医学文献翻译中英对照

Theclinicalandcost-effectivenessofPharmalgen®for

thetreatmentofbeeandwaspvenomallergy

1TITLEOFPROJECT

TheclinicalandcosteffectivenessofPharmalgen®forthetreatmentofbeeandwaspvenom

allergy

2TARTEAM

LiverpoolReviewsandImplementationGroup(LRzG),UniversityofLiverpool

Correspondenceto:

RumonaDickson,Ms

Director,LRzG

UniversityofLiverpool

Room2.12

WhelanBuilding

TheQuadrangle

BrownlowHill

Liverpool

L693GB

Tel:+44(0)1517945682

Fax:+44(0)1517945585

Email:R.Dickson@liv.ac.uk

FordetailsofexpertisewithintheTARteam,seesection7.

3PLAINENGLISHSUMMARY

Allergicreactionstobeeandwaspvenommayoccurinvenom-sensitivepatientsimmediately

followingasting,andcanvaryinseverity,withinitiallymildsymptomssometimes

progressingtocriticalconditionswithinseconds.Themostseveresystemicallergicreactions

(generalisedreactions)areknownasanaphylaxis,areactioncharacterisedbyabnormallylow

bloodpressure,faintingorcollapse,andinextremereactionsthesesymptomscancause

death.

EachyearintheUKtherearebetweentwoandninedeathsfromanaphylaxiscausedbybee

andwaspvenom.Theimmediatetreatmentforsevereallergicreactionstobeeandwasp

venomconsistsofemergencytreatmentwithdrugstodecreasethepatient'sresponsetothe

venomandsupportbreathing,ifrequired.

Toavoidfurtherreactions,theuseofsensitisationtobeeandwaspvenom,throughaprocess

knownasvenomimmunotherapy(VIT),hasbeeninvestigated.Venomimmunotherapy

consistsofsubcutaneousinjectionsofincreasingamountsofvenomintopatientswitha

historyofanaphylaxistobeeandwaspvenom.Pharmalgen®hashadUKmarketing

authorisationforthediagnosisandtreatment(usingVIT)ofallergytobeevenom(using

Pharmalgen®BeeVenom)andwaspvenom(usingPharmalgen®WaspVenom)sinceMarch

1995,anditisusedbymorethan40centresacrosstheUK.Thisreviewaimstoassess

whetherusingPharmalgen@inVITisclinicallyusefulwhentreatingpeoplewithahistoryof

severereactiontobeeandwaspstings.Thereviewwillcomparepreventativetreatmentwith

Pharmalgen®toothertreatmentoptions,includinghighdoseantihistamines,adviceonthe

avoidanceofbeeandwaspstingsandadrenalineauto-injectorprescriptionandtraining.If

suitabledataareavailable,thereviewwillalsoconsiderthecosteffectivenessofusing

Pharmalgen®forVITandothersubgroupsincludingchildrenandpeopleathighriskoffuture

stingsorsevereallergicreactionstofuturestings.

4DECISIONPROBLEM

4.1Clarificationofresearchquestionandscope

Pharmalgen®isusedforthediagnosisandtreatmentofimmunoglobinE(IgE)-mediated

allergytobeeandwaspvenom.Theaimofthisreportistoassesswhethertheuseof

Pharmalgen®isofclinicalvaluewhenprovidingVITtoindividualswithahistoryofsevere

reactiontobeeandwaspvenomandwhetherdoingsowouldbeconsideredcosteffective

comparedwithalternativetreatmentoptionsavailableintheNHS.

