09-5006-cr

United States v. Caronia U N I T E D S TAT E S C O URT O F A P P E AL S F O R T H E S E C ON D C I RC U I T Augus t Ter m 201 0 (Argu ed: December 2 , 201 0 Deci ded: Dece mber 3, 20 12) Docke t No. 09-5 006-c r



### U N I T E D 

### S T A T E S O F 

### AM E R I C A 

### , Appel lee , v. 

### A L F R E D 

### C A R O N I A 

### , Defen dant- Appel lant . *

Befor e: RA G G I , L I V I N G S T O N , and C H I N , Circu it Ju dges .

Appea l fro m a j udgme nt of the Unite d Sta tes Distr ict C ourt for t he Ea stern Dist rict of Ne w Yor k (Er ic N. Vital iano, J. ) con victi ng de fenda nt-ap pella nt Al fred Caron ia of co nspir acy t o int roduc e a m isbra nded drug into inter state

The Clerk of the Court is directed to amend the * official caption in accordance with the above.comme rce i n vio latio n of the F edera l Dru g andCosm etic Act.

Caron ia co ntend s tha t he was c onvic ted f or hi s spe ech - - for promo ting the o ff-la bel u se of an a pprov ed pr escri ption drug -- in viol ation of t he Fi rst Amendm ent.

VACAT ED an d REMANDED . Judge L I V I N G S T O Ndiss ents in a separ ate o pinio n.

D O U G L A S L E T T E Rand MA R T I N C O F F E Y (Jo A nn M. Navic kas, Assis tant Unite d Sta tes Attor ney, Scott R. M cInto sh, Attor ney, Appel late Divis ion, Unite d State s Dep artme nt of Just ice, Anne K. Wa lsh, Assoc iate Chief Coun sel, Offic e of Gener al Co unsel , Foo d and Drug Divis ion, on th e bri ef ), for Loret ta E. Lync h, Un ited State s Attor ney f or th e Eas tern Distr ict o f New Y ork, Brook lyn, New Y ork, for Appel lee . J E N N I F E R L. M C C AN N (Thom as F. Liot ti, on th e brief ), La w Off ices of Th omas F. Liott i, Ga rden City, New York, for Defen dant- Appel lant . E R I C E. MU R P H Y , Jon es Da y (Mi chael A. Carvi n, Jo nes D ay, D aniel J. P opeo, Richa rd A. Samp , Was hingt on Le gal Found ation , on th e bri ef ), for Amicu s Cur iae Washin gton Legal Found ation .

-2-Joan McPhe e, Ro pes & GrayLLP (Doug las Hallw ard-D rieme ier, Alan Benne tt, Ropes & Gr ay LL P, an d Pau l Kal b, Colee n Kla smeie r, Si dley Austi n LLP , on th e bri ef ), for Amicu s Cur iae The Medic al In forma tion Worki ng Gr oup.

C H I N , Circu it Ju dge :

Defen dant- appel lant Alfre d Car onia appea ls fr om a judgm ent o f con victi on en teredin t he Un ited State s Dis trict Court for the E aster n Dis trict of N ew Yo rk (E ric N . Vital iano, J. ) on November 3 0, 20 09, f ollow ing a jurytria l at wh ich C aroni a was foun d gui lty o f con spira cy to intr oduce a mis brand ed dr ug in to in terst ate c ommer ce, a misd emean or viola tion of 21 U.S. C. §§ 331( a) an d 333 (a)(1 ). Speci fical ly, C aroni a, a pharm aceut ical sales repre senta tive, prom oted the d rug X yrem for " off-l abel use," that is, f or a purpo se no t app rovedby t he U. S. Fo od an d Drug Admin istra tion (the "FDA" ). C aroni a arg ues t hat h e was convi cted for h is sp eech -- fo r pro motin g an FDA-a pprov ed drug for o ff-la bel u se -- in v iolat ion o f his righ t of free speec h und er th e Fir st Am endme nt. We ag ree. Acco rding ly,

-3-we va cate the j udgme nt of conv ictio n andrema nd th e cas e to

the d istri ct co urt. STATE MENT OF TH

E CAS E 1. The Regula tory Scheme

Under the Feder al Fo od, D rug a nd Co smeti c Act (the "FDCA "), b efore drug s are dist ribut ed in to in terst ate

comme rce, they must be ap prove d by the F DA fo r spe cific

uses. 21 U.S.C . § 3 55(a) . To obta in FDA app roval , dru g manuf actur ers a re re quire d to demon strat e, th roughclin ical trial s, th e saf ety a nd ef ficac y of a newdrugfor each inten ded u se or indi catio n. 2 1 U.S .C. § 355( d); see Weinb erger

v. H ynson , 412 U.S. 609, 612- 14 (1 973). 1 Once FDA-a pprov ed, p rescr iptio n dru gs ca n be presc ribedby d octor s for bothFDA- appro ved a nd -u nappr oved uses; the FDA g enera lly d oes n ot re gulat e howphys ician s use

The FDCA provides: "No person shall introduce or 1 deliver for introduction into interstate commerce any new drug, unless an approval of an application filed pursuant to subsection (b) or (j) of this section is effective with respect to such drug." 21 U.S.C. § 355(a). A "new drug" is defined as: "Any drug . . . not generally recognized . . . as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof." 21 U.S.C. § 321(p). -4-appro ved d rugs. See Buckm an Co . v. Plain tiffs ' Legal Comm. ,

531 U .S. 3 41, 3 50 (2 001); Weave r v. Reage n , 886 F.2d194, 198 ( 8th C ir. 1 989); John E. O sborn , Can I Tell You The Truth ? A C ompar ativePerspecti ve on Regu latin g Off -Labe l Scien tificand Medic al In forma tion , 10 Yale J. He alth Pol'y L. & Ethic s 299 , 303 (201 0) (" Physi cians may presc ribe FDAappro ved d rugs . . . for any t herap eutic use that is appro priat e in their medi cal j udgme nt.") ; Ran dall S. Staff ord, Regul ating Off- Label Drug

Use: Reth inkin g theRole of th e FDA , 358 N. E ngl. J. Me d. 14 27, 1 427 ( 2008) (disc ussin g 200 3 stu dy of 160 commo n dru gs wh ere o ff-la bel

use a ccoun ted f or ap proxi matel y 21 perce nt of presc ripti ons).

Indee d, co urts and t he FDA hav e rec ogniz ed th e propr iety and p otent ial p ublic valu e of unapp rovedor o fflabel druguse. See B uckma n , 531 U.S. at 3 50 (O ff-la bel u se is an "acc eptedand neces sary corol lary of th e FDA 's mi ssion to re gulat e in this area witho ut di rectl y int erfer ing w ith the p racti ce of medi cine. "); Weave r , 886 F.2dat 1 98-99 ("FDA [-]ap prove d ind icati ons w ere n ot in tende d to limit or

-5-inter fere with the p racti ce of medi cine nor t o pre clude

physi cians fromusin g the ir be st ju dgmen t in the i ntere st of the p atien t." ( inter nal q uotat ion m arks omitt ed)); U.S. Food and D rug A dmini strat ion, DraftGuid ance, Good Repr int Pract ices for t he Di strib ution of Medica l Jou rnal Artic les and Medica l or Scien tificRefe rencePubl icati ons o n Unapp roved

New Uses of Approve d Dru gs an d App roved or Clear ed Me dical Devi ces3 (2 009) ("[O] ff-la bel u ses o r treat ment regim ens m ay be impo rtant and may e ven c onsti tute a med icall y[-]r ecogn ized stand ard o f car e."). The FDA 2 itsel f has obse rved:

Once a dru g has been appr oved for marke ting, a ph ysici an ma y pre scrib e it for u ses o r in treat ment regim ens o r patie nt po pulat ions that are n ot in clude d in ap prove d lab eling . Su ch "u nappr oved" or, m ore p recis ely, "unla beled " use s may be ap propr iate and r ation al in cert ain circu mstan ces, and m ay, i n fac t, re flect appro aches to d rug t herap y tha t hav e bee n exten sivel y rep ortedin m edica l liter ature .

See alsoJames M. Beck & Elizabeth D. Azari, FDA, Off- 2 Label Use, and Informed Consent: Debunking Myths and Misconceptions , 53 Food & Drug L.J. 71, 76-77 (1998); cf. 21 U.S.C. § 396 (protecting physician authority to prescribe or administer any legally-marketed device to patient). -6-U.S. Food and D rug A dmini strat ion, FDA D rug B ullet in , 12 FDA

Drug Bull. 1, 5 (198 2).

The F DCA p rohib its " misbr andin g," o r "[t ]he intro ducti on or deli very for i ntrod uctio n int o int ersta te

comme rce o f any. . . dru g . . . th at is . . . mis brand ed." 21 U. S.C. § 331 (a). A dr ug is misb rande d if, inter alia , its l abeli ng fa ils t o bea r "ad equat e dir ectio ns fo r use ," 21 U.S.C . § 3 52(f) , whi ch FDA reg ulati ons d efine as " direc tions under whic h the lay[ perso n] ca n use a dr ug sa fely and f or the p urpos es fo r whi ch it is i ntend ed," 21 C. F.R. § 201 .5. 4 FDA r egula tions defi ne in tende d use by r efere nce t o "th e objec tive inten t of the p erson s leg ally respo nsibl e for the label ing o f dru gs," whichmay be de monst ratedby, among other evid ence, "ora l or writt en st ateme nts b y suc h per sons or th eir r epres entat ives" and "the circu mstan ces t hat t he artic le is , wit h the know ledge of s uch p erson s or their

A drug is also misbranded if, inter alia : its label is 4 false or misleading; the label fails to display required information prominently; its container is misleading; or it is dangerous to health when used in the dosage, manner, frequency, or duration prescribed, recommended, or suggested on the label. See 21 U.S.C. §§ 352(a)-(n). -7-repre senta tives , off ered and u sed f or a purpo se fo r whi ch it

is ne ither labe led n or adverti sed." 21 C.F.R . § 2 01.12 8.

The c onseq uence s for misb randi ng ar e cri minal . 21 U.S.C . § 3 33(a) (2) ( "[I]f any perso n commits such a viola tion . . . suchpers ons s hall be impriso ned f or no t

more than three year s or finednot more than $10,0 00, o r both. "). Pharm aceut ical manuf actur ers a nd th eir repre senta tives can face misde meano r cha rges for m isbra nding or fe lony charg es fo r fra udule nt mi sbran ding. 21 U.S.C . § 333(a ); see Osbor n, Can ITell You The Truth? , supra , at 328-2 9 (co llect ing c ases) . Th e gov ernme nt ha s rep eated ly prose cuted-- a nd ob taine d con victi ons a gains t -- pharm aceut ical compa nies and t heir repre senta tives for misbr andin g bas ed on thei r off -labe l pro motio n. See, e.g. , Judgm ent, Unite d Sta tes v . Gla xoSmi thKli ne, L LC , 12- cr-10 206 (RWZ) , ECFDoc. No. 13 (D . Mas s. Ju ly 10 , 201 2) (Info rmati on, Glaxo Smith Kline , No. 12-c r-102 06 (RWZ), ECF Doc. No. 1 (D. Mass. July2, 2 012)) ; Jud gment , Unite d Sta tes v. Me rck Sharp & Doh me Co rp. , No. 11-c r-103 84 (P BS), ECF Doc. No. 3 0 (D. Mass . May18, 2012) (Inf ormat ion, Merck , No.

-8-11-cr -1038 4 (PB S), E CF Do c. No . 1 ( D. Ma ss. N ov. 2 2, 20 11));

Agree d Ord er of Forf eitur e, Unite d Sta tes v . Abb ott L abs. , No. 1 2-cr- 26 (S GW), ECF D oc. N o. 7 (W.D. Va. May 7 , 201 2) (as a resu lt of the guilt y ple a to the I nform ation (Info rmati on, Abbot t , No. 12-c r-26 (SGW) , ECFDoc. No. 5-1 (W.D. Va. May 7 , 201 2))); Judgment, Unite d Sta tes v . Aller gan, Inc. , No. 10-c r-375 (ODE ), EC F Doc . No. 20 ( N.D. Ga. O ct. 7 , 201 0) (I nform ation , Aller gan , No. 10-c r-375 (ODE) , ECFDoc. No. 1 (N. D. Ga . Sep t. 1, 2010 )); see Sente ncingTran scrip t, Merck , No. 11-c r-103 84 (P BS), ECF Doc. No. 2 7 (D. Mass . Apr il 30 , 201 2) (" I wan t to empha size that off-l abel marke ting has b een . . . a bigprob lem

. . . . I hope in a way t hat t he . . . f act t hat a ll th ese

cases are beingpres sed b y the fede ral a nd st ate gover nment s, th e 44 state Atto rney Gener als, will be a signa l tha t it isn't acce ptabl e con duct. "); see a lso Press Rele ase, U.S. Depar tment of J ustic e, Glaxo Smith Kline to Pl ead G uilty

and Pay $ 3 Bil lion to Re solveFrau d Allegation s and

Fail ure t o Rep ort S afety Data , Lar gest Healt h Car e Fra ud Se ttlem ent i n U.S . His tory (July2, 2 012); Osbor n, Can ITell You The Truth? , supra , at 328-2 9. -9-The F DCA a nd it s acc ompan ying regul ation s do not

expre ssly prohi bit t he "p romot ion" or "m arket ing" of dr ugs for o ff-la bel u se. The r egula tions do r ecogn ize t hat promo tiona l sta temen ts bya ph armac eutic al co mpanyor i ts repre senta tives can serve as p roof of a drug' s int endeduse. See 21 C. F.R. § 201 .5 . Off -labe l pro motio nal s tatem ents couldthus pres umabl y con stitu te ev idenc e of an in tende d use of a drug that the F DA ha s not appr oved. See i d . Th e FDA , howev er, h as co nclud ed th at "[ a]n a pprov ed dr ug th at is marke ted f or an unap prove d use (whe ther in la belin g or not) is mi sbran ded b ecaus e the labe ling of su ch dr ug do es no t inclu de 'a dequa te di recti ons f or us e.'" SeeFDA, Draf t Guida nce, supra , at 2- 3 (qu oting21 U .S.C. § 35 2(f)) ; accor d Unite d Sta tes v . Car onia , 576 F. S upp. 2d 38 5, 39 2 n.5 (E.D. N.Y. 2008) ; see a lsoGov' t Br. 48 n .18 ( conte ndingno set o f dir ectio ns ca n con stitu te ad equat e lab elingfor drug' s off -labe l use ). T hus, the g overn ment has t reate d promo tiona l spe ech a s mor e tha n mer ely e viden ce of a dr ug's inten ded u se -- it h as co nstru ed th e FDC A to prohi bit promo tiona l spe ech a s mis brand ing i tself .

