## In the



# U n ited S ta tes Co urt o f Ap p ea ls

F o rth eS e v e n th C ir cu it
N o. 08

- 2265 B O NN IE J. M A S ON, i ndi vi dual l ya nd as co- adm i ni str ato r ofthe est ate o f Tr i ci a M
. M as o n, de ce as ed, a nd W I LL I AML . M A S ON, in d ivid u ally an d a s co - admi ni st r at o r o fthe e s t a t e o fT r i c i a M. Mas o n, de c e a s e d, P la intif fs-A pp ella nts, v.

S MI T HK LI NE B EE CHA M C ORPO RA T I ON, doi ng business as Glaxo Sm i thK l i ne, a Pe nns y l va ni a co r po r at i o n, D efend a nt-A pp ellee.

A pp eal from the United S t ates Di strictC our t fo r the C entral D istricto f Illino is. No . 05 C1252

—Mi ch ael M . M ihm, Judg e.
A RG UE D O CT OB ER 5, 2009

— D ECI DE D F EB RU AR Y 23, 20102 N o. 08

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The H onorab le P hil ip P. Si m on, Un it ed Stat es D is tr ic t Court  J ud ge f or the N orther n D is tr ic t ofIndiana, s it ti ng b y d es ignat i on. Befo re E VANSa nd S YKES, C ircu it Ju dg es , a nd S I MO N , D i s t r i ctJudg e .  E VANS, Cir cu i tJudg e . T w en ty -th r e e - ye ar -old T ric ia M aso n com m i tte d sui ci d e on M ar ch 2, 20 03, two days aftershe sta rt ed tak i ng Paxi l, a popu l arantid ep re ssa nt. H erpa r en ts s ue d the manuf ac turer o fthe dr ug, the Sm i thkl i ne Beecham Cor pora ti on, cl ai m i ng i t was negl i gent ( am ong o therthi ngs) f ornotwarni ng tha t ta kin g P ax il inc re as es th e ris k o f su icid e, es p ec ially a mo n gy o u n ga d u l t s . The d i s t r i c tc o u r tg r a n t e d s u mm ar y j udg m en t f o r the c o m pan y i n 2 00 8. The cour t co ncl ud ed that the M aso n s’ c lai m s were preem pted und er fed er al la w be c a u s e t h e w ar n in gs th ey sa y s h ou ld h av e be e n i n c l u d e d ab o u tP a x i lc o n fl i c t e d wi th th e F DA

approve d w ar ni ng l abel i ng f orthe drug. One y ea r a fte r the di st r i ctc o ur t g ran ted the de fen d an t’s m otion for su m m ary j ud gm en t, th e Sup rem e C ou rt de c i de d W

ye t h v
. Le vi ne, 555 U
. S. ___, 129 S. Ct
. 1187 (2009), a ca se that re p re se n ts a sea change i n the w ay cour ts ar e to c o ns i deri ss ue s o ffede r alpr eem p tio n. Kee pi ng th e ch an ged lan dsc ape i n mi nd, we to dayc o ns i derthe M ason s’ app eal in li gh t of Le vi ne . Befo re goin g further, however, we note that the di str i ct c o u r t, o n th e o p e n i n g pa g e o fi t s o p i n i o n g r a n t i n gs u mmar y j ud g men t, s a i d:N o. 08

- 2265 3 Th e Co ur tn o t e s tha tthe p or ti o ns o fthe b r i e f s a ddress i ng st ate m ents ofundisputed and dis p uted fact th at ha ve been su bm itted by both Plaintiff s and D efendant ar e s o re ple te w i th ar gum entat i ve p osturi ng that they ar e ess enti al l y usel ess bot h in det er m i ni ngthe b as i c f ac tu ali nf o r m at i o n un der l y i ng thi s ca se, as w el las i n re sol vi ng the pending m oti ons. The i ncl usi on o f13 and 11 pages of “I ntro du cti on” that is re m in is c e n t o f clo sin g a rg u m en t is als o w h olly i napp ro pri ate
. Counselsho uld co nsi der th em sel ves on not i ce that future fi lin gs o f thi s nature w i l lbe i m m edi ate l y s tr i cken by the Cour t. Any i m pr ovem enti n the t o ne a nd s ubs ta nc e o fthe br i ef s o n a ppea li s sl i g hta t be st
. The y a r e st i l l, a s th e dist ri ct c ourto bser ved, “r epl ete with a rgum entat i ve postur i ng. ” That’ s unf or tunate. A t th i s point i n the proc ee d in g, all th at rea l l y n ee d s t o b e s aid is th at T ric ia M as on co m m itt ed su icid e t w o d a y s a fte r ta kin g P ax il. The b r i ef s, ho wev er, go f arb ey o nd thi s st at ement
. The pla i nti ff s pai nt a ra therbr igh t p ictur e o fTri ci a. The defend an t’s pictu re i s m uc h d arker. T he M ason s tellus th is about their da ug ht er: Thr o ug ho uthe r l if e, Tri ci a M as o n was a n e xc el l en t student, she w as c l ose with he r f am i l y a nd enj oye d dancing. S he was the sal utato ri an o fherhi gh sc hool gr aduati ng cl ass , exce l l ed i n sci ence and aspi re d to bec om e a pe d iatri cian. She w as p urs uin g a M asters degre e a t I l l i noi s S tat e Un i ver si ty. O n Fe b ru ar y 2 7, 20 03 , T ric ia w en t to a m ed ica l clin ic com pla i ni ng o fa sor e thro at. Duri ng herco nsul tat ion4 N o. 08

