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This Provisional PDF corresponds to the article as it appeared upon acceptance. Fully formattedPDF and full text (HTML) versions will be made available soon.
Clinical trials to estimate the efficacy of preventive interventions against malariain paediatric populations: a methodological review
Malaria Journal 2009, 8:23 doi:10.1186/1475-2875-8-23
Vasee S Moorthy ([email protected])Zarifah Reed ([email protected])
Peter G Smith ([email protected])
ISSN 1475-2875
Article type Review
Submission date 13 October 2008
Acceptance date 10 February 2009
Publication date 10 February 2009
Article URL http://www.malariajournal.com/content/8/1/23
This peer-reviewed article was published immediately upon acceptance. It can be downloaded,printed and distributed freely for any purposes (see copyright notice below).
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2009 Moorthy et al. , licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Clinicaltrialstoestimatetheefficacyofpreventiveinterventionsagainstmalariainpaediatric
populations:amethodologicalreview
VaseeSMoorthy*1,2
,ZarifahReed2
,PeterGSmith3
1NuffieldDepartmentofClinicalMedicine,JohnRadcliffeHospital,Oxford,OX39DU,UK
2InitiativeforVaccineResearch,WorldHealthOrganization,20AvenueAppia,1211Geneva27,
Switzerland.
3LondonSchoolofHygieneandTropicalMedicine,London,WC1E7HT,UK.
*Correspondingauthor
Emailaddresses:
VaseeMoorthy:[email protected]
ZarifahReed:[email protected]
PeterSmith:[email protected]
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Abstract
Background
Recentyearshaveseenpublicationofaconsiderablenumberofclinicaltrialsofpreventiveinterventions
againstclinicalmalariainchildren.Therehasbeenvariabilityinthespecificationofend-points,case
definitions,analysismethodsandreportingandtherelativelackofstandardizationcomplicatestheability
tomakecomparativeevaluationsbetweentrials.
Methods
ToprepareforaWHOconsultationondesignissuesinmalariavaccinetrials,controlledtrialsof
preventiveinterventionsagainstmalariainchildreninendemiccountrieswereidentifiedinwhichclinical
malaria,ordeath,hadbeenoneofthemainend-points.Trialswereincludedthatevaluatedtheimpactof
vaccines,insecticide-treatedbednets(ITN),intermittentpresumptiveorpreventivetherapyininfants
(IPTi)or,inoneinstance,vitaminAsupplementation.Methodsthathadbeenusedinthesetrialswere
summarizedandcomparedinordertoidentifyissuesthatweredirectlyrelevanttothedesignofmalaria
vaccinetrials.
Results
29controlledtrialsofpreventivemalariainterventionswereidentified,ofwhicheightwerevaccinetrials.
Vaccinetrialsthatweredesignedtodetectaneffectonclinicalmalariaallreportedtheincidencerateof
firstepisodesofclinicalmalariaastheirprimaryendpoint.Onlyonetrialofapreventiveintervention(of
ITN)wasidentifiedthatwasdesignedtodetectaneffectonseveremalaria.Agroupoflargertrialswere
designedtodetectaneffectofimpregnatedbednetsorcurtainsonall-causemortalityastheprimaryend-
point.Keymethodologicalandreportingdifferencesbetweentrialsarenotedinthetext.Twoissueshave
beenidentifiedthatareofsomeconcern.Firstly,thechoiceofprimaryendpointisnotstatedinthe
reportsofanumberofthetrialsand,secondly,therelationshipbetweenpre-specifiedanalysisplansand
trialreportsisrarelymadeclear.
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Conclusions
Thisarticlereportsaninvestigationintothewaysinwhichtrialdesignandreportingcouldbeimproved
andstandardizedtoenablecomparativeevaluationoftherelativemeritsofmalariacontrolmeasures,and
specificallywithrespecttothedesignofmalariavaccinetrials.Theneedforstandardizationofclinical
trialdesign,conduct,analysisandreportinghasbeenalsoaffirmedasapriorityareabytheMalaria
VaccineTechnologyRoadmap.
