View
9
Download
0
Category
Preview:
Citation preview
C A S E S T U DY
Chlorhexidine for
Umbilical Cord Care
February 2012 Revised version, July 2012
Prepared for the United Nations
Commission on Commodities for
Women’s and Children’s Health
ii
Authors
JoelSegrè1,PatriciaCoffey2,MutsumiMetzler2,ShirleyVilladiego2,Neal
Brandes3,SteveHodgins4,LukeMullany5,SaulMorris6.
1ConsultanttotheBill&MelindaGatesFoundation;2PATH;3UnitedStatesAgencyforInternational
Development;4MaternalandChildIntegratedProgram;5TheJohnsHopkinsUniversityBloomberg
SchoolofPublicHealth;6theBill&MelindaGatesFoundation.
Acknowledgments
Theauthorswouldliketothankthefollowingindividualsfortheircontributions:AbraGreene,
JanetSaulsbury,JillSherman‐Konkle,andGretchenShively.
PATH’scontributiontothiscasestudywasmadepossiblebythegeneroussupportoftheAmericanpeoplethroughtheUnitedStatesAgencyforInternationalDevelopment(USAID)underthetermsof
theHealthTechCooperativeAgreement#AID‐OAA‐A‐11‐00051.ThecontentsprovidedbyPATH
aretheresponsibilityofPATHanddonotnecessarilyreflecttheviewsofUSAIDortheUS
Government.
Cover photograph credits
Photograph1:AmotherinNepallieswithherbaby.©2008Suaahara/JHUCCP;courtesyofPhotoshare.
Photograph2:AbabyinDjoliba,Mali.©2000HannahKoenker;courtesyofPhotoshare.
Photograph3:AnewbornchildsleepsnexttohismotherattheTinhGiaDistrictHealthCenterinVietnam.©2004PhilippeBlanc;courtesyofPhotoshare.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
iii
Acronyms
ASHA Accreditedsocialhealthactivist
CDK Cleandeliverykit
CHX Chlorhexidine
EMA EuropeanMedicinesAgency
EMLc Pediatricessentialmedicineslistormodellistofessentialmedicinesforchildren
FCHV FemaleCommunityHealthVolunteer
HDPE High‐densitypolyethylene
ICH InternationalConferenceonHarmonizationofTechnicalRequirementsfor
RegistrationofPharmaceuticalsforHumanUse
RCT Randomizedcontrolledtrial
RH Relativehumidity
TBA Traditionalbirthattendant
USFDA UnitedStatesFoodandDrugAdministration
WHO WorldHealthOrganization
WTP Willingnesstopay
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
iv
TableofContents
ExecutiveSummary..............................................................................................................................................v1.EfficacyandEffectivenessofChlorhexidine............................................................................................11.1.Historicaluseoftheproductandsafetyrecord............................................................................................11.2.Completedstudiesforumbilicalcordcare......................................................................................................21.3Additionalstudiesunderwayonumbilicalcordcare..................................................................................3
2.GlobalPolicyandRegulation........................................................................................................................42.1WHOguidelinesforumbilicalcordcare............................................................................................................42.2.TheWorldHealthOrganizationModelListofEssentialMedicinesforChildren............................4
3.NationalRegulatoryPolicy............................................................................................................................63.1.SouthAsiancountries:Nepal,India,Bangladesh..........................................................................................73.2.Africancountries:Zambia,Tanzania,others..................................................................................................7
4.FinancingChlorhexidine................................................................................................................................74.1Costandcost‐effectivenessdata...........................................................................................................................74.2CurrentuseinNepal..................................................................................................................................................84.3Potentialforpublicprocurement.........................................................................................................................84.4Potentialforprivatepurchase...............................................................................................................................8
5.User‐CenteredProductDesign:WhatWomenWant............................................................................95.1Formulationconsiderations....................................................................................................................................95.2Packagingconsiderations......................................................................................................................................105.3Bundlingwithcleandeliverykits.......................................................................................................................12
6.Manufacturing.................................................................................................................................................126.1Theglobalchlorhexidineindustry.....................................................................................................................126.2Thefinishedproductmanufacturer’sbusinesscase..................................................................................136.3Localversuscentralizedmanufacturingoffinishedproducts...............................................................136.4Formulationdetails..................................................................................................................................................146.5Packagingdetails.......................................................................................................................................................15
7.SupplyChainManagement.........................................................................................................................157.1Shippingconsiderations.........................................................................................................................................157.2Shelflife.........................................................................................................................................................................16
8.CultivatingDemandfromCaregivers.....................................................................................................179.CultivatingDemandfromConsumers....................................................................................................1810.MonitoringandEvaluation......................................................................................................................1811.Recommendations......................................................................................................................................19
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
v
ExecutiveSummary
Globally,neonatalinfectionsareestimatedtoaccountforover1millionnewborndeathsannually(overathirdofthetotalburden).Inmanyregions,infectionistheleadingcauseofneonatal
mortality,andinhigh‐mortalityregionsinfectionsareresponsibleforaroundhalfofallnewborn
deaths.Manyoftheseinfectionscomefromcontaminationoftheumbilicalcordstump.
Chlorhexidinedigluconateisawidelyused,low‐costantisepticeffectiveagainstmajoragentsof
neonatalinfection.Sinceitsintroductioninthe1950s,ithasbeenusedregularlyasasurgicalanddetailantisepticandcarefullystudiedforsafetyandefficacy.Recentcommunity‐levelrandomized
controlledtrialsinNepal,Pakistan,andBangladeshhaveshownthatapplyinga4%chlorhexidine
product(7.1%chlorhexidinedigluconate)totheumbilicalcordsaveslives(thePakistanandBangladeshfindingswerepublishedinTheLancetonFebruary8,2012).Acrossthethreecountries,
datafromover54,000newbornsshowedanaggregate23%reductioninneonatalmortality(not
includingdeathsinthefirstfewhoursoflife)anda68%reductioninsevereinfectionsforthechlorhexidineinterventiongroups.Thesearesomeofthelargesteffectsizesseeninanyneonatal
intervention.
Thereareliterallydozensofmanufacturerscurrentlymakingchlorhexidine‐basedproductsaround
theworld,atconcentrationsfrom<1%to20%.Chlorhexidinedigluconate—usedtomakeavarietyofchlorhexidinefinishedproducts—isreadilyavailableoneveryinhabitedcontinentatlowcost.
Thefinishedproductforcareoftheumbilicalcordstump(4%freechlorhexidine,or7.1%
chlorhexidinedigluconate)cancostlessthanUS$0.01inrawmaterialsperbaby.Ithasalongshelflife,requiresnocoldchain,andisextremelyeasytoapplywithminimaltrainingandnoequipment.
Thesefactorsmakeitsuitableforhospital,healthcenter,andhomecarealike.Fewother
interventionshavedemonstratedsuchpotentialforrapidlyreducingnewbornmortalityacrossso
manysettingsforsuchalowcost.
Whiletherehavebeeneffortstoimproveumbilicalcordhygienebyadvocating“drycordcare,”
theseeffortshavenotalwayshadtheintendedeffectinallsettings.Millionsofmothersaroundthe
worldcontinuetohaveastrongdesiretoapplysomethingtotheumbilicalcordstumpoftheirnewborns.Intheabsenceofaspecificallyrecommendedproduct,theyresorttoavarietyof
traditionalandnon‐traditionalsubstancesincludingedibleoils,ash,dirt,andfeces.Where
consumerresearchhasbeenconducted,mothershaveshownastronglatentdemandforapurpose‐madeantisepticlikechlorhexidineandalsohavedemonstratedtheabilitytousechlorhexidine
correctly.
