Rev. Bras. Hematol. Hemoter. vol.39 número1

revbrashematolhemoter.2017;39(1):1–3

w w w . r b h h . o r g

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Editorial

Paradoxes

of

hematology:

When

the

old

disappears

and

the

new

does

not

arrive

Angelo

Maiolino

,

Belinda

Pinto

Simões

,

Claudio

Galvão

de

Castro

Junior

,

Dimas

Tadeu

Covas

_,

_Gustavo

_dos

_Santos

_Fernandes

_,

_Nelson

_Hamerschlak

,

Teresa

Cristina

Cardoso

Fonseca

_,

_Vergilio

_Colturato

a_{Associac¸ãoBrasileiradeHematologia,HemoterapiaeTerapiaCelular(ABHH),ComitêdeMielomaMúltiplo,Brazil}

b_{InternationalMyelomaFoundation-LatinAmerica(IMF),Brazil}

c_{SociedadeBrasileiradeTransplantedeMedulaÓssea(SBTMO),Brazil}

d_{LatinAmericanBoneMarrowTransplantAssociation(LABMT),Brazil}

e_{SociedadeBrasileiradeOncologiaPediátrica(SOBOPE),Brazil}

f_{SantaCasadePortoAlegre,UnidadedeHematologia/OncologiaPediátrica,PortoAlegre,RS,Brazil}

g_{Associac¸ãoBrasileiradeHematologia,HemoterapiaeTerapiaCelular(ABHH),Brazil}

h_{SociedadeBrasileiradeOncologiaClínica(SBOC),Brazil}

i_{UniversidadedeSãoPaulo(USP),FaculdadedeMedicina,SãoPaulo,SP,Brazil}

j_{HospitalIsraelitaAlbertEinstein,ProgramadeHematologiaeTransplantedeMedulaÓssea,SãoPaulo,SP,Brazil}

k_{Associac¸ãoBrasileiradeLinfomaeLeucemia(ABRALE),Brazil}

Over the last few decades, we have seen considerable progressincancertreatmentwithpatientssurvivingfor ever-increasingtimes. Animportantpartofthis progressisthe resultofnewdrugswithmechanismsofactiondistinctfrom classicchemotherapy, sometimesbased on disease control ratherthancure.However,despitethegreatadvances,many drugsdevelopedinthe60s,70sand80sareamongthe main-staysofthecurativetreatmentofleukemias,lymphomasand solidtumorsuntiltoday.1,2_{Evenhavingextremeimportance,}

theseold,cheapdrugshavedisappearedfromthemarketin thelastdecade,prejudicingthetreatmentofmanypatients becausethereisnosubstituteforthem.Forusphysiciansand forpatientsthequestionremains:whydocheapbut essen-tialoldmedicinesdisappearwhilemodernandincreasingly expensivemedicinesappearinthemarketdaily?Theanswer

∗ _{Correspondingauthorat:UniversidadedeSãoPaulo,FaculdadedeMedicinadeRibeirãoPreto(FMRP.USP),AvBandeirantes3900,Monte}

Alegre,14048-900RibeirãoPreto,SP,Brazil.

E-mailaddress:bpsimoes@gmail.com(B.P.Simões).

seemssimple:theolddrugsarecheapandthepharmaceutical industrynolongerhasanyinteresttoproducethem.

