Advertisement

Is the UK NICE “Reference Case” Influencing the Practice of Pediatric Quality-Adjusted Life-Year Measurement within Economic Evaluations?

Open ArchivePublished:April 28, 2014DOI:https://doi.org/10.1016/j.jval.2014.02.007

      Abstract

      Objectives

      To report findings from a systematic review, this article sought to address two related questions. First, how has the practice of UK pediatric cost-utility analyses evolved over time, in particular how are health-related outcomes assessed and valued? Second, how do the methods compare to the limited guidance available, in particular, the National Institute for Health and Care Excellence (NICE) reference case(s)?

      Methods

      Electronic searches of MEDLINE, Embase, and Cochrane databases were conducted for the period May 2004 to April 2012 and the Paediatric Economic Database Evaluation database for the period May 2004 to December 2010. Identified studies were screened by three independent reviewers.

      Results

      Forty-three studies were identified, 11 of which elicit utility values through primary research. A discrepancy was identified between the methods used for outcome measurement and valuation and the methods advocated within the NICE reference case. Despite NICE recommending the use of preference-based instruments designed specifically for children, most studies that were identified had used adult measures. In fact, the measurement of quality-adjusted life-years is the aspect of economic evaluation with the greatest amount of variability and the area that most digressed from the NICE reference case.

      Conclusions

      Recommendations stemming from the review are that all studies should specify the age range of childhood and include separate statements of perspective for costs and effects as well as the reallocation of research funding away from systematic review studies toward good quality primary research measuring utilities in children.

      Keywords

      Introduction

      In the United Kingdom, the National Institute for Health and Care Excellence (NICE) operates as a decision-making body by making treatment recommendations for the UK National Health Service on the basis of economic and clinical evidence. NICE advocates a standardized approach to economic evaluation to ensure comparability of results and consistency of decision making [

      National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. Available from: http://www.nice.org.uk/media/D45/1E/GuideToMethodsTechnologyAppraisal2013.pdf. [Accessed July 6, 2013].

      ]. To facilitate this process, NICE has issued a “reference case” for all technology assessment economic evaluations to adhere to. The reference case includes recommendations for the adoption of a National Health Service/Personal Social Services perspective for costs; the use of the quality-adjusted life-year (QALY), measured using the EuroQol five-dimensional (EQ-5D) questionnaire; the application of a 3.5% discount rate to both costs and outcomes; and, where appropriate, the use of probabilistic sensitivity analysis and a lifetime time horizon [

      National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. Available from: http://www.nice.org.uk/media/D45/1E/GuideToMethodsTechnologyAppraisal2013.pdf. [Accessed July 6, 2013].

      ]. Results are expressed in terms of “cost per QALY” gained, and the difference in costs and QALYs is expressed as an incremental cost-effectiveness ratio.
      Although the reference case is designed to ensure quality and consistency, there are certain population subgroups in which a straightforward application of this “reference case” is problematic, with the evaluation of health interventions for children being one example. There are many well-documented reasons [
      • Kromm S.
      • Bethell J.
      • Kraglund F.
      • et al.
      Characteristics and quality of pediatric cost-utility analyses.
      ,
      • Ungar W.
      • Gerber A.
      The uniqueness of child health and challenges of measuring costs and consequences.
      ] why child health should be conceptualized differently to adult health, such as the rapid rate of development in childhood; dependency on parents or other caregivers; differences between children and adults in terms of disease epidemiology and treatment focus [
      • Griebsch I.
      • Coast J.
      • Brown J.
      Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health.
      ,
      • Ladapo J.
      • Neumann P.
      • Keren R.
      • Prosser L.
      Valuing children’s health: a comparison of cost-utility analyses for adult and paediatric health interventions in the US.
      ]; and differences in access to, and uptake of, health care resources. It may also be inappropriate to apply preference values that have been elicited for descriptions of health states experienced by adults with in the context of health interventions targeted at children.
      Indeed, NICE acknowledge that some adjustments will need to be made to the standard reference case when assessing the cost-effectiveness of health care interventions for children. The NICE “reference case” has changed over time in relation to guidelines for the practice of pediatric cost-utility analysis (CUA). NICE’s 2004 reference case specifies the use of a generic preference-based instrument to assess quality of life but proposes no modifications for pediatric CUA [

      National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. Available from http://www.nice.org.uk/niceMedia/pdf/TAP_Methods.pdf. [Accessed July 31, 2012].

      ]. The 2008 reference case specifies that:When necessary, consideration should be given to alternative standardised and validated preference-based measures of HRQL, such as the Health Utility Index 2 (HUI 2), that have been designed specifically for use in children. [

      National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. Available from: http://www.nice.org.uk/media/B52/A7/TAMethodsGuideUpdatedJune2008.pdf. [Accessed July 21, 2012].

      ]
      HUI is a family of preference-based instruments that comprises two versions, HUI2 and HUI3. A scoring system applies for children aged 5 years and older and is under development for children aged 3 to 5 years. It is recommended that where possible, the HUI3 should be used for primary studies.
      No specific instrument was suggested by NICE’s Decision Support Unit in 2011 [

      Brazier J., Longworth L. NICE DSU technical support document 8: an introduction to the measurement and valuation of health for NICE submissions. Available from: http://www.nicedsu.org.uk/TSD8%20Introduction%20to%20MVH_final.pdf. [Accessed October 20, 2012].

      ], and likewise, no specific instrument was advocated for pediatric CUA in the 2013 guidance [

      National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. Available from: http://www.nice.org.uk/media/D45/1E/GuideToMethodsTechnologyAppraisal2013.pdf. [Accessed July 6, 2013].

      ], which simply reiterates that[C]onsideration should be given to alternative standardised and validated preference-based measures of health-related quality of life that have been designed specifically for use in children.
      Therefore, from a methodological perspective, there remains no definitive, clear guidance on which instrument is the most appropriate to use for measuring health-related quality of life in children. There is disagreement about the age range to which generic preference-based instruments can be applied, and there is also little consensus regarding the extent to which proxy scores should be used for children across a broad age range between the “very young” and adolescence [
      • Eiser C.
      • Morse R.
      Quality-of-life measures in chronic diseases of childhood.
      ]. Eiser and Morse [
      • Eiser C.
      • Morse R.
      Quality-of-life measures in chronic diseases of childhood.
      ] describe a range of generic preference-based instruments. The recently developed Child Health Utility 9D (CHU-9D) [
      • Stevens K.
      Developing a descriptive system for a new preference-based measure of health-related quality of life for children.
      ] is one of few child-focused instruments that can claim to meet NICE’s specification of being “designed specifically for use in children” [

      National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. Available from: http://www.nice.org.uk/media/D45/1E/GuideToMethodsTechnologyAppraisal2013.pdf. [Accessed July 6, 2013].