-10-2. The F acts 5

a. Orphan Medical and X yrem Orpha n Med ical, Inc. ("Or phan" ), no w kno wn as Jazz Pharm aceut ical, was a Del aware -inco rpora ted p harma ceuti cal compa ny th at pr imari ly de velop ed dr ugs t o tre at pa in, s leep disor ders, and centr al ne rvous syst em di sorde rs. Orpha n manuf actur ed th e dru g Xyr em, a powe rful centr al ne rvous syste m dep ressa nt. In 20 05, a fter Jazz Pharm aceut icals acqui red O rphan , Jaz z con tinue d to manuf actur e andsell Xyre m, gr ossin g $20 mill ion i n combined Xyremsale s in 2005.

Xyremcan cause seri ous s ide e ffect s, in cludi ng diffi cultybrea thingwhil e asl eep, confu sion, abno rmal think ing, depre ssion , nau sea, vomit ing, dizzi ness, head ache, bedwe tting , andslee pwalk ing. If a bused , Xyr em ca n cau se addit ional medi cal p roble ms, i nclud ing s eizur es, d epend ence,

sever e wit hdraw al, c oma, and d eath.

The facts are drawn primarily from the trial record. 5 On appeal, this Court must view the evidence in the light most favorable to the government, drawing all reasonable inferences in its favor. See United States v. Amico , 486 F.3d 764, 780 (2d Cir. 2007). -11-Xyrem 's ac tive ingre dient is g amma- hydro xybut ryate

("GHB "). GHB h as be en fe deral ly cl assif ied a s the "dat e rape drug" for its u se in the commi ssion of s exual assa ults. b. The F

DA's Regul ationof X yrem Despi te th e ris ks as socia ted w ith X yrem and G HB, the F DA ap prove d Xyr em fo r two medi cal i ndica tions . In Ju ly 2002, the FDA a pprov ed Xy rem t o tre at na rcole psy p atien ts who e xperi ence catap lexy, a co nditi on as socia ted w ith w eak or pa ralyz ed mu scles . In Nove mber 2005, the FDA a pprov ed Xyremto t reat narco lepsypati ents with exces sive dayti me sleep iness ("ED S"), a neu rolog ical disor der c ausedby t he brain 's in abili ty to regu late sleep -wake cycl es.

To pr otect agai nst i ts se rious safe ty co ncern s, in 2002, the FDA r equir ed a "blac k box " war ning to ac compa ny Xyrem . The b lack box w arnin g is the m ost s eriou s war ning place d on presc ripti on me dicat ion l abels . Xyrem 's bl ack b ox label ing s tated , amo ng ot her t hings , tha t the drug 's sa fety and e ffica cy we re no t est ablis hed i n pat ients unde r 16 years of ag e, an d the drughad "verylimi ted" exper ience amon g elder ly pa tient s.

-12-To id entif y pat ients suff eringside effe cts f rom

the d rug, the F DA al so re gulat ed Xy rem d istri butio n, allow ing o nly o ne ce ntral ized Misso uri p harma cy to distr ibute Xyre m nat ional ly.

c. Caron ia's Emplo ymentwithOrph an In Ma rch 2 005, Orpha n hir ed Ca ronia as a Spec ialty Sales Cons ultan t to promo te Xy rem. Caro nia p rimar ily w orked in Qu eens, Nass au, a nd Su ffolkcoun ties. Caro nia's sala ry was b ased on hi s ind ividu al sa les.

In Ju ly 20 05, C aroni a sta rted Orpha n's " speak er progr ams" for X yrem. Spe aker progr ams e nlist phys ician s, for p ay, t o spe ak to othe r phy sicia ns ab out F DA-ap prove d drug use. Orph an's speak er pr ogram s for Xyre m pre sente d the benef its o f the drugamon g pat ients withcata plexyand

narco lepsy . Or phan hiredDr. Peter Glea son t o pro mote Xyrem throu gh it s spe aker progr ams.

Under Orph an's proce dures , if Caron ia, a s a s ales

consu ltant for Xyrem , was aske d abo ut th e off -labe l use of Xyrem , he was n ot pe rmitt ed to answ er; i nstea d, wh en su ch quest ions were posed , Orp han s ales consu ltant s wou ld fi ll out " medic al in forma tion reque st fo rms" and s end t hem t o -13-Orpha n, an d Orp han w ould send infor matio n to the i nquir ing

physi cian. In contr ast, physi cians empl oyed by Or phan as

6 promo tiona l spe akers for Xyremwere perm ittedto a nswer offlabel use quest ions; thei r res ponse s wer e oft en in forme d by their own exper ience s wit h Xyr em. d. Caron ia's Parti cipat ion i n theCons pirac y In th e spr ing o f 200 5, th e fed eral gover nment launc hed a n inv estig ation of O rphan and Gleas on. The inves tigat ion f ocuse d on the o ff-la bel p romot ion o f Xyr em. Caron ia an d Gle ason were audio -reco rded on tw o occ asion s as they promo ted X yrem for u nappr oved uses, incl uding unapp rovedindi catio ns an d una pprov ed su bpopu latio ns. The first conv ersat ion w as re corde d on Octob er 26 , 200 5 bet ween Caron ia an d Dr. Step hen C harno , a p hysic ian w ho, a s a gover nment coop erato r, po sed a s a p rospe ctive Xyre m custo mer. The secon d con versa tion was r ecord ed on Nove mber 2, 20 05; i t tap ed a meeti ng ar range d by Caron ia to intr oduce Charn o to Gleas on.

In December of 2011, the FDA released recommendations 6 for the pharmaceutical industry with respect to how manufacturers and their representatives can respond to "unsolicited requests for off-label information." See generally U.S. Food and Drug Administration, Guidance for Industry, Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices(2011). -14-On Oc tober 26, 2005, Caro nia p lainl y pro motedthe

use o f Xyr em in unap prove d ind icati ons w ith C harno :

[Caro nia]: Andrigh t nowthe indic ation is fo r nar colep sy wi th ca taple xy . . . exces sive dayti me . . . a nd fr agmen ted sleep , but beca use o f the prop ertie s tha t

. . . it h as it 's go ing t o ins omnia , Fibro myalg ia[,] peri odic leg m oveme nt, restl ess l eg, a hh al so lo okingat a hh Parki nson' s and. . . oth er sl eep disor ders are u nderw ay su ch as MS. [Char no]: Okay , so then so th en it coul d be us ed fo r mus cle d isord ers a nd ch ronic pain and . . . [Caro nia]: Rig ht. [Char no]: . . . anddayt ime f atigu e and exces sive sleep iness and stuff like that ? [Caro nia]: Abs olute ly. Absol utely . Ah h with the F ibrom yalgi a. (Octo ber 2 6, 20 05 Re cordi ng Tr . (I) at 4 -5). Caro nia furth er di recte d Cha rno t o lis t dif feren t "di agnos is co des" when presc ribin g Xyr em, f or in suran ce pu rpose s, in cludi ng Fibro myalg ia, c hroni c fat igue, or c hroni c pai n.

On se parat e occ asion s, Ca ronia and Gleas on ea ch expla ined to pr ospec tive physi cian- custo mers that Xyrem couldbe u sed w ith p atien ts un der a ge si xteen , an unapp roved Xyremsubp opula tion: -15-[Caro nia]: Um, the young est p atien ts we have are s ixtee n in the s tudie s as old a s sixty -five . Ah h the re ha ve be en re ports of pa tient s as youngas f ourte en us ing i t and o bviou sly g reate r tha n six ty-fi ve. It's a ver y saf e dru g. (Octo ber 2 6, 20 05 Re cordi ng Tr . (I) at 7 ).

[Glea son]: Wel l, it 's ac tuall y app roved for s ixtee n andabov e um, I've had peopl e under thir teen and I 've c ertai nly t alked to ne urolo gists that have narc olept ics

. . . betw een e ight and t en . . . [ but] I start at t wo-th irds the d ose, but [ if] they' re re al fr ail I onlystar t wit h one

thirdthe dose. (Nove mber 2, 20 05 Re cordi ng Tr . (II ) at 51). 3. Proce edings Bel ow

a. The C

harge s On Ju ly 25 , 200 7, a grandjuryretu rned its f irst Indic tment agai nst C aroni a. T he ch argin g doc ument at i ssue on th is ap peal, howe ver, is th e Sup ersed ing I nform ation filedby t he go vernm ent o n Aug ust 1 9, 20 08, w hich charg ed Caron ia wi th th e fol lowin g two misd emean or of fense s:

Count One: Con spira cy to intr oduce a misbr andeddruginto inte rstat e commerce in vi olati on of 21 U .S.C. §§ 3 31(a) and 333(a )(2); and Count Two: Int roduc ing a misb rande d drug, Xyre m, in to in terst ate c ommer ce, i n -16-viola tion of 21 U.S. C. §§ 331( a) an d 333(a )(2). (Inf. ¶¶ 1 2-17) .

With respe ct to Coun t One , the Info rmati on al leged a two -pron g con spira cy. The f irst prongchar ged t hat betwe en ap proxi matel y Mar ch 20 05 an d Mar ch 20 06, C aroni a, "toge ther with other s, di d kno wingl y andinte ntion ally consp ire t o" in trodu ce Xy rem a nd ca use t he in trodu ction of Xyreminto inte rstat e commerce when Xyre m was misb rande d withi n the mean ing o f the FDCA . (I nf. ¶ 13). The seco nd prongalle ged t hat " [i]t was p art o f the cons pirac y tha t [Caro nia], toge ther with other s, ma rkete d Xyr em fo r med ical indic ation s tha t wer e not appr oved by [t he] F DA wh en, a s [they ] . . . we ll kn ew an d bel ieved , Xyr em's label ing l acked adequ ate d irect ions for a nd wa rning s aga inst such uses, where suchuses coul d be dange rous to th e use r's h ealth ." (Inf. ¶ 14 ).

The I nform ation alle ged, in Co unt O ne, t hat Caron ia, " toget her w ith o thers , committe d andcaus ed to be commi tted, " the foll owingtwo overt acts . (I nf. ¶ 15).

-17-a. On or abou t Oct ober 26th, 2005 ,

. . . Caro nia p romot ed Xy rem t o [Char no], a phy sicia n, so as t o cause [Cha rno] to pr escri be Xy rem for f ibrom yalgi a, ex cessi ve da ytime sleep iness , mus cle d isord ers, chron ic pa in an d fat igue, whic h wer e "off- label " ind icati ons. b. On or abou t Nov ember 2, 2 005, . . . Caron ia in trodu ced [ Charn o] to [Glea son], a ph ysici an, w ho wa s pai d by Or phan and w hom O rphan usedto promo te Xy rem f or "o ff-la bel" indic ation s, in cludi ng fi bromy algia , exces sive dayti me sl eepin ess, weigh t loss and c hroni c fat igue. (Inf. ¶¶ 1 5(a), (b)) .

With respe ct to Coun t Two , the Info rmati on al leged that betwe en ap proxi matel y Mar ch 20 05 an d Mar ch 20 06, Caron ia "w as ma rketi ng Xy rem f or me dical indi catio ns th at

were not a pprov ed by[the ] FDAwhen , as the d efend ant t hen and t here well knew and b eliev ed, X yrem' s lab elinglack ed adequ ate d irect ions for s uch u ses a nd ad equat e war nings again st su ch us es wh ere u ses c ould be da ngero us to the user' s hea lth." (Inf. ¶ 17 ).

Addit ional ly, t he In forma tion alleg ed: "A dr ug that was m arket ed to the publi c for an ' off-l abel' indic ation or u se di d not cont ain ' adequ ate d irect ions for -18-use' becau se su ch an 'off -labe l' in dicat ion o r use and

relat ed in forma tion were not i nclud ed in the FDA-a pprov ed label ing f or th e dru g." (Inf. ¶ 8) . Th e Inf ormat ion furth er st ated: "Xy rem's labe ling lacke d ade quate direc tions for such uses and a dequa te wa rning s aga inst such

uses where suchuses coul d be dange rous to th e use r's healt h." (Inf. ¶¶ 1 4, 17 ).

Orpha n andGlea son w ere a lso c harge d und er th e misbr andin g pro visio ns of the FDCA; bothpledguil ty. Unite d Sta tes v . Car onia , 576 F. S upp. at 38 9-90 & n.1 . b. Caron ia's Pre-T rial Motion to Dismi ss On Oc tober 9, 2 007, befor e tri al, C aroni a mov ed to dismi ss th e cha rges again st hi m. I n par t, Ca ronia argu ed that the a pplic ation of t he FD CA's misbr andin g pro visio ns to his o ff-la bel p romot ional stat ement s unc onsti tutio nally restr ictedhis right to f ree s peechunde r the Firs t Amendment and t hat t he pr ovisi ons w ere u ncons titut ional ly vague and broad .

On Se ptemb er 11 , 200 8, th e dis trict cour t den ied Caron ia's motio n, in cludi ng hi s Fir st Am endme nt ch allen ge, whichit r ecogn ized as ra isingcons titut ional issu es "v ery -19-much unset tled, not only in th is ci rcuit but natio nwide ."

Id. at 40 3. A lthou gh ru ling for t he go vernm ent, the distr ict c ourt rejec ted t he go vernm ent's argu ment that Caron ia wa s bei ng pr osecu ted f or th e unl awful cond uct o f misbr andin g andcons pirin g to misbr and a drugand not f or his p romot ional spee ch, t he la tter of wh ich t he go vernm ent conte nded only const itute d pro of of Xyre m's i ntend ed us e. See i d. at 3 94-95 . Th e cou rt ob serve d tha t "th e cri minal infor matio n . . . al lege[ d] Ca ronia 's pr omoti on of off- label

uses of an FDA- appro ved d rug," and concl uded that Caron ia stoodchar ged w ith a crim e the actusreus of wh ich w as Fi rst Amendment speec h. Id. at 3 95. Never thele ss, t he di stric t court heldthat , to the e xtent the FDCA crimi naliz es sp eech, the l aw pa ssed const ituti onal muste r und er th e commerci al speec h doc trine beca use t he FD CA wa s not more exte nsive than

neces sary to ac hieve the FDA's obje ctive s. Id. at 4 01-02 . c. The T

rial The c ase w as tr ied b efore a ju ry fr om Oc tober 6 to Octob er 16 , 200 8.

The r ecordmake s cle ar th at th e gov ernme nt prose cutedCaro nia f or hi s off -labe l pro motio n, in viol ation -20-of th e FDC A. T he go vernm ent, in it s summatio n andrebu ttal,

repea tedlyasse rted that Caron ia wa s gui lty b ecaus e he, with other s, co nspir ed to prom ote a nd ma rket Xyremfor off-l abel

use. For examp le, t he go vernm ent a rgued :

• "[Car onia is] p romot ing, he's marke ting a dange rous drug for u se no t app rovedby the F DA" ( id. at 8 25);

• "He k new t he ru les: you c an't promo te an d marke t Xyr em fo r use s tha t hav e not been appro ved b y the FDA. He admit s it" ( id. at 83 9);

• "[Car onia] cons piredthro ugh s ome a ct of misbr andin g, an d tha t act of m isbra nding

. . . was the p romot ion o n Oct ober 26th and N ovemb er 2n d[,] marke ting [a] d rug for u nappr oved uses" ( id. at 8 48);

• "That 's mi sbran ding. Tha t's p romot ing and m arket ing a drugby a phar maceu tical compa ny re prese ntati ve fo r mus cle disor ders, chro nic p ain, dayti me fa tigue , exces sive sleep iness " ( id. at 8 70); and

• "[Car onia was] promo ting, prom oting , selli ng, s ellin g, tr ying to ge t Cha rno t o presc ribe Xyrem . He trie d on the 2 6th. He tr ied w ith G leaso n on the 2 nd" ( id. at 875). 7

7 The government's summation and rebuttal include numerous additional examples of the government's assertion that Caronia was guilty because he conspired to promote and market Xyrem for unapproved uses. ( See, e.g. , Trial Tr. 834 ("On -21-Thus, the gover nment 's th eory of pr osecu tion ident ified

Caron ia's speec h alo ne as the prosc ribedcond uct.

The d istri ct co urt, in it s jur y cha rge, reinf orced the i dea t hat C aroni a's p romot ional spee ch wa s eno ugh t o suppo rt a guilt y ver dict:

A mis brand ed dr ug ma y be shown by a promo tion of th e dru g by a dis tribu tor for a n int endeduse diffe rent from the use f or wh ich t he dr ug wa s app rovedby the [ FDA].

. . . The m anufa cture r, it s age nts, repre senta tives and emplo yees, are not permi tted to pr omote uses for a dru g tha t have not b een c leare d by the U nited State s Foo d andDrugAdmi nistr ation . These non- clear ed us es ar e commonly November 2nd . . . Gleason, comes in to pitch to [Charno] and he right away goes off-label, promotes and markets Xyrem for uses that are not approved by the FDA, clear as a bell."); id. ("[Caronia is] misbranding. He's promoting a drug, Xyrem, that's dangerous for unapproved uses."); id. at 836 ("[H]e crossed the line and here's the labeling and you can only promote Xyrem for cataplexy associated with narcolepsy and you can't do it for anything else."); id. at 847 ("The conspiracy is promoting it and then trying to persuade through off-label communications to get Charno to write prescriptions off-label"); id. at 883 ("And the facts are one prong the drug was promoted for unapproved uses in a meeting with Charno on the 26th of October and the 2nd of November with the expectation or with the effort or with the attempt or with the conspiracy that by promoting it for off-label use, Charno would write a prescription and cause the drug to be shipped from St. Louis to some patient out of state."); see also id. at 821-22, 827, 829, 840-43, 847-48, 872-74, 878). -22-refer red t o as 'off- label uses ' bec ause they are n ot in clude d in the d rug's label ing. (Tria l Tr. 920- 21) .

Prior to j ury d elibe ratio n, th e dis trict cour t provi ded a prop osed verdi ct sh eet t o the part ies. With respe ct to Coun t One , the verd ict s heet read as fo llows :

1. How d o you finddefe ndant , ALFRE D CAR ONIA, on C ount One o f the I nform ation ? (a) Consp iracyto i ntrod uce o r deliv er fo r int roduc tion into inter state comm erce a drug, Xyre m, th at wa s misbr anded ? NOT G UILTY____

_ GUILT Y ___

__ (b) Consp iracyto d o an act with respe ct to a dr ug, Xyrem , whe n suc h dru g was held for s ale a fter shipm ent i n int ersta te comme rce w hen s uch a ct wouldresu lt in Xyre m bei ng misbr anded ? NOT G UILTY____

_ GUILT Y ___

__ (Verd ict S heet, ECF Doc. No. 1 03, Unite d Sta tes v . Car onia , No. 0 6 Cr. 229 (E.D. N.Y. Oct. 23, 2 008)) . The d istri ct court over ruledCaro nia's obje ction that the verdi ct sh eet -23-was e rrone ous a nd th erefo re pe rmitt ed th e jur y to reachan

incon siste nt ve rdict .

On Oc tober 23, 2008, the jury foundCaro nia g uilty as to the first pron g of Count One of th e Inf ormat ion (Ques tion 1(a)) : co nspir acy t o int roduc e a m isbra nded drug into inter state comm erce under 18 U .S.C. § 37 1(a) and 2 1 U.S.C . § 3 31(a) . As to t he se cond marke ting prongof C ount One ( Quest ion 1 (b)), the jury foundCaro nia n ot gu ilty. The jury also foundCaro nia n ot gu ilty of Co unt T wo of the Infor matio n. d. Caron ia's Post- TrialMoti on fo r Acquitta l After the jury verdi ct an d bef ore j udgme nt wa s enter ed, C aroni a ren ewed his R ule 2 9 mot ion f or ac quitt al. SeeFed. R. C rim. P. 29 . On Dece mber 13, 2 008, after brief ing, the d istri ct co urt d eniedthe motio n.

e. Caron ia's Sentence On No vembe r 30, 2009 , the dist rict court sent enced Caron ia to one year of pr obati on, 1 00 ho urs o f communit y servi ce, a nd a $25 s pecia l ass essme nt.

This appea l fol lowed .

-24-DISCU SSION On ap peal, Caro nia p rinci pallyargu es th at th e misbr andin g pro visio ns of the FDCA prohi bit o ff-la bel promo tion, and there fore, unco nstit ution ally restr ict speec h. Car onia argue s tha t the Firs t Ame ndmen t doe s not

8 permi t the gove rnmen t to prohi bit a nd cr imina lize a pharm aceut ical manuf actur er's truth ful a nd no n-mis leadi ng promo tion of an FDA- appro ved d rug t o phy sicia ns fo r off

label use where suchuse is no t its elf i llega l andothe rs are p ermit ted t o eng age i n suc h spe ech.

We re view Caron ia's First Amen dment chal lenge to his c onspi racy convi ction de no vo . See C onn. Bar A ss'n v. Unite d Sta tes , 620 F.3d81, 89 (2 d Cir . 201 0) (" We re view const ituti onal chall enges to a fede ral s tatut e de no vo .");

see a lso U

nited Stat es v. Dhafir , 461 F.3d211, 215 (2d C ir. 2006) (sam e). We ag ree t hat C aroni a's c onvic tion must be vacat ed, b ut fo r nar rower reas ons t han h e urg es.

Caronia also argues that the verdict sheet was 8 improperly phrased and the jury's verdict was inconsistent. In light of our disposition of the First Amendment issue, we need not reach these issues. -25-While the FDCA makes it a crim e to misbr and o r

consp ire t o mis branda dr ug, t he st atute and its

accompanyi ng re gulat ions do no t exp ressl y pro hibit or crimi naliz e off -labe l pro motio n. See supra 7-8, 10. Rathe r, th e FDC A andFDA regul ation s ref erenc e "pr omoti on" only as ev idenc e of a dru g's i ntend ed us e. See 21 U. S.C. § 201 .128 (disc ussin g howdrug 's in tende d use can be demon strat ed). Thus , und er th e pri ncipl e of const ituti onal avoid ance, expl ained infra , we const rue t he FD CA as not crimi naliz ing t he si mple promo tion of a drug' s off -labe l use becau se su ch a const ructi on wo uld r aise First Amen dment

conce rns. Beca use w e con clude fromthe recor d in this case that the g overn ment prose cutedCaro nia f or me re of f-lab el promo tion and t he di stric t cou rt in struc ted t he ju ry th at it couldconv ict o n tha t the ory, we va cate the j udgme nt of convi ction .

We be gin b y add ressi ng th e gov ernme nt's conte ntion that Caron ia's off-l abel promo tion was u sed o nly a s evi dence of in tent in th is ca se. Findi ng th e gov ernme nt's argum ent unper suasi ve, w e tur n to the p rinci pal q uesti on on appe al: wheth er th e gov ernme nt's prose cutio n of Caron ia un der t he -26-FDCA only for p romot ing a n FDA -appr oved drug for o ff-la bel

use w as co nstit ution ally permi ssibl e. I. Speech versus Eviden ce of Intent The g overn ment conte nds - - andthe disse nt ag rees -- th at th e Fir st Am endme nt is not impli catedin t his c ase. Speci fical ly, t he go vernm ent a rgues that "[p] romot ing a n appro ved d rug f or of f-lab el us es is not itsel f a p rohib ited act u nder the F DCA" and " the p romot ion o f off -labe l use s plays an evide ntiary role in d eterm iningwhet her a drugis misbr andedunde r 21 U.S.C . § 3 52(f) (1)." (Go v't B r. 51 (citi ng 21 U.S. C. § 331)) . Th e gov ernme nt co ntend s tha t Caron ia wa s not pros ecute d for his speec h, bu t tha t Caron ia's promo tion of Xy rem f or of f-lab el us e ser ved m erely as "e viden ce of inte nt," or ev idenc e tha t the "off -labe l

uses were inten ded o nes[] for whichXyre m's l abeli ng fa iled to pr ovide any direc tions ." ( Gov't Br. 52).

Even assum ing t he go vernm ent c an of fer e viden ce of a def endan t's o ff-la bel p romot ion t o pro ve a drug' s int ended

-27-use a nd, t hus, misla belin g for that inte nded use, that is 9 not w hat h appen ed in this case .

First , the gove rnmen t's c onten tion that it di d not prose cute Caron ia fo r pro motin g the off- label use of an FDAappro ved d rug i s bel ied b y its cond uct a nd ar gumen ts at trial . Th e exc erpts quot ed ab ove d emons trate that the gover nment repe atedl y arg ued t hat C aroni a eng aged in crimi nal c onduc t by promo ting and m arket ing t he of f-lab el

use o f Xyr em, a n FDA -appr oved drug. See s upra 21-22 & n. 7. The d istri ct co urt r ecordthus conf irms overw helmi ngly that Caron ia wa s, in fact , pro secut ed an d con victe d for prom oting Xyremoff- label . See s upra 12-24 . In deed, in t he gover nment 's su mmati on an d reb uttal at t rial, Caro nia's offlabel prom otion of X yrem is hi ghlig hted over fortytime s. ( SeeTria l Tr. 819- 49, 8 70-80 , 883 -85).

See Wisconsin v. Mitchell , 508 U.S. 476, 489 (1993) 9 (concluding First Amendment "does not prohibit the use of speech to establish . . . intent"); Whitaker v. Thompson , 353 F.3d 947, 953 (D.C. Cir. 2004) (holding product's labeling may be used to infer its intended use and, thus, whether it is an unapproved drug under FDCA). -28-Secon d, th e gov ernme nt's asser tion now t hat i t

used Caron ia's effor ts to prom ote X yrem for o ff-la bel u se only as ev idenc e of inten t is simpl y not true . Ev en if the gover nment coul d hav e use d Car onia' s spe ech a s evi dence of inten t, th e dis trict cour t rec ord c learl y sho ws th at th e gover nment did not s o lim it it s use of t hat e viden ce. See Mitch ell , 508 U.S. at 4 89-90 (ins truct ing t hat, when speec h is in trodu ced a s evi dence of i ntent , "'[ s]uchtest imonyis to be scru tiniz ed wi th ca re to be c ertai n the stat ement s are not e xpres sions of m ere l awful and permi ssibl e dif feren ce of opini on wi th ou r own gove rnmen t'" ( quoti ng Hauptv. U nited State s , 330 U.S. 631, 642 (1947 ))). The gover nment neve r argue d in summa tion or re butta l tha t the prom otion was evide nce o f int ent. ( SeeTria l Tr. 819- 49, 8 70-80 , 883 -85). The g overn ment never sugg estedthat Caro nia e ngage d in any form of mi sbran ding other than the promo tion of th e off

label use of an FDA- appro ved d rug. The gover nment neve r sugge sted, for examp le, t hat C aroni a con spire d to place false or d efici ent l abeli ng on a dr ug. See 21 U. S.C. §§ 352(a )-(n) . Ra ther, the recor d mak es cl ear t hat t he

-29-gover nment pros ecute d Car onia for his promo tion and marke ting effor ts.

Third , the gove rnmen t's s ummat ion a nd th e dis trict court 's in struc tion left the j ury t o und ersta nd th at Caron ia's speec h was itse lf th e pro scrib ed co nduct . See supra 21-2 3. I ndeed , the dist rict court flat ly st ated to the j ury t hat p harma ceuti cal r epres entat ives are p rohib ited from engag ing i n off -labe l pro motio n. See i d. Alt houghthe distr ict c ourt expla ined the r emain ing e lemen ts of misbr andin g andcons pirin g to misbr and t o the jury , thi s speci fic i nstru ction -- t ogeth er wi th th e gov ernme nt's

summa tion -- wo uld h ave l ed th e jur y to belie ve th at Caron ia's promo tiona l spe ech w as, b y its elf, deter minat ive of hi s gui lt. See g enera lly U nited Stat es v. Dyer , 922 F.2d 105, 107-0 8 (2dCir. 1990 ) (st atingspec ific jury instr uctio n maybe r eview ed in isol ation if " it is so f ar

remov ed fr om th e sta ndard s set by t he la w tha t the appe llate court is c onvin ced t hat t he ju ry mi ght h ave b een m isled " (inte rnal quota tion marks omit ted)) .

-30-Fourt h, th e gov ernme nt cl earlypros ecute d Car onia

for h is wo rds – - for his speec h. Aphar maceu tical repre senta tive' s pro motio n of an FDA-app roveddrug 's of flabel use is sp eech. As the S uprem e Cou rt ha s hel d: "Spee ch in aid of ph armac eutic al ma rketi ng . . . i s a f orm of ex press ion p rotec ted b y the Free Spee ch Cl ause of th e First Amen dment ." Sorre ll v. IMS Healt h, In c. , 131 S. C t. 2653, 2659 (201 1). Here, the prosc ribedcond uct f or wh ich Caron ia wa s pro secut ed wa s pre cisel y his spee ch in aid of pharm aceut ical marke ting.