This, however, is only part of the answer. Thereasons arediverse,but notalwayseasytounderstand,as pharma-ceuticalcompaniesdonotrevealtheirproductionpoliciesor marketingstrategies.3–5_{Weknowthatthelegalandsanitary}

requirements to produce medicines are always increasing. Thisisclearwhenwenoticethatinjectabledrugshave disap-pearedthemost.Withthenewrequirements,factoriesneed tomakeadjustmentsduringwhichproductionisinterrupted. Thelackofapatentoftenleadstoproductionbyalimited numberofcompanieswiththisnumberbeinginsufficientto supplytheinternationalmarket.Theestimateisthatatleast fourfactoriesofaparticulardrugare neededtoreducethe riskofadrugshortagetotheminimal.Withthedifferencein

http://dx.doi.org/10.1016/j.bjhh.2017.01.001

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pricebetweenreferenceandgenericmedications,the inter-estinproducingthesemedicineshasfallendrastically.Inrich countries, the‘renewal’ oftechnologyispartofthe strate-gicprocessofthepharmaceuticalindustrythatrecompenses thenationwithtaxes,jobsanddividendstoshareholders.3,4

Forus,peoplefrom low-andmiddle-incomecountries,the shortageofoldandeffectivedrugsisaseriousthreattothe healthsystemandtothechancesofcureforcancerpatients, especiallythosedependingonthepublicsystem.5–7

Thelackofmedicationsstartsasnowballthatfurther wors-ensthealreadycriticalsituation.Withthefearofabreakin thesupply,manyhospitalswillstockdrugsleavingother hos-pitalswithoutanystockwhatsoever.Thestrongestwins,in thiscasetherichest.Thepriceisyetanotherissue.Iftheyare cheap,duetothelawofsupplyanddemand,wepayahigher pricefordrugsthataremissingfromthemarket.

What does the law say? Current legislation is weak in respecttocurbingbothshortagesandhighprices.InBrazil, aswell asabroad,itisonlynecessarythatthe pharmaceu-ticallaboratorieswarnoneyearinadvancethattheywillno longermarketspecificdrugsandnothingelse.Thisisthelegal requirement.Isthatenoughtimeforlocalauthoritiesto orga-nizethemselves?Isthereanyotherwaytostopinterrupting thedeliveryofessential medications sincethe unavailabil-ityofthesedrugscanaffect thetreatmentofthousandsof patientsbysubstantiallylimitingtheirchancesofcure?Are theauthoritiessufficientlyawareabouthowtheshortageof thesemedicinesaffectspatientcare?

Thecurrentepisodewiththesuspensionoforaland intra-venousmelphalanandchlorambucilandthesituationrelated toasparaginaseareexamplesofsituationsthatshowusthat theBrazilianhealthauthoritiesarestillunawareofthe seri-ousnessoftheabsenceofthesedrugs.5,7 _{Itisessentialthat}

thedelaybeforetakingactionismuchshorterthanwehave seenuntilnow.

Thereisalsonoplausibleexplanationfortheshortageof thalidomide,whichismanufacturedbyastatelaboratoryand usedtotreatmyeloma,myelodysplasiaandmyelofibrosisin theareaofhematologyinadditiontoitsroleinleprosy.

Ontheotherhand,wearenowexperiencinganotherdrama withtheadventofnewdrugsthatbreakparadigms,increase survival,decreasetoxicity,improvequalityoflifeand trans-formlethaldiseasesintochronicones.

Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML); we already have many patients treatedforalmost17yearswhodonotshowsignsofdisease.8

Evenin ourscenario,wewere not onlyabletotreat these patients, but alsoproducenumerousscientific articlesand participateinvariousprotocolsandstudies.9_{AfterImatinib}

wehavealreadyreachedsecondandthirdgenerationtyrosine kinaseinhibitors.TheexampleofCMLisoneofthebestand mostinteresting.Withthebreakingofpatentsovertimeand negotiationsbetweentheMinistryofHealthandlaboratories withtheforcefulparticipationofhematologists,patientshave accesstomedicinesandtheirprogresscanbemonitoredwith molecularbiologytestsfollowingprotocolsrecommendedby severalinternationalgroups.10

