Genaal's P, el~Ort, 1"988, chtl~. 2-6. See AR (Vol. 129 Ref. 1592). ld. at 85-88. tt3 Marks MJ, Btttr.h JB, Collint AC, Effects of chronic nicotine infusion on tolerance development and mcoune receptors, ./ourrm/of Pharmacology and Experimental ~'herapeurica 1983;226:817-825. ,See AR (VoL 41 Ref. 103). Surgeon General's Report, 1988, at 53-54. See AR (VoL 129 Ref. 1592). ld. at 32-33. Benwell MEM, Balfour D/K, Anderson JNL Evidence that tobacco smoking inazases the density of (-)-[SH]nicotine binding sites in human brai~ Journal of Neurochemi~ry 1988;50:1243-1247. See AR (Vol. 136 Ref. 1570). 282207305 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rubs and Regulations 44747 II.A.5. function powerfully to engender repetitive drug-seeking behavior in monkeys,ts4 In the late 1980's, Corrigall and Coen developed a rat model utilizing key dosing parameters of ~igarette smoking and smokeless tobacco use. This model provided for the delivery of very rapid and small doses and led the animals to repeatedly administer nicotine to themselves,ls~ Nicotine Control of Tobacco Use. Nicotine's key pharmacological role in actual tobacco products is also confirmed by evidence that tobacco users adjust their consumption based on the products' nicotine levels. Man/puhtion of nicotine levels in .maintenance of cigarette smoking behavior. Cigarette srnokms given eiganmes with a high nicotine content decrease the number of cigarettes smokedJ.6 Modifying the amount of nicotine available by varying the length of ciga~te smoked will influence the amoum ofthe cigareae smoked~s~ and the chal~aeri~cs of smoldng (e.g., number of puff~ puffdura~n, puff size, depth of in~ation, amount of ~ol~x~o smoked),m When cigareues are shorter, ~u Goidber8 SR, Spealman RD, Goldberg DM, Pe~isteat behavior at high nues ~ by intravenous setf-~tratinn of nicotine, So/ante 1981;214:573-575. S~ AR (Vd. 5 Re£ 35-2). ~ ~ Comgall WA, Coen KM, Nicotine ~ robust sell-administration in rats on a limited acc~s schedule, Psychopharmacology 1989;,99:473-478. See AR (VoL 347 Ref. 5495). ~ '6 ~ T, Grdz ER, Jarvik ME, eta/. RenaJ0m ~ ciga.-el~ as a funai~ c/" nicmine and "far," C//n/ca/ Pharmacology and ~rapeur~s 1976;1~767-772. See AR O/d. 39 R~ 53). ~ Jarvik M~ Pq:gk P, Schneider NG, e~ a/., Can ci~'~e size and n/co~e cc~mt influmce sm~ng and puffang rates? Psychopharmaco/ogy 1978;58:303-306. See AR (VoL 41 ~ 86). ~*s Surge~a General's Relx~ 1988, at 158-1153. See AR(VoL 129P-~ 1592). 91 282207306 PRODUCED FROM B&W WEB SITE 44748 Federal Register / Vol. 61. No. 168 / Wednesday. August 28, 1996 / Rules and Regulations [I.A.5. people smoke rflol'e of Ihen'L189 Nemcth-Coslett and Griffiths showed that puff duration and • puff volume are inversely proportional to the length of the c~ucttc. provide convincing evidence that tobacco products provide ~logk:ally active doses of rlilsotine. PretreaLrr~rlt of ci~tIette sl~skcIs with l~a~al~,le, all al]Iagot2~ U3 [ik~ot.il~ that enters the brain, produced a dose-dependent increase in cigarette smoking (i.e., increases in puffs per cigarette, puff duration, and cigan~es per session and ~ in intercigarette in the cigaw~e had been decreased. An increase in nicotine plasma levels also accompanied the enter the train had n~ such effects. These studies clearly demonswate that obtaining a pharmacobgically active dose of ni~tine in the brain m~fivates the amount of tobacco consumed on a daily trois. Evidence fi'om Nicotine Replacement Produ~s. As described in the Jurisdictional Analysis, 60 FR 41565-41566, the ability of nicotine nasal spray to produce some of the classic characteristics of addiction to nicotine supports the position that tobacco users ~*o Surgem General's Reix~ 1988, at 161. See AR (Voi. 129 Re£ 1592). ,9~ Stoicrman IP, Goldfarb T, Fink R. eta/., Influencing cigarct~ smoking wi~ mmtine an~t~snir~ Psychopharmacolog~a 1973;28:2A7-7.59. See AR (Vol. 42 Ref. 149). ) 92 Nemeth-Cosleu l~ Henningfieid JE, O" Keffe MI~ ctal., Effects of mecamyhlzl~c o~ hmam~ ciga~tte smoking and subjective ra~ings, Psychopharmacology 1986;88:420-425. See AR (VoL 41 Ref. ~*~ Pomerleau CS, Pomerleau OF, Majchtzak MJ, Mecamylanlille pfelxea~ent increases subseqllelit nicotine serf-administration as indicated by change~ in plasma nicotine level~ Psychopharmacology 1987;91:391-393. See AR (VoL 42 Ref. 112). 92 282207307 PRODUCED FROM B&W WEB SITE Federal .Register / Voi. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44749 II.A.5. seek nicotine primarily for its systemic pharmacological effects and not for its acute sensory effects. In contrast to cigarette smoke, aqueous nicotine spray does not provide ~the user any pleasing sensory characteristics. In fact, the spray can be irritating and ~npleasant to use, and excessive use can cause ulcerations of the nasal mueosa. Notwithstanding the unpleasantness of the nicotine delivery mechanism and the presence of painful ulcerations that were further aggravated by its continued use, the spray was used to maintain nicotine dependence for some participants in clinical trials submitted to 17DA.t~4 Studies of nicotine replacement therapies also demonstrate efficacy in maintaining abstinence from smoking}9~ The ability of nicotine to promote abstinence, even when delivered through the skin, without any taste or flavor, demonstrates its key role as a reinforcer of tobacco consumption. Based on these data, among others, organizations with expertise in pharmacology and addiction have determined that cigarettes and smokeless tobacco deliver pharmacologically active doses of nicotine. In the 1986 analysis of smokeless tobacco, the Surgeon General determined that smokeless tobacco use can be addictive.I~ In 1988, after an even more extensive consideration of the potential addictiveness of nicotine, the Surgeon General determined that: (1) "cigarettes and other forms of tobacco are addicting;" (2) "nicotine is the drug in tobacco that causes tu FDA Drug Abuse Adviso~ Commitlee Backgroend Information (Aug. 1, 1994), Joint kbese Litbility Review of Nicotine Nasal Spray. See AR (VoL 9 Ref. 117). ~9~ 3ee appendix 1 to Jurisdictional Analysis. See AR (VoL 1 Appetldix 1). 1~ Deparmaent of Health and Human Se~,ice~ Public Health Service, The Health Consequences of Using Smokeless Tobacco: A Report of the Advisory Committee to the Surgeon General, 1986, NIH Pllbficafton No. 86-2874 (Bethesda MD: DHHS, PHS, 1986) (hereinafter cited as Surgeo~ General's Relxgt, Smokeless Tobacco. 1986), at viii. See AR(VoL 128 Ref. 1591). 93 282207308 PRODUCED FROM B&W WEB SITE 4475O F~leral R~gister / Vol. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations II.A.6. addiction;" and (3) "the pharmacological and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine."'~7 On August 2, 1994, FDA's Drug Abuse Advisory Committee, an independent group composed primarily of experts on addiction science, concluded that nicotine as delivered by commonly used tobacco products can produce strong physiological effects, including addiction.~ 9~ 6. Conclusion Nicotine is addictive and produces foreseeable psychoactive and pharmacological effects in a substantial proportion of tobacco users. This conclusion is so robust---and the evidence for it is so voluminous--that every major public health organization and relevant scientific authority in the world is in agreement. It is FDA's responsibility to base its regulatory actions on well-founded and accepted scientific facts. In this case, FDA believes that a very strong scientific basis exists on which to conclude that it is foreseeable that nicotine will produce pharmacological effects in a substantial number of tobacco consumers and that those consumers will use tobacco products to satisfy their addiction and to obtain the other pharmacological effects of nicotine. To conclude otherwise would not be credible. ~97 Sttrgeoa General's Report, 1988, at 13-17. See AR (Vol. 129 Ref. 1592). ~ ,s Transclipt to the FDA Drag Abm¢ Advisot~" Commitlee, M~ 27, "~ Coning Ni~- Conm~g Cig~et~s-~d ~er T~ ~uc~" (Aug. X 1994), ~ 33~342. See ~ (Vol. ~5 ReI. 3~5). 94 282207309 PRODUCED FROM B&W WEB SITE FederM Register / Vol. 61, No. 168 ! Wednesday. August 28. 1996 ! Rules and Regulations 44751 II.A.7. 7. Response to Additional Comments a. Comments on the Professional Consensus That Nicotine Is Addictive 1. More than 150 professional health organizations or chapters, representing over 600,000 individuals and organizations, oommented on whether nicotine is addictive. Virtually all concluded that it is. These groups include the following: • The American Cancer Society • The American College of Physicians • The American Heart Association • The American Lung Association • The American Medical Association • The American Psychiatric Association • The American Psychological Association • The American Society of Addiction Medicine • The College on Problems of Drug Dependence • The Society of General Internal Medicine • The Society for Head and Neck Surgeons • The Society for Research on Nicotine and Tobacco • The Virginia Society of Hospital Pharmacists FDA also notes that, of the more than 1,100 physicians, pharmacists, and other health professionals who commented on whether nicotine is addictive, virtually all agreed that it is. The Agency concurs with the unanimous conclusion of these organizations, most of which have expertise in this area. FDA notes that organizations with vast experience 95 282207310 PRODUCED FROM B&W WEB SITE 44752 Federal R~gister / Vol. B1, No. 1B8 / Wednesday, August 28, 1996 / Rules and Regulations I1.A.7. examining other addictive drugs reached the same conclusion as organizations with vast experience studying nicotine. The former organizations include the American Psychiatric Association, the American Society of Addiction Medicine, the National Institute on Drug Abuse, and the World Health Organization. The latter include the American College of Chest Physicians and the Surgeon General'~ expert committees on tobacco. '2. The tobacco industry disputes the process by which the American Psychiatric Association concluded that nicotine is addictive. The industry quotes se~teral critical comments about the Diagnostic and Statistical Manual to suggest that the entire DSM structure of classifying all psychiatric diagnoses is flawed. Th/s position, held by a small minority of psychiatrists, has been decisively rejected by the profession as a whole. The DSM-IV is now used throughout the world to classify psychiatric disorders, including drug dependence. IDA notes that, aside from this argument against the American Psychiatric Association, the industry does not dispute the expertise or decision-making capabilities of any of the other medical authorities originally cited by FDA. These authorities--which unanimously have concluded that nicotine is addictive--include the U.S. Surgeon General, the World Health Organization, the American Medical Association, the American Psychological Association, the Royal Society of Canada, and the Medical Research Council of the United Kingdom. b. Comments on the Definition of Addiction 1. Several tobacco industry comments argue that cigarettes and smokeless tobacco are not addictive under a now-discarded definition of addiction developed in the 1950's and used by the U.S. Surgeon General in 1964. 282207311 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44753 II.A.7. FDA disagrees with these comments. First, the tobacco industry borrows only selectively from the 1950's definition of addiction, emphasizing only certain criteria from t~t definition. Second, while the scientific community has rejexaed this historical definition in part because it failed to clearly classify cocaine and amphetamines as addictive, see section II.A.3.b., above, subsequent evidence has shown that nicotine would now qualify as addictive even by this outdated defimtiom The criteria cited by the Surgeon General,~99 which were not met by mcotine on the basis of data available in the early 1960's, are all met on the basis of dam available today. These include the following: • Surgeon General's 1964 conclusion: No overpowering compulsion to use the drug. $~Jlosea.uent data: Ample documentation exists today that persons dependent upon cocaine, heroin, or alcohol find it as difficult to abstain from tobacco as from these other drugs and that persons who know that their lives are in imminent danger from smoking nevertheless continue to smoke.2°c • Surgeon General's 1964 conclusion: No tendency to increase the dose. t~ Dcparunent of Health, Education. and Welling, Public Health Sea'vice, Smoking and Health: Report of the Advisory Comminee to the Surgeon General of the Public Health Service (Vl~.slftllgton DC.: GPO, 1964), at 349-352. See AR (Vol 43 Rcf. 156). ~ Henaingfield JE, Cohen C, Slade JD, Is nicotine more addictive than cocaine? British Journal of Addiction 1991;86:565-569. See AR (VoL 277 Ref. 3904). Kozlowski LT, Wilkinson DA, Skinner W, et al., Comparing tobacx, o cigarette dependence with other drug dependencies, Journal of the American Medical Association 1989;261:898-901. See AR (Vol. 84 Rcf. 350). West R, Himbury S, Smoking habits after laryngcctomy, British Medical Journal 1985;291:514-515. See AR (Vol. 6 Ref. 5~). Davison G, Duffy M, Smoking habits of long term survivors of surgery for lung cancer, Thora~ 1982:37:331-333. See AR (Vol. 6 Rcf. 58). 97 282207312 PRODUCED FROH B&W WEB SITE 44754 Federal Register / Vol. 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.7. Su[~sequent data: We now know that only about 10% of cigarette smokers are able to sustain a level of intake of five or fewer cigarettes per day. For example, one study found that 90% of people who smoke escalate to daily doses of five or more cigarettes.~'°l Cigarettes are similar to morphine-like drugs in that, when either substance is readily available to the user, intake often escalates over a period of months or years and then stabilizes at a level that may vary little from day to day for many years.2°2 Surgeon General's 1964 ¢oncl.usion: No physical dependence on the effects of the drug. Subsequent data: The documentation that nicotine produces physical dependence has now been provided by scores of clinical treatment studies and laboratory studies with humans and animals.2°3 There is a characteristic .,01 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Climes of North America 1992;76(2):415-~,37. See AR (Vo[. 535 Ref. 96, vol. Ill.A). Heuningfield JE, Cohen C, Slade JD, [s nicotine more addictive than cocaine? British Journal of Addiction 1991;86:565-569. See AR (Vol. 277 Ref. 3904). zo~ Ja£fe JH, Drug addiction ~d drug abuse, in Goodman and Gilman's The Pharmacoio~ic~ Basis of Therapeutics, 8th ed. (New York: Pergamon Press, 1990), eAaap. 22 (522-573). See AR (VoI_ 535 Ref. 96, vol. III.G). z0.~ Henningfield JE, Cohen C, Slade JD. Is nicotine more addictive than c~caine7 British Journal of Addiction 1991;86:565-569. See AR (Vol. 277 Ref. 3904). Koz[o~'ski LT, Wilkinso~ DA, Skinner W, et al., Comparing tobacco cigarette dependence wir~ olher drug dependencies. Journal of the Ame~'ican Medical Association 1989;261:898-901. See AR (Vol. 84 Ref. 350). Surgeon General's Report, 1988, at |45-240. See AR (Vol. 129 Ref. t592). Corrigall WA, Hcrlin8 S, Coen KM, Evidence for a behavioral deficit durin8 withdrawal from nicotine treatmenL Pharmacology Biochetrustry and Behavior 1989; 33:559-562. See AR fVol. 139 Ref. 1626). 98 282207313 PRODUCED FROM B&W WEB SITE F~der~! R.egister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44755 II.A.?. tobacco withdrawal syndrome that has been recognized by leading medical organiTations.2°~ * . Surgeon General's 1964 conclusion: Detrimental effects on society are not well documented. Subsequent data: The detrimental effects on smokers themselves were recognized in 1964; however, it was not until the 1980's that the direct adverse effects of smoking upon nonsmokers and the fetuses of pregnant smokers were unequivocally documented.2°s Moreover, it is now recognized that nicotine has a severe adverse economic impact on many aspects of society.2°~ In addition to these four specific criteria, the Surgeon General in 1964 mentioned several other reasons for failing to categorize nicotine as addicting. These conclusions and the current data are as follows: . Surgeon General's 196zl conclusion: Cigarette smokers did not become intoxicated. Levin ED, Morgan MM, C_raivez C, et al., Chrot~c ~:otin¢ ~d withdr~wtl ¢ff~ts ® body weight ~ld food and water consumption in female rats, Physiology and Behacior 1987; 39:441--444. See AR (Vol. 278 Re£ 3932) American Psychiatric A.~soci~.tiOlk Diagnostic and Statistical Manual o/Mental Disorders, 4111 ed. (W~kiagtoa DC: Amexiean Psychiatric Association. 1994), tt 244-245. See AR (Vol. 37 P~I. 8). ~os Department of Htalth and Human Servicer~ Office oil Smoking ~ Health, The Health Consequences of Involuntary Smoking: A Report of the Surgeon Genera/(Atlan~ DHHS, 1986) (het~inaI~ cited ~s S wcgeon General' s Repor~ Involuntary Smoiting, 1986). $¢e AR (VoL 128 l~f. 1591 ). 2~ McOinnis JM, Foege WH, Actual causes of death in the Uniled State~ Journal of the American Medical Association 1993;270(18):2207-2212. See AR (Vol 2 Re/. 15-1). Hearing on Preventive Health: An O~nce of Prevention S~ves a Pound o/Cure, Before the Sl~cial Comminee on Aging, U.S. Senate, iff3d Cong., 1st Se~s. 2 (May 6, 1993) (statement of Roger Hentman, Maria Hewitt, Mary Laschober on smoking-related deaths and financial ¢,e~ls: Office of Technology A~sessm~t Estimates for 1990). See AR (VoL 170 P.~. 2024). Hodgson TA, Cigaxctte smoking aad lifetime medical cxl~nditutes, National Center for Health Suttistics, Milbank Quarterly 1992;70(1):81-125. See AR (VoL 19 Re/. 22). 282207314 PRODUCED FROM B&W WEB SITE 44756 Federal Register / Vo|. 61, No. 168 / Wednesday, August 28, 1996 1 Rules and Regulations II.A.7. Subsequent data: It is now well understood that nicotine can intoxicate, intoxication is a sign of nicotine overdose, and first-time users often become intoxicated.2°7 The ability of nicotine to produce strong physiological and behavioral effects, including death at high doses, is no less than that of amphetamine or morphine,z°~ In practice, intoxication is rarely evident in regular users because they have developed an extremely high level of tolerance to this effect of nicotine,z°9 • Su~eon General's 1964 conclusion: Subjective effects of nicotine itself were not well documented. The 19~2 study by Johnston showing that intravenous nicotine could mimic the effects of smoking21° was apparently given little weight because the study did not have the appropriate control conditions to rule out bias. Subsequent data: By the 1980's and 1990's, many properly controlled studies using nicotine delivered intravenously, intranasally, and by inhalation essentially confirmed Johnston' s findings,zt t 207 Surgeon General's Report, 1988, at 593-594. See AR (Vol. 129 Ref. 1592). ~os Id. at 2"72-274, 594. 2o~ ld. at 593-595. 2~o Johnston LM, Tobacco smoking and nicotine, Lancet 1942;2:742. See AR (VoL 278 Ref. 3947). 2tJ See. e.g.. Jones RT, F~xt~ll TR I~ Hmliag RI, To~ac~ smolang ~nd nicotill¢ Administration of Abused Substances: Methods for Study, ¢d. Mo~:)~ph 20 (Rockville MD: Naficoal Imfi-,u~ on Drug Abuse, 197g), at 202-20g. See AR (Vol. 41 Ref. ~d inhal¢~ mo:~dne, Journal of Pharmacology and F_.l~erim~ntal Thcrat~utics 1985;23~: 1-12. See AR (Vol. 39 Ref. Pomerleau CS, Pomerleau OF, Euphoriam effect of nicotine in smok~t~, Psychopharmacotogy 1992;108:460-465. See AR (Vol. 87 Ref. 426). Perkins KA, Grobe JE, Epstein LH, et al., Chronic and acute tolerance to subjective effects of nicotine, Pharm~cology, Biochemistry and Behavior 1993;45:375-381. See AR (Vol. 27l Ref. 3728). 100 282207315 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44757 II.A.7. Surgeon General's 1964 conclusion: No well-controlled demonstration that nicotine substitution could facilitate tobacco abstinence. $ubsequent data: The absence of a nicotine-delivering medication effective in helping people to achieve abstinence was also noted in the 1964 report. There is now powerful evidence that products devoid of any tobacco constituent except nicotine are effective aids to smoking cessation and to providing relief of withdrawal symptoms)t2 Su~eon General's 1964 conclusion:. Personality deficit criteria did not appear satisfied. Subsequent data: It was" noted that not categorizing tobacco use as an addiction avoided the inference that smokers would be considered to have "serious personality defects" under the definition of addiction then in place. We now understand that many people who develop addictions to cocaine, heroin, alcohol, or nicotine have no documented underlying personality disorder. Rather, the major cause of addiction is Perkins KA, Grobe JE, Epstein LH, et aL, Effecm of nicotine on subjective arousal may be dependent on baseline subjective state, Journal of Substance Abuse 1992;4:131-141. See AR (Vol. 34~ Ref. 5516). Suthcflaad G, Staplcton JA, Russell MAlL e: al., P-,~domi.ced coalrollevd trial of tmsal nicotine spray in Sl~Okilag cessation, Lancet 1992;340:.324-329. See/fit (VoL 91 l~f. 527). Sutherland G, Russell MA, Slapieton J, et al., Nasal ~fi~otine spray:, a rapid mcofme delivery system. PsychotTharmacology 1992;10~:512-518. See AR (VoL 91 Ref. 526). 212 Fagmstrom KO, Sawe U, Tonnesen P, Therapeutic use of nicotine patches: efficacy and s~fety, Journal of Drug Development 1993;5:191-205. See AR (Vol. 76 Ref. 156). Fiore M C., S mi~ SS, Joreaby DE, et al., The effectiveness of the nicotine l~ld~ for smoking cessation" a recta-analysis, Journal of the American Medical Associatian 1994;271:194~-1947. See AR (Voi. 6 Ref. 64-I). I;iore MC, Jorenby DE, Baker TB, et al., Tobacco dependence ~nd tile llieotine l~tch, Journal of the American Medical Association 1992;268:2687-2694. See AR (Vol. 351 Ref. 5609). Surgeon General's Report, 1988, at 208. See AR (Vol. 129 ReL 1592). 101 282207316 PRODUCED FROM B&W WEB SITE ~1758 Federal Register / Vo|. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.7. the presence of a psychoactive, reinforcing drug and adequate access to the drug to enable the development and sustenance of addiction. Thus, it is virtually certain that tobacco use would be considered an addiction under the definition used by the Surgeon General in 1964. Indeed, FDA notes that a study sponsored by the tobacco industry in 1963 concluded that tobacco was addictive under the same definition used by the Surgeon General in 1964.213 2. The tobacco industry observ .es that definitions of addiction from several medical authorities are not identical, quotes several experts stating that whether tobacco is addictive depends on the definition of addiction, and presents excerpts from several scientific publications to suggest that no precise definition of addiction exists. The industry also argue.s that the use of the word "addiction" rather than "dependence" is political and claims that the modern clef'tuition of addiction is motivated by public health goals, morality, and lawsuits. The industry concludes that the modem definition of addiction is inappropriate for use in considering whether a product is a drug under the Act. FDA disagrees. As discussed in section II.A.3.b., above, there is remarkable consensus among medical authorities around the world on the meaning of addiction. The subtle variations among written definitions reflect wording and emphasis, not significant differences in concepts; such variations are not surprising, given that medical organizations often write their own definitions of diseases and disease progression. International consistency on the meaning of addiction is demonstrated by the fact that all relevant :~ Kaapp PH, Bliss CM, Wells H, Addictive aspects in heavy cigarette smoking, American Journal of Psychiatry 1963; 119:966. See AR (Vol. 528 Ref. 97, appendix 16). 102 282207317 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and RegUlations 44759 II.A.7. scientific bodies have concluded that nicotine is addictive. Indeed, the tobacco industry fails to suggest any reason to believe that the current international understanding of nicotine as addictive will change in the future. The mdustry's quoting of addiction experts on the importance of defining addiction is not an a,-gument against FDA's position. It is axiomatic that whether nicotine is addictive depends on the definition of addiction. The industry fails, however, to show that nicotine would not be considered addictive under any of the current definitions of addiction. The industry's use of an article from the Journal of the American Medical Association to show that the definition of addiction is imprecise is equally unpersuasive.2t4 The article describes how a national panel was appointed in 1983 to try to settle variations in defimtions relating to substance abuse. The panel surveyed dozens of experts from major scientific orgamzatiom and produced a consensus definition of addiction: "A chronic disorder characterized by the compulsive use of a substance resulting in physical, psychological, or social harm to the user and continued use despite that harm.''~t5 This definition again is entirely consistent with the modem definition of addiOon relied on by FDA, not the tobacco mdustry's preferred version from the 1950's. The industry selectively quotes from several scientific publications that discuss subtle arguments over the precise definition of addiction. But these debates occur within a 2~, Rmaldi RC, Steindler EM, Wilford BB, er al., Clarification and standmdization of subsmuce abuse temainology, Journal of the American Meddcal Association 1988;259(4):555-557. See A.R, (Vol. 535 Ref. 96 vol. Ill.L). 103 282207318 PRODUCED FROM B&W WEB SITE 447@I} Feder~d~ R~ister/ Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations II.A.7. broad understanding of addiction that has garnered overwhelming consensus. This understanding universally considers nicotine to be addictive. FDA, like many scientific and public health authorities, uses "addiction" and "dependence" interchange, ably. Regardless of the terminology used, the concept that nicotine has substantial pharmacological effects on the brains of users that cause people to use tobacco compulsively is the same. Furthermore, any implication that the modem scientific understanding of addiction is motivated by public health goals, morals, or lawsuits is mistaken. As discussed in section II.A.3.b., above, the tobacco industry's preferred definition was discarded on scientific grounds in 1964, 15 years before nicotine was first considered addictive. ~ Thus, there is no basis upon which to conclude that FDA's f'mding that mcotine is addictive--a conclusion with nearly universal scientific backing--is not useful in determining whether nicotine is a "drug" under the Act. The fact that nicotine meets all currently accepted scientific definitions of a dependence-producing drug and that these definitions include as a criterion psychoactive effects on the brain is highly relevant to the Agency's mqtm-y. c. General Comments on Laboratory Evidence of Acklictive Potential -I. Conm~nts from nun~rous health professionals and scientists agree with FDA that laboratory data in animals and hurmm provide con,~lling evidence tlmt nicotine in cigarextcs and sn~keless tobacco is a pharmacologically active agent that causes addiaion. For example, the American Medical Association stated that it "concurs with the sciantific rationale and legal basis for the FDA proposed action," and that it "strongly supports the sciemific basis regarding mcotine.., and its essential role in maintaining demand for tobacco I04 282207319 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 447§1 II.A.7. products." Similarly, the Coalition on Smoking OR Health---an organization representing the American Heart Association, American Lung Association, and American Cancer Society-- carefully reviewed the Jurisdictional Analysis "for accuracy, objectivity, and completeness" and concluded that "[he FDA documents represem the most comprehemive, objective and scientifically accurate analysis of the impaa of nicotine containing cigarettes and smokeless tobacco on the body ever conducted." 2. The tobacco industry repeatedly comments that evidence from one laboratory test by itself is not enough to justify the conclusion that nicotine is addictive. For example, the industry argues that positive results in drug discrimination tests in animals are not sufficient to prove that nicotine.is addictive, as some nonaddictive substances also test positive. The industry repeats this same argument for subjective effects testing and animal self-administration studies. On several occasions, the industry uses quotations from addiction experts to support these arguments. FDA agrees that evidence from each test a/one may not prove conclusively that nicotine is addictive. But addiction author~.ies around the world determine whether a substance is addicting by considering results from all of the tests together. Nicotine tests positive in animal and human drug discrimination tests, subjective effects tests, and animal and, human self-a&rdnigmtion tests. Considering such evidence, the sciemiTac community has overwhelmingly concluded that nicotine is addictive. The tobacco industry's selective use of quotations from addiction experts illustrates the point. On several occasions, the industry tries to make it appear that the individuaJs quoted believe that addiction testing methods are not reliable or that nicotine is not addictive. In fact, these individuals are on record as reaching the opposite conclusions. For example, the 105 282207320 PRODUCED FROH B&W WEB SITE Federal Register / Vot. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations ) II.A.7. tobacco industry, selectively quotes from the work of Balster that "It]he results of self- administration studies should not be used alone for evaluating abuse potential. A number of drugs which probably possess minimal or no abuse potential have been shown to function as reinforcers in preclinical drag self-administration studies." 2~6 The industry also culls a quote from Woods that "lilt should be clear that the proposition, viz., that the drugs that serve as reinforcers in animals are abused by humans, is greatly oversimplified.''2~7 In both cases, however, the authors believe that demonstrating that a drug tests positive in both self-administration studies and drug discrimination studies is sufftcient evidence of its abuse liability,zL~ Nicotine has repeatedly proved positive in both tests. d. Comments on Tests of Psychoactivity 1. The tobacco industry disputes FDA's analysis of drug discrimination tests in animals. The industry argues that the purpose of drug discrimination studies is merely to demonstrate that the test subject "recognizes" or "identifies" a substance that has been admimgtered. The industry further claims that laboratory animals have been able to 2~6 Balster RL, Drug abuse po~ntial evaluation in animals, British Journal of Addiction 1991;86:1549- 1558, at 1555. See AR (Vol. 8 Ref. 89). ~ Wools J, Sortie thoughts on the relations between animal and human drug-taking, Progress in Neuro- psychopharmacotogy and Biological Psychiatr." 1983;7:577-584, at 582. See AR (Vol. 535 Ref. 96, vol. I[I.N~. :t~ Balster RI., Drug abuse potential evaluation m animals, British Journal of Ad,t,'ction 1991 ;86:1549- 1558. at 1555. See AR (Vol. 8 Ref. 89). Woods J, Some thoughls on the relations between animal and human drug-taking, Progress in Neuro- psychopharmacolog3." and Biological Psychiatry 1983;7:577-584, at 582. See AR (Vol. 535 Ref. 96, vol. III.N). 106 282207321 PRODUCED FROH B&W WEB 8ITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44763 II.A.7. discriminate tricotine in the studies cited by FDA because researchers used amounts of mcotine that vastly exceed the nicotine yields m commerctal cigarettes. , FDA disagrees. Drug discrmaination studies are not just a measure of whether or not the subject can "'recogni~" or "'identify" a substance; these studies assess the psychoactivity of a drgg. Drugs that can be successfully discriminated from placebo are psychoactive.~9 FDA also disagrees that animals can di.~-'riminate nicotine's stimulus properties only when receiving doses that vastly exceed those absorbed by human smokers. It is misleading to make a duect comparison between the training dose administered to animals and the nicotine yields of commercial cigarettes. Pharmacological effects elicited by a drug are the result of its plasma concentration and the amount of drug at the receptor site (i.e., site of action), not necessarily of how much drug is in the product or the amount of drug administered per kilogram of body weight. This distinction becomes critical when comparing animals with different abilities to metabolize drugs. The same amount of drug per kilogram administered to two species may lead to radically different plasma concentrations, for example, if one specr.s breaks dov, aa and excretes the drug faster than the other. A study by Pratt et al.~2° Oed by the conm3em actually demonstrates that doses of nicotine that can be discriminated by rats yield a plasma concentration of " .nk:gtine that is compaJable to the plasma concentration of nicotine in htumn smokers. Accordingly, rats can learn to discriminate a dose of nicotine physiologically comparable to the dose received by z~9 Surgeon General,s Report. 1988. at 170-171. See AR (VoL 129 Rcf. 1592). :z: Pratt J A. S tolerrnan IP, G-arc.ha I-IS, et a/., Diso~ainative stimulus prop~es d nicotin~ funhe~ evidence for mediatitm at a cholinergic recepta-. P.sychopharmacology 1983;81:54-60. See AR (Vol. 8 l/.e.~ 90-2). 107 282207322 PRODUCED FROH B&W WEB SITE Register / Vol. 61, No. 168 / Wednesday, August 2B, 1996 / Rules and R~.~guiations II.A.7. cigarette srnoker~ and smokeless tobacco users. Two studies by Stolerman et al.?:~ ~ demonstrated that rats can discriminate from saline a dose of nicotine that is comparable to the dose delivered to human tobacco users. 2. The tobacco industry argues that nicotine's action as a discriminative stimulus is not exactly the same as that of cocaine and amphetamine. _ It is well known that nicotine does not behave identically to cocaine and amphetamine in drug discrimination experiments. This difference does not mean that nicotine is not an addiaive drug, however. Amphetamine, morphine, alcohol and nicotine can all be differentiated from one another by animals and humans because of their unique effects. The fact that nicotine is not identical to cocaine is no more relevant than the fact that cocaine is not identical to morphine. What is critical is that all of these drugs are psychoactive because of their effects on the brain. The published data have shown that there are qualitative differences in these drugs' discriminative stimulus effects and that nicotine produces effects more amphetamine-like than morphine-like in annmls and humans.::: Thus, while nicotine's discriminative stimulus effects are unique, they resemble the effects of stimulants more closely than those of sedatives. These data confian that nicotine produces critical discriminative and subjective effects shared by dependence-producing drugs. "2' Stoterman IP, Ga~cha I-IS, Prau J/L et aL, Role of wainmg d~se in discrimination of mootme and related co~ds by rats, P~chopharmocology 1984;84:413-419. See AR (Vol. 8 Re£ 90-5). Stolerman IP, Discriminative stimulus effects of nicotine in rats named under different schedules of reinforcement, Psvchopharma¢ology. 1989;97:13 I- 138. See AR (Vo[. 9 Ref. 90-6). ::: Pvau J A, Stolerman IP, Garcha }iS, et ,,/., Discriminative stimulus pr~mies of nicame: funhe~ evidence f~ mediauon at a cholinergic receptor, P33,chopharmacolo.~' 1983;81:54450. See AR (Vol. 8 Re,.f 90-2). Stolea-n'm,n IP, Garcha 1-IS, Pratt JA. a at, Rote of naming dc~e in discrimimtim ~' ~icotiae and related otmapc~nds by ra~ Psychopharmocology 1984;84.:413-419. See AR (Vol. g Rd. 9G-5). 108 282207323 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44765 II.A.7. 3. The tobacco industry contests FDA's interpretation of three studies on drug discrimination in humans cited in the Jurisdictional Analysis. The industry concludes that there is no evidence to suggest that nicotine functions as a discrimmtive stimulus in humans. Upon review of these studies and the administrative record, FDA concludes that there is convincing evidence that nicotine tests positive in human drug discrimination studies. The industry disputes the conclusion that a study by Kallrmn et aL proved that discrimination occurred in the central nervous system.2z~ FDA, however, never drew this conclusion. FDA cited this study to demonstrate that smokers can differentiate between high- and low-nicotine cigareues, a finding conceded by the industry. Much other evidence in the administrative re~rd, described in section ll.A.3.c.i of this docu_rmax and in the 1988 Surgeon General's report,224 demonstrates that the discrimination occurs in the central nervous system. The industry also claims that a study by Perkins et al. did not demonstrate discrimination.2Zs Noting that male subjects identified 2 ug/kg of nicotirt¢ (administered by nasal spray) versus placebo correctly 50% of the time, the industry claims that this is exactly the percentage that would do so by chance. The industry concludes that the drug discrimination demonstrated by this study was due purely to chance and was not due to any effects of rticotme in the brain. 