Five Years Postmarketing Ex U.S. Orjan Mortimer, M.D., MPA by tob11086

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o ur preclinical st udies , ou r post marke t ing v is u a l

c ommitments study and o ur t wo pha rmaco epid em i ol o g i c

s tudies.

            These pr ovide the basi s fo r the str eng t h

o f the evidence th at we pre sent t oday and to m or r o w .

            Thank yo u.

            DR. EDWA RDS:      Tha nk yo u ve ry muc h.

            At this time, I a m goi ng t o retu rn to t h e

F DA and ask Dr. Mo rtime r, w ho is from the Eu r op e a n

M edicines Agency, or th e EM EA, to disc uss th e

p ostmarketing ex U .S. s tudi es.

            Dr. Mort imer.

             Five Y ear s Pos tmar ketin g Ex U.S.

                 Orj an Morti mer, M.D. , MP A

            DR. MORT IMER:      Th ank y ou.        I wan t t o t h a n k

y ou for the invita tion from the FDA to pre se n t t h e

s ituation on the e valua tion of Ke tek i n th e

E uropean Union sys tem.

            [Slide.]

            First of all, an outli ne, I will pr ese n t

f or you the rather diff eren t syst em we hav e i n

E urope in comparis on wi th t he FDA and the U. S . f o r



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o ne country and th en th e sp ecific s for Ket ek , t h e

l egal status, asse ssmen t of hepat ic sa fety ,

r enewal, which is a spe cifi c proc edure we ha v e w i t h

r enewal this year in Eu rope , and asses smen t a ft e r

t he renewal, also summa rize them.

          [Slide.]

          The Euro pean syst em, i t is a de cent ral i z e d

n etwork, so what y ou se e he re is a bri ef o ve r vi e w

o f the European FD A.

          [Slide.]

          We also have asso ciate d tw o, thr ee mor e

c ountries, but we don't dis cuss t hose toda y.

          Here we are w ith the e xper tise.          Th ey a r e

s ituated in the co mpete nt a uthor itie s, na tio n al

c ompetent authorit ies, so t here w e hav e th e

s cientific teams.

          Furtherm ore, we h ave a s Eu ropean

a dministration loc ated in D ocklan ds, L ondo n.          It is

t he European Medic ines Agen cy.         I t has a s ta f f I

t hink about 400 pe ople, and they are proj ect te a m

l eaders, and so on , and the y admi nistr ate, f i rs t o f

a ll, the centraliz ed pr oced ure, a nd I come b a ck t o



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t hat.

          They hav e sci enti fic c ommi ttees for hu m a n

m edicine of produc ts ve teri nary a rea, ofte n h er b a l s

a nd, in relation t o tho se c ommit tees , you hav e a

n umber of working parti es d own th ere t hat

c onstitutes, so to say, the exper tise in t he

r espective area.

          I am the dele gate of t he p harmac ovi gil a n c e

w orking party for Swede n.        We als o hav e tw o

d elegates per memb er st ates in th is Sc ien tif ic

C ommittee for Huma n Med icin al Pro ducts .

F urthermore, for t hese prod ucts t hey a re

a uthorized through this sys tem.           There are a l so

a lternative system s, so to say, f or ot her pr o du c t s ,

b ut I will not tou ch on tha t beca use i t's to o

c omplicated.

          The dele gate for count ries is t he

r apporteur.     Then, you can see an X is her e f or

p roducts.     Ketek i s aut hori zed th rough the c e nt r a l

s ystem and Sweden is th e ra pporte ur.          We p re s en t

s afety issues, pha rmaco vigi lance issue s in t h e

p harmacovigilance worki ng p arty a n d dis cuss th a t



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w ith the other mem ber s tate s and it is ado pt e d b y

t he committee here .

            Above he re yo u ha ve th e Eu ropean

C ommission which t akes the legal decis ions .

            Those co untri es m entio ned here, Swe den ,

G ermany, Netherlan ds, U .K. and Fr ance, we ar e t h o s e

t hat have the larg est n umbe r of r appor teur sh i ps .

W ee are, so to say , res pons ible f or mo st p ro d uc t s

a mong all these me mber stat es. To day, I th in k i t i s

U .K. and Sweden to gethe r th at are in t he f ro n t o f

t hat.     In France, for e xamp le, I think abo ut 1, 2 0 0

p eople employe.       U .K. h as a bout 1,000.     Sw ed e n h a s

a bout 450.     German y mus t ha ve ove r 1,0 00, as we l l ,

a nd Netherlands is abou t th e size of S wede n I

t hink.

            [Slide.]

            The Euro pean Medi cines Age ncy, d isc uss i n g

t hen the role they have , th ey coo rdina te t he

e valuation and sup ervis ion of me dicina l pr od u ct s

t hroughout the Eur opean Uni on and the Agen cy br i n g s

t ogether the scien tific res ources of t hese m e mb e r

s tates.



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           It is qu ite a dvan ced n etwo rking.       I t's

a bout 3,500 Europe an ex pert s that are, so to sa y ,

n otifying us, taki ng pa rt i n the sci entif ic

a ssessment on qual ity, safe ty and effi cacy .

           This net work by l egisl atio n was sta rte d i n

1 995 when the Euro pean Unio n memb er st ates w e re

e xpanded from 12 t o 15 and, now, in Ma y of 2 0 05 , t o

2 5 now.   It is pri maril y on ly inv olve d in th e

c entralized proced ure, the EMEA.

           [Slide.]

           The Comm ittee of the H uman Medic ina l

P roducts, they hav e a n umbe r of w orkin g pa rt i es .

H ere are some of t hem; biot ech, p harma covi gi l an c e ,

h erbal, as well, s afety , qu ality, effi cacy .         We

h ave SAC, scientif ic ad viso ry gr oup, set up f or

s pecific matters f or so me t herape utic area s.         As

w ell, they are on a ste ady basis.

           [Slide.]

           The resp onsib ilit ies o n th e Scie nti fic

C ommittee are, the n,       o pini ons on gran ting

v ariation.    Variat ion i s an expre ssion for

p rocedure for upda ting the produ ct inf orma ti o n, t h e



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S PC in Europe, sus pensi ons, and s o on, and o p in i o n

o f any scientific matte r co ncerni ng th e ev al u at i o n

o f medicinal produ cts f or h uman u se in the E u ro p e a n

U nion, which then may b e re queste d by the EM E A, b y

t he member states, or b y al so th e Comm issi on .

          [Slide.]

          So they shoul d fo rmula te a n opin ion fo r

t hese procedures a nd, w hen there is a disa gr e em e n t

i n any procedure a t nat iona l leve l or othe r l ev e l s

o f the procedures, they are then refer red to th e

C HMP opinion by le gisla tion .        Th ey a lso p rov i de

g eneral guidance a nd pr ovid e guid eline s th at ar e

d eveloped by these diff eren t work ing p arti es .

          [Slide.]

          For the centr aliz ed pr oced ure, w hic h i s

t he procedure appl icabl e fo r Kete k, wh en t hi s i s

u sed, then, the co mpani es s ubmit one sing le

a pplication to all memb er s tates at th e sa me ti m e

a nd a single evalu ation is carrie d out , th en ,

t hrough the CHMP.

          [Slide.]

          If the c ommit tee then conc ludes tha t



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q uality, safety an d eff icac y of t he me dici na l

p roduct is suffici ently pro ven, then , it is a

p ositive opinion a dopte d an d then the Comm is s io n

w ould make it vali d in the Europe an Un ion an d a l l

m ember states at t he sa me t ime.

          [Slide.]

          To also prese nt t he sc ope of the

c entralized proced ure, it i s mand atory for b i ot e c h

p roducts for AIDS, canc er, neuro dege nerat ive

d isorders, diabete s.      I t wi ll add late r on , i n

2 008, or so, for o ther diso rders, vira l di se a se s ,

a lso for orphans, where we have a spec ific

c ommittee, that pr epare s th e stat us of the p r od u c t

f or the CHMP and t hen i t wi ll go t h roug h the s a m e

k ind of procedure as fo r ot her pr oduct s.

          It is al so op tion al fo r ot her ne w a cti v e

s ubstances.   Some gener ics may ap ply, as w el l , a n d

b iosimilars like f or er ythr opoiet in, f or e xa m pl e ,

i s a recent biosim ilar prod uct ap prove d in E u ro p e .

          To look at th e me dical rev iew p roce ss,

t hen, the CHMP the n iss ues its ra pport eur an d a

c o-rapporteur when you have the first appl ic a ti o n



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f or marketing auth oriza tion like for K etek i n 2 0 0 1

w hen it was approv ed.

          So, then , we make up t wo d iffere nt --a

r apporteur and the co-r appo rteur ass essme nt r ep o r t

o n the quality, pr eclin ical safet y, cl inic al sa f e t y

a nd efficacy.

          There is also one memb er s tate m aki ng a

p eer review of the asse ssme nt.         W hen y ou s en d o u t

t hose assessment r eport s, y ou als o add que st i on s

f or clarification, outs tand ing i ssue s, so to sa y ,

f or clarification.

          Then, th ere i s a peer revi ew in all me m b e r

s tates, so they co mment on the as sessm ent an d o n

t he list of questi ons.

          [Slide.]

          Further in th e pr ocedu re, which is 210

d ays, 7 months, wi th cl ock stop s, b ut s uffic ie n t

t ime, and so on.      But t he s uffici ent t ime, y o u h a v e

t he assessment rep orts pool ed and you have f u rt h e r

r esponses to list of qu esti ons an d fur ther

a ssessments within this pro cedure .

          If it is down her e, go ing to the CH MP,



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t hen, they can cho ose t hen to no t ad opt a pos it i v e

o pinion and, then, in g ener al, th ere i s a

w ithdrawal of the appli cati on.         B ut    t he d ec i si o n ,

t heir position is prese nted at th e web sit e o f t h e

E MEA and, if it's okay, it' s then adop ted ma r ke t i n g

a uthorization in E urope .

          [Slide.]

          To come into deta ils, the rappor teu r t h e n ,

t hey have a scient ific team , so w e are loo ki n g i n t o

t he files and meet with the m as a pres ubmi ss i on a n d

a ssessment of the marke ting autho rizat ion

a pplication, as we ll.

          Then, fo r the aut horiz atio n, we ha ve a

l ife-cycle perspec tive and here we hav e a nu m be r o f

d ifferent tools by legi slat ion th en to fol lo w ..              We

h ave periodic safe ty up date repor ts th at a re si x

m onths during the first two years and then a n nu a l .

          We have risk mana gemen t pl ans by th e n e w

l egislation set up one year ago.            The risk

m anagement plans, they shou ld in detai l pr es e nt a

s afety specificati on, w hich then take care o f

e stablished risks, pote ntia l risk s or miss in g



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i nformation.

          Then, th ere y ou h ave a pha rmacov igi lan c e

p lan, which takes care of t he po tent ial a nd m is s i n g

i nformation, let's say, fir st of all.          And y o u a l s o

h ave a risk minimi zatio n pl an.      S o for eac h s af e t y

i ssue, you should consi der if it' s app lica bl e o r

a ppropriate to pro pose risk -mini miza tion meas ur e s

l ike restriction o r cha nges to t he p roduc t

i nformation or com munic atio n, and so o n.

          We also have then foll ow-u p mea sure s t h a t

a re conditions tha t may be relate d to upda ti n g,

f ollow up of   resi stanc e fo r Kete k, fo r ex am p le .

F or clinical issue s, th ere may be also the

p ostmarketing stud ies, and so on , an d to p ro v id e

p rotocols and to h ave m iles tones when you sh o ul d

s ubmit the results and so o n.

          Then, we have the rene wal system , w hic h i s

n ow the mandatory one, that you h ave, afte r f iv e

y ears, you have su m-up of a ll th at h as be en

a ssessed during fi ve-ye ar p eriod sin ce th e fi rs t

a pproval, and then you can adopt it fo r li fe t im e o r

f or another five y ears.     Fo r exam ple, I co me ba c k



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t o that for Ketek.

          [Slide.]

          Ketek wa s gra nted in E urop ean Un ion th e n

i n June 2001.    The mark etin g auth ori zat ion h ad t h e

f ollowing indicati ons.       I t hink t hey a re q ui t e

s imilar with appro ved i n th e U.S.

          In patie nts a ged 18 ye ars or old er, yo u

h ave community-acq uired pne umoni a, m ild t o

m oderate, acute ex acerb atio n of c hroni c br on c hi t i s ,

a cute sinusitis, a nd al so a s an alte rnati ve t o

b eta-lactams for t onsil liti s and phary ngit is in

p atients 12 years or ol der.         This may be d if f er e n t

w ith the U.S.    I t hink this is ap prove d in C a na d a ,

f or example.    The dose reco mmende d is 800 mg on c e

d aily for 5 to 10 days.

          [Slide.]

          The usag e in the Europ ean Union, to tal l y ,

i t is estimated to be 1 3 mi llion cours es, a l ar g e

p roportion then of the esti mate o f 27 mill io n

c ourses worldwide, which was the d ata l og p oi n t f o r

t hat I think was a bout July 2006           Thes e ar e

e stimates, of cour se, p rovi ded b y th e MAH .



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           France m akes up o ver 5 0 pe rcent of the u s e

of   prescriptions in Eu rope .          But we a lso ha v e v e r y

e xtensive use in I taly, Ger many, Spain and G r ee c e .

 This will reflect also the probl em wi th

m ulti-resistance i n tho se c ountr ies.          In

S candinavian count ries and U.K., for e xamp le , t h e

u se is not as exte nsive and not e ither the p r ob l e m

w ith multi-resista nce.        But ther e em erged so m e

m ulti-resistance p roble ms i n tho se cou ntri es , a s

w ell, of course.

           [Slide.]

           There ar e the mos t imp orta nt pro duc t

u pdates of product info rmat ion.           You r ecog ni z e

t hose interactions with rif ampici n, wh ich im p ai r s

t he efficacy by in terac tion of th e met abol is m t o

p 450 level.

           There al so ha s be en an upd ate re gar din g

v isual disturbance s, ag grav ation of my asth en i a

g ravis.

           [Slide.]

           In 2003 was u pdat es co ncer ning h epa tic

A DRs in the Side E ffect s se ction, anap hyla ct i c



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r eactions and visu al di sord ers.         The D rivi ng

s ection has also b een u pdat ed acc ordin gly wi t h t h e

v isual disorders.

          [Slide.]

          Monitori ng of the prot on b eam ti me whi l e

p atients are recei ving teli thromy cin i s al so

r ecommended in an updat e.        Also t ransi ent lo s s o f

c onsciousness was added and a dri ving warn in g

a ccordingly.

