Lecture5Newdrugapplicationanddrugapprovalinformedconsentstrengthgenericdrugthalidomidemislabelingsponsordesignationcompliancerevokeadulteration1.FDA’scurrentresponsibilities—reviewing____________________________________________;—inspecting____________________________________________;—monitoring___________________________________________________________________________________________________________________________________________________;—issuing__________________________________________________________________________________________________.individualapplicationstomarketspecificdrugsmanufacturingfacilitiesItalsomonitorsadvertisements,websitesandotherpromotionalmaterialsbydrugdevicecompaniesotherhelpfulinformationtotheindustryimportsofoverseas,esp.foodanddrugproducts.summariesofdrugapprovaldataforthepublicandprovides2.FDAprotectsthepublichealthby—reviewing____________________________________________;—takingappropriateactionon_____________________________;—ensuring_____________________________________________;—participating__________________________________________________________________________________________________________________________________________________.—servingas________________________________________________________________________________________________.theclinicalresearchthemarketofregulatedproductshumandrugsaresafeandeffectiveharmonizingregulatoryrequirementsacrossbordersthroughtheappropriateprocesswithrepresentativesinothercountriestoreducetheburdenofregulation,anddeliverymarketplaceacriticalguidepostforinnovationinhealthcareunmetbiologicslife-threateningpreliminarymagnitudesurrogateoncologydiagnosisMakeacomparisonbetweenthefourexpeditedapprovalpathways.()1.Regulatorsrequirethreecategoriesofregulatorysubmissions,INDA,NDAorBLA,andANDAbeforeclinicaltrialscanbestarted.()2.INDAisarequestfromaclinicaltrialsponsortotheFDA,inwhichprotocolsofanimalpharmacologyandtoxicologystudies,manufacturinginformationandinvestigatorinformationaretypicallyincluded.()3.NDAistheformalprocessbywhichadrugsponsorseeksFDAapprovalformarketinganewpharmaceuticalintheUnitedStates.TFT()4.Genericdrugapplicationsaretermedabbreviatedbecausesomestepshavebeensimplified,likepreclinicalstudiesandclinicalstudies.()5.Thegenericdrugproductisanalternativetotheinnovatordrugproductitreferencesiningredients,dosageform,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.FFTrytobrieflydescribethedifferencesbetweenNDAprocessandANDAprocess.1.Howaregenericdrugsthesameasbrand-namedrugs?Theyhavethesameactiveingredient.TheFDArequiresgenericdrugmanufacturerstomanufacturegenericdrugsandmeetthesamestandardsasbrand-namedrugs.Theyhaveequalquality,safety,andeffectiveness.2.Howdogenericsdifferfrombrand-namedrugs?Theymaylookdifferent.TheFDAallowsthemtohavedifferentinactiveingredients,likethebinders,theflavoring.Thecolorsofthemmightbedifferent.Thepackagingofthegenericdrugsisdifferentinlabeling.3.Whyaregenericdrugscheaperthanbrand-namedrugs?----Thedirectmanufacturingcostsarejustasmallpartofthecostofdevelopingadrug.Alotofmoneyisspentonnewdrugresearchanddevelopment,marketingandadvertising.----FDAgivesmanufacturers20yearsofpatentprotectiontorecouptheircostsofdevelopment.Oncethat20yearspass,otherdrugcompaniesmanufacturegenericdrugs.Andthenthecostforthegenericsismuchcheaper.4.Shouldpatientsbetakinggenericmedicationiftheyfindoutthatit’scheaperthanthebrandnamedrugs?Itdepends.Generally,theanswerisyes.Ifthegenericisequivalentforthepatientsasthebrand-namedrug,theyareencouragedtogetgenericstosavemoneyandkeeptheirhealthcostdown.Ifthegenericisnot,patientsarenotrecommendedtoswapthebranddrugstheyaretaking.1.Howwassulfanilamidedeveloped?Sulfanilamidewasdevelopedfromanearlierdrugcalledprontosil,whichwasactuallydevelopedbythedyeindustry.Furtherresearchshowedthatprontosilhadtwoparts:onewasthedye,andtheotherwastheantibiotic.Theantibiotichalfwassulfanilamide,whichresearchersfoundcouldbeusedonitsown.2.Pleasediscusstheprocessofsulfanilamideelixirdisaster.DiscoveryofProntosilGerhardDomagkdiscoversprontosil,adrugwithavividredcolordevelopedbythedyeindustry.DevelopmentofSulfanilamideResearchersfindthatprontosilhastwoparts:oneisthedye,andtheotheristheantibioticsulfanilamide,thelatterisidentifiedasapotentialstandaloneantibiotic.FormulationofElixirMassengillcompanyuseddiethyleneglycoltoformulatesulfanilamideintoanelixirandmarketedthenewproductwithoutanysafetytesting.ConsumptionandDeathPatientsconsumedthesulfanilamideelixirasprescribedbytheirhealthcareprovidersandstaredexperiencingsevereadversereactions,includingdeath,duetothepresenceofthetoxicsolvent.InvestigationandRecallofProductAninvestigationislaunchedtodeterminethecauseoftheadversereactionsandtheelixirwasrecalledfromthemarket.3.Itwasthesolventofthesulfanilamideelixir,diethyleneglycol,thattriggeredthetragedy.Pleasemakeacommentontheresponsibilitythatthepharmaceuticalcompany,theFDA,andthelegislaturesshouldtake.PharmaceuticalCompany:Thepharmaceuticalcompanybearsasignificantresponsibilityinthiscase.Theywereresponsibleforformulatingthesulfanilamideelixirandselectingthesolvent,diethyleneglycol.Theyshouldhaveconductedthoroughtestingtoensurethesafetyandefficacyoftheirproductbeforereleasingittothemarket.Theuseofdiethyleneglycolasasolvent,despiteitsknowntoxicity,indicatesalackofproperresearchandregardforpatientsafety.Thecompanyshouldhavebeenawareofthepotentialrisksassociatedwiththissolventandtakenstepstoavoidusingitortoensurethatitwasusedinasafemanner.FDA:TheFDA,astheregulatorybodyresponsibleforoverseeingthesafetyandefficacyofdrugsintheUnitedStates,alsohasaresponsibilityinthiscase.WhiletheFDAdidnotdirectlyapprovethesulfanilamideelixir,theywereresponsibleforsettingstandardsandguidelinesfordrugmanufacturingandtesting.Theagencyshouldhavehadstricterregulationsinplacetopreventtheuseoftoxicsolventsinmedications.Additionally,theFDAshouldhaveconductedmorerigorousinspectionsandauditsofpharmaceuticalcompaniestoensurecompliancewithsafetystandards.Legislatures:Legislaturesplayacrucialroleinsettingthelegalframeworkfordrugregulationandsafety.Theyshouldenactlawsthatprovideclearguidelinesandpenaltiesfornon-compliancewithsafetystandards.Inthiscase,thelegislaturecouldhaveimposedstricterpenaltiesforusingunsafesolventsinmedicationsandprovidedmorefundingforregulatorybodiestoconductinspectionsandaudits.Additionally,theycouldhaveencouragedpublicawarenesscampaignstoeducateconsumersaboutthepotentialrisksassociatedwithcertainmedications.FTTFTF1.WhydidtheFDAstillapproveAduhelm(aducanumab)despitethedisagreementovertheeffectivenessofthedrug?WhatdidtheFDAbaseitsapprovalon?TheFDAstillapprovedAduhelm(aducanumab)becauseitattacksakeyproteininAlzheimer'sdisease,amyloid,whichclumpsintoplaquesinthebrainsofpatientswithAlzheimer's.TheFDAacknowledgedthattherewasnotclearevidenceofclinicalbenefitandsomemurkinessintheevidenceregardingwhetherthedrugwouldactuallyhelppatientsslowdowntheirmemoryandthinkingproblems.FDAbaseditsapprovalonthesuggestionthatthedrugmightoffersomebenefitforpatientsymptomsandtheneedfornewtreatmentsforAlzheimer's,giventhatthelasttreatmentcameonthemarket18yearsago.Additionally,theFDArequiredthecompanytoconductanotherclinicaltrial,andiftheresultsofthattrialdonotshowbenefit,theFDAmightrevoketheapproval.2.WhatarethebenefitsandrisksofAduhelm?ThebenefitsofAduhelm,basedonthetrialsconducted,arerelativelyuncertainandmild.Onlyoneofthetrialsshowedanypotentialbenefit,andeventhen,theimprovementwasquiteslight.However,itisworthnotingthatthedrugisintendedtotargettheamyloidprotein,whichisbelievedtoplayaroleinthebiologyofAlzheimer'sdisease.RegardingtherisksofAduhelm,therearesomeseriousconcerns.Thedrughasbeenshowntocausebrainswellingandbrainbleedinginabout40%ofpatientsinthetrials,althoughmostofthesecasesdidnotproduceanysymptoms.However,asignificantnumberofpatientsdidexperiencesymptoms,andabout6%hadtoquitthetrialsduetothesesideeffects.Asaresult,anyonetakingAduhelmwillneedtoundergoregularbrainMRIstomonitorforpotentialcomplications.3.AlthoughAduhelmgainedtheapprovalfromtheFDA,theeffectivenessseemsnotsoclear.So,whatisFDA’sroleinthisprocess?----Inthisprocess,theFDA'sroleistoevaluatethesafety,efficacy,andoverallbenefit-riskprofileofthedrugbasedontheavailablescientificevidenceandclinicaltrialdata.TheFDAconsiderstheseriousnessofthedisease,theunmetmedicalneed,andthepotentialbenefitsthedrugmayoffertopatients.----Inthiscase,despitetheuncertaineffectivenessandthehistoryoffailedanti-amyloiddrugs,theFDAmayhavedecidedtoapproveAduhelmbasedonitshintofbenefitanditsabilitytotargetthekeyproteinimplicatedinAlzheimer'sdisease.----However,itisimportanttonotethattheFDA'sapprovaldoesnotguaranteethedrug'seffectivenessorsafetyinallpatients,andongoingmonitoringandresearcharenecessarytofurtherassessitsbenefitsandrisks4.ThereisgreatcontroversyovertheapprovalofthisnewAlzheimer’sdrug,Aduhelm.Doyouthinksuchadrugshouldbeapproved?Pleasemakeacommentonit.SupportingArguments----AddressinganUnmetMedicalNeedAlzheimer'sdiseaseisadevastatingconditionthataffectsmillionsofpeopleworldwideandhasasignificantimpactonpatientsandtheirfamilies.Thereisapressingneedfornewtreatmentsthatcanslowtheprogressionofthediseaseandimprovethequalityoflifeforpatients.AduhelmrepresentsapotentialbreakthroughinAlzheimer'streatmentbytargetingtheamyloidprotein,whichisimplicatedinthediseaseprocess.----PotentialforClinicalBenefit:AlthoughtheevidenceforAduhelm'seffectivenessisnotconclusive,someclinicaltrialshaveshownahintofbenefitinreducingcognitivedeclin