223 Kallman WM, Kallman MJ, Hany 13.1, eta/., Nicotine as a discriminative stimldus ill human subjects, in Drug Discrimination." Applicariorts in CNS Pharnmcology, ¢d~. Coll~eax FC_, Slaagen JL (AlI~ttt'd~ Elsevier Biomedical Press, 1982), at 211-218. See AR (Vol. 41 R~f. gg). Surgeon General's Report, 198g, tt 176-178. See AR (Vol 129 R~. 1592). ~:~ Perkins K, Grobe J, Scierka A, et al., Discriminative sdmulus effects of mcotine in smokers, in International Symposium on Nicotine: The Effects of Nicmin¢ on Biological Systen~ 11, eds. Clarke PBS, Quik M, Thurau K, et al. (Basel: Bitkhauser Verlag, 1994), nt 111. See AR (Vol. 42 R~f. 111). 109 282207324 PRODUCED FROH B&W WEB SITE 44766 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.7. Upon review of the Perkins study, FDA notes that the industry has seriously misinterpreted its results. The study's objective was to determine whether subjects could differentiate the low dose of 12 ug/kg of nicotine versus placebo, and its finding was that 100% of all subjects correctly identified nicotine at this dose at least 80% of the time. The authors concluded, "These findings indicate that humans are able to discriminate among low doses of nicotine.''2:6 (The dose of 12 ug/kg of nicotine is less than the typical dose of nicotine received from a cigarette.227) Having demonstrated this finding, the authors went on to test even smaller doses to demrmine the lowest dose of effective discrimination, that is, the dose at which subjects discriminated nicotine at least 50% of the time. That such a dose exists does not disprove nicotine's role as a discriminative stimulus, as implied by the tobacco industry; a minimal dose that cannot be differentiated from placebo exists for a/l psychoactive drugs. Finally, the industry contends that a study by Go|dfarb et al. 2~s is not a formal "discrimination" study. The Goldfarb study was cited not as a discrimination study but to demonstrate that humans can differentiate between cigarettes with different nicotine yields, a conclusion conceded by the industry. 4. The tobacco industD- argues that studies of the "subjective ¢ffetas" of tticotia~ have vague methods and use subjects who are not representative of all smokezs. These 2~ ld. at 111. ~'~ Perkim KA, Grobc JE, Epstein LH, eta/., Chronic and acu~," tole~'~c ~o subjecliv¢ cffec~ of ~ Pharmacology.. Biochemistry and B~havior 1993:45:375-3~]1. See AR(VoL 271 Ref. 3728). 2~, Goldfarb TL, Cvitz ER, Jar~k ME, eta/., R~eli~ meism, etm m a famctim ~t'~ ~tl "~t," Clin/ca~ Pharmacology and 7"~rapeutivs 1976;19:.767-772. See AR (Vol. 39 R~ 53). 110 282207325 PRODUCED FROM B&W WEB SITE Fm:leral Register / Vol. 81, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44767 II.A.7. comments c~icize a study by Henningfieid eta/.2z~ which was cited by the Agency. The industry further argues that the "subjective effects" of cigarett~ could be secondary to tar and cites a study to suggest that nicotine-free ~ cause "liking.''z~° The industry thus disputes FDA's conclusion that nicotine produces subjoclive effects that are similar to those of other addictive drugs. FDA disagrees. A wide range of e,~ience, discussed in section II.A.3.c.i., above, demonstrates that nicoti~ whether administered alone or in a eigaretm, behaves like other addictive drugs in "subjective effects" testing. Upon review of this evidence, FDA notes that the industry criticized only one of ~s cited studies. FDA further concludes that the Henningf~id study is accurate and consistent with the findings of other researchers. The study design used by Henningfield et al. is a ~ procedure for qualifying the abuse liability of drugs in humans; it is used nationally and internationally by addiction researchers,z~t The use of subjects with histor~s of drug abuse is also standard practice in such studies; indeecL as described in section lI.A.3.e.i., above, these subjects are employed because they can use their history to distinguish the psychoactive ettects of different drugs. Thus, for this type of abuse liability testing, it is critkal that the population be composed of smokers with cxpe~nee with other addictive drugs to enable th~ to compm~ the effects of nicotine to those of other drugs. ~a~ Henmngt-mld JE, Miymato K. Jmimki DR, Abuse liability and pharmacvdynamic charact~tSstics of intravenous and inhaled mcotine, Journa/of Pharmacologyand F_~pcrimental Thtrapeuacs 1985;234:1- 12. See AR (VoL 39 Ref. 69). ~s~ Jasinski DI~ Famnmgtield JE, ttuman abuse lia/tility assemmem by m~asta~meat ~subjccli~¢ and physiological effects, in Testing/or Abuse Liability of Drags m Hmnan~ ~ F~timlm IHW, M¢llo NK, NIDA Rty~arch Monograph 92 (Rockville biD: Nati~ml lnstitt~ en Drug Abu~ 1989). See AR ('CoL 76 R~ 172). 111 282207326 PRODUCED FROH B&W WEB SITE 44768 Federal R~i~ter / Vol. 51, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations II.A.7. The results from the study by Hermmgfieid ez a/. deanonsuate that nicotine, delivered by intravenous injection or by inhalation of tobacco smoke, produces similax subjective effects. These effects include dose-related elevation in the Morphine-Benzedri~ Group Scale and the "i~ng" scale. There is no possibility that the subjects were responding to the "flavor" of nicotine or tax when they were able to discriminate nicotine injected intravenously. Nicotine produced results similar to those of other dependence-producing drugs (e.g., morphine, eoeaim, and amp~) on the scales used in this study. Futthern~re, resca~hers who preceded and followed Henningfield otxained consistent fnxtings. Researchers other than Henningfield eta/., using rne~ods other than the MBG and the "hiring" scale, also confrmed that nicotine produces positive subjective effects aider intmmsal and intravenous adminimation.232 Subje~ in these studies used the following adjectives to descr~ the positive subjective effects of nicotine: "head rush," "feeling good," or"high." This evidence strongly demonstrates that nicotine---and not tar--is x~sponsible for the "subjective effects" of cigarettes. 2~2 Suthetland G, Stapleton JA, Russell MAIL et al., Randomised controlled a'ial of nasal nicotine spray in smoking cessation, Lancet 1992;340:.324-329. See AR (Vol 91 Ref. 527). Suthcxtand G, Russell MA, Stapleton J, et a/., Nasal nicotine spray: a rapid nicotine delivery system, Psychopharmacology 1992;108:512-518. See AR (VoL 91 Ref. 526). Perkins KA, Grobe JE, Epstein LH, et aL, Chronic and acut~ tolet-ance to.subjective ¢ffecJ.s of nicotine,, Pharmacology, Biochemi~ry and Behavior 1993;45:375-381. See AR (VoL 2"/1 Ref. 3728). P~ KA, Grobe JE, Epstein LH, et al., Effects of nicotine on subjective arousal may be depender on baseline subjective state, JournaJ of Subztance Abuse 1992;4:131-141. See ~ (VoL 348 ReL 5516). Johnston LM, Tobacco smoking and nicotine, Lancet 1942;2:742. See AR (Vol. 278 Ref. 3947). Jones RT, FaxreIi TR III, Hemm8 RI, Tobacco smokill8 lind nicotine toleraltce, ill Stir.Administration of Abused Substances: Mefhod~for Study, ed. Ki-asncgor HA, IqIDA Resealdl Moll~Sraph 20 (Rock-ville MD: National Institute on Dnag Abus~ 19783, at 2(Y2-208. See AR(Vol 41 Rcf. 88). 112 282207327 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, Aug6st 28, 1996 / Rules and Regulations 447~'9 II.A.7. Finally, the industry cites a study by Butschky et al.233 to suggest that nicotine-free cigarettes cause "liking" too. What the industry does not mention is that the study was conducted in newly abstinent smokers and that these nicotine-free eigarenes wer~ "lil~l" on}y when compared to letrace cigarettes that the r~searcl~rs acknowledged to be unpalatable. As described in section II.B.3., below, the repeated association of pharmacological effects and sensory effects over thousands of r,~titions causes the sensory aspects of addictive behaviors (such as taste) to come to be associated with the pharmacological effect (such as "liking") of addictive substances. Much as Parlor's dog salivated at the sound of the bell (a conditioned response), individuals addicted to drugs actually experience some of the effects of the psychoactive drug by conditioned cues associated with the act of self-administering the drag in the early stages of abstinence.TM This phenomenon has been described for many drugs, including heroin,us Just as a heroin addict may experience a rush simply by inje~ing a saline solution, a ciga~tte smoker may experience pleast~e when smoking a denicotinized ciga~tte. Thus, the finding that a denicotmized cigarette can trigger "liking" during withdrawal does not t~ll into question the conclusion that ~icotine has "subjective effects" in humans. 23~ Butschky MF, Bailey D, Henningfield JE, e: ,,I., Smoking wilhout nicotine delivery ~ withdrawal in 12-hour abstinent smokers, Pharmacology, Biochem/srry and Behav/or 1995;5lX1):91-96. See AR (VoL 442 Ref. 7484). z~ O' Bnen CP, Testa T, Temes J, e: aL, Coatiitio~iag effects of narcotics in humans, in Behavioral Tolerance: Re~earch and Treatment lmplicadons, NIDA ReSejLrCh Monograph 18 (Washillgtoll Government Printing Office No. 017-024-00899-8, Jan ,1978), at 67-71. See AR (VoL 535 Ref. 96, vol. JILL). Surgeon General's Repo~ 1988, at 308-311. See AR (VoL 129 Ref. 1592). 113 282207328 PRODUCED FROH B&W WEB SITE 44770 Federal Register / VoL 81. No. 168 J Wednesday, August 28, 1998 / Rules and Regulations II.A.7. e. Comments on Self.Administration and Reinforcement I. Tt~e tobacco industry argues that nicotine's reinforcing effects are different from those of heroin and cocaine, that animals need to be trained to seE-administer nicotine, that the reinforcing effacacy of nicotine is more 1~ that of ~ffeine, and that in one study cited by FDA a light stimulus a&sociated with nicotine was required for self-administration. The industry concludes that animal self-adminisuation studies do not support the finding that nicotine is addictive. FDA disagrees. Upon review of the evidence in the adminisuative record, FDA notes that there are over ten studies demonstrating self-administration of nicotine by animals,z~6 Only one of there is specifically contested by the tobacco industry. F~re, none of the industry's arguments seriously call into question FDA's finding that animals self-administer nicotine in a manner comistent with other addieu've substances. It is true that the reinforcing effects of nicotine do differ from those of cocaine and heroin; all dependence-producing drags are not alike. In fact, FDA noted that the nmge of environmental conditions under wb.i~h nicotine ftmtaions as a positive reinforcer appears more limited than for cocaine.237 The limited conditions ~-der which animals self-administer nicotine, however, closely correspond to the conditions of human tol~acco use. That is, animals self-administer nicotine when it is given intermittently---in a fashion similar to nicotine delivery ...,) See appendix I to Jurisdictional Analysis. See AR (Vol. 1 Appendix 1). Id. 114 282207329 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations 44771 II.A.7. FDA agrees that ammals can be trained to self-administer mcotine. This method is widely accepted as standard practice in self-administration testing in animals. What is important is that, under these conditions, nicotine is self-administered significantly more than placebo and in a manner consistent with other addictive substances. The tobacco industry cites a review chapter in a textbook on psycbopharmacoiogy to suggest that caffeine and nicotine self-adminiswation are similar. The review article cited focuses on whether caffeine is a drug of abuse and, while casually noting similarit~ between some data on nicotine and call~ine, does not purport to analyze the studies on nicotine at all.~ Indeed, caffeine self-administration in animals is weak and sporadic.239 FDA further notes that the chapter on nicotine m this same textbook unequivocally concludes that nicotine is addictive.24° Finally, FDA agrees that the study by Goldberg et aLTM showed that squirrel monkeys self-admimster nicotine most actively when associated wixh a light stimulus. The toOacco z~s Cn'iffifl~s RP~ Mumford GK. Caff¢ine--A drag of abuse?, in Psychopharmacology: The Fourth Generation of Progress, eds. Bloom FE, Kupfer DJ (New YoA= Raveal Press, 1995). at 1699-1713. See AR (VoL 535 Ref. 96, voL III.E). 2s* Heishman SJ, Henningficld JE, Stimulus functk~m of caffeine in humam: relaticm, to dq3emdence i~tml~k Neurosc/ence an~ B/obehav,~,a/Rev/ew,s 1992;16:273-287. See AR (V~I. 791~. 230). Grittitlas RR, Wo0ds~x 1~, Reinlcax~ lm:gnaes of cattein~ smdi~ in humam m~d ~ anim~ Pharmaco/~gy, B/ochem/m-y and Behatior 1988;29(2):419-427. See AR (3/ol. 535 R~ 96, voL Ill.E). Jaffe IH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed. (New York: Pergamon Press, 1990). chap. 22 (522-573), at 524. See AR (VoL 535 R.ef. 9~, voL III.G), 2,0 Henninglield JE, Sehuh LM, Jarvik ME, Pathophysioiogy ol tobacco ¢kpenden~ in Psyclwpharmacology: I'he Fourth Generation of Progress, eds. Bloom FE, Kul~er DJ (New York: Raven Press, 1995), at 1715-1729. See AR (Vol. 39 Ref. 72). 2,, Goldbetg SR, Spealman RD, Gcld~g Dlvl, Persistent izha','~" at high rates maintained by intraven~s seif- adnfm~traf~a ofnico(m~ Science 1981;214:573-575. See AR (Vet 5 P,~ 35-2). 115 282207330 PRODUCED FROM B&W WEB SITE 44772 F~era] R~gister / Vol. 61, No. 188 / Wednesday, August 28, 199(5 / Rules and Regulations II.A.7. industry implies that this finding means that the light stimulus--not nicotine--was responsible for nicotine self-admirtistration in this study. FDA disagrees. Rates of self-administration of nicotine with the light stimulus ~ere markedly higher than rates of self-administratwn of placebo with the light stimulus. Indeed, the monkeys' self-adminiswation of nicotine was so imcnse that it resembled cocaine use. Thus, the conclusion that nicotine was not self- administered is incorrect; the correct conclusion is that nicotine self-administration was most dramatic when associated with environmental cues that had been linked to nicotine injections. 2. The smokeless tobacco industry claims that its products provide a constant dose of nicotine, a regimen that animals did not self-administer. This claim is contrary to the evidence. As described in section ILD., below, moist snuffand chewing tobacco do not provide uniform release of nicotine from the products. In fact, each pinch of smokeless tobacco provides nicotine that is absorbed rapidly for the first 5 minutes; the rate of absorption then tapers off until the next pinch is comumed. This pattern of nicotine consumption is similar to the regimen that was self-administered by animals. 3. The tobacco industry criticizes the human self-admime.ration study conducted by Hennmgfxld et al.~'2 on the grounds that the number of subjects used in the study was too small that the study should have been conducted witla subjects without a hi~tory of drug abuse, and that the subjects also self-adminismred saline. FDA believes that the study's design was sound and that the results are reliable. The procedure utilized by these researchers is the standard procedure u "tflized by all investigators evaluating the abuse liability of a compound in humans. This well- 2,2 l-Iemimgfi¢|d JE, Miy~to K, J~imki DR. Ci~axttm smok~ ~e/f-~dmittit~ mtrtt~ou~ nicotine, Pharmacdo~', Biochemistry and Belmvior 1983; 19:887-890. S~e AR (Voi. 39 R~ 71). 116 282207331 PRODUCED FROH B&W WEB SITE Federal Registar / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Reg'alations 44773 II.A.7. established procedure has been used to examine the abuse potential of a variety of compounds, such as alcohol, marijuana, heroin, and sedatives, in both inpatient and outpatient settings. In the evaluation of a new moleSular entity (NME) that shows some structural and/or pharma, cological similarities to known drugs of abuse, FDA requires that studies similar to this one be conducted in order to reach a regulatory decision on the abuse-potential of the NME being considered for drug approval,z~ In response to the concerns of the tobacco industry about the study methodology, the sample size of six is acceptable and the use of volunteers with histories of drug abuse is a valid method of conducting such research, according to the National Institute on Drug Abuse}" Human studies evaluating the abuse potential of a compound in subjects without a history of drug abuse do not produce valid results. Such tests in non-drug abusers could lead to the conclusion that drugs, including heroin, have alow potential to produce dependence because f'~st-time users may not find them pleasant,us • With respect to the self-administration of saline, the comment overlooks major distinctiom between nicotine and saline: (1) "subjective effects" were not associamd with the saline deliveries, ttms saline was not psychoactive; (2) in comparison to the orderly pattern of serf-administra~n observed with the nicotine inj~tions, the p~ttem of ~line deliveries was highly variable; (3) the number of self-~dministered s~Line injections z,~ See Surgeon General's Repork 1988, at 270. See AR (VoL 129 Ref. 1592). 2. Jasmski DR. Hmnmgfietd JE, ttuman abase Iiabil~ assessamat by ~t ¢[ subjective and physiological ¢ffecls, in Tesring for Abase Liability of Drags in Htmmzts, ¢d$. FtSdlRlan MW, Me.llo NK, NID A Research Monograph 92 (Rockville MD: Naliclxal [ustitnle em Drub AIx~s¢, 1989). See AR (Vol. 76 Re£ 172). a45 Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman "s The Pharmacological Basis of Therapeutics, 8th Igl. (New York: Pergamon Press, 1990), chap. 22 (522-573), at 529. See AR (VoL 535 Ref. 96, voL IILG). 117 282207332 PRODUCED FROM B&W WEB SITE 44774 Federal R~ster / Vo|. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations II.A.7. decreased across sessions while nicotine injections were constant in those subjects who were tested repetitively with saline and nicotine; and (z~) when saline and nicotine were simultaneously available in a follow-up study, the volunt~rs self-administered nicotine almost exclusively and not saline.2~ Thus, saline was not psychoactive and did not function as a "positive reinforcer." : 4. The tobacco industry argues that caffeine, rapid eye movement (REAM) sleep, magnetic fields, and st.mss incrmse dopamine levels in the brain. According m the industry, then, nicotine's effect on dopamine activity is shared by several other compounds or experiences. This argument is based on a mischaracterization of the relationship between addictive substances and dopamine activity. FDA found that nicotine and other addictive substances do more than increase dopamine levels in the brain; they increase dopamine activity in a specific system that signals reward and pleasure, thus leading to reinforcing behavior. Nicotine's effect in this system is similar to that of other dependenee-producing substances. These conclusions are Imsed on reproducible studies and are widely accepmd in the scientific community. Indeed, none of the industry's cited studies casts any doubt on the profound effects of nicotine on this brain system. One study, cited by the industry as proof of the effect of caffeine on dopamine levels, actually examined the effect of caffeine on aggressive behavior of rats. Dopamine levels were not even measttt~. The authors merely speculated at the end of the article 2~ Surgeon General's Report, 1988, at 192. See AR (Vo/129 Ref. 159~). llg 282207333 PRODUCED FROH B&W WEB SITE Federal Register / Vol. ill, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44775 II.A.7. that caffeine may affect rat aggression via dopamine. Moreover, they did not extend their speculation to reward or reinforcement.247 Another study, cited by the industry as proof of the effect of REM sleep and magnetic fields on dopamine, actually described two patients treated with magnetic fields--without any control group. The authors merely speculated that REM sleep deprivation and magnetic fields may affect dopamine in the mesolimbic system. But without a control group, it is impossible to assess whether there was any true response to magnetic fields.2~s The industry cites a third study to suggest that stress increases.dopamine levels. 249 This study delivered severe stimuli such as electric shocks to mice and studied dopamine responses. The authors concluded that a dopamine-based reward pathway exists and is altered under conditions of severe stress. This conclusion casts no doubt on the finding that nicotine also critically affects this pathway. 5. In a footnote, the tobacco industry argues that "it is not clear that nicotine's effects on dopaminergic mechanisms play a significant role in smoking behavior." This argument refers to a study by Comgall and Coen.zs° :~ Petkov W, Rousseva S, Effects of eaff "C..~ on ~ggtmsiv¢ b~havior and avoidan~ learning of rats wi~h isolation syndrome, Method~ and Findings in E,~perim~raal and Clinical Pharmacoh~gy 1984;6(8):433- 436. See AR (Vol. 535 Ref. 96, vol. Ill.L). 2,, Sandyk R~ Tsasas N, Annin~ PA, et aL, Magnetic fields m~fte the behayioral effects of REM sleep deprivation in humans, International lournal of Neuroscience 1992;65(1-4):61-68. See AR (VoL 535 Ref. 96, vol. II1.L). 2~ Puglisi-Allegra S, Kempf E, Cabib S, Role of genotype in the adaptatioti of the brain dopamine syslem to slxess, Neuroscience and Biobehavioral Re~iews 1990; 14(4):523-528. See AR (Vot 535 Ref. 96, vol. III.L). 2~ Corrigall W, Coen K, Dopamin¢ mechanisms play at best a small role in the nicotine discriminative stimulus, Pharmacology, Biochemistry and Behavior 1994;48(3):817-820. See AR (Voi 535 Ref. 96, vol. 119 282207334 PRODUCED FROM B&W WEB SITE 44776 Federal Register / Vol. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations It.A.7. FDA has reviewed the study in question and concludes that the tobacco industry's conclusion seriously misrepresents the research. In this paper, the authors suggested that dopamine activity may not explain why smokers recognize low doses of nicotine m their bra~q, but the authors never doubted that dopamine activity is ~scntial to the reward associated w/th smoking. The same article cited by the industry includes the statement that "the minfo~ing eff(~'zts of nicotine have a doparnmergic substrate, likely the ascending mesolimbic dopamine system"ZSL-exactly the finding of FDA. These researchers, misrepresentcxl by the industry to suggest a small role for dopamine in smoking behavior, have demonstrated in their own laboratory that dopamine activity significantly affects nicotine comumption.~ Comments on Withdrawal, Tolerance, and Nicotine Replacement i. The tobacco industry argues that the effects of withdrawal from nicotine are not substantial. This argument is based upon multiple overlapping and sometimes contradictory contentions: (l) nicotine withdrawal is no¢ as severe as withdrawal from ~ other drugs, and some people quit smoking easily; (2) physical and psychological symptoms experienced during nicotine withdrawal are not the same among all ab~Jnent users; (3) withdrawal from nicotine produces psychological but not physical symptoms; (4)the psychological symptoms of abstinence may actually be a psychopathological condition previously suppressed by nicotine or may be fru,~ration with losing a pleasurable activity; (5) what is thought to be nicotine withdrawal may actually be caffeine withdrawal 2sJ M. atSL7. ~s~ Comgall WA, Franklin KBL Coen KM, et aI., The mesolimbic dOl~m~gic sysl~m is implicmle(I in the ~einforcing effects of nicotine, Psychopharmacology 1992; 107:285-289. Sac AR (VoL 8 Ref. 93-4). 120 282207335 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations 44777 II.A.7. or caffeine toxicity; (6) the severity of withdrawal symptoms does not always correlate with relapse; and (7) epidemiologicat studies cited by FDA do not 9rove a substantial withdrawal syndrome. , Upon careful review of the industry's comments and the administrative record, FDA finds that nicotine clearly produces a withdrawal syndrome among abstinent tobacco use~. This syndrome--which includes both psychological and physiological symptoms~ is described in numerous scientific articles and reviews cited by FDA,~ only a few of which were criticized by the tobacco i~dustry. Of the studies on withdrawal from smokeless tobacco cited by FDA, none is contested by the industry. The tobacco industry also:accepts FDA's finding that tobacco withdrawal causes many significant autonomic changes, such as changes in heart rate. Several of the industry's arguments do not seriously contest the fact that nicotine has a substantial withdrawal syndrome. The remaining arguments contradict each other. The Agency's specific responses to the major industry contentions ate as follows: * Nicotine withdrawal is not as severe as withdrawal from certain other drugs, and some people quit smoking easily. FDA agrees that withdrawal from nicotine is not as acutely life-threatening as withdrawal from certain addictive drugs such as alcohol or short-acting barbitmat~. But the severity of nicotine withdrawal is comparable to that of otl~r addictive drugs such as 2s3 See Jurisdictional Analysis, 60 FR ~,1560-41562 See also Surgeon General's Report, 1988, at 197-207. See AR (VoL 129 Red'. 1592). American Psychiatric Assotfiafio~ D~ag~o~ic a~d ~a~s~d Manual of Mental Disorders, 4th (Washington DC: American Psychiatric Association, 1994), at 7./M-7.45. See AR(VoL 37 Ref. 8). 121 282207336 PRODUCED FROM B&W WEB SITE 44778 Federal Register / ~oi. 6~, No. ~68 / ~ec~nes~ayo ~ugust 28, ~ / Ruie~ ~-~d Regulations II.A.7. cocaine.TM Medical authorities around the world have recognized the existence of a nicotine withdrawal syndrome that causes "clinically significant distress or impairment ~n social, occupational, or other areas of functioning.''2s5 FDA agrees that some people quit tobacco products easily. Similarly, some people quit cocaine and other addictive substances easily.~--~ However, for most addicted users of tobacco, quitting is very difficuit. See section II.A.3.c.il., above. The characteristic feature of an addictive substance is that it is difficult for most people to quit. Thus, the fact that some people can quit smoking easily is in'elevant to nicotine's addietiveness and to the seientilie consensus supporting a nicotine withdrawal syndrome. Moreover, it may actually be easier to quit other powerful substances than to quit nicotine. Smokers who consume about a pack or more of cigarettes per day are more ttmn twice as likely to report withdrawal symptoms during abstinence as people who consume five or more drinks on five or more occasions in a month, people who repeatedly use cocaine, and people who repeatedly use marijuana.~ s Physical and psychological symptoms experienced during nicotine witlxlmwal are not the same among all abstinent ttscrs. 2s~ lle~owitz NL, Cigarette smoking and nicotine addictio~ Medical Clinics of North America 1992;76(2):415-437, ~t 429. See AR (VoL $35 Ref. 96, voL I/I A). ~ss ~ Psychial~ Assoei~ol~ Diagnostic and Statistical Manual of Mental Disorders, ~ eel t~Washiagton D42: Amet'ican Ps~ As~3eiltlion, 1994), at 245. See ~ (~fOl 37 Ref. 8). 2u Kleber l-h Don't you believe that nicoli~ i~'t addictive, New York Times, Apr. 4, 1994. $e¢ AR (VoL 196 Ref. 2497). Beoowilz NL, Cigarette smoking and nio3tilze addiction, Medical Clinics ofiqorth America 1992;76(2):415-437, at 429. See AR (VoL 535 Re, f. 9~, vol. I]I.A). ~ Hetmingfield IE, Clayton R, Pollm W, Involvement of tobacco In alccttolism and illicit drag use, British Journal of Addiction 1990;85:279-292, at 280-7.81. See AR (VOI- 39 Re[. 66). 122 282207337 PRODU@ED FROH B&W WEB SITE Federal Re~ister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44779 282207338 PRODUCED II.A.7. FDA agrees that there is variation among tobacco users' physical and psychological responses to abstinence. But, as described in section ILA.3.c.i., above, and in reviews cited by the Agency, several symptoms are so common as to be part of a defined syndrome.~8 These symptoms include depressed mood, insomnia, irritability, anxiety, difficulty concenwating, restlessness, decreased heart rate, and increased appetite. Thousands of individuals around the world have r~ported these symptoms in studies of tobacco abstinence. • Withdrawal from nicotine produces psychological but not physical symptoms. The tobacco industry goes on to quote selectively from some researchers to suggest that mcotine withdrawal does not pmcluce physical symptoms. This argument is at odds not ordy with the consensus understanding of nicotine withdrawal but also with other quotations used by the tobacco industry in tl~ same comment, which suggests that common withdrawal symptoms include, for example, "headache.''2s9 Indeed, the very sources cited by the tobacco industry clearly agree with FDA's t'mding of a substantial tobacco withdrawal syndrome. For example, Balfour, who is quomd by the industry to suggest that withdrawal ks mainly psychological, states that "many habitual smokrds experience signifu:ant and unpleasant withdrawal effects when they fLrSt StOp smoking which can be ameliorated by giving nicotine in another form.''u° American Psyclfiatric A~x~om DiagnoSe and St~i~cM (W~hmg~ DC: ~ ~y~c ~~ 1~ at 2~5. See ~ ~ot 37 ~f. g). (B~m~: M~by), 33&35~ ~ ~7. See ~ (Vot 535 ~. Biolo~cd ~es of Dmg Tder~¢ ~ ~~, ~ ~ IA (N~ Y~ ~e M, 1~1), 1-151, it 1 ~ (eimaon o~) (e~ ~). See ~ (Vo~ 535 Ref. ~ vol. ~.A). 123 FROM B&W WEB SITE 44780 F~deral R~ister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.7. Similarly, a quotation culled from a review by Hughes et aL is used to support the conclusion that the effects of nicotine withdrawal are not substantial. In fact, Hughes et aL artribute multiple physical and psychological symptoms to nicotine withdrawal and conclude that some symptoms can be so severe that they may "prevent smoking cessation.''~6t • The psychological symptoms of abstinence actually may be a psychopathological condition previously suppressed by nicotine or may be frustration with losing a pleasurable activity. The tobacco industry cites the Diagnostic and Statistical Manual of Mental Di~orde.rs of the American Psychiatric Association for this assertion, but offers no evidence to suggest that any significant number of quitting smokers have psychiatric diagnoses or are just frustrated. Nor does the DSM. Its actual text merely alerts clinicians not to mistake symptoms of abstinence for psychopathology or frustration "in any given ~l~e.''~ * What is thought to be nicotine withdrawal may actually be caffeine withdrawal or caffeine toxicity. FDA agrees that some symptoms a~ common to caffeine a~d nicotine withdrawal, and som~ are common to nicotin~ withdraw~l and caffeine toxicity. Withdrawal from nicotine and cocaine also causes common symptoms of depressed mood, increased 261 Hugl~s JR, Higgins ST, Halsuim~ D, Effects of abstiaem~ from tolx~:o: n critical review, Re~earch Advances in Alcohol and Drug Problem~ 1990;10:.317-39~, at 381. See All (Vol. 535 Ref. 96, vol. IILG). American Psychialric Assoei~ticm, Diagnostic and ~tatistical Manual o/Mental Disorders. 3d ~1., revise.xl (Washington D~: Al~nc~ Psychiatric Association, 1987), at 150. See AR (Vol. 535 Ref. 96, vol. III.A). 124 282207339 PRODUCED FROM B&W WEB SITE Federal Register / VoL 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44781 II.A.7. appetite, and insomnia. :~s Such overlap has not led any credible scientific source to conclude that nicotine withdrawal has been confused with another drug's syndrome and therefore does not exist. • The severity of withdrawal symptoms does not always correlate with relapse. ~: On several occasions in its comments, the tobacco industry claims that the severity of Withdrawal does not directly predict relapse. Based on this observation, the industry concludes that the symptoms of withdrawal from tobacco are not significant and that physical dependence to nicotine is not real. FDA disagrees. Severity of withdrawal does predict relapse; most people who quit smoking relapse within 1 week,~ when withdrawal symptoms are at or near their peak.a~ Moreover, studies indicate that light smokers, who are less lil~ly to suffer withdrawal symptoms, are more likely to succeed in quitting than are heavier smoke~.~ The industry' s argument is based on the mistaken assumption that, if withdrawal symptoms were significant, their presence would perfectly correlate With relapse. But, as described in depth in the 1988 Surgeon General's Report, multiple confounding factors are associated with relapse to use of any addictive subslance, no matter how significant the withdrawal syndrome.~ These factors include psychiatric impaimaent, expectations, 2~ American Psychiatric Associatiolk Diagnostic and Statistical Manual of Mental Disorders, 40a e~ (Washiagt~ DC: American Psycbiau'ic Associatm~ 1994). $ee AR (Vot J35 Rnf. 96, vol. 2~ Hughes JR. Gulliver SB, Feuv~ick JW, et aL, Smoking cessation among self-quitu~, Health Psychology 1992;11:331-334, at 333. See AR (VoL 348 Ret'. 5512). as5 Hughes JR, Gust SW, Skoog K, et aL, Symptoms of tolmcco withdrawal: a replication sed extension, Archives of General Psychiatry 1991;48:52-59, at 56. See AR (VoL 129 Ref 1~04). 2~ Surgeon General's Report, 1988, at 315-316. See AR (Vol 129 Ref. 1592). ze7 Id. at 315-324. 125 282207340 PRODUCED FROM B&W WEB SITE 44782 F~lera] Register / Vol. 61. No. 168 / Wednesday, August 28, 1996 / Rules and R~gulations I1.A.7. demographics, enrollment in treatment programs, peer influence, and social support. Even life-threatening withdrawal symptoms associated with drugs such as alcohol do not necegsarily lead to r~lapse. After a complete review of available evidence, the Surgeon General concluded that nicotine's pharmacological role in relapse is similar to the role of opioids and alcohol.2~ Thus, the absence of a perfect correlation between withdrawal . severity and the precise timing of a relapse does not compel the conclusion that withdrawal symptoms are insignificant or that physical dependence to nicotine is not real. * Epidemiological studies cited by FDA do not prove a substantial withdrawal syndrome. The tobacco industry criticizes several studies cited by FDA in support of a tobacco withdrawal syndrome. Upon review of these studies, FDA t-rods that the industry's comments tak~ quotations out of context and make inappropriate inferences from researchers' findings. For example, the industry objects to a study by Hughes et aLu° on the grounds that the researchers tabulated withdrawal symptoms on only 105 of the 315 subjects. In fact, the analysis of withdrawal appropriately included every subject in the study who was abstinent from both tobacco and mcotine. The other 210 subjects received nicotine gum to reduce their withdrawal symptoms; these subjects were thus inappropriate for research on the severity of withdrawal. • Similarly, the industry claims to provide data to contradict FDA's citation of the 1991 and 1992 National Household Surveys. But FDA's data reported the prevalence of withdrawal symptoms for smokers who consume sixteen to twenty-five cigarettes per day. ~Id. at 323. m Hughct IP.. Gust SW, Skoog IL et al., Sy~o~ of ~ widOwS: a ~ ~d e~mio~ A~ves ofGe~r~ Psychi~ t~1;48:52-59. See ~(VoL 129 ~f. 1~). 126 282207341 PRODUCED FROM B&W WEB SITE Federal R~i~er / Vol. 61, No. 168 / Wednesday, August 28, 1995 / Rules and Regulations 44783 282207342 PRODUCED II.A.7. The industry's data are based on a different set of smokers and, at any mtc, are hardly different from FDA's. Such arguments cannot seriously challenge the scientific consensus that led the American Psychiatric Association to define Tobacco Withdrawal Syndrome in 1980 and to ratify its decision again as recently as 1994 in DSM-IV. 2. The tobacco industry argues that nicotine does not induce pharmacological tolerance. This conclusion is based upon several arguments: (1)tolerance can be both pharmacological and nonpharrnacological; (2) smokers and users of smokeless tobacco do not continue to increase their tobacco consumption over the course of their lives and thus do not escalate their dose; (3) FDA's studies on dose escalation are not persuasive; and (4) a study on low-nicotine snuff disproves tolerance. FDA disagrees with the indusu'y's analysi~ and conclusion. Much uncontested evidence in the administrative record demonstrates conclusively that nicotine causes tolerance in tobacco users. For example, the industry does not dispute evidence of diminished cardiovascular and nervous system respouses to nicotine over the course of a day. Nor does the industry deny that many cigarette ~mokers escalate their doses of nicotine to daily use~7° or that the age of young consumers of smokeless tobacco correlates with the amount of use.27J Furthermore, the arguments that the industry does make are not'persuasive, as discussed below. ~ Benowi~ NL, Cigarette smoking and nicotine addiction, Medical Clinics o/North America 1992;76(2):415-437. Set AR (VoL 535 R~f. 96, vol. IILA). Heanmgfield JE,.