4.2Background

BeesandwaspsformpartoftheorderHymenoptera(whichalsoincludesants),andwithin

thisorderthespeciesthatcausethemostfrequentallergicreactionsaretheVespidae(wasps,

yellowjacketsandhornets),andtheApinae(honeybees),I

Beeandwaspstingscontainallergenicproteins.Inwasps,thesearepredominantly

phospholipaseA1,2hyaluronidase?andantigen5,3andinbeesarephospholipaseA2and

hyaluronidase.4Followinganinitialsting,atype1hypersensitivityreactionmayoccurin

someindividualswhichproducestheIgEantibody.Thissensitisescellstotheallergen,and

anysubsequentexposuretotheallergenmaycausetheallergentobindtotheIgEmolecules,

whichresultsinanallergicreaction.

Theseallergenstypicallyproduceanintense,burningpainfollowedbyerythema(redness)

andasmallareaofoedema(swelling)atthesiteofthesting.Thesymptomsproduced

followingastingcanbeclassifiedintonon-allergicreactions,suchaslocalreactions,and

allergicreactions,suchasextensivelocalreactions,anaphylacticsystemicreactionsand

delayedsystemicreactions.5-6Systemicallergicreactionsmayoccurinvenom-sensitive

patientsimmediatelyfollowingasting,7andcanvaryinseverity,withinitiallymildsymptoms

sometimesprogressingtocriticalconditionswithinseconds.1

Themostseveresystemicallergicreactionisknownasanaphylaxis.Anaphylacticreactions

areofrapidonset(typicallyupto15minutespoststing)andcanmanifestindifferentways.

Initialsymptomsareusuallycutaneousfollowedbyhypotension,withlight-headedness,

faintingorcollapse.Somepeopledeveloprespiratorysymptomsduetoanasthma-like

responseorlaryngealoedema.Inseverereactions,hypotension,circulatorydisturbances,and

breathingdifficultycanprogresstofatalcardio-respiratoryarrest.

Anaphylaxisoccursmorecommonlyinmalesandinpeopleunder20yearsofageandcanbe

severeandpotentiallyfatal.8

4.3Epidemiology

Itisestimatedthattheprevalenceofwaspandbeestingallergyisbetween0.4%and3.3%.9

Theincidenceofsystemicreactionstowaspandbeevenomisnotreliablyknown,but

estimatesrangefrom0.15-3.3%,10-11Systemicallergicreactionsarereportedbyupto3%of

adults,andalmost1%ofchildrenhaveamedicalhistoryofseverestingreactions.9,12Aftera

largelocalreaction,5-15%ofpeoplewillgoontodevelopasystemicreactionwhennext

stung.13Inpeoplewithamildsystemicreaction,theriskofsubsequentsystemicreactionsis

thoughttobeabout18%.13Hymenopteravenomareoneofthethreemaincausesoffatal

anaphylaxisintheUSAandUK.14-15Insectstingsarethesecondmostfrequentcauseof

anaphylaxisoutsideofmedicalsettings.16BetweentwoandninepeopleintheUKdieeach

yearasaresultofanaphylaxisduetoreactionstowaspandbeestings.17Onceanindividual

hasexperiencedananaphylacticreaction,theriskofhavingarecurrentepisodehasbeen

estimatedtobebetween60%and79%.13

In2000,theregisteroffatalanaphylacticreactionsintheUKfrom1992onwardswas

reportedbyPumphreytodeterminethefrequencyatwhichclassicmanifestationsoffatal

anaphylaxisarepresent.18Ofthe56post-mortemscarriedout,19deathswererecordedas

reactionstoHymenopteravenom(33.9%),Aretrospectivestudyin2004examinedalldeaths

fromanaphylaxisintheUKbetween1992and2001,andestimated22.19%tobereactionsto

Hymenopteravenom(47/212).Thisfurtherbreaksdowninto29/212(13.68%)asreactionsto

waspstings,and4/212(1.89%)asreactionstobeestings.Theremaining14/212were

unidentifiedHymenopterastings(6.62%).19

4.4Currentdiagnosticoptions

Currently,individualscanbetestedtodetermineiftheyareatriskofsystemicreactionsto

beeandwaspvenom.Theprimarydiagnosticmethodforsystemicreactionstobeeand/or

waspstingsisvenomskintesting.

SkintestinginvolvesintradermalinjectionwiththefiveHymenopteravenomproteinextracts,

withvenomconcentrationsintherangeof0.001to1.0p.g/ml.Thisestablishestheminimum

concentrationgivingapositiveresult(areactionoccurringintheindividual).Asvenomtests

showunexplainedvariabilityovertime,20andasnegativeskintestscanoccurfollowing

recentanaphylaxis,itisrecommendedthattestsberepeatedafter1to6months.21

Othermethodsofdiagnosisinpatientsfollowingananaphylacticreactioninclude

radioallergosorbenttest(RAST),whichdetectsallergen-specificIgEantibodiesinserum.

Thistestislesssensitivethanskintestingbutisusefulwhenskintestscannotbedone,for

exampleinpatientswithskinconditions.22-23

4.5Currenttreatmentoptions

Preventativetreatmentsincludeeducationonhowtoavoidbeeandwaspvenom,and

prescriptionofhighdoseantihistamines.Patientswithahistoryofmoderatelocalreactions

shouldbeprovidedwithanemergencykit,24containingaHl-blockingantihistamineanda

topicalcorticosteroidforimmediateusefollowingasting.Patientswithahistoryof

anaphylaxisshouldbeprovidedwithanemergencykitcontainingarapid-actingHl-blocking

antihistamine,anoralcorticosteroidandanauto-injectorforselfadministration,containing

epinephrine.

Injectedepinephrine(asympathomimeticdrugwhichactsonbothalphaandbetareceptors)is

regardedastheemergencytreatmentofchoiceforcasesofacuteanaphylaxisasaresultof

Hymenopterastings.25Foradults,therecommendeddoseisbetween0.30mg/mland0.50

mg/mlI.M,and0.01ml/kgI.M.forchildren.Individualswithahistoryofanaphylactic

reactionsarerecommendedtocarryautoinjectorscontainingepinephrine(commonlyknown

asEpiPen®,Adrenaclick®,Anapen®orTwinject®).Theseareintendedforimmediate

self-administrationbyindividualswithahistoryofhypersensitivitytoHymenopterastings

andotherallergens.

Preventivemeasuresfollowingsuccessfultreatmentofasystemicallergicreactionto

Hymenopteravenomconsistsofeitherallergenavoidanceorspecificallergenimmunotherapy,

knownasVIT.Venomimmunotherapyisconsideredtobeasafeandeffectivetreatment.26

Currently,VITcanbeusedwithseveralregimes,includingPharmalgen®(manufacturedby

ALKAbello,andlicensedintheUK),Aquagen®andAlutardSQ®(bothmanufacturedby

ALKAbelloandunlicensedintheUKbutlicensedinsomepartsofEurope),

VENOMENHAL®(HALAllergy,Leiden,Netherlands,unlicensedintheUK),Alyostal®

(Stallergenes,AntonyCedex,France,unlicensedintheUK),andVenomil®(Hollister-Stier

LaboratoriesLLC,unlicensedintheUK).Venomimmunotherapyisrecommendedtoprevent

futuresystemicreactions.ItisrecommendedthatVITisconsidered"whenpositivetest

resultsforspecificIgEantibodiescorrelatewithsuspectedtriggersandpatientexposure9.27

Venomimmunotherapyconsistsofsubcutaneousinjectionsofincreasingamountsofvenom,

andtreatmentisdividedintotwoperiods:thebuildupphaseandmaintenancephase.Venom

immunotherapyisnowthestandardtherapyforHymenopterastingallergy,28andisamodel

forallergen-specifictherapy,29-30withsuccessrates(patientswhowillremainanaphylaxisfree)

