Lecture7Post-marketSurveillancemeta-analysissafetyspecificationwithdrawalpharmacovigilancedispensertriageblackboxwarningpsychiatrypediatricsteratogenicFTTTTOnlyasmallpercentageofpatientsparticipateinclinicaltrialsandsubsequentlyaverysmallpercentageofadversedrugreactionscanbedetectedduringthisperiodClinicaltrialsmainlyaimtoprovetheefficacyofadrugandthusasimpleprotocolthatremovesvariousinterferingfactorsisadoptedChildrenandpatientsover75yearsoldareusuallyexcludedfromclinicaltrials,buttheymaybeexposedtothedrugafterapprovalAllfactorssuchastheadministrationtimingofdrugs,testingscheduleandmonitoringarecontrolledunderprotocolsandspecialistsThedurationofaclinicaltrialisusuallyoneyear,shorterthanthedurationofreal-worldtreatmentThepossibilityofsafety-relatedproblemsishighatthebeginningduetolimitedinformation,butwillgraduallydecreaseduetotheaccumulationofsafety-relatedinformationsafetyandefficacyinformationofdrugsinactualclinicalpracticeaftermarketingappropriatefeedbacktopatientspositivebalanceriskminimizationadverseeffectassessedstakeholdersspecificationcharacterizeprofilemitigation1.InOctober2004,theFDAannouncedblackboxwarningassociatedwiththeuseofantidepressantsinpatientsundertheageof18.WhatwasthebasisfortheFDAtoissuethisblackboxwarning?TheFDAissuedthisblackboxwarningbasedonameta-analysisof24randomizedcontrolledtrialsthatlookedatyouthonantidepressants,includingSSRIsaswellasnon-SSRIs.Itwasfoundthattherewasanincreasedriskofsuicidalthinkingandbehavioramongpatientsreceivingtheactivedrugcomparedtothosereceivingplacebo.2.Aftertheblackboxwarningonantidepressantwasissued,therewasafollow-upstudythatwascompletedin2007.Whatdidthefollow-upstudyfind?----Thefollow-upstudyfoundthattherateofsuicidalityintheactivedruggroupwas3%comparedto2%forthosereceivingplaceboandthiswasnotstatisticallysignificant.----Thecalculatedriskdifferenceresultedinanumberneededtoharm(NNH)of112andanumberneededtotreat(NNT)of10.----Nocompletedsuicideswerereportedduringtheclinicaltrial.3.HowdidSSRIprescribingpatternschangeaftertheblackboxwarningwasissued?TherewasadecreaseduseofSSRIsinpediatricpopulation,andtherewasalsoashiftfromprimarycareprovidersprescribingthesemedicationstopsychiatrists.4.Whatshouldfamiliesbeinformedabout?----ThereisanFDAblackboxwarningforSSRIsinyouth.----ThiswarningwasissuedafterastudythatfoundtherewasincreasedsuicidalthinkingandbehaviorinyouthonSSRIs,butnotcompletedsuicides.Thisdatawasnotreplicatedinafollow-upstudy.----DecreasedSSRIsprescriptionresultedinincreasedsuicideratesindepressedyouth.----ThebenefitsoftreatingwithSSRIsfaroutweightherisks.Itisextremelyimportanttomonitorforsuicidality.5.HowtomonitorforkidswhoareonSSRIs?----Thegreatestriskforsuicidalityoccurswithmedicationinitiationanddosechangesandsomakesuretopayextraattentionduringthesetimes.----Frequentmonitoringforsuicidalityhasbeenfoundtoreducetheriskofsuicide.----Weeklycheck-insafterstartingthemedicationorincreasingadoseisneeded.----Don’tbeafraidtoasksuicidality.FTFTTFT1.WhydoesFDArequireREMSonlenalidomide?Lenalidomide,similartothalidomide,hasbeenassociatedwithsevere,life-threatening,orfatalbirthdefects.Therefore,itiscrucialtoimplementstrictmeasurestopreventwomenofchild-bearingagefromtakinglenalidomide.Thisincludesusingtwoformsofeffectivecontraception,undergoingregularpregnancytesting,andimmediatelystoppinglenalidomideifpregnancyissuspected.2.WhatarethestrategiesintheREMSprogramtoreducetheriskofusinglenalidomide?----Patientregistry:AllpatientstakinglenalidomidemustberegisteredtomonitortheirsafetyandcompliancewiththeREMSprogram.----Prescriberanddispensertrainingandcertification:Healthcareprovidersmustundergospecializedtrainingandobtaincertificationtoprescribeanddispenselenalidomide.----Patienteducation:Providepatientswithclearandconciseinformationaboutlenalidomide'srisksandbenefits.----PeriodicReviewandAssessment:TheREMSprogramforlenalidomideissubjecttoperiodicreviewandassessmentbytheFDA.Thisensuresthattheprogramremainseffectiveinminimizingrisksandmaximizingbenefitsovertime.3.ShouldthalidomideanditsderivativelenalidomidebeusedagaineventhoughaREMSprogramisrequiredbyFDA?WhatdoyouthinkarethechallengesofimplementingREMS?Whetherthalidomideanditsderivativelenalidomideshouldbeusedagain,eventhoughaRiskEvaluationandMitigationStrategies(REMS)programisrequiredbytheFDA,isacomplexquestionthatinvolvesconsideringmultiplefactors.TherapeuticEffects:Thalidomideandlenalidomidehavedemonstratedtherapeuticeffectsintreatingcertainconditions,suchasmultiplemyelomaandmyelodysplasticsyndromes(MDS).Lenalidomide,inparticular,hasbecomeafirst-linetreatmentforlower-riskMDSwitha5qdeletion.SafetyConcerns:Thalidomidewasinitiallywithdrawnfromthemarketduetosevereteratogeniceffects,causingbirthdefectsknownas"phocomelia"or"seallimbs".Bothdrugshavespecificsideeffectsandrisks,whichneedtobecarefullymanaged.Thedecisiontousethalidomideandlenalidomide,despitetherequirementforaREMSprogram,shouldbebasedonacomprehensiveassessmentofthepatient'scondition,thepotentialbenefitsandrisksofthemedication,andtheavailabilityofalternativetreatments.ItiscrucialtoensurethatpatientsandprovidersarefullyinformedandcompliantwiththeREMSrequirementstominimizepotentialharm.ChallengesofImplementingREMS----PatientCompliance:EnsuringthatpatientsunderstandandcomplywiththesafetymeasuresoutlinedintheREMSprogramcanbechallenging.Patientsmaynotfullyappreciatetheseverityoftherisksassociatedwiththemedicationormayforgettofollowtheprescribedsafetyprotocols.----ProviderTrainingandAwareness:ProvidersneedtobethoroughlytrainedontheREMSprogramandthespecificrisksassociatedwiththemedication.EnsuringthatallproviderswhomayprescribeordispensethemedicationareawareofandcomplywiththeREMSrequirementscanbedifficult.----ResourceAllocation:ImplementingaREMSprogramrequiressignificantresources,includingfundingforpatienteducationmaterials,providertrainingprograms,andmonitoringsystems.Theseresourcesmaynotbeavailableormaybelimitedincertainhealthcaresettings.----RegulatoryOversight:TheFDAneedstocontinuouslymonitorandevaluatetheeffectivenessoftheREMSprogram.EnsuringcompliancewiththeREMSrequirementsandtakingappropriateenforcementactionsfornon-compliancecanbechallengingandresource-intensive.1.WhywasVioxxwithdrawnfromthemarketinspiteofthefactthatitwasdesignedtobeasaferNSAID?----Vioxxwaswithdrawnfromthemarketbecausestudiesshowedadoubledincreaseinheartattackandstrokerisksamongpatientstakingthedrug.Thisdiscoveryraisedserioussafetyconcerns,promptingMerck,themanufacturer,tovoluntarilyrecallVioxxfromthemarketinSeptember2004.----Thedrughadbeenwidelyprescribedforthetreatmentofosteoarthritic,menstrual,andacutepaininadults,anditswithdrawalcausedsignificantcontroversyandconcern,asithadbeentakenbyapproximately20millionpeopleworldwideandwasestimatedtohavecausedatleast50,000deaths.2.WhydidtheFDAapprovalprocesscomeunderfirebycriticsafterthewithdrawalofVioxx?Firstly,thecontroversiallawpassedin1992allowedtheFDAtochargeuserfeestomanufacturers,withtheintentionofspeedinguptheapprovalprocessbyhiringadditionaldrugreviewers.However,criticsarguedthatthislawleftlessmoneyforpost-approvalmonitoring,potentiallyleadingtomissedsafetyconcerns.Secondly,itwasrevealedthroughlaterleaksofMerckdocumentsthatstudiesasearlyas1998mayhavesuggestedtheincreasedriskofcardiaceventsassociatedwithVioxx,yetthedrugstillreceivedonlyasix-monthpriorityreview.ThisraisedquestionsaboutthethoroughnessoftheFDA'sreviewprocess.Additionally,someassertedthatthefinancialcontributionsofdrugcompaniesmadetheFDAlesslikelytoconfrontthem,whichcouldhaveinfluencedtheagency'sdecision-makingregardingVioxx.3.WhoshouldbeblamedfortheoccurrenceofVioxxdisaster?TheoccurrenceoftheVioxxdisasterisacomplexissuethatinvolvesmultiplepartiesandfactors.Itisnotstraightforwardtoassignblametoasingleentity.However,severalpartiescouldpotentiallybeheldaccountable:----Merck&Co.,themanufacturerofVioxxMerckisultimatelyresponsibleforensuringthesafetyandefficacyofitsdrugs.CriticsarguethatMerckmayhavedownplayedoroverlookedpotentialsafetyrisksassociatedwithVioxx,particularlyitscardiovascularsideeffects.Thecompany'smarketingefforts,whichfocusedonabroadconsumerbaseratherthanspecificpatientgroups,mayhavealsocontributedtothedisasterbypromotingthedrugtopatientswhowereathigherriskofadverseevents.----TheFoodandDrugAdministration(FDA)Astheregulatorybodyresponsibleforapprovingnewdrugs,theFDAhasadutytoensurethatdrugsonthemarketaresafeandeffective.CriticshaveaccusedtheFDAofbeingoverlyreliantonthemanufacturer'sdataandofnotconductingthoroughenoughreviewsofnewdrugs.Additionally,theagency'sfocusonspeedinguptheapprovalprocessthroughuserfeesmayhavecompromiseditsabilitytoadequatelymonitordrugspost-approval.----PhysiciansandhealthcareprovidersWhilephysiciansarenotdirectlyresponsibleforthedevelopmentorapprovalofdrugs,theyplayacrucialroleinprescribingmedicationstopatients.CriticsarguethatsomephysiciansmayhavebeenoverlyreliantondrugcompanymarketingandmaynothaveadequatelyinformedpatientsaboutthepotentialrisksassociatedwithVioxx.4.IsitpossibleforVioxxtocomeback?Whyandwhynot?ReasonsforUnlikelyReturn----SeriousSafetyConcerns:Vioxxwaswithdrawnfromthemarketduetoserioussafetyconcerns,particularlyitsassociationwithanincreasedriskofcardiovasculareventssuchasheartattacksandstrokes.Thisriskwasidentifiedthroughclinicaltrialsandpost-marketingsurveillance.ThewithdrawalofVioxxwasasignificantblowtoMerck&Co.,themanufacturer,whichfacednumerouslawsuitsandsubstantialfinanciallossesasaresultofthedrug'ssafetyissues.----RegulatoryBarriers:TheFDAhasstrictregulationsinplacetoensurethesafetyandefficacyofdrugsonthemarket.Anydrugseekingre-approvalafterbeingwithdrawnwouldneedtodemonstrateahighlevelofsafetyandefficacy.GiventheserioussafetyconcernsassociatedwithVioxx,itwouldbedifficultforthedrugtomeettheFDA'sstandardsforre-approval.----PublicPerce