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w i th the nurse prac ti ti oner, she i nfo rm ed the nurse that sh e was a l so ha vingdi ffi cul tyg et tingup i n the m o r ni ng, s he was e at i ngl es s an d b el i ev ed sh e m i g ht be s uffer i ngfr o m s ea so na la ffec ti ve di so r der

. The nurse pract i ti onerdi agno sed Tri ci a with depres si on and gave herso m e s am ple s o fPaxi l

. On M ar ch 2, 2003 , two d ay s afterst ar ti ng Paxi l, Tri ci a co m m i tte d sui ci de by i ngest i ng cy ani de. H er e’ s ho w the defe nd ant pai nts the pi cture : Tri ci a M aso n had a f am i l y hi sto rym ar ked by depressio n an d su icid e a tt em p ts . M s. M as on h er se lf s t r ug g l ed w i th de pr e s s i o n l o ngb e f o r e h e r s ui c i de i n Mar ch2 00 3. In 1 99 9- 20 00 , M s. M ason b eg ane xperi enci ng depres si on duri ng the winterm onths. A s t i m e pr ogr ess ed, M s. M aso n’s d ep re ssi on worsened. A ftera N ew Year ’ s Eve part y, Dones [ M s. M aso n’ s bo y fri en d] a g ain t o l d M s. M as o n the r el at i o nshi p had no future. U pon hear i ng tha t, M s. M aso n to ld D on es sh e h ad p re p ar ed a m ix of let h al c h em ica ls a nd i nt e nd e d t o k i l lh e r s e l f

. Do ne s ma de Ms. Mas on prom i se she would notco m m i t s uic i de. M s. M as o n’ s d epr es si o n c o nt i nue d thr o ug ho ut February20 03. A ro und Val enti ne’ s D ay, M s. M aso n to l d J a s o n P e mb e r t o n, a n o th e r b o y fr i e n d , s he inten d ed to ki llherself.

. . . . On Febr uary27, 2 00 3, M s. M aso n vi si ted hernurse pract i ti onerco m pla i ningo fc o l d s y mpt o ms. M s. M aso nN o. 08

- 2265 5 to o k th e o ppo r tu ni ty to di sc us s he r depr es si o n and ex p re ssed int er esti n see i ng a counsel or . Contr ar y t o the s ui c i de thr e a t s s he h a d r e c e nt l y e xp r e s s e d, M s. M as on deni ed she had been hav i ng sui ci dal thoughts

. The nurse prov ided M s. M aso n w i th sa m p les an d a p re sc rip tio n for P ax il. Tw o days l ate r, o n M ar ch 2, M s. M aso n co rresp on d ed w ith D on es b y in st an t m es sa gin g. D on es to ld M s. M as o n h erb eh av i o r o ve r the past few months mad e i t“ i mp o s s ib l e ” t o c o n t i n u e th e i r r e l a t i o n s h i p. M s. M as o n to l d Do ne s, “ F ar ewe l l, my l o ve . ” S he th en signed offher com p ut er. H ours l ate r, T ri ci a M aso n com m i tte d sui ci de by i ng e s t i ngc y a ni de

. S he wa s 2 3 y e a r s o l d. I fthi s ca se e ve r g et s to a j ur y, i t w il lc o ns i dera l lthe f ac ts a nd c i r cumst an ce s su r r o undi ngTr i ci a’ s l i fe an d su i ci de. W e ne ed no t co nc ern o ur se l ve s wi th how she sh o ul d b e vi ewe d. In a ddi ti o n, a j ury m i g htwel lc o nc lu d e t h a t s h e c om m itt ed su icid e w ith ou t a n y h elp fro m Paxi l

. These ar e no t o ur co ncer ns. Our i ssue i s a l ega lo ne , a n d so w e s ol die r on, m i nd ful, however, that the par ti es have been extr em ely part i san in the w ay they have prese nted the case to us. The c en tr al i ss ue o fthi s ca se i s fede r alpr ee m pti o n, w h ich oc c u rs w h en a st at e l a w is inv alid at ed be c au se it c o nfl i c t s wi th a fe de r a ll a w. T he c o ns t i t ut i o na lb a s i s f or federa lp re em pti on i s found in the Sup re m acy Clause ( A rt i cl e VI, Cl ause 2 o fthe U
. S. Con st ituti on) , wh i ch st at es , “ [ T] he La ws o fthe Uni te d S ta te s . . . shal lb e th e6 N o. 08

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su p re m e L aw of th e L an d [.]” P re em p tio n co m es in thre e f o r ms. F i r s t, a nd the e a s i e s tt o a pp l y, i s e xpr ess preem pti on w hi ch oc curs w hen Congre ss cl ear l y decl ar es i ts i ntenti on t o preem pt sta te l aw . S eco nd , we have im p li ed pree m p tion w hich occu rs w he n th e “stru ctu re an d purpose ” o ffede r all aw s ho ws Co ng r es s’ s i nt en t t o p r e e mpts t a t e l a w. F i na l l y, we co me t o c o nfl i c tp r e e mpti on wh i ch oc curs w hen ther e i s a n actualco nfl i ct b et w e e n st at e a n d fed er al la w su c h th at it is im p os sib le for a p er so n to ob ey bo th