Nepalisthefirstcountrytohaveregisteredachlorhexidineproductspecificallyforumbilicalcord
stumpcare.Additionally,Nepalhasincludedchlorhexidineintheir2011nationallistofessentialmedicines.Oneofthelargestpharmaceuticalproducersinthecountrymanufacturesitfornewborn
careprograms.ThegovernmentofNepalhasplanstoallocatefundsinthecomingyearfor
procuringtheproductforbroaderuse.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
vi
Severalactionsarerequiredtotakeadvantageofthisopportunity,beyondNepal,andtoaddress
oneoftheleadingcausesofneonatalmortality:
Add4%chlorhexidine(7.1%chlorhexidinedigluconate)forumbilicalcordcaretotheWHO
modellistofessentialmedicinesforchildren.
CorrectthecommonmisconceptionthatWHOadvocatesdrycordcareonly.TheWHOumbilical
cordcareguidelinesrecommendthatantimicrobialsbeused“…asatemporarymeasure,accordingtoalocalsituation(e.g.,inneonataltetanus‐endemicareasortoreplaceaharmful
traditionalsubstance).”TheseexceptionsarerarelycitedindiscussionsofWHO’sdrycordcare
recommendationbutmayapplytomorethanhalfofallbirthsaroundtheworld.
Fasttrackregistrationof4%chlorhexidine(7.1%chlorhexidinedigluconate)forumbilicalcordcarewithnationalregulatoryauthoritiesandencourageadditionalmanufacturerstoproduce
thedrugwithguaranteedminimumvolumes.
Trainbirthattendantstocorrectlyapplychlorhexidinetotheumbilicalcord,aspartofnewborn
caretrainingprograms.
Allocateresourcestointegratechlorhexidineforumbilicalcordcareintoessentialnewborncareprogramsinordertogeneratesustainabledemandandattractivemanufacturingvolumes
fortheproduct.
Throughtheseactions,wearemuchmorelikelytoseeincreaseduseofthisoverlooked
intervention,therebycontributingtohundredsofthousandsofnewbornslivessavedannually.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
1
1.EfficacyandEffectivenessofChlorhexidine
1.1.Historicaluseoftheproductandsafetyrecord
Chlorhexidine(digluconateorgluconate)1isabroad‐spectrumantiseptic,effectiveagainstmajoragentsofneonatalsepsis.Sinceitsdevelopmentin1950,chlorhexidine(CHX)hasbeenwidelyused
inarangeofapplicationsincludinghandwashes,preoperativebodyshower,woundcare,
cosmetics,oralhygiene,generaldisinfection,andveterinarycare.Commonformulationscanbewater‐based,alcohol‐based,gels,orpowdersandarecommonlyappliedtoadult,infant,and
neonatalskin.
Consideringtheextentofitsuseasatopicalantisepticonhumans,reportedsideeffectsarerare,
buthaveincludeddelayedreactionssuchascontactdermatitisandphotosensitivity.Today,topical
solutionsatthelowerconcentrationof0.5%chlorhexidine(4%chlorhexidinedigluconatemixedwithothersubstancessuchasisopropylalcohol)arecommonlyusedforwoundcareandarewidely
availableoverthecounterintheUnitedStatesandinothercountriesundermultiplebrandedand
genericlabels.
Inthe1970sCHXbecamepopularforneonataluseintheUnitedStatesandelsewhereashexachlorophenewasdiscontinued.BathingofnewbornsinCHX‐basedsolutionsquicklybecame
routinepracticeinmanyclinicalsettingstoreducetheoccurrenceofstaphylococcaloutbreaksin
nurseries.2,3,4,5Additionally,theWorldHealthOrganization(WHO)hasrecognizedCHXasasuitable
antimicrobialforcordcarewherenecessaryandespeciallytodisplaceharmfulcordcarepractices.6
Inrecentyears,tensofthousandsofneonateshavereceivedarangeofCHX‐basedcleansing
interventions,includingfull‐bodyandumbilicalcordcleansing,withoutreportedadverseeffects.7
TherearenoreportsofadversehealthconsequencesasaresultofabsorptionofCHXinneonates,andthereisnodatatosuggestthatthelevelsofabsorptionreportedhaveanyclinicalimportance.
Transientcontactdermatitishasbeenreportedinpretermvery‐low‐birth‐weightinfantsafterlong‐
term(>7days)placementofchlorhexidine‐impregnateddressingsforcentralvenouscatheters,and
1NOTE:Itiscommonpracticetouse“chlorhexidinegluconate”and“chlorhexidinedigluconate”interchangeablywhenreferringtotheconcentratedchemicalantiseptic.“Chlorhexidinedigluconate:isusedthroughoutthisdocumentforprecisionandconsistency.2MullanyLC,DarmstadtGL,TielschJM.Safetyandimpactofchlorhexidineantisepsisinterventionsforimprovingneonatalhealthindevelopingcountries.PediatricInfectiousDiseaseJournal.2006;25:665–675.3MaloneyMH.Chlorhexidine:ahexachlorophanesubstituteinthenursery.NursingTimes.1975;71(37):21.4RosenbergA,AlatarySD,PetersonAF.Safetyandefficacyoftheantisepticchlorhexidinegluconate.Surgery,Gynecology,&Obstetrics.1976;143(5):789–792.5TukeW.Hibiscrubinthecontrolofstaphylococcalinfectioninneonates.NursingTimes.1975;71(37):20.6WorldHealthOrganization.CareoftheUmbilicalCord:AReviewoftheEvidence.Geneva:WHO/RHT/MSM;1999.Availableat:https://apps.who.int/rht/documents/MSM98‐4/MSM‐98‐4.htm.7MullanyLC,KhatrySK,SherchandJB,etal.Bacterialcolonizationofhospital‐borninfantsinNepalandimpactofchlorhexidineskincleansing:arandomizedcontrolledtrial.PediatricInfectiousDiseaseJournal.2008;27(6):505–511.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
2
thusthistypeofapplicationintheseinfantsshouldbemonitoredcarefully.Overall,CHXisvery
safe.8
1.2.Completedstudiesforumbilicalcordcare
In2004,aCochranereviewconcludedthattherewasinsufficientevidencetorecommendtopical
antisepticsforpreventionofumbilicalcordinfection(RR=0.53[0.25−1.13]).9Ofthe21studies
includedinthemostrecentversionofthereview,allbutonetookplaceindevelopedcountries(onewasinaBangkoktertiarycareteachinghospital).Insuchenvironments,onlysevenstudies
reportedcordinfection,andtheoverallrateofinfectionwaslow.CHXwasonlyusedinonestudy.
Nodeathswerereportedinanyofthestudies.ThiscombinationoffactorslimitstheextenttowhichthatCochranereviewcaninformdecision‐makingaboutoptimalcordcarepracticesinthe
developingworldcontextswhereneonatalinfectionishighest.
Inrecentyears,threelargecommunity‐basedrandomizedcontrolledtrials(RCT)evaluatingthe
effectivenessofCHXforumbilicalcordcareaspartofapackageofnewborninterventionshavebeenconductedinNepal,Pakistan,andBangladesh.Asimplifiedsummaryofeachstudyisprovided
inTable1below.
Table 1. Clinical trials evaluating the effectiveness of chlorhexidine for umbilical cord care.
Study Characteristic Nepal Bangladesh Pakistan
Overall NMR* (at time of study) 30/1000 36/1000 30/1000
Percent of Births at Home (at time of study) 92% 88% 80%
Total Sample Size 15,123 29,760 9,741
Primary Outcomes Neonatal mortalityOmphalitis
Neonatal mortality Omphalitis
Neonatal mortalityOmphalitis
Comparison Group Dry cord care Dry cord care Dry cord care
Frequency of Multiple Applications (day) 1,2,3,4,6,8,10 1,2,3,4,5,6,7 Daily for 14 days
Intervention Provider Project staff Project staff TBA† and caretaker
*Neonatal mortality rate. †Traditional birth attendant.