      ]. In other cases, adjustments have been made to existing adult instruments such as the EQ-5D youth version questionnaire, which was derived from the EQ-5D 3 level questionnaire [
      • Wille N.
      • Badia X.
      • Bonsel G.
      • et al.
      Development of the EQ-5D-Y: a child friendly version of the EQ-5D.
      ].
      Published systematic reviews have noted an increase in the annual number of pediatric [
      • Kromm S.
      • Bethell J.
      • Kraglund F.
      • et al.
      Characteristics and quality of pediatric cost-utility analyses.
      ,
      • Griebsch I.
      • Coast J.
      • Brown J.
      Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health.
      ,
      • Ladapo J.
      • Neumann P.
      • Keren R.
      • Prosser L.
      Valuing children’s health: a comparison of cost-utility analyses for adult and paediatric health interventions in the US.
      ,
      • Ungar W.
      • Santos M.
      The Pediatric Economic Database Evaluation (PEDE) Project: establishing a database to study trends in pediatric economic evaluation.
      ] evaluations but with respect to the methods used, Griebsch et al. [
      • Griebsch I.
      • Coast J.
      • Brown J.
      Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health.
      ] argue that the limited use of generic preference-based instruments means that incremental cost-effectiveness ratios generated by pediatric CUA are not comparable across diseases and patient groups. Griebsch et al. [
      • Griebsch I.
      • Coast J.
      • Brown J.
      Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health.
      ] conclude that the limited use of generic preference-based instruments represents either a reflection of how underdeveloped methods are in CUA pediatric practice or a failure of the guidelines to keep up to date with standards in CUA pediatric evaluations.
      This article reports a systematic literature review with two distinct objectives:
      • 1.
        To report how methods within UK pediatric CUAs have evolved over time, assessing in particular whether methodological and design issues noted previously by Griebsch et al. in a review of studies to 2004 persist over the period 2004 to 2012.
      • 2.
        To describe and assess the relationship between pediatric CUAs in the United Kingdom and the pediatric CUA recommendations set out by NICE, particularly in relation to the derivation of utility values.
      A supplementary objective was to assess whether methods used in published pediatric CUAs indicate a need for amendments to NICE Technology Assessment methods guidance to improve consistency and to ensure that the guidelines are in line with “best practice.”

      Methods

       Search Strategy

      Electronic searches were undertaken using MEDLINE, Embase, and Cochrane databases for the period from May 2004 to April 2012 and the Paediatric Economic Database Evaluation database for the period May 2004 to December 2010, which was the most recent complete year available. An upper age limit of 16 years was selected to ensure compatibility with the rationale outlined by Griebsch et al. [
      • Griebsch I.
      • Coast J.
      • Brown J.
      Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health.
      ]. Search terms were developed in MEDLINE, and adapted to Embase, using a combination of Medical Subject Heading terms and free text. Three groups of search terms related to 1) children, infants, and pediatric; 2) economic evaluation/quality of life; and 3) the UK. The focus of interest was children, for whom there are fewer validated instruments and proxy measurement is common; therefore, practice is more varied. Full details of the searches can be found in the online appendices (see Appendix A in Supplemental Materials found at http://dx.doi.org/10.1016/j.jval.2014.02.007). Search terms were modified for relevant Cochrane databases.

       Selection

      All identified studies were screened by three independent reviewers. First, titles were screened for obvious rejection on the basis of the exclusion criteria; then, all abstracts were screened. If there was uncertainty regarding the rejection of the article, then full text was requested. Inclusion criteria were defined as follows:
      • CUA entailing the generation of a QALY score, including health technology assessment
      • Analysis includes children aged 16 years and younger and measures health utility in relation to disease sequelae in this age group
      • Includes children in any part of the United Kingdom
      • English language
      • Human only
      • Primary CUA or a combination of systematic review and primary CUA
      • Full manuscript publication available
      Identified studies that failed to match the inclusion criteria were excluded. Where the abstract met the inclusion criteria, the full manuscript was requested. Any differences in opinion regarding the inclusion of articles were resolved by discussion between the reviewers. A citation search was undertaken for publications included in the review to identify any additional publications that might not have been previously identified.

       Assessment and Data Extraction

      Data extraction criteria (see Appendix C in Supplemental Materials found at 10.1016/j.jval.2014.02.007) were developed from checklists for evaluation of adult CUA [
      • Philips Z.
      • Ginnelly L.
      • Sculpher M.
      • et al.
      Review of guidelines for good practice in decision-analytic modelling in health technology assessment.
      ] combined with criteria from the Paediatric Quality Assessment Questionnaire [
      • Ungar W.
      Santos. The Pediatric Quality Appraisal Questionnaire: an instrument for evaluation of the pediatric health economics literature.
      ] and the framework adopted by a previous review [
      • Griebsch I.
      • Coast J.
      • Brown J.
      Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health.
      ]. Where possible, data extraction queries were framed in a binary or restricted list format. Methods used for derivation of utility scores within the economic evaluation were the focus of the review.

      Results

      After the elimination of duplicates, the search strategy identified 76 titles and abstracts. These 76 articles were retrieved for assessment, and 41 publications were identified for inclusion in the final review. A further 2 articles were identified from citation searches. Data were therefore extracted from 43 articles (see Appendix B in Supplemental Materials found at http://dx.doi.org/10.1016/j.jval.2014.02.007).