Accor dingl y, we conc lude that the g overn ment did prose cute Caron ia fo r his spee ch, a nd we turn to w hethe r the prose cutio n was perm issib le. II. The Prosec utionof Caroni a's S peech While the gover nment and the F DA ha ve co nstru ed the F DCA's misb randi ng pr ovisi ons t o pro hibit off- label promo tion by ph armac eutic al ma nufac turer s, see s upra 10; see FDA, DraftGuid ance , supra , at 2-3, as we have obse rved, the FDCA itsel f doe s not expr esslyproh ibit or cr imina lize offlabel prom otion . See s upra 7-8, 10. The F DCA d efine s

-31-misbr andin g in terms of w hethe r a d rug's labe ling is

adequ ate f or it s int endeduse, and permi ts th e gov ernme nt to prove inte nded use b y ref erenc e to promo tiona l sta temen ts made by dr ug ma nufac turer s or their repr esent ative s. See id . As sumin g tha t thi s app roachto t he us e of evide nce o f speec h is permi ssibl e, it a fford s lit tle s uppor t to the 1 0 gover nment on t his a ppeal beca use C aroni a was not prose cuted on th is ba sis. Rath er, t he go vernm ent's theo ry of prose cutio n ide ntifi ed Ca ronia 's sp eech alone as t he prosc ribedcond uct. The distr ict c ourt accep ted t his theor y. To th e ext ent t here is an y amb iguit y as to wh ether off-l abel promo tion is ta ntamo unt t o ill egal misbr andin g, we

Although we assume, without deciding, that such use of 1 0 evidence of speech is permissible under Mitchell, 508 U.S. 476, we observe that it still remains unclear how the government would identify criminal misbranding from communications between drug manufacturers and physicians authorized to prescribe drugs for off-label use. For example, would a manufacturer be guilty of misbranding if it ships Xyrem to a doctor who, in placing his order, reveals that he prescribes the drug for off-label use -- on a theory that the manufacturer now knows that the drug is not properly labeled for that use -- but not if the manufacturer ships to a doctor who does not reveal that he prescribes the drug off-label? Because this case does not present us with that circumstance or others that might raise questions about the scope of the misbranding proscription, we need not address them here. -32-const rue t he FD CA na rrowl y to avoida se rious cons titut ional

quest ion. See S killi ng v. Unit ed St ates , 130 S. C t. 28 96, 2929- 30 (2 010) (inst ructi ng co urts to "a void const ituti onal diffi culti es byadop ting a lim itinginte rpret ation if s uch a const ructi on is fair ly po ssibl e" (i ntern al qu otati on ma rks and b racke ts om itted )); Edwar d J. DeBar tolo Corp. v. Fla. Gulf CoastBldg . & C onstr . Tra des C ounci l , 485 U.S. 568, 575 (1988 ); Allst ate Ins. C o. v. Seri o , 261 F.3d143, 150 (2d Cir. 2001) ("Th us, t he co urts will take pains to g ive a statu te a limit ing c onstr uctio n in order to a void a const ituti onal diffi culty .").

As we now expla in, w e dec line the g overn ment' s invit ation to c onstr ue th e FDC A's m isbra ndingprov ision s to crimi naliz e the simp le pr omoti on of a dr ug's off-l abel use by ph armac eutic al ma nufac turer s andthei r rep resen tativ es becau se su ch a const ructi on -- and a con victi on ob taine d under the gover nment 's ap plica tion of th e FDC A -- wouldrun afoul of t he Fi rst Amendm ent. A. Appli cableFirs t Amendmen t Doc trine The F irst Amendment prote cts a gains t gov ernme nt regul ation and suppr essio n of speec h on accou nt of its -33-conte nt. Turne r Bro ad. System , Inc . v. F.C.C . , 512 U.S.

622, 641-4 2 (19 94); see Ward v . Roc k Aga inst Racism , 491 U.S. 781, 791 ( 1989) ; R.A.V . v. City of St . Pau l , 505 U.S. 377, 386 ( 1992) . Co ntent -base d spe ech r estri ction s are subje ct to "str ict s cruti ny" – - tha t is, the gover nment must show that the r egula tion at is sue i s nar rowlytail ored to

serve or p romot e a c ompel ling gover nment inte rest. See Brown v. Entm'tMerc hs. A ss'n , 131 S. C t. 27 29, 2 738 ( 2011) (citi ng R.A.V . , 505 U.S. at 3 95). Cont ent-b ased gover nment regul ation s are "pre sumpt ivelyinva lid." R.A.V . , 505 U.S. at 38 2. M eanwh ile, non-c onten t-bas ed re gulat ion a nd regul ation of c ommer cial speec h -- expre ssion sole ly re lated to th e eco nomic inte rests of t he sp eaker and its a udien ce --

are s ubjec t to inter media te sc rutin y. See Turne r Bro ad. , 512 U .S. a t 642 ; Cent. Huds on Ga s & E lec. Corp. v. P ub. Serv. Comm 'n of

N.Y. , 447 U.S. 557, 563- 64 (1 980). Cri minal regul atorysche mes, moreo ver, warra nt ev en mo re ca reful scrut iny. See Holder v. H umani taria n Law Proj ect , 130 S. Ct. 2 705, 2724 (2010 ) (ap plyin g mor e rig orous scru tiny) ; id. at 27 34 (B reyer , J. , dis senti ng) ( "It i s not surp risin g tha t the m ajori ty, i n det ermin ing t he co nstit ution alityof -34-crimi nallyproh ibiti ng th e pla intif fs' p ropos ed ac tivit ies,

wouldappl y . . . a more deman ding stand ard. Inde ed, w here, as he re, a stat ute a pplie s cri minal pena lties . . . I s hould thinkwe w ould scrut inize the statu te an d jus tific ation s stric tly." (int ernal quot ation mark s andcita tions omit ted) (citi ng ca ses)) ); see a lso City o f Hou ston v. Hi ll , 482 U.S. 451, 459 ( 1987) ("Cr imina l sta tutes must be s cruti nizedwith parti cular care ." (i ntern al ci tatio ns om itted )).

In ap plyin g the se pr incip les, we ha ve a benef it not a vaila ble t o the dist rict court : th e Sup reme Court 's decis ion i n Sorre ll v. IMS Healt h, In c. , 131 S. C t. 26 53 (2011 ), a case invol ving speec h res trict ions on pharm aceut ical marke ting. In Sorre ll , the Verm ont Presc ripti on Co nfide ntial ity L aw (t he "V PCL") proh ibite d pharm aceut ical compa nies and s imila r ent ities fromusin g presc riber -iden tifyi ng in forma tion for m arket ing p urpos es; it wa s cha lleng ed on Firs t Ame ndmen t gro unds. Id. at 26 61- 62; see a lso Vt. S tat. Ann., Tit. 18 § 4631 (e)(4 ).

The Sorre ll Court heldthat "[s] peechin a id of pharm aceut ical marke ting . . . is a formof e xpres sion prote cted by th e . . . Fi rst Amendm ent. . . . [The ] cre ation -35-and d issem inati on of info rmati on ar e spe ech w ithin the

meani ng of the [Cons titut ion]. " Id. at 2 659, 2667. The Court heldthat the Vermo nt st atute set forthcont ent- and speak er-ba sed r estri ction s, an d tha t the stat ute w as there fore subje ct to heig htene d scr utiny . Id. at 2 662-6 5. Becau se th e VPC L dis favor ed sp eech with a par ticul ar co ntent (mark eting ) whe n exp resse d by certa in di sfavo red s peake rs (phar maceu tical manu factu rers) , the Cour t hel d tha t it

uncon stitu tiona lly r estri cted speec h. Id. at 26 62-65 , 267 2.

In re achin g thi s con clusi on, Sorre ll engag ed in a two-s tep i nquir y. F irst, the Court cons idere d whe ther the gover nment regu latio n res trict ing s peechwas conte nt- a nd speak er-ba sed. See i d. at 2 662-6 4. T he Co urt h eld t hat i t was; the r egula tion was t heref ore s ubjec t to heigh tened scrut iny a nd wa s "pr esump tivel y inv alid. " See id. Sec ond, the C ourt consi deredwhet her t he go vernm ent h ad sh own t hat the r estri ction on s peechwas consi stent withthe First Amendment under the appli cable leve l of heigh tenedscru tiny. Id. at 2 663, 2667- 68. The C ourt did n ot de cide the l evel of heigh tenedscru tiny to be appl ied, that is, s trict , inter media te, o r som e oth er fo rm of heig htene d scr utiny . -36-Id. Rat her, after obse rvingthat "[i] n the ordi nary case,

it is all but d ispos itive to c onclu de th at a law i s con tentbased ," th e Cou rt co nclud ed th at th e Ver mont statu te wa s

uncon stitu tiona l eve n und er th e les ser i nterm ediat e sta ndard set f orth in Centr al Hu dson . Id. at 2 667; see C ent. Hudso n , 447 U .S. a t 566 . Th e Cou rt fu rther obse rved that the "outc ome i s the same whet her a spec ial c ommer cial speec h inqui ry or a st ricte r for m of judic ial s cruti ny is appl ied." Sorre ll , 131 S. C t. at 2667 .

In co nside ring wheth er th e gov ernme nt ha d sho wn that the r estri ction on s peechwas consi stent withthe First Amendment, the Sorre ll Court turn ed to Centr al Hu dson . See id. at 2 667-6 8. Centr al Hu dsonsets fort h a f our-p art t est to de termi ne wh ether comm ercia l spe ech i s pro tecte d by the First Amen dment . Cent. Huds on , 447 U.S. at 5 66. First , as a thr eshol d mat ter, to wa rrant Firs t Ame ndmen t pro tecti on, the s peechin q uesti on mu st no t be misle adingand must

conce rn la wful activ ity. Id ; see i nfranote 11 a nd

accompanyi ng te xt. Secon d, to just ify r egula tions restr ictin g spe ech, the a ssert ed go vernm ent i ntere st mu st be subst antia l. Id. Third , the regu latio n mus t dir ectly -37-advan ce th e gov ernme ntal inter est a ssert ed, id. , "to a

mater ial d egree ," 44 Li quorm art, Inc. v. Rh ode I sland , 517 U.S. 484, 505 ( 1996) (quo ting Edenfield v. Fa ne , 507 U.S. 761, 771 ( 1993) ). " [A] c ommer cial speec h reg ulati on 'm ay not b e sus taine d if it pr ovide s onl y ine ffect ive o r rem ote suppo rt fo r the gove rnmen t's p urpos e.'" Liquo rmart , 517 U.S. at 50 5 (qu oting Cent. , 447 U.S. at 5 64). Four th, t he regul ation must be " narro wly d rawn, " andmay not b e mor e exten sive than neces sary to se rve t he in teres t, Cent . Hudso n , 447 U.S. at 5 65-56 ; see a lso S orrel l , 131 S. C t. at 2667- 69 (c iting Bd. o f Tr. of S tate Univ. of N .Y. v . Fox , 492 U .S. 4 69, 4 80-81 (198 9)); Thomp son v . W. State s Med . Ctr. , 535 U.S. 357, 374 (2002 ). T he go vernm ent c annot "comp letel y sup press info rmati on wh en na rrowe r res trict ions

on ex press ion w ould serve its inter ests as we ll." Cent. Hudso n , 447 U.S. at 5 65. "Unde r the comm ercia l spe ech inqui ry, i t is the [ gover nment 's] b urden to j ustif y its conte nt-ba sed l aw as cons isten t wit h the Firs t Ame ndmen t." Sorre ll , 131 S. C t. at 2667 (cit ing Thomp son , 535 U.S. at 373).

-38-B. Appli cation In pr osecu ting Caron ia, t he go vernm ent c onstr ued the F DCA's misb randi ng pr ovisi ons t o pro hibit and crimi naliz e the prom otion of o ff-la bel d rug u se. We re view the g overn ment' s the ory o f pro secut ion u nder the Sorre ll Court 's tw o-ste p ana lysis to d eterm ine w hethe r it runs afoul of th e Fir st Am endme nt. First , we concl ude t hat t he gover nment 's co nstru ction of t he FD CA's misbr andin g provi sions impo ses c onten t- an d spe aker- basedrest ricti ons on sp eech subje ct to heig htene d scr utiny . Se cond, we concl ude t he go vernm ent c annot just ify a crim inal prohi bitio n of off-l abel promo tion even under Centr al Hudso n 's le ss ri gorou s int ermed iate test.

1. Heigh tened

Scru tiny The g overn ment' s con struc tion of th e FDC A's misbr andin g pro visio ns to proh ibit and c rimin alize the promo tion of of f-lab el dr ug us e by pharm aceut ical manuf actur ers i s con tent- and speak er-ba sed, and, there fore, subje ct to heig htene d scr utiny . See i d.

First , the gove rnmen t's i nterp retat ion o f the FDCA' s mis brand ing p rovis ions to pr ohibi t off -labe l -39-promo tion is co ntent -base d bec ause it di sting uishe s bet ween

"favo red s peech " and"dis favor ed sp eech on th e bas is of the ideas or v iews expre ssed. " See T urner Broa d. , 512 U.S. at 643; accor d Sor rell , 131 S. C t. at 2663 . Un der t his const ructi on, s peechabou t the gove rnmen t-app roveduse of drugs is p ermit ted, while cert ain s peechabou t the off- label

use o f dru gs -- that is, uses not a pprov ed bythe gover nment -- is proh ibite d, ev en th ough the o ff-la bel u se it self is not. See21 U .S.C. §§ 3 31(a) , 333 (a)(2 ). I ndeed , the conte nt of the regul ated speec h dri ves t his c onstr uctio n of the F DCA; as in Sorre ll , the "exp ress purpo se an d pra ctica l effec t" of the gover nment 's ba n on promo tion is to "dim inish the e ffect ivene ss of [off -labe l dru g] ma rketi ng by manuf actur ers." See S orrel l , 131 S. C t. at 2663 .

Secon d, th is co nstru ction is s peake r-bas ed be cause it ta rgets one kind of sp eaker -- p harma ceuti cal manuf actur ers - - whi le al lowin g oth ers t o spe ak wi thout restr ictio n. See i d. at 2 663. In Sorre ll , pha rmace utica l compa nies were barre d fro m obt ainin g andusin g pre scrib erident ifyin g inf ormat ion f or ma rketi ng pu rpose s, bu t a w ide range of o ther speak ers, inclu ding priva te an d aca demic -40-resea rcher s, co uld a cquir e anduse the i nform ation . Id.

Simil arly, here , bec ause off-l abel presc ripti ons a nd dr ug

use a re le gal, the g overn ment' s app licat ion o f the FDCA permi ts ph ysici ans a nd ac ademi cs, f or ex ample , to speak about off- label use witho ut co nsequ ence, whil e the same speec h is prohi bitedwhen deli veredby p harma ceuti cal manuf actur ers. See 21 U. S.C. §§ 33 1(a), 333( a). This const ructi on "t hus h as th e eff ect o f pre venti ng [phar maceu tical manu factu rers] -- a nd on ly [p harma ceuti cal manuf actur ers] -- fr om co mmuni catin g wit h phy sicia ns in an effec tive and i nform ative mann er." Sorr ell , 131 S. C t. at 2663. Addit ional ly, a clai m to First Amen dment prote ction here is m ore c ompel ling than in Sorre ll becau se this case invol ves a crim inal regul atorysche me su bject to

more caref ul sc rutin y. See 21 U. S.C. § 333 (a); Human itari an Law Projec t , 130 S. C t. at 2724 .