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Background
Thedevelopmentanddeploymentofnewandimprovedinterventionmethodsformalariacontrolshows
promisingsignsofreducingsignificantlytheglobalburdenofmalaria.However,thesearchformore
effectivecontrolmethodsstillhasveryhighpriority.Controlledtrialsremainessentialfortherigorous
assessmentofthepotentialimpactofnewtoolsandstrategiestoreducemorbidityandmortalitycaused
bymalaria.Inrecentyears,therehavebeenaconsiderablenumberofrandomizedcontrolledtrialsof
newmalariainterventionsdirectedatchildren,includingtrialsevaluatingcandidatemalariavaccines,
insecticide-treatedbednets(ITN)andintermittentpresumptiveorpreventivetherapyininfants(IPTi).
Theappropriatechoicesoftheprimaryend-pointsinsuchtrialsandthemeasurementmethodsare
prerequisitesfortheproperevaluationoftheinterventions.Theend-pointsandmeasurementmethods
mustallowcomparabilityoftheperformanceofthesameinterventionindifferentlocationsandage
groupsandovertimeatthesamelocation.Inaddition,thecomparabilityofperformanceofalternate
controlmeasures,orcombinationsofmeasures,reliesonstandardizedmethodsofassessment.
ToprepareforaWorldHealthOrganization(WHO)consultationondesignissuesinmalariavaccine
trials,themethodsthathavebeenusedinreportedmalariapreventiveinterventiontrialstoestimate
efficacyagainstclinicalmalariaandrelatedend-pointswerereviewedandthestrengthsandweaknesses
ofthedifferentapproachesweresummarized.Theaimistoprovidearesourceforthoseplanningclinical
trialsofpreventivemalariainterventions.Thetargetaudienceisclinicaltrialists,statisticiansandother
technicalpersonnel.Acompanionpaper,resultingfromaWHOconsultationontheissues,wasdirected
atpolicymakers,fundersandregulators[1].
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Methods
Identificationofstudies
Reportsoftrialspublishedbetween1990and2007evaluatingtheimpactofpreventivemalaria
interventionswereidentified(specificallyvaccines,impregnatedbednetsandIPTi).Trialreportswere
foundprimarilythroughPubMeddatabasesearches.Papersweresoughtusingthefollowingsearchterms:
malariavaccin*,malariavaccines[MeSH],(malariaorinsecticide-treatedorimpregnatedorpyreth*or
deltamethr*)and(bednetorbednetormosquitonetorcurtain),malariaipti,malariaintermittenttherapy
infants,malariapresumptivetherapyinfants,malariapreventivetherapyinfants,malariapreventive
clinicaltrial.Furthertrialswereidentifiedthroughthereferencesofretrievedarticles.Inaddition,
investigatorsresponsibleforthedesignandanalysisofclinicaltrialsofpreventiveinterventionsagainst
malariawereinterviewedaspartofaWHOconsultationprocessondesignofphase3trialsofmalaria
vaccines.Eachintervieweewasaskedtoidentifyfurthereligiblestudies.Dataontrialmethodsand
reportingforeachstudywereextractedintotablesandaresummarized[seeadditionalfile1].
Eligibilitycriteria
Paperswereincludediftheyreportedrandomizedcontrolledtrialsofpreventivemalariainterventions
withaprimaryorsecondaryobjectivestatedastheestimationofefficacyagainstclinicalmalaria,severe
malariaorall-causemortality.Trialswereexcluded,tocoincidewiththeintendedscopeofthereview,if
theywereconductedinadultpopulationsorinareasofunstablemalariatransmission(i.e.annual
entomologicalinoculationrate
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causemortality.Sixtrials,allofinsecticide-treatedbednetsorcurtains,wereclusterrandomized.The
other23wereindividuallyrandomized.
Choiceoftheprimaryend-point
Thetrialscouldbeclassifiedbroadlyintotwogroups.Thelargestgroupconsistedoftrialsdesigned
primarilytodetectaneffectonclinicalmalaria.Insomeofthesebothclinicalmalariaandanaemiaare
describedasefficacymeasuresinthesametrial.Inseveraltrials,itwasnotpossibletoidentifywhethera
singleprimaryend-pointhadbeenspecifiedamongstseveralend-pointsthatwereostensiblyreportedas
co-primaries.
Theothergroupoftrials,allofITNs,werethosedesignedtodetectaneffectonall-causemortality.
Severemalariawasaprimaryoutcomemeasureinonlyonetrial[2].