ThefulldetailsoftheNepalstudywerepublishedinTheLancetin200610whileresultsoftheother
twotrialswerepublishedonlineonFebruary8,2012.11,12Allthreestudiesshowedsubstantial
8MullanyLC,DarmstadtGL,TielschJM.Safetyandimpactofchlorhexidineantisepsisinterventionsforimprovingneonatalhealthindevelopingcountries.PediatricInfectiousDiseaseJournal.2006;25:665–675.9ZupanJ,GarnerP,OmariAA.Topicalumbilicalcordcareatbirth.CochraneDatabaseofSystematicReviews.2004;(3):CD001057.10MullanyLC,DarmstadtGL,KhatrySK,etal.TopicalapplicationsofchlorhexidinetotheumbilicalforpreventionofomphalitisandneonatalmortalityinsouthernNepal:acommunity‐based,cluster‐randomizedtrial.TheLancet.2006;367:910–918.11SoofiS,CousensS,ImdadA,BhuttoN,AliN,BhuttaZA.TopicalapplicationofchlorhexidinetoneonatalumbilicalcordsforpreventionofomphalitisandneonatalmortalityinaruraldistrictofPakistan:acommunity‐based,cluster‐randomisedtrial.TheLancet.PublishedonlineFebruary8,2012.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
3
reductionsinneonatalmortality(20%to38%)andevengreaterreductionsinomphalitis(24%to75%)intheCHXgroups.Severalgroupshaveconductedmeta‐analysesusingthedataasreported,
andtheunpublishedanalysessuggestreductioninmortalityofapproximately20%to23%.More
formalmeta‐analysesaredueforpublicationinthecomingmonths.
Additionally,Hodginsetal.publishedatrialshowingthenon‐inferiorityof4%CHXgelto4%CHXliquid.Thestudy,basedinKathmandu,recruited653neonatesinahospitalsettingandshowed
that24hoursafterapplication,liquidCHXoffereda64%reductionintheproportionofsamples
positiveforbacteria,whereasgelCHXofferedan86%reductionintheproportionofsamples
positiveforbacteria.13
Overall,thereiscurrentlysufficientevidencetorecommenda4%CHXproduct(7.1%CHX
digluconate)forumbilicalcordcleansingasastrategytoreduceneonatalmortalityinsettingswith
poorhygieneandhighneonatalmortality.
1.3Additionalstudiesunderwayonumbilicalcordcare
TwoadditionalRCTsareunderwaytodeterminetheeffectivenessofCHXinAfrica.Bothare
expectedtoreportresultsin2014.
Table 2. Clinical trials currently under way.
Pemba (Tanzania) Zambia
Institutional Lead The Johns Hopkins University Boston University
Trial Type Individually randomized, double‐blind, placebo‐controlled trial
Cluster randomized, unmasked comparison versus “dry” cord care
Sample Size 24,000 + additional 4,000 42,570 (90 clusters)
Product Type 10‐mL dropper bottle of liquid 4% CHX(7.1% CHX digluconate)
10‐mL dropper bottle of liquid 4% CHX(7.1% CHX digluconate)
Delivery Method Project staff demonstrate for mothers four times, mothers apply in other cases
Mothers
Intervention Duration 10 days, or three days after the stump separates, whichever is longer
Ten days, or three days after the stump separates, whichever is longer
Outcomes Primary: mortality. Sub‐study will examine impact on omphalitis as well as the etiology, sensitivity, and specificity of diagnosing omphalitis
Primary: mortality, Secondary: Incidence of omphalitis through 28 days
12ElArifeenS,MullanyLC,ShahR,etal.TheeffectofcordcleansingwithchlorhexidineonneonatalmortalityinruralBangladesh:acommunity‐based,cluster‐randomisedtrial.TheLancet.PublishedonlineFebruary8,2012.13HodginsS,ThapaK,KhanalL,etal.Chlorhexidinelotionvs.aqueousforpreventativeuseonumbilicalstump:arandomizednon‐inferioritytrial.PediatricInfectiousDiseaseJournal.2010;29(11):999–1003.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
4
2.GlobalPolicyandRegulation
2.1WHOguidelinesforumbilicalcordcare
ThereisacommonmisconceptionthattheWHOguidelinesadvocatefortheexclusiveuseofdrycordcare.Infact,inthe1999WHOdocumententitled“CareoftheUmbilicalCord:AReviewofthe
Evidence”WHOrecommendsthattopicalantimicrobialsbeusedonthestumpaftercuttinginhome
deliveries“…asatemporarymeasure,accordingtoalocalsituation(e.g.,inneonataltetanus‐endemicareasortoreplaceaharmfultraditionalsubstance).”14Additionally,WHOrecommends
thatininstitutionaldeliveries,antimicrobialsmaybeused“accordingtolocalsituation”and
specificallyidentifiesCHXasoneoffiverecommendedantimicrobialagents.
2.2.TheWorldHealthOrganizationModelListofEssentialMedicinesforChildren
The2011WHOModelListofEssentialMedicinesforChildren(EMLc)15includesCHXforumbilical
cordcareundersection15.DISINFECTANTSANDANTISEPTICS,subsection15.1Antiseptics.The
listingisasfollows:
Chlorhexidine
Solution:5%(digluconate);20%(digluconate)(needstobedilutedpriortouseforcord
care).
The17thExpertCommitteeontheSelectionandUseofEssentialMedicinesconvenedbyWHOin2009concludedthatdatafromacommunity‐based,cluster‐randomizedtrialinNepalshoweda
significantreductioninneonatalmortalityafteruseofa4%CHXsolution(7.1%CHXdigluconate)
forumbilicalcordcare.ThiswassufficienttoincludesuchaproductandindicationforuseintheWHOEMLc.Nevertheless,duetotheabsenceofacommerciallyavailable4%CHXproductatthat
time,thisrecommendationoftheexpertreviewcommitteeresultedinlisting20%CHX
(digluconate)withaninstructiontodiluteforumbilicalcordcareuse.Atthetimeofpublicationofthe2009WHOmodellist,PATHandtheUSAgencyforInternationalDevelopmentsubmittedajoint
lettertotheWHOexpertreviewcommitteestatingthattheindicationwasnotclearandsuggesting
thatitshouldberevisedtostipulateuseof4%CHXforumbilicalcordcare.WHOrespondedby
sayingthatsuchanissuewouldbetakenupduringthenextreviewoftheEMLcin2010–2011.
Clarityontheuseof4%CHXforumbilicalcordcareiscriticalbecausethereisaverycommon
confusionaroundtheconcentrationsoffreechlorhexidineversuschlorhexidinedigluconate.The
conversionbetweenthetwoislistedinTable3below.Itisworthnotingthatthecurrentlistingof5%CHXdigluconatewoulddeliverapproximately2.8%freeCHX,alevellowerthanwhatwasused
14WorldHealthOrganization.CareoftheUmbilicalCord:AReviewoftheEvidence.Geneva:WHO/RHT/MSM;1999.Availableat:https://apps.who.int/rht/documents/MSM98‐4/MSM‐98‐4.htm.AccessedFebruary10,2012.15WorldHealthOrganization.ModelListofEssentialMedicinesforChildren.3rdlist.Geneva:WHO;March2011.Availableat:http://whqlibdoc.who.int/hq/2011/a95054_eng.pdf.AccessedFebruary10,2012.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
5
intheRCTsforumbilicalcordcare.Ifoneisnotawareofthisdifference,onemaysee5%CHXontheEMLcandincorrectlythinkthatonedoesnothavetogothroughanyin‐countryregulatory
processbecausethe5%ishigherthanthe4%forumbilicalcordcare.
