title: The impact of structural uncertainty on cost-effectiveness models for adjuvant endocrine breast cancer treatments: the need for disease-specific model standardization and improved guidance.
abstract: BACKGROUND
  Structural uncertainty relates to differences in model structure and parameterization. For many published health economic analyses in oncology, substantial differences in model structure exist, leading to differences in analysis outcomes and potentially impacting decision-making processes. The objectives of this analysis were (1) to identify differences in model structure and parameterization for cost-effectiveness analyses (CEAs) comparing tamoxifen and anastrazole for adjuvant breast cancer (ABC) treatment; and (2) to quantify the impact of these differences on analysis outcome metrics.
  
  
  METHODS
  The analysis consisted of four steps: (1) review of the literature for identification of eligible CEAs; (2) definition and implementation of a base model structure, which included the core structural components for all identified CEAs; (3) definition and implementation of changes or additions in the base model structure or parameterization; and (4) quantification of the impact of changes in model structure or parameterizations on the analysis outcome metrics life-years gained (LYG), incremental costs (IC) and the incremental cost-effectiveness ratio (ICER).
  
  
  RESULTS
  Eleven CEA analyses comparing anastrazole and tamoxifen as ABC treatment were identified. The base model consisted of the following health states: (1) on treatment; (2) off treatment; (3) local recurrence; (4) metastatic disease; (5) death due to breast cancer; and (6) death due to other causes. The base model estimates of anastrazole versus tamoxifen for the LYG, IC and ICER were 0.263 years, €3,647 and €13,868/LYG, respectively. In the published models that were evaluated, differences in model structure included the addition of different recurrence health states, and associated transition rates were identified. Differences in parameterization were related to the incidences of recurrence, local recurrence to metastatic disease, and metastatic disease to death. The separate impact of these model components on the LYG ranged from 0.207 to 0.356 years, while incremental costs ranged from €3,490 to €3,714 and ICERs ranged from €9,804/LYG to €17,966/LYG. When we re-analyzed the published CEAs in our framework by including their respective model properties, the LYG ranged from 0.207 to 0.383 years, IC ranged from €3,556 to €3,731 and ICERs ranged from €9,683/LYG to €17,570/LYG.
  
  
  CONCLUSIONS
  Differences in model structure and parameterization lead to substantial differences in analysis outcome metrics. This analysis supports the need for more guidance regarding structural uncertainty and the use of standardized disease-specific models for health economic analyses of adjuvant endocrine breast cancer therapies. The developed approach in the current analysis could potentially serve as a template for further evaluations of structural uncertainty and development of disease-specific models.
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Science Faculty, Utrecht University, Utrecht, The Netherlands, G.W.J.Frederix@uu.nl.
authors.forename: Gerardus W J
authors.initials: GW
authors.lastname: Frederix
authors.forename: Johan G C
authors.initials: JG
authors.lastname: van Hasselt
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Anke M
authors.initials: AM
authors.lastname: Hövels
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Raaijmakers
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Johan L
authors.initials: JL
authors.lastname: Severens
mesh_terms: D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000191:economics* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000191:economics / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003362:Cost-Benefit Analysis; D005260:Female; D006801:Humans; D018803:Models, Economic; D008961:Models, Structural; D009570:Nitriles / Q000191:economics* / Q000627:therapeutic use; D019057:Quality-Adjusted Life Years; D016019:Survival Analysis; D013629:Tamoxifen / Q000191:economics* / Q000627:therapeutic use; D014230:Triazoles / Q000191:economics* / Q000627:therapeutic use; D035501:Uncertainty
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077384:Anastrozole