RevPaulPediatr.2016;34(1):1---2
www.rpped.com.br
REVISTA
PAULISTA
DE
PEDIATRIA
EDITORIAL
Challenges
on
off
label
medicine
use
O
desafio
do
uso
off
label
de
medicamentos
Marisa
Lima
Carvalho
InstitutoAdolfoLutz,SãoPaulo,SP,Brazil
Received1September2015
AftertheSecondWorldWar,theso-calledpharmacological explosiontookplace,leadingtomajoradvancesinthe treat-mentofdiseasesthatwereonceinevitablyfatalordisabling. Thispharmacologicalexpansioncontributedtothe occur-rence of catastrophic incidents, such as the phocomelia epidemic attributed tothalidomide. Sincethen, concerns aboutdrugsafetyhavecontributedtothedevelopmentand applicationofclinicalandepidemiologicalmethodstoassess thebenefitsandpotentialrisksofanytypeoftherapeutic intervention,whetherpharmacologicalornot.1
Indisputably,theadministrationofamedicationaimsto obtainabeneficialeffectforthosewhotakeit.Nonetheless, itisimportantthattheassumptionsarisingfromtheanalysis ofscientificevidencearenotforgotten:firstly,somedrugs donothave thedesired efficacy,and secondly,regardless of theirbeneficialeffects,every medication mayproduce undesiredeffects.
Whenadrugislaunchedonthemarket,alltheknowledge aboutitisbasedonpre-marketingstudies:duringthe devel-opmentofthemolecule,experimentalstudiesonitseffects andtoxicityareconductedinanimals(pre-clinicalstudies). Ifnounacceptabletoxiceffectsareobserved,thefirst clini-caltrialsinhumansareconducted.Thesearetermedphase I,II,andIIIstudies,whichinvestigateaspectsofthe phar-macokinetics,toxicity,andefficacyinhumans.
In clinical trials, several factors may interfere with the results,such asinclusion andexclusion criteria, sam-plesizes, andeven ‘‘apparentlyethical’’ criteria, which,
E-mail:marisalima@ial.sp.gov.br
while fullyjustified inthe early stages of the assessment of a new drug, preclude scientific study in certain popu-lations. For a long time, with some exceptions, children have been excluded fromclinical trials. Only in phase IV (post-marketing)arethedrugsusedinchildren,whichmay leadthem tobecomethesubjectsofuncontrolled clinical practice.1,2
This practice of pediatric prescription without clini-cal evidence, in situations that are different from those studiedandadvocated(indications,dosages, extemporane-ousformulations,age groupinwhich tested),is knownas off-labeluse, which hasbeen demonstrated tobe associ-atedwithan increase in adverse effects3---5 andshouldbe
discouraged.
In this issue of the Revista Paulista de Pediatria, Gonc¸alves andHeineck conducteda cross-sectional study, with a simple methodology.6 In their study, the authors
demonstratedthat,of thetotal,232(31.7%)prescriptions wereoff-label,andthefollowingtypesandfrequencywere observed:off-labeldose---90(38.8%);age---73(31.5%);and administrationfrequency---68(29.3%).Thegreatestconcern wasthefindingofoverdoseofmedicationswhoseuseinthis situationmaybefatal,suchassalbutamol.
InBrazil,off-labelprescriptioninpediatricsisafrequent practice.Is thispracticenecessary? What can be done to ensurethesafetyofchildren?
Inordertoprotectthehealthofchildrenandtoensure thatmedications areusedin a moreethicalway, in 2007 theEuropeanUnionissuedlegislationforthedevelopment andauthorizationofpediatricdrugs.7 Sincethen,
pharma-ceutical companies have been required to develop their
http://dx.doi.org/10.1016/j.rppede.2015.12.007
2 LimaCarvalhoM.
medicinesbothfortheadultandpediatricpopulations, aim-ingtoadapt thedrugtotheneeds,dosage, dosage form, andadministrationroute,amongothers,inordertoensure effectivenessandthatsafetyisnotaffectedbytheriskof overdose.APediatricCommitteewasalsocreatedto eval-uatethe pediatric investigation plans (PIPs) presented by pharmaceuticalcompanies. The committee consists of 12 representativesofthememberstates;amongitsfunctions, theelaborationofaninventoryofspecificpediatricneeds isnoteworthy.7
Alsoin2007,theWorldHealthOrganization(WHO) pub-lished the first list of Essential Medicines for Children, whichisreviewedevery2years,andlaunchedthe‘‘make medicines child size’’ campaign, in orderto raise aware-nessandpromoteaglobalactionontheproblemoflackof pediatricformulations.8
In 2012, under the Investigational New Drug (IND) program,theFoodandDrugAdministration(FDA),the reg-ulationagencyoftheUnitedStates,createdtheSafetyand InnovationAct(FDASIA-2012), which establishedthe Pedi-atricStudy Plan.This planisrequired for newmolecules, newindications,newdosageforms,newdosages,andnew administrationroutes.9,10
In Brazil, there are isolated initiatives by healthcare institutionsthat,bystandardizingdrugsandcreating phar-macologycommittees,amongothermeasures,areableto evaluate the off-label use of drugs. In the state of São Paulo,theHealthSurveillanceCenter(CentrodeVigilância Sanitária[CVS]) acts in thepharmacovigilanceareabased onthe reports of adverse events, publishing Therapeutic AlertsonPharmacovigilanceintheOfficialJournal.TheCVS hasrecentlypublishedtwoalerts,‘‘Methylphenidate: indi-cations and adverse reactions’’ (July 2013) and ‘‘Risk of pancreaticcancerassociatedwithincretin-basedtherapy’’ (February 2014). Both are focused on alerting, following adversereactionsfromtheoff-labeluseofdrugs.Thefirst iswidelyusedinchildren.11,12Atthefederallevel,the
Col-legiateBoardResolution (Resoluc¸ãodaDiretoriaColegiada [RDC]) No. 9, of 20 February 2015, which aims to estab-lish the procedures and requirements for the conduction of clinical drug trials,indicated that post-marketing clin-icaltrials are subject only to the Notification of Clinical Trial.13
Aboveall,tofosterethicaloff-labeldruguse,itis nec-essarythatthisexceptionaluseisclinicallyjustified, even ifitisaccompaniedbyclarificationandconsentofthe par-entsorguardians.14Thismeasurecanbetakenbyhealthcare
facilities.TheBrazilianNationalHealthSurveillanceAgency (AgênciaNacionaldeVigilânciaSanitária[Anvisa]), follow-ing the example of the regulatory body of the European Union, shouldestablish criteriaand standardsthat stimu-latecomparativestudiesanddemonstratetheefficacyand safetyofmedicationuseinchildren.Whenpromising, ther-apiesshouldbetestedincontrolledclinicaltrialsandtheir packageinsertsshouldbereformulated.
Funding
Thestudyreceivednofunding.
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
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