       Study Characteristics

      Full study characteristics for all the included articles are available in a supplementary online file for Web publication; a summary is presented in Table 1. It was possible to determine details of the study population in all 43 studies. It was found that 30 studies targeted children exclusively, while 13 studies also included adults. Overall, the reporting of the details of the childhood population was poor, with no explicit definition of upper and lower age range in 23 of the 43 (53%) studies (Table 2). Most of the identified studies contained a decision-analytic model (38 of 43 studies), and none adopted a purely societal perspective. The time horizon was justified either explicitly or by inference in 36 of 43 (80%) studies, and a lifetime horizon was adopted in 17 of 43 (40%) studies. With respect to objective two, the evidence indicated conformity to the NICE guidelines that were applicable at the time each study was published (either the reference case guidelines from 2004 or 2008) in all aspects of evaluation unrelated to utility. Perspective was stated explicitly, or easily inferred, in all but one study, and the perspective selected is that of the NHS in 36 of 43 (86%) studies. The studies also conformed to the NICE reference case in terms of time horizon, discount rates, and probabilistic sensitivity analysis. Therefore, it would appear that there is evidence of conformity to NICE standards in all aspects of the identified CUAs that do not pertain to utility measurement.
      Table 1Study characteristics in relation to the assessment and valuation of HRQOL.
      Source of utility valuesn%
      Only generic preference-based described2351
      Generic preference-based + disease specific613
      SG613
      Not specified37
      TTO37
      Expert opinion24
      Disease specific with utility mapped12
      Various12
      Utility assessment technique usedn%
      EQ-5D questionnaire919
      HUI2613
      SG613
      EQ-5D questionnaire modified510
      TTO48
      HUI336
      Not specified36
      HUI3 modified24
      IHQL and expert panel24
      Index of well-being24
      QWB24
      None12
      TTO and VAS12
      Various12
      VAS12
      Utility score derived fromn%
      Child2860
      Adult (not specified as parent)1226
      Not specified36
      Child and adult24
      Parent12
      Various12
      QOL assessment performed byn%
      Parents or caregivers1633
      HCPs1224
      Not specified1020
      Self-assessment816
      Not applicable24
      Various12
      EQ-5D, EuroQol five-dimensional; HCP, health care practitioner; HRQOL, health-related quality of life; HUI, health utilities index; IHQL, Index of Health-Related Quality of Life; QOL, quality of life; QWB, Quality of Well-Being Scale; SG, standard gamble; TTO, time trade-off; VAS, visual analogue scale.
      Table 2Summary of studies identified as meeting the inclusion criteria.
      First author (year)Principle funding source?Health interventionDefinition of child (age range) specified? (yes/no)Age range of patient group (y)QOL assessed byUtility values derived viaUtility value elicited forDescribes limitations of available evidence with respect to utility values
      Baguelin (2010) [
      • Baguelin M.
      • Van Hoek A.
      • Jit M.
      • et al.
      Vaccination against pandemic influenza A/H1N1v in England: a real-time economic evaluation.
      ]
      DOHVaccination against influenzaNo<1–10Proxy (parent)Modified EQ-5D questionnaireChildNo
      11–18Self-assessmentModified EQ-5D questionnaireChild
      <18 hospitalizedSelf-assessmentVASAdult
      Bamford (2007) [
      • Bamford J.
      • Fortnum H.
      • Bristow K.
      • et al.
      Current practice, accuracy, effectiveness and cost-effectiveness of the school entry hearing screen.
      ]
      NIHRHearing screeningNA4–6Self-assessmentHUI3AdultNo
      Proxy (health care provider)TTO
      Barton (2006) [
      • Barton G.
      • Stacey P.
      • Fortnum H.
      • Summerfield A.
      Hearing-impaired children in the United Kingdom, IV: cost-effectiveness of pediatric cochlear implantation.
      ]
      MRC and NGOCochlear implantsNA3 and 6Proxy (parent)Modified HUI3ChildYes
      Bond (2009) [
      • Bond M.
      • Mealing S.
      • Anderson R.
      • et al.
      The effectiveness and cost-effectiveness of cochlear implants for severe to profound deafness in children and adults: a systematic review and economic model.
      ]
      NIHRCochlear implantsYes1, 8Proxy (parent)Modified HUI3ChildNo
      Brown (2009) [
      • Brown K.
      • Wray J.
      • Lunnon
      • et al.
      Cost utility evaluation of extracorporeal membrane oxygenation as a bridge to transplant for children with end-stage heart failure due to dilated cardiomyopathy.
      ]
      ?Extracorporeal membrane oxygenation (ECMO)Yes1–18Proxy (health care provider)Expert opinion (based on HUI2 health states)ChildNo
      Christensen (2010) [
      • Christensen T.
      • Buckland A.
      • Bentley A.
      • et al.
      Cost-effectiveness of somatropin for the treatment of short children born small for gestational age.
      ]
      IndustryTreatment of children born short for gestational ageNoNSSelf-assessmentEQ-5D questionnaireAdultNo
      Claxton (2004) [
      • Claxton K.
      • Ginnelly L.
      • Sculpher M.
      • et al.
      A pilot study on the use of decision theory and value of information analysis as part of the NHS Health Technology Assessment programme.
      ]
      NIHRTreatment of UTIsYesNSSelf-assessmentIndex of Well-beingAdultNo
      Colquitt (2011) [
      • Colquitt J.
      • Jones J.
      • Harris P.
      • et al.
      Bone-anchored hearing aids (BAHAs) for people who are bilaterally deaf: a systematic review and economic evaluation.
      ]
      NIHRBone-anchoring hearing aidsYesNSNAHUI3AdultYes
      Connock (2006) [
      • Connock M.
      • Burls A.
      • Frew E.
      • Fry-Smith A.
      • et al.
      The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review.
      ]
      NIHREnzyme replacement therapy for type I Gaucher’s diseaseNoBirth cohortNSTTOAdultYes
      Cottrell (2008) [
      • Cottrell S.
      • Tilden D.
      • Robinson P.
      • et al.
      A modeled economic evaluation comparing atomoxetine with stimulant therapy in the treatment of children with attention-deficit/hyperactivity disorder in the United Kingdom.
      ]
      IndustryAttention deficit/hyperactivity disorderNoNSProxy (parent)SGChildNo
      Craig (2011) [
      • Craig D.
      • Fayter D.
      • Stirk L.
      • Crott R.
      Growth monitoring for short stature: update of a systematic review and economic model.
      ]
      NIHRComparison of growth screening referral strategiesNo5+NSIHQL and expert panelChildYes
      Dretzke (2011) [
      • Dretzke J.
      • Edlin R.
      • Round J.
      • et al.
      A systematic review and economic evaluation of the use of tumour necrosis factor-alpha (TNF-α) inhibitors, adalimumab and infliximab, for Crohn’s disease.
      ]
      NIHRAdalimumab and infliximab for Crohn’s diseaseNoNSSelf-assessmentTTOAdultYes
      Epps (2005) [
      • Epps H.
      • Ginnelly L.
      • Utley M.
      • Southwood T.
      • et al.
      Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis.
      ]
      NIHRHydrotherapy for juvenile rheumatoid arthritisYes4–19Proxy (parent)EQ-5D questionnaireChildYes
      Fayter (2007) [
      • Fayter D.
      • Nixon J.
      • Hartley S.
      • et al.
      A systematic review of the routine monitoring of growth in children of primary school age to identify growth-related conditions.
      ]
      NIHRMonitoring of growthNo4+NSIHQL and expert panelChild and adultYes
      Monitoring of obesity11+NANoneAdult
      Frew (2007) [
      • Frew E.
      • Sandercock J.
      • Whitehouse W.
      • Bryan S.
      The cost-effectiveness of newer drugs as add-on therapy for children with focal epilepsies.
      ]
      ?Antiepileptic drugsYes3–18Proxy (health care provider)Expert opinion (based on health states from modified EQ-5D questionnaire)ChildYes
      Garside (2005) [
      • Garside R.
      • Stein K.
      • Castelnuovo E.
      • Pitt M.
      • et al.
      The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.
      ]
      NIHRPimecrolimus in atopic dermatitisYes2–16Proxy (parent)SGChildYes
      Healy (2011) [
      • Healy E.
      • Bentley A.
      • Fidler C.
      • Chambers C.
      Cost-effectiveness of tacrolimus ointment in adults and children with moderate and severe atopic dermatitis: twice weekly maintenance treatment vs. standard twice-daily reactive treatment of exacerbations from a third party payer (U.K. National Health Service) perspective.
      ]
      IndustryTacrolimus ointment in atopic dermatitisNoNSProxy (parent)SGChildNo
      Jit (2007) [
      • Jit M.
      • Edmunds W.
      Evaluating rotavirus vaccination in England and Wales Part II. The potential cost-effectiveness of vaccination.
      ]
      DOHVaccination for rotavirus gastroenteritisYes>0–5Proxy (parent or caregiver— unclear)HUI2ChildNo
      Karnon (2008) [
      • Karnon J.
      • Tolley K.
      • Oyee J.
      • et al.
      Cost-utility analysis of deferasirox compared to standard therapy with desferrioxamine for patients requiring iron chelation therapy in the United Kingdom.
      ]
      IndustryOral deferasirox in patients with chronic iron overloadNoNSNSQWBAdultNo
      King (2006) [
      • King S.
      • Griffin S.
      • Hodges Z.
      • et al.
      A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.
      ]
      NIHRMethylphenidate in combination with behavioral therapyYes6Proxy (parent)SGChildYes
      Martin (2009) [
      • Martin A.
      • Battya A.
      • Roberts J.
      • Standaert B.
      Cost-effectiveness of infant vaccination with RIX4414 (RotarixTM) in the UK.
      ]
      IndustryVaccination with RIX4414 to prevent rotavirus gastroenteritisYes>0–<18 moProxy (GP)Modified EQ-5D questionnaireChildYes— develops own data
      18 mo to 5 yProxy (hospital physician)
      Melegaro (2004) [
      • Melegaro J.
      • Edmunds W.
      Cost-effectiveness analysis of pneumococcal conjugate vaccination in England and Wales.
      ]
      DOHUniversal vaccination with pneumococcal conjugate vaccineNo<6 mo, 6–11 mo, and 5 y age bandsVariousVariousVariousYes
      Nuijtjen (2007) [
      • Nuijten M.
      • Wittenberg W.
      • Lebmeier M.
      Cost effectiveness of palivizumab for respiratory syncytial virus prophylaxis in high-risk children: a UK analysis.
      ]
      IndustryPalivizumab for prevention of respiratory syncytial virus (RSV)Yes≤35 wk of gestationProxy (parent)HUI2ChildNo
      Petrou (2010) [
      • Petrou S.
      • Dakin H.
      • Abangma G.
      • et al.
      Cost-utility analysis of topical intranasal steroids for otitis media with effusion based on evidence from the GNOME trial.
      ]
      NIHR and DOHTopical intranasal steroids for otitis mediaYes4–11Proxy (parent)HUI3ChildNo
      Pitt (2006) [
      • Pitt M.
      • Garside R.
      • Stein K.
      A cost-utility analysis of pimecrolimus vs. topical corticosteroids and emollients for the treatment of mild and moderate atopic eczema.
      ]
      NIHRPimecrolimus in atopic dermatitisNoNSProxy (parent)SGChildNo
      Prasad (2009) [
      • Prasad S.
      • Arellano J.
      • Steer C.
      • Libretto S.
      Assessing the value of atomoxetine in treating children and adolescents with ADHD in the UK.
      ]
      IndustryTreatment of attention deficit/hyperactivity disorderNoNSProxy (parent)SGChildNo
      Price (2011) [
      • Price D.
      • Musgrave S.
      • Wilson E.
      • et al.
      A pragmatic single-blind randomised controlled trial and economic evaluation of the use of leukotriene receptor antagonists in primary care at steps 2 and 3 of the national asthma guidelines (ELEVATE study).
      ]
      NIHRController therapy in asthma and add-in therapy for uncontrolled asthmaYes12–80NSEQ-5D questionnaireChildNo
      Punekar (2010) [
      • Punekar Y.
      • Sunderland T.
      • Hawkins N.
      • Lindsay J.
      Cost-effectiveness of scheduled maintenance treatment with infliximab for pediatric Crohn’s disease.
      ]
      IndustryInfliximab in children with severe active Crohn’s diseaseYes6–17Self-assessmentEQ-5D questionnaireAdultYes
      Proxy (hospital physician)Expert opinionChild
      Rautenberg (2012) [
      • Rautenberg T.
      • Zerwes U.
      • Foerster D.
      • Aultman R.
      Evaluating the cost utility of racecadotril for the treatment of acute watery diarrhea in children: the RAWD model.
      ]
      IndustryRacecadotril plus oral rehydration solution (ORS) vs. ORS aloneYes>0–<18 moProxy (GP)Modified EQ-5D questionnaireChildNo
      18 mo to 5 yProxy (hospital physician)
      Renfrew (2009) [
      • Renfrew M.
      • Craig D.
      • Dyson L.
      • et al.
      Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis.
      ]
      NIHREnhanced staff contact promoting breast-feedingNoBirth cohort weighing <2500 gProxy (hospital physician)EQ-5D questionnaireChildYes
      Rice (2010) [
      • Rice S.
      • Craig D.
      • McCormick F.
      • Renfrew M.
      Economic evaluation of enhanced staff contact for the promotion of breastfeeding for low birth weight infants.
      ]
      NIHREnhanced staff contact promoting breast- feedingNoBirth cohort weighing <2500 gProxy (hospital physician)EQ-5D questionnaireChildYes
      Simpson (2005) [
      • Simpson N.
      • Anderson R.
      • Sassi F.
      • et al.
      The cost-effectiveness of neonatal screening for Cystic Fibrosis: an analysis of alternative scenarios using a decision model.
      ]
      ?Screening for cystic fibrosisNoFrom birth to deathOtherQWBChild and adultNo
      Summerfield (2010) [
      • Summerfield A.
      • Lovett S.
      • Bellenger H.
      • Batten G.
      Estimates of the cost-effectiveness of pediatric bilateral cochlear implantation.
      ]
      ?Bilateral vs. unilateral cochlear implantsYes6Proxy (experts and parents of children without hearing difficulties)TTO and VASChildYes
      Takeda (2010) [
      • Takeda A.
      • Cooper K.
      • Bird A.
      • et al.
      Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation.
      ]
      NIHRGrowth hormone in short stature childrenNo7–10Proxy (study nurse)EQ-5D questionnaireAdultYes
      van Hoek (2012) [
      • van Hoek A.
      • Melegaro A.
      • Gay N.
      • et al.
      The cost-effectiveness of varicella and combined varicella and herpes zoster vaccination programmes in the United Kingdom.
      ]
      DOHVaccination program against varicella or varicella and herpes zosterNoNS(Proxy) parentHUI2ParentNo
      Verdian (2010) [
      • Verdian L.
      • Yunni Y.
      Cost-utility analysis of rufinamide versus topiramate and lamotrigine for the treatment of children with Lennox–Gastaut Syndrome in the United Kingdom.
      ]
      IndustryAdjunctive therapy for children with Lennox-GastautNoNSNSTTONSYes— develops own data
      Walker (2011) [
      • Walker S.
      • Burch J.
      • McKenna C.
      • et al.
      Omalizumab for the treatment of severe persistent allergic asthma in children aged 6–11 years.
      ]
      NIHROmalizumab plus high-dose inhaled corticosteroids (ICS) and long-acting beta agonist (LABA) vs. ICS plus LABA aloneYes6–11NSNSNSNA
      Wang (2008) [
      • Wang D.
      • Cummins C.
      • Bayliss S.
      • et al.
      Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.
      ]
      NIHRPalivizumab prophylaxis against RSV vs. standard care in infantsYes>28 wk of gestational ageProxy (parent)HUI2Child
      Wang (2011) [
      • Wang D.
      • Bayliss S.
      • Meads C.
      Palivizumab for immunoprophylaxis of respiratory syncytial virus (RSV) bronchiolitis in high-risk infants and young children: systematic review and additional economic modelling of subgroup analyses.
      ]
      NIHRPalivizumab prophylaxis against RSV in high-risk infantsNo≤24 wk to ≥35 wk of gestational ageProxy (parent)HUI2Child
      Whiting (2006) [
      • Whiting P.
      • Westwood M.
      • Bojke L.
      • et al.
      Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model.
      ]
      NIHRDiagnostic testing for UTINo<5Self-assessmentIndex of Well-beingAdultYes
      Wilson, Price (2010) [
      • Wilson E.
      • Price D.
      • Musgrave S.
      • et al.
      Cost effectiveness of leukotriene receptor antagonists versus long-acting beta-2 agonists as add-on therapy to inhaled corticosteroids for asthma: a pragmatic trial.
      ]
      NIHRAdd-on therapies to ICS for asthmaNo12–80NSEQ-5D questionnaireChildNo
      Wilson, Sims (2010) [
      • Wilson E.
      • Sims E.
      • Musgrave S.
      • Shepstone L.
      • et al.
      Cost effectiveness of leukotriene receptor antagonists versus long-acting beta-2 agonists as add-on therapy to inhaled corticosteroids for asthma: a pragmatic trial.
      ]
      NIHRInitial asthma controller therapyNo12–80NSEQ-5D questionnaireChildNo
      Yao (2006) [
      • Yao G.
      • Albon E.
      • Adi Y.
      • et al.
      A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.
      ]
      NIHRMMF, MPS, and sirolimus for renal transplant graft rejectionYes<18NSNSNSYes
      DOH, Department of Health; EQ-5D, EuroQol five-dimensional; GP, general practitioner; HUI, health utilities index; IHQL, Index of Health-Related Quality of Life; MMF, mycophenolate mofetil; MPS, mycophenolate sodium; MRC, Medical Research Council; NA, not applicable; NGO, nongovernmental organization; NIHR, National Institute for Health Research; NS, not specified; QWB, Quality of Well-Being Scale; SG, standard gamble; TTO, time trade-off; UTI, urinary tract infection; VAS, visual analogue scale.