Clinicalmalariaasaprimaryend-point
Allmalariavaccinetrials[3-8]andseveraltrialsofIPTi[9-15],whosestatedmainobjectivewasthe
estimationofefficacyagainstclinicalmalaria,hadastheirprimaryend-pointtheincidencerateofthe
firstepisodeofmalaria(timetofirstoronlyepisodeofmalaria).Forthisend-point,followingentryinto
thetrial,onlythefirstepisodeofclinicalmalariaforeachchildcontributestowardsthecalculationofthe
malariaincidencerate.Episodesofthediseaseafterthefirstareignored.Eachchildcontributesavariable
amountoftimeatrisktothedenominatorfortheratecalculation,fromthebeginningoftheefficacy
follow-upperiod(i.e.fromfirstvaccinationforintentiontotreatanalysesandgenerally14daysfrom
finalvaccinationforaccordingtoprotocolanalyses)untiltheonsetofthefirstepisodeofmalariaorthe
endofthefollow-upperiod(whicheveristheshorter).Thepointestimateofefficacyiscalculatedas1-
(incidencerateratio)orbyusingCoxproportionalhazardsregressionmodelsorPoissonregression
models,ifadjustmentforotherfactorsisnecessary.Theuseofsuchtime-to-first-eventanalyseshas
beencommoninevaluatingpreventiveinterventionsagainstmalaria,unlikeinsomestudiesofother
infectiousdiseases[16-19].Methodssuchasthesethatallowvariablefollow-uptimebetweenindividuals
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tobetakenintoaccountaregenerallyacceptedtobepreferableforfieldefficacytrials.Asimple
comparisonoftheratioofproportionsinfectedremainsthemethodofchoiceforartificialchallengetrials;
hereequalfollow-uptimeforeachindividualisareasonableassumption.However,theutilityoftime-
to-first-eventanalysesforpublichealthpolicymakershasbeenquestionedasitisarguedthatitdoesnot
measuretheoverallburdenofmalaria,whichincludessecondandsubsequentepisodesinthesame
individual.
Analternativeend-pointfortrialsdesignedtoexaminetheoverallimpactagainstclinicalmalariaisthe
rateofallepisodesofmalaria.Onlyonetrialwasidentifiedreportingmultipleepisodesofmalariaasits
primaryend-point[20].Forthisend-point,thetotalnumberofmalariaepisodesarecounted,including
multipleepisodesinthesamechild,usingarulefortheminimumnumberofdaysbetweenepisodesto
distinguishanewepisodefromacontinuationofthepreviousone(usually28daysbutdependenton
thechemotherapyused).Insometrialsmolecularmarkershavealsobeenusedtodistinguishrecurrences
fromnewinfections.Thisend-pointmaybeofmorerelevancetopublichealththanonebaseduponthe
firstoronlyepisodeofclinicalmalaria.However,theanalysisofdataincludingmultipleepisodesinthe
samechildisnotstraightforwardasmultipleepisodesarenotindependentevents.Thatis,onceachild
hashadoneepisode,thechildismorelikelytohaveanotherepisode,foravarietyofreasons,thanachild
whohasneverhadanepisode.Thus,attacksofmalariatendtoclusterwithinindividuals.Complex
modelsareneededtoanalysethesesortsofdata,onwhichthereisstillnotaconsensusandonwhich
furthermethodologicalresearchisrequired.Todate,uneaseaboutthisissueseemstohaveinhibitedthe
useofthisasaprimaryend-pointinmosttrials.ArecentWHOconsultationhighlightedtheneedforan
explanatorydocument,outliningthemeritsanddisadvantagesofthedifferentapproachestomeasurement
ofefficacyagainstclinicalmalariainpreventiveinterventiontrials[21].Draftingofsuchadocumentis
underway.