~ohen C~ Slade JD, Is nicotine more addictive than cocaine? British Journal of Addiction t991;86:565-569. See AR (Vol. 277 Ref. 390~). :71 World Health Organization. Smokeless Tobacco Control: Report of a WHO Study Group, WHO Technical Report Series No. 773 (Geneva: WHO, 1988), at 36. See AR (Vol. 7 Ref. 83). 127 FROH B&W WEB SITE 44784 Federal Register / Vo|. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.7. The industry's description of two kinds of tolerance is irrelevant. Sources in the administrative record cited by FDA refer exclusively to pharmacological tolerance. See sections II.A.3.c.i. and lI.A.3.c.ii., above. The tobacco industry makes the observation that smoking behavior reaches a plateauas the smoker grows older. Similarly, the smokeless tobacco industry points out that middle-aged users may consume less than young adults. But these observations do not disprove the existence of tolerance, which does not reqtm'e forever-increasing consumption of a substance. Tolerance is a phenomenon that develops rapidly, leads the vast majority of beginning tobacco users to escalate their dose, and then can eventually result in a stable pattern of consumption. Some heroin addicts also eventually reach a level of consumption that may remain constant for yeal'S.272 The tobacco industry asserts that a study cited I~y FDA on the proportion of smokers who report needing more cigarettes to obtain desired effects does not support the idea of tolerance to nicotine and also does not prove that such tolerance is widespread or marked. FDA disagrees with these assertions. The industry cites no data or references to explain why the study does not demonst~te tolerance. In fact, the study's findings perfectly fit the tobacco industry's own clef'tuition of tolerance that "more drug is necessary to produce the desired effect," People who have tried cigarettes at least once m'e more likely to report the need for larger doses to get the same effect than people who have tried 272 J~t'e JH, Drug addiction alld drug abuse, in Goodman and Gilman's T~e Pharmacological Basis of Therapeutics, 8th ed. (New York: Pergamon Press, 1990), chap. 22 (522-573), at 531-532. See AR fVol. 535 Ref. 96, vol. Ill.G). 128 282207343 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations 44785 II.A.7. cocaine, marijuana, and alcohol at least once.273 Moreover, FDA notes that epidemiological data are just one demonstration of tolerance; most of the evidence on tolerance to nicotine presented by IDA is uncontested by the tobacco industry. : Finally, the smokeless tobacco industry cites a study that measures the response of oral tobacco users to a low-nicotine snuff. In the study, users increased their consumption of tobacco to compensate for its lower nicoane content. The industry's argument here confuses tolerance with compensation, b"DA addresses the mdustry's comments on compensation in section ILA.7.i., above. 3. The tobacco industry cites research on nicotine replacement therapies to argue that mcotine is not a key reason for tobacco use. According to the industry, if nicotine were central to tobacco consumption, providing nicotine rephcement should eliminate smoking behavior and all withdrawal symptoms. The industry contends that nicotine replacement trials cited by IDA do not demonstrate either efficacy of replacement therapy or elimination of withdrawal symptoms. The industry disputes IDA's summary of nicotine replacement trials and makes multiple objeetious to individual studies. The industry also contends that the study population is not generalizable to the entire smoking population. Upon review of the industry's detailed comments and the dam in the administrative record, IDA disagrees with the mdustry's position on nicotine replacement therapies. Scientific consensus supports the view that such therapies not only reduce withdrawal symptoms but increase abstinence. An extensive preapproval evaluation of such therapies .,r~ Hennmgfield/E, Clayton R, Pollin W, Involvement of tobacco i~ alcoholism and illicit dnig use, Briush Journal of Addiction 1990;85:279-292~ See AR (VoL 39 R~f. 66). 129 282207344 PRODUCED FROH B&W WEB SITE 44786 Federal l~ister / Vol. 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.7. by FDA also concluded that they were safe and effective, and even sources cited by the tobacco industry agree. The efficacy of nicotine replacement therapies is strong proof of the central role of nicotine in tobacco consumption. The industry's position is based upon mistaken assumptions, rni~interpretation of clinical trials, and misuse of FDA reviews. According to the tobacco industry, replacing one form of an addictive substance with another form should completely eliminate the addict's de.sire to use the substance. If this assumption were correct, then no methadone user would ever relapse to heroin. In fact, providing oral methadone in substance abuse clinics helps only some opioid users to remain totally abstinent,274 and abstinence rates of former heroin users on methadone are similar to those of former smokers receiving nicotine replacement therapy.27s The industry's simplistic formulation ignores many factors, such as the importance of the route and speed of drug administration. Just as a heroin addict may want a "rush" from injection and reject the steady dose of oral methadone, a tobacco user may prefer the "rapid, peaking" dose of inhaled nicotine over the more steady dose from mplacemem therapy.2~6 Given the strength of addiction to tobacco products, it is noteworthy that there is a 2~4 Jldte JH, Drug addiction mid drug abuse, in Goodman and Gilman's The Pharmacological Basis of Therat~c,~tics, 8di ed. (New Y¢~tc Pergamon Pre~s, 1990), clu~, 22 (522-573t, at 531-532. See AR (VoL 535 Rd. 96, voL re.G). 2~5 Henningficld JE, GriIfiths RR, Jasinski DR, Cigarette smoking and opioid dependence: common factors, Presented at the meeting of the American Psychological Association (Sep. 2, 1980). See AR (Vol. 80 Ref. 254). Surgeon General's Report, Smokeless Tobacco, 1986, at 155. See/~(VoL 128 R~f. 1591). Goreliek D, Tt'aascript to the FDA Drug Abuse Advisory Committee, Meetiag 27, "Issues Conceramg Nicotiae-Containing Cigarettes ~d Other Tobacco Products" (Aug. 2, 1994), 292. See AR (Vol. 255 Ref. 3445). Research and Development/Quality, Transdermal Nicotine, at 3. See AR (Vol. 531 Ref. 124). 130 282207345 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44787 II.A.7. significant increase in abstinence with replacement therapy, but it is not surprising that these products are not always effective. The industry also argues that replacing an addictive substance with another form should eliminate all withdrawal symptoms. In fact, providing nicotine does dramatically reduce physiological withdrawal symptoms.27~ Psychological withdrawal is reduced but not eliminated, primarily because users have associated tobacco consumption with certain stimuli, such as taste and ritual. Such "conditioned" cues become part of the tobacco consumption experience, and the denial of such cues can lead to behavioral symptoms. In this sense, nicotine is ~ other addictive drugs.278 The industry misinterprets data on the efficacy of mcotine replacement therapies. First, the industry argues that FDA's data do not support the conclusion that the initial quit rate is "about 50%." The actual studies cited l-month quit rates of 35%, 61%, 50%, 50%, 26%, 57%, 47%, and 36%. The ovendl average for all studies was 49%.279 Second, the industry argues that some individual studies do not show a statistically significant increased quit rate with nicotine replacement therapy. The Jurisdictional Analysis, however, included a chart showing the ore .ryvhelming consistency among nineteen studies on nicotine replacement tl~mpies in demonstrating eftieaey,m Sttrgeon General's Report, 198~, at 20~. ;Sac ~ (VoL 129 ~f. 15~). Benowi~ ~ Cig~ s~g ~ ~ a~ Me~c~ Climes of North A~r~a 1992;7~2):415~37, at 418. See ~ ~ot 535 R~. ~ ~1. ~.A). See a~n~x 1 m J~O~ ~ys~. See ~ (VoL I A~ 1). 131 282207346 PRODUCED FROM B&W WEB SITE 44788 Federsd R~ister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Ru|es and Regulations m H.A.7. A definitive recta-analysis on the efficacy of the hicotine patch was cited by FDA, and ~ts methods and results were not disputed by the tobacco industry. This study, published in the Journal of the American Medical Association. reviewed seventeen studies involving over 5,000 patients and concluded that "this recta-analysis provides compelling evidence that the nicotine patch is a consistently effective aid to smoking cessation. Individuals wearing the active nicotine patch were more than twice as likely to quit smoking as were individuals wearing a placebo patch.'asi Third, the industry makm multiple objections to individual studies on nicotine replacement therapy. These objections dispute free points of methodology and often cite FDA reviewers' own criticisms of the studies. To the extent that the industry heavily relies on FDA's critique of the stt~dies, the industry should accept FDA's conclusion that the studies demonstrate the efficacy of nicotine replacement therapy. Indeed, FDA has not only the statutory authority but also the expertise to determine whether a new drug therapy is efficacious. After extensive prernarket review, FDA concluded that nicotine replacement therapies are efficacious. FDA's conclusion is consistent with scientific COFIseI1SUS. The tobacco industry also ~.rgues that the subjects in trials on nicotine replacement therapy are not representative of all smokers. But FDA's reason for citing the research was to demonstrate that providing nicotine by another means enhances abstinence and reduces withdrawal where it has been studied. These results show the critical :,s~ Fiofc MC, Smith SS, Jorenby DE, et al., The cf'Iectivctacss of ~ ~ patch for smoking cl~slttiOU: a mcta-analys is, Journal of the American Medical Asso ciation 1994;271:1940-1947, at 1945 (emphasis added). See AR (Vol. 6 Ref. 64-1). 132 282207347 PRODUCED FROH B&W WEB 8ITE F~deral Regi~er / Vol. 61, No. 168 / Wednesday. AuEust 28. 1996 / Rules and R~gulations 447~ II.A.7. pharmacological role of nicotine in tobacco use. Indeed, if the tobacco industry were correct that mcotine's only important role in tobacco is for "flavor," then there should be absolutely no benefits in any study of transdermal nicotine replacement therapy. That nicotine replacement is effective is conclusive evidence of nicotine's role as a ptmmmcological rc~orcer. 4. The tobacco industry argues tlmt studies on nicotine replacement tahcmpy cannot bc relied upon to dcmoustmte tl~ a high proportion of smokers m~ addicted. FI)A agrees with this comment. Other studies, cited in sc~xion II.B.2~., below, however, do dcmons~tc that a high proportion of smokers are addicted. g. Commenls on EI)iflem~ologie~l Sm~lies I. The ~obacco indusu'y claims lhat studies of individual DSM critcrm do not demonstrate that any group of smokers satisfied sufficient crimri~ to qualify for diagnosis of addiction. FDA cited these studies as support for the conclusion that a significant proportion of tobacco consumers arc addicted to nicotine. "[his conclusion is primarily demonstmmd by population-based studies, including the DSM-IV fmld trial, which show that tl~ v~st majority of smokers do meet suff~cm DSM crimri~ to b~ cons~ nicotine del~ndenl, discussed in more detail in s~xion II.B., below. The field ~ w-as a large, multicenlcr study conducuxl in 1991 and 1992 at flv¢ silgs across ~¢ country (Bm-lington, VT; Philadelphia, PA; Denver, CO; St. Louis, MO; and San Diego, CA).~2 Tl~ popul~ion 2~ Woody GE, Cog.let LB, Cacciola AaAictio~ 1993;88:1573-1579. See AR (Vol. 13 I~. 1.50). Cotflcr L, Comparing DSM-rlI-R S~e AR (Vok 13 Rcf. 149). 133 282207348 PRODUCED FROM B&W WEB SITE 44790 Federal Register / Vo|. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.7. studied represented a diverse sample and included African-Americans, women, others randomly selected from the general ~opulation, and still others with a range of diagnoses and substance use patterns. The field trial documents that 8(}% to 87% of smokers studied qualified for the diagnosis of nicotine d~pendence. In its comments, the American Psychiatric Association concurs with the Agency's findings: "DSM based studies also found that 80% to 90% of adult smokers arc nicotine dependent.''253 The tobacco indust~'s conmmnts on population-based studies are addressed in section II.BA.b., below. It is relevant to mention here that, ff tl~ induso'y's assertion that these population-based studies are not representative of all smokers is correct, then large surveys of whether all smokers meet individual DSM criteria would show inconsistem results. But this is not the case. Overwhelming evidence, cited in section II.A.3.c.ii., above, conclusively demonstrates that the vast majority of tobacco consumen meet individual criteria for addiction. 2. The tobacco industry disputes that use of tobacco products p~rsisis longer and in greater amounts than the user intends. According to the industry, studies cited by FDA demonstrate that, at most, 30% of ImOple who have cvcr tried tobacco become "del~ndent" by FDA's d~finifion The industry also argtm$ that tl~ desire to quit is not evidence of intent to cut down. FDA disagrees with the industry's position. It is Widely accepted that users of tobacco products consume morn than they originally intended.2~ Longitudinal data, cited x~s Allterican Psychiatric Association, Comment (Jan. 2, 1996), at 2. See AR (VoL 700 R~f. 1020). 2~ American Psychiatric Assoc~tiot~ Diagno,ac and $tari$~cal Manual of Mental Disorders, 4*J~ ed. (Washington DC: American Psychiatric Association, 1994), at 243. See AR (Vol. 37 Rcf. 8). 134 282207349 PRODUCED FROH B&W WEB 8ITE F~leral Regi~er / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations 44791 II.A.7. in section ll.A.3.c.ii., above, demonstrate that smokers frequently underestimate how much they will be smoking in the future. As many as 90% of current users smoke more tlum five cigarettes a day,~ss despite the evidence that neaxly half of young consumers do not intend to become daffy smokers.~ Although estimates vary from study to study, persons who have smoked at least one cigarette are about twice as likely to develop dependence as are persons who have ever tried cocaine or alcohol,z~7 If an individual wants to quit smoking but cannot, then the individual is smoking more than he or she intends. The overwhelming evidence prese~lted in section II.A.3.c.ii., above, that many would-be quitters cannot attain abstinence supports the contention tl~t consumers use cigarettes longer and in greater amounts than intended. 3. The tobacco industry disputes that tobacco use continues despite attempts to~]uit. The industry observes that 90% of cigarette smokers who quit succeed by themselves, and the smokeless tobacco industry suggests tlmt 75% of successful quitters fend it easy to quit. The tobacco industry also alleges tJmt FDA mischa~cterizes data on self-reports of dependence from the National Household Surveys and misrepresents m Be~o~d~z NL, Cigare~e smola~ and nicotine addictio~. Medical Clinics of North Arntrica 1992;76(2):415-437. See AR (VoL 535 Ref. 9(x voL HI.A). Henningfield JE, Cohen C, Shtd~/D, Is nicotine mo~ ~dictive ~ cooties? 8riash Journal of Addition 1991;86:565-569. See AR (Voi. 27"/R~t'. 3904). ~, Eldcxs MJ. Perry C'L, Eriksen IV[P, a a/., The report of the Surgeon ~: preventin8 ~bacco use among young people, American .tournal of Public Health 1994;84(4):543-547. m 544. See AR (VoL 38 Re[. 39). ~ Anthony ~C Warner LA, lfamslet RC, Compm'adv~ ¢pidemioiogy off d~pendeme tm tob~:co, alcohol controlled subsmc~ and in]~al~: b~ic findin~ f~om ~e Natio~i Comodaidity Survey, Exper/me~ and Clinical P~ychopharmacology 1994:2:24¢-268. See AR (Vol. 37 Ref. 4). 135 282207350 PRODUCED FROM B&W WEB SITE 44792 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.7. abstinence failure rates from a CDC study. The industry further argues that smokers may lie on surveys about their desire to quit. - After reviewing industry comments and the administrative record, FDA concludes that there is overwhelming evidence that.tobacco use continues despite attempts to quit. Indeed, this fact is well known to the tobacco industry. For example, Brown & Williamson's data show that, while 32 million Americans attempted to quit each year from 1981 to 1983, fewer than a third were successful for 6 months. See Jurisdictional Analysis, 60 FR 41668. Philip Morris' data show similar success rates.2ss The argument that most smokers and users of smokeless tobacco who quit do so without assistance relies on surveys of the small proportion of tobacco users who are able to quit each year. This population is not representative of the vast majority of current tobacco users, who have tremendous difficulty quil~ing. Furthermore, the fact that some smokers are able to quit without assistance does not reveal the difficulty experienced by these individuals or the extent to which they have previously relapsed. More than half of people presenting for treatment of alcohol or drug abuse who also smoke cigarettes report that quitting smoking would be harder than giving up their other drug of abllSe.2s9 Two- thirds of smokers who try to quit ota their own rehpse within 2 days, and approximately 2u Ry~l~ l:J (Philip Morris Inc.), Cold tufltey in ~el(l, Iowa: It follow-up study, in Srnolang Bahavior: Motives and Incentives, ¢d. Du~n WL (W~hillgton DC:. VH Wil~toll & Sol~ 1973), at 231- 234. See AR (VoL 8 Ref. 105). ~ Kozlowski LT, Wilkinson A~ Slcimler W, eta/., ~g tol~.eo cig~et~ dcllcndenee with other dru8 del~endencies. Journal of the Am.~rican Medical Association 1989;261:898-901. 5¢¢ AR (Vol 41 Ref. 92). 136 282207351 PRODUCED FROM B&W WEB SITE Federal Re~/ster / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations 44793 II.A.7. 90% relapse within 3 months.2~° Sixty-eight percent of smokeless tobacco users who have attempted to quit have tried to do so an average of four times.TM • The industry disputes FDA's analysis of 1991 and 1992 National Household Survey data, which reveal that 83% to 87% of moderate to heavy smokers feel addicted. The industry first argues that the question to smokers has no validity; FDA disagrees and notes that the industry cited the same survey result from the 1985 survey at another point in its comments. The industry then suggests that FDA's analysis of the 1991 and 1992 data is inconsistent with published reports. This is not true. The Substance Abuse and Mental Health Services Administration (SAMHSA) conducted two National Household Surveys, one in 1991 and another in 1992. The data referred to in the Proposed Rule were a calculation by the Centers for Disease Control and Prevention (CDC) of raw data obtained in the 1991 and 1992 surveys and presented at FDA's Drug Abuse Advisory Committee meeting in August 1994.292 The CDC pooled the raw dam from both surveys, weighted them accordingly, and then evaluated the data using parameters different from those outlined in the main findings of each survey. The CDC used the data to look at different age groups of users and different numbe2s of cigarettes smoked per day than did SAMHSA. Even if the calculations performed by SAMHSA ~d been used, the data z~ Huglaes IIL Gulliver SB, Fenwick JW, et al., Smoking cessatioa among seif-qffatms, Health P~cholog'y 1992;11:331-334. See All (VoL 3~ Re_,f. 5512). 2~z Sevetson HIt, Ig~o~tgla s'~uff: ST cessation from r, be behavioral clinical, and public bealth flet~peclives, in Smokeless Tobacco or Health, an International Perspective, Smoking mid Toilacoo Control Monograph 2. NIIt Publication No. 93-3461 (Washington DC: OI~O, 1993), at 281-282. See AN (Vol. 18 Ref. 5-1). • 29: Giovino GA, Z~u BP, Tomar S, et al., Epiclemiology of Tobace~ Use and Symptoms of Nicotine Addiction in the United States: A Compilation of Data from Large National Surveys, presentation of~e Centers {or Disease Control and Preventio~ to the FDA's Dt~g Abuse Advisory Committee (Aug. 2, 1994). See AR (VoL 459 Ref. 7820). 137 282207352 PRODUCED FROM B&W WEB SITE 44794 Federal Register / Vol. 6~_, No. ~_68 / Wednesday, August 28, 1996 / Rules and Re~ulations II.A.7. would still show that, among those who smoke about a pack or more of cigarettes per day, 81% report feeling dependent.293 The tobacco industry also argues that FDA rnischatacterized a 1993 report from the CDC that FDA cited in the Jurisdictional Analysis for the statement that more than 15 million Americans "'reed to quit" each year and about 3% ultimately succeeded.2~t The industry contends that the survey did not ask specifically whether smoke~ had tried to quit, but whether smokers-did not smoke at least 1 day during the preceding year. The industry concludes that this report is not relevant to whether smokers try to quit. FDA disagrees. For daily smokea~, the CDC counted one day of abstinence only if the smokers stated "they quit for at least 1 day.''295 The CDC logically interpreted these results as showing that 17 million daily smokers who reported not smoking for at least 1 day made an attempt to quit. According to the report, "the findings from this sttt~ey indicate that, in 1990 and 1991, approximately 42% of daily smokers abstained from smoking cigarettes for at least I day but that approximately 86% of these persons subsequently resumed smoking. The high rate of relapse is likely because of the addieti'~e nature of nicotine.''~ FDA accepts CDCs interpretation of its survey. 2~ Deparmw.nt of Health and Human Service& S~slance Abuse and Mental Health Services Ad~ni~u-ation. Office of Applied Snuties, National Household Survey on Drug Abuse: Main Findings, 1991. DHHS Publicati~ Number (SMA)93-1980 (Rockville MD: DHHS, Public Health Service, 1993), at 127. See AR (VoL 535 Ref. 9(~ voL Ill.M). 2u Cemers for Disease Control and Prevention, Smoking cessatio~ dining lx~evious year among adults-- United S tares, 1990 and 1991; Morbidity and Mortality Weekly Report ! 993;42(26):504-507. See AR (Vol. 66 Ref. 2). 2~5 ld. at 504. ~ ld. at 504-507. 138 282207353 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44795 II.A.7. FDA also notes that CDC's estimate is consistent with other published estil'fiates297 and the tobacco industry's own tabulations of long-term quit rates. For example, a tobacco company has estimated that fewer than 4% of smokers who attempt to quit are able to quit permanently. See JurisdictiDnal Analysis, 60 FR 41668-41669. FDA disagrees that survey results significantly distort the numbers of smokers who want to and have tried to quit. This method of data collection is a scientifically recognized and accepted mode of inquiry for prevalence studies, which is relied upon to determine the population prevalence of other disorders, including alcohol dependence, cocaine dependence, and depression.29s Some of these are disorders for which, compared to tobacco use, interview methods would be less likely to reveal accurate results because of the criminal consequences associated with illicit drug use. Moreover, the authors of a study on this subject cited by the tobacco industry merely speculate that some smokers who say they want to quit may be dissembling, primarily on the basis of evidence that some smokers who claim to have quit smoking have been shown to be still smoking. At no time do these authors suggest that most smokers do not want to quit.2~ 4. The tobacco industry disputes that tobacco consumers contiaue to use despite knowledge of physical problems attribulable to tobacco. The industry notes thak in one survey, a majority of smokers rated their overall heath ~ good or excellent a~d 297 See, e.g., Hughes JR, C_mllivex SB. Fenwick PN. et al., Smoking cessation among self-quitters, Health Psychology 1992;11:331-334. See AR (Vol. 348 Ref. 5512). American Psychiatric Association. Diagnoxtic and Statistical Manual of Meraal Disorders, 40a ed. (Washinglon DC: American Psychialric Associahon. 1994), at 175-272. See AR Otoi. 535 Ref. 96, vol. Ill.B). :~ Kozlowski LT, Herman CP, Frecker RC, What ~esearchers make of what cigaret~ smokers say. filtering smokers' hot air, l_zmcet 1980;1(8170):699-700. See AR (Vol. 535 Ref. 96, voL lII.I). 139 282207354 PRODUCED FROM B&W WEB SITE 44796 Federal lte~ister / Vol. 61, No. 168 1 Wednesday, August 28, 1996 / Rules and Regulations ) II.A.7. concludes from this that the smokers were not suffering ill health from tobacco use. The industry also criticizes studies cited by FDA that document high rates of smoking after catastrophic illness on the basis that (1) the sample sizes were small; and (2) some fraction of the subjects in the studies were able to quit. After reviewing the evidence in the adminisuative record, FDA disagrees with the industry's position. To argue that a majority of smokers generally believe themselves in "g .opal'" or "excellent" health, the industry eite.s a Gallup poll originally cited by FDA.s°° In fact, contrary to the industry's argument, this Gallup poll demonstrates that smokers continue to use tobacco despite health problems. Sixty-five percent of smokers in the survey admitted that "smoking has already affected their health." Moreover, the data reveal that: (1) significamlyfewer smokers than nonsmokers rated their health as "excellent"; and (2) smokers rated their overall condition as significantly less healthy than nonsmokers did. Thus, this survey supports FDA's contention that smokers persist in using tobacco despite knowledge that their health has beeff harmed by smoking. The mdustry's criticism of data cited by FDA on smokers continuing to use. tobacco after myocardial infarction, lung cancer, and laryngeal cancer is not persuasive. The industry offers no contradi .c.ting evidence, nor does it suggest any reason why the studies cimd by FDA might not be generalizable to the larger populatio.n. In the absence of such reasons, FDA believes that the sample sizes were adequate to permit such generalization. ~0o Gallup GH, Smoking Prevalence, Beliefs, and Aclivitias by Oender and Other Demographic Indicators (Princeton NJ: Gallup Organization, 1993), at 20, 37. See AR (VoL 86 Ref. 1165). 140 282207355 PRODUCED FROM B&W WEB SITE Federal Register / Vol. ill, No. 188 / Wednesday, August 28, 1996 / Rules and Regulations 44797 II.A.7. The industry finally makes the argument that some people with devastating disease from tobacco are able to quit smoking. This contention misses the point. Even in the most drastic of circumstances, when patients have lost part of their body to cancer from smoking or had part of their heart muscle die from smoking, many still cannot stop. That any significant number of people return to smoking after such devastating tobacco-related disease is a powerful illustration of the addictivcness of nicotine. h. Comments on Nicotine's Other Significant Pharmacologiotl Effects 1. The tobacco industry argues that many substances and activities tangentially affect the brain, but that a reliable criterion for a "substantial" pharmacological effect is intoxication. According to the comment, nicotine does not produce intoxication, and therefore its pharmacological effects are not substantial. FDA disagrees. FDA has presented dozens of scientific studies and reviews to show that nicotine has numerous substantial pharmacological effects on the human body. The most significant of these is addiction, discussed at length in section ]LA.3., above. Other examples of substantial effects include significant molecular changes ,in the brain, effects on weight regulation, and substantial alterations of mood, alertness, and cognition, none of which the industry contests. The vast majority of dru~ that FDA already regulates, whose pharmacological effects ar~ indisputable, do not pmdue~ intoxication. FDA notes that nicotine can cause intoxication. Indeed, fkrSt-time users often become intoxicated.TM Regular users do so rarely because they have developed an extremely high level of tolerance to this effect of hicotine.3°2 Surgeon General's Report, 1988, at 594. See AR (Vol. 129 l~f. 1592). ld. at 593-596. 141 282207356 PRODUCED FROM B&W WEB SITE 44798 F~deral R~ister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and R~gulations II.AA i. Comments on Whether Cigarettes and Smokeless Tobacco Deliver Pharmacologically Active Doses of Nicotine 1. Several professional organizations with cxpertkse in pharmacology and addiction comment on the ability of cigarettes and smokeless tobacco to provide addictive doses of nicotine. These comments uniformly agree with the conclusion that cigarettes- and smokeless tobacco do provide pharmacologically active doses of nicotine capable of producing addiction. These organizations include the College on Problems of Drug Dependence, which states: Nicotine is appropriately categorized as an addictive drug. Data from both animals and hul~ns indicate that nicotine produces tolerance, physical dependence, reinforcin~ psychoactive effects and it thus has the potential for becoming an abused substance. Regular cigarette smokers and habitual smokeless tobacco users obtain sufficient quantities of nicotine to produce these effects .... Cigarettes and smokeless tobacco serve as highly effective and efficiem drug delivery devices. They provide nicotine in quantities and patterns that enable users readily to develop and sustain dependence.3°3 The American Society of Addiction Medicine concludes that "'mcotine in cigarettes and in smokeless tobacco is a pharmacologically active agem that causes addiction in a high proportion of users. Similar conclusions were reached by the American Psychological ~on, which observes that "' [ c ]i gar ettes and smokeless tobacco serve as highly effective and College on Problems of Drug Dependence, Comment (Nov. 6, 1995), at I (emphasis added). See AR (Vol. 700 Ref. 1021 ). American Society of Addiction Medicine, Commit (De*:. 29, 1995), at I (emphasis re;Ideal). See AR (Vol. 528 Ref. 97). lZ[2 282207357 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44799 II.A.7. efficient drug delivery systems, which by their very design enable people to readily develop and sustain nicotine addiction. .305 FDA agrees with these independent scientific bodies. 2. The tobacco industry takes issue with FDA's citations of studies to show that certain levels of nicotine cause pharmacological effects. The tobacco industry argues that three studies cited by FDA to estimate the minimum pharmacological dose of nicotine do not show that tobacco products cause significant pharmacological effects. The industry also contends that two studies cited by FDA to show that smokers can control their nicotine intake do not reflect common tobacco consumption behavior. The industry mischaracterizes FDA's reasons for citing the studies. FD.A did not citeanimal research and a study on the nicotine nasal spray to prove tlmt cigarettes cause pharmacological effects in humans. Rather, the studies were cited to demonstrate that a very low blood level of nicotine that is easily attainable with cigarettes produces 'pharmacological effects across species. This observation complements overwhelming evidence from clinical, epidemiological, and In,oratory studies showing that cigarettes mad smokeless tobacco cause significant phatmacolol~al effects in • Simi~rly, FDA did not cite studies on the extremes of nicotine intake to demonstrate exactly how much nicotine every smoker obtains. Rather. the studies were cited to demonstrate that nicotine retake from c~s has the potential to vary widely across a range of levels that produce significant pharmacological effects in humans. American Psychological Association, Comment (Dec. 28, 1995), at 2 (emphasis added). See AR (Vol. 531 Ref. 123). 143 282207358 PRODUCED FROM B&W WEB SITE 44800 Federal Re~ister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.7. FDA also notes that the industry offers no data contradicting FDA's studies. The industry also fails to contest other sources cited by FDA--includmg some from the tobacco industry--that clearly support the conclusion that nicotine levels in commercial tobacco products produce significant pharmacological effects in consumers. See Jurisdictional Analysis, 60 FR 41571-41572, 41632-41640. ,~ Finally, FDA notes that the industry misinterprets a study by Perkins et al.30+ on nicotine nasal spray. See section II.A+7.d., above. 3. The industry contends that nicotine doses provided by cigarettes produce only a "minimal response in laboratory animals and a small number of human subjects" and that, therefore, FDA has not established that nicotine doses delivered by cigarettes produce substantial phaxmacological effects. FDA disagrees. Many studies demonstrate such significant effects as systemic cardiovascular reactions in nontolerant humans and animals,3°7 siekn~s produced by a single tobacco exposure in nontolerant individuals,3m and changes in brain electrical activity comparable to those produced by other addictive drugs.3°9 As described in sections I.I.A.4., above, and ILB.2., below, use of tobacco also produces signitieant effects on attention, mood, cognition, and weight regulation. These are not minimal effects. ~oe Perifins K, Grobe J, S~ka A. eta/., Discriminative stimulus effects of nicotine in smoke~ in International Symposium on Nicotine: The Effect~ of Nicotine on Biological Systen~ II, eds. ~ PBS, Quik M, Thurau K, Adlkofer F (Basel: Bixktmuset Verlag, 1994), at ! 11..gee AR (Vol. 42 Ref. 111 ). sot Sm'geon General's Report, 1988, at 47. See AR (VoL 129 ReL 1592). ~o, ld. at 594. +o~ Pritchard WS, Eiecttoencephalographic effects of cig~'ette smoking, P.sychopharmacology 1991; 104:~5-490, at 485, 488. See AR (Vol. 105 Ref. 965). 282207359 PRODUCED FROM B&W WEB SITE Federal R~ister I Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44801 II.A.7. Nicotine's capacity to produce and sustain addiction, as described in section II.A.2., above, is another example of a significant pharmacological effect. Because the vast majority of chronic smokers are highly tolerant to nicotine, not all of~he pharmacological effects of nicotine are evident with every cigarette and pinch of smokeless tobacco. As described in section ILA.3.c.i_, above, the severe degree of tolerance produced by nicotine seems to greatly exceed that produced by cocaine and to be more comparable to that produced by morphine in the reduction of responsiveness to acute doses after a period of repeated exposure. 4. The tobacco industry argues that there is nb "addictive level" of nicotine. This contention is partly based on the claim that nicotine intake is not well correlated with quitting success. The industry also argues that FDA's Drug Abuse Advisory Committee did not identify a threshold addictive dose of nicotine. Without such an "addictive level," the industry concludes, the nicotine in tobacco products cannot have a substantial pharmacological effect. FDA disagrees. The tobacco industry misinterprets the scicmific litcmtttre on cessation studies, the actual conclusion reached by the Commitme, and the concept of "addictive level." A large body of literature has shown that nicotine dependence level is among the strongest general predictors of withdrawal severity and duration of abstinence. See section II.A.7.f., above.3to These dam support the conclusion that the relationship between level of drug intake and dependence level is similar to that observed with other 310 Surgeon Gcnerars Report, 1988, at 315-321,522-523. See AR (Vol. 129 Rcf. 1592). 145 282207360 PRODUCED FROM B&W WEB SITE 44802 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.7. forms of drug addiction, namely that level of drug intake is generally but not precisely correlated positively with dependence level and that there is wide individual variability.~ It is because drug intake alone is not a perfect measure of dependence that diagnostic instruments such as the DSM are necessary for clinical practice. -~ The industry also misrepresents the findings of the FDA Committee, which concl~led that all currently marketed cigarettes contain an addictive dose of nicotine, but that the data were not sufficient to determine a threshold dose below which the product would not pose a risk of addiction.