          [Slide.]

          Recently , the n, a fter the public ati ons i n

J anuary 2006, like the situ ation was f or t h e U . S .

a nd the FDA action s, we iss ued wa rning s re ga r di n g

s evere hepatitis a nd li ver failur e, wh ich ma y o c c u r

w ith short latency and, in most c ases. wer e

r eversible.     Patie nts s houl d be i nform ed o f s ig n s

a nd symptoms, and we sp ecif ied th e sig ns a nd

s ymptoms.     That ha s bee n im pleme nted by th e c om p a n y

o n request from th e CHM P.

          In Septe mber 2006 , con trai ndicat ion in

p atients with prev ious live r reac tions dur in g

e xposure to telith romyc in, and al so ad ded th a t



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f atalities have oc curre d wi th suc h rea ctio ns .

          [Slide.]

          We also had, duri ng 20 06, conduc ted a

n umber of reassess ments of hepati c saf ety an d , i n

J anuary, after the firs t pr elimin ary o ne, th e

w orking party unde r CHM P co nsider ed th e

c haracteristics of seri ous hepati c rea ctio ns we r e

n ot well described in t he p roduc t in forma tion .

          The shor t lat ency to o nset of th ese

r eactions was of c oncer n, p rimari ly in pri ma r y c a r e

c onsidering that t he la rge propor tion of u se wa s i n

p rimary care and q uite mild types of i nfec ti o ns ,

r espiratory infect ions, and an up date of t he

p roduct informatio n was the n requ ested .

          [Slide.]

          A furthe r ass essm ent w as s chedul ed and t h e

r isk management pl an ta ilor ed on hepat ic s af e ty w a s

a lso to be request ed, a nd a n earl y sup pres si o n a

c oncern to the com pany.

          [Slide.]

          This was desi gned as a fol low-u p me asu r e ,

w hich is a procedu ral s ubty pe of title the n, an d



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m ost of the availa ble d ata then, when we r et u rn e d

t o that in May 200 6, mo st o f the avail able d a ta o n

h epatic safety was cons ider ed con siste nt w it h t h e

c urrent labeling a fter the update in F ebru ar y w i t h

r egard to hepatic safet y.

          No speci fic r isk facto rs c ould b e

i dentified except a ten denc y then for pati en t s w i t h

c ommunity-acquired pneu moni a to be a t high r i sk o f

l iver reactions in line wit h what has been t h e

i mpression in clin ical stud ies pe rha ps becau se o f

l onger duration of trea tmen t or t he pr oble m t o

d ifferentiate betw een w hat is the risk wit h t he

i nfection on the h epati c si de and what is re l at e d

t o the treatment.

          [Slide.]

          In May, also, a r isk m anag ement pla n w a s

c onsidered satisfa ctory and ther e wa s a p roto co l

f or the U.S. study .      Th at w as all plan ned by th e

c ompany here I thi nk an d th at wil l be pres en t ed

l ater today, the P HARMe tric s and the I ngen ix st u d y .

 That has also bee n loo ked at, at the prot oc o l i n

E urope. and the co mpany has provi de d us with s o m e



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p reliminary result s.

           The risk -bene fit was s till cons ider ed

f avorable after th at as sess ment.

           [Slide.]

           The asse ssmen t of avai labl e data on

h epatic safety in the E urop ean Me mber Stat es wa s

c ontinued to say t hat w as v ery im porta nt f or us .

           [Slide.]

           Then cam e the ren ewal and that w as

s ubmitted in paral lel w ith the re asses smen t d ur i n g

t he first half-yea r of 2006 .          So , in June , af te r

t he first reassess ment, the CHMP consi dere d t he

b enefit-risk of Ke tek t o be cont inue d to b e

f avorable based on the revi ew of ava ilabl e

i nformation from a ll pa rts of qua lity, eff ic a cy a n d

s afety.

           [Slide.]

           Further then incr eased awa reness of sa f e t y

i ssues especially hepat ic s afety.               The CHM P w as o f

t he opinion then t hat a ddit ional five -y ear r en e w a l

s hould be requeste d and tha t MAH sho uld a lso

c ontinue to submit annu al p eriodi c saf ety up d at e



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r eports.     By legis latio n, a fter t he fi rst re n ew a l ,

t he next one is af ter t hree addit ional yea rs .                  This

i s mandatory repor ting by l egisla tion norm al l y.

            [Slide.]

            Assessme nt on cas es of ser ious hepa tic

A DRs was also cond ucted in Europe by s peci fi c al l y

r equesting informa tion from all c ompet ent

a uthorities in Eur ope w ith regard to s erio us

h epatic ADRs.

            In summa ry, t here were 49 cases.              We have

s ome application p roble ms a s usua l but mo st of t h e m

w ere from France a nd Ge rman y.          We had 3 fa ta l it i e s

i n Europe.     This w as do ne u p to J uly 2 006.           A ll

t hree of them were from Fra nce an d the y pr ov i de d

l imited informatio n.        T here were other exp la n at i o n s

f or the hepatic re actio ns i n thos e thr ee c as e s, s o

t hey could not be attri bute d to t elith romy ci n

a ccording to the a ssess ment , acco rding to th e

a ssessment of the Frenc h ag ency.

            [Slide.]

            Furtherm ore, the repor ting rate was ab o u t

4 to 10 cases per milli on c ourses .               Th ese da t a



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a gain are in line with the curre nt p roduc t

i nformation and di d not alt er the conc lusi on s d r a w n

b y the CHMP in Jun e.      T his was do ne in Sep te m be r , a

q uite recent one.

          [Slide.]

          Taking g lobal dat a the n in to

c onsideration, the repo rt o f the fatal cas es fr o m

t he U.S. should be adde d to the prod uct i nfor ma t i o n

a nd further evalua tion and prescr iptio n an d

r eporting of ADRs in th e Eu ropean Unio n is

w arranted.   A full risk man agemen t pla n on a l l

s afety issues with teli thro mycin is re ques te d , a n d

i t has also been p rovid ed v ery re centl y, t hi s w e e k .

 So we have not lo oked into that yet.             It wi l l t a k e

s ome time.

          [Slide.]

          Some add ition al r egula tory measu res do n e

i n Europe, but we have intr oduced cont rain di c at i o n

I think the same a s in the U.S.            Patie nts wh o h a v e

e xperienced a hepa tic r eact ion d uri ng t reatm en t

w ith Ketek is cont raind icat ed, of cour se t o

r e-explore and add this inf ormat ion of fat al i ti e s .



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          [Slide.]

          So, in s ummar y, K etek was author ize d o v e r

f ive years ago in the E urop ean Un ion.         The p r od u c t

i nformation has be en up date d with safe ty

i nformation, all t he sa fety issue s we have

d iscussed today an d pre sent ed bef ore.

          [Slide.]

          Reassess ments of hepat ic s afety wer e m a d e

i n parallel with t he re newa l, and the mark et i ng

o rganization was r enewe d by the E urope an C om m is s i o n

i n July, then, bas ed on the CHMP opi nion.           Th e

s econd five-year r enewa l wi ll ta ke p lace.

          [Slide.]

          We have annua l sa fety upda te rep ort s a n d

s everal safety iss ues a re c losely moni tore d.            The

f ull risk manageme nt pl an a nd the use of K et e k i n

t he European Union is e xten sive a nd w il l be

f ollowed closely.

          Thank yo u.

          DR. EDWA RDS:      Tha nk yo u ve ry muc h, Dr.

M ortimer.

          We now h ave t ime for q uest ions p rio r t o



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t he lunch break.     I wil l op en the disc ussi on up f o r

q uestions from the pane l.

                    Com mitte e Qu estio ns

          DR. HECK BERT:      Ye s, I have a qu esti on f o r

y ou, Dr. Mortimer, I ma y ha ve jus t mis sed it .         When

y ou gave the estim ated repo rting rate base d o n t h e

m ost recent inform ation fro m the Europ ean Un i on , I

j otted down 4 to 1 0 per mil lion p rescr ipti on s , i s

t hat what you said , 4 t o 10 per m illio n ?

          DR. MORT IMER:      Ye s, 4 to 1 0, yes .

          DR. HECK BERT:      4 to 10 , bu t not per 10

m illion, per milli on, r ight ?

          DR. MORT IMER:      Pe r mil lion , yes.

          DR. HECK BERT:      Th ank y ou.

          DR. EDWA RDS:      Dr. Guti erre z.

          DR. GUTI ERREZ :     I have a q uestio n f or D r .

J enkins, and it ha s to do w ith s usce ptibi lity

t esting for telith romyc in.       In yo ur Sl ide No . 4 - 1 4 ,

y ou say that in yo ur er ythr omycin -r esis tant

i solates, that 0.5 perc ent of tho se we re r es i st a n t

t o telithromycin, is th at c orrect ?

          DR. S. J ENKIN S:     Yes.



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          DR. GUTI ERREZ :    T he re ason that I a m

a sking the questio n is that there was an a rt i cl e

t hat was published in A ntim icrobi al Ag ents i n

C hemotherapy in Ma y of this year.             Thi s is f r om a

g roup from Finland wher e th ey too k 210

e rythromycin-resis tant pneu mococ ci a nd th ey t es t e d

i t by agar diffusi on, w hich I un dersta nd i s

d ifferent than the way the PROTEK T stu dy i s t es t i n g

i solates, and they foun d th at act ually , 13 p e rc e n t

o f their isolates were resi stant to te lith ro m yc i n

b y this different metho d of susce ptibi lity t e st i n g .

          I guess the q uest ion I hav e for you is I

j ust wondered if y ou co uld commen t on this a n d I

w ondered if you co uld a lso commen t on your m e th o d s

o f susceptibility testi ng a nd whe ther you wo u ld

c onsider looking a t aga r di ffusio n in the is o la t e s

t hat you get in th e PRO TEKT stud y.

          DR. S. J ENKIN S:    Yes, the study you ar e

r eferring to looke d at disk diffu sion

s usceptibility tes ting and what t hey f ound i s t h a t

t here was a small subpo pula tion o f the org an i sm s ,

i n other words, yo u wou ld h ave co lonie s gr ow i ng



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w ithin the zone of inhi biti on in a s malle r, i n

a bout I think     you said 13 percen t.          I thi nk th a t

i s pretty close.

            When the MIC test ing w as d one us ing th e

s tandard method, t he Cl inic al Lab orato ry S ta n da r d s

I nstitute methods are c onsi dered those tha t a re

r ecommended all ac ross the world inc ludin g th e E U

a nd the United Sta tes.

            The MICs of t hose orga nism s were no t

e levated, so there was a di sconne ct be twee n w ha t

w as being seen in disk diff usion testi ng v er s us

t hat that was bein g see n us ing st andar d CL SI

m ethodology, and h ow to int erpre t th ose r esul ts I

t hink is impossibl e.

            DR. GUTI ERREZ :     T hank you.

            DR. EDWA RDS:      Dr. Foll mann .

            DR. FOLL MANN:      I wante d to ampli fy on a

c omment that was j ust m ade about the r ate fo r D r .

M ortimer.

            You ment ioned the rate of 4 to 1 0 c ase s o f

s erious hepatitis adver se e vents , 4 to 10 pe r

m illion.    The FDA in th eir docume nts h ave re p or t e d



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a rate of 23 per 1 0 mil lion of ac ute l iver f a il u r e ,

s o the rates are a bit diff erent.

          I am gue ssing it has t o do with per hap s

t he definition of what acut e live r fai l ure i s i n

t he U.S. and then whate ver you ar e def inin g a s

s erious hepatic ad verse eve nt to be.

          I would just like to k now the de fin iti o n a

l ittle more clearl y abo ut t he U.S . and the E u ro p e a n

d efinition of this seri ous advers e eve nt.

          DR. MORT IMER:     Mo st of the se ca ses, of

c ourse, are seriou s by clas sical, they are

h ospitalizations i n a w ay, so tha t is the cr i te r i a

a s such, or prolon gatio n or life -th reat ening o r

f atalities.

          So, when we c ome to lo okin g at l ive r

f ailures, then, I agree tha t is v ery d iffi cu l t h e r e

t o clearly specify what is the cl assif icat io n o f

a cute liver failur e, fo r ex ample, made by th e F D A

o r made by the com pany, or made i n tho se s tu d ie s

t hat we are going to he ar t his af terno on.

          Accordin gly, the compa ny, for ex amp le,

a pplies encephalop athy as s uch a s a prere quis it e



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f or acute liver fa ilure , an d it d epend s.     We mu s t

c ome somewhere her e to real ly hav e the sam e

c riteria to compar e the est imates we m ake.        I t' s

t he only comment I have so far.

          DR. AVIG AN:     As y ou wi ll s ee lat er thi s

a fternoon, you wil l get a r ather exp ansiv e

d iscussion about t he ca se d efinit ions, whi ch ar e

d ifferent, so we h ave a ctua lly so rt of mor e

s egmented or fract ionat ed t he def initi ons wh i ch

a ppear to be more encom pass ing in the case o f t h e

E uropean, so I am not s ure at the e nd t hat y ou

w ouldn't conclude that we a re not that far a p ar t .

B ut let's see the data this after noon.

          DR. EDWA RDS:     Tha nk yo u.

          Mr. Levi n.

          MR. LEVI N:     M y qu estio n is , is t he sum

t otal experience w ith A DEs postma rketi ng i n t he

E uropean community also dep enden t, a s it is h er e ,

m ostly on a sponta neous rep orting syst em?

          Are thos e cen tral ized or a re the y

m aintained by the membe r st ates, the m embe r

n ations, and are t hey m anda tory o r vol unta ry an d



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h as anybody ever e stima ted the pe rcent of

u nreported spontan eous even t tha t ma ybe o ccur ?

          DR. MORT IMER:    Wi th re gard to th e s yst e m

a s such, each comp etent aut hority is r espo ns i bl e

t ogether with the compa ny i n its terri tory .        Th e n ,

t he national repor t wit hin the te rrito ry t he n a r e

e lectronically pro vided to the ce ntral Europ ea n

d atabase for centr alize d ap proved prod ucts l i ke

K etek.

          It's a l ittle bit mess y, o f cour se,

b ecause you have 2 5 cou ntri es.      S ome h ave a v er y

d eveloped system l ike F ranc e, UK, Swed en a nd

G ermany--Spain is one, and with a qu ite hi gh e r

r eporting rate.    B ut un derr eport ing, of c our s e, i s

a problem.

          There ar e a n umbe r of stud ies, o f c our s e ,

o f underreporting and o ther facto rs th at i mp a ct s o n

t he spontaneous re porti ng i n Euro pe, s ever al

c ountries, mostly with rega rd to skin reac ti o ns ,

o verall serious re actio ns, and s o on .