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Whatisclinicalmalaria?Definingwhatconstitutesanepisodeofclinicalmalariaisnot
straightforwardinareasinwhichthediseaseishighlyendemic.Insuchareas,atanyonetime,a
significantproportionofchildreninacommunitymayhavemalariaparasitesintheirblood.Manywill
beasymptomaticandotherswillhavesymptomsconsistentwithmalaria.Insomeofthislattergroupthe
symptomsmaybedirectlyattributabletomalariabut,becausemalariasymptomsarenotspecifictothe
illness,inothersthesymptomsmaybeduetoanotherconditionandthemalariaparasitesintheirblood
aremerelycoincidental.Ingeneral,thehigherthebloodparasiteload,themorelikelyitisthatthe
symptomsareduetomalaria.Thus,inpreventivetrials,itiscommonpracticetodefineclinicalmalariaas
beingpresentinthosewhohavesymptomsandsignsconsistentwithmalariaandwhoalsohaveadensity
ofparasitesintheirbloodgreaterthansomespecifiedlevel.Choiceoftheappropriateminimalparasite
densitylevel(cut-off)fordefiningmalariawilldependupontheendemicityofmalariainthestudyarea.
Forexample,inareaswheremalariaisrelativelyuncommon,thefindingofanymalariaparasitesinthe
bloodofsomeonepresentingtoahealthfacilitywithfeverprovidesasensitiveandspecificdiagnosisof
thedisease.Formalariaendemicareas,Smithetal[22]devisedamethodforcalculatingthesensitivities,
specificitiesandmalariaattributablefractionofdifferentparasitedensitycut-offs,usingbaselinedataon
theprevalenceofdifferentlevelsofparasitedensitymeasuredinchildreninthecommunitynot
presentingwithmalariasymptoms.Tochoosetheappropriatecut-offlevelinaspecificinterventiontrial,
itisimportantthatthedatausedforderivingthislevelarefromthesameepidemiologicalsettingasthe
interventiontrial(includingage,transmissionintensity,healthcarefacilitiesandinteractionwithstudy
staff).Thisisoftennotspecifiedinthereportsoftrials.
Inrecentmalariavaccinetrialsinchildren,efficacyestimatesusingdifferentparasitedensitycut-offs,in
thesametrial,havebeenpresented.Casedefinitionswithlowerspecificity(lowerparasitecut-offlevels)
shouldtheoreticallyyieldlowerpointestimatesofefficacy.Curiously,thisexpectedeffecthasnotbeen
seengenerallyinthetrialsreviewed.Furtherresearchintothisissueiswarranted.Also,itwouldaid
interpretationifthesensitivitiesandspecificitiesofthevariouscasedefinitionsandparasitedensitycut-
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offsused,asderivedbytheSmithetalmethod,werepresentedinpublicationsofinterventiontrials.This
hasgenerallynotbeendone.
AdifferentapproachtodefiningclinicalmalariawasusedinanITNtrialperformedinCtedIvoire[23].
Inthistrial,eachparticipantwasregularlytestedforthelevelofmalariaparasitesintheirblood.Each
childwasthenassignedaprobabilityofhavingsufferedanepisodeofclinicalmalariainagivenperiod,
accordingtothehighestparasitedensityrecordedduringthatperiod,theprobabilitybeingdetermined
usingalogisticregressionapproach.Thesumoftheprobabilitiesacrossindividualswastakenasthetotal
episodesofmalariainthegroup.Foranalysispurposes,onlyoneepisodewasincludedwithinanysix-
weekperiod.Whilethisapproachdoesnotgoasfarasavoidinganyestimationofincidenceofmalariaat
theindividuallevel(ashasbeenproposedasapossibility[24,25]),thisstudydoesmoveawayfrom
classifyingoutcomesinanindividualchildinasimplebinaryway.
Anothermeasureofclinicalmalariawasusedinatrialofintermittentpreventivetherapywith
sulphadoxine/pyrimethamine(SP)andironsupplementationperformedinKenya[26].Theanalysiswas
basedontheriskratherthantherateofmalaria.Thus,thenumberofcasesofmalariawasdividedbythe
numberofchildrenatriskratherthanbytheperson-timeatrisk.
Useofpre-treatment.Intrialsofmalariavaccines,anassessmenthascommonlybeenmadeofthe
effectofthevaccineontheincidenceofparasitaemiaaswellasonclinicalmalaria.Theformerhasbeen
measuredbytakingrepeatedbloodsmearsfromsomechildrenfollowingvaccination.Inordertobeable
tomeasurenewinfections,inmosttrials,anti-malarialtreatmenthasbeengivenpriortovaccinationto
clearasexualparasitaemia.Thus,infiveoutofeightmalariavaccineefficacytrialsinchildren,
participantsweretreatedformalariaatthestartofthetrial.Asixthtrialusedamodiaquine/SPpre-
treatmentinaseparatecohort,whereonlyanti-infectionefficacydatawasgenerated[7].Inonetrial,
therewasadoublerandomization(byvaccinevscontrolandpre-treatmentvsnopre-treatment)to
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examinetheimpactofpre-treatmentonvaccineefficacy[27].Althoughthenumbersweresmallinthis
study,andtheprimaryend-pointwasparasitedensity,therewasamarkedsterilizingeffectofSPpre-
treatmentforseveralweeksintothefollow-upperiod,suchthatefficacycouldnotbedeterminedinthe
pre-treatmentgroup.EpidemiologicalstudiesinKisumu(unpublished)andMali[28]havebeenconducted
inchildrentoestimatethedurationofeffectofartemether/lumefantrineandSP,respectively,ontimeto
clinicalmalaria.Inthelatterstudy,SPpre-treatmentdelayedthemediantimetofirstclinicalepisode
from38daysto68days.Thedatanowavailablesuggestthatpre-treatmentofvaccinetrialparticipants
mayhavecomplexeffectsofunpredictabledurationonobservedvaccineefficacy.Thus,itmaybe
appropriatetorestrictpre-treatmenttotrialswheretimetoinfectionistheprimaryend-point.Wherepre-
treatmentisused,itmaybeamajorcomplicatingfactorforinterpretationofmorbidityend-points.
Surveillancemethods.Allmalariavaccinetrialsinchildrenpublishedtodatehaveincludedsomeform
ofactivecasedetection(ACD)foratleastsometrialparticipants.Twotrials[3,7]usedactive
surveillanceinonegroupandpassivecasedetection(PCD)onlyinothergroup(s)inthesamestudy.In
oneofthestudycohortsinthestudyofAlonsoetal[7]thescheduledinteractionbetweenstudystaffand
participantsduringtheefficacyfollow-upperiodwaslessthanforanyothercohortinthevaccinestudies
identified.Participantswerevisitedathomeonceamonthtoestablishpresenceinthestudyareaandto
recordanyunreportedseriousadverseeventsbutthevisitsdidnotinvolvemalariamorbiditysurveillance.
Clinicalmalariaepisodes,identifiedonlybychildrenpresentingataclinic,arethereforelikelytohave
beenmoresevere,onaverage,thanthoseexperiencedinothervaccinetrialsinwhichactivecase
detectionwasemployed.Theclinicalmalariacasesidentifiedinthisstudyarelikelytoaccordmore
closelytothoseencounteredinnormalhealthpracticeinthestudyareaand,therefore,itmightbeargued
thatthetrialresultswillbemorerelevanttopublichealth.
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Thecriteriausedtotriggerthetakingofabloodsmeartoassessforapossibleclinicalmalariaepisode
variedfromtrialtotrial.Thisalsoaffectsinterpretationofefficacyresults.Thus,theresultsoftrialsmust
beinterpretedinthelightofthecasedetectionsystemsused.
Insometrials,bothACDandPCDwereusedtodetectclinicalmalariacasesandefficacyresultswere
reportedforcasesdetectedbyeachofthesemethods[3].Withsuchdualsurveillancetheseverityofthe
clinicalmalariadetectedbyPCDislikelytobelesssevere,onaverage,thaniftherehadbeennoACD.
Intrialswherethechoiceoftheend-pointisdesignedtoapproximatewhatmighthappenintheusual
healthcaresystemtheuseofACDshouldbeavoided.Monthlyvisitstotrialparticipantsforpurelysafety
informationwouldappeartobeanappropriatelevelofinteractionforstudiesplanningPCDonly
surveillance.
Bloodsmearmethods.Therearethreemethodsforcalculatingparasitedensitythathavebeen
employedinpublishedinterventiontrials.Firstly,reading100or200highpowerfields,withthe
assumptionthatthevolumeofeachhighpowerfieldis1/500l.Secondly,anassumptionthatthetotal
whitecellcountis8,000/landreadingto200whitebloodcells.Thirdly,acalculationofwhitecellcount
individuallyandthenreadingto200WBC,withadjustmentusingthecalculatedcount.Itisdifficultto
comparetheresultsofstudiesinwhichdifferentcountingmethodshavebeenused.Standardizationon
onemethodisdesirableforaccuracy,precisionandtoaidcomparisonsoftheresultsindifferenttrialsand
isessentialforamulti-sitelicensuretrial.Doublereadingofallbloodsmearsforefficacyend-pointsis
alsoundertaken,andishighlydesirable,inmostinterventiontrials.Theelementsofslidetakingand
readingthatrequirestandardizationinclude:stainingofbloodsmearsincludingwhereFieldsstainand
Giemsastainareused;procedurefordoubleandthirdreadingofsmears;internalqualitycontrol(QC)
procedures;externalQCofaproportionofbloodsmearsandtheprocessforresolutionofdiscrepancies
foundthroughexternalQC.
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Otherend-points
Whileclinicalmalariahasbeentheprimaryend-pointinmoststudiesofpreventiveinterventionsstudies,
somestudieshavemeasuredtheimpactonmoreseverediseaseordeathandothershaveevaluatedthe
impactonhospitalutilizationforanycause.
Severemalaria,malaria-relatedmortalityandall-causemortality.Whilstthepresentingfeaturesand,tosomeextent,predictorsofmortalityinhospitalizedcasesofmalariahavebeenadequately
describedinahandfulofsettingsinsub-SaharanAfrica[29-40],onlyasinglepublishedpreventive
interventiontrialincludedseveremalariaastheprimaryend-point[2],thoughothertrialshavehadthisas
asecondaryend-point.Identifyingdeathsduetomalariaisproblematicinsituationswherepost-mortem
isuncommonandmanychildrenmaydieoutofahospitalsetting.Thereisawellestablishedprecedent
fortheuseofverbalautopsiestoassigncausesofdeathinbothsub-SaharanAfrica[41]andAsia[42],but
thereislimitedexperienceofusingthesemethodstoassesstheimpactofapreventativeinterventionon
malaria-relatedmortality[43]andthesensitivityandspecificityoftheassignmentofamalariadeathis
poor.However,withagoodsurveillancesystemalldeathsfromanycausecanbeidentifiedwith
considerablereliability.Thus,insometrials,specificallysomeoftheITNtrials[2,43-46],deathfrom
anycausehasbeentheprimaryend-point.Whilstnotappropriateforalicensuretrial,theimpactofa
vaccineonthisend-pointmaybeimportantforassessingthepublichealthimpactofamalariavaccine
post-licensure,andmightbeafocusforPhase4studies.Insomesettings,aneffectonseveremalariamay
alsobeascertainableinastudyinwhichall-causemortalityistheprimaryend-point[2].
Hospitaladmissions.Insometrialsanattempthasbeenmadetoestimatetheextenttowhicha
preventivemalariainterventionhasreducedtheoverallburdenofillnessonthehealthservice,suchasthe
impactonall-causeclinicorhospitalattendance.Forexample,thismeasurewasincludedinthe
evaluationoftheAsembo/GemKenyanITNtrial[47].Over20,000clinicattendanceswereincludedin
theprimaryanalysisandastatisticallysignificantefficacyof27%againstall-causeclinicattendancewas
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reported.Nosamplesizecalculationwasprovided,butitappearslikelythatsuchlargenumbersare
necessarytoprovideadequatepowertodetectsuchaneffect.Thisend-point,thoughpotentiallydifficult
tomeasureinsomecircumstances,wouldbehighlyinformativeforthosemakingimplementation
decisionsinmalariacontrol,asitprovidesageneralmeasureofthepotentialsavingtothehealthservice.
Useofmultipleefficacyendpoints.Arelativelylargenumberofpossibleefficacyend-pointsare
potentiallyavailabletomalariainvestigatorsandmalariapreventiveinterventiontrialsmaybe
particularlyvulnerabletothemultiplecomparisonsproblemsintrialdesign.Manyofthetrialsreviewed
reportedalargenumberofdifferentefficacyend-points(morethan20insometrials).Furthermore,itis
notgenerallymadeclearinpapershowmanyefficacyend-pointswereanalysedbutwerenotreported.A
rankingofend-pointspre-unblinding,intheanalyticplan,withpublicationinthepre-specifiedrankorder
wouldbeonewaytoaddressconcernsaboutmultiplecomparisons.Conservativemethodssuchas
adjustingsignificancelevelsforthenumberofend-pointsexaminedhavenotbeenusedintrialsreported
todate.Inpractice,inadditiontotheprimaryend-point(ifoneisspecified!)thesumoftheevidencefrom
alloftheend-pointsmeasuredisusuallytakenintoaccount,togetherwiththeirbiologicalplausibilityand
theirconsistency,intheoverallassessmentofthepotentialimpactofanintervention.Assessmentwould
beaidedif,foralltrials,thereportingandanalysisplansweremadeavailableforreviewtogetherwiththe
trialprotocol.