. See Engl i s h v. Gen
. Ele c. Co. , 49 6 U
. S
. 7 2, 7 9, 1 10 S
. Ct
. 2 27 0, 1 10 L. Ed. 2 d 6 5 ( 19 90 )
. Co nflictp re em p tio n is th e t yp e o f p re em p tio n a t iss u e in thi s ca se. I nt er est i ngl y e nough, the i dea ofco nfl i ct pr eem pti on i n pr es cr i pti o n dru g c ase s i s r el at i ve l y ne w. Unti lthe ea rly 20 00 s, p re sc rip tio n d ru g c om p an ies infr eq u e n t ly i nv o k e d the p r e e mpt i o n de fe ns e , a nd wh e n the y di d, it ra re ly su c c ee d ed

. S e e, e . g. , To bin v . Astra P ha rm . P rod s., Inc. , 99 3 F .2d 5 2 8 , 53 7 (6 th C ir.), cert. denied , 51 0 U
. S. 91 4 (19 93 ); H ill v. Sea rle La bs. , 88 4 F
. 2d 1064, 10 68 ( 8th Ci r. 19 89)
. Thi s ch an ge d i n 200 1 when d i str i ct c ourt s we r e i nu nd a t e d wi th pr e e mpt i o n mot i o ns in p r e s c r i pt i o n dr ug cases. In a n umb e r o fthe s e c a s e s , the F DA fi l e d a m icu s br i ef s i n s uppo r t o fthe phar m ac eu ti ca li ndus t r y . In 2 0 0 6 , th e F DA a l s o r e l e a s e d s t a t e me n t s a nd r ev i se d i ts r egul at i o ns i n a n a tt empt t o b o l st erthe dr ug m anufacture rs ’ pre em pti on defense. N ot surpri si ngl y, cour t s b e g a n t o i s s ue c o nt r a di c t i ngo pi ni o ns , wh i ch l ed th e S upr eme Co ur t to g ran t c er ti o r ar ii n Lev ine to deci de the i ssue.N o. 08

- 2265 7 I n Le vi ne, the Suprem e Cour t r est or ed the preem pti on landsc ape t o i ts pr e- 20 01 f o r m . The pl aint i ffi n L e vi ne w as seve re l y inj ured ( she deve l oped gangr ene a nd her forearm had to be am p u t a ted ) w he n a p hy sician’s as si stan t inj ec te d he r a r te r y wi ththe a nt i na us ea dr ug Phe ne r g anb y us i ngthe “ I V- pus h” metho d o fi nj ec ti o n. She sued W yeth, the m anufa cture r ofPhener gan, f or fai ling to provid e an ad eq ua t e w arn ing abou t the diff e r e n tr i s k s i n v o l v e d w i th th e v a r i o u s me th o d s o fa dm i ni ste ring the drug. A j ury concl ud ed that W yeth had i nde ed f ai l ed to pr o vi d e an a dequa te war ni ngabo ut th e si g ni fi ca ntr i sk s in vo l ve d whenPh en er g ani s admi ni s t e r e d b y u s i ngthe I V- pu s h metho d. On app eal, W yeth ar gued that the pla i nti ff’ s s tat e l aw f ai l ure- to-w ar n cl ai m s were preem pted because i t was i m possibl e forthe m anufac tu rer to com plywith b oth sta te l aw duti es and fe de ra ll abel i ng o bl i gat i ons. I t a l so ar gue d tha t th e st at e l aw s ui ts woul d unde r m i ne Co ngr ess ’ s intent to tr us t lab el i ng deci si ons to the e xperti se o fthe F DA
. The S upr eme Co ur t rej ec te d b o thc o nt en ti ons an d hel d that there was no pre em pti on in ei ther i n s t a n c e . Inf a c t, th e C o u r tn o t e d th a ts t a t e l a w c l a i ms ar e a n i m port ant co m p lem ent t o the F DA ’ s Hercul ean tas k o fr egul ating t h e safetyand effecti venes s o fal lpre s c r i pt i o n dr ug s . Al tho ugh the Co ur tf o un d t hatp r e e mpti o n di d no t e xi sti n Le vi ne, i t h eld th at th er e c ou ld be pr ee m pti o n i fthe manuf ac tu r ermet th e st r i ng en t sta nd ar d ofpro vi ng tha t there was cle ar e videnceth e F DA w ou ld h ave rej ecte d the p rop osed cha ng e in the d rug’s l abel