          So there are a nu mber of p ublica tio ns, a s

w ell, from Europe, from the U.S.          I th ink it ' s



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a bout the same, I would say .

            DR. EDWA RDS:    Dr. Joha nn-L iang.

            DR. JOHA NN-LI ANG:     I w ante d to offe r a

c omment in respons e, sh ifti ng gea rs fr om D r. Lo n k s '

p resentation regar ding the transl ation of ma c ro l i d e

r esistance in the lab t o wh at is in th e cl in i c,

b ecause I think it is s uch an imp ortan t to pi c t h a t

n eeds more discuss ion a s we move antib ody tr i al s

f orward.

            The prob lem, I th ink t hat you ha ve sho w n

s lides that there are c ase report s of

m acrolide-resistan t tre atme nt fa ilur es.      T he

p roblem is that wh en we are tryin g to buil d a

c oncordance betwee n in vitr o data to w hat is

r elevant for peopl e for cli nical outco me, I s or t o f

t hink of as simpli stic in a 4 by 4 t able.

            We are a ble t o po pulat e th ese up on cas e

r eports only reall y one cel l, tre atmen t fa il u re

b ased upon positiv e res ista nt pat hogen .      W e a re n o t

a ble to really mak e goo d po pulati on of the o t he r

c ells, so it is pa tient s wh o are resis tant /n o t

r esistant but resu lt in tre atmen t fail ure, o r



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p atients who have succe ss a nyway regar dles s o f w h a t

t he drug is.

          Probably a lo t of that has to do wi th f o r

d iseases, and we t hink of i t in d iseas es, fo r

d iseases with high spon tane ous re solut ion.

          The host immu ne r espon se p robab ly i s a b l e

t o take care of th e bur den of the path ogen w h et h e r

i t's resistant to an an tibi otic o r not , wh ic h

b rings us to some of th e ot her to pics that I th i n k

o ther speakers hav e tal ked about, what are t h e

o ther risk factors , the sev erity of the illn es s ,

t he fact that mayb e the re i s an i mmune com pr o mi s e d

s tate of the patie nt.

          In those case s, p erhap s ha ving a n

e ffective antimicr obial tha t we r eally can a c co u n t

f or the resistance will mat ter, b ecaus e th at

p atient needs that help .

          Then, la stly, reg ardin g th e dru gs

t hemselves, maybe perha ps e ven in thos e pa ti e nt s

w ith the underlyin g ris k fa ctors, the diff er e nc e s

i n the drugs, not just the antibi otic effe ct , a n d a

p athogen effect ac tuall y by killi ng th e bu g.      But



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p erhaps what Dr. B artle tt h ad all ud ed t o reg ar d i n g

i mmuno-modulating effec t, m aybe that i s wh y t he r e

i sn't that exact c oncor danc e goin g fro m th e i n

v itro to the actua l cli nica l outc ome o f th e

p atient.

            I think there are many fac tors t hat we

r eally need to acc ount for rather than jus t t ry i n g

t o say the drug, y ou kn ow, the re sista nce of th e

b ug and therefore the c once rn tra nslat ed a nd

m agnified, et cete ra.

            I think we wi ll t alk m ore about thi s i n

f uture topics but that is s omethi ng th at I w a nt e d

t o offer as a comm ent.

            DR. EDWA RDS:    Tha nk yo u.

            Dr. Legg ett.

            DR. LEGG ETT:    A b rief ques tion f or Dr.

M ortimer.

            In the a pplic atio n for the five -ye ar

r enewal, was any o f the 301 4 data incl uded ?

            DR. MORT IMER:    I canno t gi ve you th e

e xact, but I assum e we have the s ame f iles a t t h i s

t ime.   I think you shou ld p erhap s as k the com pa n y .



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            DR. LEGG ETT:    We will.

            DR. EDWA RDS:    Tha nk yo u.

            Dr. Wied erman n.

            DR. WIED ERMAN N:    I had a c ouple of

q uestions, first, for D r. J enkins , ref erri ng to

y our Slide 15 wher e you had the s ix co untr ie s

a ggregate data on that red line.

            I am won derin g if you look at in div idu a l

c ountries, especia lly o nes that s tarte d ea rl i er ,

l ike Germany, is t here a di fferen ce in the n u mb e r s

o f isolates you ha ve am ong those count ries a n d

w ould the curve lo ok an y di fferen t if you lo o ke d

j ust, say, at Germ any, the ones that start ed

s ooner?

            DR. S. J ENKIN S:    We di dn't speci fic all y

l ook by country in this ana lysis.               Tha t ha vi n g b e e n

s aid, it is actual ly qu ite easy t o go back a n d d o

t hat.     I am not su re if thi s is s ometh ing we ca n

e ven do during the lunc htim e per iod to cu t th e d a t a

b y country but it can b e do ne wit h the sof tw a re

t hat is available to us .        B ut, at this poi nt in

t ime, I have not s een t hose data, so I rea ll y c a n ' t



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a nswer the questio n.

          DR. WIED ERMAN N:     Thank you .

          May I do my s econ d que stio n for Dr. Lo n k s ,

a little similar t o tha t pr evious ques tion .           Wi t h

y our Slide 4 that had t he C DC stu dies and th e n t h e

c ase reports, and I ass ume your r efere nces t h at y o u

h ad at the end ref erred to that s lide.

          I just w anted to clari fy, these are al l

U .S. studies, so y ou di d no t loo k at a nyth in g

o utside the U.S.?

          DR. LONK S:    I f I can j ust step b ack fo r a

m inute, at the beg innin g th ese we re ca se r ep o rt s .

T hen, there were c ase-c ontr olled stu dies.          Th e

c ontrols were pati ents with susce ptibl e is ol a te s .

          A study I was inv olved in was

m ulticentered, two hosp ital s in P rovid ence , R ho d e

I sland, one in Bos ton, one in Bar celon a, S pa i n, s o

t hey were populati on ba sed.       We a lso h ad c on t ro l s .

 We tried to match two cont rols p er ca se a nd ,             in

o ur particular stu dy, t here wer e no fai lures w i t h

t he susceptible st rains .

          Dr. Low is he re a nd if he can co mme nt o n



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h is study, they ha d a b road er loo k at the

s usceptibles.     The y did n't do mat ching or co n tr o l s .

 They actually loo ked a t al l susc eptib les an d d i d

f ind a couple of t reatm ent failu res in th e

s usceptibles but i t was sti ll sta tisti call y f ar

m ore likely to occ ur wi th r esista nt st rain s.

           Overall, the majo rity of t his da ta is f r o m

t he United States and C anad a.         If you want t o j u s t

t ake the grand tot al, 4 fro m Belg ium y ou c an

s ubtract out, and Spain was abou t 12 t hat yo u c a n

b ack out of this p artic ular data.              But mos t o f t h i s

h ere, the treatmen t fai lure s are from the Un i te d

S tates.     The CDC s tudy that was p ublis hed al s o

l ooked at suscepti ble, as w ell as resi stan t

i solates.

           What I w anted to do he re, my po int was

j ust to show that the r esis tance probl ems ar e

a ffecting patients . The se p atient s wer e tr ea t ed a s

o utpatients, they faile d. T hey we re ho spit al i ze d

a nd there were dea ths a mong these pati ents .

           Seeing D r. Mu sher just a l ittle ear lie r

r eminded me there was a 20 some -odd -old pati en t ,



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w ho was a very hea lthy male , went into the

h ospital, got IV a zithr omyc in and died bec au s e h e

r eceived azithromy cin, azit hromyc in -res istan t

i solate, so these are n ot j ust be nign fail ur e s a n d

t here have been co ntrol led studi es t aking a l oo k a t

s usceptible isolat es, a s we ll.

          DR. WIED ERMAN N:     Was t here a sys tem ati c

l iterature review, syst emat ic app roach to se l ec t i n g

t he studies you in clude d in that, or w ere th e se

j ust things you we re aw are of?

          DR. LONK S:    I sta rted in t his p arti cul a r

a rea in 1991.    I d id an ext ensive lite ratu re se a r c h

a nd only found a c ouple of case r eport s go in g b a c k

t o the 1960s, tryi ng to loo k at t his i ssue o f

r esistance.

          As you s aw up in the s lide , ther e i s o n l y

a couple of case r eport s.       Then, the re wa s a ca s e

w here I had a heal thy 3 2-ye ar-ol d ge ntlem an w ho

c ame into the hosp ital.

          He had g one t o an outp atie nt dep art men t ,

h ad an X-ray done, and had a rig ht l ower l ob e

p neumonia.    He was trea ted with e rythr omyc in .     Two



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d ays later he went to h is i ntern ist becau se h e w a s

f eeling no better, a co llea gue of mine .

            A sputum Gram 's s tain was done i n t he

o ffice.     It was ve ry re mark able.      He s till s a w s o m e

g ram-positive cocc i and tol d the patie nt t o w ai t

u ntil the next day to s ee i f he h ad a resp o n se .

T hat night he beca me co nfus ed, st arted

h allucinating.      Th e nex t mo rning was b roug ht in t o

t he hospital.      Thi s has bee n publ ished in my

p ublications, as w ell, desc ribing this cas e.

            The gent leman the n cam e in , he w as ver y

s ick.     We saw the gram- posi tive cocc i in the

s putum.     Because o f the hal lucina tions and a l so t h e

f act it required a lumb ar p unctur e to make s u re

t hat he did also d id no t de velop menin giti s.           This

i s a healthy guy, he ha d re ceived no a ntib io t ic s .

            The othe r poi nt t hat w as b rought up is ,

y ou know, with the case -con troll ed s tudy, the re i s

a host response. W ell, if y ou tak e a l ook at th e

s tudy I published in CI D a couple of y ears a g o, w e

a lso included all their com orbidi ties.            If y o u l o o k

a t the table in th at pu blic ation, you will f i nd o u t



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t hat there was rea lly n o di fferen ce be twee n t he

c ases and controls and thos e that fail ed a s f ar a s

t heir medical illn esses .     T hat it is r eall y n ot a

h ost response but a res ista nce is sue.

          DR. EDWA RDS:     Dr. Lonk s, b ased o n

m odeling, can you estim ate the ma gn itud e of th a t

p ublication lag ar tifac t fr om 200 4 on?

          DR. LONK S:     T he s tudy done in To ron to,

t hat was a surveil lance -bas ed st udy, was betw ee n

2 000 and 2004, was not publ ished until the s u mm e r

o f 2006, so there were fail ures i n 200 0 th at di d

n ot get into the p ublis hed liter atur e unt il 6 1 / 2

y ears later.

          The CDC study tha t was jus t pres ent ed a s

a n abstract at ICA AC th is y ear wa s pat ient s f ro m

2 001 to 2003, so y ou ar e lo oking at a time l a g o f 3

t o 5 years on when that get s pres ented , an d t ha t i s

y et to be publishe d.

          DR. EDWA RDS:     Tha nk yo u.

          Dr. Brad ley.

          DR. BRAD LEY:     Tha nks.    I h ave go t a

g eneral observatio n and que stion of th e FD A t o



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c larify the charge that you have to th e Co mm i tt e e

d uring these two d ays.

          We have certa inly hear d in format ion

p resented by Dr. A lexan der that refl ected

p resentations to t he Co mmit tee ov er th ree ye a rs

a go, and I had the plea sure of be ing h ere at th a t

t ime and saw the d ata.

          Based on a no n-in ferio rity tria l de sig n

w ith the issues of AEs that were discu ssed , w e

v oted for recommen ding appr oval.        As we g o th ro u g h

c urrent risk asses sment s, b oth in the U.S. a n d i n

t he European Union look ing at pos tmark etin g

s urveillance with spont aneo us rep ortin g, c le a rl y ,

p ostmarketing surv eilla nce won't give you as

a ccurate a view of adve rse events a s pr ospec ti v e

c ollected data whe re al l of the A Es ar e ni ce l y

d efined and you ha ve a beau tifull y cap ture d

p opulation that yo u can fol low.

          Some of the d iffe rence s in defin iti on i n

h epatic toxicity h ave c erta inly a lread y be en

d iscussed.   So I t hink look ing a t ri sk as sess me n t

n ow with telithrom ycin, and compa ring it w it h



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s omething like ery throm ycin , has some inhe re n t

d angers.

            I don't know if t he er ythr omycin AE

r eporting rate in 2006 will be th e sam e as

t elithromycin.

            In terms of c lini cal t rial desig n, the

n on-inferiority cl inica l tr ial d esign for si n us i t i s

a nd acute exacerba tion of c hronic bron chit is , w h i c h

w as felt to be app ropri ate in the late '90 s, wh e n

t hese studies were star ted and up on wh ich we ba s e d

o ur votes in 2003, has cert ainly been reas se s se d

j ust a few months ago w ith gemifl oxaci n.

            With a s uperi orit y tri al d esign, th at

r ecommendation for appr oval was n ot ma de b as e d o n

g uidances that you have wit hin th e FDA tha t y ou

d iscussed with the comp any, which we s till a r e

h oping to see soon .      Bu t no w the fa ct t hat

t elithromycin in y our d iscu ssions with the s p on s o r

h ad an approved no n-inf erio rity clin ical tria l

d esign, now raises the ques tion t hat f or e ac h o f

t he 12 drugs that Dr. C ox h ad pre sente d, t ha t a r e

c urrently approved and used for s inusi tis, a n d 1 8



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f or acute exacerba tion of c hronic bron chit is - -a n d I

p resume all of the se we re a pprove d on a

n on-inferiority tr ial d esig n--if we are g oing t o

h old telithromycin up t o a superi ority tri al de s i g n

s tandard, we shoul d do the same f or al l of t h es e

d rugs and assess e ach a nd e very one in th e c o nt e x t

o f the risks and b enefi ts t hat on e mig ht s ee fo r

a ll of these drugs .

          In that conte xt, we mi ght see a dru g l i k e

t rimethoprim sulfa with its Steve ns -Joh nson si d e

e ffect actually be ing w ithd rawn f rom t he m ar k et f o r

l ower respiratory tract , up per r espira tory t r ac t

i ndications.

          I am hop ing t o lo ok to the Agenc y t o h e l p

u s define how it i s tha t yo u want us t o lo ok at

t hese issues, beca use i f yo u are going to go ba c k

a nd look at every drug this way, and w e wo ul d

c ertainly support it, y ou w ill n eed to inc re a se

y our staff by two- or t hree fold, it will be a

p retty large job.

