It Takes 2 to Tango. Setting Out the Conditions in Which Performance-Based Risk-Sharing Arrangements Work for Both Parties.

OBJECTIVES: Faster regulatory approval processes often fail to achieve faster patient access. We seek an approach, using performance-based risk-sharing arrangements, to address uncertainty for payers regarding the relative effectiveness and value for money of products launched through accelerated approval schemes. One important reason for risk sharing is to resolve differences of opinion between innovators and payers about a technology's underlying value. To date, there has been no formal attempt to set out the circumstances in which risk sharing can address these differences. METHODS: We use a value of information framework to understand what a performance-based risk-sharing arrangements can, in principle, add to a reimbursement scheme, separating payer perspectives on cost-effectiveness and the value of research from those of the innovator. We find 16 scenarios, developing 5 rules to analyze these 16 scenarios, identifying cases in which risk sharing adds value for both parties. RESULTS: We find that risk sharing provides an improved solution in 9 out of 16 combinations of payer and innovator expectations about treatment outcome and the value of further research. Among our assumptions, who pays for research and scheme administration costs are key. CONCLUSIONS: Steps should be undertaken to make risk sharing more practical, ensuring that payers consider it an option. This requires additional costs to the health system falling on the innovator in an efficient way that aligns incentives for product development for global markets. Health systems benefits are earlier patient access to cost-effective treatments and payers with higher confidence of not wasting money. Innovators get greater returns while conducting research.

The value of treatment for infertility: A systematic literature review of willingness-to-pay thresholds and approaches for determining the cost effectiveness of fertility therapies.

Willingness to pay (WTP) for an infertility treatment is the maximum amount of money a patient is willing to pay per treatment, or to achieve a live birth or pregnancy. Such thresholds are important to determine the cost effectiveness of a treatment. A systematic review was conducted to identify and explore the studies that attempt to ascertain WTP for infertility and compare them with the cost-effectiveness studies that claimed to use WTP thresholds. For comparison, all the costs were converted and inflated to 2021 euros. The results demonstrated that there were no standard outcomes or WTP thresholds for an outcome/treatment, and the methodologies used vary. Cost-effectiveness studies either used the incremental cost-effectiveness ratio to imply a WTP threshold, or used thresholds that were previously accepted for a quality-adjusted life year outcome converted, inappropriately, to an infertility outcome. There is a need for further research by health economists to develop a consensus for the meaningful assessment of WTP for ART.

A Guide to Selecting Flexible Survival Models to Inform Economic Evaluations of Cancer Immunotherapies.

OBJECTIVES: Parametric models are routinely used to estimate the benefit of cancer drugs beyond trial follow-up. The advent of immune checkpoint inhibitors has challenged this paradigm, and emerging evidence suggests that more flexible survival models, which can better capture the shapes of complex hazard functions, might be needed for these interventions. Nevertheless, there is a need for an algorithm to help analysts decide whether flexible models are required and, if so, which should be chosen for testing. This position article has been produced to bridge this gap. METHODS: A virtual advisory board comprising 7 international experts with in-depth knowledge of survival analysis and health technology assessment was held in summer 2021. The experts discussed 24 questions across 6 topics: the current survival model selection procedure, data maturity, heterogeneity of treatment effect, cure and mortality, external evidence, and additions to existing guidelines. Their responses culminated in an algorithm to inform selection of flexible survival models. RESULTS: The algorithm consists of 8 steps and 4 questions. Key elements include the systematic identification of relevant external data, using clinical expert input at multiple points in the selection process, considering the future and the observed hazard functions, assessing the potential for long-term survivorship, and presenting results from all plausible models. CONCLUSIONS: This algorithm provides a systematic, evidence-based approach to justify the selection of survival extrapolation models for cancer immunotherapies. If followed, it should reduce the risk of selecting inappropriate models, partially addressing a key area of uncertainty in the economic evaluation of these agents.

Assessing the value of orphan drugs using conventional cost-effectiveness analysis: Is it fit for purpose?