~1~ The main concern of the Committee was that, in attempting to set a lower limit, any error on the high side would permit the industry to market products that would be addictive to some persons. The Committee was particularly concerned that persons who have not developed tolerance to nicotine, such as children, might find even the doses posed by Benowitz and Henningfield (approximately one-tenth of the delivery of a typical cigarette) to be addictive,m ' FDA concurs with the Committee that all currently marketed cigarettes contain addictive levels of nicotine. 5. The tobacco industry argues that any compensation occurring in response to cigarettes with lower yields of tar and nicotine is limited and of short duration. Thus, according to the industry, smolm~ of low-yield cigarettes do not obtain pharmacologically active doses of nicotine. The industry contends that this proposition is supported by an 3~ Icl. at 315-321. ~ Transcript to the FDA Drug Abuse Advista'y Committee, Meeting 27, "Issues Coaceming Nicotine- Con~alning Cigaretms and Other Tobacco Products" (Aug. 2, 1994), at 346-353. See AR (Vol. 255 Ref. 3445). 3~ ld. at 346-353. 146 282207361 PRODUCED FROM B&W WEB SITE Feder~l Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44803 II.A.7. article by Benowitz and Henningfield.3'4 The industry also argues that smokers actually compensate for changes in tar delivery rather than nicotine delivery. Furthermore, it denies that cigarette vent-hole blocking is a significant means of compensation. The industry thus argues that compensation for nicotine does not occur. FDA disagrees. Tobacco industry research demonstrates that smokers significantly compensate for nicotine. For example, research presented at a tobacco industry conference in 1974 demonstrated that, "whatever the characteristics of cigarettes as determined by smoking machines, the smoker adjusts his pattern to deliver his own nicotine requirements." See Jurisdictional Analysis, 60 FR 41663. Other examples of the tobacco industry's understanding of compensation are documented in the Jurisdictional Analysis. See 60 FR 41572-41575. Furthermore, FDA cited research in the Jurisdictional Analysis demonstm~g that the actual amount of nicotine delivered to the smoker does not correlate with the machine- measured yield of the cigarette and that smokers who smoke "low-yield" cigarettes have been shown to obtain substantially more nicotine than the advertised yield. See 60 FR 41659-41665. In one study, for example, the advertised yield ol t~t~d cigarettes ranged from 0.1 to 1.6 mg of nicotine, but the actual nicotine intake by the .~mokers asked to smoke these cigaretms ranged from 0.75 to 1.25 rag.3~50thex studies have also found that the nicotine levels measured in smokers' blood beatr either no relationship or a minimal ~' Benowi~ ~ Hennmgfield JE, Establishing a nicotine tlneshold for addiction, New England Journal of Medicine 1994;331:123-125. See AR (Vol. 28 Rgf. 218), 3,~ Gori GB, Lynch C_J, Analytical ¢igmetle yiekls as predictors of smoke bioavailablity, Regulatory Toxicology. and Pharmacology 1985;5:314-326. See AR (VoL 12 Per. 142). 147 282207362 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday. August 28, 1996 / Rules and ReRulations II.A.7. relationship to the nicotine yield of the cigarettes being smoked and that machine- measured yields of low-tar/low-nicotine cigarettes significantly underestimate true rates of nicotine absorption. In most of these studies, the subjects were people whq were smoking their usual brand of cigarettes and showed levels of nicotine not related to Federal Trade Commission (FTC) yields, thus refuting the suggestion t~t compensation is short-li~ed)~6 : The tobacco industry misrepresems the position of Benowitz and Henningfield on compensation. These authors hav~ repeatedly published research demonstrating that smokers compensate with current cigarettes by smoking harder or by blocking the vent holes. ~ I 7 In the Benowitz and Henningfield paper cited by the tobacco industry, the authors were discussing cigarettes--not currently on the market--with so little available nicotine that it would be impossible to compensate for reduced nicotine except by smoking an impractical number of cigarettes. The total nicotine content of these cigarettes would have been only about 5% of the conmnt of currently marketed cigarettes and would have permitted a maximum delivery of only about 10% that of currant cigarettes. The authors predicted that few smoke~s would permanently smoke the 200 or more cigarettes needed to obtain the nicotine intake typically d~livea~ by 20 conventional eigarel~. Thus, B~nowitz and Henningfield befievcd that, if denied ace.s Io r~gular nicotine cigarette, smokers would either quit or adjust over time to substantially redtw~ nicotine intake. 316 Surgeon General's Report, 1988, at 158-159. See AR (Vol. 129 Re/. 1592). ~1~ Id. at 158-163. Heauingfield JE~ Kozlow~ki LT, Benowilz NL. A proposal to develop meaningful labeling for cigarettes, Journal o/the American Medical Association 1994;272:312-314. See AR (VoL 313 l~f. 4846). 148 282207363 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.A.7. This prediction is entirely inapplicable to currently marketed "low-yield" cigarettes delivering 0.1 mg of nicotine as measured by the smoking machine; a smoker need smoke only about 30 of these to obtain the amount of nicotine obtained with 20 "full flavor" cigarettes.3's , The tobacco industry's denial that vent blocking occurs misses important points of FDA's position on this issue. FDA has simply posed vent blocking as the most likely explanation for the well-documented fact that there is almost no difference in the nicotine levels observed in the bodies of smokers who smoke brands with widely varying FTC yields. Smoking more cigarettes is only one means by which smokers compensate. Vent blocking is another means at the smoker' s disposal to compensate. Indeed, the studies relied on by the tobacco industry suggest that the frequency of vent blocking is inversely proportional to the yield of the cigarette. In other words, the lower the tar and nicotine yield of the cigarette, the more the smoker blocks the vent holes. These data support the position that vent blocking plays an important role in compensation. There are, in additiom other compensation mechanisms, such as smoking more of the cigarette than is smoked in testing machines, smoking more aggressively, and taking deeper inhalations.3~ The tobacco industry contends that smokers may compensate for tar rather than for nicotine. This contention is contradicted by a very extensive body of literature, documented in detail in the 1988 Surgeon General's Report,32e showing that, when the 3~. Transcript to the FDA Drug Abuse Advisory Commilte~ Meeting 27. "Issues Concerning Nicotine- Containing CiRarettes and Other Tobacco Products" (Aug. 2, 1994), at 106. See AR (Vol 255 Ref. 3445). 3~ Surgeon Genend's-Report. 1988, at 153-158. See AR (VoL 129 Ref. 1592). 320 ld. at 153-169, 282-283. 149 282207364 PRODUCED FROM B&W WEB SITE 44~06 Federal Register / Vol. 61, No. 168 / Wednesday, August 28. 1996 I Rules and Regulations II.A.7. level of nicotine in cigarcaes is manipulated, smokers alter their smoke intake. Although the relationship is not perfect, it is similar to that which has been observed with other addictive drugs in numerous animal studies and some human studies. That is, when the dose of the drug in the cigarette is increased, the number of unit doses that arc self- administered decreases generally, although not proportionally. This results in the frequent observation of increased overall drug intake.32~ Conversely, when the dose is decreased, the number of unit doses that are self- administered generally increases, although usually not proportionally. The relationship has been demonstrated with respect to cigarette smoking by: (1) administering nicotine to smokers via other routes, which results in decreased smoking; and (2) administering the nicotine blocker mecamylamine to smokers (which reduces the effects of nicotine on receptors in the brain), resulting in increased smoking.3~ A study on compensation for smokeless tobacco cited by the smokeless tobacco industry showed that users increased their consumption when switched to a low-nicotine product.3~3 32~ ld. at 282-283. ~2 ld. at 165-169. ~ ~23 Andc~sson G, AxeH T, C~vall M, Reduction in nicotine intake and onfl mucosal clmnges ~mong users of Swedish oral moist snuff after swi~ to a low-nicotine pmdnc~ 3ournal of Oral Pa:hology & Medicine 1995;24:244-250. See AR (Vol. 526 Ref. 95, voL VH). The tow-nicotine product had a lowex pH than the higher-nicotine product Because lower pH [educes absozption tee section IID., below, meastuements of nicotine intake cited by the industry do not accurately reflect compensation in this study. 150 T 282207365 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44807 ll.B. B. CONSUMERS USE CIGARETTES AND SMOKELESS TOBACCO TO OBTAIN THE PHARMACOLOGICAL EFFECTS OF NICOTINE AND TO SATISFY THEIR ADDICTION In section II.A., above, the Agency concludes that the foresee, able pharmacological uses of cigarettes and smokeless tobacco establish that tobacco manufacturers intend their products to affect the structure and function of the body. The Agency may find additional evidence of such intent through evidence that consumers commonly use tobacco products for pharmacological effects. Where consumers use a product predominantly or nearly exclusively to obtain any of the effects on the structure or function of the body produced by a substance, such evidence would alone be sufficient to establish manufacturer intent. See ASH v. Harris, 655 F.2d 239-240. The Agency made extensive findings regarding consumer use of tobacco products in the Jurisdictional Analysis. See 60 FR 41576-41581. FDA received comments from the tobacco industry, public health and medical organizations and practitioners, and other members of the public. Upon review of the evidence in the administrative record and careful analysis of the comments on the Jurisdictional Analysis, the Agency .concludes that o the evidence demonstrates that consumer use of cigarettes and smokeless tobacco for the pharmacological effects of nicotine is predominant, in fact nearly exclusive. Moreover, the Agency finds that othcr factors associated with tobacco use---including taste and lmbit-- are significant to almost all consumers only by their association with nicotine's pharmacological effects on the brain. Thus, FDA finds that actual consumer use of cigaxettcs and smokeless tobacco for the pharmacological effects of nicotine provides an 151 282207366 PRODUCED FROM B&W WEB SITE Federal ~e~istsr / Vo]. 61, No. 168 / Wednesday, August gS, 1996 / Rules and Regulations II.B.I. independent basis for the conclnsion that these products a~e intended Io affect the structure and function of the human body.s2~ In section I'I_B. I., below, FDA discusses its authority to consider evidence of consumer use in establishing intended use. FDA presents its major findings and responds to significam comments in sections ILB.2. and 3., below. In section ILB.4., below, FDA responds to all other substantive comments. 1. "Intended Use" May Be Established on the Basis of Actual Consumer Use The legislative history of the Act clearly states that consumer use can be probative of a product's intended use. For example, the House Report on the Medical Device Amendments of 19"/6 states that "'It]he Secretary may consider.., use of a product in determining whether or not it is a device." H.R. Rep. 853, 9ztth Cong., 2d Sess. 14 (1976) (emphasis added), reprinted gn An Analytical Legislative History of the Medical Device Amendments of 1976, Appendix [] (Daniel F. O'Keefe, Jr. & Robert A. Spiegel, eds. 1976). Similarly, the legislative history of the 1938 Act states expressly that "the use to which the product is to be put will determine the category into which it will fall." S. Rep. No. 361, 74th Cong., 1st Sess. 4 (1935) (emphasis addod), reprinted in 3 Legislative History 660, 663. ~ In this case, there is evickace eo~ only of actual om~'ume~ use, but other evidence of manufactm~ latent, including: (I) evidence that nicotine's addictive properties and o~her pharmacological effects foot.able to • reasonable tobao~ manufacturer, and (2) evidence from Ihe stalemeals, research, and ac~ons of manufacuae~s establishing ~hat they intend their products to affe~ e~e structure o~ f~action of the bo~es of tobacco users. See secticms ILA,, C., and D. Thus, although the evidence establishes that consume~ use cigarettes and smokeless tobacco predominantly or nearly exclusively fo~ the pharmacological effects of nicotine, this finding is not necessary, to permit reliance ¢m the evidence of actual consumer use. Relied on in conjunction with the other evidence of manufacu~er intent, evidence of actual consumer use provides substantial additional support for the Agency's conclusion. 152 282207367 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations 44809 II.B.I. Like the legislative history, FDA's regulations on adequate directions for the use of drugs and devices also demonstrate that actual consumer use can be a basis for establishing a product's intended use. 21 CFR 201.5 (drugs); 2,~ CFR 801.5 (devices). Section 201.5, which specifies the "adequate directions" that must be provided on drug labeling, provides examples of the "intended uses" of a drug that must be included in any adequate labeling. These intended uses include both: (1) "uses for which it is prescribed, recommended, or suggested in its oral, written, print, or graphic advertising;" and (2) "uses for which the drug is commonly used." 21 CFR 201.5 (emphasis added). Section 801.5 contains parallel provisions for devices. Because adequate directions for use are required only for the intended uses of a product, these regulations make the "common use" of a product a basis for determining "intended use." Courts have also recognized that actual consumer use can be a persuasive basis for determining intent~ven in the absence of other evidence that the manufacturer intends to affect the structure or function of the body. In ASH, the court explicitly recognized that actual "consumer intent" by itself could be a basis for imputing intent to the manufacturer. Clearly, it is well established "that the 'intended use' of a product, within the meaning of the Act, is determined from its label, accompanying labeling, promotional el~m, ~lv~ti~ing, and nny other relevant source." Whtth~r tvidence of consura~r intent is a "relevant source" for th~$e purposes depends upon wh~th~r such evidence is strong enough to justify an inference as to the vendors' intent. This requires a substantial showing.... In cases such as the one at hand, consumers must use the product predominantly~d in fact nearly exclusivelymwith the appropriate intent before the requisite statutory intern can be inferred. 655 F.2d at 239-240 (emphasis added). Similarly, in NNFA v. Weinberger, the court held that evidence before the Commissioner that vitamins "were used almost exclusively for 153 282207368 PRODUCED FROM B&W WEB SITE 44810 F~leral Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.B.1. therapeutic purposes" could be a proper basis to determine that the manufacturer imended a pharmacological use. 512 F.2d at 703. When a finding of an intent to affect tt~ structure and function of the body is based exclusively on evidence of actual consumer use, the evidence must meet a high threshold, As quoted above, the courts in ASH and NNFA have indicated that the evidence should show that the actual consumer use for drug purposes is "predominant" or "nearly exclusive." FDA's regulations contemplate that the use be shown to be at least "common." 21 CFR 201.5. There is no requirement, however, that a product be used nearly exclusively as a drug before FDA may regulate it as a drug. To the contrary, a product that has both pharmacological uses and nonpharmacological uses can be regulated as a drug. See United States v. Guardian Chemical Corp., 410 F.2d 157, 162-163 (2d Cir. 1969)(a solvent used both to dissolve kidney stones (a drug use) and to clean instruments (a nondrug use) was properly regulated as a drug). Consistent with this principle, the courts recognize that where, as here, there is other evidence of manufacturer intent, consumer use for drug purposes may be relevent evidence of intended use even if that use is not predominant or nearly exclusive. See, e.g., United States v. An Article of Device.., Toftness Radiation Detector, 731 F.2d 1253, 1257 (Tth Cir. 1984); United States v. 789 Cases... Latex Surgeons' Gloves, 799 F. Supp. 1275, 1285, 1294-95 (D.P.R. 1992); United States v. 22. .. devices... "The Ster-o-lizer MD.200," 714 F. Supp. at 1165; United States v. An Aracle of Device... . "Cameron Spitler Amblo-S3eatonizer," 261 F. Supp. 243, 245 (D. Neb. 1966). 154 282207369 PRODUCED FROH B&W WEB SITE Fsdsr~l Re~i~er / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.B.2. Consistcnt with these authorities, the Agency finds that actual consumer use can be a basis for establishing the manufacturer's intended use for the product. Where the only evidence of inu'.nded use is the actual consumer use of the product, the Agency may need to show that the use of the product for pharmacological purposes is "predominant" or "nearly exclusive" before establishing that a product is intended to affect the structure or any function of the body. At a minimum, as set forth in FDA's regulations, the Agency should show that the use is "common" before relying exclusively on evidence of consumer use to establish intended use. Where, however, actual consumer use is only one of several types of evidence relied upon by the Agency, more limited evidence of consumer use can. be used to support a finding that a product is "intended to affect the structure or any function of the body." , In the case of cigarettes and smokeless tobacco, as discussed below, the evidence establishes that the standard of "predominant" or "nearly exclusive" consumer use is met even though other types of evidence exist. Thus, the evidence of actual consumer use of cigaxettes and smokeless tobacco provides an independent basis fox establishing lhese products' intended pharmacological uses. 2. Consumers Use Cigarettes and Smokeless Tobaceo for the Pharmacological Effects of Nicotine The evidence on consumer use of cigarettes and smokeless tobacco convincingly demonstrates the intended use of such produc~s for phamm~logical purposes, in the following sections, FDA explains this conclusion and the epidcmiological and experimenud dam that confu'm that consumers do use cigaxenes and smokeless u~bacco predominantly for one or more of the pharmacological effects of nicotine. 155 282207370 PRODUCED FROM B&W WEB SITE 44~12 F~leral Register / Vo|. 61. No. 168 / Wednesday, August 28. 1996 / Rules and R~gulations lI.B.2. a. Epidemiological Evidence Shows That Consumers Use Cigarettes and Smokeless Tobacco for Pharmacological Effects Epidemiological studies establish that the vast majority of consumers use tobacco for at least one of three pharmacological purposes: to satisfy a nicotine addiction; to receive the accompanying psychoactive effects, such as relaxation and stimulation; or to control weight. TO ~atisfy nicotine addiction. If a tobacco consumer is addicted to nicotine, then the key reason for use of the tobacco product is a pharmacological effect: the satisfaction of the addiction. Based upon internationally accepted definitions of addiction from the American Psychiatric Association and the World Health Organization (WHO), major recent studies show that 77% to 92% of smokers are addicted to cigarettes. In various studies, smokers who met the criteria for addiction included those identified I~y self-report (90% addicted),3z5 those who used tobacco six or more times (87% addicted),32~ those who were daily users for at least one month (77% to 92% addicted),327 and those who reported any current use of cigarettes (80% addicted).3~ Studies show a higher percentage of Hughes JR, Gust SW, Pechaeek TF, Prevaleeee of tobacco ~ and withdrawal, J~urnal of Psychiatry 1987;14~(2):205-208. 5e¢ AR (VoL 81 Ref. 292). 326 Woody GF~ Cottler LB, Caeeioit J, Severity of depmdenee: data from the DSM-IV field trials, Addiction 1993;88:1573-1579. See AR (Vol 13 Ref. 150). 327 Cottler L, Comparing DSM-III-R and ICD-10 sul~tanee use disord~t~ Addiction 1993;88:689-696. See AR (Vol. 13 Ref. 149). 32s Hale KL, Hughes JR, Oliveto AH, Helzar IK Higgins ST, Bickel WK, Cottler LB, Nicotine dependence in a population-based sample, in Problems of Drug Dependence, 1992, NID A Research Monograph 132 rWashington DC: Government Printing Office, 1993). See AR (Vol. 39 Ref. 60). 156 282207371 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44813 II.B.2. addiction among tobacco users than among users of other addictive drugs, including cocaine and heroin.329 Although there have been no population-based studies using DSM or WHO criteria to assess rates of addiction to smokeless tobacco, substantial evidence demonstrates that a high proportion of smokeless tobacco users meet individual criteria for addiction. See section ri.A.3.c.ii., above. This evidence strongly supports the conclusion that a sfibstantial proportion of such users are addicted. 3~o In 1992, the Inspector General of the U.S. Department of Health and Human Services estimated that approximately 75% of young regular users of smokeless tobacco are addicted.33~ Evidence also demonstrates that many tobacco users continue to consume tobacco for an additional pharmacological re'on related to addiction: to avoid withdrawal symptoms,m As addiction specialist Jerome Jaffe has noted, "[w]ithdmwal from nicotine •.. regularly motivates continued smoking.''a~ ~ Anthony JC, Warner LA, Kessle~ RC, Comparative epidemiology of dependence on tobacco, alcohol, cont~lled substances and inhalants: basic findings farm the National Comorbidity Survey, ~menm/ and Clinical Psycho~oi~gy 1994;2:24~7.68. See AR (VoL 37 Ref. 4). ~o Benowitz N-L, Pharmacology ¢~ smcd~ess tobn¢.co use: nic~ine addiction lad nicxxiae-relaled health consequence, in Smokeless Tobacco or Health, Smoking and Tobacco C,¢mlroi Monograph 2 (Washingto~ DC: Government Printing Office, 1993), at 224. See AR (Vol. 93 Ref. 606). ~1 Department of Health and Human Services, Office on Smoking and Healtik Spit Tobacco and Youth (Washington DC: Government Printing Office, 1992), atS. See AR (VoL 7 Ref. 76). 332 Hughes JR, Higgins ST, }lalsukami D, EHecls of abstinence from tobacco: a critical t~view, Research Advances in Alcohol and Drug Problems 199~,10:.3170398, at 381. See AR (VoL 535 Ref. 96, vol. HI.G). 333 Jaffe JH, Drug ~ddiclion and drug abuse, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed. (New York: Pergamon Press, 1990), chap. 22 (522-573), at 529. See AR (Vol. 535 Ref. 96, vol. HI.G). 157 282207372 PRODUCED FROH B&W WEB SITE ~14814 Federal Register / Vol. 61. No. 168 / Wednesday, August 28. 1996 / Rules and Regulations II.B.2. For stmaulation, sedation, mood alteration, and cognition. Studies also reveal that a large proportion of consumers use tobacco for other psychoactive effects. For example, a recent survey of young people 10 to 22 y ~ears old found that 72.8% of daily_smokers and 53.8% of daily consumers of smokeless tobacco said they used tobacco for relaxation)~4 The 1988 Surgeon General's Report reviewed the epidemiological litarature on the effects of smoking on mood: "The conclusion from this literature is that in the general population, persons perceive that smoking has functions that are relevant for mood regulation. Persons report that they smoke more in situations revolving negative mood, and they perceive that smoking helps them m feel better in such situations.''335 The Surgeon General's Report also noted that "some cigarette smokers believe that smoking helps them to think and concentrate.''336 This is the belief of several prominent tobacco industry resem-chers.337 Data demonstrating significant consumer use for the pharmacologically mediated effects of nicotine on mood and arousal are summarized in the Jurisdictional Analysis. See 60 FR 41579--41580. To control weight. Numerous studies show that tobacco use by many people is at least partially motivated by their belief that tobacco will help them control their weight. s~ Centers for ~ Comml and P~evealion, Reasons for tobacco use and sympwms of nicotine withdrawal anmag adolesc~Is and young adult tobncco use~s~Umled $lmes, 1993, Morbidity and Mortality Weekly Report 1994;43(41):745-750. See AR (Vol 43 Ref. 162). 33s Sargeo~ General's Report, 1988, at 399. See AR (Vol. 129 Ref. 1592). ~ Id. ~t 382. Robinson J, Transcript to the FDA Drug Abuse Advisory Committee, Me~tmg 27, "Issues Com~ing Nieotine-Con~ining Cigarettes and Other Tobacco Products" (Aug. 2, 1994), at 227. See AR (Vol. 255 Ref. 3445). Warburton DM, Nicotine: an addictive subslance or a therapeutic agent, Progress in Drug Research 1989;33:9-,41, at 25. See AR (Vo]. 140 R el. 1657). 158 ,) 282207373 PRODUCED FROM B&W WEB SITE F~lerM Re~isler / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44815 II.B.2. For example, in two surveys of young people, between one-third and one-haft of smokers said that weight control was a reason for their smoking.3~ Additional data on the use of tobacco products for weight control are summarized in the Jurisdictional Analysis. See 60 FR 41580-41581. b. Experimental Evidence Shows That Comammrs Use Cigarettes and Smokeless Tobacco Products for Pharmacological Effects As described in section ILA.3.c.i., above, overwhelming laboratory data demonstrate that nicotine' s pharmacological effects are central to tobacco use. Three findings from experimental studies particularly show that consumers smoke cigarettes and consume smokeless tobacco for the pharmacological effects of nicotine. Nicotine reinforces tobacco consumption. Like other addictive substances such as amphetamine, morphine, and cocaine, nicotine acts on a key "reward" pathway in the brain--known as the mesolimbic system~ reinforce its own consumption.339 As even the tobacco industry has noted, the "reward" generated by tltis pathway may explain why people eat food, drink water, and consume salt. The ability of nicotine to generate a similar "reward" for tobacco consumption reflects its pharmacological power and represents a clear reason why consunmrs use tobacco products. The data supporting nicotine's role in the "reward" system are discussed in section ILA.3.c.i., above. Nicotine controls smoking behavior. It has b~n con "vmeingly de.momtratcd that smokers adapt their cigarette consumIxion to maintain tlm phanmcological e/lea of nicotin~ in ~s Surgeon Generars Rcpo~ 1988, at 438-441. See AR(VoL 129 Ref. 1592). See, e.g., Corrigall W A, Frallklin KBJ, Coen KM~ et al., The ~ dol~aillergic sy~n is implicaled in the reinforcing effects of nicotine, Psychopharmacology 1992;107:285-289. See AR (Vol. 8 Ref 93-4). 159 282207374 PRODUCED FROM B&W WEB SITE Federal Re~ister / Vol. 61, No. 168 / Wednesday, August 28. 1~9~ / Rules and Re~u~a~ions II.B.2. the brain, Thus, smokers given cigarettes lower in nicotine change their smoking behavior to obtain more nicotine, and those given cigarettes higher in nicotine than their usual brand modify their behavior to of:rain less. When given a drug to reduce the effect of nicotine in the brain, smokers will consume more of the same cigarettes, even though nothing else has changed. This is.con~lling evidence that nicotine plays a pivotal role m why com~ use tolmeco products. These data are discussed in detail in ~ction II.A_5., above. Nicotine in.other forms affects tobacco comumers. The ability of nicotine nasal spray to produce some of the classic characteristics of addiction to nicotine supports the position that tobacco users seek tobacco primarily for the systemic pharmacological effects of nicotine. In contrast to cigarette smoke, aqueous nicotine spray does not provide any pleasing sensory characteristics. In fact, the spray can be irritating and unpleasant to use, and excessive use can cause nasal ulcerations. Notwithstanding the unpleasantness of the mcotme delivery mechanism and the presence of painful ulcerations that were further aggravated by continued use of the spray, some participants m clinical trials submitted to FDA used the spray to maintain nicotine dependence.~° Studies on nicotine replacement therapies also demonstrate efficacy in maintaining abstinence from smoking.~ The ability of nicotine to promote abstinence, even when delivered through the skin; without any taste or flavor, demonstrates its key role m maintaining tobacco consumption. ~o FDA Drug Abuse Advisory Committee background/aformation (Aug. I, 1994), Joint Abuse Liability Review of Nicotim Nasal Spray. See AR (VoL 9 Ref. 117). See appendix 1 to Jm'isdictiotlal Analysis at 62-82. See AR (Vol. 1 Appendix 1). 160 28220737~ PRODUCBD FROH B&W WBB 8ITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44817 II.B.2. c. The Data Do Not Support the Industry's Claim That Consumers Seek Nicotine for Its Sensory Effects Rather than Its Pharmacological Effects • The tobacco industry responds to the overwhelming evidence that nicotine' s pharmacological actions are central reasons for tobacco consumption by arguing instead that nicotine's key role in tobacco products is for flavor. According to the industry, the nonpharmacological actions of nicotine such as "flavor" are so essential to consumers that the nicotine level in each cigarette and unit of smokeless tobacco must be carefully controlled. This argument in no way contradicts any of the experimental and epidemiological evidence showing that consumers use tobacco products for the pharmacological effects of nicotine. These studies prove nicotine' s central pharmacological importance by demonstrating, for example, that: (1) nicotine causes psychoactive effects characteristic of addiction even when delivered by nonoral routes, where there is no "flavor" at all; and (2) the vast majority of smokers are addicted to tobacco products. Moreover, the industry's position that nicotine's primary role is to~rovide flavor is inconsistent with the evidence. First, the industry's position is l~tly eontradiemd by numerous statements of its own scientists and executives. Several industry doeunmnts dismiss the role of nicotine in flavor. For example, in 1974, an American Tobacco Company manager concluded that Pall Mall and Lucky Strike cigarettes tasted virtually the same even after the addition of extraneous nicotine (referred to as "Compound W"); according to the manager, "increasing the level of nicotine in the smoke by the addition of 161 282207376 PRODUCED FROM B&W WEB SITE 44818 FedermJ R~gister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.B.2. Compound W has little, if any, effect on taste.''3~2 A Philip Morns presentation that discusses the importance of flavor in ultra-low cigarettes states flatly that "nicotine is an inexpensive, tasteless constituem.''~ Philip Morris' comments similarly contradict the industry's position that nicotine has a significant role in the flavor of cigarettes. These comments state that Philip Morris conducted extensive investigations into theflavors in cigarette smoke using an "olfactometer," yet Philip Morris claims that "[nlone of that olfactometer work involved nicotine at all," an unlikely omission if nicotine is an important flavor component,an Tobacco industry documents also reveal that the industry draws a consistem distinction between nicotine' s role in tobacco use and the rote of flavor. A Brown & Williamson study emphasized the importance of nicotine delivery over all other product features and specifically distinguished the effects of nicotine from the taste and flavor characteristics of tobacco: In considering which product features are important in terms of consumer acceptance, the nicotine delivery is one of the more obvious candidates. Others include the taste and flavour characteristics of the smoke, physical features such as draw resistance and ram of bum, and the general tmifomaity of the product, to name but a few. The importance of nicotine hardly needs to be stressed, as it is so widely recognised,us ~ Memorandum from I~oy RM (umnager, new pt'oducts division) to McCItthy $B (¢xeculiv¢ vice pcesidenl, research and development), Nicotine Content of Recon.aituted Tobacco (Jun. 5, 197,1), at (¢mplmsis added). See AR (Vol. 26 Ref. 357-3) ~ Philip Morris Inc., First Speaker, Merit Team Remarks (Jan. 14, 1976), at 3 (emphasis added). See AR (Vol. 64O Rt/. 2). ~ Philip Morris lnc.~ Comment (Apr. 19, 1996), at 47. See AR (Vol. 700 Ref. 226). ~ B ATCO, Project Wheat-Part 1: Cluster profiles of U,K. male smokers and their general smoking habits, Southampton. England (Jul. 10, 1975), at 3-4 (emphasis added). See AR (Vol. 20 Ref. 204-1). 162 282207377 PRODUCED FROH B&W WEB SITE Federal R.esi~ter / VoI. 61, No. 168 / Wednesday, ,~ugust 28, 1996 / Rules and Regulations 44819 II.B.2, An internal PJR document shows that the industry views nicotine's role as pharmacological and distinct from the smoke components that provide flavor:. If nicotine is the sine qua non of tobaoco products, and tobacco products are recognized as being attractive dosage forms of nicotine, then it is logical to designour product - and where possible our advertising - around nicotine delivery rather than tar delivery or j~avor.~ Other industry documents further demonstrate that the industry understands that j nicotine's role is primarily pharmacological and that any sensory role is secondary. A variety oI industry documents shows that industry knows that "'satisfaction" comes from inhalation of nicotine into the lungs and absorption into the bloodstream. See Jurisdictional Analysis, 60 FR 41773-41774. Inhalation is necessary only to provide systemic pharmacological effects; it would be unnecessary if nicotine's role were to provide sensory effects. The statements of tobacco industry scientists confn'm that nicotine's pharmacological effects are the primary reason for tobacco use. A leading tobacco research director noted as early as 1972 that "[t]he prinmry incentive to cigarette smoking is the immediate salutary effect of intmled smoi~ upon body function ....the physiological effect serves as the primary incenti~; all other incentives are secondary."~'7 As re~ntly as 1992, IUR~ recognized tim"~molmm use cigarettes primarily as a 'tool' or 'resource' that provides them with needed psychological benefits (increased mental alertness; anxiety reduction, coping with stress)."~ ~*~ Tongue CE, Research Planning Menwrandum on the Nature of lhe Tobacco Business and the Crucial Role ~fNicotine Therein (Feb. 2, 1973), &t3 (©mpl~sis a~kled). See AR (Vol. 531 Ref. 125). ~7 Dunn WL, Philip Mort'is R~e,~lreh Center, Motives ~ Incentives in Cigaretl¢ Smoking (1972), |t 3-4 (emphasis added). See AR (Vot 34 R~f. 5~2). ~8 Robinson JH, Pritchard WS, The role of nicotine in tobacco me,, Psych~.pharmacology 1992; 108: 397- 407 (emphasts added). See AR (Vol. 104 Ref. 945). 163 282207378 PRODUCED FROM B&W WEB SITE ,!.48~-0 F~deral Rt~ist~r / Vol. 61, No. 168 / Wednesday, Augus~ 28, 1~5 1 Rules and Regulations II.B.2. Literally dozens of such statements--made over decades by tobacco researchers and executives from virtually every major company---expose the industry's knowledge that consumers use tobacco products primarily for pharmacological effects. These statements are analyzed in depth in section II.C.2., below. By conl~ast, over this long period, there are virtually no tobacco company studies supporting the importance of the purported "'sensory effects" of nicotine. Second, the industry offers no persuasive data that mcotine contributes signfftcantly to desirable flavor. FDA has reviewed all seven studies cited by the tobacco mdusuy to demonstrate a significant "sensory" role for nicotine and grads them unpersuasive. The industry cites a single abstract, based on research partially funded by R JR, to justify the claim that nicotine provides "trigeminal ('throat g~b') stimulation that is enjoyed by smokers." The abstract describes a single study of uigeminal nerve manipulation in rats.349 It is impossible to conclude from this study that nicotine stimulates the human trigcminal nerve in any manner significant to smears.3s° The industry cites a single paper to show that nicotine provides aroma "that is enjoyed by smokers." This research is based on recordings of the olfactol~ nerve in frogs. ~ Silva" WI,, Walimr DB, Nasal lrigemina~ eheraareceplio~_, response to nicotine, presented at the Ninth Annual Meeting of the Association for Chemoreceptor Sciences, Sarasom FL (1987). ,~ee AR (VoL 535 Ref. 96, voL IILM). sso The indusu'y's "trigemi~l nerve" theory seems to be based in part on an anatomi~ misundeasmnding. The industry proposes that the seamation of"throat grab" is caused by nico~ne stimulation "in the hack of the throat ( where trigenfmal'nerve enc~ngs am located)." In fact, sensation .m the hack of the throat (l~arynx) in humans is provided by the ~lossopharyngcal nerve, not by lhe trigcminal nerve. See Willial~ PL, Warwick R, e.ds., Gray's Am~omy, 37th cal. (Philadelphia: WB Satmde.as, 1989), all I 12. See AR (VoL 711 Rcf. 164 282207379 PRODUCED FROH B&W WEB SITE F~der~ Register / Vol. 