title: Clinical effectiveness and cost-effectiveness of use of therapeutic monitoring of tumour necrosis factor alpha (TNF-α) inhibitors [LISA-TRACKER® enzyme-linked immunosorbent assay (ELISA) kits, TNF-α-Blocker ELISA kits and Promonitor® ELISA kits] versus standard care in patients with Crohn's disease: systematic reviews and economic modelling.
abstract: Systematic reviews and economic modelling of clinical effectiveness and cost-effectiveness of therapeutic monitoring of tumour necrosis factor alpha (TNF-α) inhibitors [using LISA-TRACKER®enzyme-linked immunosorbent assay (ELISA) kits (Theradiag, Marne La Vallee, France, or Alpha Laboratories, Heriot, UK), TNF-α-Blocker ELISA kits (Immundiagnostik AG, Bensheim, Germany) and Promonitor®ELISA kits (Proteomika, Progenika Biopharma, Bizkaia, Spain)] versus standard care for Crohn's disease (CD).
  
  
  
  Multiple electronic databases were searched from inception to December 2014 in order to identify primary studies and meta-analyses.
  
  
  
  Patients with moderate to severe active CD treated with infliximab (IFX) (Remicade®, Merck Sharp & Dohme Ltd, Kenilworth, NJ, USA) or adalimumab (ADA) (Humira®, AbbVie Inc., North Chicago, IL, USA).
  
  
  
  Monitoring of serum anti-TNF-α (IFX or ADA) and/or of anti-drug antibody levels using test assays with a test-treatment algorithm.
  
  
  
  Standard care.
  
  
  
  Any patient-related outcome, test agreement and cost-effectiveness estimates. The quality assessments used recognised checklists (Quality Assessment of Diagnostic Accuracy Studies-2, Cochrane, Philips and Consolidated Health Economic Evaluation Reporting Standards). Evidence was synthesised using narrative review and meta-analysis. A Markov model was built in TreeAge Pro 2013 (TreeAge Software, Inc., Williamstown, MA, USA). The model had a 4-week cycle and a 10-year time horizon, adopted a NHS and Personal Social Services perspective and used a linked evidence approach. Costs were adjusted to 2013/14 prices and discounted at 3.5%.
  
  
  
  We included 68 out of 2434 and 4 out of 2466 studies for the clinical effectiveness and cost-effectiveness reviews, respectively. Twenty-three studies comparing test methods were identified. Evidence on test concordance was sparse and contradictory, offering scant data for a linked evidence approach. Three studies [two randomised controlled trials (RCTs) and one retrospective observational study] investigated outcomes following implementation of a test algorithm. None used the specified commercial ELISA immunoassay test kits. Neither of the two RCTs demonstrated clinical benefit of a test-treatment regimen. A meta-analysis of 31 studies to estimate test accuracy for predicting clinical status indicated that 20-30% of test results are likely to be inaccurate. The four cost-effectiveness studies suggested that testing results in small cost reductions. In the economic analysis the base-case analysis showed that standard practice (no testing/therapeutic monitoring with the intervention tests) was more costly and more effective than testing for IFX. Sensitivity and scenario analyses gave similar results. The probabilistic sensitivity analysis indicated a 92% likelihood that the 'no-testing' strategy was cost-effective at a willingness to pay of £20,000 per quality-adjusted life-year.
  
  
  
  Rigorous systematic reviews were undertaken; however, the underlying evidence base was poor or lacking. There was uncertainty about a linked evidence approach and a lack of gold standard for assay comparison. The only comparative evidence available for economic evaluation was for assays other than the intervention assays.
  
  
  
  Our finding that testing is not cost-effective for IFX should be viewed cautiously in view of the limited evidence. Clinicians should be mindful of variation in performance of different assays and of the absence of standardised approaches to patient assessment and treatment algorithms.
  
  
  
  There is substantial variation in the underlying treatment pathways and uncertainty in the relative effectiveness of assay- and test-based treatment algorithms, which requires further investigation. There is very little research evidence on ADA or on drug monitoring in children with CD, and conclusions on cost-effectiveness could not be reached for these.
  
  
  
  This study is registered as PROSPERO CRD42014015278.
  
  
  
  The National Institute for Health Research Health Technology Assessment programme.
authors.affiliation: Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Karoline
authors.initials: K
authors.lastname: Freeman
authors.affiliation: Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Connock
authors.affiliation: Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Auguste
authors.affiliation: Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Taylor-Phillips
authors.affiliation: Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Hema
authors.initials: H
authors.lastname: Mistry
authors.affiliation: Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Deepson
authors.initials: D
authors.lastname: Shyangdan
authors.affiliation: Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Court
authors.affiliation: Clinical Sciences Research Institute, University of Warwick, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Arasaradnam
authors.affiliation: Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Sutcliffe
authors.affiliation: Warwick Evidence, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Aileen
authors.initials: A
authors.lastname: Clarke
mesh_terms: D000068879:Adalimumab / Q000276:immunology / Q000627:therapeutic use; D000465:Algorithms; D003362:Cost-Benefit Analysis; D003424:Crohn Disease / Q000188:drug therapy*; D016903:Drug Monitoring / Q000191:economics* / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D005858:Germany; D006801:Humans; D000069285:Infliximab / Q000276:immunology / Q000627:therapeutic use; D008390:Markov Chains; D017059:Models, Econometric; D019057:Quality-Adjusted Life Years; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab