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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

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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

clinical trials to estimate the efficacy of preventive

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