. The S up re m e Cour t, however, di d not cl ar i fy what8 N o. 08

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I t ’ s pe rh aps worth n ot i ng thatj us ta few m onths ag o, the 1 Ei ghth Ci rc ui tr ej ec t ed, r athe r s um m ar i l y, a pre em pt i on argum en t f air l y c lose to the o ne Sm ithk line B eech am ad v an ces in this cas e. I n In rePre m pro Products Li abi l i ty Li t igat i on , 5 8 6 F
. 3d 54 7 ( 8th Ci r. 20 09 ) , the pl ai nt i ffal l eg ed thatas a re s ul toft aki ng es tr ogen and progest in drugs, s he developed breas t c ancer. Sh e sue d th e d ru g m an u factu rers for failur e to w arn of the risk ofb reas t cancer
. In rej ect ing p reem ption in less than halfa page, the Ei ghth Ci rc ui ts ai d, “Th e Su pre m e Cour t ’ s r ec en tdec i s i on i n [ Le vi ne ] ha s fo re cl o se d th is p re em p tio n ar g u m en t.” co ns ti tu te s “c l ea r e vi den ce . ” The r efo r e, the o nl y thi ng w e k n ow f o r s u re is th at th e e vid en c e p re se n te d in Le vi nedi d n o tme e tthi s e xa c t i ngs t a nd a r d. 1 T he j ou rney to dec iph ering th e “c l ear evid en ce” sta nd ard begins w ith un d erstan d ing how d rug m an ufac tu rers re cei ve approvalto m ar ketnew p re scr i pti on drugs an d to chan ge a label onc e it h a s b e e n ap p roved

. Be fore m ar ke tin g a n ew d ru g, th e m an u fac t u re r m u st su b m it a N ew Drug Ap pli cati on t o the FDA , wh i ch dem onst ra tes by “subst anti ale vid en ce” that the m edi cati on i s e ffi caci ous. 21 U
. S. C. 35 5(d ) ( 5)
. The FDA ’ s a pp ro vali s then c on d itio n e d o n t h e m an u fac tu re r’s u se of th e la b el it sugge sts
. 21 C .F.R. § 314. 105(b)

. Even afterthe m edi cati on i s a pp ro ved, the FDA co nti nues to have autho ri ty o ve r i t an d i ts l ab el

. 2 1 C. F
. R. 3 14
. 80

- . 81
. The manuf actur er, howe ve r, h as the abi l i ty to change the l abel wi tho utFD A a pp r o v a lthr o ugh a “ c ha ng e s b e i nge ffe c t e d” ( CB E) l abel i ng change

. T h e C B E regula ti on a l l ows a m an uf ac tu r ert o modi fy a l ab elt o “ add o r s tr en g th ena con trai nd i cati on, warni ng, pre cauti on, o r advers e r eac-N o. 08

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Section20 1. 57was am en ded i n 2 00 6. The s t anda rd for 2

“ o l de r d r u gs , ” i n c l u di n g P a x i l , i s n o w l o c a t e d a t2 1 C
. F
. R. § 20 1 .80 (e). ti o n” o r t o “ add o r s tr ength ena n ins truct i o n abo ut dosage and a dm i ni str ati on that i s i ntended t o in c re ase th e s afe u se o f th e d ru g p ro d u c t” an d to d o s o w h en it fi l es i ts supp l em entalappli cati on, bef or e the FDA has the o pp o r t un i t y t o c o ns i de r wh e the r o r n o ti tw i l la c c e pt th e ch an g e. 2 1 C. F
. R. § 3 14
. 70 ( c) ( 6) ( i i i ) ( A), ( C)
. The ability to m ake CB E l abel i ng change s undersc or es a centr alpre m i se offedera ldrug re gul ati on: A “m anufa cture r bear s r esponsibi l i ty f orthe conte n t of its l abelat al lti m es. ” Le vi ne, 129 S. Ct
. at 1197 -9 8 . W h ile i t is im p ortant f ora m an u fac ture r to w ar n ofpote nti alsi de effects , i t i s e qually i m port ant that i t no t o ver w ar n beca use o ve r war ni ngc ande ter po te nt i al l y b en efi ci alus es o fthe drug by m aking i t s eem r i ski erthan w ar ra nted and can di l ut e the e ffe c t i v e ne s s o fv a l i d wa r ning s . T he r e f or e, w ar n in gs m ay on ly b e ad d ed w h en th er e is “re as on ab le ev i dence o fa n a ss o ci at i o n o fa s er i o us ha za r d wi ththe drug. ” 2 1 C. F. R. § 201. 57( e) ( 2003 )
. I t i s t ech ni cal l y a 2 vi ol ati on o ffed er al law to pr opose a CB E that i s no t base d on r eas onabl e e vi dence. 18 U
. S. C. § 1 001. Si nce Le vi nei s o ur int ellectualanchor

— i fthe evi dence h e r e i s l e s s c o mpe l l i n g th a n i t wa s i n Le vi ne, we w i l lnot fi nd p r e e mpti on

— w e m u st look atth e lon g a n d fairly e x t e n s i v e a d mi n i s t r a t i v e h i s t o r y o fP h e n e r g a n a n d c o mpa r e i t t o the a dmi ni s t r a t i v e hi s t o r y o f Pa xi l

. The F DA approve d Phener gan i n 1955
. W yeth subm i tted supple-10 N o. 08

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Phe n e r g a n c a u s e s g a n g r e n e wh e n i nj e c t e d i n t o a n a r t e ry , 3 whic h was the e xa c tm i s hap re s pons ibl e f or th e inj ur y t o the pl ai nt i ffi n Le vi ne . The m aj or i t y a nd di s s en tdi s agr ee abo utthe c at eg or i za t i on of 4 th e w a rn in g W y et h p ro p o se d in 19 8 8
. C om pare, Le vi neat 1 2 1 8 n .1 (co n tin u ed ...) m entalnew d rug appli cations in 197 3 a nd 19 76 w hi ch th e F D A ap p ro ve d aft er p ro p os in g la b elin g c h an ge s. In 1981 W yeth subm i tte d a thi rd supplem entalappli cati on i n r es po ns e to a ne w FDA r ul e g o ve r ni ngdr ugl ab el s. The Court then not es that “[ o] verthe next 17ye ar s, W yeth an d t he FD A int er m i tt en tl y c o r r es po nde d a bo ut Phenerg an’ s l abel