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44821 II.B.2. It is impossible to conclude from this study that nicotine creates an aroma of any significance to smokers)51 Indeed, another study also cited by the industry concluded that reducing the olfactory stimulus of cigarettes had a minor effect on smoking behavior.3s2 R JR cite~ one article from 1952 and three recent studies to support the contention that the sensory aspects of nicotine consumption are more important to users than its pharmacological effects. In a 1952 article cited by RJR for the proposition that nicotine plays an important role in the taste and flavor of cigarette smoke, there are no data on this subject. ~s~ The relevant statements are merely the authors' speculations. In fact, the authors speculated about the flavors of various types of tobacco leaves, not about the specific flavor of nicotine. Nor did the authors distinguish between flavor and pharmacological effects of nicotine; to the contrary, a portion of the article omitted by th~ comment states that "the smoker's desires are not satiated by" a low-nicotine leaf. This observation is consistent with the conclusion that consumers value nicotine for its pharmacological effects. A more recent study cited by RJR attempted to quantify tbe sensory responses to cigarettes containing v~]ing leveis of nicotine.3~ "llais study did not even oonsider sst ~anntuf N, Retmer B, Kob~ G, Resp~ses n~xmled from tl~ frog olf~ary el~helium ~'t~r stimulation with ~+) - a~l S(-) - nlc~oti~e, Chemical ,~n.~a 1995;20(3):337-3~, ~t 342. See AR (Vol. 535 Ref. 96, voL I1LM). ~s~ Bnldinger B, Haseu~'a~z M. Barn8 K, Switehiag to ulttalow ~i~oli~ ci811~ttes: efffeets of diffenmt t~r yields m~l bloekiall of oif~ory eue~ Pharmacology, Bioehemim'y and Behavior 1995;50(2):233-239, at 238. See AR (Vol. 535 R~f. 96, vol_ Ill.A). ss~ Darkis FR, Baisden LA, Gro~ PM, WolIFA, Flue-ct~d tobaeco: chemical composilion of rib aad blade tissue, Industrial and Engineering Chemistry 1952;44(2):29%301, at 300-301. See AR (VoL 519 Ref. 103, vol. II). 3~ Gordin HI'L Perfetti TA, Mangan PP, A qmmfificalion of sens¢~ t'~ponses related to dynamic cigarette performance variables, Tobacco Science 1987;31:23-27. See AR (Vol. 519 Ref. 103, vol. II). 165 282207380 PRODUCED FROM B&W WEB SITE 44822 Feder~l Register / Vol. 61, No. 188 / Wednesday. August 28, 1996 / Rules and Regulations II.B.2. whether any sensory responses to nicotine are important to smokers. The authors did not mention the number of subjects in the study. Nor did they account for the fact that cigarettes with varying nicotine levels also were different in many other ways; for example, they had different tip drafts, tipping porosities, plug wrap.< and air dilution. Much of the data were not published with the study. FDA notes that this study--despite serious flaws--still found that tobacco taste was not associated with nicotine content. A second recent study cited by ILIR attempted to determine the smallest amount of nicotine change detectable to the user.3s5 It did not address whether any nicotine change produces any important sensory effects. The authors concluded only that there is a detectable "perceptual response" to nicotine, which could be described as either throat harshness or "strength." The study did not distinguish between sensory and central pharmacological effects of nicotine. The third recent study is an RJR presentation at a conference held in 1994, after FDA'~ investigation into nicotine was under way.3~ The presentation purported to show that nicotine's sensory effects are important in a consttrner's acceptance of tobacco products, but the study failed to sup, port this claim. Indeed, a principal author of the study conceded to FDA m 1994 that "we were not able to separate out the importance of the ~ss Gocdm HH, Pexfetti TA, l-l~wlcy RW, Nicotine just noticeable difference study of full flavor low "lot" nnd ullra low "mr" non-menthol 85ram l~c~lucts, Tobacco Science 1988;32:62-65. See AR (VoL 519 Ref. 103, vol. II). 3s Prite~atd WS, Robimon Jl'l, The Sensory Role of Ni¢oti~ in C.igareue "Taste," Smoking Satisfaction and Desire to Smoke, prcscnll~l at tl~ Inteax~tional Sxmlmsium on Nicotii~: ~ F,,tle, cts of Nicotine on Biological Sysmms II, Montreal (Jul. 21-24, 1994). See AR (Vol. 519 Reg. 103, vol. [I). 166 282207381 PRODUCED FROM B&W WEB SITE F~deral Register / Vol, 61, No. 168 / Wednesday, August 28, 1006 / Rules and R~gulations 44823 II.B.3. sensory aspects versus the pharmacological.''3s7 FDA notes that this study, despite serious flaws, still found that nicotine levels had no effect on smooth taste, harsh taste, or aftertaste of cigarettes. Thus, the industry has presented no data that show that nicotine's flavor or sensory effects are important to consumer acceptance. Even if the industry had produced evidence to support its position, however, nicotine's pharmacological effects would still explain virtually all consumer use. As described in section II.B.3., below, the sensory aspects of tobacco consumption are important to consumers only in how they are linked to the pharmacological ef-f'~ts of nicotine. Compared with the hundreds of studies conducted around the world demonstrating the phammcological significance of nicotine to tobacco eonsumers--a conclusion that reflects universal scientific agreement---the evidence to support the assertion that nicotine's sensory role is important to consumers is unconvincing. Thus, the industry has provided no basis to conclude that nicotine's role in tobacco use is to provide taste, flavor, or any other nonpharmacological sensation. 3. Other Factors Associated with Tolmgeo Use Ar~ Secondary to Pharmacological Effects FDA has established above that comumers me tobacco products for the pharmacological effects of nicotine. The toKacco industry argues that consumers me tobacco for a variety of nonpbarmacological purposes, including for taste, out of habit and ritual, and for social reasom. The Agency recognizes that there are many effects of ~s7 Robi~so~ J, Tra~cript to Ihe FDA Drug Abuse Advisory Commltl~ Mee, ti~g 27, Nicotine-Containing Cigaretms sad Other Totacco Products" (Aug. 2, 1994), at 228. See AR (Vol. 255 RcI. 3445). 167 282207382 PRODUCED FROH B&W WEB SITE 44824 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.B.3. tobacco use perceived by some consumers as nonpharmacological in nature. In surveys, for example, some tobacco users say they like the taste of the product; others report enjoying the ritual involved in its consumption. The evidence before the Agency demonstrates, however, that the nonpharmacological factors associated with tobacco consumption are secondary to the phammcological reasons for consumer use of tobacco. Ind~d, FDA concludes that consumers use tobacco products "nearly exclusively" for the pharmacological effects .of nicotine. This conclusion is supported by comments from the Coalition on Smoking OR Health, representingthe American Heart Association, American Lung Association, and American Cancer Society. The Coalition explains: The physicians and health professionals who comprise our organizations provide the health care for virtually all tobacco users in the United States. Based upon our Ions term exporienee as well as our review of the scientific literature, it is our conclusion that the vast majority of people who use nicotine containing cigarettes and - smokeless tobacco products do so to satisfy their craving for the pharmacological effects of nicotine; that is, to satisfy their drug dependence or addiction. While the published scientific literature on the point is conclusive in our scientific opinion, there may he no better evidence of the reason people use these products than the accumulative, daily experience of the health care professionals who One basis for IDA's finding of nearly exelnsive tobacco use for nicotine's pha_maacologieal effects is flaat tobacco products do not exist eomme~tlly without, nicotine. If taste, for ex,~nple, were an independent reason for use of tobacco products~ as claimed by the industry---one would expect to fred that very-low-nicotine products that Coalition on Smoking or Health, Commeat (Jan. 2, 1996), at 6 (emphasi~ added). See AR (Vot 533 Ref. I02). 168 282207383 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 51, No. 168 / Wednesday, August 28, 1995 / Rules and Regulations 44825 II.B.3. preserve tobacco taste would be popular on the market. But there are no such products. The tobacco industry itself knows that a tobacco product without nicotine is not acceptable to consumers. For example, an attorney representing RJR stated that the company would never eliminate nicotine from its cigarette alternative, because "without nicotine, you don't have a cigarette.''3s9 A former Philip Morris researcher similarly starad that it was well-known within Philip Morris that nicotine delivery was more important than flavor in consumer acceptance of cigarettes. According to this researcher, it was believed within the company that. while consumers might accept a cigarette that had adequate nicotine but marginal flavor, they were unlikely to accept a cigarette with relatively good flavor but "not enough" nicotineJ~° A second basis for FDA's finding is that the details of tobacco use can be distinguished from the basic motivation for tobacco use. For example, researchers have demonstrated that consumers will pick a favorite cigarette brand among several that deliver adequate nicotine.~61 Habits may also explain specific patterns of cigarette consumption. For example, a smoker may enjoy smoking during his afternoon work break; another may like to smoke in the company of a particular friend. These factors commonly determine the details of use of many addictive substances, including opioids ~ Memorandum of meeting between Hun PB, represemtmg RJR Nabisco Inc., and FDA representatives (Oct. 23, 1987). See AR (VoL 34 Ref. 558). ~o Declaration of Uydess IL (Feb. 29, 1996), at I 1-14. Commems concerning this ~tion are addressed in section II.C.6., below. See AR (Vol. 638 Ref. I). ~6~ Boren JJ, Stitzer M/., Henningfield/E, l~fetenc¢ ttmong rtseatrch cigttretlts with vtsying'nieotine yields, Pharmacology'. Biochemistry and B~havior 1990;,36(1):191-193. See AR (Vol. 535 Ref. 96, vol. III.A). 169 282207384 PRODUCED FROM B&W WEB SITE 44820 Federal Register / Vo|. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.B.3. and alcohol.36: But they are separate from the underlying reason for such use, the pharmacological effects of the drugs. Third, FDA agrees with experts in the field of addiction medicine that nonpharmacological factors associated with tobacco use are important to consumers only because they have become mexmcably linked to nicotine's pharmacological effects. Extensive research in the field of behavioral psychology has demonstrated how animals and people come to associate environmental stimuli (taste, rituals, etc.) with the pharmacological effects of addicuve drugs. In the exueme form, providing the stimulus alone leads to the user experiencing the pharmacological effect of the drug. This is called a "conditioned response." Thus, a heroin user who says he likes the feel of the needle in his arm has linked the sensation with the pharmacological "high" that inevitably follows. This heroin addict may even report a "high" after the injection of saline.363 But he or she still injects "nearly exclusively" for the pharmacological effects of heroin. Similarly, evidence in animals and humans demonstrates that nonpharmacological factors such as taste and habit are important to tobacco consumers only because they have become inextricably linked to the effects of the addictive drug. As one prominent addiction specialist noted, "Animal experiments support the view that the sensory and Surgeon General's Report, 1988. at 15. See AR (VoL 129 R~L 1592) 36~ O'Bnen CP, Testa T, Teraes J, Green.stem R~ Conditioning Effects of Narcotics m Humam, m Behavioral Tolerance: Research a~l Treazm~nt lrap~ications, NIDA Research Monograph 18 (Washington DC: Government Printing Office No. 017-024-00899-8, Jan. 1978), at 67-71. See AR (Vol. 535 Ref. 96, vol. III.L). 170 282207385 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61. No. 168 I Wednesday, August 28. 1996 I Rules and Regulations 44827 lI.B.3, olfactory stimuli associated with tobacco-using behavior function as conditioned stimuli due to their previous association with nicotine.''~6~ Clinicians who treat patients dependent upon tobacco products have reached the same conclusion.36s For example, some smokers identify the sensation of "tracheal scratch" associated with inhalation as pleasurable. But, as the American Society of Addiction Medicine (ASAM)comments: The tracheal 'scratch' which arises from the inhalation of cigarette smoke is a sensation which has become paired with the absorption of nicotine into the bloodstream and the consequent effects of nicotine on the brain. People do not smoke for the 'scratch'; they smoke for the nicotine. The "scratch" tells the smoker that nicotine is on its way to the brain and provides some indication of the relative dose which will shortly be coming.36~ Other evidence of "conditioned responses" comes from studies of the early stages of tobacco withdrawal, when providing the environmental stimuli of smoking without nicotine (i.e., very-low-nicotine cigarettes) alleviates some of the abstinent smokers' discomfort.367 This is analogous to heroin users feeling a psychological benefit from injecting saline when heroin is not available)~s In both cases, the benefits of the 36~ Jaffe JH, Tobacco smoking ~md nicotine ~ in Nicotine Psycho~ology Oxford University Press, 1990), 1-29, at 14. See AR (VoL 535 l~f. 96, voL 111G). s6~ Bcnowitz NL, Cigare, t~ smoking and nicotine addiction, Medical Clinics of North America 1992;76(2):415--437. See AR (Vol 535 Ref. 96, voL IILA). American Society of Addiction Mezlicine, Comment (I)ex.. 29, 1995), at 5 (emplmsis added). See AR (Vol. 528 Ref. 97). ~7 Butschky M]:, Bailey D, Hcnnmgficld JE, Pickworth WB, Smoking without nicot£nc d~livcry decreases withdrawal in 12-hour absancnt smok¢~ pharmacology, Biochemistry and Behavior 1995;50(I):91-96. See AR (Vol. 442 Rcf. 7484). ~6s O' Bricn CP, Testa T, Tcrnes J, Gmenstein R, Conditioning F~ects of N~tcotics in Hun~ns, in Behavioral Tolerance: Research and Treatment Implications, NIDA Rese.,atch Monograph 18 (Washington DC: Government Printing Offic~ No. 017-024-00899-8. Jan, 1978), at 67-71. See AR (Vol. 535 Ref. 96, vo|. IILL). 171 282207386 PRODUCED FROM B&W WEB SITE 44828 Federal Register / Vol. 61, No. 1615 / Wednesday, August 28, 1996 / Rules and Regulations I1.B.4. nonpharmacological stimuli rapidly decrease as the stimuli are no longer associated with the drug' s effects. 369 AS AM concluded: "People who use tobacco products build up rituals around nicotine ingestion and experience sensations in the process of using tobacco that become valuable to them. However, these rituals would not exist, and the sensations would be of no value, but for the associated delivery of mcorine to the brain.''37° Thus, when someone says he or she smokes for the "taste" or "feel" or "ritual" of cigarette consumption, these "reasons for use" are inextricably tied to the pharmacological effects of nicotine)7~ Accordingly, FDA concludes that consumers use tobacco products "'predominantly" and "nearly exclusively" for one or more of the pharmacological effects of nicotine. 4. a. i. Respomes to Additional Comments Genera] Comments on Consumer Use The American Society of Addiction Medicine (ASAM) argues that the common practice of inhaling cigarette smoke demonstrates that consumers use cigarettes for the pharmacological effects of nicotine. According to ASAM, because of the relatively Butsclaky MF. Bailey D, Henningfield JE, Pickworth WB, Smoking without nicotine delivery decreases withdrawal in 12-houx abstinent smokers, Pharmacology, Biochemistry and Behavior 1995;50( 1 ):9 !-96. See AR (Vo]. 4,42 Rcf. 7484). 370 American Society of Addiction Medicine. Comment (Dec. 29, 1995), at 14 (emphasis added). See AR ¢Vol. 528 Ref. 97). Surgeon General's Report, 1988, at 58-59. See AR (Vol. 129 Ref. 1592) 172 282207387 PRODUCED FROM B&W WEB SITE Federal Register / Vol, 61, No, 168 / Wednesday, August 28, 1996 / Rules and Regulations 44829 low pH of cigarette smoke, nicotine absorption occurs to a significam extent only m the lungs. Conversely, ASAM notes that no important sensory effects are known to result from cigarette smoke in the lungs. Thus, ASAM concludes that "inhalation is the key to nicotine absorption from cigarettes, and there is no reason other than nicotine absorption for the consumer to inhale the smoke.''3n ASAM further notes that tobacco advertisements historically encouraged consumers to inhale cigarette smoke; according to ASAM, such evidence demonstrates industry intent to ensure adequate nicotine delivery to smokers and thereby achieve substantial pharmacological effects. FDA agrees that inhalation demonstrates that consumers use cigarettes for substantial pharmacological effects. According to Gray's Anatomy, there are no taste or smell receptors below the level of the larynx.373 No evidence suggests that smokers enjoy any physical sensations associated with smoke in their lungs other than by association with the pharmacological effects of nicotine. Yet smokers learn to inhale---despite such unpleasant reactions as coughing--when the only reason to do so is nicotine absorption. Indeed, the industry itself has recognized that nicotine absorption is the reason people inhale smoke. In 1982, a leading industry researcher wrote that "lilt is well k~own that nicotine can be removed from smoke by the lung and transmitted to the brain within seconds of smoke inhalation. Since it is the major or sole pharmacologically active agent 3~a American Society of Addiction Medicine, Comment tCDec. 29, 1995), at 5. See AR (Vol. 528 Ref. 97). 373 Williams PL, Warwick R, eds., Gray'sAnatomy, 3701 ecl. (Philadelphia: WB Saundem, 1989), at 1169-1180. SeeAR(Vol. 711 Ref. 8). 173 282207388 PRODUCED FROM B&W WEB SITE 44830 Federal Register / Vot. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.B.4. in smoke, it must be presumed that this is its preferred method of absorption and thus why people inhale smoke.''3~4 2. The smokeless tobacco industry argues that FDA fails to distinguish among different smokeless tobacco products. The comment contends that FDA has based its conclusions entirely on evidence about moist snuff and that this evidence is inapphcable to chewing tobacco. FDA disagrees that it has ignored the distinction between moist snuff and chewing tobacco or that its evidence applies only to moist snuff. As described in the Jurisdictional Analysis, Benowitz and colleagues found that the rate and amount of nicotine absorption was similar for oral snuff and chewing tobacco in ten healthy volunteers.37s See Jurisdictional Analysis, 60 FR 41572. The total amount of nicotine absorbed from snuff and chewing tobacco was estimated to be 3.6 mg and 4.5 rag, respectively,aT~ This study confu-ms that as much or more nicotine is absodxxl from each of these products as from cigarettes. Additionally. in a study submitted by the industry, Walsh and colleagues reported on the use of smokeless tobacco in 1,300 U.S. college athletesY~ Of those surveyed who ~ Letmr from Ayres CI (BATCO) to Kotmhorst EE (Brown & Williamson), tr~mmitling ~ summary of issues presemcd at Montebello Research Confca'ence in 1982, at BW-W2-03949 (emphasis added). See AR(VoL 34Ref. 58~1). ~75 Benowitz NL, Porc~et H, Sheiner L, et aL, Nicotine absorption and cardiovmcttlar effects with smolzless Iobac~o use: comparison with cigaretles and nicotine gum, ¢|i~c~ Pharm~ology and Therapeutics 1988~44:23-28. See AR (Vol. 12 Ref. 134-1). ~r~ Walsh MM, Hilton IF, Ernsmr VL, Ma~uredis CM, Grady DG, Prevalence, patterns, and correlate, of spit tobacco use in a college athlete population, Addictive Behavior 1994; ! 9:411-427. See AR (Vol 526 Ref. 95, appendix VIII). 174 282207389 PRODUCED FROM B&W WEB SITE Federal Re~is[er / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations 44831 II.B.4. used smokeless tobacco, 39% reported using snuff only, 41% reported using both snuff and chewing tobacco, and 16% reported using chewing tobacco only. (Four percent failed to indicate the type of smokeless tobacco used.) Athletes who used both snuff and chewing tobacco generally reported patterns of use that were similar to those of athletes who used snuff only. This study supports similar patterns of use in both snuff and chewing tobacco users and demonstrates use of either moist snuff or chewing tobacco for similar pharmacological effects, such as relieving stress, satisfying strong cravings, and relieving the discomfort of withdrawal. Thus the use, effects, and nicotine absorption from chewing tobacco compare with moist snuff and cigarettes. See also section II.D., below. b. Comments on Tobacco Use To Satisfy Addiction 1. The tobacco industry argues that FDA's claim in the Jul-isdictional Analysis that 75% to 90% of smokers consume cigarettes to satisfy addiction is factually unsupported. The tndustry contends that FDA selectively extracted pieces of data from various studies to support this rate of nicotine dependence and that the studies FDA relied upon were conducted in sample populations of patients of substance abuse climcs who would have higher "scales of dependence" than the general population. FDA disagrees. The Agency did not selectively choose studies or selectively extract data from the studies on which it relied to support the reported rates of nicotine dependence. Rather, FDA chose from the published literature those studies that met the following criteria: the study used a definition of addiction established internationally by major public health organizations, the study was capable of estimating the prevalence of nicotine addiction in a well-defined population, and the study used appropriate research 175 282207390 PRODUCED FROM B&W WEB SITE 44832 Federal R~gister / Vo[. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.B.4. methods, such as random sampling of a well-defined population, to estimate the prevalence of nicotine addiction. No study relied on surveying smokers at tobacco cessation clinics. The four studies identified by FDA as satisfying the stated selection criteria for determining the population prevalence of nicotine addiction utilize two data sets and smoking populations. These sample populations represent a generalizable spectrum of smokers. One of these populations (utilized in a study by Hughes et al.)37s included otherwise healthy, non-drug-abusing patients representative of a weli-def'med population. This was not a selectively extracted population, nor did it have an elevated prevalence of nicotine addiction, as argued by the tobacco industry. It consisted of over 1,000 middie- aged smokers randomly sampled from a well-defined population of male heads of households, who were otherwise representative of men of that age. The men entered the study by identifying themselves as smokers. These men, on average about 51.1 years of age, were estimated to have a lifetime prevalence of nicotine addiction of 90%. The authors report that smoking habit~ of the men in this study were similar to those reported in previous studies of middle-aged men. The tobacco industry contests these data on the grounds that: (1) the subject~ are representative of the heaviest 22% of U.S. smokers; and (2) the authors at the time argued that the DSM criteria for nicotine addiction were too expansive. The industry's first point is based on a statistical misinterpretation. The industry argues that since the average Hughes JR, Gust SW, Pechacek TF, Prevalence of tobacco dependence and withdrawal, American Journal of Psychiatry 1987; 144(2):205-208. See AR (VoI. g l R~f. 292). 176 282207391 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.B.4. cigarette consumption in the study was 28 cigarettes per day, and because 22% of smokers in 1991 consumed over 25 cigarettes per day, then the study applies to "at most, 22 percent of smokers." But this reasoning confuses average and median consumption. The heaviest 22% of smokers, on average, consume far more than 25 or 28 cigarettes per day. For example, in 1985, almost half of the smokers in the group who smoked more than 21 cigarettes per day reported smoking 40 or more cigarettes a day.37~ Thus, the average number of cigarettes smoked by heavy smokers is well above 28 per day. Accordingly, the smokers represented in the Hughes study smoke less, on average, than "the heaviest" smokers identified by the commem. The industry's second argument concerning the authors' view of the DSM criteria is irrelevant. Although the researchers were initially surprised at the high rotes of dependence revealed in this study, the DSM criteria have retained credibility and are widely accepted by clinicians for diagnosing substance dependence. The second sample of data (utilized in studies by Woody et al., Cottler, and Hale et al.)3"~ is derived from a population studied during the Substance Abuse Disorders Field Trials for DSM-IV. This sample population came from five sites around the United States 3~ Department of Health and Human Services, Public Health Service, National Center for Chronic Dtsea.se Prevention and Health Promotion, Office on Smoking and Health, Reducing the Health Consequences of Smoking--25 Years of Progress, a Report of the Surgeon General (Atlallla: 1989), at 295. See AR (Vol. 130 Ref. 1593). Woody GE. Cottler LB, Cacciola J, Severity. of dependence: dam from the DSM-IV field trials, Addwtion 1993;88;1573-1579. See AR (VoL 13 ReL 150). Corder L, Companng DSM-II1-R and ICD-10 substance use disorders, Addiction 1993;88:689-696. See AR (Vol. 13 Ref. 149). Hale KL, Hughes JR, Oliveto AH, Helzar JE, Higgins ST, Bickel WK, Cottler LB, Nicotine dcpeadenee in a population-based sample, in Problema of Drug Dependence, 1992, NIDA Research Monograph 132, (Washington DC: Govemmem Printing Offtce, 1993). See AR (VoL 39 Ref. 60). 177 282207392 PRODUCED FROH B&W WEB SITE ~4834 Federal Regisler / Vol. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations II.B.4. and ranged in age from 18 to A4 years. Some of the subjects were from the general population, and others were selected, by a random digit dialing method, from subjects treated for substance abuse. Three separate analyses, using different assumptions and methods, were performed on these data, and the estimates of nicotine dependence reported in three published articles ranged from 77% to 92%. There is no evidence that these rotes of nicotine dependence in these sample populations arc greater than those for a nonpredisposed population that smoked for the same period. Indeed, the population of non-drug-abusing middle-aged men studied by Hughes et al. had a rate of nicotine dependence that was consistent with, and even higher than, the rates found in the Woody et al., Cottler, and Hale et al. studies. One study of nicotine addiction rates cannot be used to establish the prevalence of nicotine addiction because the population examined was not representative of the specu-um of smokers. The sample population in this study by Breslau et al. consisted of 394 smokers 21 to 30 years of age who were randomly selected from a well-defined population in a health maintenance organization (HMO).TM The median age was 26 years, and 5 ] % of the smokers were addicted to nicotine. These studies reflect that rates of dependence on nicotine increase substantially with duration of exposure and with the smoker's age: Although 51% of these young smokers were dependent on nicotine, fully 90% of the rmddle-aged smokers in the study by Hughes et aL were dependent on nicotine. Moreover, Breslau et al. acknowledge that the rate of dependence found in this sample of young smokers may not be representative of the rate among all smokers. ~s~ Breslau N, Kilbcy MM, Andr~ki MA. Nicotine dependence, major depression, and anxiety in young adults. Archives of Genera! Psvchiatr) 1991;48:1069-1074. See AR (VoI. 37 Rcf. 17). 178 282207393 PRODUCED FROM B&W WEB SITE Federnl Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44835 II.B.4. In conclusion, the studies relied on by FDA were not chosen in a preferentially selected manner, but on the basis of study design and methodological considerations. The data sets reflect populations that can be considered representative of cross sections of the U.S. smoking population. There is no evidence to suggest that these studies are not generalizable to the population of smokers. FDA believes that these studies support the claim that 75% to 90% of smokers consume cigarettes to satisfy nicotine addiction. Comments of the American Psychiatric Association agree with this assessment, stating that "DSM based studies.., found that 80%-90% of adult smokers are nicotine dependent."'382 2. The tobacco industry argues that dependence can never be measured in a large population. This contention is disproved by the successful population-based studies just described. The industry's comments were premised on selective quotations from researchers, none of whom were actually agreeing with the assertion that all such studies are impossible or invalid. 3. The tobacco industry, criticizes the data collection methods m the population studies FDA relied upon to support tobacco dependence rotes. The industry argues that self-reporting results in inaccurate conclusions and cites an article by Koztowski et al. to support this contention.383 FDA disagrees. This method of data collection is a scientifically recognized and accepted mode of inquiry for prevalence studies and is relied upon to determine the as: American Psychiamc Associatiom Comment (Jan_ 2, 1996), at 2. See AR (Vol. 700 Ref. 1020). 3~.~ Kozlowski LT, Hct'n~ CP, Frecker RC, What researchers ~ of whal cigm,~tle smok~t~ .~.y: filtering smokers' hot air, Lancet 1980,1 (8170):699-700. Set AR (Vol. 535 Ref. 96, vol. III.I). 179 282207394 PRODUCED FROM B&W WEB SITE  44836 Federal Register / Vol. 61, No. 168 / Wednesda>, August 28, 1996 / Rules and Regulations II.B.4. population prevalence of other disorders, including alcohol dependence, cocaine dependence, and depression.3s4 Some of these are disorders for which, compared to tobacco use, interview methods would be less likely to reveal accurate results because of the criminal consequences associated with illicit drug.use. Moreover, agencies that have expertise in tracking the prevalence of disease in this counn'y, such as the Centers for Disease Control and Prevention, rely on such studies.3~5 The tobacco industry itself cites multiple surveys based on self-reporting in its comments. The industry also mischaracterizes the article by Kozlowski et al. The article does not support the indus~"s argument that all self-reported data in population studies are inaccurate. In the article, the authors suggest that self-reports of abstinence among people quitting smoking may be inflated. The authors do not suggest that any other information obtained by self-reporting is unreliable, nor do they give any reason to extrapolate their observations to reportmg of other information about smoking behavior. Finally, despite their belief that some smokers may exaggerate the number and success of their attempts at abstinence, the author~ never doubt that a large proportion of smokers tr3.' to quit. Accordingly, FDA concludes that the methods used in r.he population prevalence studies are accepted and rehable. American Psychiatric Association. Diagnostic and Statistical Manual o.[ Mental Disorders. ~th ed. (Wa,shtngton DC: American Psychiatric Associataom 1994), at 175-272. See AR (Vol. 535 Ref. 96, vol. III.B). 3~ See. e.g.. Centers for Disease Control and Prevention, Reasons for tobacco me and symptoms of mcotine widadsawal among adolescents and young adult tobacco ~ers~United States, 1993, Morbidity and Mortalicy Weeldy Report 1994:43(41 ):745-750. See AR (Vol. 43 Ref. 162). 180 282207395 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations 44637 II.B.4. c. Comments on Tobacco Use for Effects on Mood and Weight 1. The tobacco industry contends that FDA has not established that consumers use cigarettes or smokeless tobacco nearly exclusively either to affect mood or to control weight. According to the comment, the studies cited by FDA do not show that a high perccntagc of consumers use tobacco to affect mood or control weight and that there are an insufficient number of such studies upon which to base a conclusion. This comment misinterprets the standard for establishing that a product is "intended to affect the su-ucturc or any function of thc body" tkrough consumer use. As noted in section II.B.1., above, some courts have suggested that where the Agency relies solely on consumer use to establish intended use, consumers must use the product predominantly or nearly exclusively for pharmacological purposes. These cases contain no requixcmcnt, however, that consumers use thc product in question nearly exclusively for each individual pharmacological effecl the product produces. Thus, there is no requirement that consumers use nicotine nearly exclusively for cach of its pharmacological effects. It is sufficient to establish that consumers as a group use tobacco to obtain any of the several effects on structure or function sought by consumers (for example, to satisfy addiction, for other psychoactive effects, and to control weight). See ASH v. Harris, 655 F.2d at 240; NNFA r. Mathews, 557 F.2d at 335336. FDA also disagrees that there arc insufficient studies to support the conclusion that consumers use tobacco to affect mood and control weight. The many studies cited by FDA conclusively show that the majority of tobacco consumers rely on tobacco products to achieve a relaxing or calming effect See Jurisdictional Analysis, 60 FR 41579-41580. 181 282207396 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations I1.B.4. For example, one survey found that over 60% of smokers aged 16 to ztA believe that smoking reduces nervous irritation.3s6 The use of cigarettes for weight control is similarly established in numerous studies. These studies show that smokers believe that smoking keeps weight down and that weight control is a significant motivation to continue smoking. The Surgeon General's 1988 Report on Nicotine Addiction reviewed a large number of studies demonstrating that weight control is a powerful motivator for initiation and maintenance of smoking in as many as one-third to one-half of young smokers.3'7 d. Comments on Nonpharmacological Factors Associated with Tobacco Use 1. The tobacco industry' quotes several addiction experts stating that there are social, emotional, and behavioral variables that explain patterns of tobacco use. The industry concludes that consumers do not use tobacco products "nearly exclusively" for the pharmacological effects of nicotine. FDA disagrees. The industry confuses the details of tobacco use with the reason for use. While multiple factors may explain why a particular person decides to smoke a particular cigareue at a particular moment, data support only one reason why the vast majority of consumers use tobacco products day after day, year after year: to obtain the drug effects of nicotine. ~ McKennell AC, Smoking motivation factors, British Journal of Social and Clinical Psychology 1970;49(I):8-22. See AR (Vol. 13 Ref. 152-1). 3s7 Surgeon General's Repor~ 1988, at 438-439. See AR (Vol. 129 Ref. 1592). 182 282207397 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44839 II.B.4. Indeed, the scientific consensus holds that nonpharmacological factors are tmponant to consumers only because they are lilaked to the pharmacological effects of nicotine. Thus, Jed Rose, one of the key researchers cited by the industry to support the contention that consumers use tobacco for nonpharmacological reasons, refers to nonpharmacological factors as "sensory cues" that are used to meter nicotine intake.3ss As described in section ILB.3., above, such cues become "conditioned" as they are associated wi~ the pharmacological effects of nicotine on the brain. These environmental factors are certainly important to tobacco consumers, as they are to users of other addictive drugs,389 but they are not the primary reasons for use. As a tobacco industry executive tn a speech to the company's board of directors said: IT]he psychosocial motive is not enough to explain continued smoking. Some other motive force takes over to make smoking rewarding in its own right. Long after adolescent precx~upation with self-image has subsided, the cigarette will even preempt food in times of scarcity on the smoker's priority list...We are of the conviction.., that the ultimate explanation for the perpetuated cigarette habit resides in the pharmacological effect of smoke upon the body of the smoker, the effect being most rewarding to the individual under stress.39~ 2. The cigarette manufacturers cite research suggesting that nicotine-free cigarettes have flavor~9~ and may help smokers to quit.