Conventional cost-effectiveness analysis-i.e., assessing pharmaceuticals through a cost per quality-adjusted life year (QALY) framework-originated from a societal commitment to maximize population health given limited resources. This "extra-welfarist" approach has produced pricing and reimbursement systems that are not well- aligned with the unique considerations of orphan drugs. This framework has been slow to evolve along with our increased understanding of the impact of rare diseases, which in turn has complicated the assessment of orphan drugs meant to treat rare diseases. Herein, we (i) discuss the limitations of conventional cost-effectiveness analysis as applied to assessing access to, as well as the pricing and reimbursement of, orphan drugs, (ii) critically appraise alternative and supplemental approaches, and (iii) offer insights on plausible steps forward.

An Innovative Approach to Modelling the Optimal Treatment Sequence for Patients with Relapsing-Remitting Multiple Sclerosis: Implementation, Validation, and Impact of the Decision-Making Approach.

INTRODUCTION: An innovative computational model was developed to address challenges regarding the evaluation of treatment sequences in patients with relapsing-remitting multiple sclerosis (RRMS) through the concept of a 'virtual' physician who observes and assesses patients over time. We describe the implementation and validation of the model, then apply this framework as a case study to determine the impact of different decision-making approaches on the optimal sequence of disease-modifying therapies (DMTs) and associated outcomes. METHODS: A patient-level discrete event simulation (DES) was used to model heterogeneity in disease trajectories and outcomes. The evaluation of DMT options was implemented through a Markov model representing the patient's disease; outcomes included lifetime costs and quality of life. The DES and Markov models underwent internal and external validation. Analyses of the optimal treatment sequence for each patient were based on several decision-making criteria. These treatment sequences were compared to current treatment guidelines. RESULTS: Internal validation indicated that model outcomes for natural history were consistent with the input parameters used to inform the model. Costs and quality of life outcomes were successfully validated against published reference models. Whereas each decision-making criterion generated a different optimal treatment sequence, cladribine tablets were the only DMT common to all treatment sequences. By choosing treatments on the basis of minimising disease progression or number of relapses, it was possible to improve on current treatment guidelines; however, these treatment sequences were more costly. Maximising cost-effectiveness resulted in the lowest costs but was also associated with the worst outcomes. CONCLUSIONS: The model was robust in generating outcomes consistent with published models and studies. It was also able to identify optimal treatment sequences based on different decision criteria. This innovative modelling framework has the potential to simulate individual patient trajectories in the current treatment landscape and may be useful for treatment switching and treatment positioning decisions in RRMS.

Cost-effectiveness analysis of a single-inhaler triple therapy for COPD in the UK.

UK management costs for COPD, estimated at £1.9 billion/year, are rising. In the FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) study, single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (100/62.5/25 µg) improved clinical outcomes versus budesonide/formoterol (400/12 µg) in patients with symptomatic COPD at risk of exacerbations. We assessed the cost-effectiveness of fluticasone furoate/umeclidinium/vilanterol versus budesonide/formoterol for treating COPD from a UK National Health Service perspective. A model was developed combining a trial-based and Markov component and populated with baseline and treatment effect data from FULFIL, together with UK healthcare resource costs and disease-related utilities. Costs per life year and per quality-adjusted life year gained (costing year 2017) for fluticasone furoate/umeclidinium/vilanterol versus budesonide/formoterol were calculated for a lifetime horizon. Results were explored using deterministic sensitivity, scenario and probabilistic analyses. Fluticasone furoate/umeclidinium/vilanterol was associated with gains in life years (0.533) and quality-adjusted life years (0.506) versus budesonide/formoterol, but at slightly increased total costs (£26 416 versus £25 860). This translated to incremental cost-effectiveness ratios of £1042/life year and £1098/quality-adjusted life year for fluticasone furoate/umeclidinium/vilanterol versus budesonide/formoterol. In scenario analyses, incremental cost-effectiveness ratios ranged from dominant to £1547/quality-adjusted life year gained. Fluticasone furoate/umeclidinium/vilanterol provides a cost-effective treatment option versus budesonide/formoterol for patients with symptomatic COPD in the UK.