          But if t he sc ient ific comm unity and th e

A gency and the pol itica l co mmunit y all bel ie v es



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t hat in order to p rotec t th e popu latio n, b ot h o f

t he U.S. and the E U, th at w e now hav e a n ew

s tandard, then, ju st li ke i n 1962 , wit h th e

K efauver-Harris am endme nt t hat s aid drugs ne e d t o

b e effective and e very drug that was a ppro ve d

n eeded to show eff icacy bef ore it coul d st il l b e

m arketed, we may b e at the same m oment ou s po in t

h ere that when you come up with a new appr ov a l b a r

t hat is higher tha n bef ore, that every dru g t ha t

h as been approved previ ousl y now needs to go

t hrough a re-evalu ation .

          Again, I am h appy to s uppo rt tha t e ffo r t .

 But to go back an d pic k on a sin gl e dr ug wh ic h w a s

a pproved by non-in ferio rity tria l de sign, and

p articularly pick on a drug that is st ill br a nd e d

a nd has a sponsor where the re is money to do th e

t rials compared to trim eth sulfa, I th ink it is

m aking things more conf usin g for all o f us .     I

b elieve we need co nsist ent scient ifica lly -ba se d a n d

t ransparent criter ia to be applie d to all

a ntibiotics for al l ind icat ions.

          Thanks.



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            DR. EDWA RDS:    Joh n, I assu me tha t w as a

c omment, not a que stion .

            DR. BRAD LEY:    Bot h, Ja ck.

            DR. EDWA RDS:    Not to i n an y way dim ini s h

t he magnitude of t he is sue you ar e bri ngin g u p

b ecause it really is a majo r prob lem f or u s a ll ,

t hat we are all tr ying to w restle with her e.               But I

t hink we are going to t ouch on th e iss ue o ve r a n d

o ver again during the d iscu ssions .            I am n ot s u r e

t hat we want to do it a t th is mom ent u nles s - -I s o r t

o f am getting the affir mati ve nod -- we a re re al l y

b eyond the moment we ar e su pposed to b reak f o r

l unch right now.

            I think we wi ll d efini tely come bac k a n d

r e-talk about this issu e as the discus sio ns go o n .

            Dr. Jenk ins, did you w ant to mak e a

c omment?

            DR. J. J ENKIN S:    I wil l ju st mak e a br i e f

c omment on that po int.        It' s a ve ry go od o ne th a t

D r. Bradley is rai sing.        In the n atura l co ur s e o f

r egulating drugs, the s tand ards f or ap prov al , t h e

c linical, scientif ic st anda rds c hang e over t i me ,



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n ot just in antimi crobi als but in all area s.

            You are right .     I t wou ld b e a mo num ent a l

t ask to go back an d rea sses s ever ythin g th at ha s

b een done before a nd we gen erally don' t do t h at a t

t he FDA.    What we do is we look back when the re i s

a reason to look b ack, so i f ther e is a ne w s af e t y

s ignal that may th row o ut o f bala nce t he p re v io u s

r isk-benefit asses sment tha t was made at t he ti m e

o f the original ap prova l, t hen, t hat i s a tr i gg e r

t o go back in a se lecte d fa shio n an d lo ok.

            So, that is w hy w e are loo king a t K ete k

t oday, is because of th e sa fety s ignal s th at ha v e

a risen since it wa s mar kete d.        Yo u are rig ht , y o u

c ould do the same thing for all t hose othe r

a ntimicrobials tha t are use d for the s ame

i ndication.

            A simila r sit uati on ca me u p a c oupl e y e a r s

a go when we were l ookin g at the C ox -2 a gents a n d

t he nonsteroidal a gents .       T he dat abase s th at we

h ave for the appro val o f Co x-2 a gent s is much m o r e

e xtensive than the data base s we h ad at the t i me o f

a pproval for the t radit iona l non ster oidal s.



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            We have not g one back and tried to req u i r e

o r reassess the ol d non ster oidals .           Yo u co ul d a r g u e

s cientifically tha t wou ld b e opti mal.            But ,

p ragmatically, it is ve ry d ifficu lt an d ve ry

b urdensome to try to th ink about how t o do t h at .

            We gener ally look to l ook back a t t he

r isk-benefit asses sment whe n som ething new c o me s t o

l ight, generally o n the saf ety si de.

            DR. EDWA RDS:    Cla rify, Dr. Jenki ns.               We

t hink or we are de batin g th e issu e of whet he r t h e r e

i s a signal here r egard ing safe ty, so w e are

s electively going back with this parti cula r a ge n t .

 But in materials we ha ve b een se nt pr ior to th i s

m eeting, we have b een a sked to co nside r th e

r isk-benefit ratio in l ight of r ecent disc us s io n s

w hich have been ce ntere d on non -inf erio rity tr i a l

d esign in certain of th ese indica tions .              I s t ha t

c orrect?

            DR. J. J ENKIN S:    That is c orrect .           We

c ertainly don't wa nt yo u to exclu de th e ev ol u ti o n

o f science that we now have a mor e tho roug h

u nderstanding of n on-in feri ority and we a re t ry i n g



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t o take a more rig orous sci entif ic a pproac h.           We

c ertainly don't wa nt yo u to exclu de th at e vo l vi n g

s cience and that e volvi ng a pproac h and we wa n te d

y ou to factor that in a s yo u are makin g yo ur

a ssessment of bene fit-r isk.

          I was ju st re spon ding to D r. Bra dle y's

p oint that you cou ld ma ke t he sa me app roac h f or t h e

1 2 and 18, I think you said , othe r ant imic ro b ia l s

t hat are currently appr oved for t he sa me

i ndications.

          Ketek is bein g tr igger ed b ecause of th e

s afety concerns th at ha ve a risen.           If one of th o s e

o ther 12 or 18 had a sa fety conc ern, a ne w on e t h a t

d eveloped, we woul d do the same t hing.

          DR. EDWA RDS:    Tha nk yo u.

          I am goi ng to do the u npop ular t hin g o f

o bviating about fi ve mo re q uestio ns, w hich I ha d o n

t he list here of p eople int ereste d in aski ng , a n d I

a m just going to I am a frai d hav e to do th at , s o

t hat we are able t o kee p as much on sc hedu le as

p ossible.

          At this point we are g oing to br eak fo r a n



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h our roughly, and we ar e go ing to retu rn a t 1 :3 0 t o

r esume the meeting .

         Thank yo u.

         [Whereup on, a t 12 :40 p .m., the proc eed i n g s

w ere recessed, to be re sume d at 1 :30 p .m.]




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      A F T E R N O O N         P R O C E E D I N G S

                                                  [1 :35 p . m . ]

          DR. EDWA RDS:      We are g oing to pr oce ed n o w

and it is a pleasu re to int roduce Dr. Jona th a n

Levine, who will g ive o ur d iscuss ion o n th e d at a

mining evaluations of t he A ERS.

Data Mining Eval uat ion o f AE RS/Mul tiple Ant i bi o t i cs

               Jon ath an G. Lev ine, Ph.D .

          DR. LEVI NE:      Good afte rnoo n.

          [Slide.]

          I am goi ng to tal k abo ut a data min ing

analysis that Dr. Szarf man and I did o f mu lt i pl e

AERS antibiotics. This was reque sted by t he

Division of Anti-I nfect ives and Opht halmo logy

Products last spri ng.

          [Slide.]

          Let's st art o ff t alkin g ab out wh at is d a t a

mining. To my mind , dat a mi ning i s sta tist ic a l

analysis applied t o lar ge d atabas es wh ere th e re

aren't any a prior i hyp othe ses. So i t's l ook i ng f o r

answers without ne cessa rily havin g the que st i on s

set up ahead of ti me.



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            We didn' t do mill ions and millio ns of

s tatistical techni ques on a large data base .

I nstead, we used a spec ific techn ique, the M G PS

a lgorithm, to anal yze a ll s uspec t dr ug an d ad ve r s e

e vent pairs in AER S.

            I am goi ng to bri efly disc uss AE RS and t h e

M GPS algorithm.       T he de tail s are in th e br ie f in g

p ackage.

            [Slide.]

            So, what is A ERS?        Com pute rized adv ers e

e vents case report ing s yste m.          Vo lunta ry r ep o rt i n g

b y health care wor kers and the pu blic.

M anufacturers are requi red to rep ort s erio us

u nexpected events.

            The adve rse e vent s are cod ed usi ng Med D R A ,

t he Medical Dictio nary for Regula tory Acti vi t ie s .

T here are about 3 milli on r eports in A ERS at th e

m oment.    A relativ ely s mall numbe r of data

e lements, and ther e is lots of mi ssing dat a, so i f

y ou have an AERS r eport , yo u prob ably have a li s t

o f drugs the perso n too k, y ou hav e a b unch o f

e vents and no guar antee abo ut the othe r st uf f .



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          [Slide.]

          Dispropo rtion alit y ana lysi s usi ng B ill

D uMouchel's MGPS m ethod .       T he bas ic id ea i s t ha t

y ou calculate and obser ve a n expe cted numb er of

r eports for a part icula r dr ug- e vent comb inat io n .

          Here, th e obs erve d rat e, n umber of rep o r t s

f or a particular e vent for the dr ug of inter es t

d ivided by the num ber o f re ports for t he d ru g .           So

y ou wind up with, say, 5 pe rcent of th at r ep o rt f o r

a particular drug or fo r he adache .

          You can, for head ache, cal culate th e

e xpected rate.    Th is is bas ically the frac ti o n o f

r eports in the ent ire d atab ase a nd. from that , y o u

c an calculate this obse rved rate over expe ct e d

r ate, or the relat ive r epor ting r atio, whi ch we

w ill abbreviate as RR.

          That num ber i s th en sh runk towar ds 1 a n d

t he shrunk or adju sted valu e is r eferr ed t o a s t h e

E BGM score. The am ount of s hrink age that is d on e i s

a function of the amoun t of infor matio n th at AE R S

c ontains about the drug -eve nt co mbin ation , an d j u s t

e xpand a little bi t on that .



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          [Slide.]

          Expected coun ts a re of ten very, ver y

s mall, so that a s ingle rep ort ca n yi el d a h ug e R R .

          So, for examp le, in AE RS, acetam ino phe n

h as a report for A lice in W onderl and s yndr om e ,

w hich has 9 report s in all of AER S.             T he e xp e ct e d

n umber of cases is 0.01 1, w hich g ives you an RR o f

c lose to 90.

          Well, th at is a v ery i mpla usible re sul t ,

t he EBGM shrinks t hat, taki ng int o acc ount t h e f a c t

t hat it is a very rare even t and aceta mino ph e n h a s

a large number of repor ts a nd shr inks it t o a m u c h

s maller sensible n umber of 1.37.

          The shri nking is reall y wh at giv es you a

h andle on the fals e pos itiv e rat e.           If yo u ju st u s e

R R, you get drowne d in sign als fo r thi ngs th a t y o u

o nly observe 1 or 2 cas es o f.

          [Slide.]

          I should just say in s ome sense, we on l y

d id 3 analyses.     W e did an EBGM a nalys is o n 3

d ifferent looks on AERS and that yield ed m il l io n s

a nd millions of EB GM va lues , so t he fi rst, I am n o t



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g oing to present a ll 26 mil lion o r so EBGM v a lu e s

t oday.   We had to winno w th em dow n.

          What we did i s we look ed a t EBGM sc ore s

f or 16 drugs that were sele cted b y the rev ie w in g

d ivision.   We init ially loo ked a t al l adv erse

e vents that were i n the AER S data base and th e n w e

s elected the ones that had to hav e an EBGM o f

g reater than or eq ual t o 2, and i t end ed a t l ea s t 2

f or at least 1 of the c umul ative time peri od s t h a t

w e analyzed.

          We also didn' t lo ok at adv erse even ts t h a t

w ere probably rela ted t o th e indi catio n be in g

t reated, pneumonia , men ingi tis, e t cet era, a n d w e

o pted to look more at t he s erious adve rse ev e nt s

r ather than the le sser ones , so " hepat ic f ai l ur e "

w as considered ins tead of " aspart ate

a minotransferase i ncrea sed, " et cetera .

          [Slide.]

          So that winno wed thing s do wn to som ewh a t

m ore manageable si ze bu t we still had abou t 1 70

a dverse event term s, st ill had cl ose t o 3, 00 0 E B G M

v alues to present.



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          We could n't p rese nt th em a ll, so we we n t

t o another level o f dat a re ducti on; that i s, we

g rouped similar ad verse eve nt ter ms in to t he bi n s

t hings that we tho ught were getti ng at the s a me

a dverse event.     We only con sidere d the max im u m E B G M

s core over both th e adv erse event s in that

p articular groupin g and ove r a c umul ative sub se t o f

t ime.

          [Slide.]

          So we st ill c ould n't n eces sarily pr ese n t

a ll of those.     But we a re g oing t o loo k at 1 1 o f

t hose today.     Ther e is a re view i n the bri ef i ng

p ackage that does descr ibe the ot her e vent s i n

g reater detail.

          [Slide.]

          So, to c onden se t hem a ll d own, w e p ut t h e m

i n this table.     No w, th e co lors i n the tab le

r epresent the EBGM scor e, t he act ual E BGM va l ue s

a re also there.     T he co lumn s repr esent dru gs an d

r ows represent adv erse even ts.         S o 16 drug s a re

a cross the top.

          The left colu mn i s for tel ithro myci n.           The



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n ext 4 columns are for macr olides and then t h er e

a re 5 cephalospori ns, a moxi cillin /clav ulan at e , 3

q uinolones, nitrof urant oin and ac etami noph en is

t here as both a po sitiv e an d nega tive cont ro l f o r

t his case.

          [Slide.]

          You look ed at the se gr oupe d adve rse

e vents, eye, myast henia , sy ncope, hepa toto xi c

e vents, drug inter actio n, d rug in effec tive ,

c lostridial infect ion, toxi c skin and

h ypersensitivity a nd th e ke y here at t he b ot t om ,

p eople can't see t he ke ys a ll tha t wel l, I g ue s s .

          Basicall y, th e li ghtes t co lor, w ell , s t a r t

a t the beginning.      The cell s that have not hi n g i n

t hem, that are com plete ly w hite, those mea n t ha t a n

e vent was not obse rved for that d rug.          The s l ig h t l y

d arker light color indi cate s that the EBGM s c or e

w as between 1 and 1.5.        The n the next leve l, th e

n ext gradation up from that is 1. 5 to 2.

          The next is 2 to 4, an d th e dark est

o range-brown color indi cate d an EBGM g reat er th a n

4.   So the darkest colo r, y ou are seei ng s om e th i n g



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t hat occurs at 4 t imes what you woul d exp ect it t o

o ccur in the AERS datab ase.

           [Slide.]

