TheVioxxStory

KellyCra1GroupMee6ngPresenta6on

Nov30,2016

Vioxx(Rofecoxib):Whatisit?

•  Nonsteroidalan6-inflammatorydrug(NSAID)

•  Selec6vecyclooygenase-2(COX-2)inhibitor(coxib)

•  Usedintreatmentof:– Osteoarthri6s– Acutepain–  Primarydysmenorrhea

•  MarkedbyMerck&Co.

Cyclooxygenases(COX):Whatdotheydo?

•  Beginbiosynthe6ccascadetoconvertpolyunsat.faZyacidstoprostaglandinsandthromboxane

Kalgutkar,A.M.andMarneZ,L.J.TiPS.1999,20,465.

Prostoglandains:Whatdotheydo?

•  Func6ons:–  Promotepainandinflamma6on–  Protectstomachandintes6nallining– Havean6-coagula6oneffectonplatelets

Blobaum,A.L.andMarneZ,L.J.J.Med.Chem.2007,50,1425.

COX-1andCOX-2:AComparison

•  COX-1–  Cons6tu6velyexpressed–  Involvedinproduc6onofprostaglandinstomediatehousekeepingbodilyfunc6ons(ex.plateletaggrega6on)

– WidelyfoundthroughoutGItract(maintainGImucosa)

•  COX-2–  Primarilyinducibleenzyme(ac6vatedbycytokines,etc.)

–  Foundinleukocytes,synoviocytes,andCNS—roleininflamma6on,fever,andpain

– MostlyundetectableinGItract

Kalgutkar,A.M.andMarneZ,L.J.TiPS.1999,20,465.Blobaum,A.L.andMarneZ,L.J.J.Med.Chem.2007,50,1425.

Tradi6onalNSAIDs:AnOverview

•  Whatdotheydo?–  Blockprostaglandinforma6on

•  Howtotheywork?– Actbyinhibi6ngCOX-1and-2

•  Whataretheeffects?– Analgesic,an6pyre6c,andan6-inflammatory(COX-2inhibi6on)

– GIirrita6onandforma6onofpoten6allylifethreateningGIulcers(COX-1inhibi6on)

Blobaum,A.L.andMarneZ,L.J.J.Med.Chem.2007,50,1425.

COX-2Inhibitors:TheAppeal

•  COX-2enzymelocatedinareascommonlyinvolvedininflamma6on,butnotinstomach

•  COX-2inhibi6on!an6-inflammatorywithlowergastrictoxicity

•  ExamplesofCOX-2inhibitors–  Celecoxib(Celebrex):availableinUS(Pfizer)–  Rofecoxib(Vioxx):withdrawnin2004(Merck)–  Valdecoxib(Bextra):withdrawnin2005(Pfizer)

COX-2Inhibitors:StructuralFeatures

•  SARstudiesshowrequirementofcis-s6lbenewith4-methylsulfonylorsulfonamideforCOX-2specificity

Kalgutkar,A.M.andMarneZ,L.J.TiPS.1999,20,465.

Rofecoxib(Vioxx):Synthesis

Thérien,M.et.al.Synthesis,2001,12,1778.

Celecoxib(Celebrex):Synthesis

Cue,B.W.andZhang,J.,GreenChem.Le:.Rev.,2009,2,193.

Penning,T.D.et.al.J.Med.Chem.,1997,40,1347.

TheVioxxStory:TheHistoryataGlance

•  May1999:FDAapprovesVioxx

•  Nov2000:VioxxGastrointes6nalOutcomesResearch(VIGOR)Studypublished–  ShowedlowernumberofGIeventsbutgreaternumberofheartaZacksinpa6entstakingVioxxthannaproxen

•  April2002:VioxxlabelchangedinUSduetoVIGORdata

•  Sept2004:MerckwithdrawsVioxxa1erAdenomatousPolypPreven6onofVioxx(APPROVe)Study–  ShowedVioxxpa6entshadhigherriskofheartaZacksa1er18months

hZp://www.pharmaceu6cal-journal.com/news-and-analysis/features/s6ll-feeling-the-vioxx-pain/20066485.ar6clehZp://www.npr.org/templates/story/story.php?storyId=5470430

TheVioxxStory:TheRoadtoFDAApproval

•  Dec1994:MerckopensInves6ga6onalNewDrug(IND)forosteoarthri6sandacutepain

•  Nov1998:MercksubmitsNewDrugApplica6on(NDA)forVioxx–  Included~5000subjectsexposedtorofecoxibfrom1dayto86weeks(12.5and25mgdailyforchronicuse,50mgdailyfor>6months)

–  Includedtwo6weekplaceboandibuprofen-controlledstudies

– NocardiovascularsignalobservedinoriginalNDAapplica6on

TheVioxxStory:TheRoadtoFDAApproval

•  April1999:Arthri6sAdvisoryCommiZee(AAC)meetstoconsiderefficacyandsafetyof12.5to25mgdose!recommendsapproval

•  May1999:FDAapprovesVioxxforacutepain,dysmenorrhea,andosteoarthri6s

TheVioxxStory:TheRoadtoFDAApproval

•  StatementofSandraKweder,M.D.(DeputyDirectoroftheOfficeofNewDrugsattheCenterforDrugEvalua6onandResearch(CDER),USFDA)beforetheSenateCommiZeeonFinance:–  “Vioxxreceivedasix-monthpriorityreviewbecausethedrugpoten6allyprovidedasignificanttherapeu6cadvantageoverexis6ngapproveddrugsduetofewergastrointes6nalsideeffects,includingbleeding.Aproductundergoingapriorityreviewisheldtothesamerigorousstandardsforsafety,efficacy,andqualitythatFDAexpectsfromalldrugssubmiZedforapproval.”

TheVioxxStory:TheNextStep

•  StatementofSandraKweder,M.D.:–  “Intheclinicaltrialsconductedbeforeapproval,theriskofgastrointens6nal(GI)sideeffectswasdeterminedthroughtheuseofendoscopy.Atthe6methatFDAapprovedVioxx,theavailableevidencefromtheseendoscopystudiesshowedasignificantlylowerriskofgastrointes6nalulcers,asignificantsourceofserioussideeffectssuchasbleedinganddeath,incomparisontoibuprofen.”

TheVioxxStory:VIGORStudy

•  Jan1999:MercklaunchesVioxxGastrointes6nalOutcomesResearch(VIGOR)Study–  ComparenumberofupperGIeventsinpa6entswithrheumatoidarthri6stakingrofecoxibvs.naproxen

–  8076pa6entsreceivedeither50mgofrofecoxibdailyor500mgofnaproxentwicedaily

–  “Thisstudywasdesignedtoprovidelongertermclinicaloutcomedatatoconfirmtheshortertermendoscopyfindingsandtoevaluateoverallsafety.”(SandraKweder,M.D.)

•  March2000:VIGORstudycompleted

•  Nov2000:VIGORstudypublishedinNEJM

VIGORStudyResults:TheGood

•  Pa6entstreatedwithrofecoxibexperiencedsignificantlylessupperGIevents

•  Rofecoxibandnaproxenhadsimilarefficaciesagainstrheumatoidarthri6s

Bombardier,C.M.D.,et.al.NEJM2000,343,1520.

VIGORStudyResults:TheGood

Bombardier,C.M.D.,et.al.NEJM2000,343,1520.

VIGORStudyResults:TheGood

Bombardier,C.M.D.,et.al.NEJM2000,343,1520.

VIGORStudyResults:TheNotSoGood

•  Result:Incidenceofmyocardialinfarc6onsignificantlyhigherinrofecoxibgroupthannaproxengroup(0.4%vs.0.1%)

•  Explana6on:Naproxenhasacoronaryprotec6veeffectrofecoxibdoesnothavebecauserofecoxibisaselec6veCOX-2inhibitor

•  “VIGORdidnothaveaplacebogroupbecausetodosowouldhavemeantpa6entswithrheumatoidarthri6swouldhavebeenrandomizedtoreceivenopainrelief….Thestudyalsoexcludedsubjectstakinglowdoseaspirinforcardiovascular(CV)preven6onbecauseuseofaspirinmighthavecontributedtoincreasedratesofGIbleedinginthestudyandconfoundtheresults.However,theexclusionofpa6entsonlowdoseaspirinmayhaveinfluencedCVeventsinthestudy,sincelowdoseaspirinhasbeenshowntoreduceCVrisk.”(SandraKweder,M.D.)

Bombardier,C.M.D.,et.al.NEJM2000,343,1520.

TheVioxxStory:TheYearsPost-VIGORStudy

•  Aug2001:StudyinJAMAques6onssafetyofVioxxandvalidityofnaproxenhypothesis(Mukherjee,D.M.D.,et.al.JAMA2001)

•  Sept2001:FDArecommendsinclusionofbalancedinforegardingVioxxsafetyandde-emphasisofGIsafetyadvantageinVioxxlabel

•  Oct2001:Labelnego6a6onsini6atedbyFDA•  April2002:LabelchangesincludingresultsofVIGORstudyandcau6onaboutpoten6alriskforcardiovascular(CV)thrombo6ceventswithVioxxapproved

TheVioxxStory:FDAWarningAboutVIGOR

•  Sept2001:FDAwarningleZertoMerck–  “Youhaveengagedinapromo6onalcampaignforVioxxthatminimizesthepoten6allyseriouscardiovascularfindingsthatwereobservedintheVioxxGastrointes6nalOutcomesResearch(VIGOR)study,andthus,misrepresentsthesafetyprofileforVioxx…YouassertthatVioxxdoesnotincreasetheriskofMIsandthattheVIGORfindingisconsistentwithnaproxen’sabilitytoblockplateletaggrega6onlikeaspirin.Thatisapossibleexplana6on,butyoufailtodisclosethatyourexplana6onishypothe6cal,hasnotbeendemonstratedbysubstan6alevidence,andthatthereisanotherreasonableexplana6on,thatVioxxmayhavepro-thrombo6cproper6es.”

InReMerck&co.,inc,Securi6es,Deriva6ve&“ERISA”li6ga6on.Documentrelatesto:TheConsolidatedSecuri6esAc6onMDL.No.1658(SRC),CivilAc6onNos.05-1151(SRC),05-2367(SRC).USDistrictCourt,D.NJ.April12,2007.

TheVioxxStory:TheYearsPost-VIGORStudy

•  2002-2004:VariousepidemiologicstudiessuggestincreasedriskforCVeventswithVioxx

Karha,J.M.DandTopol,E.J.M.D.Cleve.Clin.J.Med.2004,71,933.

TheVioxxStory:TheYearsPost-VIGORStudy

•  Tes6monyofDavidJ.Graham,MD,MPHtoUSSenateCommiZeeonFinance–  “IworkedwithKaiserPermanenteinCaliforniatoperforma

largeepidemiologicstudy….WehadplannedtopresentthesedataattheInterna6onalConferenceonPharmacoepidemiology,inBordeaux,France.Weconcludedthathigh-doseVioxxsignificantlyincreasedtheriskofheartaZacksandsuddendeathandthatthehighdosesofthedrugshouldnotbeprescribedorusedbypa6ents.ThisconclusiontriggeredanexplosiveresponsefromtheOfficeofNewDrugs,whichapprovedVioxxinthefirstplaceandwasresponsibleforregula6ngitpost-marke6ng.TheresponsefromseniormanagementinmyOffice,theOfficeofDrugSafety,wasequallystressful.Iwaspressuredtochangemyconclusionsandrecommenda6ons,andbasicallythreatenedthatifIdidnotchangethem,IwouldnotbepermiZedtopresentthepaperattheconference.”

TheVioxxStory:TheYearsPost-VIGORStudy

•  2002-2004:VariousepidemiologicstudiessuggestincreasedriskforCVeventswithVioxx

Karha,J.M.DandTopol,E.J.M.D.Cleve.Clin.J.Med.2004,71,933.

•  Aug2004:FDAapprovesVioxxfortreatmentofjuvenilerheumatoidarthri6s

TheVioxxStory:YearsPost-VIGORStudy

•  Nov2002:MerckproposesanalysisofCVthrombo6ceventsinthreeplacebo-controlledstudies: – APPROVe:Does3yearrobecoxibtreatmentreduceriskofrecurrentsporadicadenomatouscolonpolyps?

–  VICTOR:DoesVioxxhaveamaintenanceroleincolorectalcancerpa6entsa1erpoten6allycura6vetherapy?

–  ProstateCancerPreven6onstudy:Does6yearrofecoxibtreatmentinfluenceincidenceofdevelopingprostatecancer?

APPROVeStudy:TheFinalBlow

•  Sept28,2004:Merckrequestsemergencymee6ngwithFDAuppermanagement– MercksharesdatafromAPPROVetrial

–  Foundthatlong-termuse(>18months)wasassociatedwithanincreasedriskofcardiovascularevents

•  Sept30,2004:MerckpublicallyannouncedproductwithdrawalofVioxx

APPROVeStudy:ThePublishedResults

•  2586pa6entswithhistoryofcolorectaladenomasreceivedeither25mgrofecoxibdailyorplacebo

Bresalier,R.S.M.D.et.al.N.Engl.J.Med.2005,352,1092.

APPROVeStudy:ThePublishedResults

•  ReferencemadetoVIGORstudy:–  “Arecentmeta-analysissuggestedthatthemagnitudeofanycardioprotec6veeffectofnaproxenisunlikelytoaccounten6relyforthesefindings”

•  Quotefrommeta-analysisstudy:(Jüni,P.et.al.Lancet,2004)–  “Ourfindingsindicatethatrofecoxibshouldhavebeenwithdrawnseveralyearsearlier.Thereasonswhymanufactureranddruglicensingauthori6esdidnotcon6nuouslymonitorandsummarizetheaccumula6ngevidenceneedtoclarified.”

Bresalier,R.S.M.D.et.al.N.Engl.J.Med.2005,352,1092.