       Critical Assessment of Outcome Measures

      It was found that utility estimates were generated from primary research in 11 of 43 (26%) studies. Two CUAs were difficult to classify: Martin et al. [
      • Martin A.
      • Battya A.
      • Roberts J.
      • Standaert B.
      Cost-effectiveness of infant vaccination with RIX4414 (RotarixTM) in the UK.
      ] provide evidence of utility generation in a separate publication by the same authors, whereas Walker et al. [
      • Walker S.
      • Burch J.
      • McKenna C.
      • et al.
      Omalizumab for the treatment of severe persistent allergic asthma in children aged 6–11 years.
      ] offer insufficient detail on utility sources to enable classification. The majority of CUAs obtained utility scores by proxy using either parent or health care professionals, and more than 25% of the studies applied utility scores derived from adults. Wide variation with utility assessment was observed with respect to the use of the standard gamble approach, the EQ-5D questionnaire (modified or unmodified), and the use of various versions of the HUI.
      Although 11 of the 43 (26%) CUAs used primary research (see Appendix D in Supplemental Materials found at http://dx.doi.org/10.1016/j.jval.2014.02.007), only 1 study, Baguelin et al. [
      • Baguelin M.
      • Van Hoek A.
      • Jit M.
      • et al.
      Vaccination against pandemic influenza A/H1N1v in England: a real-time economic evaluation.
      ], applied utility scores to children’s own self-assessed/reported health states in an 11 to 18 year age group (Table 2); completion in younger children was by proxy. Those CUAs that focused on both adults and children did not report different methods of generating utility scores and of the 14 CUAs that derive utility scores from adults, 5 do not highlight the limitations of this approach (Table 2).

      Discussion

      In areas unrelated to utility assessment, the review shows that the methods applied within UK-based pediatric CUA conform to the NICE reference case guidance, but with utility assessment, there is wide variation in methodological practice.
      There has been a growth in the use of preference-based instruments in children, but NICE’s suggestion to use the HUI2 in 2008 is matched in application by no increase in its use, but instead an increase in the use of the EQ-5D questionnaire. The 2013 NICE guidance calls for instruments specifically developed for use with children; the review has shown that instruments such as the CHU-9D have never been used; and while the EQ-5D questionnaire was modified in four CUAs, the modified version does not relate to the EQ-5D youth version questionnaire. It should, however, be acknowledged that with newly developed instruments such as the CHU-9D, there is always a time lag between application of the instrument within studies and subsequent publications.
      With almost every study identified it was apparent that there is a paucity of utility data in children, which raises an important issue about the allocation of research funding. Given this wide issue of data unavailability, it is recommended that future research funding be targeted toward high-quality primary research studies that focus on generating utility data directly from children instead of relying on reviews of poor evidence.
      Although this review was focused on children rather than adolescents, findings have shown that there is little consensus in the literature on the upper age range of childhood, with ages between 16 and 24 years considered in different contexts [
      • Griebsch I.
      • Coast J.
      • Brown J.
      Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health.
      ,
      • Juniper E.
      • Guyatt G.
      • Feeny D.
      • et al.
      Minimum skills required by children to complete health related quality of life instruments for asthma: comparison of measurement properties.
      ,
      • Clarke S.
      • Eiser C.
      The measurement of health-related quality of life (QOL) in paediatric clinical trials: a systematic review.
      ,
      • Garvie P.
      • Lawford J.
      • Banet M.
      • West R.
      Quality of life measurement in paediatric and adolescent populations with HIV: a review of the literature.
      ]. Birth cannot be assumed the starting age for childhood; for example, different gestational ages are used by three respiratory syncytial virus studies [
      • Nuijten M.
      • Wittenberg W.
      • Lebmeier M.
      Cost effectiveness of palivizumab for respiratory syncytial virus prophylaxis in high-risk children: a UK Analysis.
      ,
      • Wang D.
      • Bayliss S.
      • Meads C.
      Palivizumab for immunoprophylaxis of respiratory syncytial virus (RSV) bronchiolitis in high-risk infants and young children: systematic review and additional economic modelling of subgroup analyses.
      ,
      • Wang D.
      • Cummins C.
      • Bayliss S.
      • et al.
      Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.
      ]. With this in mind, it should not be recommended that guidance specify an age range of childhood because such a definition varies according to the disease context and the type of health care provision being evaluated. In more than half of our identified studies, the age range for childhood was not reported, so the assumed point of transition from childhood to adulthood is not known. This creates challenges when attempting to use published data for long-term decision-analytic modeling of treatment, and these challenges need to be considered when a lifetime horizon is recommended. So, rather than specifying an age range for childhood, it is instead recommended that published pediatric CUAs define, at the very least, the age range they have used for children.
      This review has compared the practice of CUA within the United Kingdom against the NICE reference case guidance. A limitation of this approach is that some of the CUAs included in the review have not been conducted to inform NICE recommendations and thus there is no reason why they would conform to NICE guidance. We believe that the strength of economic evaluation for decision making rests on consistency in methodology. It is noteworthy that almost all the CUAs identified in this review follow NICE guidance in areas unrelated to utility data regardless of their objectives in relation to NICE; for example, 57% of the identified CUAs use a discount rate of 3.5% for effects, but there is no similar consistency for the derivation and application of utility scores. If economic evaluation results are to be used to inform resource allocation decisions across different disease and treatment contexts, then it is fundamental that we strive for consistency in methods in all areas, including assessment of utility scores. It is recommended that future research funding be focused on high-quality methodological studies in children and on studies that generate utility data for childhood populations. This will help move forward methods in this underdeveloped area, which will, in turn, help organizations such as NICE achieve the consistency that is required.
      Source of financial support: No funding received.

      Supplementary Materials

      References

      1. National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. Available from: http://www.nice.org.uk/media/D45/1E/GuideToMethodsTechnologyAppraisal2013.pdf. [Accessed July 6, 2013].

        • Kromm S.
        • Bethell J.
        • Kraglund F.
        • et al.
        Characteristics and quality of pediatric cost-utility analyses.
        Qual Life Res. 2012; 21: 1315-1325
        • Ungar W.
        • Gerber A.
        The uniqueness of child health and challenges of measuring costs and consequences.
        in: Ungar W. Economic Evaluation in Child Health. Oxford University Press, New York2010
        • Griebsch I.
        • Coast J.
        • Brown J.
        Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health.
        Pediatrics. 2005; 115: e600
        • Ladapo J.
        • Neumann P.
        • Keren R.
        • Prosser L.
        Valuing children’s health: a comparison of cost-utility analyses for adult and paediatric health interventions in the US.
        Pharmacoeconomics. 2007; 25: 817-882
      2. National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. Available from http://www.nice.org.uk/niceMedia/pdf/TAP_Methods.pdf. [Accessed July 31, 2012].

      3. National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. Available from: http://www.nice.org.uk/media/B52/A7/TAMethodsGuideUpdatedJune2008.pdf. [Accessed July 21, 2012].

      4. Brazier J., Longworth L. NICE DSU technical support document 8: an introduction to the measurement and valuation of health for NICE submissions. Available from: http://www.nicedsu.org.uk/TSD8%20Introduction%20to%20MVH_final.pdf. [Accessed October 20, 2012].

        • Eiser C.
        • Morse R.
        Quality-of-life measures in chronic diseases of childhood.
        Health Technol Assess. 2001; 5: 1-157
        • Stevens K.
        Developing a descriptive system for a new preference-based measure of health-related quality of life for children.
        Qual Life Res. 2009; 18: 1105-1113
        • Wille N.
        • Badia X.
        • Bonsel G.
        • et al.
        Development of the EQ-5D-Y: a child friendly version of the EQ-5D.
        Qual Life Res. 2010; 19: 875-886
        • Ungar W.
        • Santos M.
        The Pediatric Economic Database Evaluation (PEDE) Project: establishing a database to study trends in pediatric economic evaluation.
        Med Care. 2003; 41: 1142-1152
        • Philips Z.
        • Ginnelly L.
        • Sculpher M.
        • et al.
        Review of guidelines for good practice in decision-analytic modelling in health technology assessment.
        Health Technol Assess. 2004; 8 (iii–iv, ix–xi): 1-158
        • Ungar W.
        Santos. The Pediatric Quality Appraisal Questionnaire: an instrument for evaluation of the pediatric health economics literature.
        Value Health. 2003; 6: 584-594
        • Martin A.
        • Battya A.
        • Roberts J.
        • Standaert B.
        Cost-effectiveness of infant vaccination with RIX4414 (RotarixTM) in the UK.
        Vaccine. 2009; 27: 4520-4528
        • Walker S.
        • Burch J.
        • McKenna C.
        • et al.
        Omalizumab for the treatment of severe persistent allergic asthma in children aged 6–11 years.
        Health Technol Assess. 2011; 15: 13-21
        • Baguelin M.
        • Van Hoek A.
        • Jit M.
        • et al.
        Vaccination against pandemic influenza A/H1N1v in England: a real-time economic evaluation.
        Vaccine. 2010; 28: 2370-2384
        • Juniper E.
        • Guyatt G.
        • Feeny D.
        • et al.
        Minimum skills required by children to complete health related quality of life instruments for asthma: comparison of measurement properties.
        Eur Respir J. 1997; 10: 2285-2294
        • Clarke S.
        • Eiser C.
        The measurement of health-related quality of life (QOL) in paediatric clinical trials: a systematic review.
        Health Qual Life Outcomes. 2004; 2: 66
        • Garvie P.
        • Lawford J.
        • Banet M.
        • West R.
        Quality of life measurement in paediatric and adolescent populations with HIV: a review of the literature.
        Child Care Health Dev. 2009; 35: 440-453
        • Nuijten M.
        • Wittenberg W.
        • Lebmeier M.
        Cost effectiveness of palivizumab for respiratory syncytial virus prophylaxis in high-risk children: a UK Analysis.
        Pharmacoeconomics. 2007; 25: 55-71
        • Wang D.
        • Bayliss S.
        • Meads C.
        Palivizumab for immunoprophylaxis of respiratory syncytial virus (RSV) bronchiolitis in high-risk infants and young children: systematic review and additional economic modelling of subgroup analyses.
        Health Technol Assess. 2011; 15 (iii–iv): 1-124
        • Wang D.
        • Cummins C.
        • Bayliss S.
        • et al.
        Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.
        Health Technol Assess. 2008; 12 (iii, ix–x): 1-86
        • Bamford J.
        • Fortnum H.
        • Bristow K.
        • et al.
        Current practice, accuracy, effectiveness and cost-effectiveness of the school entry hearing screen.
        Health Technol Assess. 2007; 11 (iii–iv): 1-168
        • Barton G.
        • Stacey P.
        • Fortnum H.
        • Summerfield A.
        Hearing-impaired children in the United Kingdom, IV: cost-effectiveness of pediatric cochlear implantation.
        Ear Hear. 2006; 27: 575-588
        • Bond M.
        • Mealing S.
        • Anderson R.
        • et al.
        The effectiveness and cost-effectiveness of cochlear implants for severe to profound deafness in children and adults: a systematic review and economic model.
        Health Technol Assess. 2009; 13: 44
        • Brown K.
        • Wray J.
        • Lunnon
        • et al.
        Cost utility evaluation of extracorporeal membrane oxygenation as a bridge to transplant for children with end-stage heart failure due to dilated cardiomyopathy.
        J Heart Lung Transplant. 2009; 28: 32-38
        • Christensen T.
        • Buckland A.
        • Bentley A.
        • et al.
        Cost-effectiveness of somatropin for the treatment of short children born small for gestational age.
        Clin Ther. 2010; 32: 1068-1082
        • Claxton K.
        • Ginnelly L.
        • Sculpher M.
        • et al.
        A pilot study on the use of decision theory and value of information analysis as part of the NHS Health Technology Assessment programme.
        Health Technol Assess. 2004; 8 (iii): 1-103
        • Colquitt J.
        • Jones J.
        • Harris P.
        • et al.
        Bone-anchored hearing aids (BAHAs) for people who are bilaterally deaf: a systematic review and economic evaluation.
        Health Technol Assess. 2011; 15 (iii-iv): 1-200
        • Connock M.
        • Burls A.
        • Frew E.
        • Fry-Smith A.
        • et al.
        The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review.
        Health Technol Assess. 2006; 10: 24
        • Cottrell S.
        • Tilden D.
        • Robinson P.
        • et al.
        A modeled economic evaluation comparing atomoxetine with stimulant therapy in the treatment of children with attention-deficit/hyperactivity disorder in the United Kingdom.
        Value Health. 2008; 11: 376-388
        • Craig D.
        • Fayter D.
        • Stirk L.
        • Crott R.
        Growth monitoring for short stature: update of a systematic review and economic model.
        Health Technol Assess. 2011; 15 (iii–iv): 1-200
        • Dretzke J.
        • Edlin R.
        • Round J.
        • et al.
        A systematic review and economic evaluation of the use of tumour necrosis factor-alpha (TNF-α) inhibitors, adalimumab and infliximab, for Crohn’s disease.
        Health Technol Assess. 2011; 15: 1-244
        • Epps H.
        • Ginnelly L.
        • Utley M.
        • Southwood T.
        • et al.
        Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis.
        Health Technol Assess. 2005; 9 (iii–iv, ix–x): 1-59
        • Fayter D.
        • Nixon J.
        • Hartley S.
        • et al.
        A systematic review of the routine monitoring of growth in children of primary school age to identify growth-related conditions.
        Health Technol Assess. 2007; 11 (iii, xi–xii): 1-163
        • Frew E.
        • Sandercock J.
        • Whitehouse W.
        • Bryan S.
        The cost-effectiveness of newer drugs as add-on therapy for children with focal epilepsies.
        Seizure. 2007; 16: 99-112
        • Garside R.
        • Stein K.
        • Castelnuovo E.
        • Pitt M.
        • et al.
        The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.
        Health Technol Assess. 2005; 9 (iii, xi-xiii): 1-230
        • Healy E.
        • Bentley A.
        • Fidler C.
        • Chambers C.
        Cost-effectiveness of tacrolimus ointment in adults and children with moderate and severe atopic dermatitis: twice weekly maintenance treatment vs. standard twice-daily reactive treatment of exacerbations from a third party payer (U.K. National Health Service) perspective.
        Br J Dermatol. 2011; 164: 387-395
        • Jit M.
        • Edmunds W.
        Evaluating rotavirus vaccination in England and Wales Part II. The potential cost-effectiveness of vaccination.
        Vaccine. 2007; 25: 3971-3979
        • Karnon J.
        • Tolley K.
        • Oyee J.
        • et al.
        Cost-utility analysis of deferasirox compared to standard therapy with desferrioxamine for patients requiring iron chelation therapy in the United Kingdom.
        Curr Med Res Opin. 2008; 24: 1609-1621
        • King S.
        • Griffin S.
        • Hodges Z.
        • et al.
        A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.
        Health Technol Assess. 2006; 10 (iii–i, xiii–146)
        • Melegaro J.
        • Edmunds W.
        Cost-effectiveness analysis of pneumococcal conjugate vaccination in England and Wales.
        Vaccine. 2004; 22: 4203-4214
        • Nuijten M.
        • Wittenberg W.
        • Lebmeier M.
        Cost effectiveness of palivizumab for respiratory syncytial virus prophylaxis in high-risk children: a UK analysis.
        Pharmacoeconomics. 2007; 25: 55-71
        • Petrou S.
        • Dakin H.
        • Abangma G.
        • et al.
        Cost-utility analysis of topical intranasal steroids for otitis media with effusion based on evidence from the GNOME trial.
        Value Health. 2010; 13: 543-551
        • Pitt M.
        • Garside R.
        • Stein K.
        A cost-utility analysis of pimecrolimus vs. topical corticosteroids and emollients for the treatment of mild and moderate atopic eczema.
        Br J Dermatol. 2006; 154: 1137-1146
        • Prasad S.
        • Arellano J.
        • Steer C.
        • Libretto S.
        Assessing the value of atomoxetine in treating children and adolescents with ADHD in the UK.
        Int J Clin Pract. 2009; 63: 1031-1040
        • Price D.
        • Musgrave S.
        • Wilson E.
        • et al.
        A pragmatic single-blind randomised controlled trial and economic evaluation of the use of leukotriene receptor antagonists in primary care at steps 2 and 3 of the national asthma guidelines (ELEVATE study).
        Health Technol Assess. 2011; 15: 1-32
        • Punekar Y.
        • Sunderland T.
        • Hawkins N.
        • Lindsay J.
        Cost-effectiveness of scheduled maintenance treatment with infliximab for pediatric Crohn’s disease.
        Value Health. 2010; 13: 188-195
        • Rautenberg T.
        • Zerwes U.
        • Foerster D.
        • Aultman R.
        Evaluating the cost utility of racecadotril for the treatment of acute watery diarrhea in children: the RAWD model.
        Clinicoecon Outcomes Res. 2012; 4: 109-116
        • Renfrew M.
        • Craig D.
        • Dyson L.
        • et al.
        Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis.
        Health Technol Assess. 2009; 13 (iii–iv): 1-146
        • Rice S.
        • Craig D.
        • McCormick F.
        • Renfrew M.
        Economic evaluation of enhanced staff contact for the promotion of breastfeeding for low birth weight infants.
        Int J Technol Assess Health Care. 2010; 26: 133-140
        • Simpson N.
        • Anderson R.
        • Sassi F.
        • et al.
        The cost-effectiveness of neonatal screening for Cystic Fibrosis: an analysis of alternative scenarios using a decision model.
        Cost Eff Resour Alloc. 2005; 3: 8
        • Summerfield A.
        • Lovett S.
        • Bellenger H.
        • Batten G.
        Estimates of the cost-effectiveness of pediatric bilateral cochlear implantation.
        Ear Hear. 2010; 31: 611-624
        • Takeda A.
        • Cooper K.
        • Bird A.
        • et al.
        Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation.
        Health Technol Assess. 2010; 14 (iii-iv): 1-209
        • van Hoek A.
        • Melegaro A.
        • Gay N.
        • et al.
        The cost-effectiveness of varicella and combined varicella and herpes zoster vaccination programmes in the United Kingdom.
        Vaccine. 2012; 330: 1225-1234
        • Verdian L.
        • Yunni Y.
        Cost-utility analysis of rufinamide versus topiramate and lamotrigine for the treatment of children with Lennox–Gastaut Syndrome in the United Kingdom.
        Seizure. 2010; 19: 1-11
        • Wang D.
        • Cummins C.
        • Bayliss S.
        • et al.
        Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.
        Health Technol Assess. 2008; 12 (iii, ix-x): 1-86
        • Whiting P.
        • Westwood M.
        • Bojke L.
        • et al.
        Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model.
        Health Technol Assess. 2006; 10 (iii–iv, xi–xiii): 1-154
        • Wilson E.
        • Price D.
        • Musgrave S.
        • et al.
        Cost effectiveness of leukotriene receptor antagonists versus long-acting beta-2 agonists as add-on therapy to inhaled corticosteroids for asthma: a pragmatic trial.
        Pharmacoeconomics. 2010; 28: 597-608
        • Wilson E.
        • Sims E.
        • Musgrave S.
        • Shepstone L.
        • et al.
        Cost effectiveness of leukotriene receptor antagonists versus long-acting beta-2 agonists as add-on therapy to inhaled corticosteroids for asthma: a pragmatic trial.
        Pharmacoeconomics. 2010; 28: 597-608
        • Yao G.
        • Albon E.
        • Adi Y.
        • et al.
        A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.
        Health Technol Assess. 2010; 14 (iii-iv,ix-xi): 1-157