           The firs t thi ngs to lo ok a t, the si gna l s

f or eye and for my asthe nia.         The signa l fo r e ye

e vents is clearly much larg er tha n any of th e

o thers, it is over 100.         It is a uniqu ely la r ge

s ignal.   Similarly , the mya sthen ia s ignal is qu i t e

l arge, as is the s ignal for azith romyc in.

           Some of the o ther s do have doubl ing s a n d

t riplings EBGMs bu t the two that stand out r e al l y

f or myasthenia are teli thro mycin and a zith ro m yc i n .

           [Slide.]

           Syncope, ther e is a hi gh s ignal for

s yncope with telit hromy cin, not a s hig h as t h e o n e

t hat is observed f or mo xifl oxacin .

           [Slide.]

           Hepatic failu re a nd he pati tis.       Hep ati c

f ailure, the stron gest sign als ar e wit h

t rovafloxacin and nitro fura ntoin, stil l a fa i rl y

h igh signal for te lithr omyc in.         Teli throm ycin

s ignal is similar to th e am oxicil lin/c lavu la n at e



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s ignal.

           Hepatiti s.     A gain , hep atit is loo ks a l o t

l ike amoxicillin/c lavul anat e and trova flox ac i n a n d

n itrofurantoin.      E rythr omyc in is in th e ba ll p ar k

t here.

           [Slide.]

           A fairly low sign al fo r ch olest asis .           The

h igher signals are with the macro lides and t h e

a moxicillin/clavul anate .

           [Slide.]

           Drug Int eract ion.       Aga in, the dr ug

i nteraction scores are ther e with all of t he

m acrolides, somewh at sm alle r for telit hrom yc i n a n d

f or three others.       I gu ess I sho uld mentio n t ha t

t he erythromycin t ends to h ave lo w sig nals b e ca u s e

i t has fairly low usage and I bel ieve it i s n o

l onger on the mark et, s o as a con trol.

           Drug Ine ffect ive Signa l.         There rea lly

i sn't much of anyt hing for telith romyc i n for d r u g

i neffective, large sign als for az ithro myci n a nd f o r

c efditoren.

           [Slide.]



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          Clostrid ial I nfec tion.        No thing for

t elithromycin, lot s of sign als fo r the

c ephalosporins, am oxici llin /clavu lanat e.

          [Slide.]

          A weaker sign al f or to xic skin r eac tio n s .

 Most of the stron g sig nals are w ith t he

c ephalosporins, so methi ng f or azi throm ycin .

          [Slide.]

          Again, h ypers ensi tivit y, m uch st ron ger

r eactions with the ceph alos porins , qui nolo ne s , l e s s

s o at the moment w ith t elit hromyc in.

          [Slide.]

          So, to s ummar ize that, the re is a v ery

l arge signal for t he ey e ev ents w ith t elit hr o my c i n .

 There is an unusu ally larg e sign al fo r my as t he n i a

w ith telithromycin and also a les ser s igna l w it h

a zithromycin but t here is c learly one ther e.

          There is a la rge signa l fo r teli thr omy c i n

a nd syncope and th at is sec ond on ly to the o n e

o bserved for moxif loxac in.

          [Slide.]

          Hepatic failu re a nd he pati tis bo th hav e



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s ignals with telit hromy cin.        Hepa tic f ailu re is

l ess than that for trov aflo xacin and

n itrofurantoin, co mpara ble to amo xicil lin an d

c lavulanate.

          Hepatiti s has a s ignal com parabl e t o

t rovafloxacin, nit rofur anto in and amox icil li n a n d

c lavulanate.

          Cholesta sis o nly has a wea k sign al wit h

t elithromycin.

          The majo rity of t he an tibi otics hav e a

s tronger signal fo r cho lest asis.

          [Slide.]

          Drug int eract ion does have a hig h s ign a l

s core with telithr omyci n bu t azit hromy cin,

c larithromycin and eryt hrom ycin a ll ha ve h ig h er

s ignal scores than does tel ithrom ycin.

          Toxic sk in an d hy perse nsit ivity rea cti o n s

h ave weak signals for t elit hromyc in co mpar ed t o t h e

m ajority of the ot her a ntib iotics .

          Drug ine ffect ive and c lost ridial in fec t i o n

d o not have signal s for tel ithrom ycin.

          DR. EDWA RDS:      I a ctual ly h ave ti me for o n e



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o r two questions.      Are ther e any quest ions ?

                   Com mitte e Qu estio ns

          DR. WIED ERMAN N:     I don 't t hink you can g e t

u s, or at least no t get me, up to spee d on t h e

d erivation of this algo rith m but if I aske d f ou r

s tatisticians abou t the val idity of us ing th i s

a pproach with this kind of data, would I g et fi v e

d ifferent answers, or h ow s olid i s thi s ?

          DR. LEVI NE:     I th ink i t is prett y s oli d .

I t is something th at I thin k stat istic ians w h o

a ren't used to dea ling with this type of d at a w o u l d

h ave to think abou t for a w hile a nd th ey w ou l d a l s o

n eed to be comfort able with some of th e Ba ye s ia n

t hinking.

          I think what make s it most unusu al is t h a t

i t is an analysis of st ruct ure in AERS , so i t i s

w hat is unusual in AERS .       I t is n ot sa ying t h is i s

u nusual in the gen eral popu lation .           AE RS c an ' t d o

t hat, AERS is not some wond erful sampl e fr om th e

g eneral population .     It is a col lect ion o f

s pontaneous report s.

          So this says it's real ly u nusual to ge t



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t his many reports of ey e ev ents f or a drug i n A E R S

a nd to make some k ind o f de finiti ve st atem en t a b o u t

t hat is not someth ing t hat a stat istic al m et h od c a n

d o.   It is only ap plica ble to th e AE RS dat ab a se

u ltimately.

            But I ad d to that , tho ugh, I thi nk it

l ooks about right.      I m ean the ad verse eve nt s t h a t

i t does pick up an d hav e se emed t o mat ch f ro m w h a t

c linicians tell me , mat ch u p with clin ical

e xperience.     I wil l let oth ers a rgue the vera ci t y

o f that.

            DR. EDWA RDS:    I w ould like to as k a

q uestion.     I have done some thing here that I am

s ure is statistica lly h ighl y ille gal b ut I w a nt t o

a sk this question anywa y.

            If I add the numb ers u p fo r hepa tit is,

c holestasis and he patic fai lure, tho se bo xes, f o r

t elithro and trova , I g et a total of 1 1.4 as a s u m

o f those numbers v ersus 15. 3 for trova .

            Hepatic failu re, can y ou s ee tha t?

H epatitis and chol estas is.        I am compa ring t h at

g roup of numbers t o the sim ilar g roup for tr o va



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o ver here.    This o ne, t his one, a nd th is o ne

c ompared to this o ne, t his one, a nd th is o ne , a n d I

g et 11.4 for telit hro a nd 1 5.3 fo r tro va.

            DR. LEVI NE:    Oh, addin g th em.

            DR. EDWA RDS:    I w ant t o kn ow wha t t he

m agnitude of that diffe renc e is.         As I say , I

r ealize this may b e com plet ely st atist ical ly

i llegal.

            DR. LEVI NE:    Well , the y ar e rati os.

            DR. EDWA RDS:    Dr. Legg ett, did y ou wan t t o

a mplify?

            DR. LEGG ETT:    Ins ignif ican tly,

s tatistically, or just as p oorly stati stic al l y.        In

t he packet, we had EB-5 to EB-95 , so rt of lik e t h e

e quivalent of a co nfide nce interv al an d I as s um e

t hat it is not a s harp conf idence inte rval t h at w e

u se for non-inferi ority .

            DR. LEVI NE:    Righ t.

            DR. LEGG ETT:    Can we t ell if 5.8 is

d ifferent than, sa y, 12 , or we ca n't r eall y t el l ?

            DR. LEVI NE:    No, that' s in the p ack et.    I

d on't recall offha nd.



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         DR. LEGG ETT:     I j ust h ad a hard tim e

l ooking at the tab les t o se e if t rova was

s tatistically sign ifica ntly more than teli th r o,

b ecause all the 90 perc ent confid ence inte rv a ls , s o

a ll we have to do is lo ok a t tha t an d just l o ok a t

t hat one number, c orrec t?

         DR. LEVI NE:     I am sorr y?

         DR. LEGG ETT:     In the d ata mining th ing ,

t here is the EB-5 and t he E B-95.        Th en th e nu mb e r s

p rovided on the le ft on ly f or tel ithro and t h en

t here is a table t hat j ust has t he n umber s.

         So what I was won derin g is if th at

c onfidence interva l on the leftha nd co lumn f o r t h e

t elithro overlaps with one of the numb ers in on e o f

t he cells.

         DR. LEVI NE:     Righ t.     T hat can be

c autiously interpr eted.

         DR. LEGG ETT:     Oka y, ca utio usly.

         DR. LEVI NE:     Corr ect.

         DR. LEGG ETT:     My other que stion is, is

t his data per year a pe rson since AERS has s t ar t e d ?

         DR. LEVI NE:     This is t he m aximum va lue



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o ver all of the cu mulat ive years, so i t mi gh t b e

a ll of it, it migh t jus t be throu gh a part ic u la r

y ear.   We just loo ked a t th e wors t cas e.

          DR. LEGG ETT:    So, for inst ance, if

e rythromycin, you would hav e all the d ata fr o m 3 0

y ears ago or whene ver t his thing had s tart ed .

          DR. LEVI NE:    Righ t.

          DR. LEGG ETT:    Whe reas, for telit hro , y o u

w ould only have it the last thre e ye ars.

          DR. LEVI NE:    That is c orre ct.

          DR. LEGG ETT:    So there is inhere nt bia s i n

b oth, because eryt hromy cin 30 yea rs ag o, w e d id n ' t

e ven know about my asthe nia gravis , for ins ta n ce .

          DR. LEVI NE:    Righ t, ye s.

          DR. EDWA RDS:    Wel l, no t qu ite t hat bad .

          DR. LEGG ETT:    It was p resu mably def ine d

d ifferently for th e AER S 30 years ago.

          DR. LEVI NE:    Yes.

          DR. LEGG ETT:    So that when we ha ve a

c olumn that says a spec ific entit y, it is ev e n m o r e

c onfusing because what we c all it now is n ot wh a t

w e called it two y ears ago.



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          DR. LEVI NE:     Righ t, al thou gh I m ean it ' s a

l ittle bit fuzzy b ecaus e we did t ry --th at's wh y w e

p ut multiple terms into eac h of t hese bins .           Bu t

t he myasthenia ter ms, I thi nk we concl uded a r e a l l

f airly recent.

          DR. EDWA RDS:     Dr. Brad ley, did you hav e a

q uestion?

          DR. BRAD LEY:     No, that was exact ly my

q uestion, thank yo u ver y mu ch.

          DR. EDWA RDS:     Dr. Foll mann .

          DR. FOLL MANN:     Th anks.     I just w ant ed t o

m ake a couple comm ents on t his.         First , as w e a l l

k now, this is base d on the report ing da ta, w hi c h i s

s ort of a shaky da tabas e.      It is based on

s elf-report by the phys icia ns as sociat ed w it h

g iving the drug.

          In the p aper that desc ribe s this

m ethod--and so you can' t re ally asse ss cau sa t io n

w ith this,   The pa per t hat descri bes t his

m ethodology has an inte rest ing e xamp le whe re th e y

l isted side effect s for pol io vac cinat ion an d 7 o f

t he 15 or so were assoc iate d with the inje ct i on



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s ite but it was an oral pol io vac cinat ion an d s o i t

d idn't really make sens e.

          What was happ enin g was tha t they go t t h a t

v accination with s ome v acci nation that inv ol v ed

i njections. So I w ouldn 't p lace a lot of p re c is e

d escriptions about this dat a and I am a li tt l e

u ncomfortable sort of i n sa ying t hat t hese

c onfidence interva ls or wha tever overl ap.

          I think it is enc ourag ing and i nter est i n g

t hat it really ide ntifi es t he mya sthen ia g ra v is ,

w hich was identifi ed in Eur ope, I gues s, b ut no t

h ere, so that is a n app eali ng thi ng ab out th i s.

A lso, the eye adve rse e vent s.

          But one thing I w as wo nder ing ab out in t h e

E uropean report, t hey m enti oned I th ink 3 3 pe rc e n t

o f all adverse eve nts w ere relate d to the ey e .         So

I think what this would mea n for this data ba s e, i f

w e removed eye, so me of the signa ls fo r he pa t it i s ,

e t cetera, might b e inc reas ed som ewhat , be ca u se y o u

a re looking at a s ignal of stati stic al in depe nd e n c e

b etween adverse ev ent a nd d rug re lativ e to t h e

u niverse of advers e eve nts you ar e inc ludi ng , t h i s



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w ill change a bit with what you d ecide to in c lu d e

i n terms of advers e eve nts.

            So, sinc e eye is so co mmon for K ete k, i f

w e eliminate this, it m ight make the o ther a d ve r s e

e vents have strong er si gnal s or l arger rat io s

t here.

            I guess the b igge r iss ue r eally is wha t I

a m really wrestlin g wit h in these two days i s t h e

h epatitis signal, the r isk of hep atiti s.       I d on ' t

t hink this analysi s can rea lly g ive us a l ot of n e w

i nsight about that part icul ar ris k.

            DR. LEVI NE:     I di d at one point do an

a nalysis removing the e yes, and m y rec olle ct i on i s

t hat it didn't mak e all tha t much impa ct.        But we

p robably could rer un th at a nalysi s and see w ha t

h appens.

            DR. EDWA RDS:     Yes .

            DR. PROS CHAN:     I think tha t it i s v ery

d ifficult to take a hug e da ta set like thi s a nd

f igure out exactly what is going on an d I do th i n k

t hat this is a rea sonab le w ay to do it .      I t h in k a

l ot of statisticia ns wo uld agree tha t thi s ha s a s



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l ot of nice proper ties.

          I also a gree that it c an o nly re all y g i v e

y ou rough signals and y ou c an't g et as pre ci s e a s I

t hink some of the membe rs a re try ing t o ge t.         But

i t is interesting that it i dentif ies t he t hi n gs

t hat I think were the s tron gest, nam ely, the ey e ,

w hen you look at a ll th e ev idence in t he p ac k et , i t

i s pretty clear.

          I think both side s agr ee r eally tha t t h e r e

a re eye problems w ith t his drug, how s erio us th e y

a re there might be disa gree ment.         But I th in k t h e

s trongest evidence was in t erms of t he eye , b lu r r e d

v ision, that kind of th ing, and t his i s de te c ti n g

t hat.