beingreportedasmorethan98%insomestudies.4,31Therearenow44centresacrosstheUK

whichprovideVITtopeopleforbeeandwaspstingallergy.Venomimmunotherapyis

normallydiscontinuedafter3to5years,butmodificationsmaybenecessarywhentreating

peoplewithintenseallergenexposure(suchasbeekeepers)orthosewithindividualrisk

factorsforseverereactions.Thereisnomethodofassessingwhichpatientswillbeatriskof

furtheranaphylacticreactionsfollowingadministrationofVITandthosewhowillremain

anaphylaxisfreeinthelongtermfollowingVIT.27

LocalorsystemicadversereactionsmayoccurasaresultofVIT.Theynormallydevelop

within30minutesoftheinjection.Eachpatientismonitoredcloselyfollowingeachinjection

tocheckforadversereactions.Progressiontoanincreaseddoseonlyoccursiftheprevious

doseisfullytolerated.

4.6Thetechnology

Pharmalgen®isproducedbyALKAbello,andhashadUKmarketingauthorisationforthe

diagnosis(usingskintesting/intracutaneoustesting)andtreatment(usingVIT)of

IgE-mediatedallergytobeevenom(Pharmalgen®BeeVenom)andwaspvenom

(Pharmalgen®WaspVenom)sinceMarch1995(marketingauthorisationnumberPL

10085/0004).TheactiveingredientispartiallypurifiedfreezedriedVespulaspp.venomin

Pharmalgen®WaspVenomandfreezedriedApismelliferavenominPharmalgen®Bee

Venom,eachprovidedinpowderformforsolutionforinjection.

Beforetreatmentisconsidered,allergytobeeorwaspvenommustbeconfirmedbycase

historyanddiagnosis.TreatmentwithPharmalgen®BeeorWaspVenomisperformedby

subcutaneousinjections.Thetreatmentiscarriedoutintwophases:theinitialphaseandthe

maintenancephase.

Inthebuildupphase,thedoseisincreasedstepwiseuntilthemaintenancedose(the

maximumtolerabledosebeforeanallergicreaction)isachieved.ALKAbellorecommends

thefollowingdosageproposals:conventional,modifiedrush(clustered)andrushupdosing.In

conventionalupdosing,thepatientreceivesoneinjectionevery3-7days.Inmodifiedrush

(clustered)updosing,thepatientreceives2-4injectionsonceaweek.Ifnecessarythisinterval

maybeextendeduptotwoweeks.The2-4injectionsaregivenwithanintervalof30minutes.

Inrushupdosing,whilebeinghospitalisedthepatientreceivesinjectionswitha2-hour

interval.Amaximumoffourinjectionsperdaymaybegivenintheinitialphase.

Thebuildupphaseendswhentheindividualmaintenancedosehasbeenattainedandthe

intervalbetweentheinjectionsisincreasedto2,3and4weeks.Thisiscalledthe

maintenancephase,andthemaintenancedoseisthengivenevery4weeksforatleast3years.

Contra-indicationstoVITtreatmentareimmunologicaldiseases(e.g.immunecomplex

diseasesandimmunedeficiencies);chronicheart/lungdiseases;treatmentwithP-blockers;

severeeczema.Sideeffectsincludesuperficialwhealandflareduetoshallowinjection;local

swelling(whichmaybeimmediateordelayedupto48hours);mildgeneralreactionssuchas

urticaria,erythema,rhinitisormildasthma;moderateorseveregeneralreactionssuchas

moresevereasthma,angioedemaorananaphylacticreactionwithhypotensionand

respiratoryembarrassment;anaphylaxis(oftenstartingwitherythemaandpruritus,followed