Table 3. Free chlorhexidine versus chlorhexidine digluconate.
Chlorhexidine Digluconate Free Chlorhexidine Notes
20% 11.3% Concentration listed on the EMLc
7.1% 4.0% Concentration used in the RCTs in five countries
5% 2.8% Concentration listed on the EMLc
Toavoidthisconfusion,theEMLcshouldstate:
Chlorhexidine
7.1%chlorhexidinedigluconatesolutionorgel,delivering4%chlorhexidineforumbilical
cordcare.
In2010,PATHsubmittedanamendmentwithadditionaldatatotheWHOexpertreviewcommittee
tosupporttheclarificationoftheindicationforuseofCHXforumbilicalcordcarebystipulatinguse
of4%CHXineithergeloraqueoussolution.TheexpertcommitteedecidedtomaintainthepreviouslistingforCHXuntilaproductofthestrengthandformulationusedinthetrialsis
commerciallyavailable(i.e.,availabilityoftheproductontheopenmarket,notjustfortrial
purposes).Specifically,TheUneditedReportof18thExpertCommitteeontheSelectionandUseof
EssentialMedicines(21to25March,2011)notedthat:
“Theproblemremainsthat,asin2009,acommerciallyavailablepreparationof7.1%chlorhexidinedigluconatesolutionorgel(delivering4%chlorhexidine)isnotyetavailable.
Whilethe20%requiresdilutionandmanipulationandisclearlynotoptimal,untilthereis
acommerciallyavailableproductofthestrengthandformulationusedinthetrials,thecurrentlistingcannotbeamended.However,theCommitteenotedthatanoptimized
4%chlorhexidineislistedasoneofthepriorityproductsfordevelopmentbyWHOonthe
PriorityMedicineslistformaternalandchildhealthandthereforeflaggeditasa‘missing’
essentialmedicine,giventheimpactonmortalitysuggestedinthetrials.”
Today,thereisonecompany,LomusPharmaceuticalsPvt.Ltd(Kathmandu,Nepal),producinga4%
CHXproductcommercially.Ithasbeeninuseinfourdistricts(andalargerprocurementis
currentlyunderway),butcouldbemadeavailableforsaleanywhereinthecountryandforexport.LomushasregisteredtheproductwiththeDepartmentofDrugsAdministrationinNepal.
Additionally,4%CHX(7.1%CHXdigluconate)isonNepal’snationalessentialmedicineslistfor
2011asasolutionorgelforumbilicalcordcare.Thisdatamayhelptoadd4%CHX(7.1%CHX
digluconate)totheWHOEMLc.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
6
3.NationalRegulatoryPolicy
CHXisincludedinsomenationalessentialmedicineslists,butNepalistheonlycountryknowntohaveaddedittotheirnationalessentialmedicineslistata4%concentrationforumbilicalcord
care.Inothercountriesitisnotatthecorrectconcentrationforumbilicalcordcare.Experiencein
BangladeshandNepaltodatedemonstratesthatCHXforumbilicalcordcarehasbeenclassifiedbycountryregulatoryagenciesasamedicine,andtheproductisrequiredtoberegisteredincountry
withtheappropriatedrugauthority.Over‐the‐counterdistributionoftheproductisindependentof
theneedtoregistertheproductasamedicine.
In2011,PATHreviewedvariousglobalregulatorypathwaysforCHXforumbilicalcordcare.
PathwaysinvestigatedincludedUnitedStatesFoodandDrugAdministration(USFDA),EuropeanMedicinesAgency(EMA),WHOprequalificationofmedicines,andacountry‐by‐countryapproach.
TheresultsofthisreviewsuggestthattheEMAprocedure(termedArticle58)mightappeartobe
promisingincertainrespects.Article58wasestablishedin2004tofacilitatedeveloping‐country
registrationofmedicinestopreventortreatdiseasesofmajorpublichealthinterest.
PerArticle58requirements,sincetheCHXproductisasimpleformulation,regulatoryassessment
ofthemanufactureandcontrolofthisdrugproductwouldbeconsideredtobestandard.Results
fromclinicaltrialsinSouthAsiaarealsoavailable;however,certainfactorsmakethisoptionless
thandesirable:
SignificantresourcesarerequiredtocompleteanArticle58applicationandmaintainthe
positivescientificopinionresultingfromsuccessfulsubmission.Itisquestionablewhethersuch
costcouldbejustifiedwhenusingpublicfunds.Also,itmightnotmakesensetomakesuchan
investmentofseveralhundredsofthousandsofdollarswhenrevenuesareexpectedtobelow.
Theholderofthepositiveopinionhassubstantialresponsibilities,includingpost‐opinion
submissionofresultsfromanyongoingandfutureclinicaltrialsandprovisionofadditional
informationontheproduct’sefficacyandsafety.Althoughanonprofitorganizationcanbeanopinionholder,itisquestionablewhetheranonprofitorganizationwouldbewillingtoassume
thosesubstantialresponsibilitiesonanongoingbasis.
Manufacturerswouldneedtoensuremanufactureoftheproductfromcertifiedsourcesof
activeingredientsifthemanufacturersweretopursueArticle58.Thismightincreasecostsand
thereforepricingoftheproduct.
RegistrationoftheCHXproductonacountry‐by‐countrybasiswouldstillneedtobe
undertaken.
Consideringtheabove,acountry‐by‐countryapproachwouldappeartobethebetterapproachto
taketosecureregistrationforaCHXproduct.AnexpertconsultationwithWHOshouldtakeplaceafterpublicationofrecentRCTresultsinBangladeshandPakistan.Favorablefindingsfromthis
consultation,alongwithanupdatedlistingontheEMLc,willlikelyfacilitateregulatoryreviewsat
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
7
thecountryand/orregionallevel.ObtainingWHOprequalificationcouldbeexploredconcurrently
ifthisapproachisdeterminedtobereasonableconsideringtimeandresourcerequirements.
3.1.SouthAsiancountries:Nepal,India,Bangladesh
Country‐levelregulatoryprocessesvaryfromcountrytocountry.Acountry‐levelregistration
processshouldonlybeundertakenwheretheCHXproductinterventionwillberolledoutinthe
samecountry.Thisisthecase,forexample,inNepal,wheretheinterventionhasbeenrecentlyapprovedbytheMinistryofHealthandPopulationandtheproducthasobtainedregistrationin
country.InBangladesh,forexample,registrationwouldbeverystraightforwardtoobtainby
PopularPharmaceuticalLtd,themanufactureroftheproductusedinthemostrecentstudy.However,theywouldneedanincentivetodo(i.e.,assuranceofmarketdemand)thatcouldbe
demonstratedbyanenablingpolicyenvironmentandfirmsupportfortheinterventiononthepart
oftheMinistryofHealthandotherkeystakeholders.WhileIndiamayappeartobeagoodentrypointforproductregistrationintheregion,productregistrationissubjecttoapprovalbytheDrug
ControllerGeneralofIndia,andthedatarequirementsforapprovalareyettobedetermined.
3.2.Africancountries:Zambia,Tanzania,others
GiventhestatusofongoingRCTsinZambiaandTanzania,nationalregulatoryauthoritieswilllikely
bemostinterestedinproductregistrationaftertheRCTsarecompleted.IfRCTresultsarefavorable,andcorollaryministryofhealthpolicyandstakeholdersaresupportiveofthe
intervention,itispossiblethatthattheproductcouldberegisteredrelativelyeasily.Regulatory
approvalobtainedinonecountrymaybeappliedtoothercountriestherebyfacilitatingmarketclearanceinsub‐SaharanAfrica.Somecountriesintheregion,however,mayprefertohavemore
localizeddataabouttheinterventionbeforegivingmarketclearancefortheCHXproduct.