          I think the f act that it m akes s ens e f r o m

a statistical poin t of view , it h andle s a lo t o f

d ifferent aspects, name ly, the tr adeof f be tw e en a

r elative risk that is v ery unsta ble.          The oth er

o ption which would be t o lo ok at a p -va lue i ns t e a d

o f looking at a re lativ e ri sk, wh ich i s to o f ar t h e

o ther way.   It is not s ensi tive e nough - -you kn o w ,

s mall data sets wi th ki nd o f dras tic t hing s g oi n g



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o n, and this is so rt of a c ompro mise betw een th e m .

          So I thi nk bo th f rom a sta tistic al poi n t

o f view and from t he fa ct t hat it seem s to b e

m atching at least my im pres sion o f wha t th e

s trength of eviden ce wa s fo r the diffe rent

c omponents, I thin k bod es f airly well.

          DR. EDWA RDS:     Tha nk yo u.

          Mr. Marc o, la st q uick ques tion.

          MR. MARC O:     I was wond erin g if y ou cou l d

j ust walk us throu gh.     It's in th e bri efin g

d ocument, the back groun d ma terial s, pa ge 1 8, Ta b l e

6.   That has the c onfid ence inter vals and ma y be

t hat will help wit h Dr. Edw ards' que stion abo ut a r e

t hings either over lappi ng m ore or less .

          Can you pull that up?

          DR. LEVI NE:     Righ t.

          MR. MARC O:     T hat seems eas iest t o l ook a t

v ersus the other.

          DR. LEVI NE:     Mayb e the bes t thin g, I c a n

a sk Dr. Szarfman.

          DR. SZAR FMAN:     I think tha t her e wh at y o u

h ave, in our revie w, th ere are lo ts of mor e d et a i l s



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o f how this was do ne.        You have a lso a tim e c ou r s e

o f the signals cou rse a nd t he num ber o f re po r ts

a cross the whole d ataba se.

            Here, wh at we are look ing is we are

c omparing telithro mycin for diff eren t eve nt c od e s ,

t hat in the memora ndum we h ave co llaps ed h ep a ti c

f ailure.     We have used hepa tic fa ilure , li ve r

t ransplant, liver repro cess , you have it e xa c tl y .

            On hepat ic fa ilur e eve nt c ode is mo re

a ssociated with fa tal o utco me fro m the res t of t h e

e vent codes except with one excep tion that w e w i l l

k now when we get t o cho lest asis.

            But esse ntial ly, in re d, y ou hav e t he

d rugs that are hig her, non- overl appi ng si gnal s d o n e

w ith telithromycin teli thro mycin is al ways i n

g reen.     In blue ar e the dru gs th at h ave c onfi de n c e

l imits that overla p wit h th e ones for

t elithromycin, and in b lack is wh en te lith ro m yc i n

h as higher, non-ov erlap ping sign als.

            Then, yo u see for hepa tic failur e,

a cetaminophen and trova flox acin h ave h ighe r a nd

n on-overlapping.       Telit hrom ycin over laps the



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s ignals with nitro furan toin and a moxic illi n a nd

c lavulanic acid.

            There is no o verl appin g wi th

c larithromycin. Cl arith romy cin is high er f or

t elithromycin, lar ithro myci n, azi throm ycin ,

g emifloxacin, and you h ave the to tal n umbe r o f

r eports.    We analy ze 13 ,000 , over 13,0 00 r ep o rt s .

            For hepa titis , es senti ally , you see th a t

m ost are overlappi ng or tel ithrom ycin is h ig h er .

W hat you are seein g is that excep t for

a moxicillin-clavul anic acid , tha t is high er a nd

n on-overlapping.        The r est are e ithe r ove rlap pi n g

w ith claritho or t he te lith romyci n is high er .

            [Slide.]

            If we go to t he n ext h ere, chole sta sis i s

d ifferent, because if w e lo ok at chole stas is

a cross, essentiall y, wi th c holest asis, you h a ve

m ore drugs.

            For chol estas is, these dru gs ha ve h igh e r ,

a re non-overlappin g.        B ut t elith romy cin ov er l ap s

w ith all of these.

            If we go and look at t he n ext pa ge, fo r



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f atal outcomes, th e fat al o utcome s you don 't ha v e

r eports of five ev ents.     I am ans werin g yo ur

q uestion, and it i s not int erferi ng.

          Next pag e.    T hese are fata l out come s, t h e y

a re all overlappin g ess enti ally.

          Let's no w go to t he ne xt o ne.        N ext pa g e .

 For cholestasis, the f asci nating thin g is w h en y o u

a re looking at cho lesta sis and fa tal o utco me ,

e ssentially, the o bserv er w ill ex pect the re is o n e

i n the whole datab ase.     But for a moxic illi n a nd

c lavulanate, they are h ighe r and non -ov erlap pi n g

t han the other one s.

          It is no t onl y ch olest asis but i t i s

e ssentially instea d of havi ng an obser ver ex p ec t e d

o f one, you have 1 3.86.     Th is was a si m ultan eo u s

a nalysis across th e who le d atabas e.        T here i s

a nother problem th at wa s re ally d iffic ult to

s ummarize everythi ng th at w e have done .         B ut ,

e ssentially, the p roble m of if th is is a s ig n al o r

i s not a signal is real ly e asy to asce rtai n b ec a u s e

w ith one mouse cli ck, y ou w ould do the rep or t .

          Essentia lly, we h ave o ther graph ic



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d isplays that are essen tial ly the y opt imiz e

v isualizing where the a ctio n is w ith e vent s.      I

h ave some other pr esent atio ns, on e at the In s ti t u t e

o f Medicine that I can show you h ow thi s wor ks ,

b ut, essentially, the I nsti tute o f Med icin e r ep o r t

r ecommends the use of t his method ology , so me of t h e

g raphic displays t hat w e us e.

          DR. EDWA RDS:     Tha nk yo u ve ry muc h.

          Dr. Dal Pan, did you h ave a quic k c omm e n t ?

          DR. DAL PAN:      I j ust w ant to ma ke a qu i c k

c omment to just ex plain to the me mbers of th e

C ommittee how we u se th is i n our work in

p ostmarketing safe ty in the Offic e of Surv ei l la n c e

a nd Epidemiology.

          Our data base is v ery b ig, it has ov er 4

m illion records.     One o ptio n is j ust t o lo ok at

t hem one at a time .     Th at i s not very effi ci e nt .

S o tools like this help us by tel ling us w ha t i s

m ore common with o ne dr ug v ersus what is l es s

c ommon with that d rug.

          It helps us t o ge nerat e si gnals and

g enerate hypothese s, wh ich then r equir e fu rt h er



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e valuation.    So wh en Dr . Le vine a nd Dr . Sz ar f ma n

p ut up terms like hepat ic f ailure , hep atit is , e y e ,

w hatever, these ar e cod ed b ioinfo rmati c te rm s t h a t

r equire further ev aluat ion at the leve l of t h e

i ndividual case.

           So, if y ou we re t o, sa y, b e inte res ted i n

t elithromycin, you woul d lo ok in the d atab as e , y o u

w ould see this big sign al f or eye .           Yo u wo ul d t h e n

g o to all those re ports on eye an d loo k at t h em t o

s ee what they are telli ng y ou.

           So we us e thi s as the firs t step to or i e n t

u s in a very large comp lex datab ase to he lp g ui d e

u s.   It is helpful , as Dr. Levine said , it l o ok s u p

a ll these combinat ions with out an y a p rior i

h ypotheses.    So th ings we m ight n ot ha ve t ho u gh t o f

m ight come up this way.

           The basi c mes sage is i n ou r work , i n

p ostmarketing safe ty, w e re ally use this as a f i r s t

s tep for further c linic al e valuat ion a nd w e w il l b e

p resenting some of thos e re sults throu ghou t t he

c ourse of the meet ing.

           DR. EDWA RDS:    Tha nk yo u.



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          At this point , I need to t urn th e m eet i n g

o ver to Mark Moyer agai n fr om San of i-Av entis , w h o

i s going to introd uce t he n ext se ries of s pe a ke r s .

          Mark.

                   Spo nsor Pres entat ion

          MR. MOYE R:    I am going to take t he

o pportunity to int roduc e th is as a ser ies of fi v e

p resentations that the spon sor ha s put tog et h er .

O nce the signal is iden tifi ed of con cern, suc h a s

h epatic events, as has alre ady be en su gges te d , i t

n eeds to be furthe r eva luat ed.

          So we wi ll ha ve a pres enta tion o n t he

s afety overview of hepa tic events by D r. B ar b ar a

R ullo from our Pha rmaco vigi lance group .

          That wil l be foll owed by a n exp ert rev i e w

b y Dr. James Lewis , who is a Prof essor of Me d ic i n e

a nd Director of He patol ogy at Geo rgeto wn

U niversity, who wi ll pr ovid e his persp ecti ve on

t hose individual e vents .

          We will then go t o ano ther appro ach th a t

f urther enhances o ur ab ilit y to eval uate thes e a n d

t hat is two epidem iolog ic i nvesti gatio ns.     One is



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t hrough the PHARMe trics dat abase, and Dr. Wa n ju D a i

w ill present that. She is t he hea d of our

E pidemiology group over in our Ph armac ovig il a nc e

a nd Epidemiology D epart ment at Sa nofi -A venti s.

          We will then have Dr. Alex Walke r, who i s

t he head of I3 Dru g Saf ety and an Adju nct Pr o fe s s o r

o f Epidemiology at the Harv ard Sc hool of P ub l ic

H ealth, present hi s dat a fr om the Inge nix da t ab a s e .

          A final revie w of the epid emiolo gy by D r .

J udith Jones from the D egge Grou p, w ho is al s o a n

A djunct Professor of Ph arma cology at t he G eo r ge t o w n

S chool of Medicine .

          I would like to i ntrod uce Dr. Ru llo at

t his time.

     Adverse Even ts of Sp ecia l Int erest: Hep a ti c

                       S afety Ove rview

                    Bar bara Rull o, M. D.

          DR. RULL O:     G ood after noon .

          [Slide.]

          As I ind icate d th is mo rnin g, I w oul d n o w

l ike to describe o ur he pati c safe ty ex peri en c e w i t h

t elithromycin sinc e the dru g was appro ved in Ap r i l



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2 004.

          [Slide.]

          I am fir st go ing to br iefl y summ ari ze o u r

p re-approval hepat ic sa fety expe rien ce an d th en w e

w ill examine our p ostap prov al hep atic expe ri e nc e ,

a nd we will look a t a c oupl e of p oints in ti m e.

          In April of 2 005, at t he o ne yea r t ime

p oint, we received thre e re ports of li ver fa i lu r e

f rom North Carolin a. Th ese were s ubseq uen tly

w ritten up in the Annal s of Inter nal M edic in e i n

J anuary of this ye ar.       So w e are going to lo o k a t

t wo points in time , we are going to lo ok a t t he

o ne-year time poin t whe n we rece ived t he c as e s, a n d

t hen we are going to lo ok a t the two -ye ar ti me

p oint shortly afte r the Ann als a rticle app ea r ed ,

a nd then conclusio ns.

          [Slide.]

          Prior to U.S. app roval , we perfo rme d t w o

i n vitro studies t o ass ess potent ial h epat ic

e ffects of telithr omyci n.       The fi rst s tudy e x am i n e d

c ovalent binding t o hum an l iver m icros omal

p roteins, and the other , in hibiti on of



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m itochondrial beta -oxid atio n.

          In both cases , te lithr omyc in beh ave d

s imilar to clarith romyc in a nd azi throm ycin .

          We also exami ned precl inic al eff ect s.        We

s tudied the precli nical eff ects i n the rat , t he d o g

a nd the monkey, an d the hep atic effe cts we re ag a i n

c omparable to macr olide s.

          [Slide.]

          Based on the macr olide -lik e pre clin ica l

h epatic effects, w e use d so me sta ndard def in i ti o n s

f or hepatic events duri ng o ur cli nical pro gr a m a n d

m onitored these cl osely .

          During o ur co ntro lled Phas e III stu die s ,

w e found no differ ence in c linica l hep atic e v en t s

o r hepatic enzyme chang es b etween teli thro my c in a n d

c omparators.    Thos e com para tors w ere a moxi ci l li n ,

a moxicillin-clavul anic acid , cla rith romyc in a nd

c efuroxime.

          During t he co ntro lled clin ical stud ies , w e

h ad two serious ev ents in p atient s rec eivi ng

t elithromycin and one f or a patie nt re ceiv in g

c larithromycin.



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          We also did a stu dy in pat ients tha t h a d

h epatic impairment and we f ound t hat n o do se

a djustment was nee ded i n th is po pula tion.

          We had a vast amo unt o f po stmark eti ng

e xperience that we had subm itted at th is t im e .

T here was one pati ent t hat had a hepat itis A Q

f ever, acute liver fail ure but no drug - relat ed

s evere hepatotoxic ity w as i dentif ied.

          [Slide.]

          As a res ult o f th e dat a th at we had

r eviewed, there wa s in our label at th e ti me of

a pproval a precaut ions rega rding hepat ic

d ysfunction includ ing i ncre ased l iver enzy me s a n d

h epatitis with or witho ut j aundic e.

          Also, a note to u se wi th c aution in

p atients that had devel oped hepa titi s wit h pr ev i o u s

K etek use.

          [Slide.]

          So what happe ned in ou r po stappr ova l

e xperience?

          Well, as I me ntio ned, at t he one -y ear t i m e

p oint, in April 20 05, w e re ceived 3 re port s o f



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a cute liver failur e fro m th e same hosp ital i n N o r t h

C arolina.   This ho spita l wa s a r egio nal t ran s pl a n t

c enter and a refer ral c ente r, and thes e ar e t he

t hree patients tha t sub sequ ently appea red in th e

A nnals of Internal Medi cine .

          Now, pri or to thi s, we had 4 rep ort s o f

a cute liver failur e wor ldwi de, an d thi s is a f te r a n

e xposure of 17 mil lion cour ses of trea tmen t.

          The firs t was the pati ent that w e k new

a bout prior to U.S . app rova l, the pati ent wi t h t h e

h epatitis A and Q fever .       T hen th e oth er t hr e e

p atients occurred in 20 04 a nd ear ly 20 05 a nd th e y

w ere patients with sept ic s hock and ische mic

i njury, and they h ad co mpel ling a ltern ativ e

e xplanations for t heir live r fail ure.

          Now, Dr. Jame s Le wis i s go ing to sp eak t o

h is causality asse ssmen t fo r each of t hese c a se s

v ery shortly but, at th is t ime we did a qu al i ta t i v e

a nd quantitative r eview of our d ata.