Conclusions
Thereisawealthofdataavailablefromrandomizedcontrolledtrialsofmalariapreventiveinterventions
directedatchildren,muchpublishedinrecentyears.Furtherinformationwillbecomeavailablethrough
ongoingiPTitrialsandtheplannedlargemulti-sitephase3trialoftheGlaxoSmithKline/MalariaVaccine
InitiativevaccinecandidateRTS,S.Attentiontothedesignissuesidentifiedabovewillaidthegeneration
ofdatathatcaninformpublichealthdecisions.
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Itisnotablethatmanyofthetrialsidentifiedinthisreviewreporttheincidencerateoffirstepisodesof
clinicalmalariaastheprimaryendpoint.Giventhepublichealthinterestinapotentialnewinterventions
impactonthecommunityburdenofclinicalmalaria,furtherattentiontoanalysismethodsforthe
incidencerateofallepisodesofmalariaappearstobeonepriorityforthoseundertakingclinicaltrialsin
thisfield.Thismayhelpbridgethegapbetweenproof-of-conceptandevaluationofpublichealthbenefit
forpreventiveinterventionsagainstclinicalmalaria.
Anambitious,buthighlylaudablegoal,statedasapriorityareainthestrategicframeworkoftheMalaria
VaccineTechnologyRoadmap[48],isclinicaltrialstandardization.Thehopeisthatthoseengagedin
preventiveinterventiontrialsagainstmalaria,andespeciallythoseengagedinvaccinetrials,willdiscuss
andcometoagreementonoptimaltrialdesign,analysismethodandreportingrequirements.Having
agreedtheseaspectstheplanistoproducestandardizedclinicaltrialmethods,protocolsandreporting
templates.Thisreportformsonepartofthebackgroundtosuchharmonizationandstandardization
efforts.TheInitiativeforVaccineResearch,WorldHealthOrganizationisengagedinongoingactivities
tofacilitatenorms,standardsandbestpracticeinthisarea[21].
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Competinginterests
Theauthorsdeclarethattheyhavenocompetinginterests.
Authorscontributions
VSMperformedtheliteraturesearch,extractedthedataonmethodsandreportingandwrotethefirstdraft
ofthemanuscript.ZRconceivedthescopeforthereviewandprovidedinputintothefinalmanuscript.PS
providedinputandreviewintothefinalmanuscript.
Acknowledgements
ThisworkwasperformedaspreparationforaWHOconsultation.Weacknowledgediscussionsheldwith
thefollowingexpertsaspartoftheconsultation:TSmith,SwissTropicalInstitute;JAponte,University
ofBarcelona;WRogers,NavalMedicalResearchCenter;BGreenwoodandDSchellenberg,London
SchoolofHygieneandTropicalMedicine;ALeach,GlaxoSmithKlineBiologicals;CRogier,Institutde
MdecineTropicaleduServicedeSantdesArmes,France.Theauthorsaloneareresponsibleforthe
viewsexpressedinthispublicationandtheydonotnecessarilyrepresentthedecisionsorthestatedpolicy
oftheWorldHealthOrganization.FinancialsupportfromtheMontedeiPascidiSienaandfromPATH
MalariaVaccineInitiativeareacknowledged.
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Additionalfiles
Additionalfile1Fileformat:DOC
Title:Tables1-4
Description:Tablessummarisingmethodsandreportingforidentifiedrandomizedcontrolledtrialsof
preventivemalariainterventions
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Additional files provided with this submission:
Additional file 1: tables 1-4.doc, 149Khttp://www.malariajournal.com/imedia/1204422785253623/supp1.doc
http://www.malariajournal.com/imedia/1204422785253623/supp1.dochttp://www.malariajournal.com/imedia/1204422785253623/supp1.doc