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 t