Another drug that changed the treatment and survival ofpatientswithlymphoiddiseasesisrituximab.Thousands ofpatientsofallageswithBlymphomashadtheirdisease

cured,ortheirsurvivalsignificantlyincreasedwiththisdrug developed about 20 years ago. Patients with chronic lym-phocyticleukemia(CLL),adiseasestillconsideredincurable, havegainedyearsofsurvivalwiththisnewmedication.More recently,obinutuzumabandibrutinibhavebeenaddedtothe drugarsenal,butunlikethehistoryofCML,CLL,eventhough itisaleukemiaandchronicdisease,isanexampleof inconsis-tencybothinourregulatorysystemandinourpublichealth system.Whiletreatmentcontinuestoadvance,inthe Brazil-ianpublichealthservice,namedtheSistemaÚnicodeSaúde

(SUS),patientsaretiedtotreatmentsusedforalmost60years, suchas chlorambuciland atmosttheyreceive fludarabine andcyclophosphamide,butwithoutanimportantdrug, ritux-imab.Thisisjustoneexampledemonstratingthat,depending onthesocialclassandtheaccesstoagoodhealthcareplan, patientsmayormaynotenjoyagreaterchanceofanadequate responsetotreatment.Acontradiction,inacountrythathas definedthatallcitizens havethe righttohealthinits con-stitution.Lookingatregulatoryandmarketaspects,wewere strugglingtoincludeanoldbutefficientdrug,bendamustine, intheBrazilianmarket;thisfinallyseemstohavehappened in2017.ThisisacheapdrugusedinthetreatmentofCLLthat couldimprovethelivesofthousandsofSUSpatientsandthose insuredbyhealthcareproviders.

Anotherparadoxexistsinthecaseofmultiplemyeloma. Bortezomib,usedasfirstlinetreatmentthroughouttheworld, isnotaccessiblethroughtheSUS.Thegreatestironyliesin thefactthatinDecreenumber708ofAugust6,2015issuedby theBrazilianHealthMinistryitself,bortezomibappearsasthe first-line drugtotreatpatientswithmultiplemyeloma,but without reimbursementforitsuse.11 _{Carfilzomibisalready}

approvedanddaratumomab,amonoclonalantibody,should beapprovedsoon.Noneofthesewillbemadeavailabletothe SUSand,giventhehighcostofthesemedications;evenhealth insuranceplanswillhavedifficultiestopayforthetreatment. LenalidomidehasbeenontheshelfoftheBrazilianregulatory board,theAgênciaNacionaldeVigilânciaSanitária(ANVISA),for eightyearsand indevelopedcountries, morepotentdrugs, suchaspomalidomide,arealreadyareality.

As doctors we live a very serious situation, with irreplaceabledrugsdisappearingfromthemarketandarange ofnewefficientbutexpensivedrugsappearing.Wehaveno hopethattheBrazilianpublichealthsystemwillprovidethe newdrugstoSUSpatientsintheshortormediumterm.Itis theworstoftheworlds,treatmenthasbecomevery expen-sive becauseofthe newdrugs, but patientswillsuffer the consequencesintermsofsurvivalbecausetheolddrugsare missing.Eveninthemostmodernprotocols,thereisno rec-ommendationtosubstituteeffectivedrugs,suchasmelphalan andL-asparaginaseforothernewercompounds.

revbrashematolhemoter.2 0 1 7;39(1):1–3

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Wecan no longer avoidor postponethe discussion on thisseriousproblem!Wehavetoguaranteeaccessof Brazil-iancitizenstominimally adequatetreatmentsinafairand transparentprocesswithinpossiblecostrestraints.

Conflict

of

interest

Theauthorsdeclarenoconflictsofinterest.

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9.CortesJ,DeSouzaC,Ayala-SanchezM,BenditI,Best-Aguilera C,EnricoA,etal.Currentpatientmanagementofchronic myeloidleukemiainLatinAmerica:astudybytheLatin AmericanLeukemiaNet(LALNET).Cancer.

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11.Brasil,MinistériodaSaúde,PortariaSAS/MS708de6de agostode2015.(citedJan10th2017)Availablefrom: