Cost-effectiveness analysis with informative missing data: tools and strategies

Cost effectiveness analysis (CEA) of randomised trials are an important source of evidence for informing policy makers on how to best allocate limited resources. Missing data are a common issue in trial-based CEA, and methods such as multiple imputation are now commonly used to account for the missing values, assuming the data are ‘missing at random’ (MAR). This implies that the reasons for the missing data can be explained by the observed data. However, the missingness is often related to unobserved values, that is data are ‘missing not at random’ (MNAR, or ‘informative’). For example, patients whose health status is relatively poor may be less likely to return health questionnaires, even conditional on their observed characteristics. In these settings, methodological guidance recommends assessing whether conclusions are sensitive to departures from the MAR assumption. Sensitivity analysis strategies for handling MNAR is an area of rapid development in medical statistics, but this form of uncertainty has not yet been appropriately addressed in health economics. This PhD thesis aims to develop practical, accessible sensitivity analysis strategies and software tools to handle MNAR data in trial-based CEA. The thesis critically assessed the statistical methods for handling MNAR data in CEA practice, and identified barriers to more widespread use of these methods, via a systematic review and stakeholder focus groups. The research then focused on two strategies to conduct sensitivity analysis under MNAR assumptions: pattern-mixture models, which involve imputing the data assuming MAR, then modifying the imputed values to reflect possible departures from that assumption; and reference-based imputation, where the data are imputed assuming a distribution borrowed from a ‘reference group’. These approaches were illustrated in CEAs of 10TT and CoBalT trials, which evaluated weight loss and depression interventions. Software code and practical guidance are provided to facilitate implementation in practice

Early mortality, quality of life and cost-effectiveness of palliative radiotherapy for bone metastases in the English NHS

Introduction: Palliative radiotherapy is a standard of care for localised pain due to bone metastases. International guidance recommends single fraction treatment in preference to multiple fractions, but variation in practice exists. The cost-effectiveness of stereotactic radiotherapy in this setting is unclear. This study aimed to assess the quality of life benefits from response to treatment, cost-effectiveness and routine use of these treatments in the context of varying survival. Methods: A mixed methods approach was used: A systematic review; secondary use of trial data to assess an alternative trial end-point and support multi-level regression modelling of treatment related quality of life benefits; a qualitative interview study to understand patients values and experiences of treatment; time-driven activity-based costing to determine radiotherapy cost; cost-utility analysis, to balance the quality of life benefits and cost of treatment in the context of varying survival and identify levels of 30-day mortality which reflect cost-effective care; and an analysis of the national radiotherapy dataset to provide insight into current practice and outcomes in the English NHS. Results: With increasing proximity to death the quality of life benefits of palliative radiotherapy diminish markedly, to the extent that in the final months of life, treatment is unlikely to be cost-effective and may be associated with a net harm to the healthcare system. For those with longer survival, stereotactic radiotherapy may offer a cost-effective means to improve the quality and durability of pain control, once treatment costs have reduced beyond an initial learning-curve. Wide variation in fractionation pattern persists, with marked variation in 30-day mortality. Conclusions: A value-based approach to the use of palliative radiotherapy for bone metastases offers an opportunity for improved decisions that avoid futile treatment and improve the cost-effectiveness of care. These analyses can form the basis of a novel approach to the commissioning of stereotactic radiotherapy

Mind the Gap! - Geographic transferability of economic evaluation in health

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Background: Transferring cost-effectiveness information between geographic domains offers the potential for more efficient use of analytical resources. However, it is difficult for decision-makers to know when they can rely on costeffectiveness evidence produced for another context. Objectives: This thesis explores the transferability of economic evaluation results produced for one geographic area to another location of interest, and develops an approach to identify factors to predict when this is appropriate. Methods: Multilevel statistical models were developed for the integration of published international costeffectiveness data to assess the impact of contextual effects on country-level; whilst controlling for baseline characteristics within, and across, a set of economic evaluation studies. Explanatory variables were derived from a list of factors suggested in the literature as possible constraints on the transferability of costeffectiveness evidence. The approach was illustrated using published estimates of the cost-effectiveness of statins for the primary and secondary prevention of cardiovascular disease from 67 studies and related to 23 geographic domains, together with covariates on data, study and country-level. Results: The proportion of variation at the country-level observed depends on the appropriate multilevel model structure and never exceeds 15% for incremental effects and 21% for incremental cost. Key sources of variability are patient and disease characteristics, intervention cost and a number of methodological characteristics defined on the data-level. There were fewer significant covariates on the study and country-levels. Conclusions: Analysis suggests that variability in cost-effectiveness data is primarily due to differences between studies, not countries. Further, comparing different models suggests that data from multinational studies severely underestimates country-level variability. Additional research is needed to test the robustness of these conclusions on other sets of cost-effectiveness data, to further explore the appropriate set of covariates, and to foster the development of multilevel statistical modelling for economic evaluation data in health.This study is funded by MATCH, the Engineering and Physical Science Research Council (EPSRC), and the German Academic Merit Foundation

Economics of primary caries prevention in preschool children

Background: Childhood caries continues to be a pandemic disease and a significant but preventable public health problem worldwide. Caries can have a major impact on children's health and quality of life as well as represent cost to individuals, the health sector and society. Research indicates that children who develop caries in early childhood are likely to have a high risk of the disease in adolescence and adulthood. Dental caries is a preventable disease and currently a range of nationwide programmes, community-based programmes and clinical strategies exist to reduce caries prevalence in children. Notwithstanding the fact that childhood caries is very widespread and that it poses a substantial economic burden, there is a paucity of economic evaluations of caries prevention interventions in preschoolers. The lack of high-quality economic evaluations makes it difficult for decision-makers to determine which interventions to provide within the remit of health services and local authorities. Aim: To explore the role of economic evaluation in primary caries prevention in preschool children aged 2-5 years. This aim was met through answering the following three research questions. (1) What is the existing evidence in the field of economic evaluation of primary caries prevention in children aged 2-5 years? (2) Which general health and oral health-related quality of life measures have been used in 3-5-year-old populations? And which of these measures are best suited to be used in a caries prevention randomised controlled trial for this age group? (3) Is the application of fluoride varnish delivered in nursery settings in addition to the other usual components of the Scottish child oral health improvement programme, Childsmile, (treatment as usual) cost-effective in comparison with treatment as usual only? Methods: Three interlinked empirical work segments were undertaken to address these research questions. (1) A systematic review of economic evaluations of primary caries prevention in 2-5-year-old preschool children. (2) A non-systematic review of instruments for measuring general and oral health-related quality of life in 3-5-year-old children. (3) An economic evaluation of the Protecting Teeth @ 3 randomised controlled trial (trial registration: EUDRACT: 2012-002287-26; ClinicalTrials.gov: NCT01674933). Results: (1) The systematic review of economic evaluations of primary caries prevention in 2-5-year-olds found that cost analysis and cost-effectiveness analysis were the most frequently used types of economic evaluations. Only one study employed cost-utility analysis. The systematic review highlighted wide variation in: (a) types of caries prevention interventions investigated; (b) effectiveness measures used; (c) how costs and outcomes are reported; and d) study perspective (when indicated). The parameters not reported well included study perspective, baseline year, sensitivity analysis, and discount rate. The results of the quality assessment of the full economic evaluations using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist showed substantial variation in reporting quality. The CHEERS items that were most often unmet were characterizing uncertainty, study perspective, study parameters, and estimating resources and costs. (2) The review of general health and oral health-related quality of life measures identified a range of existing questionnaires for use in preschool populations (age 3-5 years) and their strengths and limitations were considered. Only two preference-based general health-related quality of life instruments that had been used in 3-5-year-olds were identified. No preference-based oral health-related quality of life measures for preschoolers were identified. Four instruments were selected to be used in the Protecting Teeth @ 3 trial: the Child Health Utility 9 Dimensions, PedsQL (Paediatric Quality of Life Inventory) Core, PedsQL Oral Health (an oral health specific add-on to PedsQL Core) and the Scale of Oral Health Outcomes for 5-year-old children. (3) The findings of the Protecting Teeth @ 3 trial economic evaluation demonstrated that there were no statistically significant differences in total costs, quality adjusted life years (QALYs) accumulated, the change in the clinical effectiveness outcome (d3mft), and in general health and oral health-related quality of life measures at 24 months between the intervention and control groups. The mean difference in total costs between the fluoride varnish (intervention) and treatment as usual (control) group was £68 (p=0.382; 95% confidence interval £18, £144). The mean difference in QALYs was -0.004 (p= 0.636; 95% confidence interval -0.016, 0.007). The probability that the fluoride varnish intervention was cost-effective at the £20,000 threshold was 11%. Conclusions: The systematic review of economic evaluations of primary caries prevention in 2-5-year-olds found that within the past two decades, there has been an increase in the number of economic evaluations of caries prevention interventions in preschool children. However, there was inconsistency in how these economic evaluations of primary caries prevention were conducted and reported. Lack of use of preference-based health-related quality-of-life measures was identified. The use of appropriate study methodologies and greater attention to recommended economic evaluations design are required to further improve quality. Due to small numbers of studies investigating each intervention type (for example, fluoride varnish, oral health education, dental sealants, toothbrushing, water fluoridation) and the questionable methodological quality of many of the reviewed economic evaluations, it was not possible to arrive at reliable conclusions with regards to the economic value of primary caries prevention. With dental caries being one of the most common diseases affecting humans worldwide, the identification of cost-effective prevention strategies in children should be a global public health priority. In order for this to be achieved, studies should be designed to include economic evaluations using best practice methods guidance and adhering to standards for reporting and presenting. The review of general health and oral health-related quality of life measures used in 3-5-year-olds identified a range of existing questionnaires for use in preschool populations – both for parental proxy reporting and child self-reporting. Four instruments were selected to be used in the Protecting Teeth @ 3 trial. Further research and development of new preference-based measures suitable for preschoolers (or their parents/guardians as a proxy) are required. The results of the economic evaluation of the Protecting Teeth @ 3 trial show that applying fluoride varnish in nursery settings in addition to the existing treatment a usual (all other components of the Childsmile programme, apart from nursery fluoride varnish) is not likely to be cost-effective. In view of previously proven clinical effectiveness and economic worthiness of the universal nursery toothbrushing component of Childsmile, which was shown to be highly cost saving, as well as being effective and cost saving in the most deprived populations, continuation of the programme of targeted nursery fluoride varnish in its most recent (pre-COVID-19) form and shape in addition to nursery toothbrushing and other routine Childsmile components needs to be reviewed in consultation with policy makers. The findings also have wider implications for other countries looking to develop their own childhood caries prevention programmes