~92 They draw particular attention 3s~ Rose JE, Bchm FM, Levln ED, Role of nicotine dose and sensory cues in the regulation of smoke intake, Pharmacoiog>.., Biochemistry. and Behavior 1993;44:891-900. See AR (Vok 8 Ref. 100). ~*~ Surgeon General's Repork 1988, at 59. See AR (Vol. 129 Ref. 1592). 39( Wakeham H (Philip Morns, Inc.), Smoker Psychology Research, prcseat~l to Philip Morns boatd of directors (Nov. 26, 1969), at 237, 240. See AR (Vol. 11 Ref. 142). a~ Levin ED, Behm FM, Rose JE, The use of flavor in cigarette substitutr~ Drug and Alcohol Dependence 1990;26:155-160, at 159. See AR (Vol. 535 Ref. 96, III.J). 39: Butschky IV[P, Bailey D, Hetmmgfield JE, Pickworth WB, Smoking without nicotine delivery deerea,c~,s withdrawal in 12-hour abstinent smokers, Pharmacology, Biochemistry and Bthavior 1995;50(1):91-96. See AR (Vol. 442 Ref. 7484). 183 282207398 PRODUCED FROM B&W WEB SITE ~1~t1140 F~lernl R~gi~ter ! Vol. 151, No. 168 [ Wednesday, August 28, 1996 t Rules and Regulations II.B.4. to a recent presentation by Rose et aL, in which smokers given a denicotinized cigarette r~ported the same or slightly less relief of craving than smokers given intravenous nicotine, and less relief than smokers given their usual brand of cigarettes.393 They also reported more immediate satisfaction from the denicotinized cigarette than from intravenous nicotine, although less than from their usual brand. The denicotinized cigarette provided less psychological reward than did intravenous nicotine. The smokeless tobacco manufacturers also suggest that no-nicotine substitutes for smokeless tobacco may have helped some users remain abstinent. According to the industry, this research demonstrates that consumers use tobacco products for reasons other than nicotine. FDA disagrees. The cited studies do suggest that low- or no-nicotine products can be used in research and in a small proportion of former users of tobacco products. Yet the products have been uniformly rejected by tobacco consumers, who do not view them as acceptable substitutes for cigarettes. When given a choice, tobacco users will not abandon nicotine for flavor, demonstrating the real reason they smoke. For example, Next, a denicotinized cigarette that was briefly marketed by Philip Morris, was removed from the market because, according to the company, it was not accepted by consumers. The cited studies replicate many others that show that the most consistent and s~ongest effects are produced by nicotine-delivering cigarettes. It is not surprising that nicotine injections, which, according to the studies produced significant pain and burning at the site of injection, do not produce all the satisfaction of smoking nor duplicate the ~9~ Rose JE, Westma~ EC, Beam FM, Comparative effects of intmvet~o~ ~icoti~e and de-nicoti~ized cigarette smoke, poster presented at Ihe amatml meeting of the Society for Research on Nicotine ~md Tobacco (Mar~ 15-17, 1996), Washington. D.C. See AR (Vol. 711 Ref. 21 ). 184 282207399 PRODUCED FROM B&W WEB SITE Federal Register / VoL 61, No. 1B8 / Wednesday, August 28, 1996 / Rules and Regulations 44841 II.B.4. taste and throat sensations of smoking. As described in section II.B.3., above, the efficacy of nicotine-free cigarettes m aLlevmting some of the symptoms of withdrawal is consistent with the conclusion that social and environmental factors become associated with obtaining the pharmacological effects of nicotine, and thus are perceived as pleasurable as a "conditioned response," but in and of themselves are not the reason people smoke. Low- or no-nicotine cigarettes may temporarily provide some relief to consumers as a • result of the conditioned response to the sensorimotor aspects of smoking, but this response is subject to "rapid extinction" when nicotine is withheld.39~ This phenomenon is similar ~o the temporary finding that heroin addicts feel pleasure from in)ecting themselves with saline.395 The study by Rose is entirely consistent with these findings. The study evaluated only the immediate effects of a denicotinized cigarette on craving reduction, satisfaction, and psychological reward. It did not attempt to evaluate any effects of deni,eotinized cigarettes on sustained satisfaction or relief of withdrawal symptoms. Rose himself has stated that smokers seek the sensory cues of smoking because "the repetition of the smoking act thousands of times per year by a moderately heavy smoker leads to a strong condi~oned association between the sensory aspects of smoking.., and the pharmacological effects of nicotine.''3% Therefore, according to Rose, "effective ~ ld ~ O' Brien CP, Testa T, Ternes J, C-reenstein IL Conditioning effects of narcotics ha humans, in BehavEor a! Tolerance: Research and Treatment Implications. NIDA Research Monograph 18 (Washington DC: Goverament Printing Office No. 017-024-00899-8, Jan. 1978), at 6"7-71. See AR (Vol. 535 Ref, 90, vol, III,LI. ~ Rose JE, Levin ED, Inter-relationships between conditioned and primary reinforcement in the maintenance of cigarette sraoidng, British Journal of Addiction 1991;86:605-609, at 605. See AR (Vol. 67 Ref. 58) 185 282207400 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations II.B.4. treatment of tobacco abuse needs to take into account the influence of these sensory CUES,''397 by, for example, providing the smoker with de-nicotinized cigarettes, in addition to strategies to eliminate nicotine dependency.398 He is explicit, however, that nicotine is the primary reinforcer of smoking behavior, and that desire for the sensory aspects of tobacco use is the result of conditioned reinforcement maintained by nicotine' s primary reinforcement.39~ 3. To support the argument that consumers use tobacco products for flavor, the tobacco industry cites research in which smokers' satisfaction with smoking decreased when their upper airways were anesthetized. Upon review of this research, FDA finds that the studies do not support the contention that consumers smoke cigarettes primarily for flavor. As described above, the researcher who led the study, Rose, believes that nonpharmacological factors associated with tobacco consumption are "cues" important to smokers only by association with nicotine's pharmacological impact. Moreover, the research cited does not establish that the reason for the drop in smoking satisfaction upon airway anesthetization was the blockade of sensory input from smoke. These decreases m satisfaction might have been due simply to the unpleasant sensation of upper airway anesthetizatiom not to any blockade of sensory input from smoke. In this study, satisfaction with "sham smoke" also dropped with anesthesia. Sham smoke was so diluted as to provide few pharmacological or sensory effects. Thus, 307 ld. ~ ld. at 607. ~ 1d at 605-606. 186 282207401 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations 44843 I1.B.4. t providing anesthesia decreased t_he satisfaction of consuming real cigarette smoke and placebo smo~ J°° The study does, however, provide data addressing the importance of the pharmacological aspects of smoking. Thirty minutes after smoking, the subjects who had received smoke delivering mcotJne--regardless of whether their throats had been anesthetized--feh similarly satisfied. And their satisfaction was greater than that of those who had received "sham smoke." Thus, the study indicated that nicotine produces smoking satisfaction even in the absence of mouth and throat sensation. 4. The tobacco industry cites three studies to suppor~ the ~gument that consumers use tobacco producL~ out of "habit and ritual." Upon review of these studies, FDA concludes that they provide no evidence that "habit and ritual" are the primary motivation for use of tobacco products. As described at len~h above, "'habit and ritual" are important to consumers of all addictive drugs, but only through their linka~oc to the pharmacological effects of the drug. First, the industry cites a study in which some smokers did not consider the fn-st cigarette of the day their favorite,n°~ The observation relates to a detail of smoking rather than to underlying motivation; as described m section II.B.3., above, there are many reasons why an individu',d may desire a particular cigarette at a particular time. This is not evidence that "habit or ritual" is the driving biological force for maintenance of tobacco use. ,0¢ Rose JrE, Tashkm DP, Ertle A, Zmscr MC, Lafcr P,, $cnsory blockade of smoking satisfaction, Pharmacology, Biochemistry." and Behavior 1985;23:289-293, at 290 (emphasis added). See AR (Vol. 42 Ref. 124). ac: Jarvik M, Killen JD, Varady A, Fortmalln SP, The favorite cigarette of the day, Journal of Behavioral Medicine 1993;16:413-422. See AR (Vol. 535 Ref. 96, III.A). 187 282207402 PRODUCED FROM B&W WEB SITE 44844 Federal Register / Vol. 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.B.4. The industry then quotes the speculative conclusion of a study without any description of the research. In fact, the study's main finding was that the smell of cigaxettes was not important for smoking behavior.4°2 The industry cites another conclusion of a study without any description of the research. 4o~ One of the study's major findings was that enforced abstinence (smokers were not allowed to smoke for an afternoon) had different effects on subsequent smoking behavior than natural abstinence (smokers did not smoke while asleep at night). Basic biological imperatives undoubtedly affect the details of smoking behavior but certainly cannot explain the reason for tobacco use. 5. The tobacco industr3' argues that the "social aspects" of smoking explain consumer use of tobacco. No studies are cited to support this conclusion. As the Surgeon General's Report noted in 1988, social factors influence initiation and patterns of use of many addictive drugs:"~ the primary, reason for the drug's use, however, is pharmacological. In this respect, nicotine is similar to heroin.~°5 6. The smokeles~ tobacco industu' argues that the evidence cited by FDA in support of its conclusion that consumers use tobacco product~ nearly exclusively for pharmacological effects has little to do with smokeless tobacco. Five studies were ~: Baldinger B, Haseufratz M, Batug K, Switching to ultra.low ttiootirtc cigarettes: effects of differem tar yields and blocking of offactory cues, Pharmacology, B, ochemistry and Behavior 1995;50(2): 233-239, at 238. See AR (Vol 535 Rcl. 96, vol. Ill.A}. ~0) Jacober A, Hasenfratz M, Batug K, Cigarette smoking: habit of nicotine maintenance? Human Psychopharmacotogy 1994:9:117-123, at i 17. See AR (Vol. 535 Ref. 96, vol. III.G). ~ Surgeon General's Report, 1988. at 15. See AR (Vol. 129 Ref. 1592). • o~ Jaffe JH, Drug addiction and drug abuse, m Goodman and Gilman "s ?'he Pharmacological Basis of Therapeutics, 8th ed. (New York: Pergamon Press, 1990), chap. 22 (522-573), at 529. S~e AR (VoL 535 ReI. 9~, vol. Ill.G). 188 282207403 PRODUCED FROM B&W WEB SITE Federal Register / VoL 61, No. 168 / Wednesday. August 28, 1996 / Rules and R~gulations 44845 II.B.4. submitted with the comment that are claimed to demonstrate that smokeless tobacco consumers use those products because they "enjoy the taste" or simply "like it," not for any "pharmacological effects.''~°~ FDA disagrees with the industry' s interpretation of these studies. As discussed in section ld.B.3., above, when people use drugs with powerful pharmacological effects such as nicotine they commonly associate many environmental stimuli with the pleasurable experience of consuming the substan~. Thus, a survey result that consumers "enjoy the taste" indicates only that a significant portion of consumers have linked the sensory cues to the pharmacological effects of nicotine. None of the fivestudies cited by the industry noted whether users who did not give pharmacological reasons for using smokeless tobacco had ever tried to quit. Thus, many of these users may not have been aware of their pharmacological addiction. As an expert quoted by the Inspector General of the Department of Health and Human Services '~ Walsh MM. Hilton .IF, Ernater VI~ Masouredis CM, C-vady DG, Prevalemce, patmms, aad con'eht~s of spit tobacco use m a college athlete population, Addictive Behavior 1994;19:411-427. Set AR (Vot 526 Ref. 95, voI. VIII). Lopez LC, Smokeless tobacco consumption by Mexican-American university students, Psychology Reports 1994;75:279-284. See AR (Vol. 526 Ref. 95, vol. VIII). Glover ED, Laflin M, Flannery D, Albntton DL, Smokeless tobacco use among/~nerican college students, Journal of American College Health 1989;38:gl-84. See AR (Vol. 526 Ref. 95, vol. VII). '~'tsmewski .IF, Bartolucci AA, Compatalive patterns of smokeless tobacco usage among major league baseball personnel- Journal of Oral Pathohggy and Medicine 1989; 18:322. See AR (VoI_ 526 Ref. 95, vol. VIII). Connolly GN, Orleans GT, Kogan M, Use of smokeless Iobacco m major-le~tgue baseball, New England Journal of Medicine 1988;318(19):1281-12.85. See AR (Vol. 526 Ref. 95, vol. VII). 189 282207404 PRODUCED FROM B&W WEB SITE 44848 | Federal Register / Vol. 61, No. 168 / Wednesday. August 28. 1096 / Rules and Regulations explained, "'Man), haven't tried to quit. and then they try to quit, the), can't.''~°7 II.B.4. But when we tell them the health consequences, In studies cited by the industry, some users of smokeless tobacco stated that they "'enjoy the taste," but a significant percentage of these users also reported that they use smokeless tobacco for psychological reasons. For example, in one study, a majority of 195 users of snuff and chewing tobacco reported using tobacco for one or more pharmacological effects, including relieving stress, relief of "strong cravings," and relieving the discomfort of withdrawal.4°~ These statements support the conclusion that the majority of people who use smokeless tobacco do so for the well-established pharmacological effects of nicotine: stimulation, sedation, and addiction. These studies thus constitute additional evidence that smokeless tobacco is primarily used by consumers to obtain the pharmacological effects of nicotine. Department of Health and Humaa Service~, Office on Smoking and Health, Spit Tobacco and Youth (Wa.shtagton DC: Government Printing Office, 1992), at 8. See AR (Vol. 7 Ref 76). ,oa Walsh MM, Hilton JF, Erns~er VI_ Masouredis CM, Grad.v DG, Prevalence, patterns, ~nd correlates of spit ~bacco use in a college athlete population. Addictive Behavior 1994;19:411-427. ~ee AR (VoL 526 Rcf. 95, ~ol. VIII). 190 282207405 PRODUCED FROM B&W WEB SITE Federal Register / Vo]. 61. No. 168 / Wednesday, August 28, 1995 ! Rules and Regulations 44847 I1.C. C. THE STATEMENTS, RESEARCH, AND ACTIONS OF THE CIGARETTE MANUFACTURERS SHOW THAT THE MANUFACTURERS INTEND THEIR PRODUCTS TO AFFECT THE STRUCTURE AND FUNCTION OF THE BODY In sections H.A. and II.B., above, the Agency has concluded that cigarettes and smokeless tobacco are intended to affect the structure and function of the body on the basis of the foreseeable pharmacological effects and uses of cigarettes and smokeless tobacco and the widespread actual use of cigarettes and smokeless tobacco by consumers for pharmacological purposes. In this section, the Agency considers another category of persuasive evidence of intended use: the statements, research, and actions of the cigarette manufacturers themselves. In section [I.D., below, the Agency considers the statements, research, and actions of the smokeless tobacco manufacturers. The administrative record includes extensive evidence of the cigarette manufacturers' statements, research, and manufacturing practices. Much of this evidence has only recently become available as a result of the Agency's investigation, congressional hearings, and other investigations and sources. This evidence is part of the relevant objective evidence that the Agency may consider in determining the manufacturer's "intended uses" of a product. In the Jurisdictional Analysis, the Agency made extensive findings based on the evidence then available regarding the statements, research, and actions of the cigareue manufacturers. FDA received comments on these findings from the individual tobacco companies and tobacco industry trade associations, as well as from public health organizations and other interested groups and members of the public. After careful consideration of the evidence in the record and the public comments, the Agency finds that 191 282207406 PRODUCED FROM B&W WEB SITE 44848 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations II.C. the evidence described in this section provides a third independent basis for concluding that cigarettes are in fact imended to affect the structure and function of the bodies of smokers. In section II.C. 1., FDA discusses its legal authority to consider evidence of the manufacturers' statements, research, and actions in establishing, intended use. This discussion shows that an intent to affect the structure or function of the body can be established by evidence showing that (1) the manufacturer "has in mind" that the product will be used by consumers for pharmacological purposes, or (2) the manufacturer has "designed" the product to provide pharmacological effects. The Agency's role in making these demrminations is that of a fact finder. It weighs the statements, research, and actions of the manufacturer to determine the particular uses the manufacturer has in mind or designs its product to provide. The Agency's fact-finding task has been made more difficult by the manufacturers' general refusal t~ cooperate with the Agency's investigation. Although some manufacturers did permit FDA investigators to visit their manufacturing plants in the spring of 1994, the manufacturers have failed to provide FDA with information and documents requested by FDA in July 1994 regarding nicotine in cigarettes.4°~ In particular, the manufacturers have failed to comply with FDA's request for company documents regarding the pharmacological effects of nicotine and the role of nicotine in cigarette design and manufacturing. The limited number of company documents provided See, e..~., Letter from Chesemore RG (FDA) to Bible GC (Philip Morris Inc.) (Jul. 11, 1994). See AR (VOl. 54 Ref. 617). Similar |euers were sent to other cigarette and smokeless tobacco manufacturers. 192 282207407 PRODUCED FROM B&W WEB SITE Federal l~,~i~ter / Vol. 61, No. 168 / Wednesday, August 2e, 1996 / Rules and Regulations 44849 II.C. by the manufacturers with their comments sheds little light on the role of mcotine in cigarettes and does not significantly change the evidence in the record. The Agency' s discussion of the evidence of the manufacturers' statements, research, and actions is divided into several parts. In section II.C.2., the Agency discusses the statements and research of each of the major cigarette companies and the Council for Tobacco Research, a trade association to which they belong. This evidence sh6ws that the manufacturers have known for decades that nicotine has the characteristics of addictive drugs and causes other significant pharmacological effects and that consumers use cigarettes primarily to obtain the pharmacological effects of nicotine, including satisfaction of their addiction. This evidence also shows that in internal discussions, senior researchers for the cigarette manufacturers refer to cigarettes as drug delivery systems, calling them a "'dispenser for a dose unit of nicotine,''~1° a vehicle for delivery of nicotine,''~1~ and other similar terms. This evidence is sufficient by itself to establish that cigarettes are intended to affect the structure and function of the body, because it shows that the manufacturers "have in mind" that their produ~s wil] be used specifically for pharmacological purposes. In sec~ons Id.C.3. and I1.C.4., the Agency discusses the second basis for determining the manufacturers' intent through their statements, research, and aetionsm namely, the evidence that manufacturers have "designed" cigarettes to provide pharmacologically active doses of nicotine to consumers. In section I.C.3., the Agency discusses the product research and development activities of the manufacturers. This ~ Dunn WL (Philip Morris Inc.), Motives and Incentives in Cigarette Smoking (1972), at 5. See AR (Vol. 12 Ref. 133). 4~ Teague CE (R.J. Reynolds Tobacco Co.), Research Planning Memorandum on The Nature of the Tobacco Business and the Crucial Role of Nicotine Therein (Apt. 14, 1972), at I. See AR (VoL 53 l Ref. 125). 193 282207408 PRODUCED FROM B&W WEB SITE ~II150 Federal llt~istez / Vo]. 61, No, 168 / Wednesday, August 28, 1996 / Rules and Regulations II.C. evidence shows that the manufacturers have conducted extensive product research and development to establish the dose of nicotine necessary to produce pharmacological effects and to optimize the delivery of nicotine to consumers. In section rl.C.4., the Agency discusses the evidence that the manufacturers do m fact manipulate and control nicotine deliveries in their commercial cigarettes. "This evidence supports a finding that the manufacturers manipulate and control the delivery of nicotine in commercial cigarettes to provide a pharmacologically active dose of nicotine to consumers. Taken together, the evidence in sections II.C.3. and II.C.4. establishes yet another basis for finding that cigarettes are intended to affect the structure and function of the body. In section II.C.5., the Agency concludes that, when considered cumulatively, the evidence from the statements, research, and actions of the manufacturers is internally consistent and mutually corroborating, further supporting the finding that the effects of cigarettes on the structure and function of the body are "intended" by the manufacturers. Finally, in section I1.C.6., the Agency responds to substantive comments concerning the evidence of the manufacturers' statements, research, and actions that are not addressed in sections II.C.2. to II.C.5.4~2 • la The discussion of the statements, research, and actions of the manufacturers in this section cites hundte, ds of docamacnts. It is the totality of the evidence from these documents that the Agency relies upcm No single document cite~d by the Agency is essential to tlm Age.ney's conclusion in section II.C that the manuf~cturet~ intend their products to affect the slructum ~nd function of the body. In particular, although considerable evidence of ~c statements, research, and actions of the manufacturers was subtmtt~d to the Agency ~ter the publication of the Atrisdictio~tl Analysis on August l I, 1995, none of this evidence is essential to the Agency's finding of inlcndcd use m section II.C. The new evidence is summanze~l below because it provides persuasive corroboration that tlm cigaretm nmnufactttrcrs do intend to affect the stracturc and function of the body. However, the Agency would t~,~ch the same conclusions mgm'ding the inumt of the manufacturers cvcn without this additio~ml evidence. In ~tddition, none of the documents in the Agency's dock,~t of confidential documents is essential to the Agency's determination. See AR (Vol. 505-518). 194 282207409 PRODUCED FROM B&W WEB SITE Federal Regi~er / Vol. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations 44851 II.C.1. 1. "Intended Use" May Be Established on the Basis of the Statements, Actions, and Research of the Manufacturers Reliance on the statements, research, and actions of manufacturers to establish intended use is consistent with the plain language of the statute. The statute provides that products "intended" to affect the structure or any function of the body are drugs or devices. Sections 201(gX1)(C) arid 201(h)(3). According to a canon of statutory construction, words used by Congress, unless otherwise defined, will be interpreted as taking their ordinar).' meaning. See, e.g., Smith v. United States, 508 U.S. 223, 228 (1993); Chevron v. Natural Resources Defense Council, Inc., 467 U.S. 837, 860 (1984). In this case. the ordinary meaning of "intend" includes "to have in mind" and "to design" for a particular use. These plain meanings allow the Agency to consider the manufacturer's statements, research, and actions in determining intended use. The American Heritage Dictionary, for instance, defines "intend" as: "1. To have in mind: plan. 2.a. To design for a specific purpose, b. To have in mind for a particular use .... ,,a13 Consistent with this meaning, the Agency interprets "intended" uses to include those specific uses that are "in the mind" of the manufacturer or for which the manufacturer "designs" the product. The plain meaning of the statute thus permits the Agency to inquire into the statements, research, and actions of the manufacturer. What the manufacturer says in internal documents, the kind of research the manufacturer conducts, and the actions of the manufacturer in producing its product can all be evidence ,13 The American Heritage Dictionary of the English Language. 2d ed. (Boston: Houghton Mifflin Co., 1991 ), 668. See AR (VoL 526 Ref. 95; vo[. V). Other dictionary definitions are similar. See, e.g., Webster's New World Dictionary of American English, 3d college ezl. (New York: Simon & Schuster, Inc., 1988), 702 ("Intend 1. to have in mind az a purpose', plan 2. to mean (something) to b~ or be used (for): design .... ") (emphasis added). 195 282207410 PRODUCED FROM B&W WEB SITE 44852 Federal Register / Vol. 61, No, 168 / Wednesday, August 28, 1996 / Rules and Regulations I1.C.I. of the particular uses the manufacturer has in mind or for which the manufacturer has designed the product. FDA's regulations.on the meaning of "intended uses" are consistent with the statutory language and explicitly contemplate that FDA may examine the knowledge, actions, and expressions of manufacturers and other vendors. 21 CFR 201.128 and 801.4. These regulations state that intended uses are to be established on the basis of "objective intent." FDA's "objective intent" standard means that the Agency may consider objective evidence to determine a manufacturer's intent, notwithstanding the manufacturer's assertions that pharmacological effects and uses are not intended. As the courts have recogn~.ed, "'FDA is not bound by the manufacturer's subjective claims of intent but can find actual therapeutic intent on the basi's of objective evidence." NNFA v. Mathews, 557 F.2d at 334 ~emphasis added): accord United States v. Storage Spaces Designated Nos. "8" and "49," 777 F.2d 1363, 1366 n. 5 (9th Cir. 1985) ("self-serving labels cannot be used to mask true intent"), cert. denied, 479 U.S. 1086 (1987). The regulations recognize that as a fact finder, FDA may consider a broad range of evidence of tntended use, including evidence of the statements, research, and actions of the manufacturer. For example, the regulations state that "the objective intent is determined by such persons' expressions.., or oral or written statements." 21 CFR 20t. I28 (emphasis added). These "expressions" and "oral or written statements" can include relevant and probative intracompany memoranda or research. Indeed, the regulations provide express authority for FDA to consider evidence of the manufacturer's actual inten~. The regulations state that "objective intent.., may be shown by the circumstances that the article is, with the knowledge of[the manufacturer], 196 282207411 PRODUCED FROH B&W WEB 8ITE Federal Register / Vol. 61, No. 168 / Wednesdsy, August 28, 1996 / Rules and Regulations II.C.I. offered and used for a purpose for which it is neither labeled nor advertised." Id. (emphasis added). The regulations also direct FDA to consider circumstances in which the manufacturer "'knows, or has knowledge of facts that would give him notice" that a product is to be used for purposes other than those expressly promoted by the manufacturer, ld. (emphasis added). Proving whether a manufacturer "knows" or has "knowledge of facts that would give him notice" of pharmacological uses of a product can include an inquiry into the actual understanding of the manufacturer, including consideration of the statements, research, and actions that may be probative of the manufacturer's actual knowledge. Moreover, the regulations provide that objective intent may be shown by the "circumstances surrounding the distribution of the article.'" ld. (emphasis added). This broad phrase allows the fact finder to infer the intended uses of a product based on, among other factors, the conduct of the manufacturer that occurs prior to distribution. For example, evidence that shows how distributed tobacco products are designed and formulated is reasonably considered a "circumstance surrounding distribution of the article." Courts have also recognized that the Agency may comider "objective evidence" to determine a manufacturer's intent. See NNFA v. Mathews, 557 F.2d at 334; United States v. Storage Spaces, 777 F.2d at 1366; Latex Surgeons' Gloves, 799 F. Supp. at 1295 (circumstances surrounding manufacture and distribution of product demonstrated intended use despite manufacturer's claim to FDA that product was not a device); Hanson. 417 F. Supp. at 35 (statements by plaintiff distributors and importers that drug was needed by patients to treat cancer is relevant to intended use). 197 282207412 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / We£nesday. August 28. 1996 1 Rules and Regulations I1.C.2. The Agency' s role in determining intended use on the basis of the statements, research, and actions of the manufacturer is that of a fact f'mder. The Agency's responsibility is to reach the best factual judgments it can from the record of the statements, research, and actions before it, including evidence submitted during the comment period. 2. The Cigarette Manufacturers Understand That Nicotine Has Addictive and Other Pharmacological Effects and That Smokers Use Cigarettes To Obtain These Effects As discussed below, the evidence in the record shows that the cigarette manufacturers have extensive knowledge of effects of nicotine on smokers. The manufacturers know that nicotine has the characteristics of other addictive drugs; that it provides other significant pharmacological effects; and that it ~s the primary reason that smokers use cigareaes. This evidence establishes that when the manufacturers offer cigarettes to the public, they "'have in mind" that their cigarettes will be used by smokers to obtain the pharmacological elf ecru of nicotine. This evidence is thus sufficient by itself to establish that the manufacturers intend the pharmacological uses of their products. a. The Statements and Research of Philip Morris The administrative record includes over three decades of internal statements and research on nicotine by Philip Morris, the nation's largest cigarette manufacturer. These doctm~ents indicate that senior researchers and officials at Philip Morris have long viewed nicotine as a "powerful pharmacological agent''~t4 and "the primary reason''~5 people ~" Charles JL (P~ailip Morris Inc.), Nicotine Receptor Program-Universi~. of Rochester (Mar. 18, 1980), in 141 Cong. Rec. H7680 (daily ed. Jul. 25, 1995). See AR (Vol. 14 Ref. 175a). ,~s PhiIip Morns Inc., Draft Report Regarding a Proposal for a "Safer" Cigarette, Code-named Table, al 1. See AR (Vol. 531 Ref. 122). 198 282207413 PRODUCED FROM B&W WEB SITE Federal Register / Vcl. 61. No, 168 / Wednesday, August 28, 1996 / Rules and Regulations 44855 II.C.2. smoke. This knowledge shows that Philip Morns understands that its product will affect the structure and function of the body and will be used by consumers for these drug effects. i. The Views 0f Senior Researchers and Officials. Philip Morris officials recognized the importance of the pharmacological .effects of nicotine in cigarettes as early as 1961. That year, Helmut Wakeharn, a senior Philip Morris research scientist, informed the company's research and development committee that "nicotine is believed essential to cigarette acceptability.''4~6 Wakeham also explained the pharmacological effects of nicotine, stating that "low nicotine doses stimulate, but high doses depress functions" and that nicotine contributes to the "'pleasurable reactions or tranquillity" produced by smoking.~ By 1969, the views of the Philip Morns scientists on the pharmacological effects of cigarettes were communicated to the Philip Morris board of directors. During that year, Wakeham, who was then vice president for research and development, briefed the Philip Morr~ board of directors on why people smoke. He expressed his department's "'conviction'" that "'the ultimate explanation for the perpetuated cigaret habit resides in the pharmacological effect of smoke upon the body of the smoker." He further stated that smokers' craving for cigarettes is so strong that "the cigaret will even preempt food in urnes of scarcity": Farone WA, The Manipulation and Control of Nicotin~ and Tar in the Design and Manufacture of Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 6. See AR (VoI_ 638 Ref. 2). a~. W',tkeham H (Philip Morns Inc.), Tobacco and Heahh--R&DApproach (Nov. 15, 1961), It 43. See AR(Vol 125 Ref. 1314). "~:~ ld at 40. 199 282207414 PRODUCED FROM B&W WEB SITE 44856 Federal Register / Vol. 61. No. 158 / Wednesday, August 28, 1995 / Rules and Regulations [T]he psychosocial motive is not enough to explain continued smoking. Some other motive force takes over to make smoking rewarding in its own right. Long after adolescent preoccupation with self-image has subsided, the cigaret will even preempt food in times of scarcity on the smoker's priority list .... The question is "Why.'?" .... We are of the conviction .... that the ultimate explanation for the perpetuated cigaret habit resides in the pharmacological effect of smoke upon the body of the smoker, the effect being most rewarding to the individual under stress.4~ II.C.2. Wakeham's views on the central importance of the "pharmacological effect" of nicotine were shared by other senior researchers and officials at Philip Morris, as the following examples demonstrate: • In 1972, Philip Morris scientist William Dunn characterized cigarettes as a nicotine delivery system in the following language: Think of the cigarette pack as a storage container for a day's supply of nicotine .... Think of the cigarette as a ohspenser for a dose unit of nicotine .... Think of a puff of smoke as the vehicle of nicotine .... Smoke ts beyond question the most optirmzed vetucle of mcotine and the cigarette the most optimized dispenser of • In 1974, Philip Morris' director of research, Thomas Osdene, who subsequently became vice president for science and technology, approved and sent to Wakeham and other senior Philip Morris officials a report that analogized smoking to drug use. The report's "working hypothesis" is that "[d]ose-control continues even after the puff of smoke is drawn into the mouth." The report postulates that the consumer regulates ~s Wakeham H (Philip Morns Inc.), Smaker P~eh,~logy Research, presented to Philip Morris board of directors (Nov. 26, 1969), at 237, 24~3. See AR (Vol. I 1 Ref. 142). • ~9 Dtttm WL (Philip Morris Inc.), Motives and Incentives in Cigarette Smoking (1972), at 5-6 (emphasis added~. See AR (VoI. 12 Ref, 133). 2O0 282207415 PRODUCED FROM B&W WEB SITE Federal Re~ister / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44857 II.C.2. smoke intake "to achieve his habitual quota of the pharmacological action," and notes that if smokers deprived of cigarettes display an increase in aggression, it may be explained as "the emergence of reactions.., not unlike those to be observed upon withdrawal from any of a number of habituating pharmacological agents.''~2° In 1976, Philip Morris researcher A. Udow wrote a memorandum on "Why People Start To Smoke." The memorandum observes that once people start to smoke, one of the reasons they will continue to smoke is that cigarettes serve as "a narcotic, tranquilizer, or sedative."'~2~ In 1978, the authors of philip Morris' 5-year plan for research and development stated that "nicotine may be the physiologically active component of smoke having the greatest consequence to the consumer.''~22 In 1980, Philip Morris researcher Jim Charles, who subsequently became vice president for research and development, wrote the then vice president for research and development. Robert Seligman, that: Nicotine is a powerful pharmacologic~al agent with multiple sites of action and may be the most important component of cigarette smoke. Nicotine and an understanding of its properties are important to the continued welt being of our cigarette business since this alkaloid has been cited oflen as "the reason for smohng."