Accor dingl y, th e gov ernme nt's const ructi on of the FDCA' s mis brand ing p rovis ions to pr ohibi t andcrim inali ze off-l abel promo tion is co ntent - andspea ker-b ased, and subje ct to heig htene d scr utinyunde r Sorre ll . -41-2. Central Hu dson The f irst two p rongs of Centr al Hu dson are e asily satis fied here. Fir st, p romot ing o ff-la bel d rug u se

conce rns l awful acti vity (off- label druguse) , andthe promo tion of of f-lab el dr ug us e is not i n andof i tself false or m islea ding. See C ent. Hudso n , 447 U.S. at 5 66. 1 1 Secon d, th e gov ernme nt's asser ted i ntere sts i n dru g saf ety and p ublic heal th ar e sub stant ial. See i d. Speci fical ly, the g overn ment asser ts an inte rest in pr eserv ing t he

In Whitaker , cited by the dissent (Diss. Op. 14), the 1 1 D.C. Circuit held that the labeling of a product, which was not approved by the FDA as a drug, constituted speech about unlawful activities and therefore did not enjoy First Amendment protection because it was unlawful to sell an unapproved product pursuant to claims about disease treatment. See Whitaker , 353 F.3d at 953.

The government does not contend that off-label promotion is in and of itself false or misleading. Of course, off-label promotion that is false or misleading is not entitled to First Amendment protection. See Cent. Hudson , 447 U.S. at 566. Under 21 U.S.C. § 331(a), a defendant may be prosecuted for untruthfully promoting the off-label use of an FDA-approved drug, e.g. , making false or misleading statements about a drug.

The government did not argue at trial, nor does it argue on appeal, that the promotion in question was false or misleading. ( SeeTrial Tr. 823 (mentioning, in government's summation, that Caronia "did not give accurate and complete information in promoting and marketing Xyrem," but focusing on promotion as misbranding and not pursuing argument that speech was false or misleading); Gov't Br. 58 (considering whether "the commercial speech in question clears [the] hurdle" of Central Hudson 's first prong, but not contending that the speech concerns unlawful activity or is false or misleading)). -42-effec tiven ess a nd in tegri ty of the FDCA' s dru g app roval

proce ss, a nd an inte rest in re ducin g pat ient expos ure t o unsaf e andinef fecti ve dr ugs. SeeFDA v. Br own &Will iamso n Tobac co Co rp. , 529 U.S. 120, 133 (2000 ) ("[ O]ne of th e [FDCA 's] c ore o bject ives is to ensu re th at an y pro duct regul ated by th e FDAis ' safe' and 'effe ctive ' for its inten ded u se.") .

The t hird and f ourthpron gs of Centr al Hu dson requi re th at th e reg ulati on di rectl y adv ance the gover nment 's in teres ts an d be narro wly d rawn. See C ent. Hudso n , 447 U.S. at 5 66. We tu rn to the thirdand fourt h prong s bel ow.

a. Direc t Adv ancement The g overn ment' s con struc tion of th e FDC A as prohi bitin g off -labe l pro motio n doe s not , by itsel f, withs tand scrut iny u nder Centr al Hu dson 's th ird p rong. First , off -labe l dru g usa ge is not unlaw ful, and t he FDA's drug appro val p roces s gen erall y con templ ates that appro ved drugs will be u sed i n off -labe l way s. I n eff ect, even if pharm aceut ical manuf actur ers a re ba rred from off-l abel promo tion, phys ician s can pres cribe , andpati ents can u se, -43-drugs for off-l abel purpo ses. See s upra 4-7. As o ff-la bel

drug use i tself is n ot pr ohibi ted, it do es no t fol low t hat prohi bitin g the trut hful promo tion of of f-lab el dr ug us age by a parti cular clas s of speak ers w ould direc tly f urthe r the gover nment 's go als o f pre servi ng th e eff icacyand integ rity of th e FDA 's dr ug ap prova l pro cess and r educi ng pa tient expos ure t o uns afe a nd in effec tive drugs . See Sorre ll , 131 S. Ct . at 2668- 69 (h oldin g gov ernme nt in teres t in prote cting physi cian priva cy no t dir ectlyserv ed wh en la w mad e presc riber -iden tifyi ng in forma tion avail able to "a ll bu t a

narro w cla ss of disf avore d spe akers ").

Secon d, pr ohibi ting off-l abel promo tion by a pharm aceut ical manuf actur er wh ile s imult aneou sly a llowi ng off-l abel use " pater nalis tical ly" i nterf eres with the abili ty of phys ician s andpati ents to re ceive pote ntial ly relev ant t reatm ent i nform ation ; suc h bar riers to i nform ation about off- label use couldinhi bit, to th e pub lic's detri ment, info rmed and i ntell igent trea tment deci sions . See V a. Bd . of Pharm acy v . Va. Citi zens Consumer C ounci l, Inc. , 425 U.S. 748, 770 (1976 ) (di scuss ing " highl y pater nalis tic a pproa ch" o f gov ernme nt pr ohibi tions on f ree -44-flow of in forma tion) ; seealsoSorr ell , 131 S. C t. at 2670

-

72 (" [The] fear that [phy sicia ns, s ophis ticat ed an d exper ience d cus tomer s,] w ould make bad d ecisi ons i f giv en truth ful i nform ation " can not j ustif y con tent- basedburd ens on sp eech. ") (c itingsour ces); Liquo rmart , 517 U.S. at 5 03 ("[B] ans a gains t tru thful , non misle adingcomm ercia l spe ech

. . . usua lly r est s olelyon t he of fensi ve as sumpt ion t hat the p ublic will resp ond ' irrat ional ly' t o the trut h. . . . The F irst Amendment direc ts us to b e esp ecial ly sk eptic al of regul ation s tha t see k to keep peopl e in the d ark f or wh at the g overn ment perce ives to be thei r own good ."). In f act, in gr antin g saf e har bor t o man ufact urers by p ermit ting the disse minat ion o f off -labe l inf ormat ion t hroug h sci entif ic journ als, the F DA it self "reco gnize s tha t pub lic h ealthcan be se rved when healt h car e pro fessi onals rece ive t ruthf ul and n on-mi slead ing s cient ific and m edica l inf ormat ion o n unapp roveduses " of appro ved d rugs. Dep 't of Heal th an d Human Serv ., Go od Re print Prac tices , supra , at III, V; see Wash. Lega l Fou nd. v . Hen ney , 202 F.3d331, 335 (D.C. Cir. 2000) (dis cussi ng FDA "sa fe ha rbor, " whe re ce rtain foru ms for o ff-la bel d iscus sion, suchas c ontin uing medic al -45-educa tion progr ams a nd sc ienti fic p ublic ation s, wo uld n ot be

used again st ma nufac turer s in misbr andin g enf orcem ent actio ns). Here, as t he FDA rec ogniz es, i t is the p hysic ian's role to co nside r mul tiple fact ors, inclu ding a dru g's F DAappro val s tatus , to deter mine the b est c ourse of a ction for her p atien t. SeeFDA Drug Bull. , supra , at 5; Buckman , 531 U.S. at 35 0 ; Wea ver , 886 F.2dat 1 98-99 ; 21 U.S.C . § 3 96;

see a lso Thomps on , 535 U.S. at 3 67 (d iscus sing the " gener al rule" that "the spea ker a nd th e aud ience , not the gover nment , ass ess t he va lue o f the info rmati on pr esent ed") (quot ing Edenfield , 507 U.S. at 7 67); see a lso V a. Bd . of Pharm acy , 425 U.S. at 7 70 (" [T]he choi ce . . . i s not ours to ma ke or the [legi slatu re's] ."). Whil e som e off -labe l infor matio n cou ld ce rtain ly be misl eadin g or unhel pful, this

case does not i nvolv e fal se or misl eadin g pro motio n. See supra note 11. More over, in t he fi elds of me dicin e and publi c hea lth, "wher e inf ormat ion c an sa ve li ves," it o nly furth ers t he pu blic inter est t o ens ure t hat d ecisi ons a bout the u se of pres cript ion d rugs, incl udingoff- label usag e, are i ntell igent and well- infor med. See S orrel l , 131 S. C t. -46-at 26 64, 2 671; Thomp son , 535 U.S. at 3 66 (q uotin g Va. B d. of

Pharm acy , 425 U.S. at 7 65).

The g overn ment' s con struc tion of th e FDC A

essen tiall y leg alize s the outc ome - - off -labe l use -- b ut prohi bits the f ree f low o f inf ormat ion t hat w ould infor m that outco me. If th e gov ernme nt's objec tive is to shep herd physi cians to p rescr ibe d rugs only on-la bel, crimi naliz ing manuf actur er pr omoti on of off- label use while perm ittin g other s to promo te su ch us e to physi cians is a n ind irect and quest ionab ly ef fecti ve me ans t o ach ieve that goal. Thu s, the g overn ment' s con struc tion of th e FDC A's m isbra nding provi sions does not direc tly a dvanc e its inte rest in reduc ing p atien t exp osure to o ff-la bel d rugs or in prese rvingthe effic acy o f the FDA drug appro val p roces s becau se th e off -labe l use of s uch d rugs conti nues to be gener ally lawfu l. A ccord ingly , the gove rnmen t's p rohib ition of of f-lab el pr omoti on byphar maceu tical manu factu rers "prov ides only ineff ectiv e or remot e sup port for t he gover nment 's pu rpose ." See L iquormart , 517 U.S. at 5 04-05 (quot ing Cent. Huds on , 447 U.S. at 5 64).

-47-b. Narro wly Drawn The l ast p rong of Centr al Hu dsonrequ ires the gover nment 's re gulat ion t o be narro wly d rawn to fu rther the inter ests serve d. Cent. Huds on , 447 U.S. at 5 66. Here, the gover nment 's co nstru ction of t he FD CA to impo se a compl ete and c rimin al ba n on off-l abel promo tion by ph armac eutic al manuf actur ers i s mor e ext ensiv e tha n nec essar y to achie ve the g overn ment' s sub stant ial i ntere sts. See i d . Nume rous, less speec h-res trict ive a ltern ative s are avai lable , as are

non-c rimin al pe nalti es. See Thomps on , 535 U.S. at 3 72-73 .

To advance the integ rity of th e FDA 's dr ug appro val p roces s andincr ease the s afetyof o ff-la bel d rug use, the g overn ment couldpurs ue se veral alte rnati ves witho ut ex cessi ve Fi rst Amendm ent r estri ction s. See Cent. Hudso n , 447 U.S. at 5 64. For e xampl e, if the gover nment is

conce rned about the use o f dru gs of f-lab el, i t cou ld mo re direc tly a ddres s the issu e. I f the gove rnmen t is conce rned that off-l abel promo tion may m islea d phy sicia ns, i t cou ld guide phys ician s andpati ents in di ffere ntiat ing b etwee n misle adingand false prom otion , exa ggera tions and embel lishm ents, and truth ful o r non -misl eadin g inf ormat ion. -48-See Osbor n, Can ITell You The Truth? , supra , at 306-0 7.

The g overn ment coulddeve lop i ts wa rningor d iscla imer syste ms, o r dev elop safet y tie rs wi thin the o ff-la bel marke t, to dist ingui sh be tween drug s. See Colee n Kla smeie r and M artin H. R edish , Off-L abel Presc ripti on Ad verti sing, the F DA an d theFirs t Ame ndmen t: A Stud y in the V

aluesof Comme rcial Spee ch Pr otect ion , 37 Am. J .L. & Med. 315, 334 (2011 ). T he go vernm ent c ould requi re ph armac eutic al manuf actur ers t o lis t all appl icabl e or inten ded i ndica tions when they first appl y for FDA appro val, enabl ing p hysic ians, the g overn ment, and patie nts t o tra ck a drug' s dev elopm ent. To mi nimiz e off -labe l use , or manuf actur er ev asion of t he appro val p roces s for suchuse, the gover nment coul d cre ate other limi ts, i nclud ing c eilin gs or caps on o ff-la bel presc ripti ons. The FDA c ould furth er re mind physi cians and manuf actur ers o f, an d eve n per haps furth er re gulat e, th e legal liab ilitysurr oundi ng of f-lab el pr omoti on an d treat ment decis ions. Fin ally, wher e off -labe l dru g use is 1 2

Physicians and pharmaceutical manufacturers can be held 1 2 accountable for off-label drug use through medical malpractice and negligence theories of liability. See generally Boyle v. Revici , 961 F.2d 1060 (2d Cir. 1992); Sita v. Danek Med. Inc. , 43 -49-excep tiona lly c oncer ning, the gover nment coul d pro hibit

the o ff-la bel u se al toget her. See, e.g. , Bade r , 678 F.3dat 873-7 5 & n .10 ( citin g 21 U.S.C . § 3 33(e) (pro hibit ing o fflabel use of hu man g rowthhorm one)) . Th e pos sibil ities are

numer ous i ndeed .

"If t he Fi rst Amendm ent m eans anyth ing, it me ans that regul atingspee ch mu st be a la st -- not first --

resor t." Thomp son , 535 U.S. at 3 73. The g overn ment has n ot estab lishe d a " reaso nable fit" amon g its inte rests in d rug safet y andpubl ic he alth, the lawfu lness of o ff-la bel u se, and i ts co nstru ction of t he FD CA to proh ibit off-l abel promo tion. See Fox , 492 U.S. at 4 80 . The gove rnmen t's inter ests couldbe s ervedequa lly w ell b y mor e lim ited and targe ted r estri ction s on speec h. See C ent. Hudso n , 447 U.S. at 56 5. The g overn ment conte nds t hat t hese alter nativ e

means of r educi ng pa tient expo sure to un safe, unte sted drugs and m ainta iningthe integ rity of th e FDA -appr oval proce ss are " indef ensib le" ( Gov't Br. 70), becau se th ey ar e not admin istra ble, feasi ble, or ot herwi se ef fecti ve. In th e F. Supp. 2d 245 (E.D.N.Y. 1999); Retkwa v. Orentreich , 584 N.Y.S.2d 710 (N.Y. Sup. Ct. 1992). -50-absen ce of any suppo rt, s uch c onclu sory asser tions are

insuf ficie nt to sust ain t he go vernm ent's burd en of demon strat ing t hat t he pr opose d alt ernat ives are l ess effec tive than its p ropos ed co nstru ction of t he FD CA in furth eringthe gover nment inte rests iden tifie d. See Ashcr oft v . ACL U , 542 U.S. 656, 665, 669 (2004 ).

Accor dingl y, ev en if spee ch ca n be used as evide nce o f a d rug's inte nded use, we de cline to a dopt the gover nment 's co nstru ction of t he FD CA's misbr andin g provi sions to p rohib it ma nufac turer prom otion alon e as it wouldunco nstit ution ally restr ict f ree s peech . We cons true the m isbra ndingprov ision s of the F DCA a s not proh ibiti ng and c rimin alizi ng th e tru thful off- label prom otion of F DAappro ved p rescr iptio n dru gs. Our c onclu sion is li mitedto FDA-a pprov ed dr ugs f or wh ich o ff-la bel u se is not prohi bited , andwe d o not hold , of cours e, th at th e FDA

canno t reg ulate the marke ting of pr escri ption drug s. W e concl ude s implythat the gover nment cann ot pr osecu te pharm aceut ical manuf actur ers a nd th eir r epres entat ives under the F DCA f or sp eech promo ting the l awful , off -labe l use of an FDA-app roveddrug . -51-CONCL USION For t he re asons set forthabov e, we VACA TE th e judgm ent o f con victi on an d REMAND t he ca se to the distr ict court .

-52-D E B RA AN N LIVI N G S T O N , Circuit Judge , dissenting:

Alf re d C aronia w a s convicted of conspiring to introduce a prescription dru g into interstate commerce with the intent that it be us e d i n ways its labeling neither disclosed nor described. This intent was revealed, inter alia , through his speech. Because the First Amendment ha s n ever prohibited the government from using speech as evidence of motive or intent, see Wisconsin v. Mitchell , 508 U.S. 476, 489 (1993), I would affirm Caronia's conviction. By holding, instead, that Caronia’s conviction must be vacated—and on the theory that whatever the elements of the crime for which he was duly tried, he was i n f ac t c onvicted for promoting a drug for unapproved use s , in supposed violation of the First Amendment—the majority calls into question th e very foundations of our century-old system of drug regulation. I do not believe that the Supreme Court's precedents compel such a result. I therefore respectfully dissent. I. Intended Uses Alfred Caronia was convicted of conspiring to i ntroduce a “misbranded” drug into interstate commerce. See 18 U.S.C. § 371; 21 U.S.C. § 331(a). Under the Federal Food, Drug and Cosmetic Act ("FDCA"), one way in which a drug is misbranded is if its labeling lacks adequate directions for layperson use. See 21 U

. S

. C

. § 352(f)(1); 21 C.F.R. § 201.5. Whether a drug’s directions ar e “adequate

. . . for use” depends on the drug’s intended uses. This is because the

1Food and Drug Administration (“FDA”) defines “adequate directions for use” as

“directions under which the layman can use a drug safely and for the purposes for which i t is i n tended .” 21 C.F.R. § 201.5 (emphasis added). Directions are adequate only if they include, for example, “[s]tatements of all

. . . uses for which such drug is intended,” an d “usual quantities [of dose] for each of the uses for which it is intended.” 21 C.F.R. § 201.5(a), (b). This labeling provision is in part merely a disclosure requirement for the benefit of a drug’s lay users. But some

uses of drugs are never safe, at least for a layperson; because it is impossible to provide adequate direction s f or such u s e s , thi s provision also effectively prohibits introducing drugs into interstate commerce with the intent th at the drugs be used in ways that are unsafe for laypersons. 1 The labeling on the drug at issue in this case, Xyrem, stated that it was “indicated for the tr eatment of excessive daytime sleepiness and cataplexy in patients with n arcolepsy.” At all relevant times, the FDA had not approved Xyrem for any other uses. Xyrem’s labeling did not state a ny other intended

The FDA has exempted certain drugs from the requirement that their lab els 1 cont ai n adequate directions for lay use. See 21 U.S. C. § 352 (f) ; see, e.g. , 21 C.F.R. § 2 0 1 .10 0 (exempting certain prescription dru gs); cf. United States v. An Art icle of Device , 731 F.2 d 125 3, 125 9 (7th Cir. 198 4) (“Obvi ously there are many medical devices which w o uld be ineffective at best, and dangerous at worst, if left in the hands of a layman, and [FDA regulati ons] appear[] to deem any such devices ‘misbr a nded’ and thus subject to seizure. However, the regulati ons provide several exemptions from the ‘adequ at e directions for use’ requirement.”). Caronia does not argue that any such exemption a pplies here. 2uses for the drug, nor provide directions for any o ther intended uses.

Unsurprisingly, then, Caronia did not argue before th e j ury that Xyrem’s labeling included adequate directions for the off-label uses that he was alleged to have promoted. Rather, his trial focused on whether Caronia agreed with his employer, Orphan Medical, Inc. (“Orphan”), an d with others associated with Orphan, that Xyrem would be distributed for off-label use. Determining a product’s “intended uses” has long been a central concern of food and drug law. The concept originated in the Pure Food and Drugs Act of 1906, Pub. L. No. 59-384, 34 Stat. 768, which prohibited intro du ci n g any adulterated or misbranded drug into interstate commerce, id. § 2, 34 Stat. at 768, and which defined “dru g” t o include “any substance or mixture of substances intended to be used for the cure, mitigation, or prevention of disease,” id. § 5, 34 Stat. at 769 (emphasis added). Courts found violations of that statute where, as in this case, a manufacturer’s speech demonstrated an intended use that brought it within the scope of the statute such that its label was required affirmatively to disclose certain information. See, e.g. , United States v. Eleven Cartons of Drug Labeled in Part “Vapex, ” 59 F

. 2 d 4 4 6 (D. Md. 1932) (holding that “Vapex” was “intended to be used for the cure, mitigation or prevention of disease,” and was thus a “drug,” because its label stated that it was “effective to relieve a head cold instantly,” id. at 447; and further holding that the drug was 3misbranded, eve n “assum[ing] that the inhalation of Vapex is innocuous,”

because it was “required to contain a declaration on the label o f th e alcoholic content” yet failed to do so, id. at 449). When Congress expanded the law three decades later in the Food, Drug, and Cosmetic Act of 1938, Pub. L. No. 75-717, 5 2 S tat. 1040, its revisions remained anchored to the c o nc e pt of “intended uses.” The definition of “drug”

was broadened to also include “articles

. . . intended to affect the structure or any function of the body,” id. § 201(g)(3), 52 Stat. at 1041 (emphasis added), and the parallel category of “devices” wa s c r e ated and similarly defined in terms of intended uses, see id. § 201(h), 52 Stat. at 104 1 . At the same time, Congress broadened the definition of a “misbranded” drug to include any drug with labeling not bearing “a d e qu at e directions for use.” Id. § 502(f)(1), 52 Stat. at 1051. Under the 1938 Act, courts upheld convictions for introducing drugs into interstate commerce that lacked adequate labeling for their intended uses, and routinely relied on “oral represe ntations made by

. . . authorized sales distributors” to determine a product’s intended uses. V.E. Irons, Inc. v. United Sta t es , 244 F.2d 34, 44 (1st Cir. 1957) (upholding a conviction for introduc i n g into interstate commerce “articles of drug [that] were misbranded in that their labeling failed to bear ‘adequate directions for use’ for the various diseases and conditions for which they were intended,” and relying on “both graphic materials

4distributed and testimony of oral representations t o u sers and prospective

users . . . . show[ing] that the products shipped were to be used as drugs”). The modern FDCA continues to define “drugs” (and “devices”) on the basis of an article’s intended uses. See 21 U.S.C. § 321(g)(1)(B), (C); 21 U.S.C. § 321(h)(2), (3). The concept of “intended uses” th e refore largely defines the scope of the FDA’s regulatory authority. See F D A v . Brown & Williamson Tobacco Corp. , 529 U.S. 120, 126 (2000). To put the matter in practical terms: it is because of the “intended uses” principle that hardware stores are generally free to sell bottles of turp e nti ne, but may not label those bottles, “Hamlin’s Wizard Oil: There is no Sore it will Not Heal, No Pain it will not Sub due.” 2 According to regulations that have remained essentially unchanged for sixty years, see17 Fed. Reg. 6818, 6820 (1952) (codified at 21 C.F.R. § 1.106(o) (Cm. Supp. 1955)), the FDA defines a drug’s “intended uses” on an objective, rather than subjective, basis: The words intended uses or words of similar import

. . . refer to the S e e W i k i p e d i a , H a m l i n ’ s W i z a r d O i l , 2 http://en.wikipedia.org/wiki/Hamlin’s_Wizard_Oil (last visited May 30, 201 2); cf. United States v. Ruther ford, 442 U.S. 544 , 558 (197 9) (“Since the turn of the century, resourceful entrepreneurs have advertised a wide varie ty of purportedly simple and painl ess cures for cancer , including li niments of turpenti n e , m ustard, oil , eggs, and ammoni a; peat moss; arrangements of colored floodlamps; pastes made from glycerin and li mburger cheese; mineral tab lets; and ‘Fountain of Youth’ mixtures of spices , oil , and suet. . . . [H] istorical experience does suggest why Congress could reasonably have determined to protect . . . patients[] from the vast ra n g e of self-styled panaceas that inventive mi nds c an devi se.”). 5objective intent of the persons legally responsible for the labeling of

drugs. Th e i nt ent is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for e x ample, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circ u m s tances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neith e r l ab e l e d nor advertised.

. . . [I]f a manufacturer knows, or has knowledge of facts that would give him notice, that a drug introduced into interstate comme rc e 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. 21 C.F.R. § 201.128. As previously noted, Caronia did not contend at trial that Xyrem’s label (which provided dosage and other instructions for Xyrem’s use in the treat m e nt of narcolepsy patients who experience cataplexy and excessive daytime sleepiness) provided adequate i n s tru ctions for any other use. In this case, then, Xyrem was “misbranded”—and Caronia could be guilty of conspiring with others to introduce it into i nt e r s t ate commerce in such a state—if the conduct and statements of the persons legally responsible for labeling the drug (or the c o n duct and statements of their representatives) demonstrated an objective intent that Xyrem be used for off-label purposes.

II. The First Amendment and Speech as Evidence of Intent It is well settled that “[t]he First Amendment

. . . do es not prohibit the evidentiary use of speech to establish the elements of a crime or to prove motive

or intent.” Wisconsin v. Mitchell , 508 U.S. 476, 489 (1993). To demonstrate that 6Xyrem was intended for off-label u s e s ( a n d thus that it was misbranded) the

prosecution in this case relied, inter alia , upon Caronia’s statements that Xyrem could be used to treat “insomnia, [f]ibromyalgia[ , ] p eriodic leg movement, restless leg, .

. . Parkinson’s and

. . . MS.” Because Caronia’s speech was used 3 simply as evidence of Xyrem’s intended uses, I agree with the government that Caronia’s conviction does not run afoul of the First Amendment. The majority unsurprisingly agrees that speech may be used as evidence of intent. It even leaves open the possibility that speech may serve as evidence of intent to introduce a misbranded drug into interstate commerce. See Maj. Op. at 25. The majority nonetheless concludes that in this particular case “the government clearly prosecuted Caronia for his words—for his speech” and not for conspiring to introduce a misbranded drug into interstate commerc e . Maj.

This was not the only evidence on which the government relied. As the 3 maj ority acknowledges, Xyrem is a “powerful central nervous system depressant” that the FDA requires to bear a “bl ack box” warning (the most serious warning pla ced on prescription medicine) in li ght of its potential side effects, whi ch include seizure, respiratory depression, coma, and death. Maj. Op. at 11. Yet in the tape-recorded meetingof October 26, 2005 between Caronia and Dr. Charno, to whi ch the majority refers, Caronia described Xyrem as “a very s afe drug,” with no contraindicati ons. At Caronia’s second meeting with Dr. Charno on November 2, Dr. Glea so n , o n e o f Caronia’s co-conspirators , described many potentialuses forXyrem, includingin the treatment of obesity and chronic fatigue, and added that “for the problems with insomnia there’s no better dru g, no safer dru g, it’s as safe as Ambien and Sonata

. . . .” Caronia later admitted that his employer required him to meet an annual sales quota of 520bottl es of Xyrem i n 200 5, the year these conversations took place, a nd that he was unabl e to meet it. In fact, the salaries of Orphan’s sales pers onnel depen ded to a significant degree on meeting sales targets, and in 200 5 Caronia was ranked near the very bottom of Orphan’s nationalsales force. 7Op. at 27–28. I disagree that the government prosecuted Caronia for his speech.

I also fail to see how the majority’s reasoning would ever allow such speech to support a conviction under 21 U.S.C. § 331(a). For this reason, I conclude the majority’s opinion is fundamentally at odds both with Mitch ell and with the underlying premises behind much of the FDCA’s regulatory scheme. I do not agree with the majority that Caro nia was “prosecuted and convicted for p ro m o ti n g Xyrem off-label.” Maj. Op. at 26. The district court correctly instructed the jury as to all the element s necessary to prove a conspiracy, as well as the additional elements, derived from 21 U.S.C. § 331(a), to prove the conspiracy’s unlawful purpose:

To sustain the ch ar ge of conspiracy to introduce into interstat e c ommerce a misbranded drug, the Government must prove the element[s] of conspiracy as I previously described them for you and must also prove the following elements of misbranding through the introduction of a misbranded drug into interstate commerce. First, the Government must prove that the defendant conspired to introduce or conspired to cause to be introduced a drug into interstate co m m e rce or c o n s p ired to deliver a drug for introduction int o interstate commerce or conspired to cause a drug to be delivered for introduction into interstate commerce. Second, the Government must prove that the drug was misbranded, as I’ve previously defined that term. If you find that the Government has satisfied its burden with respect to each of these elements, along with satisfying the elements of conspiracy as I have previously explained them to you, then you should find 8the defendant guilty of that prong of the conspiracy count charging him with conspiracy to misbrand in violation of Section 331(a). The majority makes much of the fact that the district court also instructed the jury that “[a] misbranded drug may be shown by a promotion of the drug by

a distributor for an intended use different from the use for which the drug was approved by the Food and Drug Administration.” But this wholly appropriate charge was but part of the district court’s explanation of the “objective intent” standard with respect to “intended uses”:

The intended use of a drug can be determined from its label, acco mp anying l ab el s , p romotional material, adverti sing or any other relevant source that reveals the ma n ner in which the drug’s distributors expect[ ] the p ro duct to be used. A misbranded drug may be shown by a promotion o f the drug by a distributor for an intended use different from the use for which the drug was approved by the Food and Drug Administration, the Government agency charged with the res p onsibility for approving a drug’s use. Under 21 Code of Federal Regulations, Section 201.128, intended use or words of a similar import refer to the objective intent of the persons legally responsible f

o r th e labeling of drugs. The intent is determ in e d by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the drug. This objective intent may, for example, be shown by labeling c l aims, advertising matter or oral or written statements by such persons or their representativ e s . It may be shown by the circumstances that the drug is, with the kn owledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled, nor advertised. Granted, in a single sentence at th e conclusion of this instruction the district court stated that drug manufacturers “are not permitted to promote uses for a

9drug that have not been cleared by the United States Fo o d and Drug

Administration.” In context, however, the district court was simply instructing the jury that promotion of an off-label use may demonstrate an objective intent that a drug be used for off-label purposes—and thus that it is being placed into interstate commerce without proper labeling. And this, contrary to th e majority’s suggestion, was not error. See United States v. Sabhnani , 599 F.3d 4 215, 237 (2d Cir. 2010) (admonishing that jury instructions are not to be read in isolation, but in their entirety, to det e r m i n e whether they communicate the “essential ideas” to the jury); accord United States v. Tran , 519 F.3d 98, 105 (2d Cir. 2008); see also Cupp v. Naughten , 414 U.S. 141, 146–47 (1973) (“[A] single