. ” Le vi ne, at 1 192. The m ostnot abl e o f the s e c o r r e spo nd e nc e s o c c ur r e d in 1 9 8 7wh e n the F DA s ug g e s t e d a l t e r na t i v e wa r ni ng s r e g a r di ng ar ter i al exposure and i n 1988 w hen W yeth subm i tte d a pro posed

3 l ab elwh i c h i nc o r po r a t e d the s ug g e s t i o ns . T he F DA d id n otco n ta c t W y e t h a ga inu n til 19 96 w h en it to ld W yeth to r eta i n the w or ding on i ts cu rrent l abel

. In 199 0, th e F D A fina l l y a ppr o ve d W y eth’ s 19 81 a ppl i ca ti o n a nd m andated that the wordi ng o n the lab el m ust be i den ti ca lt o the pa cka g e i ns er t. On Apri l7, 2 00 0, the p l a i n t i f fi n Le vi ner ecei ved the dose ofPhener gan that caused heri nj ury. Whi l e th e o p i n i o n i n Le vi neco ver s the adm i ni str ati ve hi sto ryand re cor d, th e di sse nt del ves eve n deeper. W hen th e d iss en t an d th e m ajorit y d isa gr ee i n t h e ch ar ac te rizati on o fthe re cor d oradm i ni stra tiv e hi sto ry, we of co ur se f o l l o w the maj o r i ty ’ s vi ew. Acco r di ngt o the 4N o. 08

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(
. . . c on t i nu e d) 4 ( Ali t o, J ., d i s s en t i ng) ( “I ndee d, r es ponde ntc onc ede d bel ow thatW ye th di d p r o p o se a n a d e q u a t e w a r n i n g o f P h e n e r g a n ’s ri sks

. Sp eci fic all y, respond ent noted: ’ In 1988, W yeth proposed l ang uage that would have pre ven t ed thi s ac c i dent by r equi ri ng a ru nn ing IV an d exp lain ing w hy a ru nn ing IV w ill ad d ress and reduce the ri sk [ ofi ntra- art eri al inj ect ion]. ’ ”) ( int ernal ci ta tio n s o m itt ed ), w ith L evi n e a t1 1 9 9 n .6 (“ T h e d i ss e n t ’s s ugge s t i on thatthe FDA in t en ded t o pr ohibi tW ye th fro m str en g th en in g its w a rn in g d o es n o t fa ir ly re fle ct th e r ec o rd .”). diss ent, “F oratl eas t the la st 34 yea rs , the FDA has f ocuse d speci fi cal l y o n w h ether IV-push adm i ni str ati on o f Ph en ergan i s ‘safe’ a nd ‘effective’ .

. . . A nd the record co nt ains a m pl e ev i den ce tha t th e F DA s pec i fi ca l l y c o nsi der ed an d r ec o ns i der ed th e st r en g tho fPh en er gan’ s I Vpus h- r el at ed war ni ng s i n l i g hto fne w sc i en tifi c an d m edi caldata. ” Le vi ne, a t 1222. The di ss en t th enmeti culously l ists the va rious tim es th e FD A cons id e r e d a differ ent w ar ni ng l abel re gar ding the I V-push m etho d. It be g i ns i n 1 975 when several peo pl e fr o m W y eth a nd seve ral m em bers o f th e FD A m et regard ing Ph en ergan ’s l abeland the FDA pro posed thatPhener gan s h ou l d not be inj ecte d vi a Tubex, wh i ch i s a syrin ge s yst em used ex c lu siv ely f or IV p u sh . In st ea d of ba n n in g t h e u se of IV pu sh al tog ether, bo th par ti es agr eed thatther e was i nstea d a need f orbet teri nstr ucti on r egard in g the pr obl e ms o fi nt r a - a r t e r i a li nj e c t i o n. A y e arl a t e r, a n F DA com m i tt ee r ec o m m en ded an a ddi ti o na l I V- pus hspeci fi c warni ng f orPhenerga n ’ s l abelbut deci ded not to pr o hibi t us i ngthe I V- pus h metho d. In its l ab el i ng12 N o. 08

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The Sopr anos , ofcours e, w as a cr it ic all y accl aim ed d ram a that 5 ai re d bet we en 1 99 9 and 2 00 7 ( 86 e pi s odes ) onHB O. I ti s the m ost finan cially succe ssfu l cab le s e r ies in the h istory of telev is i on and i s ac knowl edge d as on e ofthe gr ea t es tt el evi s i on se ri es ofal l ti m e. o r der, the F DA c i te d num er o us s o ur ce s des cr ibingthe cos ts and benefi ts ofI V pu sh i ncl ud i ng publ i sh ed cas e r epo r ts fr o m 1 960 abo utc as es o fg an g r en e ca us ed bythe i ntra
- ar ter i ali nj ecti on o fPhener gan. Taking Le vi neas a w hol e, i t i s cl ea r fr o m the a m pl e admi ni st r at i ve r ecord that the F DA st ro ngl y c onsi dered a sim i l arwarni ng to the o ne the pl ai n tiffpro posed and the Court sti l ldi d not fi nd pr ee m pti o n. N ow th at w e kn ow w h at fa lls sh or t of “c lea r ev id en c e,” w e turn o ur a tte n tio n to the adm i ni str ati ve re cor d of Paxi land see i fit i s a ny m or e co m pel l i ng. Paxi lbel ongs to a cl ass o fpre scri pti on a nti depressa nts know n as sel ecti ve ser oto ni n re - up tak e inhib itors ( SS RI s)
. S SRI s o perat e b y c on tr ollin g t h e m an n er in w h ich se ro to n i n is proce sse d by br ai n cel l s. They for ce s er oto ni n to st ay l o ng er b etw ee n b r ain c el l s, whi cha l l eg edly i m pr o ve s th e m oo d of p at ien ts . Pr oz a c , th e firs t SS R I, is q u ite w ellk n o wn . A n y o n e w h o h a s e v e r w a t c h e d The Sopranos 5 kn o ws tha t i t ’ s the dr ug Dr
. J e nn i fe r M e l fi pr e s c r i bed f or Tony S opra no a fterte lling hi m “no o ne nee ds to su ffer fr om de p ression w ith th e w ond ers of m od ern p h ar m ac olo gy .” Sm i thl i ne Beecham ( w e’l lr eferto the com pany fro m now o n as “GSK, ” the in itia l s o fan e nti ty that i t doe sN o. 08

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T he p lain tiffs also alleg e tha t G SK c on tam ina ted the a d m inis- 6 trativ e histo ry of Pa xil by u sing the term “em otio na l lab ility” to disguis e suici dal behav ior thatw as reporte d d uring the cl ini cal tr ia l s . GS K do e s n otde ny tha ti tc od e d da t a a s “ e m ot i on al lab ility” butm ai nt ai ns thatwhenthe FDA anal yze d this data in February of2003

— a m on th b efore T r icia’s d eath

— it i nc l uded a l l ofthe pr ope r s ui c i de da t a r eg ar dl es s ofcod ing and s ti ll did not find any relat ions hip betw een s uici dal b eh av ior a nd Pa xil. T he refore , this alleg atio n d oe s no t call into qu estion the d ata the F D A used to ev alu ate P axil. O ne ofthe diffic ulti es w ith condu ct ing s tudies for Paxil i s that 7 the parti ci pants ar e frequentl y taking other m ed ic ati ons wh en they b eg in the s tudy

. In or der to s tar t the s tudy w ith a cl ean s l at e, the re i s a “was h- out ” ph as e thatus ual l y l as t s f or on e or tw o w eek s w h e r e e v e r y on e in th e stud y is g iv en a p laceb o to m ake s ur e the i r ol d drugs ar e ou t ofthe i r s ys t em s an d are notres pon sible f or any changes in m ood or behavior. b u sin es s u n d er ) rec ou n ts th e re gu lat or y h ist or y of P ax il t o s ho w tha tthe r e i s c l e a r e v i de nc e tha tthe F DA woul d no t ha ve a ppr o ve d the l ab el i ngc ha ng e th e pl ai nt iff s sa y was ne ce ss ar y . GS K fi l ed a “New Dr ug Appl i c a t i o n” ( NDA) wi th the F DA i n 1 9 8 9 s e e k i nga pprova lto m ar ketPaxi l fo r the t re atm ent o fdepres si on inad u lts . Th e F D A ap p ro ve d P ax il

— w itho uta war ni ng about sui ci de. The pla i nti ff s a l l ege that the FDA was m i sl ed beca use 6 GS K i nc l ud e d s ui c i de s a nd s ui c i de a t t e mpt s t hat o c c u r r e d d u rin g t h e w as h -ou t p h as e of th e c lin ica l tria ls 7 f o r Pa xi l an d co unt ed th em as i fthe y o cc ur r ed dur i ng the a ctualtr i alwh en a subj ect w as on a pl acebo

. S i nce14 N o. 08

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A n onc ont ro l l ed s t udy i s a s t udy wher e the re i s no contr ol 8 g ro u p . In o the r w or d s, a no nc on tro lled stud y is a s tu d y in whic h al l ofthe par t i c i pant s t ake a pre s c ri pt i on drug and n one ofthe m t ake a pl ac ebo

. Havi ng a c ont ro l gr oup i s i m por t ant whe n a na l yz i ng s ui c i da l be ha vi or da t a be c a us e s ui c i da l be ha vior is a s ym ptom ofdep res si on and rel ated d is eas es . Theref ore, a c er t ai n num berofdepr es s ed pe opl e who ar e nottak i ng m edi c at i on w i l l e xh ibi ts ui c i dal be havi or . Havi ng a c ont ro l group e stab li shes a base li ne w ith w hich the m anufac turer c an c om par e the s ui c i dal be havi or r at e ofpar t i c i pant s t aki ng the pr es c ri pt i on drug. the w ash- out ph ase o ccurs befor e the stud y b egins, ev ents tha to c c urdu r i ngtha tp ha s e s ho ul d n o tb e c o unt e d. By at tr ibut i ngthe ne g at i ve o ut co m es tha t o cc ur r ed dur i ng th is p er iod to th e p lac eb o, P ax il l o ok s b et te r b y c om p ar iso n. T his all e g ation is partiall y true. In its 1989 N D A , GSK pr es en ts the su ici d e dat a i n a t ab l e th atc o unt s was h- o ut s ui c i da lb e ha v i o r a s i fi to c c ur r e d d ur i ngthe s t ud y w hi l e s ubj ec ts w er e t aking pl acebo s. H owever, ea ch errone ou s d atu m ha d a star by it w hich not ed th a t p a rt o fthe s ui ci dalb eh av i o r o cc ur r ed dur i ngthe was h- o ut phase. I t a pp ear s that Dr. Brec her, the FDA sci enti st who r ev i ewe d GS K’ s appl i ca ti o n, unde r st o o d tha t th e was h- ou t e ve nt s wer e i nc l ude d whenhe a na l y ze d the dat a an d f o und n o r el at i o nship betwee n P ax i la nd sui ci dal behavi or . Fur ther m or e, in M ay 2002 and Fe br ua r y 2 00 3, GS K r e- an aly ze d th e dat a bye xc l udi ngwas houts and noncontrol l ed stud i es and subm i tte d that data 8 to th e F D A
. G SK ’s a n aly sis fou n d th at th er e w as st illN o. 08

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no r el at i o ns hi p b etwee n s ui ci d e a nd Pa xi l

. Ov er al l, the pla i nti ff s’ al l ega ti ons do not taint the adm i ni strat i ve h ist or y of P ax il. Tha t th e F DA i ni ti al l y a pp r o ve d Pa xi la fte r c o ns i der i ng the pr operdata does not provi de m uch, i fany, ev i dence th atthe FD A woul d ha ve r ej ec te d the war ni ngthe pl ainti ff s s ay shoul d have be en i n pla ce b efore T ri ci a t oo k he r l i fe. In Le vi ne, the Court hel d th at FD A approv alby i tse l fdoes notwarra nt pre em pt ion
. Le vi ne, 12 9 S
. Ct. at1 19 1. F ur th er m o re , s i nc e GS K, no t th e F DA , r et ains re sp on sib ility for P ax il’s lab el, th e FD A ’s init ial a p p ro va l, m or e than a deca de b efor e, i sn’ t a gr eatco m f or t t o GSK ’ s ca se. N ex t, G SK h igh ligh ts t h at t h e FD A h ad b ee n th or ou gh ly r e v i e wi ngthe da t a a v a i l ab l e ab o utS S RI s a nd s ui c i de an d conc lud e d t h e r e w as no t an inc reased ri sk of selfharm fro m S SRI s. In p ar ti cul ar, i t points o ut thato n thre e s epara te occa si ons the F DA r ej ecte d a ci ti zen peti ti on f ora l abe li ng change f orPro zac that w oul d have i ncl ud ed a warni ng ab out sui ci de. T he FDA ’ s r ej ecti on ofthe Pro zac w ar n i ngs, however, i s no t a s cl ear - cut as GS K wo ul d ha ve us be l i ev e. Dur i ng a m ee ting of th e FD A ’s ps y ch o pha r m ac o l o g i ca ldr ugc o m m i tt ee , Dr
. Pa ul Leber

— the Di re cto r ofthe D i vi si on o fN euro pharm aco l ogi calDrug Pr oducts

— g av e a pr es en ta ti o n abo utthe po te ntial l i nkb etwee n s ui ci de an d a nt i depr es sa nt s an d sta ted, “[ N ] obo dy i n the age ncy di sm i sse s the poss ib ility th at an tid ep re ss an ts in g en er al a n d flu ox et in e in p ar tic u lar m ay have

— a nd Ie mpha s i ze ‘ m ay’

— the c apaci ty to cause untow ar d inj uri ous behavi or s, acts , and/o r16 N o. 08

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In m ed ical term ino l o g y , a n ind icatio n is a d isease o r con d i- 9 tion a d ru g can treat. i ntensi fy them