... Nicotine is known to have effects on the central and ~,~0 Philip Morns Reseaxch Center, Behavioral Research Annum Report, Part II (Nov. I, 1974) (approved by Osdene "IS), in 141 Cong. Rec. H7658, H7660 (daily ed. Jul. 25, 1995). See AR (Vol. 14 Ref. 175a). a:~ Udow A (Philip Morris Inc.), Why People Start to Smoke (Jun. 2, 1976), in 141 Cong. Rec. H7664 (daily ed. Jul. 25, 1995) (emphasis added). See AR (Vol. 14 Ref. 175a). PhiLip Morris Inc., Research and Development Five-Year Plan, 1979-1983 (Sep. 1978), in 141 Cong. Rec. H7668 (daily e_d. Jul. 25, 1995) (emphasis added). See AR (VoL 14 Ref. 175a), 201 282207416 PRODUCED FROM B&W WEB SITE 44858 Fc~deral Rc~gi~er / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and R~gulations II.C.2. peripheral nervous system as well as influencing memory, learning, pain perception, response to stress and level of arousal,a'-3 A statement that the Agency received from a former Philip Morris research director, William Farone, expresses similar views. Farone was the director of applied research at Philip Morris from 1976-1984, during which period he supervised five divisions and 150 employees. According to Farone's statement: It is well recognized within the cigarette industry that there is one principal reason why people smoke~o experience the effects of nicotine, a known pharmacologically active constituent in tobacco .... The strongly held conviction of most industry scientists and product developers was that nicotine was the primary reason why people smoked.42" The administrative record contains many additional statements by Philip Morris researchers and officials acknowledging the significant pharmacological effects 6f nicotine and their importance to the smoker. See, e.g., 60 FR 4158z~41603, 41621-41667. Collectively, these statements show that Philip Morris' semor scientists and officials have known for decades that cigarettes function as a drug delivery system, providing the pharmacological effects of nicotine to consumers who smoke cigarettes for the primary purpose of obtaining these effects. ii Research into Nicotine Pharmacology. The foregoing views of Philip Moms' top research scientists and officials were based on extensive in-house research on 423 Charles Jl_, (Philip Morris inc.), Nicotine Receptor Program-University of Rochester (Max. 18, 1980), in 141 Cong. Rec. H7680 (daily exl. Jul. 25, 1995) (emphasis added). See AR (VoL 14 Ref. 175a). 42, Farone WA, The Mampulation and Control of Nicotine and Tar in the Design and Manufacture of Cigarettes: A Scientific Perspective (Max. 8, 1996), at !,6 (emphasis added). See AR (Vol. 638 Ref. 2). 202 282207417 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44859 II.C.2. nicotine pharmacology. The studies conducted by Philip Morris ranged from traditional pharmacology involving animal experiments to EEG experiments. Philip Morris conducted a large number of studies. In 1979 alone at least 16 different studies on nicotine pharmacology were conducted by three different research groups within Philip Morris' Behavioral Research Laboratory. 4z~ The Animal Behavior" Group conducted six experiments on the drug effects of nicotine in rats. The Neuropsychology Laboratory conducted five experiments to determine the pharmacological effects of nicotine on the human brain, including experiments on "[t]he Effects of Cigarette Smoking on the Electroencephalogram" and "[L]ong-Term Smoke Deprivation and the Electrical Activity of the Brain.'"~ The Smoking Behavior Group conducted studies on the behavioral consequences of smoking, including studies to determine the consequences of smoking low-nicotine cigarettes. Beginning before 1980 and continuing until 1984, Philip Morris conducted research in search of a "nicotine analogue." This research demonstrates Philip Morris' knowledge that nicotine has the hallmark properties of a drug of abuse and shows the company's intenuon to preserve these properties in new products. As described by former Philip Morris scientist Victor DeNoble, the purpose of the research was "to come up with a molecule that would mimic nicotine's effect in the brain, and would not affect the peripheral nervous system and therefore not have cardiovascular liability.''~:~ Thus, while ""~ Dunn WL (Philip Morris Inc.), Plans and Objectives-1979 (Dec. 6, 1978), m 141 Cong. Rec. H7668- 7670 (dzily ed. Jul. 25, 1995). See AR (Vol. 14 Ref. 175a). a,.6 Id. al H7669-7670. ~ :7 Regulation of Tobacco Products (Part 2): Hearings'Before the Subcomminee on Health and the Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 2d Sess. 33 (Apr. 28, 1994) (testimony of Victor DeNoble) (emphasis added). See AR (VoI_ 708 Ref. 2). 203 282207418 PRODUCED FROM B&W WEB SITE 44860 Federal Register / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Re~lations II.C.2. the company attempted to eliminate an adverse effect of nicotine, it deliberately sought to retain nicotine's effects on the brain. To conduct this work, Philip Morris scientists had to identify and compare the pharmacological and behavioral effects of nicotine on the brain. The pharmacological and behavioral profiles of the nicotine analogues synthesized by Philip Morris chemists were then compared to those of nicotine.4~ Since the primary goal of the nicotine analogue program was to develop a nicotine analogue that would retain the physiological and behavioral effects of nicotine on the brain, especially its reinforcing properties, the newly synthesized nicotine analogues were screened in animal behavioral tests designed to assess their reinforcing properties. (A substance has reinforcing properties if it is able to induce repeated, compulsive use. See section II.A.3.c.i., above.) The tests used Were "exactly the same tests" that the National Institute on Drug Abuse (NII-IA) uses "'to determine if a drug has an abuse potential.''~29 One of the principal NIDA tests used by Philip Morris was a series of "self- administration'" experiments with rats. These studies determine addiction potential by assessing whether rats will press a lever to give themselves repeated injections of the test substance. There is a strong correlation between substances that are found to be self- ~:~ ld a! 5 See alse~ Declaration of Viclor DeNoble of Feb. 2, 1995, at 2-9. See AR (Vol. 31 Rel. 524-5). azc Regulation of Tobacco Products (Part 2)." Hearings Before the Subcommittee on Health and the Envtronment of the Committee on Energ3.' and Commerce, U.S. House of Representatives, 103d Cong,, 2d Ses~. 17 {Apr. 28, 1994) (testimony of Victor DeNobl¢). See AR (Vol. 708 Ref. 2). 204 282207419 PRODUCED FROM B&W WEB SITE Federal Regi~er / Vc[. 61, No. 168 / Wednesday, August 28, 1996 t Rules and Ru,~gulations 44861 II.C.2. administered in rats and substances that are addictive in humans.43° Philip Morris found that rats would self-administer nicotine.4~ According to the director of NIDA, "'[t]hese findings from the DeNoble study indicate that nicotine has reinforcing properties, one of the hallmark characteristics of an add~ctive drug.''~32 The Philip Morris researchers also found that rats would develop a tolerance to nicotine, another characteristic of an addictive drug.433 The senior management and top officials of Philip Morris "continually reviewed •.. and approved" this research.434 In fact, in November 1983, the president of Philip Morris, Shep Pollack. visited the laboratory conducting the self-administration experiments and watched rats inject themselves with nicotine. Pollack was reformed by the Philip Morris researcher in charge of the study, Victor DeNoble, that Philip Morris' self-adminrstration studies followed "the exact procedure that NIDA would use to demonstrate abuse liability," and that the studies demonstrated that nicotine is "a • ~ " o . ,~435 remIorcmg a~ent. DeNoble further informed Pollack that although a finding of self- Gardner EL, Brain reward mechamsm, in Substance Abuse, A Comprehensive TeJabook, 2d ed., eds. Lowinson JH, Ruiz P, Millman RB, et al. (Baltimore: Williams and WilKirts 1992), at 70. See AR (VoI. 8 Ref. See aJs,~ section I1.A3.c.i ~3~ Regulation of Tobacco Products (Pan 2): Hearings Before the Subcommittee on Health and the Environment of the Committee on Energy and Commerce, U.S. House of Represematives, 103d Cong.i 2d Sezs. 5 (Apr. 28, 1994) (tesUmony of Victor DeNoble). See AR (Vol. 708 Ref. 2). "~: ld. at 20 (letter from Lestmer AI (NIDA) to Wax.man HA (Apr. 13, 1994) (emph-,sis added)). ,3~ ld. at 5 (mstimony of Victor DeNoble). The Philip Morris researchers did not, however, f'md evidence of nicoune withdrawal. *~ fd. at 5-6• ~35 ld. at 54. 205 282207420 PRODUCED FROH B&W WEB SITE 44862 Federal R~i~er / Voi. 61, No. 158 / Wednesday, Augus~ 28, 1995 / Rules and Regulations II .C.2. administration does not by itself prove that nicotine is addictive,', it "predicts abuse li;ibility."~3~ Despite several attempts. DeNoble and his colleague Paul Mele were not allowed to publish the results of the/r self-administration studies or present their results at a meeting sponsored by the American Psychological Association,437 These studies were conducted for their potential commercial applicability. The memoranclum describing the "plans and objectives" for the Behavioral Research Laborato~ in ~ 979 states expressly that "the rationale for the program rests on the premise that such knowledge will strengthen Philip Morris R&D capability in developing new and improved smo~ng products.''~ Some of Philip Morri.g' research attempted to assess the pharmacological effects of nicotine on youths. One study on the hyperkinetic child as prospective smoker observed that "amphetamines, which are strong stimulants, have the anomalous effect of quieting these children d~)wn"; the Philip Morris researchers initiated a study to determine "whether such children may not eventually become cigarette smokers in their teenage years as they discover the advantage of se(f-stimulatio~r via nicotine.''~39 This study was apparently ~ Id. at 51-52, 57-94. ~ Du_rm %~. Plans and Objectives-1979 (Dec. 6, 1978), in 141 Cong. Rec. H7669. See A.R (Vol. 1~, Ref 175a) "-~ R.van FJ (Philip Morns Inc.), Relationship bdtween smoking and personality, in Smoker Ps).'choiogy/May 1-31, 1974 (Jult 10, 1974), in 141 Cong. Rec. H7651 (daily ed Jul 25, 1995) (emphasis added)..See AR (Vol. 14 Ref. 175a). For a further description of Philip Moms' research into hyperkinetic children, see the following documents reprinted in tat Cong. Rec. H7651-7657 (daily ed. Jul 25. 1995): Ryan F.1 (Philip Morris Inc.), Relationship between smoking and personality, in Smoker Psychology~May 1-31~ ]974 (Jim. 10, 1974). See AR (Vol. lg Ref. 175a). 2O6 282207421 PRODUCED FROH B&W WEB SITE Federal Register / Voi. 61, No. 168 / Wednesday. August 28, 1996 / Rules and Regulations II.C.2. never completed because "{o]bstacles presented by school systems and physicians... have made it veD' difficult for us to conduct studies using school and medical records of minors.'~'° Another study initiated by Philip Morris involved administering "painful" electric shocks to college students to determine the anxiety-reducing effects of cigarettes."' Although preliminary findings supported the hypothesis that students with a high anxiety factor on personality tests would puff more frequently,'~2 the study apparently had to be discontinued because "fear of shock is scaring away some of our more valuable Ryan FJ (Philip Morns inc.), Hyperkinesis m a precursor of smoking, in Smoker Psychology/Feb. 1-28, 1975 (Mat. 10, 1975). See AR (Vol. 14Ref. 175a). Philip Morns Research Center, Behavioral Research Annum Report (Jul. 18, 1975) (approved by Duma WL). See AR (Vol. 14 Ref. 175a). Ryan FJ (Philip Morris Inc.), Hyperactivity, m Smoker Psychology~Apr. 1-30, 1977 (May 13, 1977). See AR(VoL 14 Ref. 175a). Ryan FJ (Philip Morns Inc.), Hyperkinetic children, m Smoker Psychology,/Feb. 1-28, 1978 (Mar. 10, 1978). See AR (Vol 14 Ref. 175a). • a~. Ryan FJ (Philip Morr~ inc.), Hyperkinetic children, m Smoker Psychology/Feb. 1-28, 1978 (Mm'. 1978), m 141 Cong. Re, c_ H7657 (daily ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). *~a Ryan FJ (Philip Morris Inc.), Proposed Research Project: Smoking and An,r.ie~y (Dec. 23, 1969), in 141 Cong. Rec. H7648 (daily e.d. Jul. 25, 1995). See AR (Vo/ 14 Ref. 175a). For a further description of Philip Morris' researc~ revolving the administralion of electric shocks, see the following docamaents printed in 141 Cong. Rec. H764,8-7649 (daily ed. Jul. 25, 1995): Ryan FJ (Philip Morris Inc.), Shock L If, IIL m~d IV. in Consumer Psychology (Sep. 16 - Oct.15, 1971). See AR (VoL 14 Ref. 175a). Ryan FJ (Philip Morris Inc.), Shock V, m Consumer Psycluglogy (Jnn. 15 - Feb. 15, 1972). See AR (Vol. 14 Ref. 175a). Duan WL (Philip Morris Inc.), Quarterly Report.Projects 1600 and 2302 (OcL 5, 1972). See AR (Vol. 14 Ref. 175a). ~2 Ryan (Sep. 16 175a). FJ (Philip Morris Inc.), Shock 1, IL HL and IV, in Consumer Psychology Monthly Report - Ocl. 15, 1971), i~ 141 Cong. Rec. H7648-7649 (daily ed. Jul. 25, 1995). See AR (Vol. 14 Ref. 207 44863 282207422 PRODUCED FROH B&W WEB SITE 44864 Federal Regi~er / Vo|. 61, No. 168 / Wednesday, August 28, 1996 / Rules ~nd Regulazions II.C.2. subjects."~3 In another study, PhiLip Morris proposed injecting mcotine into human subjects in order "to yield a broader picture of the role of the spike, the level, and the reinforcement characteristics of the substance.''~ In congressional testimony, the fomacr PhiLip Morris president, William Campbell, testified that to the extent that Philip Morris controls nicotine levels in cigarettes through blending, this is done "for taste.''~ Philip Morris's research program does not support this statement, however. The internal research documents in the administrative record show that Philip Morris exhaustively investigated the pharmacological properties of nicotine--not its gustatory properties. The intensive focus on nicotine pharmacology. reflected in the documents indicates that Philip Morris regarded nicotine's contribution to cigarettes as pharmacological, not taste-related. Moreover, in its comments Philip Morris did not provide evidence of internal Philip Morns research into the taste characteristics of nicotine. '~ Eichorn PA, Du.un WL (Philip Morns Inc.), Quarterly Reports-Projects 1600 and 2302 (Oct. 5, 1972), in141 Cong. Re~ H7649 (daily e,d. Jul. 25, 1995). See AR (Vol. 14 Ref. 175a). ~ Dram W'L (Philip Morris lnc~), Plans and Objectives-1981 (Nov. 26, 1980), in 141 Cong. Re~ H7682 (daily ed. Jul. 25, 1995). See A.R (Vol 14 Re, f. 175a). For a further description of Philip Morris' proposed research involving mcotme injecuons, see: Dunn WL (Philip Morris Inc.), BehaviorM Research Accomplishments, 1977 (Dec. 19, 1977), in 141 Cong. Rec. H7666 (daily ed. Jul. 25, 1995). See AR (Vol. 14 Reg. 175a). Dunn W~L (Philip Morris Inc.), Plans and Objective~-1979 (Dexa 6, 1978), in 141 Cong. Rec. H7669 (daily ed. Jd. 25, 1995). See AR (Vol. 14 Reg. 175a). ~ Regulation of Tobacco Products (Part 1)." Heanngs Before the Subcommittee on Health and the Environment of the Committee on F, nergy and Commerce, U.S. House of Relareaentatives, 103d Cong., 2d Sess. 764 (Apr. 14, 1994) (testimony of William Campbell). See AR (Vol. 707 Ref. 1). 208 282207423 PRODUCED FROH B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1995 / Rules and Regulations 44865 II.C.2. Further examples of Philip Moms' research on nicotine pharmacology are presented in the Jurisdictional Analysis. See 60 FR 41590-41591, 41595-41599. Taken together, these studies show that Philip Morns conducted an extensive, sustained, and sophisticated investigation into the pharmacological effects of nicotine that gave the company knowledge that mcotine has significant pharmacological effects on smokers, including reinforcing effects. The research was conducted because of its commercial significance to Philip Morris; used techniques that are employed by government agencies to identify the "abuse potential" of drags; and found that nicotine has hallmark characteristics of an addictive drug, including reinforcing effects and the development of tolerance. iti_ Project"ralple. Philip Moms' recogmtion of the important pharmacological role of nicotine m cigarettes has been consistent for over three decades. New evidence received by the Agency during the comment period, for instance, indicates that officials inside Philap Morns continued to recognize the importance of nicotine's pharmacological effects and uses tn the 1990's. A draft Phihp Morns report on "Project Table," a proposal to develop "a nicotine delivery, device" that relies on "heating rather than burning the tobacco" to "produce[I a cleaner, safer smoking experience," writmn around 1992, acknowledges that although "[d]ifferent people smoke for different reasons .... the primary reason is to deliver nicotine into their bodies." ~ The report describes nicotine in cigarettes in explicit drug- like terms: "~ Philip Morns, Inc., Draft Report Regarding a Proposal for a "S~I'cr" Ciga_re, ttc, Code-named Table, at 1,5 ¢emphasis added). See A.R (Vol. 531 Rcf. 122). 209 282207424 PRODUCED FROM B&W WEB SITE 44866 Fodera] Register / Vol. 61, No. 168 / Wednesday, August 28, 19~)6 / Rules and Regutalions II.C.2. Nicotine... is a physiologically active, nitrogen containing substance. Strml~r orgmTw che,ucals include.., quinine, cocaine, atropine and morphine. While each of these substances can be used to affect human physiology, nicotine has a particularly' broad range of influence,aa: Project Table provides a derailed description of the pharmacological action of nicotine on the brain: During the smo "~ng act, nicotine is inhaled into the lungs in smoke, enters the bloodstream and travels to the brain in about eight to ten seconds. The nicotine alters the state of the smoker by becoming a neurommsmitter and a stimulant. Nicotine mimics the body's most important neurotransmitter, acet). ,.choline ( A CH ), wtu'ch controls heart rate and message sending within the brain. The nicotine is used to change physiological states leading to enhanced mental performance and relaxation. A little nicotine seems to stimulate, while a lot sedates a person."~ The report also expressly places cigarettes and smokeless tobacco products in the same category of "nicotine delivery devices" that includes nicotine patches and inhalers, stating that "'nicotine delivery devices range from snuff, chewing tobacco, cigars, pipes and conventional cigarettes to unique smoking articles, chewing gum, patches, aerosol sprays and inhalers.""~ The report thus indicates that the views of Philip Morns on the role of nicotine in cigarettes have been remarkably consistent. Twenty years after senior Philip Morris scientist William Dunn called cigarettes "'a dispenser for a dose unit of mcotme, Philip Morns officials continue to regard nicotine as a drug and cigarettes as a "nicotine deliver)' device." The evidence of Philip Morris' statements and research on ~r ld. at 1 (cmpbasLs added). • ~s ld (emphasis added). ~o id. at 2. ~~ Dram WL (philip Morris In(;. ), Motiws anti lnctntives in Cigarttt¢ Smoking (1972), at 5. See AR (Vol. 12 Ref. 133). 210 282207425 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44867 II.C.2. nicotine pharmacology persuasively documents that its cigarettes arc intended to affect the structure or funcuon of the body. b. The Statements and Research of R. J. Reynolds R.J. Reynolds Tobacco Company (R.IR) is the nation's second largest cigarette manufacturer. The reformation in the administrative record shows that researchers and senior officials at PJR hold views on the pharmacological effects and uses of nicotine in cigarettes that are similar to those of the researchers and senior officials at Philip Morris. i. The Teague Memoranda. During the comment period, FDA received two documents written by Claude Teague in 1972 and 1973, when he was the assistant director of research at R JR. Teague was subsequently promoted to director of corporate research in 1978.4s~ These internal memoranda show that RJR scientists regarded nicotine as a "potent" and "habit-forming" drug; considered cigarettes to be "a vehicle for delivery of nicotine"; and conceived of the tobacco industry itself as "a specialized, highly ntualmed and stylized segment of the pharmaceutical industry." Teague's 1972 memorandum, entitled "Research Planning Memorandum on the Nature of the Tobacco Business and the Crucial Role of Nicotine Therein," makes four significant points. First, the memorandum describes nicotine as a powerful and habituating drug. According to the memorandum, nicotine is "a potent drug with a variety of physiological effects.'"s: It is also "known to be a habit-forming alkaloid."'(53 Nicotine's specific effects on the body are described as follows: 4~ American Men and Women of Science, 1995-1996. 19th ext. (New Providence: R_R. Bowk~r, 1995), 7:62. See AR(Vol. 711Ref. 13). ,5: Teague CE, (R.J. Reynolds Tobacco Co.), Research Planning Memorandum on the Nature of the Tobacco Business and the Crucial Role of Nicotin~ Therein (Apr. 14, 1972), at 1. See AR (Vol. 531 Ref. 125). 211 282207426 PRODUCED FROM B&W WEB SITE 44668 Federal Re~ster / Vol. 61, 14o. 168 / Wednesday, August 28, 1996 / Rules and Regulations. The habituated user of tobacco producks is said to derive "satisfactaon" from nicotine. Although much studied, the physiological actions of nicotine are still poorly understood and appear to be many and varied. For example .... at different dose levels, nicotine appears to act as a stimulant, depressant, tranquilizer, psychic energizer, appetite reducer, anti-fatigue agent, or energizer, to name but a few of the varied and often contradictory effects attributed to it.''~" I1.C.2. Second, the memorandum acknowledges that nicotine is the "primary" reason for smoking. According to the memorandum: [TJhe confirmed user of tobacco products is primarily seeking the physiological "satisfaction" derived from nicotine--and Ia~haps other active compounds. His choice of product and panern of usage are primarily determined by his individual nicotine dosage requirements .... 455 Third, the Teague memorandum describes cigaretms as drug delivery systems. According to the memorandum, "a tobacco product is, in essence, a vehicle for delivery ofmcotine, designed to deliver the nicotine in a generally acceptable and at,zactive form.''~5~ The memorandum fm~er states: If what we have said about the habituated smoker is true, then products designed for him should emphasize nicotine, nicotine delivery efficiency, nicotine satisfaction, and the like. What we should really make and sell would be the proper dosage form of nicotine with as many other built-in attractions and grcaifications as possible---that is, an efficiem meotine delivery system with satisfactory flavor, mildness, convenience, cost, ere .... Would it not be better, in the long run, to identify in our minds and in the minds of our customers what we are really selling, i.e., mcotine satisfaction.~7 ,s, Id. (emphasis added). ~ Id. at i-2 (emphasis added). ,~s ld. at 1 (emphasis added). ~ ld. ~ ld at 5 (emphasis added). 212 282207427 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44869 I1.C.2. Indeed. the memorandum describes the tobacco industry itself as a "segment of the pharmaceutical industr3,":4~ In a sense, the tobacco industry may be thought of as being a specialized, tu'ghly ritualized and s~. lized segment of the pharmaceutical industry .... Our Industry is then based upon design, manufacture and sale of attractive dosage forms of nicotine, and our Company's position in our Industry is determined by our ability to produce dosage forms of nicotine which have more overall value, tangible or intangible, to the consumer than those of our competitors. 4s9 Finally, the memorandum recommends improvements in the delivery of nicotine to consumers. In the short term, the memorandum recommends reducing tar levels while maintaining nicotine levels in cigarettes: Our critics have lumped '~w" and nicotine together m their allegations about health hazards.'... An accompanying Research Ptanmng Memorandum suggests an approach to reducing the amount of "tar" in cigarette smoke per umt of racotine. That is probably the most realistic approach in today's market for conventional cigarette products. 460 In the long term, the memorandum recommends a "more futuristic approach":46~ If our business is fundamentally that of supplying mcofine in useful dosage form, why is it really necessary that allegedly harmful "tar" accompany that nicotine? There should be some smapler, "cleaner', more efficient and direct way to provide the desired nicotine dosage than the present system involving combustion of tobacco or even chewing of tobacco .... It should be possible to obtain pure nicotine by synthesis or from high- nicotine tobacco. It should then be possible, using modifications of techniques developed by the pharmaceutical and other a~ Id. at 2. 4~ ld. (emphasis added). ~o M. at 6 (emphasis added). 213 282207428 PRODUCED FROH B&W WEB SITE 44870 Federal Regisler / Vol. 61, No. 168 / Wednesday, August 28. 1996 / Rules and Regulations industries, to deliver that nicotine to the user in ef'ficient, effective, attractive dosage form. accompanied by no "tar", gas phase, or other allegedly harmful substances. The dosage form could incorporate various flavorams, enhancers, and like desirable additives, and would be designed to deliver the rmmmum effective amount of mcotine at the desired release-rate to supply the "'satisfaction" desired by the user. Such a product would maximize the benefits derived from nicotine, minimize allegedly undesirable over-dosage side effects from nicotine, and eliminate exposure to other materials alleged to be harmful to the user. 462 II.C.2. Evidence in the record indicates that R JR acted on both of these recommendations. See sections rl.C.2.b.iii, and 11.C.3.b., below. Claude Teague's 1973 memorandum, entitled "Some Thoughts about New Brands of Cigarettes for the Youth Market," recommends that RJR develop "'new brands tailored to the youth ma.rket.''~63 According to the memorandum, one of the design features that should be tailored to the youth market is nicotine delivery. The memorandum reaffirms that the "'nicotine effects" and the other physical effects of smoking are "highly desi.mble to the confirmed smoker.''*~ For the "pre-smokcr" or "'learner," however, the memorandum states that the physical effects of smoking, including the effects of mcotinc, are "'largely unknown, unneeded, or actually quite unpleasant or awkward.''~6s Consequently, the memorandum recommends that "the effort here should be to affect a compromise to minimize the undesirable effects while retaining these which later become "~ M. at 7 (emphasis added). • 6:~ Teague CE (R.J. Reynolds Tol~c¢o Co.), Research Planmng Memorandum on Some l"houghls about New Brands of Cigarettes for the Youth Market ff:eb. 2, 1973). at I See AR (Vol. 531 Rcf. 125). "~ ld at 4. ~/d at 2, 4. 2]4 282207429 PRODUCED FROM B&W WEB SITE Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44871 II.C.2. desirable.''~6~ With respect to nicotine, the memorandum recommends that "mcotme should be delivered at about 1.0-1.3 mg/cigarette, the minimum for corff-trrned smokers. The rote of absorption of nicotine should be la~pt low by holding pH down, probably below 6.''~67 Teague's analysis shows that, as at Philip Moms, scientists at R.1R have long understood that nicotine has significant pharmacological effects on the body and is the "primary," reason people smoke. His analysis further shows that, like Philip Morris scientists, K.I'R scientists also expressly conceived of cigarettes as a drug delivery system. ii. Other Statements and Research of R.IR Scientists and Officials. The views in the Teague memoranda about the "crucial role" of the pharmacological effects of nicotine continued to be expressed within R.IR in later years. In approximately 1977, for instance, RJR researchers told the R_IR marketing department that "[w]ithout any question, the desire to smoke is based on the effect of nicotine on the body";4~ that "a confirmed smoker attempts to get a certain desired level of nicotine";4s9 and that "[t]he nicoune in the blood act.~ upon the central nervous system and produces in the average smoker a sensation one could describe as either stimulating or relaxing.''~7° According to the R.IR researchers, while nicotine has a role in "mouth taste" and "mouth satisfaction," ~" ld at 4 ~7 ld. 46s Senk-us M (R_ I Reynolds Tobacco Co.), Som~ Effect~ of Smoking (197611977), at ~1 (¢~pla~is I~lded). See AR (Vol- 700 Ref 593). ~6~ ld. at 5 (emphasis added). ~{' ld. at 3. 215 282207430 PRODUCED FROM B&W WEB SITE 44872 Federal l~er / Vol. 61, No. 168 / Wednesday, AugUst 28, 1998 / Rules ~nd Regulations II.C.2. that is not nicotine's primary role; rather, "the ultimate satisfaction comes from the nicotine which is extracted.., in the lungs."~7~ In the late 1980's and early 1990's, moreover, tLIR researchers conducted a series of experiments on how nicotine affects the brain. The published reports from these experiments revealed that 20 years after the Teague memoranda, RJR researchers continued to believe that: (I) nicotine has pharmacological effects on the brain; and (2) smokers smoke cigarettes primarily to obtain these pharmacological effects. In a 1989 report entitled "Effects of Smoking/Nicotine on Anxiety, Heart Rate, and Lateralization of EEG During a Stressful Movie," RJR used an EEG to test its hypothesis that "nicotine and smoking help smokers to relax and cope with stress and negative affect" through "activation-reducing effects on the EEG.''~n The experiment's results supported KJR's hypothesis, indicating that nicotine produced the expected "anxiolytic" or anxiety-reducing effects in the brain: The present results support the view that the electrocortical effects of smoking are a function of environmental stress level, cigarette nicotine delivery, and cortical site. They are also consistent with previous evidence that nicotine reduces anxiety and with our hypothe s~s that nicotine's anxiolytic properties are mediated by the right hemisphere. Normal/high-nicotine delivery cigarettes, relative to low-nicotine control cigarettas, produced c.ordeal activation (decreased alpha power) in both hemispheres during the no-stress control condition.., but produced the opposite effect, decreased activation (increased alpha power), at the right parietal site during 473 the three stressful movie scenes. 47~ Id, at 7-9 (emphasis added). • 7-~ Gilbert DG, Robinson JH, Clmmberlm CL (R.J. Reynolds Tobact:o Co.), et al, Effoels of smoking/nicotine on anxiety, be, an rate, ~nd lat~ralization of KEG dming a stresslul movie, P~.chophysiolog3" 1989:26(3):31 ] -319, at 3 ! 1. See AR (Vo/ 14 Ref. 174-2). "~:' Id. at 316 (citation omatted) (emphasis added). 216 282207431 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44873 II.C.2. The 1989 study used the EEG to measure smokers' brain waves while they watched a film containing graphic images of industrial accidents. In a 1991 study entitled "Electroencephalographic Effects of Cigarette Smoking," R.IR researchers measur~ the effects of smoking on brain waves under "levels of mental workload representative of those encountered in day-to-day living.''~74 They found that the pharmacological effects of smoking are affected by how deeply the smoker inhaled. According to the report: In light inhaling smokers .... smoking was found to attenuate EEG activity in the delta, theta, and alpha frequency bands .... In deep inhaling smokers, smoking produced a symmetrical central midline increase in beta2 magnitude, an EEG effect that.., is associated with anxie~, relief~ These results led the R JR researchers to propose that light inhalers and deep inhalers smoke to obtain different pharmacological effects from nicotine and that the effects produced in deep-inhalers were comparable to the effects of benzodiazepines, a class of addictive drugs used for anxiety relief. According to the report: The results of the present investigation indicate that light inhaling •.. smokers may smoke primarily for purposes of mental activation and performance enhancement. This does not appear to be the case for deeper inhaling.., smokers .... An extensive literature suggests that increased beta2 activity may reflect the anxiolytic properties of the benzodiazepines independently of sedative effects. Thus, an important smoking motive for deep inhaling smokers might be anxiety reduction.~76 A year later, the R JR researchers reported the results of a study designed to isolate the precise effects of nicotine on the brain. In this study, some smokers were given ~ Pritchard WS (l~J. Reynolds Tobacco Co.), Electroencephalographic effecl~ of cigaretm smoking, P,~ychopharmacolog3' 1991;104.'~85-~90, at ~,86. See AR (VoL 3 Ref. 23-2). "~ ld. at 485 (emphasis added). "~ Id. at 488 (citations omat~l) (emphasis added). 217 282207432 PRODUCED FROH B&W WEB SITE 44874 l:edera] Re~ister / Vol. 61. No. 168 / Wednesday, Au[~usl 28, 1996 ! Rt~|es and Regulations I1.C.2. regular "light" cigarettes to smoke while others were given experimental cigarettes with virtually no nicotine. The results from the EEG showed that the regular "light" cigarette produced "a significant increase in beta), magnitude," an effect associated with anxiety relief, and "a significant decrease in delta magnitude," an effect associated with improved mental alermess.4v7 According to the researchers, "this indicates that the beneficial effects of smoldng on cognitive performance.., are a fun~tion of nicotine absorbed.from cigarette smoke upon inhalation.''~ Ts In another report written in 1992, the RSR researchers addressed the question "why do people smoke?" The researchers reject the claim that people smoke to satisfy an addiction, but they do not reject the claim that people smoke to obtain other pharmacological effects from nicoune. To the contrary, as Claude Teague did 20 years earlier, they assert that the reason people smo~ is precisely to obtain these pharmacological effects: We believe that a more reasonable hypothesis concerning why people smoke.., is that smokers use cigarettes primarily as a "tool" or "resource' that provides them with needed psychological benefits (increased mental alermess, anxiety r~ducrion, coping with stress).47~ In its comments, R JR asserts that nicotine is important in cigareues because "'nicotine plays an important role in the taste and flavor of cigarette smoke.''~a° The 4~ Robinson JH, Pritehard WS, Davis RA (R.L Reynolds Tobac~ Co.), Psychopimrmacotogiead effects of smokinl~ a cigarette with typical "t~f' ~nd carbon monoxi~ yields but ~ nicotine, Psychopharmacology 1992;I08:466-472, at 469. See AR (Vol. II Rcf. 129-3), ~ Id. at 471 (emphasis added). '~ Robinson J, Pritchard W (R.J. Reynolds Tobacco Co.), Tile role of nieolinc ill tobls~co use., P~chaphat'ma~olog'y 1992; 108:397-.407, tt 398 (emphasis added). $¢¢ AR (Vat 34 RcI'. 589). ~ ILJ. Reynolds Tobacco Co., Comment Oan 2, 1996), m 50. See AR (Vol. 519 R~f. 103). 218 282207433 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44875 II.C.2. history of RYR's research does not support the company's public position, however. If mcotme were trnportant because of its role in taste, FDA would expect to t-tad that RJR's research would focus on nicotine's impact on taste. The administrative record, however, contains virtually no R JR research demonstrating or investigating nicotine's influence on taste.4~ In contrast, ILIR has extensively investigated the pharmacological impacts of nicotine. In total, the administrative record before FDA contains more than 20 studies published or funded by R JR on the effects of nicotine on the body.4a2 The actual number '~ There is little scientific support for the proposition that nicotine has an important role in cigarette taste. The four studies cited by RJR are all discussed m section II.B.2.c, above. Only tree of the studies relied upon by R]R was actually conducted by PJR. This limited investigation by RJR into mcotine's role in taste was presented after FDA's investigation had commenced Pritchard, WS, Robinson. JH, The Sensory Role of Nicotine in Cigareue "Taste," Smoking Satirfaction and Desire to $nmk~, p~eated at fl3e International Symposium on Nicotine: The Effeos of Nicotine on Biological Systems lI (Monn~al: ]ul. 21-24, 1994). See AR (VoL 519 Ref. 103, vol. II). As discussed in section IIB.2.c., above, RJR researchers conceded that the study was unable to distinguish the importance of any sensory aspects of mcoune from its pharmacological effects. 4s: B,,ercke RJ, Langone J J, Anti-idiotypic antibody probes of neuronal nicotinic receptors, Biochem Biophyx Rex Commun 1989;162(3): 1085-1092. See AR (Vol. 46 Reg. 53). Brazel] MP, Mitchell SN, Gray JA. Effect of acute adminlttration of nicotine on in vivo release of nota6renalme in the hippocampus of freely moving rats: a dose-response and antagonist study, Neuropharmacologg.' 