No t ably, Caronia himself does not argue that the district court’ s 4 instruction was improper. While I disagree with the majority’s conclusion that the jury was improperly instructed, moreover, I note to be clear that an identical ins tru c ti o n co u ld b e p rob l e m atic i n a dif f e r e nt case of alleged misbranding—where a defendant argued, for example, that the drug’s labeling included adequate directions for uses that were not FDA-approved. Cf. United States v. Articles of Drug, 585 F.2d 575, 585 n.20 (3d Cir. 1978) (instructing the district court, which had “entered no findings of fact as to misbranding” and did not consider the “argument that the drugs were labeled sufficiently for lay use,” to “consider these factors” on remand). Provided a drug bears adequate labeling for an unapproved use, a defendant distributing such a drug cannot be convicted under 21 U.S.C. § 331(a) f o r i ntroducing a misbranded drug into interstate commerce. Labeling a drug with directions for unapproved uses, however, may violate another provision of the FDCA. See, e.g. , Wyeth v. Levine , 555 U.S. 555, 568 (2009) (“The FDA’s premarket approval of a new drug application includes the app rov al of the exact text in the proposed label. See 21 U.S.C. § 355; 21 C.F.R. § 314.105(b) (2008). G e n e r ally speaking, a manufacturer may only change a drug label after the FDA approves a supplemental application.”). 10instruction to a jury may not be judged in artificial isolation, but must be viewed

in the context of the overall charge.”). The majority also focuses on the prosecution’s summations, arguing that the government did not use Caronia’s promotion of Xyrem as evidence of misbranding, but rather “prosecuted Caronia for his off-label promotion.” Maj. Op. at 19 (emph a s i s added). Suffice it to say, however, that any claim that Caronia was convicted for his speech, as opposed to his conspiracy, is belied by the fact that, as the majority rightly concedes, the district court explained the

e lements of conspiracy and misbranding to the jury and instructed that each element must be shown beyond a r e a sonable doubt. We presume that juries follow their instructions. United States v. Williams , 690 F.3d 70, 77 (2d Cir. 2012). Caronia, moreover, objected not at all to the prosecution’s references to his off-label promotion of Xyrem—and unsurprisingly, since read in context, the government properly referred to this promotion to prove Caronia’s participation in a conspiracy to distribute Xyrem for uses that its labeling neither described nor explained. At bottom, the majority is troubled that “the simple promotion of a drug’s off

- l ab e l u s e” can lead to criminal liability under the FDCA. Maj. Op. at 30. That is, where all that a drug manufacturer (or its representative) does is sell

a prescription drug and promote it for an off-label purpose, the majority

11concludes that prosecution raises serious First Amendment concerns—and

regardless whether the off-label promotion is presented as mere evidence or as the proscribed conduct itself. The majority’s conclusion , clearly stated, is that while speech might serve as evidence of other types of mislabeling, such as false

or deficient labeling, see Maj. Op. at 26–27, a mislabeling charge simply may not rest on off-label promotion. This is a departure from precedent. My conclusion here—that promotion of a use may demonstrate an objective int e nt th at the drug be used for that purpose—has long been endorsed by this Circuit. See United States v. Writers & Research, Inc. , 113 F.3d 8, 11 (2d Cir. 1997) (“We agree with the district court that, as a matter of law, if 714X was promoted as a treatment or cure for cancer, AIDS, or other disea s e s , it is subject to the requirements of the FDCA

. . . .”); United States v. An Article

. . . Consisting of 216 Individually Cartoned Bottles , 409 F.2d 734, 739 (2d Cir. 19 6 9) (“I t i s w ell settled that the intended use of a product may be determined from its label, accompanying labeling, promotional material, advertising, and any other r e l evant source. . . . Thus, Congress has made a judgment that a product is subject to re gul ation as a drug if certain promotional claims are made for it.”). Such use of speech, moreover, has never been prohibited by the First Amendment. See Sorrell v. IMS Health Inc ., 131 S. Ct. 2653, 2664–65 (2011) (“[T]he First Amendment does not prevent restrictions 12directed at commerce or conduct from imposing incidental burdens on speech.

That is why a ban on race-based hiring may require employers to remove ‘White Applicants Only’ signs; why an ordinance against outdoor fires might forbid burning a flag; and why antitrust laws can prohibit agreements in restraint of trade.”) (citations and some internal quotation marks omitted). It is true that the introduction of Xyrem into interstate commerce by Caronia’s employer was generally legal so long as the drug was not intended to be used for purposes that lacked ad e qu at e directions on its labeling. It is also true that, absent Caroni a ’ s speech (and speech by other Orphan representatives), the jury likely would not have found that Xyrem was intended for such off-label uses. Consistent with the First Am e n d m ent, however, otherwise permissible conduct may become impermissible if undertaken with a prohibited motive, and speech may be used as evidence o f s u ch a m o tive. An employer, for example, is generally free to refuse to promote an employee simply because he does not like the employee ’ s attitude, but he may not refuse to promote the employee because of her sex. See Wisconsin v. Mitchell , 508 U.S. at 487 (“In Hishon [ v. King & Spalding, 467 U.S. 69, 7 8 (1984)], we rejected the argument that Title VII infringed employers’ First Amendment rights.”). The First Amendment does not bar using the employer’s speech to demonstrate his discriminatory motive. See Wisconsin v . Mitchell , 508 U.S. at 490 (citing Price 13Waterhouse v . H o pkins , 490 U.S. 228, 251–52 (1989) (plurality opinion)). Indeed,

as the crimes o f attempt, conspiracy, and inducement demonstrate, “[w]ords alone may constitute a criminal o f f e n s e , even if they spring from the anterior motive to effect political or social change.” United States v. Freeman , 761 F.2d 549, 551 (9th Cir. 1985) (Kennedy, J.). See generally Kent Greenawalt, Speech, Crime, and the Uses of Language 6–7 (1989) (enume r ati n g twenty-one crimes that “critically involve communication,” id. at 7). Simply put, that Caronia was otherwise free to introduce Xyrem into interstate commerce does not give him

a First Amendment right to introduce it into interstate commerce for a ny intended purpose he wished. Caronia attempts to distinguish this line of authority by arguing that he merely discussed “a perfectly lawful practice: th e u s e of a lawful drug, Xyrem, for off-label purposes.” Appellant’s Reply Br. at 10. But the fact that a physician

or a patient could legally use Xyrem for an off-label purpose is not e n o u gh to make out Caronia’s First Amendment claim. There might be no law forbidding the con s u m p tio n of arsenic. But this would not endow Abby and Martha with

a First Amendment right to offer arsenic-laced wine to lonely old bachelors with the intent that they drink it. See Arsenic and Old Lace (Warner Bros. Pictures 1944). And any statements Abby or Martha made suggesting their intent—even if all of the statements were truthful and not misleading—would not be barred

14from evidence by the First Amendment simply because arsenic might legally be

consumed. 5 Although Caronia relies heavily on the Supreme Court’s decision in Thompson v. Western States Medical Center, 535 U.S. 357 (2002), that case did not discuss the use of speech a s evi d e nce of intent. The statute at issue in Western States, a s th e government conceded before the Supreme Court, regulated speech directly rather than as evidence of intent. See id. at 364–65 (“[T]he pharmacy, licensed pharmacist, or licensed physician compounding the drug may ‘not advertise or promote the compoundi n g o f any particular drug, class of drug, or type of drug’

. . . .”) (quoting 21 U.S.C. § 353a(c)); Western States , 535 U.S. at 370–71 (“Th e G ov ernment argues that advertising

. . . is ‘a

Indeed, speech encouragi ng others to engage in certain legal conduct has long 5 been directl

y regulated or prohib ited in a variety of areas. For exampl e, an insider who is privy to an impending corp orate merger is prohib ited from telling a friend that one of those companies is a good buy—ev en if th at st atement is truthful and even if the friend (who does not reali ze that she ha s just been ma de privyto materialnonpublic information) may l egally buy stock in that company. See United States v. Gansman , 657F.3 d 85, 92 (2d Cir. 20 11) (el ements of tipper liability); United States v. Falcone , 257 F.3 d 226 , 234 (2d Cir. 200 1 ) (e l e m e nt s of tippee li ability). Each of two corp orations may be free to raise its prices , but the Sherman Act forbi ds them from discus sing such a course of action. See In re High Fructose Corn Syrup Anti trus t Litig ., 295 F.3 d 65 1 , 6 5 4 (7 th Cir. 200 2) (Posner, J.); Louis Kaplow , On the Meaning of Hor izo n ta l Agreements in Compe tition Law , 99 Calif. L. Rev. 683 (201 1). Likewi se, nonlawyers are forbidden from giving legal advice even if the advice is sound , see, e.g. , People v. Alf

ani , 125 N.E. 671 , 673 (N.Y. 191 9), and unlicensed layperson s may not provide medical diagnoses, regardless of their accuracy, see, e.g. , Locke v. Ionia Circuit Judge , 151 N.W. 623 , 625 (Mich. 191 5); Commonwealth v. Jewelle , 85 N.E

. 8 5 8 , 859 (Mass . 19 08). 15fair proxy for actual or int e nded large-scale manufacturing

. . . .’”) (emphasis

added). The statute at issue in Sorrell v. IMS H ea l t h I n c . , 131 S. Ct. 2653 (2011), also targeted speech dir e c tly. See id. at 2660 (“Pharmaceutical manufacturers and pharmaceutical marketers shall not use prescriberidentifiable information for marketing or promoting a prescription drug unless the prescriber consents . . . .”) (quoting Vt. Stat. Ann., Tit. 18, § 4631(d) (Supp. 2010)). By contrast, Caronia’s conviction requir e d a f i n ding that Xyrem was intended by those responsible for its labeling for an off-label use—a finding which “may be sho w n b y 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 neither labeled nor advertised.” 21 C.F.R. § 201.128. See generally Kris t a Hessler Carver, A Global View of the First Amendment Constraints on FDA , 63 Food & Drug L.J. 151, 187–8 8 (2008). Put another way, if the jury had concluded there was a reasonable doubt

as to whether Caronia and Orphan actually intended to sell Xyrem to Caronia's custom e rs—to introduce it into interstate commerce—then Caronia could not have been convicted under § 331(a), no matter wh at he said. By contrast, a pharmacy would violate the statute in Western States as soon as it advertised the compounding of particular drugs. See 5 3 5 U.S. at 364–65 (citing 21 U.S.C. § 353a(c)). Similarly, a Vermont pharmacy would violate the statute in Sorrell as 16soon as it disseminated prescriber-identifying information for marketing

purposes. See 131 S. Ct. at 2660. S p e e ch alone was sufficient to trigger punishment under the challenged statutes in those cases. Speech alone is not, however, sufficient to sustain a conviction under 21 U.S.C. § 331(a). My analysis here is not original. The D.C. Circuit reached the same conclusion in Whitaker v. Thompson , 353 F.3d 947, 9 5 3 (D

. C

. Cir. 2004), in 6 which a plai ntif

f argued that he had a First Amendment right to label his product with a drug claim despite its lack of FDA approval. The Whitaker court disagreed, reasoning that: Assuming that the government may c ondition the sale of drugs on passage through the elaborate testing that the statute requires

. . . , the key step is the []FDCA principle that cla s sification of a substance as a ‘drug’ turns on the nature of the claims advanced on its behalf. That principle, i n turn , rests on the idea that claims about a product by its manufacturer and vendors, including product labeling, serve as evidence of the sellers’ intent that consumers will purchase and use the pro duct for a particular purpose—and, therefore, as evidence whether the product is or is not a drug. The question is whether this use of speech to infer intent, which in turn renders an o th e rwise permissible act unlawful, is constitutionally valid. In fact, the First Amendment allows ‘the evidentiary u s e of speech to establish the e l e m e nts of a crime or to prove motive or intent.’ Thus it is constitutionally p e r m issible for the FDA to use speech, in the form of labeling, to infer int e nt for purposes of determining that [the plaintiff’s] proposed sal e of saw palmetto extract would constitute the forbidden sale of an unapproved drug. Id. (citations and paragraph breaks omitted). Caronia attempts to distinguish Then-Judge Roberts was amember of the una nimous panel. 6 17Whitaker by arguing that “the drug itself in Whitaker could not be sold lawfully,

and so there were no lawful off-label uses to promote.” Appellant’s Reply Br. at 15 (internal quotation marks and brackets omitted)

. But the product in Whitaker

—“‘saw palmetto,’ an extract from the pulp and seed of the dw arf American palm,” Whitaker , 353 F.3d at 948—could be sold lawfully so long as it

was not a “dru g , ” and whether it was a drug depended entirely upon the plaintiff’s speech, as evidence of his intent, when he offered it for sale. That case i s therefore indistinguishable from this case; indeed, even if the FDA had no t approved Xyrem for any medical uses at all, Caronia could presumably have sold Xyrem as an industrial solvent if it happened to be excellent at removing grease and grime. Not ev e ry prohibition on conduct undertaken with a certain intent is necessarily constitutional: the problem p o s e d by a ban on “sending any leaflet with the intent to influence another’s vote” suggests the limits on the analysis here. It remains the case, h o wever, that the simple fact that one is generally allowed to sell something does not imbue one with a constitutional right to sell it for any intended purpose. And the prohibition here on distributing drugs with th e i ntent that they be used for purposes not supported by their labeling i s entirely consistent with the b ro a der p urp o s e s of the FDCA—namely, minimizing those occasions on which patients use drugs that have not been shown to be safe 18and effective. III. Applying Central Hudsonand Sorrell Finally, ev e n if using Caronia’s speech as evidence of his intent was not necessarily constitutionally permissible—in other words, even if the protection afforded to commercial speech requir e s an analysis of this question where the customers of a p ro du c t like Xyrem may lawfully use it for purposes not addressed in the label, and where the FDA does no t purport to regulate the claims made by unrelated third parties about th e efficacy of such uses, see George W. Evans & Arno l d I. Friede, The Food and Drug Administration’s Regulation of Prescription Drug Manufacturer Speech: A First Amendment Analysis , 58 Food & Drug L.J. 365, 390 (2003)—I believe the correct application of commercial speech princ ip l e s requires us to uphold Caronia’s conviction. I agree with the majority that our analysis is guided by Central Hudso n Gas & Electric Corp. v. Public Service Commission of New York , 4 4 7 U

. S

. 5 57 (1980), and Sorrell v. IMS Health Inc. , 131 S. Ct. 2653 (2011). I conclude, however, that the FDCA’s misbranding provision survives the scrutiny required by those cases because it directly advances a substantial government interest and is narrowly drawn to further that interest. “[O]ne of the [ FD CA] ’ s core objectives is to ensure that any product regulated by th e FDA is safe and effective for its intended use.” Brown & 19Williamson , 529 U.S. at 133 (2000) (internal quotation marks omitted). The

FDCA is meant to achieve this objective through a rigorous premarket approval process. See 21 U.S.C. § 355. Under this process, a manufacturer may not sell

a drug without first providing p ro o f t o the FDA that the drug is “safe for use”

a n d “e f fective in use.” See id. § 355(b). There must be “substantial evide nc e , ” including evidence from clinical investigations, “that the dru g will have the effect it purports or is represented to have.” Id. § 355(d). This process is a central, if not the central, feature of the FDCA. Prior to the passage of the FDCA, the government could combat misleading drug claims only throu gh p o st

- m arket enf orcement actions. The 1938 Act’s “most substantial innovation” was to require approval of a drug’s safety be fore it could enter the market. Wyeth , 555 U.S. at 566. This innovation became even more important after Congress amended the FDCA in 1962 to also require premarket approval of a drug’s effectiveness for its stated uses. See Drug Amendments of 1962, Pub. L. No. 87-781, § 102, 76 Stat. 780, 781. B e hi n d the 1962 amendments were

concerns th at doctors could not adequately evaluate frequently misleading claims by drug manufacturers without a body of objective, reliable information. See, e.g. , Henry A. Waxman, A History of Adverse Drug Experiences: Congress Had Ample Evidence to Support Restrictions o n the Promotion of Prescription Drugs , 58 Food & Drug L.J. 299, 301–08 (2003); Alan H. Kaplan, Fifty Years of 20Drug Amendments Revisited , 50 Food & Drug L.J. 179, 184–8 5 (1995).

The Supreme Court has accordingly stated th at “[p]reserving the effectiveness and integrity of the FDCA’s new drug approval process is clearly

an im p o rt a nt governmental interest.” Western States , 535 U.S. at 369. Given the benefits of premarket approval, “the Government has every reason to want as many drugs as possible to be subject to that approval process.” Id. The FDCA’s prohibition on off-lab e l marketing directly advances this interest. If drug manufacturers were allowed to promote FDA-approved drugs for non-approved uses, they would have little incentive to seek FDA approval for those use s . Prohibiting such promotion is thus “one of the few mechanisms available” to encourage participation in the approval process. Washington Legal F oundation v. Friedman , 13 F. Supp. 2d 51, 72 (D.D.C. 1998), vacated in p a r t , Washington Legal Foundation v. Henney , 202 F.3d 3 3 1 (D

. C

. Cir. 2000). And premarket approval improves drug safe ty and effectiveness only to the extent that drugs are not sold without such approval. In concluding that prohibiting off-label promotio n do e s not directly advance the government’s interests, the majority places great weight on the fact that “physicians can prescribe, and patients can use, drugs for off-label purposes.” Maj. Op. at 39. But this i s al so true for substances that have not been approved by the FDA for any medical use at all. The law generally permits 21a hardware store to sell turp e nti n e , and though such conduct may not be

a dvisable, the law generally permits a consumer to purchase that turp entine an d

use it a s a p ain reliever. Under the majority’s reasoning, then, any substance that may be legally sold for some purpose may be promoted by its manufacturer f o r any purpose—so long as the manufacturer’s statements are mer e ly unsubstantiated, rather than demonstrably false or misleading. But this reasoning w o uld invalidate the very definitions of “drug” and “device” that undergird the entire FDCA. The majority also emphasizes that the prohibition on off-label promotion applies only to a “particular class of speakers”— namely, drug manufacturers. Maj. Op. at 39. But drug manufacturers are the precise group that the govern m e nt must encourage to participate in the new drug approval process. Indeed, if the prohibition applied to any broader class of speakers, it would likely fail C e ntral Hudson’s fourth requirement that a regulation be “narrowly drawn.” The Supreme Court’s decision in Sor re l l i s thus inapposite in the present circumstances. The statute there did not directly advance Vermont’s interest in protecting patient privacy because it applied to only a small subset of those groups that could possibly compromise patient privacy. See 131 S. Ct. at 2668. Drug manufacturers, in contrast, form the entirety of those speakers that could possibly undermine the new drug approval process by not p artic ip ating in it. 22Furthermore, allowing dru g m anuf acturer s to p ro mote of

f

- l ab el u s e s woul d undermine the FDA’s approval process for not only new uses of pre-approved drugs, but also for entirely new drugs. As explained above, when determining whether a drug should be approved, the FDCA requires consideration not only of the drug’s safety, but also its effectiveness. See 21 U.S.C. § 355; United States

v. Rutherford , 442 U.S. 544, 555 (1979) (“[T]he [FDA] Commissioner generally considers a dru g safe when the expected therapeutic gain justifies the risk entailed by its use.”). If a drug m a nufacturer must be allowed to distribute a drug for any use so long as it is approved for one use, the government’s balancing of a drug’s benefits against its risks becomes very difficult or even i m possible. Drugs viewed as safe for certain uses might be considered unsafe overall if the benefits and risks being weighed are not for a specific intended use but rather for any use at all, whether supported by evidence or not. The prohibition of off-label promotion is thus not simply a “paternalistic” attempt to shield physicians and patients from truthful information. See Maj. Op. at 40. Rath e r , it i s a necessary tool for the effective functioning of a regulatory system that the Supreme Court has endorsed as legitimate. The

m ajority implies that prohibiting off-label promotion is unconstitutionally “paternalistic” regardless whether the dru g m anuf acturer’ s cl aim s are a ddre ssed to a physician or to a patient. See, e.g. , Maj. Op. at 40 (“[P]rohibiting off-label 23p ro motion by a ph arm ac eutical manufacturer while simultaneously allowing of f

label use ‘paternalistically’ interferes with the ability of physicians and patients to receive potentially relevant treatment information . . . .”) (emphasis added). But if drug manufacturers have a First Amendment right to distribute drugs for any use to physicians or even directly to patients, then the e ntire FDCA may well be unconstitutional. Prohibiting off-label promotion by drug manufacturers is also the least restrictive way of advancing the government’s interests. Although the majority asserts various alt e rn ativ es, none would be similarly effective. A disclaimer system or required listing of intended uses would provide manufacturers much less incentive t o submit their drugs for FDA approval, and in turn encourage promotion based on dat a much less reliable than the clinical investigations required under 21 U.S.C. § 355(d). A ceiling on off-label p r e s c rip tions would 7 require colle c ti n g d ata from countless numbers of doctors and patients and, given the medical uncertainties involved, could needlessly (and simultaneously) result in the denial of some effective treatments and the overprescription of Indeed, experts have concluded that most pre scriptions for off- label use have 7 little or no scientific supp ort. See Randall S. Stafford , Regulating Off-Label Drug Use: Rethi nking the Role of the FDA , 358 New Eng. J. Med. 1 4 2 7, 142 7 (200 8) (“In an exami nati on of off- label prescribing of 160 common dru gs, off- label use was . . . found to account for 21% of all prescriptions, and most off- label dru g uses (73%) were shown to have little or no scientific supp ort.”) (citing David C. Radley, Stan N. Finkel stein & Randall S. Stafford , Off-Label Prescri bing Among Office-Based Physic ians , 166 Archives of InternalMed. 102 1 (20 06)). 24ineffective and even dangerous ones. Finally , a b an on off-label prescriptions

would be no better. Indeed, it would constitute an unprecedented intrusion into the practice of medicine, and would result in perhaps an even greater restriction

on speech. See Central Hudson , 447 U.S. at 563–64 (government free to ban “commercial speech related to illegal activity”). And again, because a product’s very definition as a “drug” depends upon its intended use (which is often established by the manufacturer’s speech), it is unclear why the majority’s lessrestrictive-alternatives analysis is not equally applicable to the FDCA’s entire scheme of drug regulation. That the FDCA is both “content- and speaker-based” within the meaning of Sorrell , 131 S. Ct. at 2663, does not alt e r th e foregoing analysis. Every commercial speech case, by its very nature, involves both content- and speakerbased speech restrictions. See Va. State Bd. of Pharmacy v. Va. Citizens Consumer Council, Inc ., 425 U.S. 748, 761 (1976) (“If there i s a kind of commercial speech

. . . it must be distinguished by its content . ”)

. Yet the S upreme Court has long acknowledged—and acknowledged again in So rre l l

—th at “the governm ent’ s le gitim ate interest in protecting consumer s f ro m commercial h ar ms explains why commercial speech can be subject to greater governmental regulation than noncomme rc i al speech.” Sorrell, 131 S. Ct. at 2672 (i nt e rnal quotation marks omitted). Indeed, the Supreme Court struck 25down the ban on energy advertising in Central Hudson because a content-based

less-restrictive alternative existed. See Cent. Hu ds o n , 447 U.S. at 571 (“[T]he Commiss i o n could attempt to restrict the format and content of Central Hudson’s advertising. It might, for example, require that the advertisements include information about the relative efficiency and expense o f th e o ffered service, both under the current conditions and for the fores e e ab l e future.”). Sorrell did n o t purport to overrule the Central Hudson test, which has guided First Amendment doctrine in this area for thirty years. Moreover, in Sorrell the Court noted that Vermont did not argue that its challenged statute “will prevent false or misleading speech.” 131 S. Ct. at 2672. Rather, Vermont’ s “interest in burdening the speech of detailers instead turn[ed]

on nothing more than a difference of opinion.” Id. In contrast, Congress intended the FDA approval process to prevent dangerous products with false or

m i s l e a ding labels from entering the market, and also to provide a base o f reliable, objective information about prescription drugs that could help physicians and patients identify potentially misleading claims. Clearly this is the type of statute to which Sorrell intended that Centra l Hu ds o n would still apply. 8

Nor does the fact that 21 U.S. C. § 331 (a) applies criminal penalti es necess arily 8 mean that it warrants heightened scrutiny. The case that the majority cites for thi s prop osition, Holder v. Humani tarian Law Pro j ec t , di d not premise its applicati on of 26It is certainly true that "the 'fear that people would make bad decisions if

given truthful information' cannot justify co ntent-based burdens on speech." Sorrell , 131 S. Ct. at 2670–71 ( qu o ti n g Thompson , 535 U.S. at 374). But this does not mean that conveying non-demonstrably false information to consumers must take precedence over all competing government interests. Our system of drug regulation developed t o protect consumers from misleading and unsubstantiated claims about drugs’ safety and efficacy, and the prohibition on off-label promotion by drug manufacturers is esse nti al to maintaining the effectiveness of that system. Therefore, even if such a prohibition is considered

a dir e c t r egulation of speech, it is a regulation that directly advances a substantial government interest in a manner not more extensive than necessary to serve that interest. I would thus find it constitutional under Central Hudson and Sorrell

.

IV. The Verdict Sheet and the Jury’s Verdict Because I believe that the FDCA’s m i sb randing provision may

con s titutionally be applied to Caronia’s conduct, I next address Caronia’s

heightened scruti ny o n the statute’s criminal penalti es. See 130 S. Ct. 270 5, 272 4 (201 0). Mo reov er, the Supreme Court has previously applied Cent ral Hudson to statutes that provide for or trigger criminal punishment for speech. See Greater New OrleansBroad. Ass’

n, Inc . v. United States , 52 7 U .S. 173, 177 (1999); 44 Liquormart, Inc. v. Rhode Island, 517 U.S. 484 , 490 n.3 (199 6); Bolger v. Youngs Drug Products Corp

. , 46 3 U .S. 6 0, 6 1–6 2 (19 83). 27remaining arguments: (1) that th e district court erred in breaking down the

conspiracy charge on the verdict sheet into two subissues; and (2) that the jury rendered an inconsistent verdict by convicting C aronia of conspiring to introduce

or deliver for introduction i nt o i nterstate commerce a misbranded drug while finding him not guilty o f conspiring to do an act to a drug that would result in it being misbranded. The f ir st count of a two-count information charge d C aronia with con s p iring both (1) to introduce into interstate commerce a drug that was misbranded and (2) to do an act with respe c t t o a dru g that would result in that drug being misbranded. With respect to that count, the district court submitted a two-part

9 verdict sheet to the jury which asked:

1. How do you find the defe n d a nt , ALFRED CARONIA, on Count One of the Information? (a) Conspiracy to introduce or deliver for introduction into interstate commerce a drug, Xyrem, that was misbranded? NOT GUILTY _____ GUILTY _____ (b) Conspiracy to do an act with respect to a drug, Xyr e m , when such drug was held for sale af t e r s hipment in interstate commerce when such act would result in Xyrem being misbranded? NOT GUILTY _____ GUILTY _____ The jury concluded that Caronia was guilty with respect to question (a) and not guilty with respect to question (b).

The second count charged Caronia with doing an act with resp ect to a dru g that 9 resulted in that drug b eing misbranded. 28Caronia argues that the district court erred by subdividing the conspiracy

charge on the verdict sheet because, he claims, the district court essentially split the charge into two separate counts. But we have held that a conspiracy charge may allege an agreement to commit more than one offense, see United States v. Coriaty , 300 F.3d 244, 250 (2d Cir. 2002) (“We h av e u pheld convictions for multi-obj e c t conspiracies charged in the conjunctive even when there was insufficient evidence to support one of the objects of the conspiracy.”), and that

a district court does no t i m permissibly constructively amend a charge by subdividing an offense into parts, see United States v. McCourty , 562 F.3d 458, 470 (2d Cir. 2009) (“No constructive amendment resulted wh e n th e District Court broke the single offense into two parts to be a d dr e s s e d b y the jury.”). I therefore find no error in the verdict sheet. Caronia further argues that the jury rendered an inconsistent verdict by finding him not guilty of c o n s p iring to do an act to a drug that would result in it being misbranded while finding him guilty of conspiring to introduce or deliver for introduction into interstate commerce a misbranded drug. But these verdicts

were not inconsistent—for example, the jury may have concluded that the drug

w a s n o t b eing held for sale after shipment in interstate commerce. And eve n assuming the verdicts were inconsistent, “the convicted defendant’s protection

a g ainst an irrational verdict is his ability to have the courts review th e 29sufficiency of the evidence to support his conviction,” United States v. Acosta , 17

F.3d 538, 545 (2d Cir. 1994). There was ample evidence for a reasonable jury to conclude beyond a reasonable doubt that Caronia conspired to introduce or deliv e r f o r introduction into interstate commerce a misbranded drug. Indeed, Caronia was caught on tape with Dr. Gleeson suggesting off-label uses of Xyrem to doctors. I therefore see no error in the verdict sheet and no incon s istency requiring reversal or vacatur in the jury’s verdict. * * * The majority has chosen to apply heightened scrutiny to this case, though

we have not do n e s o in other cases involving the use of speech as evidence of intent—for example, in antidiscrimination actions or prosecutions for criminal inducement, attempt, and conspiracy—cases I cannot meaningfully distinguish from this one. The majority’s deci sion today extends heightened scrutiny further than the Supreme Court ever has, and calls into question a fundamental regime of federal regulation th at h a s e xi sted for more than a century. I respectfully dissent.

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