Vioxx Scientific Literature – Plaintiffs' Perspective: Why the Risks Outweigh the Benefits
The Vioxx Story - Amazon S3 · 2016-12-01 · The Vioxx Story: The Road to FDA Approval • Dec...
Transcript of The Vioxx Story - Amazon S3 · 2016-12-01 · The Vioxx Story: The Road to FDA Approval • Dec...
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.