1991;30(8):823-833. See AR (Vol. 46 Ref. 58). Byrd GD, Chang KM, C_m~ne JM~ er aL, Evidence for urinary excretion of glucuronide conjugates of mcomac, cotmm¢, and trans-3'-hydroxycofinine m smoim~ Drug Metab Dispoa Biol Fate Chain 1992'20(2):192-197, See AR (Vol. 120 Ref. 1131). Caldwell WS, Green JM, Byrd GD, et aL, Characterization of the glucuronide conjugate of cotimae: a previously unidentified major metabolize of nicotine in smokers' urine, Chem Res Taxied 1992;5(2):280- 285. See AR (Vol. 46 Ref. 62). Caldwell WS, Greene JM, Dobson GP, et al., [ntragastric nit~sation of nicotine is not a significant contributor to nitrosamine exposure, Ann NYAcad $ci 1993;686:213-227. See AR (VoL 128 Re.ft. 1388). Collins AC, Bhat RV, Pauly JR, et aL, Modulation of nicotine reoeptots by ckn'onic exposure to nicotinic agonists and antagonists, in The Biology of Nicotine Dependence, eds. Book G, Ma~h J (CIBA Fotmdation Symposium 152, 1990), at 68-82. See AR (Vol. 47 Reg. 71). deBethizy JD, Borgexding MF, Dooliule D J, Chemical and biological studies oft cigarette that heats rather than burns tobacco, J Clin Pharmacol 1990;30(8):755-763. See AR (VoL 47 Reg. 78). 166-997 (828) BI~2 96 - 9 219 282207434 PRODUCED FROM B&W WEB SITE 44876 Federal Re~ister / Vol. 61, No. 168 / Wednesday. August 28. 1996 1 Rules and Regulations II.C.2. deBeth~zy .ID, Robinson IH, Davis RA, et aL, Absorpuon of nicotine from a cigarett~ that does nol burn tobacco, Pharmacology 1988;37(5):328-332. See AR (Vol. 47 Ref. 79). Gilbert DG, Robincon JH, Chamberlin CL, et al., Effects of smoking/nicotine on anxiety, heart rote, and lateraliza~on of EEl3 during a slressfad movie. Psychophysiology 1989;26(3):311-319. See AR (Vol. 14 Ref. 174-2). Hammered DI~ Bjereke R,J, l,~ngone JJ, et aL, Metabolism of aieotine by mt liver cytoehromes P-450, Assessment utilizing monoclonal antibodies to mc~tine and cofmine, Drug Metab Dispos Biol Fate Chem 1991;19(4):804-80~. Set AR(Vol. 48 Ref 110). Ky~mamn GA, Morgan ML, Clmuopadhyay B, a a/., Disposititm of nleotiae tad ~ight met~oiims in Smokms and nonsmokers, Clin Pharmacol Ther 1990,48(6):641-651. See AR (Vol. 49 Rcff. 146). Ky~remamn GA, Taylor LH, deBethizy .ID, et al., Pharmaeokineti¢~ of nicotine ~ld 12 metalxflit~s in the rat, Application of a new radiomelric high performanc~ liquid chromatography ~ssay, Drug Metab Dispo~ Biol Fate Chem 1988;16(I):125-129. See AR (Vol. 49 Ref. 145). Lippiello PM, Fen~nde~ KG, The bitting of L,-[3Hlnicotine to a single class of ifigh ~ffmity sites in t-at brain membranes, Mol Pharmacol 1986;29(5):448~54. See AR (VoL 55 Re/. 165). Lippielio PM, Mcacherif M, Princ~ R J, The role of desensitization in CNS nicotiaic reo~ptor function, m lmernationa2 Symposium on Nicotine: The Effects of lVtcotine on Biologi¢al Systems 1994, SI 1. See AR (VoI. 55 Ref 166). Lippielio PM, Sears SB, Femandes KG, Kinetics and mechaaism of L,[3Hlnleotme binding to putative high affinity receptor sites in rat brain, Mot Pharmacol 1987;31(4):392-400. See AR (VoL 55 ReL 162). Marks M J, Grady SP~ Collins AC, Dowmtgulation of nicotinic receptor function after chromc nicotine infusion, J Pharmacol Exp Ther 1993;266(3): 1268-1276. See AR (VoL 55 ReL 176). M=mhell SN, Braz¢ll MP, Joseph MH, et al., Regionally specific effects of acut~ and chx~liC nicotine on rates of catecholamme mad 5-hydroxytxypmmin¢ synthesis m rat bra~ Fur J Pharmacol 1989; 167(3):31 I-322, See AR (VoL 57 Ref. 200). Mitchell SN, Braz¢ll MP, Schugens MM, et al., Nicoune-induc~d mtecholnmme sya~esl¢ ~I~er le~iom to the dorsal or ventral noradmnergic bundle., Earop~art Journal of Pharmacology 199~,179(3):383-391. See Aa~ (VoL 57 l~f. 197). Pntchard WS, Electrocnc~phalograplaic effects of cigarette smoking, P~ychopharmacology 1991; 104:485- 490. See AR (VoL 3 Ref. Pritc, h~rd WS, Gilbert DG, Duke DW, Flexible effects of quantified cigar~ smoke delivery on EEX3 dimeasional complexity, Psychopharmacology 1993;113:95-102. See AR (VoL 3 Re£ 23-1). Pritchard WS, Robmso~ JH, Guy TD, Ealaancement of comi~uous pefformmaee ta~k reactitm time by smoking m non-deprived smokers, Pxychopharma~ology 1992;10g:437-442. See AR (VoL 6"/l:~t'. 72). Robinson JH, Pri~'d WS, Davis RA, Psychopharmacoiogical effects of smoking a cigaretm with typical "tar" and carbon monoxide yields btlt minimal nieotil~ Psychopharmacology 1992;I08:466~72. See AR (Vol. 59 Ref. ~6). 220 282207435 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61. No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44877 -1¸ II.C.2. of RIR studies may be much higher. According to an R.IR spokesperson, "[w]e've not only done research on the pharmacological effects of nicotine but we've published it in at least 250 peer-reviewed journals and symposia.''~s3 RJR's sustained and sophisticated research into nicotine pharmacology demonstrates that R JR knows that (1) its product will affect consumers in a drug-like manner and (2) consumers will use its product to obtain these drug effects. iii R JR' s Alternative Tobacco Products. Further evidence of RJR' s understanding of the central role of nicotine in smoking is provided by RJR's development of alternative tobacco products that are designed to deliver nicotine, but not other constituents of cigarette smoke, to the consumer. R.JR' s efforts to develop alternative nicotine delivery systems began more than 20 years ago. As noted above, Claude Teague recommended in 1972 that RJR develop "some simpler, 'cleaner', more efficient and direct way to provide the desired nicotine dosage than the present system involving combustion of tobacco. In recent years, R JR has developed at least two alternative tobacco products. S math KM, MitcheU SN, Joseph MH, Effects of ~artmie end subchronic nicotine on tyrosine hydroxyl~e acuv~ty m noradrenergic and dopammergic neurones in the rat brain, J Neurochem 1991 ;57(5): 1750- 1756 See AR (Vol. 60 Ref. 266). Woanacott S. Drasdo AL, Pres.vnaptic actions of nicotine in the CNS, in Effects of Nicotine on Biological Systemz. eds. Adlkofer F, Thurau K (1991), at 295-305. See AR (Vol 62 Ref. 302). Collins G, Legal atlack on tobacco intensifies, New York Times, Jim. 9, 1995. See AR (Vol. 21 Ref. 240a~. "~' Teague CE (R_J. Reynolds Tobacco Co.), Research Planning Memorandum on the Nature of the Tobacco Business and the Crucial Role of Nicotine Therein (Apr. 14, 1972), at 7 (emphasis added). See AR (Vol. 531 Ref. 125). 221 282207436 PRODUCED FROM B&W WEB SITE 44878 Federal Register / Vol. 61~No. 168 / Wednesday, August 28. lg96 / Rules and Regu|ations I1.C.2. Fkrst, in the late 1980's, RJR developed and briefly marketed Premier, a product that worked by heating nicotine and glycerol-coated aluminum beads contained m an aluminum cylinder rather than by burning tobacco. Premier r~scmbled a conventional cigarette in appearance only. Inside, it contained a carbon tip, which served as the heat source for the aluminum cylinder. 4ss R_IR documents show that R JR was acutely interested in Premier's ability to deliver nicotine to the smoker's blood and brain. For instance, PJR conducted extensive plasma studies to show that smokers using Premier would achieve approximately the same level of nicotine in their blood as smokers using conventional cigarettes.486 Other smoke components, however, wcr~ reduced by about 90%.~s~ Premier functioned like the alternative nicotine delivery sysmm r~ommended by Teaguc. Indeed, R JR used Teaguc's terminology to market Premier, advertising the product as a "'cleaner" cigarette.488 More recently, RAR has begun test-marketing a low-smoke product called Eclipse.4~ Like Premier, Eclipse relies on a carbon tip as a heat source. The tip heats a Chemical and Biological S~udies on New Cigarene Prototypes thai Heat Instead of Burn Tobacco (Winston-Salem NC: ILL Rcynolds Tobacco Co., 19881, at 1-I0. See .MP, (VoL 107 Ref. 980). "~ ld. at vii. 457-458, 479-4.83, 490-492. deBcthtzy i'D, Borgexdmg MF, Doolittlc D], ~t al. (ILL Reynolds), Chemical and Biological Sllldi¢~ of a Cigarette that Heam Rather than Burns Tobac£,o, J. Clin. PharraacoL, 199ff,30:755-763. See AR (VoL 47 Ref. "~ ld at 757. • ts Pollay RW, Carter.Whitney D, More Chronological Notes on lhe Promotion of Cigarettes (Histm'y of Advcrttsmg Archives, Aug. 1990), at 29. See AR (Vol. 215 Red. 2891 ). Cat)ell B, Smokeless cigarette makers hope to Eclipse market, Live Report (Jun. 3, 1996). See AR (Vol. 711 Ref. 11). Jones C, Reynolds not blowing smoke when it comes to keeping a lid on Eclipse., 7he Richmond l~mes Dtsparch (Jun. 10, 1996). See AR (Vol 711 Ref. 12). 222 282207437 PRODUCED FROH B&W WEB SITE Federal .Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44879 -- II.C.2. glycerin supply in the cigarette rod, which vaporizes and extracts nicotine, but is intended to produce very little of the normal constituents of tar, as it passes through the rod to the smoker's mouth. The final Eclipse smoke vapor is 85% water, glycerol, and nicotine (versus 25% in standard cigarene smoke) and only 15% tar (versus 75% in standard smoke)ri° Thus, Eclipse is intended to deliver nicotine at levels similar to conventional ultra-low-tar cigarettes, but much lower levels of tar.491 In its comments, R JR asserts that "Premier was a cigarette" because it provided the smoker with "smoking taste and pleasure.''~9~ Likewise, RJR asserts that "Eclipse is a cigarette.'"93 But the major similarity in the vapor from Premier and Eclipse and the smoke from a conventional cigarette is the nicotine delivery. The implication of RJR's work on Premier and Eclipse is that nicotine delivery is the defining characteristic of a cigarette. As ILIR informed FDA officials during the launch of Premier, "without nicotine, you don't have a cigarette.''~u Premier and Eclipse ate thus evidence that conventional • cigarettes are, in effect, simply nicotine delivery systems. iv. tLIR' ~ Legal Briefs. Before the Agency, RIR argues that nicotine is not addictive and that the Agency should not believe the widespread "aLlegations" to the Hilts P, Little smoky., but still ~ots of mcofmc, New Fork Times. Nov. 27, 1994. See AR (Vol. 34 Rcf. 568). ,9~ Fedcr BJ, Ready to lest new cigarette, maker ferns tough rules, New York Times, Apr. g, 1996. See AR (Vol. 700 Rcf. 225). '9: R.J. Reynolds Tobac.x:o Co., Comment (Jan. 2, 1996), at 34-35 (emphasis added). See AR (VoL 519 Ref. 103). ILl. Reynolds Tobacco Co., Commmt (Apr. 19, 1996). See AR (VoL 700 l~f. 22~). • u Department of Health and Human Services, Memorandum of meetlag, RJR's "Smok, ete~" Cigarette (Oct. 23, 1987), at 3. See AR(VoL 34 R~. 558-2). 223 282207438 PRODUCED FROM B&W WEB SITE 44880 FedermJ Register I Vol. 61, No. 168 1 We ,dnesday, August 28, 1996 / Rules and Regulations , I1.C.2. contrary. However, ILIR has taken exactly the opposite position in court cases. There PJR argues that the risk of becoming addicted to cigarettes is so foreseeable to consumers that consumers mus~ be held to have assumed the risk. For instance, in one case R/R argued that consumers should not be allowed to sue cigarette manufacturers on the grounds that they become addicted, because they should have foreseen this risk: There can be no serious suggestion that ordinary consumers do not expect to find nicotine in ciga~ttes, or lhat ordinary consumers have not long been well aware that it may be very difficult to stop smoking. The common Imowledge of the alleged habituating or "addicting" properties of cigarettes has resulted in almost casual references to these properties in decisions from around the country throughout this century.49~ ILIR asserts that this statement does not acknowledge addiction because IL1R is merely stating that "allegations" concerning the addictive properties of cigarettes are well known. However, R.IR' s position m the litigation and its position before the Agency are in fundamental conflict. POR cannot consistently deny its awareness of nicotine's addictive properties while at the same time claiming that its consumers should be deemed to have an awareness of these properties. RJR's recognition of "'the common knowledge of the alleged habituating or 'addicting' properties of cigarettes" is thus further evidence of 1LIR's awareness of the addictive and other pharmacological effects of cigarettes. In sum, the internal R JR memoranda in the administrative record, ILIR's published research into nicotine pharmacology, ILIR's development of alternative tobacco products that function as nicotine delivery devices, and even 1LIR's litigation briefs all point to the 495 Appellees brief m reply to appellants' opposition to petitioa for transfer, Rogers v. R.J. Reynolds et al, (Sup. CL Ind.) (No. 49A02-8904 CV 164) (1990), al 7-8 (cRatioe omiRed) (emphllsis added). See AR (Vol. 21 Rcf. 229). 224 282207439 PRODUCED FROM B&W WEB SITE Federal Resister / Vol. 61, No. 168 / Wednesday, August 28, 1995 / Rules and Regulations 44881 II.C.2. conclusion that R JR knows that its cigarettes will have pharmacological effects, that consumers will purchase its products to obtain these effects, and that, in essence, its cigarettes function as nicotine delivery devices. This is persuasive evidence that P, JR intends its product to affect the structure and function of the body. c. The Statements and Research of Brown & Williamson The admmistiative record includes a large array of documents from the Brown & Williamson Tobacco Corporation, the third large.st cigar~tm manufacturer in the United States, and its corporate parent, BAT Industries PLC, formerly British-American Tobacco Company (BATCO). These documents show that Brown & W~on and BATCO have conducted extensive research on nicotine's pharmacological effects and that for over 30 years senior researchers and officials at Brown & Williamson and BATCO have considered nicotine to be "addictive;''~ "an extremely biologically active compound capable of eliciting a range of pharmacological, biochemical and physiological responses''~97 and the reason "why people inhale smoke.''~ The documents from Brown & Williamson and BATCO in the administrative record include many unpublished reports from company research, internal memoranda, and reports from conferences of company scientists. These documents are summarized in the foLlowing chronology, which illustrates that the companies have long regarded "~ See. e.g..Y earama A (Brown & Willmmson), Implications of Battelle tiippo I and 11 and the Griffith Filler (JuL 17, 1963), at 4. See AR (VoL 21 Ref. 221). ~9~ BATCO Cm:mp R&D. Method for Nicotine and Co,irene in B~ood and Urine (May 21, 1980), Itt 2. See AR (Vol. 23 Red. 300-1). • gs Grcig CC (BATCO), Short Lived Speciea in Smoke (Jan 26, 1984), allactmd to letl-'r from Ayms CI (BATCO) to Kohnhorst EE (Brown & Williamson) (Feb. 9, 198g), at 10. See AR (Vol. 34 Re/. 584). 225 282207440 PRODUCED FROM B&W WEB SITE 448BZ Feder-t R~ister / Vol. 61, No. 168 / WecLnesd~y. August 28. 1996 I Ru|es ~md R~btion,~ II.C.2. themselves as "'in a nicotine rather than a tobacco industry.''~ Although the statements of company scienLLsts and officials seem to become somewhat more guardcd with time, the documents show a consistent recognition of nicotine's pharmacological effeas and uses, including its role in causing and sustaining addiction. i. Statemcnt~ ~nd Research in the 1960's. In the 1960's, senior officials at BATCO and Brown & Williamson and their senior researchers candidly discussed . nicotine's "addictive" and "drug" effects in internal meetings. In a 1962 conference of BATCO researchers, for instance, Charles Ellis, the science advisor to the BATCO board, acknowledged that "smoking is a habit of addiction."s°° He described the role of nicotine in cigarettes as follows: It is my conviction that nicotine is a very remarkable beneficent drug that both helps the body to resis~ external stress and also can as a result show a pronounced tramluillising effect .... Nicotine is not only a very fine drug, but the techmques of adtmnlstration by smoking has [sic] considerable psychological advantages and a built-in control against excessive absorption. It is almost impossible to take an overdose of nicotine in the way it is onJy too easy to do with sleeping pills. Charles Ellis recommended that BATCO conduct research "to investigate whether cigarette smoke produces effects on the central nervous system characteristic of tranquitising or stimulating drugs and, if so, to see ff such activity is due solely to nicotine.''s°~ The Battelle Memorial Institute in Geneva, Switzerland, conducted this 'w Johnson Pit (BATCO), Commems on Nicotine Oun. 30, 1963), at 10-11. See AR (VoL 21 R~f. 2A2). ~eo Ellis C (BATCO), The smoking and health problem, in Smoking and Health-Policy on Research, Research Cotxfcrenet~ Southampton, England (1962), at 4 (emphasis added). See hR (Vok 21 Ref. 220). sot/~L at 15-16 (emphasis added). ~2 ld. at 16. 226 282207441 PRODUCED FROM B&W WEB SITE Federal Register / Vo]. 61, No. 168 / Wednesday. August 28. 1996 / Rules and Regulations 44883 I1.C.2. research for BATCO, producing a series of reports in 1963 called "HIPPO I," "HIPPO II," "The Fate of Nicotine in the Body," and "A Tentative Hypothesis on Nicotine Addiction.'" These reports substantiated and explained nicotine's drug-like and addictive effects. "HIPPO I1," for instance, suggested that "the .key to the explanation of both phenomena of tolerance and of addiction" to nicotine could be found through "[a] quantitative investigation of the relations with time of nicotine--and of some possible brain mediators--on adreno-corticotrophic activity.''~°3 The report further stated that "the so-called 'beneficial effects' of nicotine are of two kinds: 1, Enhancing effect on the pituitary-adrenal response to stress; 2. Regulation of body weight.''5°~ Similarly, "The Fate of Nicotine in the Body" found that nicotine "'appears to be intimately connected with the phenomena of tobacco habituation (tolerance) and~or addiction.''5°s It also reported "It]here is increasing evidence that mcotine is the key factor in controlling, through the cemral nervous ~stem, a number of beneficial effects of tobacco smoke, including its actaon in the presence of stress situations.''~°~ "A Tentative Hypothesis on Nicotine Addiction" stated that "the hypothalomo- pituitary stimulation of nicotine is the beneficial mechanism which makes people smoke, ~o~ Haselba~h C, Liben O, Fina/Report on Project HIPPO II (Mar. 1963), at 4 (¢n~.sis added). See AR (Vol. 64 Ref 321). ~o~ Gcissbuhler H, Haselbaeh C, The Fate of Nicoline in the Body (May 1963), at 1 (emphasis added). See AR (Vol. 21 Ref. 243). ~ ld. at I (emph~is 227 282207442 PRODUCED FROM B&W WEB SITE 44884 Federal Register / Vol. 81, No. 168 / Wednesday, August 211. 10915 1 Rules and Regulations II.C.2. in other words, nicotine helps people to cope with stress.''~°~ The report then suggested that nicotine addiction could be explained as follows: If nicotine intake, however, is prohibit~l to chronic smokers, the corticotropm-releasmg ability of the hypothalmus is 8xeafly reduced, so that these individuals are left with an unbalane~ endocrine system. A body le~ in this unbalanced status craves for renewed drug intake in order to remote the physiological equilibrium. This unconscious desire explains the addiction of the individual to nicotine,s°~ The Battelle reports were distributed to the top officials at Brown & Williamson and other tobacco companies. Charles Ellis sent copies of the Battelle reports to the president of Brown & Williamson, William S. Cutchins. Brown & Williamson in turn sent the Project Hippo reports to RJR.s°9 In July 1963, Brown & Williamson's general counsel, Addison Yea.man, wrote an internal memorandum entitled "Implications of Battelle Hippo I and 11 and the Griffith Filter." He stated that "nicotine is add~'ctive" and that "[wJe are, then, in the business of selling nicotine, an addictive drug... ~07 Haselba~b ~, I~ben O, A Teraa~iv~ Hypozhesi~ on Nico~in~ Addiction (May 30, 1963), at 1 adcled). See AR (VoL 20 Ref. 197). Id at 2 (emphasis added). Note to Cut, bins WS (Brown & Williamson) (Jtm. 19, 1963). Set AR (VoL 14, Ref. 165-4). L~tter from Ellis C (BATCO) to Ye,~m,an AY (Brow~ & Williamson) (Jtm. 28, 1963). See AR (Vol. Ref. 165-2). l.~t~r from Yeaman AY (Brow~ & Willi~nson) to Jacob F_,I 0LJ. Reynolds Co.) (Aug. 5, 1963). See AR (Vol. 14 Ref. 165-3). ~0 Y~I~a.u AY (Brown & Willian~on), lml~icariarts of Banelle Hilalao ! and !I and ~he Griffith Filter {Jul. 17, 1963), at 4 (emphasis added). See AR (VoL 21 l~f. 221 ). 228 282207443 PRODUCED FROH B&W WEB SITE Federal Re~ister / Vol. 61, No. 168 / Wec~nesday, August 28, 1996 / Rules and Regulations 44885 II.C.2. These views were frequently reiterated. In June of 1967, Charles Ellis stated, "~ve ' .r .. ,~511 are in a nicotine rather than a tobacco inaus r~'. Several months later, at an October 1967 meeting, BATCO researchers agreed that "'[s]molang is an adah'ctive habit attributable to nicotine.''~ t2 In 1968, Sidney J. Green, who was a member of BATCO's board as well as the company's director of research, acknowledged that one "recognisable type" of smoking behavior is "addictive" smoking. He added, "it seems a good assumption that nicotine plays a predominant role for many smokers .... [A ] good part of the tobacco industry is concerned with the admimsrration of mcotine to consumers.''st3 Similarly, at another BATCO research conference in 1968, the researchers agreed that rucotine has "pre-eminent importance" and that "the pharmacology of nicotine should continue to be kept under review.''sl* A year later, at a 1969 meeting of BATCO researchers, BATCO scientist D. J. Wood stated: The prese,nce of nicotine is the reason why the tobacco plant was singled out from all other plants for consumption m this rather unusual way. Nicotine has well documented pharmacological action. It is claimed to have a dual effect, acting both as a stimulant and a tranquilliser. It is believed to be responsible for the "'satisfaction" ~ Jolmson RR (BATCO), Commems on Nicotine (Jtm_ 30, 1963), at 10 (emptmsis added). See AR (Vol. 21 Ref. 242). s~: Minutes of BATCO Group R&D Conference at Montreal, C,a~ada (Oct 24, 1967), at 2 (emphasis added). See AR (Vol. 21 RcI. 206-4). FDA notes lJtmt ~c vcmion of ~ &xztm~t ~ public by Congress contains a handwritten edit ctmagmg "ata addictive tmbit" to "a ~~ Green SJ (BATCO), BAT Group Research (Sep. 4, 1968), at 1-2 (empll~sis i~l~d). See ~R (Vol. 15 Ref. 192). ~' Minutes of BATCO Rer, ea~ Co~Ierenc¢ at Hilton Head, SC (Sop. 24-30, 1968), at 3 (~maplaasis added). See AR (VoL 31 Ref. 525-1 ). 229 282207444 PRODUCED FROM B&W WEB SITE 44866 Federal Re~ister / Vol. 6L No. 168 / Wednesday. August 28, 1996 / Rules and Regulat!ons II.C.2. of smokang, using tkus term in the physiological rather than the psychological sense.S~ And at another 1969 conference of BATCO sci~entists, the following conclusion was reached: "'It]he Conference agreed that alt the evidence continues to demonstrate the importance of mcotine to the smoker .... ,,s~6 Numerous other similar statements were made by Brown & Williamson and BATCO researchers and officials in the 1960's. They are described in the Jurisdictional Analysis. See 60 FR 41584-41586. Collectively, these statements show that even as early as the 1960's, Brown & Williamson and BATCO officials knew the addictive and other pharmacological effects of nicotine, knew that consumers smoked cigarettes for these effects, and viewed themselves as in the drug delivery business, ii. Statements and Research in the 1970's and 1980"s. Throughout the 1970's and 1980's, Brown & Williamson and BATCO officials continued to emphasize the importance of nicotine in cigarettes. At a 1970 conference of BATCO researchers, for instance, the researchers postulated that "'[n]icotine is important, and there is probably a nunimum level necessar~ for consumer acceptance in any given market.''s17 In 1972, S.J. Green, the BATCO bom'd member and research director, stated that "'It]he tobacco smoking habit is reinforced or dependent upon the psycho- Wood DJ (BATCO), Aspects o/the R&DE Fumrtion, Not~ for a udk giv~ by Wood DJ at Chelwood, Sep. 1969 (Jul. 20, 1970), at 7 (emptumis added). See AR (Vol. 22 l~f. 287). ~J6 Minutes of BATCO Research Conference at Kronberg Oun. 2-6, 1969), at 7 (emphasis adt~l). See AR (Vol. 14 Ref. 172-4). Summary and conclusions of BAT Group Research Coafe~nce at SI. Ad~le~ Quebec (Nov. 9-13, 1970), at 1 (emphasis added). See AR (Vol. 23 R~f. 294). 230 282207445 PRODUCED FROM B&W WEB SITE Feder~ Register / Vol. 61. No. 168 / Wednesday. August 28. 1996 / Rules and Regulations 11.C.2. pharmacological effects mairdv of nicotine.''SLs Similarly, a 1972 BATCO research report observed: It has been suggested that a considerable proportion of smokers depend on the pharmacological action of mcotine for their motivation to continue smoking. If this view is correct, the present scale of the tobacco industry is largely dependent on the intensity and nature of the pharmacological action of nicotine,s19 These statements demonstrate an awareness that nicotine has "reinforcing" effects, one of the hallmarks of an addictive substance, and that the tobacco industry is built upon these effects. At a 1974 BATCO conference, company scientists reported that BATCO research had found that consumers appear to smoke to fulfill their "nicotine requirements," stating that "the Kippa study suggests that whatever the characteristics of cigarettes as determined by smoking mackines, the smoker adjusts his pattern to deliver his own nicotine requirements (about 0.8 mg per cigarette).''s~° At a 1976 BATCO conference on smoking behavior, the researchers again stated that nicotine has reinforcing eff~zts on smokers, observing that nicotine is "known to be pharmacologically active in the brain" and is "'considered to be the reinforcing factor in the smoking habit for at least 80% of smokers.''~2~ ~ts Green SJ (BATCO), The Association of Smola'ng and Disease (Jttl. 26, 1972), at I (emplmsis ~dded). See AR (VoL 15 Rel. 193). ~9 Kilburn I~), Underwood JG (BATCO), Preparation and Properties of Nicotine Analogues (Nov. 9, 1972), at 2 (cimtiom omitted) (emplmsis added). ,See AR (Vol. 31 Rcf. 524-I). no Notes on BATCO Group R&D Conftar.n~ at Duck Key, FL (Jan. 12-18, 1974), at 2 (em#mis added). See AR (Vot 25 Pet'. 32"/). sz~ Minutes of BATCO Gt~p R&D Cotlfetellce ol~ Smoking Beimviom" at $omlmml~ England (OCL 11-12, 1976), at BW-W*2-02145, BW-W2-02152-BW-W2.-(}2153 .(~it ItCki~l). See ~ (Vol. 14 Red. 180). 231 44887 282207446 PRODUCED FROM B&W WEB SITE 44888 FederaJ Reg/Mer / Vol. 61, No. 168 1 Wed.nesdey, Au{~st ~8, "I'39~, / Ru|es ~nd Reg~|ations I1.C.2. At a 1977 conference, nicotine was once more the "focal point." A Brown & Williamson summary of the conference stated that "[i}n many cases, psychological and physiological changes observed in subjects.., were shown to be due to nicotine" and "[m]ost researchers conclude that the nicotine effect is biphasic and dosage dependent: small doses stimulate and large doses depress.''Sz: A year later, BATCO board member and chief researcher S.J. Green explicitly acknowledged that nicotine is addictive. Specifically, he wrote "'[t]he strong addiction to cigarette[s] removes ~reedom of choice from many inzh'viduals.''5z3 A 1980 BATCO research report stated that "[n]iconne is an extremely biologically active compound capable of eliciting a range of pharmacological, biochemical and physiological responses in vivo."5~ A 1981 report on the pharmacology of nicotine by the Tobacco Advisory Council, which represents U.K. tobacco manufacturers including BATCO, stated that "mcotine is regarded as the most pharmacologically-active compound in tobacco smoke" and concluded that "[ i ]n a nutshell, our approach has been to regard nicotine a,~ a 'drug.'"~z~ 5:: Trip report of BATCO international Smoking Behavior Coaterence at Chelwoed Vachery, England (Jan. 6, 1978), at 1-2 (empl~asis added). See AR (VoL 178 Ref. 2075). Notes of Green SJ (1978) (emphasis added). See AR (Vol. 528 ReX. 97, appendix 18). 5~ BATCO Group R&D, Method.for Nicotine and Co~inine in Blood and Urine (May 21, 1980), at 2 (emphasis added). See AR (Vol. 23, Rex. 300-1). s~ Cohen AJ, Roe FJC (Tobacco Advisory Coullcil), Monograph on the Pharmacology and Toaicology of Nicotine (19gl), at l, 17 (emphasis edck~l). See AR (Vol. 14Ref 184). 232 282207447 PRODUCED FROM B&W WEB SITE Federal Regi~er / Vol. 61, No, 168 / Wec~nesday, August 28, 1996 / Rules and Regulations 44889 I1.C.2. In 1982. a market research report for Imperial Tobacco Ltd., BATCO's Canadian subsidiary, referred to attitudes of adolescents "[o]nce addiction does take place," and states that "addicted they do indeed become." sz~ The report goes on: Recidivism has several causes... [including] the belief that after a few weeks off cigarettes, one could begin again to smoke 'just a few.'... This 'just a few' business is actually a surrender to addiction while trying to... pretend to oneself and to others that addiction is no longer present, which is nonsense,s27 At a 1983 BATCO research conference, the minutes of the proceedings state that "It]he basic assumption is that mcotine . . . is almost certainly the key smoke component for satisfaction.. In a 198zl letter, C. I. Ayres of BATCO wrote to E. E. Kohnhorst, the executive vice president and chief operating officer of Brown & Williamson, enclosing a report stating that nicotine is "'why people inhale smoke": It is well Io,town that mcotine can be removed from smoke by the lung and transmitted to the brain within seconds of smoke inhalation. Since it is the major or sole phanmacologically active agent in smoke, it must be presumed that this is its preferred method of absorption and thus why people inhale smoke,s~9 In 1984, BATCO also held two research conferences at which nicotine was extensively discussed. At the fast conference, BATCO researchers held sessions on s26 Kwechansk3¢ Marketing Research (r~port pr~par~l for ~tl Tobacx, o Ltd.), Project Plus/Minus (May 7, 1982), at i, 26 (emphasis added). See AR (Vol. 108 R~f. 1571). s~7 id. at 36-37 (emphasis added). ~za Minutes of BATCO R~se, arch Conference at Rio de Janeiro (Aug. 22-26, 1983), at 10 (emphasis added). See AR (Vol. 179 Ref. 2087). 529 Greig CC~ Short Lived Species in Smoke (Jm3. 26, 1984), a.llached to letlet from Ayres CI (BATCO) m Koimhorst EE (Brown & Williamson) (Feb. 9, 1984), at 10 (emphasis added). See AR (VoL 34 Ref. 584). 233 282207448 PRODUCED FROM B&W WEB SITE 4489O Federal Rt,~i~er / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulstions II.C.2. "Nicotine Dose Requirement-Background," "Nicotine Dose Estimation," "Effects of Nicotine--Interaction with the Brain (Pharmacology)," and "Product Modification for Maximal Nicotine Effects.''~3° The researchers reported that "[i]ntuitivel.v it is felt that 'saasfaction ' must be related to nicotine. Many people believe it [is] a "whole body response' and involves the action of nicotine in the brain."'~ They also acknowledged "'the central role of nicotine in the smoking process and our business generally.''s~2 At the second conference, BATCO researchers reported that "'in its simplest sense puffing behaviour is the means of providing nicotine dose in a metered fashion.''~ According to one BATCO researcher speaking at the conference: Smoking is... a personal tool used by the smoker to refine his behaviour and reactions to the world at large. It is apparent that nicotine largely underpins these contributions through its role as a generator of central physiological arousal effects which express themselves as changes in human performance and psychological well-being."~ Other similar statements are summarized in the Jurisdictional Analysis. See 60 FR 4158~41666. Like the statements quoted above, they show that scientists at Brown & ~ Ayres CI (BATCO), Notes fxom the GR&DC [Group Research and Developmem Ccnlx¢] Nicoune Cou.f~'enc¢ a.t $outbamptom England (Jul. 9-12, 1994) (slide), at BW-W2-02639. See AR (VoL 14 Ref. 172). s3~ Minutes of BATCO Nicotine Conference at Southampton, England (Jun, 6-8, 1984), at BW-W2*01977 (emphasis added). See AR (VoL 22 Ref. 287-6). 53: Ayres CI (BATCO), Notes from the GR&DC [Group Research and Development Cenu~] Nioofiac Conference at Southampu)n, England (Jul. 9-12, 1984), at 62 (cmplutsis added). See AR (VoL 14 Ref. 172-1). ~3 Proccextmgs of BATCO Oroup R&.D Smoking Behaviour-~g ConfeJ~tce., Session I (|u.l. 9-1Z 1984) (slide), at BW-W2-03242 (emphasis added). See AR (VoL 21 Ref. 238). ~u Ferns RP, The rde of smoking behaviour in product development: some observatio~ on the psychological a.~pect~ of smoldng behaviour, in Ptoceediags of BATCO Grolip R&D Smoking Behaviotlt- Marketing Conference, Session III (Jill. 9-12, 1984), at 79 (emphasis atlded). See AR (VoL 192 Ref. 2172). 234 282207449 PRODUCED FROM B&W WEB SITE Federal Register / Vol. 61, No, 168 / Wednesdsy, August 28, 1996 / Rules and Regulations 44891 II.C.2. William.son and BATCO devoted extensive attention to understanding the pharmacological effects and uses of nicotine, consistently regarded nicotine as being the primary reason consumers smoked, and viewed cigarettes as nicotine delivery devices. iii. $~atements and Research in the 1990%. New documents received by FDA during the public comment period demonstrate that researchers and officials of Brown & Williamson and BATCO continue to hold similar views about nicotine in cigaretw, s in the 1990' s. The new documents are a series of memoranda relating to the potential purchase in 1992 by BATCO of a manufacturer of nicotine patches, Stowic Resources Ltd.~35 Brown & Williarnson's research department evaluated the potential purchase in a memorandum emitled "Transderrnal Nicotine Patches." Brown & Williamson researchers observed that "[t]here is currently a void in the market for a product that provides tobacco satisfaction in a form that is acceptable and available to many segments of the market" and recommended that "[w]e should be looking for opportunities to fill the void."5~ However, Brown & Williamson researchers expressed doubts that a nicotine patch could provide consumers with the same pharmacological effects obtained by smoking: The pattern of the blood nicotine concentrations attained by smoking vs the patch, however, are different. With smoking, blood nicotine absorption is very rapid. Blood nicotine concentrations go through a series of peaks and troughs with successive cigarette smoking throughout the day .... With the patch, nicotine absorption is relatively slow and continuous and peak blood levels are not as high as with cigarette smoking. A major advantage of cigarette smoking over the nicotine patch system is the ability for 535 Salu~r R, Transderrnal Nicotine (Apr. 3, 1992); Research and Developmeak Response Io BAT Industries Note on Transderrnal Nicotine (28.02.92) (M~r. 27, 1992); Kauseh, Research glad Development/Quality, Transd~rmal Nicoana ; Research aluJ Devdol~r~'n~ty, Transdcrmal Nkrotine Patches; McGraw M (Brown & William.son), Nicotine Dcl~ry Systems (Apr. 24, 1992). 5e¢ ~ (Yol. 531 Ref. 124). ~ Transd~rmal Nicotine Patches, at 3. See AR (VoL 531 Ref. 124). 235 282207450 PRODUCED FROM B&W WEB SITE 44892 Federal Register / Vo]. 61, No. 168 1 Wednesday, August 28, 1996 / Rules and ReguLations I1.C.2. the smoker to have veo' flexible control over titrating his desired dose of rdcotine.~' Similar views were expressed by other BAT Industries subsidiaries. BAT Industries' German subsidiary, for instance, stated that "'It]he rapid, peaking imake of nicotine which the smoker clearly warns cannot be achieved with nicotine application via.. i plaster.''~ The German subsidiary further acknowledged that nicotine can produce dependency and addiction. According to theGerman report, which was distribumd by BAT Industries to the then president of Brown & Williamson, R. J. Pritchard, "[tlhe disadvantage of rapid nicotine intake similar to that achieved with a cigarette is seen in the danger of people possibly becoming dependent on it.''~9 The German subsidiary observed that even with nicotine gum there is a "'danger of addiction," stating that "the smoker can organize intake to suit himsell" and achieve "[a]ctive control over mtak~ and the condition it produces.''~ Brown & Williamson's legal department argued against the purchase of Stowic on legal grounds, warning that it would suggest that Brown & Williamson is in "the nicotine delivery business" and cause Brown & Williamson to "'run a serious risk offacing FDA jurisdiction." The lawyers also argued that the purchase of Stowic would have "dtsastrous" implications for product liability litigation bezause "'It]he marketing of any ~37 ld. at 2 ~empba.sLs addeti). ~3, Research and Development/Quality, Re: Transdermal Nicotine. at 3 (emphasis added). See AR (Vol. 531 Ref. 124). ~ ld. at 3 (emphasis added). ~ld at 2. 236 282207451 PRODUCED FROH B&W WEB SITE Federal Re~ister / Vo]. 61, No. 168 / Wednesday, August 28, 1995 / Rules and Regulations 44893 II.C.2. nicotine deliver>' system undercuts our position on addic