4.FinancingChlorhexidine
4.1Costandcost‐effectivenessdata
Assumingthateverybabyrequires3gofa4%CHXproduct(asisprovidedintheNepalprograms),
afinishedpharmaceuticalproductcostslessthan$0.005inrawmaterialsandanadditional$0.09‐
0.15inpackagingcosts.PreliminaryestimatesofcosteffectivenessfromacosteffectivenessstudyinSylhet,Bangladesh,suggestthatwhenumbilicalcordcleansingwitha4%CHXproductisadded
toaplatformofcommunity‐basedmaternalandnewbornhealthservices,themeanincremental
costperdisability‐adjustedlifeyear(DALY)avertedislessthanUS$10.00.16,17,18
16NOTE:Costswerederivedincrementallyontopofexistingplatformsofmaternalandnewbornhealthservices,fromaprogramperspectiveandincludedoperationalandsupportcostsaswellascostsassociatedwithproductdeliverythroughvillagehealthworkersandsupervisingcommunityhealthworkers.Costsmaybehigherorlowerinnon‐effectivenesstrialsettings,and/orwhereanexistingplatformandinfrastructureforcommunity‐basedmaternalandnewbornhealthdoesnotexist.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
8
4.2CurrentuseinNepal
CHXforumbilicalcordcareiscurrentlyusedinfourdistrictsofNepal(Parsa,Banke,Jumla,andBajhang).Todate,theprogramshavebeendonorfinanced,effectivelyworkingas“atscale”
demonstrations.Giventhestrongresultsinthesepilots,theGovernmentofNepalisintheprocess
ofcreatingabudgettoprocureCHXfromalocalmanufacturer(LomusPharmaceuticals)fordistributionprimarilyviaFemaleCommunityHealthVolunteers(FCHV).Donorfundingislikelyto
supportcontinuedprocurementfortheFCHVsuntilgovernmentfundingisavailable(expectedin
2013).TheLomusproductislistedwithamaximumretailpriceof18NepaliRupees(approximatelyUS$0.22)forasingleapplication,buttheactualtransferpricebetweenLomusand
theGovernmentofNepalisnotknownatthistime.Additionally,Lomushopestoselltheproduct
viaitstraditionalretailchannels.
4.3Potentialforpublicprocurement
ThelowcostofCHX—andparticularlythelowcostperlifesaved—makesitamongthe“bestbuys”inneonatalhealthandanexcellentcandidateforpublicprocurementincountrieswithhigh
mortalityduetoneonatalinfection.
4.4Potentialforprivatepurchase
Themajorityofhealthcareexpenditureinmuchofthedevelopingworldisprivateexpenditure,
andthecountrieswhereneonatesdiefrominfectionsarenoexception.Table4belowshows
privateexpenditureonhealthasapercentageoftotalexpenditureonhealthforselectedcountries.
17NOTE:ThisestimatefallsbetweenchildhoodimmunizationsforTB,DPT,polioandmeasles($8.00);andothercommonprogramslikeHIV/AIDSservicesvoluntarytestingandcounseling,ARVstopreventverticaltransmission,etc.($68);surgicalservicesandemergencycare($109);communitycasemanagementofchildhoodpneumonia($146);andmaternalandnewborncare,inclusiveofincreasedprimarycare,targetednewborncare,andimprovedemergencyandnewborncare($261).18MusgroveP,Fox‐RushbyJ.Cost‐effectivenessanalysisforprioritysetting.In:JamisonD,BremanJG,MeashamAR,etal.,eds.DiseaseControlPrioritiesinDevelopingCountries(2ndedition).Washington,DC:TheWorldBankandOxfordUniversityPress;2006.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
9
Table 4. Private expenditure on health as a percentage of total expenditure on health.
Country Annual Estimated Neonatal Deaths from Infection*†
% Private Expenditure‡
India 405,848 68%
Nigeria 150,459 63%
Pakistan 119,122 68%
DR Congo 109,091 46%
Ethiopia 66,159 48%
Bangladesh 45,722 69%
Tanzania 32,037 28%
Zambia 14,461 38%
Nepal 9,004 62%
*Source: Liu L, Johnson HL, Cousens S, et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet. 2012;379:2151–2161. †Partnership for Maternal, Newborn & Child Health. ‡Source: WHO; 2008.
Private‐sectorsalesareoftenanimportantcomplementtopublic‐sectorprovision.Asarelativelylow‐cost,easy‐to‐useproductwithalongshelflife,CHXmaybeparticularlywellsuitedtoprivate‐
sectorsales.Dataonwillingnesstopay(WTP)specificallyforCHXisscarce,butthedatainTable5
providessomeindicationforSouthAsia.
Table 5. Willingness to pay in South Asia.
Country WTP Range in US$ Type Source Year
Nepal $0.05–$0.06 TBAs’ stated WTP Tuladhar et al. 2007
Bangladesh $0.42–$0.70 Actual purchases Winch et al. 2009
Bangladesh $0.21–$0.85 Mothers’ stated WTP ICDDR,B 2010
India (urban) $0.50–$0.70 Mothers’ stated WTP Synovate 2011
India (rural) $0.30–$0.40 Mothers’ stated WTP Synovate 2011
TheseWTPfiguresare50%to200%greaterthantheprojectedwholesalecostofCHX,leaving
potentialretailmarginsforprivate‐sectordelivery.
5.User‐CenteredProductDesign:WhatWomenWant
Umbilicalcordcareisaculturallymediatedpracticewhereinconsumerpreferencesareakeydriverofwhatproductsareultimatelyadoptedanddiscarded.Inmanycommunities,thereisa
deepdesiretodressthecordwithsomething,butpracticesvarywidely.Thoughtfulcombinationof
formulationandpackagingmayincreasetheproduct’sadoptioninaspecificcommunity.
5.1Formulationconsiderations
BasedontheclinicaltrialsconductedinSouthAsiancountriesandasubsequenttesttoestablishnon‐inferiorityofthe4%CHXgel,theproductcanbeformulatedintoeitheraqueoussolution
(liquid)orgel.Table6illustratesseveraleffortstoassessuserpreferencesinregionsofinterest.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
10
Table 6. Efforts to understand user preferences.
Country Preference Notes
Bangladesh Gel
In 2010, PATH and ICDDR,B assessed the demand for the product among potential users (women who were currently pregnant or had a child over the last six months, and their husbands). The study indicated that when shown concept cards depicting a gel formulation and an aqueous solution 63% of the respondents (1,109 people) preferred gel formulation over aqueous solution. However, the price they were willing to pay did not differ significantly between the two formulation concepts.
Nepal Gel
The randomized non‐inferiority trial conducted in Nepal in 2009 included questions regarding user preference of dosage forms. Of the 30 subjects originally given gel (excluding those woman reporting a negative experience), 2 preferred aqueous. However, over half of those using aqueous indicated they would have preferred gel (17/30), believing that it would stay in place more easily and be longer lasting.
India Gel
In 2011, a consumer research group polled mothers, mothers‐in‐law, and caregivers in Uttar Pradesh for product preferences using an unlabeled tube of Lomus 4% gel and an unlabeled 70‐ml bottle of aqueous. The majority of respondents across all participant groups preferred the gel.
Tanzania Liquid
The Pemba study looked at consumer preferences for aqueous formulations in 10‐ml and 100‐ml bottles as well as tubes of gel formulations. 44.6% of mothers preferred the 10‐ml bottle, 33.9% preferred the tube of gel, and 21.5% preferred the 100‐ml bottle.
Zambia Liquid
The Zambia study looked at 10‐ml and 100‐ml liquid presentations as well as tubes that would contain a gel formulation. Unfortunately, the tubes did not contain CHX gel (a major limitation of the study) and were therefore not popular among respondents.
5.2Packagingconsiderations
Primarycontainerforliquid.BoththeNepalandBangladeshtrialsusedawhiteBostonround
bottleastheprimarycontainer(aBostonroundbottlecanbeseeninFigure1below)andacottonballastheapplicator.IntheoperationsresearchconductedinBangladesh,awhitehigh‐density
polyethylene(HDPE)bottlewithanozzlewasselectedasthematerialfortheprimarycontainerfor
the4%CHXaqueoussolutionbecause:1)HDPEisthemostcommonplasticmaterialforCHXdigluconate‐baseddrugs,2)thecolorwhiteprotectsCHXdigluconatefromsunlight,and3)the
nozzleminimizesoccasionsinwhichusersdirectlycontacttheumbilicalcord.Theresultsfromthe
followingtwostudiesledtoselectingthewhiteHDPEbottlewithanozzle:
PATHconductedaproductattributestudyin2008.Thisstudycomparedthesethreeoptions:1)whiteHDPEbottlewithanozzle,2)whiteBostonroundbottle,and3)amberglassbottle.
ResultsindicatedthatthewhiteHDPEbottlewithanozzlewastheoptionmostpreferredby
usersandserviceproviders(141outof165respondents[or85.5%]chosethisoption).
ThepretestingthattheProjahnmostudygroupconductedwithhealthcounselorsin2008indicatedthatthe4%CHXaqueoussolutionwasproperlyappliedtotheumbilicalcordwitha
nozzlebottleandconfirmedtheirdecisiontoselectanozzlebottleastheprimarycontainer.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
11
Primarycontainerforgel.InNepal,apreprintedaluminumtube(acommonprimarycontainerforsemi‐soliddrugproducts)wasselectedforthe4%CHXgelformulation.Whileothertypesof
primarycontainerscouldbeapplicablefor4%CHXgelincludingsachetsandplastictubes,
consumerresearchsuggestedthatmothersandcaregiversassociatedthistypeofpackagingwith
pharmaceuticalproductsandgoodhealth.
Secondarypackaging.TheoperationsresearchinBangladeshdidnotutilizeasecondarypackage.
TheinformationrequiredbythedrugauthorityinBangladeshwasprintedonalabeldesignedby
themanufacturer,whichwasattachedtotheprimarycontainer.PictorialinstructionsforuseweredevelopedthroughcollaborationamongProjahnmostudygroupmembers,PATH,andPopular
Pharmaceuticalsinordertosupplementtheinstructions‐for‐usetextprintedonthelabel.These
supplementalpictorialinstructionswerethenattachedtothecontainerwitharubberband.InNepal,thealuminumtubecontaining4%CHXgelwaspackagedinasmallpaperboxpreprinted
withlabelinginformation.
PleaseseeFigure1belowforpackagingexamplesandFigure2forexamplesofinstructionsforuse.
Figure 1. Liquid primary packaging as produced by a manufacturer in Bangladesh for study purposes only (left); primary and secondary packaging of gel product as produced by Lomus in Nepal (right).
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
12
Figure 2. Pictorial instructions for use used in Nepal (left) and Bangladesh (right).
5.3Bundlingwithcleandeliverykits
SomehaveadvocatedthebundlingofaCHXproductwithcleandeliverykits(CDK)asawaytoincreaseavailabilityanduseoftheproduct.Todate,suchbundlinghasnotoccurred.InNepal,CHX
willnotbebundledwiththecleandeliverykitcurrentlybeingdistributedbyContraceptiveSales
Company.InBangladesh,physicallybundlinga4%CHXproductwithaCDK(puttingCHXandCDKintothesamepackage)willlikelyrequireadditionalregulatoryapprovalsinceCHXisa
pharmaceuticalproductandtheothercontentsoftheCDKarenot.Insteadofbundlingthetwo
products,nongovernmentalorganizationsthatdistributeCDKsmayusetheirowndepotholdersorcommunityworkerstopresenttheCHXandCDKconcurrentlyandexplainhowusingbothcouldbe
beneficial.
6.Manufacturing
6.1Theglobalchlorhexidineindustry
Chlorhexidinedigluconateisbroadlyavailablearoundtheworldbothinitsbulkdrugformof20%
chlorhexidinedigluconateandinmyriadfinishedproducts.InIndiaalonethereareover70brands
offinishedCHXproductsforsalefromover60differentcompanies.Theproducthasapplicationsasbothapreservativeandactiveingredientacrossabroadrangeofveterinary,dental,andother
healthcareapplications,assummarizedinTable7.
Table 7. Various uses for chlorhexidine.
Application Concentration of chlorhexidine digluconate
Veterinary 20%
Mouthwashes, toothpastes, oral rinses 0.12%–0.2%
Skin prep for surgery, procedural hand washing 0.5%–4%
Wound treatment 4%
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
13
Thedrugmonographof20%chlorhexidinedigluconateislistedinUnitesStates,UnitesKingdom,European,andJapanesepharmacopeias.Therearealsomorethan50vendorsofbulk20%
chlorhexidinedigluconateconcentrate,severalofwhichhaveDrugMasterFileswithUSFDA.The
bulkproductistypicallysoldin200kgdrums,andtherearesufficientbufferstocksoneveryinhabitedcontinent.CommoditypricingforthisproductisoftenintherangeofUS$4.50per
kilogram.
Assumingthateverybabyrequires3gofa4%CHXproduct(asisprovidedintheNepalprograms),
thetotalrequirementof20%CHXdigluconatewouldbejustover1,000Lpermillionchildrentreated,orjustfivedrumsofactivepharmaceuticalingredientpermillionnewborns.Globalsupply
oftheactivepharmaceuticalingredient,therefore,isunlikelytobeaconcern.
6.2Thefinishedproductmanufacturer’sbusinesscase
CHXforumbilicalcordcareisalow‐volume,low‐marginproductwithfewbarrierstoentry.Ifthe
productisusedinallbirthsinagivenregion,annualsaleswouldcorrelatewithcrudebirthratesof30–50birthsperthousandinhighfertilityareas.Thisisarelativelylowsalesvolumewhen
comparedwithotherpharmaceuticalmanufacturingopportunitiesformorecommonlyusedover‐
the‐counterproducts.MarginsforCHXarelikelytobesimilarlylacklusterforaproductwhichisinthepublicdomain(notpatentable)andquitesimpletomake.Thecombinationofthesefactors
meansthatlargepharmaceuticalcompaniesareunlikelytotakeaninterestinindependent
manufactureanddistributionofCHXforumbilicalcordcare.Institutionalbuyersandlargevolumeordersaremorelikelytoattracttheattentionofpotentialmanufacturers,similartowhattookplace
withLomusPharmaceuticalsinNepal.
6.3Localversuscentralizedmanufacturingoffinishedproducts
ThereareseveralreasonstoconsiderlocalmanufacturingofaCHXproductforumbilicalcordcare.
Capitalcostsofmanufacturingarerelativelylow,andstandardequipmentfoundinmostpharmaceuticalcompanieswouldbeused.Themanufacturingprocessissimpleandrobustenough
tobeeasilyreplicated.Bulkchlorhexidinedigluconatecanbepurchasedin200‐kgdrumsoreven
20‐kgpails.SmallamountsofthebulkdrugyieldalargevolumeoffinishedCHXproductforumbilicalcordcare.Forexample,a20‐kgpailofchlorhexidinedigluconatecanserveabout20,000
newbornsatthedoseanddurationusedinNepal.Localmanufacturingcanalsosimplifylocal
regulationwhereindigenouspharmaceuticalcompaniesmaybebetterequippedthanforeignfirms
tonavigateanapprovalprocess.
Centralmanufacturingalsohassomebenefits.Asingle,centralmanufacturermaybemore
compelledbythebusinesscaseofmanufacturingaveryhigh‐volume,low‐costproduct.Andshould
therebeapooledprocurement,acentralizedmanufacturerwouldalsosimplifylogisticsandqualitycontrol.Theshelflifeat40°Cwith75%relativehumidity(RH)issufficienttowithstand
warehousingandshippinginmostclimates.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
14
Ultimately,thechoiceoflocalversuscentralmanufacturingshouldbemadeforbusinessreasons,dependingonwhattypeofmanufacturerisabletoofferthemostcompetitivepriceontheshortest
timeline.
6.4Formulationdetails
CHXforumbilicalcordcaremaybeformulatedasatopicalgelorliquid,whichhaveverysimilar
manufacturingprocesses,asdiagrammedbelowinFigure3—theonlydifferencebeingtheaddition
ofguargum(boxwithdottedlines)tothickentheproductintoagelifdesired.
Figure 3. Potential manufacturing processes.
SomemanufacturershavechosentoaddsmallamountsofbenzalkoniumchloridetoCHXproducts
asapreservative,butstabilitytestsconductedbyPATHhaveshownthatthismaynotbeacrucial
addition.Additionally,somemanufacturershaveaddedperfumeandcoloringasperconsumer
preferences.
Overall,theinputsforCHXmanufacturingareinexpensive.Onerepresentativeformulationforgel
isdetailedbelowinTable8.
Table 8. A representative formulation for chlorhexidine gel.
Formula Component Formulation Cost in US$ per 3 g Source
20% CHX gluconate/digluconate, BP* 7.10% $0.004795 Viporchemicals.com
50% benzalkonium chloride (optional) 0.10% $0.000000 Alibaba.com
Guar gum, NF† 1% $0.000060 Alibaba.com
Sodium hydroxide, NF pH to 6.0 $0.000009 Alibaba.com
Purified water, USP‡ Remainder $0.000001 (estimated water tariffs)
Total $0.004865
*British Pharmacopoeia. †National formulary. ‡United States Pharmacopeia.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
15
6.5Packagingdetails
PackagingisresponsibleformostofaCHXproduct’scost.Forliquidformulations,bottlesorsachetsmaybeused.DropperbottleshavebeenusedinalloftheRCTstodateandtypicallycost
aroundUS$0.15eachincludingfilling.Sachetsmaypackmoretightlyandshipmoreeasilyand
oftenhavepackingandfillingcostsintherangeofUS$0.01inIndia.
TheonlyCHXproductpackagedforretailsalesismadebyLomusPharmaceuticalsinKathmandu.Basedonuserfeedback,theirpackagingincludesatubeforthegel,afullcolorinstructional
packageinsert,andanouterbox(pleaserefertoFigures1and2above),totalingapproximately
US$0.09(Table9).
Table 9. Packaging costs example.
Packaging Component US$ per Unit Source
Preprinted collapsible aluminum tube $0.04 Perfect Tubes Pvt
Printed paperboard box $0.04 Lomus Pharmaceuticals
Printed color package insert <$0.01 Lomus Pharmaceuticals
Total $0.09
7.SupplyChainManagement
7.1Shippingconsiderations
Temperature,pHlevel,andexposuretosunlightadverselyaffectthestabilityofCHXdigluconate,
theactiveingredientof4%CHXforumbilicalcordcare.WhenCHXdigluconateiskeptundersuboptimalconditions,itdegradestop‐chloroanilineanditspurityiscompromised.Accordingto
theUSPharmacopeia,a20%aqueoussolutionofCHXdigluconateshouldmaintainitspHrange
between5.5and7.0.Italsostatesthat20%CHXdigluconateshouldbepreservedinatightcontaineratroomtemperatureandbeprotectedfromlight.Theserequirementsshouldalsobe
maintainedforshippingandstoring4%CHXforumbilicalcordcare.
Inaddition,selectinganappropriateprimarycontainerisimportantinordernotonlytomaintain
thequalityoftheproductbuttominimizeitsshippingcost.ThequalityoftheCHXdigluconatewouldbebestpreservedwithneutralglassorpolypropylene.Also,transparentprimarycontainers
shouldbeavoidedinordertoprotectCHXdigluconatefromlight.Acommonlyusedprimary
containerforcommerciallyavailableCHXdigluconate‐basedproductsisHDPEsinceitislighterthanglass(thusreducesshippingcost)anditmaintainsproductquality.Asanexample,Medichem
S.A.(Barcelona,Spain),oneofthe20%CHXdigluconatemanufacturerslistedintheDrugMaster
FilesubmittedtotheUSFDA,providesitsproductina200‐kgHDPEdrum.Inanycase,manufacturersshouldperformcompatibilitytestsaccordingtolocalregulationsinordertoconfirm
theappropriatenessoftheselectedprimarycontainers.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
16
7.2Shelflife
Adrugproduct’sshelflifeisthelengthoftimeduringwhichitisconsideredsuitableforsale,use,orconsumption.Shelflifeisaffectedbytemperature,humidity,andlight.Forthisreason,accordingto
InternationalConferenceonHarmonizationofTechnicalRequirementsforRegistrationof
PharmaceuticalsforHumanUse(ICH),eachcountryisclassifiedintooneoffourclimaticzoneswithdefinedstorageconditionsfordrugsubstancesandproducts(seetablebelow).Basedonthis
classification,inSouthAsia,BangladeshandIndiaarebothassignedtoZoneIV,whereasNepalis
assignedtoZoneII.InAfrica,TanzaniaisassignedtoZoneIVwhereasZambiaisassignedtoZoneII.
Table 10. Climatic zones for shelf life.
Climatic Zone Definition Storage Condition
I Temperate climate 21°C/45% RH
II Subtropical and Mediterranean climates 25°C/60% RH
III Hot, dry climate 30°C/35% RH
IV Hot, humid climate 30°C/70% RH
Source: ICH Q1F Guideline, “Stability Data Package for Registration in Climatic Zones III and IV.”
Manufacturersof4%CHXproductsmustperformstabilitytestsusingtheprimarycontainerthat
theyselectedfortheirproductsinordertoestablishtheirproductshelflifeunderthestorageconditionsassignedtothecountryinwhichtheproductswillbedistributedandused.Stabilitytests
canbeperformedusingacceleratedconditions(e.g.,ingeneral,40°C±2°C/75%RH±5%RHfor6
monthsforclimaticzonesIIIandIV).InadditiontothisICHguideline,manufacturersneedtocheckwiththeirlocaldrugregulatoryauthoritytoascertainwhetherthereareanyadditional
requirements.
In2009,PATHcommissionedacontractlaboratoryintheUnitedStatestoperformstabilitytestson
the4%CHXaqueoussolutionandgel.Testingwasconductedunderthefollowingprotocol:
Primarycontainer:4‐mLHDPEbottleandpolypropylenescrewclosure(materialscommonly
usedforcommercialCHX‐basedproducts).
Testingconditions:5°C,25°C/60%RHand40°C/75%RHtoestablish24‐monthstability.
Testedat:0,1,3,and6months.
Testedfor:appearance,pH,potency,andamountofp‐chloroanilinepresent(asubstancethatis
producedwhenCHXisdegraded).
Bothformulationspassedthestabilitytest,andtherewasnosignificantdifferenceinpotency,pH,
orpurity.Thepotencyofthegelformulationtendedtodecrease(althoughitremainedwithintheacceptablerange)probablybecausesufficienthomogeneitywasnotachievedduringlaboratory
testingwithoutaproperhomogenizer.Incommercialproduction,thisisunlikelytobeanissue.
Basedontheseresultsonthestabilityoftheproductinthis6‐monthacceleratedstudy,PATH
estimatesa24‐monthshelflifeatroomtemperatureacrossallclimaticzoneslistedabove.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
17
8.CultivatingDemandfromCaregivers
MostoftherecentworkonCHXforumbilicalcordcare(Nepal,Pakistan,Bangladesh,Zambia,andTanzania)hasfocusedoncommunity‐leveluseoftheproduct.Inthesecontexts,somecaregivers
mayhavefullmedicaltraining,butmostarecommunityhealthworkersorTBAs.Ineachcase,CHX
forumbilicalcordcarehasbeenwellreceivedwhenpresentedbyprogramstaff,withspecific
highlightsinTable11.
Table 11. Caregiver demand.
Location Caregiver Synthesis of comment or direct quotes
Pemba (Tanzania)
Unspecified “We are willing to use it. Mothers can apply if they are trained.” “Most mothers will be willing to use this medicine. They pray for such thing to be introduced in the community as they are very useful.”
Bangladesh TBA TBAs were the single largest source of CHX, even when the product was both given away through government community outreach workers and sold in pharmacies. The TBAs appeared to appreciate the product as a special service they could offer (and potentially resell) to their clientele.
India ASHA* As part of government training, ASHAs are instructed to advocate for dry cord care in Uttar Pradesh. However, they are often frustrated by mothers who insist on dressing the cord in one way or another despite their advice. As dry cord care is unable to displace traditional practices, ASHAs are excited to recommend CHX as a way to finally have something to offer mothers in their communities.
Nepal FCHV FCHWs have enthusiastically embraced the product in the four districts where it is currently used today and have been able to ensure correct usage of CHX in close to 70% of all births in their catchment areas. Training is incorporated into existing FCHV training programs on other maternal and neonatal health topics.
*ASHA: Accredited Social Health Activist.
AcriticalcomponentofcultivatingcaregiverdemandhasbeentrainingcaregiverstounderstandtheCHXproductandadministeritcorrectly.InNepal,FCHVsweretrainedusingdollsmodifiedto
haveumbilicalcordsmadefromballoonsaswellastheinstructionalaidepicturedbelow(Figure
4).Inafollow‐upstudy,FCHVstrainedusingthesetoolswereabletoensurecorrectadministration
ofCHXbyhouseholdcare‐giverstoroughly70%ofthenewbornsintheircatchmentareas.
Figure 4. Instructional aide and correct chlorhexidine application.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
18
9.CultivatingDemandfromConsumers
Discouragingmothersfromputtinganythingonthecordhasbeenapersistentchallengeincommunitiesaroundtheworld.QualitativestudiesinIndia,Nepal,Uganda,Ghana,andMalawi
showthatmothersareoftenhesitanttoleavethecorddryduetoconcernsthatthecordmighttake
longertoseparate,causethebabydiscomfort,orleavethebabyvulnerabletovariousmaladies.Infact,inUttarPradesh,India,despitegovernmentprogramstopromotedrycordcare,83%of
mothersapplysomesubstancetothecord.19FormativeworkinZambiaandPemba(Tanzania)also
showthatmothershaveastrongdesiretoputsomethingontheumbilicalcordstump.
Specificmotivationstodressthestumpvarybyregionandbyindividual,butthemostcommon
reasonsincludeadesiretomakethecordstumpseparatefasterandtopreventinfection.Theactualsubstancesappliedtothestumpvarywidely,sometimesevenbetweenindividualswithinthesame
community,butoftenfallintoafewmaincategories:
Edibleoilsandbuttersincludinggheeandsheabutter,andmustard,palm,peanut,andcoconut
oils(India,Nepal,Bangladesh,Ethiopia,Mozambique,Tanzania,Nigeria,Zambia,andothers
areas).
Medicinalproductsincludingpowders,alcohols,iodine,andantibiotics(India,Ghana,Guinea
Bissau,Malawi,Mozambique,Nigeria,Tanzania,Uganda,Zambia,andotherareas).
Wasteproductsincludinganimalfeces,ash,dust,sand,dirt(India,Nepal,Nigeria,Tanzania,
Zambia,Malawi,Uganda,andotherareas).
Wherestudied,thereappearstobeasignificantlatentdemandforpurpose‐builtumbilicalcordcareproductslikeCHXandoftenawillingnesstodisplaceexistingpracticewithaproduct
specificallypackagedforthispurpose.Mothersinmanycommunitiesaroundtheworldareeager
foraproducttouseincordcareandappearlikelytoadoptCHXoncetheyaremadeawareofits
existence.
10.MonitoringandEvaluation
ThereareseveraldifferentwaystomonitorandevaluatethetransformationofCHXforumbilical
cordcarefrombeinganoverlookedcommoditytostatusasawidelyusedintervention.Anumber
ofmetrics(Table12)maybeusefulinmonitoringthatprogressionandidentifyingwhere
additionalattentionmayberequired.
19VarmaDS,KhanME,HazraA.Increasingpostnatalcareofmothersandnewbornsincludingfollow‐upcordcareandthermalcareinruralUttarPradesh. JournalofFamilyWelfare.2010;56(specialissue):31–41.
C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e
19
Table 12. Monitoring and evaluation metrics.
Supply Metrics Global monthly production volume of a 4% CHX product for neonatal use.
Geographic and demographic reach of manufacturers.
Quality of manufactured product.
Demand Metrics Number of countries recommending CHX for newborn care.
Volume of public tenders for CHX products.
% of public and private facilities with CHX in stock.
% of wholesale and retail pharmacies stocking CHX.
% of caregivers recommending the use of CHX.
% of consumers accepting CHX.
Correct‐Use Metrics
% of babies receiving CHX.
% of above within 2 hours of birth.
% of above where 3 g or more of product were used.
% of above where product was applied to the stump and surrounding areas.
% of mothers who report applying CHX and no other substance to the cord.
Impact Metrics Neonatal mortality rate.
Neonatal mortality from infection.
11.Recommendations
Severalsimpleactivitiescouldincreasetheuptakeandimpactofchlorhexidineforumbilicalcord
carearoundtheworld:
Add4%chlorhexidine(7.1%chlorhexidinedigluconate)forumbilicalcordcaretotheWHO
modellistofessentialmedicinesforchildren.
CorrectthecommonmisconceptionthatWHOadvocatesdrycordcareonly.TheWHOumbilical
cordcareguidelinesrecommendthatantimicrobialsbeused“…asatemporarymeasure,accordingtoalocalsituation(e.g.,inneonataltetanus‐endemicareasortoreplaceaharmful
traditionalsubstance).”TheseexceptionsarerarelycitedindiscussionsofWHO’sdrycordcare
recommendationbutmayapplytoamorethanhalfofallbirthsaroundtheworld.
Fasttrackregistrationof4%chlorhexidine(7.1%chlorhexidinedigluconate)forumbilicalcordcarewithnationalregulatoryauthoritiesandencourageadditionalmanufacturerstoproduce
thedrugwithguaranteedminimumvolumes.
Trainbirthattendantstocorrectlyapplychlorhexidinetotheumbilicalcord,aspartofnewborn
caretrainingprograms.
Allocateresourcestointegratechlorhexidineforumbilicalcordcareintoessentialnewborncareprogramsinordertogeneratesustainabledemandandattractivemanufacturingvolumes
fortheproduct.
Throughtheseactions,wearemuchmorelikelytoseeincreaseduseofthisoverlooked
intervention,therebycontributingtohundredsofthousandsofnewbornlivessavedannually.
Recommended