byurticaria,angioedema,nasalorpharyngialcongestion,wheezing,dyspnoea,nausea,

hypotension,syncope,tachycardiaordiarrhoea).32

4.7ObjectivesoftheHTAproject

TheaimofthisreviewistoassesstheclinicalandcosteffectivenessofPharmalgen@in

providingimmunotherapytoindividualswithahistoryoftype1IgE-mediatedsystemic

allergicreactiontobeeandwaspvenom.Thereviewwillconsidertheeffectivenessof

Pharmalgen®whencomparedtoalternativetreatmentoptionsavailableintheNHS,including

adviceontheavoidanceofbeeandwaspstings,highdoseantihistaminesandadrenaline

auto-injectorprescriptionandtraining.Thereviewwillalsoexaminetheexistinghealth

economicevidenceandidentifythekeyeconomicissuesrelatedtotheuseofPharmalgen®in

UKclinicalpractice.Ifsuitabledataareavailable,aneconomicmodelwillbedevelopedand

populatedtoevaluateiftheuseofPharmalgen®forthetreatmentofbeeandwaspvenom

allergy,withinitslicensedindication,wouldbeacosteffectiveuseofNHSresources.

5METHODSFORSYNTHESISINGCLINICALEFFECTIVENESS

EVIDENCE

5.1Searchstrategy

ThemajorelectronicdatabasesincludingMedline,EmbaseandTheCochraneLibrarywillbe

searchedforrelevantpublishedliterature.Informationonstudiesinprogress,unpublished

researchorresearchreportedinthegreyliteraturewillbesoughtbysearchingarangeof

relevantdatabasesincludingNationalResearchRegisterandControlledClinicalTrials.A

sampleofthesearchstrategytobeusedforMEDLINEispresentedin

Appendix1.

Bibliographiesofprevioussystematicreviews,retrievedarticlesandthesubmissions

providedbymanufacturerswillbesearchedforfurtherstudies.

Adatabaseofpublishedandunpublishedliteraturewillbeassembledfromsystematic

searchesofelectronicsources,handsearching,contactingmanufacturersandconsultation

withexpertsinthefield.ThedatabasewillbeheldintheEndnoteX4softwarepackage.

Inclusioncriteria

TheinclusioncriteriaspecifiedinTable1willbeappliedtoallstudiesafterscreening.

Theinclusioncriteriawereselectedtoreflectthecriteriadescribedinthefinalscope

issuedbyNICEforthereview.However,asthereislikelytobealimitedamountofRCT

data,theinclusioncriteriaofstudydesignmaybeexpandedtoincludecomparative

Studiesanddescriptivecohorts.TheclinicalandcosteffectivenessofPharmalgen®forthetreatmentofbeeand

waspvenomallergyPage11of21

Table1:InclusioncriteriaIntervention(s)Pharmalgen@forthetreatmentofbeeandwasp

venomallergy,

Population(s)Peoplewithahistoryoftype1IgE-mediated

systemicallergicreactionsto:

waspvenomand/orbeevenom

ComparatorsAlternativetreatmentoptionsavailableinthe

NHS,withoutvenomimmunotherapyincluding:

adviceontheavoidanceofbeeandwasp

venom,

high-doseantihistamines,

adrenalineauto-injectorprescriptionand

training

StudydesignRandomisedcontrolledtrials

Systematicreviews

OutcomesOutcomemeasurestobeconsideredinclude:

numberandseverityoftype1IgE-mediated

systemicallergicreactions

mortality

anxietyrelatedtothepossibilityoffutureallergic

reactions

adverseeffectsoftreatment

health-relatedqualityoflife

OtherconsiderationsIftheevidenceallows,considerationswillbe

giventosubgroupsofpeople,accordingto

their:

riskoffuturestings(asdetermined,for

example,byoccupationalexposure)

riskofsevereallergicreactionstofuturestings

(asdeterminedbysuchfactorsasbaseline

tryptaselevelsandco-morbidities)

Iftheevidenceallows,theappraisalwill

considerseparatelypeoplewhohavea

contraindicationtoadrenaline.

Iftheevidenceallows,theappraisalwill

considerchildrenseparately.

Tworeviewerswillindependentlyscreenalltitlesandabstractsofpapersidentifiedinthe

initialsearch.Discrepancieswillberesolvedbyconsensusandwherenecessaryathird

reviewerwillbeconsulted.Studiesdeemedtoberelevantwillbeobtainedandassessed

forinclusion.Wherestudiesdonotmeettheinclusioncriteriatheywillbeexcluded.

Dataextractionstrategy

Datarelatingtostudydesign,findingsandqualitywillbeextractedbyonereviewerand

independentlycheckedforaccuracybyasecondreviewer.Studydetailswillbeextracted

usingastandardiseddataextractionform.Iftimepermits,attemptswillbemadetocontact

authorsformissingdata.Datafromstudiespresentedinmultiplepublicationswillbe

extractedandreportedasasinglestudywithallrelevantotherpublicationslisted.

Qualityassessmentstrategy

Thequalityoftheclinical-effectivenessstudieswillbeassessedaccordingtocriteriabasedon

theCRD'sguidancefbrundertakingreviewsinhealthcare.33-34Thequalityoftheindividual

clinical-effectivenessstudieswillbeassessedbyonereviewer,andindependentlycheckedfor

agreementbyasecond.Disagreementswillberesolvedthroughconsensusandifnecessarya

thirdreviewerwillbeconsulted.

Methodsofanalysis/synthesis

Theresultsofthedataextractionandqualityassessmentforeachstudywillbepresentedin

structuredtablesandasanarrativesummary.Thepossibleeffectsofstudyqualityonthe

effectivenessdataandreviewfindingswillbediscussed.Allsummarystatisticswillbe

extractedforeachoutcomeandwherepossible,datawillbepooledusingastandard

meta-analysis.35HeterogeneitybetweenthestudieswillbeassessedusingtheI2test.34Both

fixedandrandomeffectsresultswillbepresentedasforestplots.

6METHODSFORSYNTHESISINGCOSTEFFECTIVENESSEVIDENCE

Theeconomicsectionofthereportwillbepresentedintwoparts.Thefirstwillincludea

standardreviewofrelevantpublishedeconomicevaluations.Ifappropriateanddataare

available,thesecondwillincludethedevelopmentofaneconomicmodel.Themodelwillbe

designedtoestimatethecosteffectivenessofPharmalgen®forVITinindividualswitha

historyofanaphylaxistobeeandwaspvenom.Thissectionofthereportwillalsoconsider

budgetimpactandwilltakeaccountofavailableinformationoncurrentandanticipated

patientnumbersandserviceconfigurationforthetreatmentofthisconditionintheNHS.

6.1Systematicreviewofpublishedeconomicliterature

Theliteraturereviewofeconomicevidencewillidentifyanyrelevantpublished

cost-minimisation,cost-effectiveness,cost-utilityand/orcost-benefitanalyses.Economic

evaluations/modelsincludedinthemanufacturersubmission(s)willbeincludedinthereview

andcritiquedasappropriate.

Searchstrategy

Thesearchstrategiesdetailedinsection5willbeadaptedaccordinglytoidentifystudies

examiningthecosteffectivenessofusingPharmalgen®forVITinpatientswithahistoryof

allergicreactionstobeeorwaspvenom.Othersearchingactivities,includingelectronic

searchingofonlinehealtheconomicjournalsandcontactingexpertsinthefieldwillalsobe

undertaken.Fulldetailsofthesearchprocesswillbepresentedinthefinalreport.Thesearch

strategywillbedesignedtomeettheprimaryobjectiveofidentifyingeconomicevaluations

forinclusioninthecost-effectivenessliteraturereview.Atthesametime,thesearchstrategy

willbeusedtoidentifyeconomicevaluationsandotherinformationsourceswhichmay

includedatathatcanbeusedtopopulateadenovoeconomicmodelwhereappropriate.

SearchingwillbeundertakeninMEDLINEandEMBASEaswellasintheCochraneLibrary,

whichincludestheNHSEconomicEvaluationDatabase(NHSEED).

Inclusionandexclusion

InadditiontotheinclusioncriteriaoutlinedinTable1,specificcriteriarequiredforthe

cost-effectivenessreviewaredescribedinTable2.Inparticular,onlyfulleconomic

evaluationsthatcomparetwoormoreoptionsandconsiderbothcostsandconsequenceswill

beincludedinthereviewofpublishedliterature.Anyeconomicevaluations/modelsincluded

inthemanufacturersubmission(s)willbeincludedasappropriate.Studiesthatdonotmeetall

ofthecriteriawillbeexcludedandtheirbibliographicdetailslistedwithreasonsfor

exclusion.

Table2:AdditionalinclusioncriteriaFulleconomicevaluationsthatconsider

(costeffectiveness)Studydesignbothcostsandconsequences

(cost-effectivenessanalysis,cost-utility

analysis,cost-minimisationanalysisand

costbenefitanalysis)

OutcomesIncrementalcostperlifeyeargained

Incrementalcostperqualityadjustedlife

yeargained

Dataextractionstrategy

Datarelatingtobothstudydesignandqualitywillbeextractedbyonereviewerand

independentlycheckedforaccuracybyasecondreviewer.Disagreementwillberesolved

throughconsensusand,ifnecessary,athirdreviewerwillbeconsulted.Iftimeconstraints

allow,attemptswillbemadetocontactauthorsformissingdata.Datafrommultiple

publicationswillbeextractedandreportedasasinglestudy.

Qualityassessmentstrategy

Thequalityofthecost-effectivenessstudies/modelswillbeassessedaccordingtoachecklist

updatedfromthatdevelopedbyDrummondetal.36Thischecklistwillreflectthecriteriafor

economicevaluationdetailedinthemethodologicalguidancedevelopedbyNICE.37The

qualityoftheindividualcost-effectivenessstudies/modelswillbeassessedbyonereviewer,

andindependentlycheckedforagreementbyasecond.Disagreementswillberesolved

throughconsensusand,ifnecessary,athirdreviewerwillbeconsulted.Theinformationwill

betabulatedandsummarisedwithinthetextofthereport.

6.2Methodsofanalysis/synthesis

Costeffectivenessreviewofpublishedliterature

Individualstudydataandqualityassessmentwillbesummarisedinstructuredtablesandasa

narrativedescription.Potentialeffectsofstudyqualitywillbediscussed.

Tosupplementfindingsfromtheeconomicliteraturereview,additionalcostandbenefit

informationfromothersources,includingthemanufacturersubmission(s)toNICE,willbe

collatedandpresentedasappropriate.

DevelopmentofadenovoeconomicmodelbytheAG

a.Costdata

TheprimaryperspectivefortheanalysisofcostinformationwillbetheNHS.Costdatawill

thereforefocusonthemarginaldirecthealthservicecostsassociatedwiththeintervention.

Quantitiesofresourcesusedwillbeidentifiedfromconsultationwithexperts,primarydata

fromrelevantsourcesandthereviewedliterature.Wherepossible,unitcostdatawillbe

extractedfromtheliteratureorobtainedfromotherrelevantsources(drugpricelists,NHS

referencecostsandCharteredInstituteofPublicFinanceandAccountingcostdatabases).

Whereappropriatecostswillbediscountedat3.5%perannum,theraterecommendedin

NICEguidancetomanufacturersandsponsorsofsubmissions.37

b.Assessmentofbenefits

Abalancesheetwillbeconstructedtolistbenefitsandcostsarisingfromalternativetreatment

options.LRiGanticipatesthatthemainmeasuresofbenefitwillbeincreasedQALYs.

Whereappropriate,effectivenessandothermeasuresofbenefitwillbediscountedat3.5%,

theraterecommendedinNICEguidancetomanufacturersandsponsorsofsubmissions.37

b.Modelling

TheabilityofLRiGtoconstructaneconomicmodelwilldependonthedataavailable.Where

modellingisappropriate,asummarydescriptionofthem