          Qualitat ively , we revi ewed all h epa tic

r eports that we ha d rec eive d up t o tha t po in t i n

t ime.   The data sh owed that the i nform atio n w as



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c onsistent with wh at we had seen durin g ou r

c linical program a nd wh at w as in our p rodu ct la b e l .

            I told y ou ea rlie r tod ay t hat we ha d a

s tandardized quest ionna ire that w e use d to c a pt u r e

a comprehensive am ount of i nforma tion, so we al s o

d id an analysis lo oking at risk f actor s.

            We looke d at age, gend er, durati on of

t reatment, indicat ions, con comit ant medic atio ns ,

m edical history, a nd we cou ld not iden tify a n y r i s k

f actors.

            [Slide.]

            We did a quan tita tive anal ysis.      We di d a

c omparative report ing r ate analys is us ing FD A

F reedom of Informa tion extr acted data to i de n ti f y

s pontaneously repo rted hepa tic e vent s tha t oc cu r r e d

w ithin one year af ter l aunc h for each of t he

p roducts that we e valua ted.

            We used two d efin ition s, b roadly de fin e d

h epatic terms and criti call y defi ned h epat ic te r m s .

 Broadly defined h epati c ev ents w ere h igh le v el a n d

p referred terms fr om th e he patob ilia ry, th e

i nvestigation in t he ne urol ogic s ystem org an cl a s s .



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          Critical hepa tic event s in cluded he pat i c

c oma, hepatic ence phalo path y, hep atic necr os i s,

f ulminant hepatiti s, ac ute liver failu re a nd

t ransplant.

          For teli throm ycin , sin ce w e wer e ju st a t

t he one-year time point .        W e wan ted to be as

c omplete and curre nt as pos sible, we u sed ou r o w n

i nternal data in t his a naly sis, b ecaus e th er e i s a

l ag time in obtain ing F DA F OI dat a.

          As you c an se e fr om th e re sults,

t elithromycin for both broa dly d efin ed an d

c ritically defined hepa tic events was with in th e

r ange of other mar keted ant ibioti cs.          Base d o n t h e

p reponderance of e viden ce, our qu alita tive a n d

q uantitative revie w of the data, a new ris k b ey o n d

w hat was already i denti fied in ou r prod uct

i nformation was no t ide ntif ied, a nd we con ti n ue d t o

m onitor closely.

          [Slide.]

          As I ind icate d wh en I bega n, the ar tic l e

a bout these three patie nts from N orth Caro li n a

a ppeared in the Ja nuary Ann als ar ticle .          Y ou ca n



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s ee the dramatic i ncrea se i n th e nu mber of c as e s

t hat we received o nce t he A nnals artic le w as

p ublished.

          Reportin g rat es w ill c hang e over ti me.           As

w e talked about th is mo rnin g, rep ortin g ra te s a r e a

m easure of reporti ng in tens ity.         They are af f ec t e d

b y many things.     O ne of the m is p re ss c overa ge t h a t

r esults in stimula ted r epor ting a nd th is i s a

c lassic picture of stim ulat ed rep ortin g.

          Now, wit h sti mula ted r epor ting, as the

n umber of cases, t he qu anti ty of cases inc re a se s ,

t he quality of tho se ca ses decrea ses.          The re f or e ,

w e had to find som e mea sure to a sses s the ca s es

t hat were being re porte d to us.

          [Slide.]

          So, in c oncer t wi th ou r ex ternal he pat i c

e xperts, we adapte d def init ions a nd th ose

d efinitions includ ed, f or a cute s evere liv er

i njury, an ALT gre ater than 3 tim es th e up pe r l i m i t

o f normal, a direc t bil i gr eater than 3 in t h e

a bsence of an elev ated alka line p hosph atas e.

          Now, sin ce th e qu ality of the re por ts i s



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n ot good in situat ions like this, they are o f te n

i ncomplete, lackin g det ails and u nconf irme d, we

d ecided to be as c onser vati ve as pos sible , so w e

a lso included any patie nt t hat ha d a s erio us

h epatic event that was asso ciated with a

h ospitalization.

          We also have incl uded them as a cas e o f

a cute severe liver inju ry.         For a cute live r

f ailure, we define d it as a n acut e ons et of se v e r e

l iver injury assoc iated wit h eith er en ceph al o pa t h y

o r coagulopathy in the abse nce of an u nder ly i ng

l iver disease.

          [Slide.]

          So, thro ughou t th e yea r, w e have do ne

s everal re-analyse s.      T his parti cula r re- anal ys i s

i s from September of th is y ear.          No w, t he gl ob a l

h epatic reporting rate in M ay of 2005, whe n w e

l ooked at this, wa s 15 case s per milli on f or al l

h epatic events.     Y ou ca n se e that in S epte mb e r o f

t his year, the glo bal h epat ic rat e is stil l a bo u t

1 5 per million aft er th e An nals a rticl e.

          However, in t he U nited Sta tes, wher eas ,



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t he hepatic report ing r ate again for a ll e ve n ts w a s

a bout 15 per milli on at the one -yea r ti me po in t

w hen we received t he ca ses origin ally, you c a n s e e

n ow that it has mo re th an d oubled .

            I want t o dra w yo ur at tent ion t o t he 1 2

c ases of acute liv er fa ilur e that we h ave re c ei v e d .

 Three of the 12 c ases were recei ved b etwe en Ap r i l

2 004 and January 2 006, afte r an e xposu re o f 4 .6

m illion.

            The rema ining 9 c ases were repor ted to u s

a fter the Annals a rticl e wi th an expos ure of 1. 3

m illion.    This ref lects the stimu lated rep or t in g .

            [Slide.]

            The Unit ed Ne twor k for Org an Sha rin g

m aintains a databa se, a tra cking syste m fo r

p atients that have unde rgon e a li ver t rans pl a nt .

T hese data are dru g-rel ated live r tr anspl ants t h a t

o ccurred between 2 004 a nd 2 006.

            You can see t hat aceta mino phen a cco unt s

f or the most commo n cau se f or dru g - rela ted l iv e r

t ransplant.     Antib iotic s, a s a cl ass, are an

u ncommon cause for live r tr anspla nt.            The on e



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t elithromycin pati ent t hat appear s her e wa s a

p atient from North Caro lina that had b een re p or t e d

t o us in April 200 5.

           If a pat ient had had a sev ere li ver in j u r y

a s a result of tak ing t elit hromyc in.          This r e su l t e d

i n a liver transpl ant, we w ould h ave b een ad v is e d

o f it because we a re mo nito ring t he sy stem .

           [Slide.]

           At the t wo-ye ar t ime p oint , we did ano t h e r

c omparative report ing r ate analys is.           The fi r st o n e

I showed you was t he on e-ye ar ti me p oint.            Th is i s

n ow the two-year t ime p oint .         Ag ain, the sam e

d efinitions, broad ly de fine d, and crit ical h e pa t i c

e vents were used.

           Now, the repo rtin g rat e ag ain ca n c han g e

d rastically over t he li fe c ycle o f a p rodu ct be i n g

a ffected by many t hings inc luding stim ulat ed

r eporting.     What y ou se e he re is for t elit hr o my c i n

f or broadly define d and cri ticall y def ined h e pa t i c

e vents.     The repor ting rate is hi gher than t h e

o ther antibiotics but t here are s evera l fa ct o rs t o

c onsider.



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          One, thi s ref lect s sti mula ted re por tin g .

T he second, we had augm ente d phar macov igil an c e

i nitiatives that w ere u nder taken, whic h I de s cr i b e d

t o you this mornin g, an d th at, c oupled wit h t he

e xpedited reportin g of all seriou s hep atic

e vents--that is, w hethe r th e eve nt w as lis te d o r

n ot, whether it wa s a U .S. case o r a f orei gn ca s e ,

w e expedited it.

          It is di fficu lt t o ass ess the im pac t t h i s

w ould have had on the r epor ting rate .

          Finally, it i s im porta nt t o emph asi ze t h a t

A ugmentin was appr oved in 1 984, c larit hrom yc i n i n

1 991, azithromycin in ' 92, moxifl oxaci n in 1 9 99 ,

a nd levofloxacin a nd tr ovaf loxaci n in 1997 ,

h owever, the repor ting prac tices have cha nge d

d ramatically over the p ast 20 yea rs, i n fa ct , t h e r e

h as been a doublin g of adve rse ev ent r epor ti n g f r o m

2 000 to 2005 alone .

          This mak es th e as sessm ent partic ula rly

d ifficult.   There are s o ma ny con found ers in he r e

t hat is hard to as sess this repor ting r ate,

c omparative report ing r ate analys is.         So y ou mi g h t



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a sk why did I even pres ent it.            R eally , ju st to

e mphasize that it is pr acti cally impos sibl e t o

i nterpret this dat a bec ause of al l the con fo u nd e r s

a nd as we discusse d thi s mo rning, repo rtin g r at e s

a re a tool, an exp lorat ory tool.

            They hel p us to u nders tand the

s ignificance of an even t an d to d ecide whe th e r o r

n ot further evalua tion is n eeded.                Wha t th is te l l s

u s is that further eval uati on is neede d.                 Th i s i s

w hy we had to go t o oth er d ata so urces in or de r t o

a ssess comparative risk of hepati c eve nts.                   T hi s i s

t he reason we cond ucted two pharm acoep idem io l og i c

s tudies to assess compa rati ve ris k.

            [Slide.]

            In concl usion , he patic eve nts ha ve bee n

w ell characterized thro ugh our in tensi ve

p harmacovigilance initi ativ es an d fu rther

i nvestigated throu gh ou r tw o phar macoe pide mi o lo g i c

s tudies.

            Our conc lusio n ba sed o n ou r own int ern a l

a ssessment and in coord inat ion wi th ou r ex pe r ts , i s

t hat telithromycin may be a ssocia ted w ith a



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r eversible hepatoc ellul ar o r mixe d inju ry

c omparable to othe r ant ibio tics a nd ra rely r e po r t s

o f severe hepatic event s or liver fail ure ha v e b e e n

s een.

          Dr. Lewi s sho rtly is g oing to di scu ss t h e

s ignature of telit hromy cin with r espec t to h e pa t i c

e vents and to disc uss t hese more sever e ca se s a n d

h is causality asse ssmen t.

          [Slide.]

          Finally, we m ade a lab elin g chan ge in J u n e

o f this year and t hat w as c ommuni cated to

p hysicians through a De ar D octor lette r an d

s pecifically, the chang e in cluded a wa rnin g a bo u t

a cute hepatic live r fai lure inclu d i ng f ulmin an t

h epatitis and hepa tic n ecro sis le ading to li v er

t ransplant and tha t thi s co uld oc cur i n so me ca s e s

s hortly after trea tment .

          Also, re comme ndat ion t o ph ysicia ns to

m onitor for signs and s ympt oms of hepa titi s a nd i f

s igns and symptoms deve lop, to d isco ntinu e

t reatment.

          I would now l ike to in trod uce Dr . J ame s



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L ewis from Georget own U nive rsity Medic al C en t er ,

w ho is going to di scuss the signa ture of

t elithromycin and its p oten tial e ffect s on t h e

l iver.

          Thank yo u.

                        Exper t Re view

           James H. Lewis , M. D., F ACP, FACG

          DR. LEWI S:    T hank you, Bar bara, and go o d

a fternoon to every body.      I am goi ng to con ti n ue o u r

d iscussion about t he li ver hepati c eve nts th i s

a fternoon.   My int erest in this g oes b ack al m os t 2 8

y ears now working with Dr. Hyman Zimme rman , w ho i s

f amiliar to many o f the peo ple in the room .        I

t hink many of us g radua ted from H y Zim merm an

U niversity either as a full -time stu dent or

c ertainly we audit ed th e co urse w ork a nd m uc h t h a t

w e know about the liver and liver toxi city i s d u e

t o Dr. Zimmerman.

          I have a lso b een worki ng, as you he ard

b efore, with a tea m of peop le fro m San ofi -Av en t i s ,

w hich included Wil lis M adri , Paul Watk ins, D r .

E manual Rubin, who is h ere with u s, fo r th e p as t



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s everal years, as well as t he Pha rmaco vigi la n ce

g roup at Sanofi.

            We have been look ing a t th ese ca ses fo r

q uite a long time and w hat we hav e don e is a n al y z e d

a ll of the cases t hat h ave been s eriou s, a nd ot h e r s

a s well, and I am going to offer you o ur

p erspective on tha t.

            [Slide.]

            You have hear d of the clin ical d eve lop m e n t

p rogram.    I am goi ng to jus t give a br ief ov e rv i e w

o f what you are go ing t o he ar aga in.           I ha ve a

f eeling from Dr. L ee an d Dr . Seef f rel ativ e t o

d rug-induced liver dise ase in th e Unit ed S ta t es ,

b ecause it is not uniqu e to telit hromy cin or th e

a ntibiotics, as yo u hav e he ard.

            What I a m goi ng t o do is d evelop ou r

a nalysis of some o f the cas es tha t we feel a r e

l ikely to be telit hromy cin and wh at th at l oo k s l i k e

a s a signature of the d rug.           I wi ll ha ve a f e w

c omments on the An nals case s and some new

i nformation that w e hav e ab out t hose .

            As you p robab ly k now, anyt ime th ere is a



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s erious case submi tted to t he com pany, all e f fo r t s

a re made to get as much inf ormati on as we ca n a b o u t

t hat, because the spont aneo us rep orts are of t en

l acking.

            [Slide.]

            Nearly a ll an tibi otics , as you have se e n

f rom all of the di ffere nt d ata, c an ca use he p at i c

e ffects and telith romyc in i s no d iffer ent.           T he r e

w as a signal with telit hrom ycin i n the pre cl i ni c a l

s tudies, and so th e foc us h as bee n int ent on wh a t

i s happening with the l iver thro ugho ut it s

d evelopment.

            I am not goin g to dwel l on these ca ses o r

t he Phase III info rmati on, you ha ve al read y s ee n

i t.   It is very co mpara ble to the comp arat or dr u g s

t hat were used in the s tudi es.           T he re st o f m y

r emarks are really goin g to be on th e p ostma rk e t i n g

i nformation.

            [Slide.]

            Now, dru g-ind uced live r di sease is ver y

c ommon, it is up t o abo ut 9 perce nt of all

d rug-related adver se ev ents can affect the l i ve r .



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Y ou will hear abou t Hy' s La w ment ioned lat er an d i t

i nvolves hepatocel lular jau ndice car rying a c as e

f atality rate or t he ne ed f or tra nspla nt i n a bo u t

1 0 percent or more pati ents .

          It has b een p rove n ove r ti me and re cen t

s tudies in Europe have vali dated that.             Le ss e r

v alues just bioche mical ly h ave no t bee n as w e ll

v alidated, however .

          You will hear tha t dru gs c ause a cut e l i v e r

f ailure about half the time .          Of all t he c as e s t h a t

o ccur in the Unite d Sta tes, that' s the est im a te a n d

w e have Dr. Lee's Acute Liv er Fai lure Stud y G ro u p

t o look to for tha t kin d of infor matio n.           Yo u h a v e

a lready seen that aceta mino phen acco unts f or a v a s t

m ajority of the ca ses o f li ver tr anspl ant fr o m

a cute liver failur e.

          [Slide.]

          The Live r Fai lure Stud y Gr oup of Dr . L e e

s uggests that acet amino phen is so mewhe re a ro u nd

h alf of the cases and I was inter ested to se e t h a t

a cetaminophen was liste d in the A ERS d atab as e a n d ,

e ven though it's a very wid ely us ed dr ug, th e



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a bsolute number of case s is quite high , an d, in

f act, is half of a ll th e ac ute li ver f ailu re an d

t hat includes vira l hep atit is and all the ot h er

c auses that we hav e.

            All othe r non -ace tamin ophe n dru gs,

i ncluding some her bals, rep resent betw een 12 an d 1 5

p ercent of all liv er fa ilur e.

            [Slide.]

            You have also hea rd fr om t he tra cki ng o f

t he UNOS database for l iver trans plant atio n t ha t

d rugs account for 15 pe rcen t of all liver

t ransplants that a re do ne a s emer genci es f or li v e r

f ailure.    Fully ha lf of tho se aga in ar e du e t o

a cetaminophen.     Al l oth er d rugs a re th e ot he r h a l f

b ut that is every other dru g that we h ave.

            [Slide.]

            The upda ted d atab ase, in f act, i ncl ude d

t he one telithromy cin c ase from N orth Caro li n a,

w hich did receive a tra nspl ant.            These are l i ve r

e nzyme values and some othe r inte resti ng t hi n gs

t hat I have taken from Dr. Lee's Acute Liv er

F ailure Study Grou p.        I wou ld lik e to poin t o ut



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t hat the majority of pe ople who deve lop i nju r y a r e

f emale.

           The mean ALT and AST v alue s I th ink ar e

i mportant to look at.         If y ou hav e ace tami no p he n o r

s ome direct toxin to th e li ver, t he en zyme s a re

o ften in the thous ands, muc h high er th an w e s ee f o r

v iral hepatitis an d, as it turns out , abo ut 1 0

t imes as high as w e see for very sever e in ju r y f r o m

o ther drugs.

           As I go throu gh t he an alys is, I wil l s h o w

y ou that I think t hat t he t elithr omyci n ca se s f i t

w ell with this def initi on o f how high the en z ym e s

a ctually can go.

           [Slide.]

           There is an e leph ant i n th e room th at w e

h ave already allud ed to , wh ich I think you c a nn o t

i gnore, and no mat ter h ow p revale nt ac etam in o ph e n

u se is, and how lo w the pre valenc e of live r

f ailure, it is far and away the m ost c ommo n c au s e

o f liver failure a nd li ver trans plan t in t he Un i t e d

S tates and in much of t he w orld.

           So any r isk o f an y oth er d rug ca usi ng



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l iver failure, I t hink we a lways have to c om p ar e i t

t o what is the ris k of acet aminop hen t hat is wi t h

u s all the time in our tran splant cent ers .

          [Slide.]

          Antimicr obial age nts a s a group top th e

l ist of drugs caus ing l iver injur y tha t ar e

n on-acetaminophen.      The ser ies h ere, t he f ir s t o n e

i s a U.S. study, 4 4 per cent were due t o

a ntibiotics, 27 pe rcent , 32 perce nt, t his co m es

f rom the Swedish r eport and the Span ish r epor t

r ecently validatin g Hy' s La w show ing h ow c om m on l y

t he antimicrobials , as a gr oup, s how u p.

          You have seen thi s in the AERS d ata bas e

a nd take your pick of a ntib iotics , the y ar e a ll

a ssociated with li ver i njur y.

          I think it is rea ssuri ng t hat w e sa w f r o m

t he European data this morn ing by Dr. Mort im e r t h a t

t elithromycin was reall y on par w ith o ther

a ntimicrobials as far a s re portin g rat es w er e s e e n .

 The AERS database I th ink also s ugges ts t ha t i t i s

f airly similar to other s, a s well .

          [Slide.]



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          Now, the re ha s be en a very large

p ostapproval safet y dat abas e for us to loo k a t.

Y ou have already h eard thes e numb ers b efor e, 28

m illion global exp osure s, a bout 6 mill ion in th e

U nited States.

          You are going to hear shor tly ab out th e

l arge epidemiologi c stu dies that off er I t hi n k

a dditional reassur ance abou t the safet y of

t elithromycin.    Ag ain, it i s a dr ug wi th a s i gn a l

o f hepatic injury but w e al ways h ave t o pu t i t i n t o

p erspective.

          [Slide.]

          The numb er of adv erse even ts tha t w ere

r ecorded since app roval in the U nite d Stat es ar e

a bout 200, you can see them here, 45 a cute s e ri o u s

l iver injury event s, an d 12 acute live r fa il u re

c ases, and then am ong t hose liver fail ure ca s es w a s

t he one transplant case .

          This did lead to revis ed l abelin g a s y o u

h ave already heard , in June , to a cknow ledg e t hi s

d egree of hepatic injur y.

          [Slide.]



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          Assignin g cau sali ty, a s yo u will he ar f r o m

D r. Seeff as well, is d iffi cult w henev er w e a re

d ealing with drug injur y, w hether it's the p a ti e n t

i n the hospital wh ere w e ha ve so me i nform atio n,

o ften more than we get with the s ponta neou s

r eports, because t hose ofte n are heavi ly

c onfounded, missin g inf orma tion.

          We rarel y hav e hi stopa thol ogy to lo ok a t ,

w hether an adequat e wor kup to exc lude othe r c au s e s

h as been done may or ma y no t be ther e and the

r eporting term is reall y le ft up to th e pe rs o n w h o

f iles the report.

          Somebody who has a hig h en zyme o r m ayb e

j aundice, they mig ht sa y th at is acute liv er

f ailure, when, in fact, it may no t mee t th e

c ritical definitio n tha t we would u se i n the

t ransplant center.

          I envy p eople who work in Infect iou s

D isease, because y ou ca n pl ate th ings out an d k n o w

e xactly what you a re de alin g with .         I can' t p la t e

t he liver out on a Petr i di sh, it won' t te ll me

w hat the cause of the l iver injur y was , so w e h a v e



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t o use a number of diff eren t mech anism s to d o t h a t .

 You will hear abo ut so me o f thos e met hods t h at a r e

i n use.

           [Slide.]

           The caus ality ass essme nt t hat we ga ve t o

t he acute liver fa ilure cas es is prese nted h e re .

T his is the same i nform atio n we prov ided in J un e t o

t he Review Divisio n.       I t re presen ts ou r be st

e stimate and opini on, t he h epatol ogist s wh o w or k e d

w ith me and the Ph armac ovig ilance grou p at

S anofi-Aventis, ab out w hat may h ave ca used t h es e

a cute liver failur e cas es.

           We accep ted t wo o f the m wh ere w e co uld n o t

e xclude the drug.       The othe rs we found mor e

p lausible explanat ions and I thin k, if you r e ad

t hrough any of the se ca ses, they are v ery di f fi c u l t

t o interpret.

           While po ssibl y me ans p ossi bly is , p oss i b l y

i sn't, we tried to say if t he pa tien t was in fr o n t

o f us, what would we re ally think the caus e o f t h e

i njury was or what did we t hink w as go ing on .

           There wa s one cas e, in fac t, tha t w as



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r etracted. The phy sicia n wh o repo rted it n ot i fi e d

t he company that i nstea d of liver fail ure, h e

a ctually meant to say r enal failu re, s o on e o f

t hose acute liver failu re c ases i sn't even r e al .

          [Slide.]

          These ar e the Ann als c ases .            I t hin k i t i s

w orth just a short revi ew t o say what they

i ncluded.

          The firs t one was a 46 -yea r-old man

t reated for otitis and sinu sitis and he h ad a

r eversible hepatoc ellul ar i njury.             He reco ve r ed

n ormal enzymes 8 w eeks late r.         Th at ca se i s

p robably related.

          Case No. 2 is the live r tr anspla nt

p atient, a 51-year -old woma n who dev elope d--w e a r e

n ot sure she devel oped acut e liv er f ailur e.             Bu t

s he certainly pres ented wit h a su bfulm inan t c ou r s e

a nd a month or fiv e wee ks l ater e nded up w it h a

l iver transplant.

          She is a ccept ed a s a p ossi ble ca se eve n

t hough there was a conf ound ing sm ooth musc le

a ntibody that was prese nt, sugges t i ng t hat s he



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m ight have had aut oimmu ne d isease , but we ma y n e v e r

k now.   But, fortun ately , sh e is d oing well a f te r

h er transplant.

          Case No. 3 as it was p rese nted w as a

2 6-year-old man tr eated aga in fo r si nusiti s a nd

b ronchitis.    He ha d hig h en zymes, as y ou can s e e .

H e had a very low plate let count. He w as i n r en a l

f ailure on present ation and what the r epor t s ai d i s

h e died after endo scopy of multis ystem fai lu r e.

          The prel imina ry a utops y re port, whi ch i s

p rovided in the An nals case repor t, sa id h e h ad

m assive hepatic ne crosi s li kely immune - media te d ,

p ossibly a hyperse nsiti vity react ion.

          Sometime s cas e re ports are not a wh ole l o t

b etter than sponta neous rep orts e ven t houg h t he y

a re published.

          [Slide.]

          This is the l iver biop sy, the li ver ti s s u e

f rom the autopsy t hat w as l imite d to the che s t a n d

t he abdomen.     Dr. Rubin and I hav e loo ked at th i s .

          We can't say a wh ole l ot f rom a pic tur e i n

a publication--and we h ave reque sted the actu al



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s lides--but it is fille d wi th ly mpho cytes an d t h e

i nformation that w as no t co ntain ed i n the rep or t I

h ave listed here.

            [Slide.]

            This is infor mati on th at h as bee n s har e d

w ith the agency, i t is new inform ation tha t h as

c ome in.    This you ng ma n co mplain ed of wea kn e ss ,

n osebleeds, nausea , hem atem esis, right - sided b e l l y

p ain for 2 months prior to going to the em er g en c y

r oom, which would have been about 6 we eks be f or e h e

e ver took telithro mycin .

            He had a card iopu lmona ry a rrest dur ing

e ndoscopy right af ter h e wa s admi tted.           On t h e

a utopsy there was fluid and blood in t he l un g s.

T he final autopsy repor t sa id th ere wa s an a b se n c e

o f eosinophils but ther e wa s a ma jor l ymph oc y ti c

i nfiltrate in the liver whi ch mad e a

h ypersensitivity r eacti on, in fac t, le ss l ik e ly ,

a nd he had a massi vely enla rged l iver and sp l ee n .

            His live r was twi ce no rmal size , hi s

s pleen was 3 times norm al.           He ha d ver y la rg e ,

p rominent mediasti nal l ymph nodes and the fi n al



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p athology report s ays h e ha d a vi ral m yoca rd i ti s ,

w hich is not liste d in the Annals repo rt.

          Dr. Rubi n and I a nd th e ot her

h epatologists have disc usse d thi s an d why thi s

m ight not be lymph oma o r so me oth er

l ymphoproliferativ e dis ease where he p rese nt e d w i t h

a cute liver proble ms as par t of t he ly mpho ma is

c ertainly I think to be tak en int o con side ra t io n .

          It certa inly show s you how diffi cul t

i nterpreting even case repo rts t hat are pu bl i sh e d

m ight be.

          [Slide.]

          Now, we have trie d to look at th e c ase s

t hat we consider p ossib ly o r prob ably rela te d i n

t he database and h ere i s wh at we have come u p w i t h .

          Again, i t's a fem ale p redo minant in jur y ,

w hich is very simi lar t o wh at we hav e seen w i th

m any other drugs. It's hepa tocell ular in

t hree-quarters of the c ases .         I was pa rtic ul a rl y

i nterested in the AERS data that sugge sted t h at

c holestasis was re ally not part o f tel ithr om y ci n

a nd I would agree with that .



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          I found that it w as mi xed injur y me ani n g

h epatocellular, or had some chole stasi s, w hi c h i s

d efined by an elev ated alka line p hosph atas e, no t

n ecessarily jaundi ce.       But that w as pr esen t i n

a bout a quarter of the case s, jau ndice was p r es e n t

i n about a quarter of t he c ases.

          The mean ALT, the mean AST , you can se e

t he values here, v ery s imil ar to the

n on-acetaminophen serio us p roble ms tha t Dr . L ee ' s

p apers have allude d to.       Ag ain, t hese are no t

a nywhere close to the r ange of wh at we see

t ypically as the m ean f or a cetam inop hen o r sh oc k

l iver.

          [Slide.]

          The late ncy i s a littl e bi t hard er to

d etermine. People had a rea ction after jus t a

s ingle dose of tel ithro myci n, all the way up to 2

a nd maybe even 3 m onths aft er the drug .

          The mean that we were able to ca lcu lat e

a fter dosing was a bout a we ek.         S o it is h ap p en i n g

f airly quickly aft er bu t no t alwa ys wh ile th e y a r e

t aking the medicat ion.       The re wer e som e



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h ypersensitivity f eatur es, rash, and e osin op h il i a

i n some of the pat ients .        I t is d iffic ult wh e n y o u

a re treating patie nts w ith a feb rile illn ess to

k now a fever means some for m of i mmuno - aller gy .

           The majo rity of t hese case s, as you ha v e

h eard, as in Europ e, we re s elf-l imit ed re acti on s ,

t he acute liver fa ilure s, s ubfulm inant liv er

f ailure appeared t o be quit e unus ual an d, in t e r m s

o f host factors th at mi ght predis pose one to

t elithromycin inju ry, I am not su re.

           Female g ender app ears to s tand o ut a

l ittle bit. Whethe r und erly ing li ver d isea se wi l l

d o it is a possibi lity and, of co urse, it sh o ul d

n ot be used in liv er di seas e. Pr ior expos ure is

a nother possibilit y.       T here were sever al c as e s

w here there was re peat expo sure t o tel ithr om y ci n

a nd liver injury o ccurr ed t he sec ond t ime.

           [Slide.]

           Delayed injur y is not uniq ue to

t elithromycin amon g oth er a ntibio tics but it is a

f airly unique late ncy I thi nk for most acu te dr u g

i njury.   Most drug s, if you get a n inj ury fr o m i t ,



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