BehindtheScenes:Ques6onableProcedures

•  Merck1996-7clinicaltrial:Reportedincreaseinurinarymetabolitesofprostacyclinbutnotthromboxanemetabolitesinhealthyvolunteerstakingrofecoxib–  Fitzgeraldhypothesis:Suppressionofprostacyclinbutnotthromboxanebyselec6veCOX-2inhibitors“mightmediateariskofthrombosisfromCOX-2inhibitorsinpredisposedindividuals.”

•  But…nointerven6onstudiesincludedinVioxx’sNDAweredesignedtoevaluatecardiovascularrisk

•  And…studiesdidnothavestandardizedproceduretocollectandadjudicatecardiovascularoutcomes

Fitzgerald,G.A.,et.al.J.Pharm.Exp.Ther.1999,289,735.

BehindtheScenes:VIGORStudy

•  Nov1999:79%greaterriskofdeathorseriousCVeventfoundinonetreatmentgroup!safetyboardallowsstudytocon6nue

•  Dec1999:Studys6llshowshigherCVeventsinonegroup!boardrecommendsanalysisplanbedevelopedtoexamineseriousCVevents

•  InternalmemoatMerckfromEdwardScolnick,Merck’schiefscien6st:–  “Itisashamebutitisalowincidenceanditismechanismbasedasweworrieditwas.[Merckemployees/consultants]wererightaboutthemetabolitemeanings,ie,urine[prostacyclin]data.”

Krumholz,H.M,et.al.BJM,2007,334,120.

VIGORStudy:Ques6onableProcedures

•  Nocardiologistondatasafetymonitoringboard

•  Neartrialend,headofsafetyboardgiven2yearconsul6ngcontractanddisclosesfamilyownershipinMercksharesof$70,000(nopoten6alconflictofinterestdisclosedpreviously)

•  Nostandardopera6ngprocedureforcollec6nginfoonCVevent•  Differenttermina6ondatesforGIandCVeventdataacquisi6on

(GIeventscounted1monthlonger),procedurenotdisclosed

•  3heartaZacksnotdisclosedinpaperoccurredinrofecoxibgroupinmontha1erstoppedcoun6ngCVevents

•  Conclusionaboutprotec6venaproxeneffect,yetnoacceptedevidencefornaproxenstrongcardioprotec6veeffect

Krumholz,H.M,et.al.BJM,2007,334,120.

BehindtheScenes:IssueswithPublica6ons

•  Dec2005:NEJMissues“ExpressionofConcern”sta6ng“inaccuraciesanddele6ons”inVIGORmanuscript“callintoques6ontheintegrityofthedata”!askauthorstosubmitcorrec6on

•  Oct2003:ResultsofADVANTAGEstudypublished(Lisse,J.R.et.al.Ann.Intern.Med.2003,139,539)

–  Statedobjec6ve:Accesstolerabilityofrofecoxibcomparedtonaproxenfortreatmentofosteoarthri6s

–  LaterconcludedADVANTAGEstudywasseedingtrialdevelopedbyMerckmarke6ngdivisiontopromoteVioxxwhenitbecameavailable(“marke6ngframedasscience”)

hZp://www.npr.org/templates/story/story.php?storyId=5470430

Hill,K.P,et.al.Ann.Intern.Med.2008,149,251.

TheVioxxStory:TheLegalFallout

•  Aug2005:TXjuryfindsMerckliableinfirstVioxxliabilitycase

•  Jul2006:NJjuryrulesinfavorofMerckinitsseventhVioxxliabilitycase(hadwon3andlost3beforeNJcase)

•  Nov2007:Mercksaysitwillpay$4.85billiontoendthousandsofVioxxlawsuits–  BelievedtobelargestdrugseZlementever

hZp://www.npr.org/templates/story/story.php?storyId=5470430

AreAllSelec6veCOX-2InhibitorsBad?:AnE.J.CoreyStudy

•  Purpose:DescribechemicalpropertyofrofecoxibthatmakesitdifferentfromotheravailableCOX-2inhibitors– WhydoesrofecoxibuseincreasecardiovascularrisksbutnototherCOX-2inhibitors?

Reddy,L.R.andCorey,E.J.Tet.Le:.2005,46,927.

AreAllSelec6veCOX-2InhibitorsBad?:AnE.J.CoreyStudy

•  Conclusion:Rofecoxibionizesunderphysiologicalcondi6onstoanion5thatreadilyreactswithO2toformthepoten6allytoxicmaleicanhydridederiva6ve6–  PropertynotsharedbytwomostusedCOX-2inhibitors,celecoxibandvaldecoxib

Reddy,L.R.andCorey,E.J.Tet.Le:.2005,46,927.