. ” Ad dit i ona lly, i n the ver y l ett erthat r ej ec te d a c i ti ze n pet i ti o n to cha ng e the l ab elo n P r o za c, the FD A noted tha t m ore research need s to occu r to exp lore the r el ati onshi p between anti de p re ssa nts a nd sui ci dali ty. Ove r al l, we do no t fi nd the F DA ’ s r ej ec ti o n ofthe c i t i z e n p e t i t i o n s o r i t s c a l lt o d o mo r e r e s e a r c h v e r y c o mpel l i ng f orei th er s id e. Even the l ate st ofthes e fi nd i ngs w as m ad e s ev er al y ea rs be for e T ric ia’s su icid e. T h is tem pora lga p i s e sp ecial l y i m port ant in the anal ysi s o f presc ri pti on drugs bec ause i t co nstantl y e vol ves as ne w dat a emer g es . F ur th er m o r e, e ve n tho ugh Pr o za c an d Paxi lar e bo th S SRI s, theyar e di ffer ent d rugs m ade by di ffer en t m an uf ac tu r er s. The r efo r e, we g i ve l i tt l e w eight to the ad m inistrativ e h istory ofProzac w he n w e are co nc erne d wi thwhethe r the r e i s cl ea r e vi den ce tha t th e FD A w ou ld h av e rej ec te d a lab elin g c h an ge in P ax il. GSK al so tr i es to show that the FDA ’ s i nacti on, as in it s f ai l ure to m andat e a w ar ni ng ab out the r i sk ofsui ci de, ar ound t he t i me o fT r i c i a ’ s de a th i s c l e a r e v i de nc e tha t th e F DA woul d no t ha ve a ppr o ve d the c ha ng e i n the label the p la in tiffs seek. GSK highlights th at after Pax il ’s approval, i t s ubm i tte d a d etai l ed annual r epor t that i ncl ud ed postm ar ket i ng adver se eve nts a nd cl i ni cal in ve st iga tio n s o f P ax il t o th e F D A . A d d itio n ally , i t po i nt s o uttha t th e F DA a ppr o ve d ni ne ne w i ndi ca ti o ns 9 f o r Pa xi l, e ac h t i m e r ev i ewi nga l lof th e sa fety da ta abo ut Pa xil, i nc lud ing the suicid e d ata. In p a rticular, G SKN o. 08

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em phasi zes thati t s ubm i tte d the a vai l abl e data o n Paxi land sui ci de ten m onths an d one m onth pri or ( M ay2 00 2 an d F ebru ary 2 00 3) t o Tr i ci a’ s su i ci de, a nd thr e e mo nths a ft e r (J un e 2 0 0 3 ) T r i c i a ’ s s ui c i de the F DA publ i sh ed a pr es s r el ea se tha t co nc l ude d the r e was no i ncre ase d ri sk of sui ci de i n adult s. GSK m ai ntai ns that the F D A appr o pr i at ely f ai l ed to i ss ue a war ni ngabo ut Paxi land sui ci dali ty because ther e was no evi dence to m erit i t from th e i nform ation ava il able. W hile w ha t G SK poi nts o ut i s t rue, it onlyte l l s o ne si de ofthe sto ry . F o r e xa m pl e, GS K i g no r es the mai n pur p ose o fthe J une 2 00 3 pr es s r el ea se , whi chwas t o r ec o m m en d that do c to rs st op usi ng Paxi lto tr eatpedia tr i c m aj or d ep ressi ve diso rder( M DD ) bec ause the F DA was c ur r e nt l y r e v i e wi ngr e po rt s ofi nc r e a s e d r i s k s o fs ui c i de and sui ci dal behavi orwith the drug. Then, i n Octob er of 2003 , the FD A i nform ed health care p rovide rs of a possibl e i ncre ase d r i sk of sui ci dali ty i n pediat ri c, b u t n ot adul t, pa ti en ts
. The r efo r e, i t se ems u nl i k ely tha t th e FDA would have re fused to all ow G SK to w ar n abo ut a possib le ris k o fsui ci de f oryo ung adult s when ithad alr ea d y w ar n ed th e p u b lic t h at P ax il w as p ot en tia lly un s a fe f o r 1 7

- y e a r - o l ds wi th M DD. Final l y, i n 20 06 , us i ng a CBE l ab el i ng ch an g e, GSK w ar ned that Paxi lwas ass oci ate d w i th an in c rease d ri sk o fs ui c i de i n a du l t s . T he n, i n M a y o f2 0 0 7, the F DA o r de r e d a l lanti de pr e s s a ntma nu f a c t ur e r s t o i nc l ud e an addit i onalwarni ng ab out the incre ase d like li hood o f su ici d ali ty in youn g ad ults u nd er the age of 24. GSK m ai ntai ns that the m etho ds used to anal yze th e d ata w ere not av ail able at the tim e of T rici a’s de ath

. Furth er-18 N o. 08

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m or e, i t cl ai m s that i t di d n ot have acces s t o the poo l ofdata that the FDA used to deter m i ne thatthes e ri sks exi st. S i nce these even ts occur re d w el lafter Tr i ci a’ s su i ci de, the y a r e no t per su as i ve i n de te r m i ni ng w h et h er th er e w as cle ar ev id en c e t h a t t h e F D A w ou ld ha ve rej ecte d the p rop osed w arn ing at th e tim e of T rici a’s death. To the e xt en t th es e su bs eque nte ve nt s ha ve a ny sw ay, howe ve r, theycl ear l y c ut to w ar ds m aking i t l ess l i kel y that the FDA would have rej ecte d the pl ai nti ff s’ pr o po se d war ni ngi n 2 00 3. The r efo r e, i n li gh t o fthe extensi ve showing re q uir ed by Le vi ne, we concl ud e that GSK di d not m eeti ts burden ofdem onst ra ti ng bycl ear evi dence thatthe FD A would have rej ecte d a l abel change w ar ni ng ab out the ri sk ofsuici de by young adults bef or e Tr i ci a’ s l i fe ca m e t o an end at 23. Consequentl y, the p l a i nt i ff s ’ c l a i ms a r e n o tp r e e mpt e d. Fo r th es e re as on s, th e ju d gm en t o f th e d ist ric t c ou rtis R EVER S ED and the case R EMAND ED f orfurtherpro ceedi ngs.

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