What Did Time Tell Us? A Comparison and Retrospective Validation of Different Survival Extrapolation Methods for Immuno-Oncologic Therapy in Advanced or Metastatic Renal Cell Carcinoma.

BACKGROUND: The immuno-oncologic (IO) mechanism of action may lead to an overall survival (OS) hazard that changes over time, producing shapes that standard parametric extrapolation methods may struggle to reflect. Furthermore, selection of the most appropriate extrapolation method for health technology assessment is often based on trial data with limited follow-up. OBJECTIVE: To examine this problem, we fitted a range of extrapolation methods to patient-level survival data from CheckMate 025 (NCT01668784, CM-025), a phase III trial comparing nivolumab with everolimus for previously treated advanced renal cell carcinoma (aRCC), to assess their predictive accuracy over time. METHODS: Six extrapolation methods were examined: standard parametric models, natural cubic splines, piecewise models combining Kaplan-Meier data with an exponential or non-exponential distribution, response-based landmark models, and parametric mixture models. We produced three database locks (DBLs) at minimum follow-ups of 15, 27, and 39 months to align with previously published CM-025 data. A three-step evaluation process was adopted: (1) selection of the distribution family for each method in each of the three DBLs, (2) internal validation comparing extrapolation-based landmark and mean survival with the latest CM-025 dataset (minimum follow-up, 64 months), and (3) external validation of survival projections using clinical expert opinion and long-term follow-up data from other nivolumab studies in aRCC (CheckMate 003 and CheckMate 010). RESULTS: All extrapolation methods, with the exception of mixture models, underestimated landmark and mean OS for nivolumab compared with CM-025 long-term follow-up data. OS estimates for everolimus tended to be more accurate, with four of the six methods providing landmark OS estimates within the 95% confidence interval of observed OS as per the latest dataset. The predictive accuracy of survival extrapolation methods fitted to nivolumab also showed greater variation than for everolimus. The proportional hazards assumption held for all DBLs, and a dependent log-logistic model provided reliable estimates of longer-term survival for both nivolumab and everolimus across the DBLs. Although mixture models and response-based landmark models provided reasonable estimates of OS based on the 39-month DBL, this was not the case for the two earlier DBLs. The piecewise exponential models consistently underestimated OS for both nivolumab and everolimus at clinically meaningful pre-specified landmark time points. CONCLUSIONS: This aRCC case study identified marked differences in the predictive accuracy of survival extrapolation methods for nivolumab but less so for everolimus. The dependent log-logistic model did not suffer from overfitting to early DBLs to the same extent as more complex methods. Methods that provide more degrees of freedom may accurately represent survival for IO therapy, particularly if data are more mature or external data are available to inform the long-term extrapolations.

Value of Information Analytical Methods: Report 2 of the ISPOR Value of Information Analysis Emerging Good Practices Task Force.

The allocation of healthcare resources among competing priorities requires an assessment of the expected costs and health effects of investing resources in the activities and of the opportunity cost of the expenditure. To date, much effort has been devoted to assessing the expected costs and health effects, but there remains an important need to also reflect the consequences of uncertainty in resource allocation decisions and the value of further research to reduce uncertainty. Decision making with uncertainty may turn out to be suboptimal, resulting in health loss. Consequently, there may be value in reducing uncertainty, through the collection of new evidence, to better inform resource decisions. This value can be quantified using value of information (VOI) analysis. This report from the ISPOR VOI Task Force describes methods for computing 4 VOI measures: the expected value of perfect information, expected value of partial perfect information (EVPPI), expected value of sample information (EVSI), and expected net benefit of sampling (ENBS). Several methods exist for computing EVPPI and EVSI, and this report provides guidance on selecting the most appropriate method based on the features of the decision problem. The report provides a number of recommendations for good practice when planning, undertaking, or reviewing VOI analyses. The software needed to compute VOI is discussed, and areas for future research are highlighted.

Value of Information Analysis for Research Decisions-An Introduction: Report 1 of the ISPOR Value of Information Analysis Emerging Good Practices Task Force.

Healthcare resource allocation decisions made under conditions of uncertainty may turn out to be suboptimal. In a resource constrained system in which there is a fixed budget, these suboptimal decisions will result in health loss. Consequently, there may be value in reducing uncertainty, through the collection of new evidence, to make better resource allocation decisions. This value can be quantified using a value of information (VOI) analysis. This report, from the ISPOR VOI Task Force, introduces VOI analysis, defines key concepts and terminology, and outlines the role of VOI for supporting decision making, including the steps involved in undertaking and interpreting VOI analyses. The report is specifically aimed at those tasked with making decisions about the adoption of healthcare or the funding of healthcare research. The report provides a number of recommendations for good practice when planning, undertaking, or reviewing the results of VOI analyses.

Uncertainty and Cures: Discontinuation, Irreversibility, and Outcomes-Based Payments: What Is Different About a One-Off Treatment?

Payers are concerned that one-off "cures" bring great uncertainty with the consequential risk of incorrect adoption decisions, and significant budget impact from large one-off payments. Innovators worry about bias against "cures" in favor of repeat treatment, which is not in patients' interests. We find that even in the absence of a difference in uncertainty of outcomes, adverse pay-offs differ. The greater financial risk associated with a cure is related to the issue of treatment discontinuation, driven by irreversibility. This paper uses a stylized example to illustrate the need to separate three different elements of the issue: (i) one-off versus repeat or ongoing treatment, (ii) duration of treatment effect, and (iii) the potential role of financial arrangements or risk sharing to mitigate the financial risk to the payer. It concludes that: (i) prevalence and discontinuation issues mean that the impact on the payer of an incorrect decision is greater with a one-off treatment than a repeat therapy; (ii) with evidence collection this risk diminishes over time (a form of CED or OWR); and (iii) financial arrangements or risk sharing can eliminate differences for the payer as between one-off and repeat therapy. The impact of (iii) also addresses payer concerns about budget impact.

Cost-effectiveness of TYRX absorbable antibacterial envelope for prevention of cardiovascular implantable electronic device infection.

AIMS: Infection is a major complication of cardiovascular implantable electronic device (CIED) therapy that usually requires device extraction and is associated with increased morbidity and mortality. The TYRX Antibacterial Envelope is a polypropylene mesh that stabilizes the CIED and elutes minocycline and rifampin to reduce the risk of post-operative infection. METHODS: A decision tree was developed to assess the cost-effectiveness of TYRX vs standard of care (SOC) following implantation of four CIED device types. The model was parameterized for a UK National Health Service perspective. Probabilities were derived from the literature. Resource use included drug acquisition and administration, hospitalization, adverse events, device extraction, and replacement. Incremental cost-effectiveness ratios (ICERs) were calculated from costs and quality-adjusted life-years (QALYs). RESULTS: Over a 12-month time horizon, TYRX was less costly and more effective than SOC when utilized in patients with an ICD or CRT-D. TYRX was associated with ICERs of £46,548 and £21,768 per QALY gained in patients with an IPG or CRT-P, respectively. TYRX was cost-effective at a £30,000 threshold at baseline probabilities of infection exceeding 1.65% (CRT-D), 1.95% (CRT-P), 1.87% (IPG), and 1.38% (ICD). LIMITATIONS AND CONCLUSIONS: Device-specific infection rates for high-risk patients were not available in the literature and not used in this analysis, potentially under-estimating the impact of TYRX in certain devices. Nevertheless, TYRX is associated with a reduction in post-operative infection risk relative to SOC, resulting in reduced healthcare resource utilization at an initial cost. The ICERs are below the accepted willingness-to-pay thresholds used by UK decision-makers. TYRX, therefore, represents a cost-effective prevention option for CIED patients at high-risk of post-operative infection.

Adjuvant HPV vaccination for anal cancer prevention in HIV-positive men who have sex with men: The time is now.

IMPORTANCE: Outcomes of treating high-grade squamous intraepithelial lesions (HSIL), a precursor to anal cancer, remain uncertain. Emerging evidence shows that post HSIL treatment adjuvant quadrivalent human papillomavirus (qHPV) vaccination improves the effectiveness of treatment. However, no recommendations exist regarding the use of qHPV vaccine as an adjuvant form of therapy. Our objective was to determine whether post-treatment adjuvant vaccination should be adopted in HIV-infected MSM (individuals at highest risk for anal cancer) on the basis of cost-effectiveness determined using existing evidence or whether future research is needed. METHODS: We developed a Markov (state-transition) cohort model to assess the cost-effectiveness of post-treatment adjuvant HPV vaccination of 27years or older HIV-infected MSM. We first estimated cost-effectiveness and then performed value-of-information (VOI) analysis to determine whether future research is required by estimating the expected value of perfect information (EVPI). We also estimated expected value of partial perfect information (EVPPI) to determine what new evidences should have highest priority. RESULTS: With the incremental cost-effectiveness ratio (ICER) of $71,937/QALY, "treatment plus vaccination" was the most cost-effective HSIL management strategy using the willingness-to-pay threshold of 100,000/QALY. We found that population-level EVPI for conducting future clinical research evaluating HSIL management approaches was US$12 million (range $6-$20 million). The EVPPI associated with adjuvant qHPV vaccination efficacy estimated in terms of hazards of decreasing HSIL recurrence was $0 implying that additional data from a future study evaluating efficacy of adjuvant qHPV vaccination will not change our policy conclusion that "treatment plus vaccination" was cost-effective. Both the ICER and EVPI were sensitive to HSIL treatment compliance. CONCLUSION: Post-treatment adjuvant qHPV vaccination in HIV-infected MSM aged 27 or above is likely to be cost-effective. Use of adjuvant qHPV vaccination could be considered as a potential strategy to reduce rising anal cancer burden among these high-risk individuals.

Emerging Use of Early Health Technology Assessment in Medical Product Development: A Scoping Review of the Literature.

Early health technology assessment is increasingly being used to support health economic evidence development during early stages of clinical research. Such early models can be used to inform research and development about the design and management of new medical technologies to mitigate the risks, perceived by industry and the public sector, associated with market access and reimbursement. Over the past 25 years it has been suggested that health economic evaluation in the early stages may benefit the development and diffusion of medical products. Early health technology assessment has been suggested in the context of iterative economic evaluation alongside phase I and II clinical research to inform clinical trial design, market access, and pricing. In addition, performing early health technology assessment was also proposed at an even earlier stage for managing technology portfolios. This scoping review suggests a generally accepted definition of early health technology assessment to be "all methods used to inform industry and other stakeholders about the potential value of new medical products in development, including methods to quantify and manage uncertainty". The present review also aimed to identify recent published empirical studies employing an early-stage assessment of a medical product. With most included studies carried out to support a market launch, the dominant methodology was early health economic modeling. Further methodological development is required, in particular, by combining systems engineering and health economics to manage uncertainty in medical product portfolios.

The CARE Plus study - a whole-system intervention to improve quality of life of primary care patients with multimorbidity in areas of high socioeconomic deprivation: exploratory cluster randomised controlled trial and cost-utility analysis.

BACKGROUND: Multimorbidity is common in deprived communities and reduces quality of life. Our aim was to evaluate a whole-system primary care-based complex intervention, called CARE Plus, to improve quality of life in multimorbid patients living in areas of very high deprivation. METHODS: We used a phase 2 exploratory cluster randomised controlled trial with eight general practices in Glasgow in very deprived areas that involved multimorbid patients aged 30-65 years. The intervention comprised structured longer consultations, relationship continuity, practitioner support, and self-management support. Control practices continued treatment as usual. Primary outcomes were quality of life (EQ-5D-5L utility scores) and well-being (W-BQ12; 3 domains). Cost-effectiveness from a health service perspective, engagement, and retention were assessed. Recruitment and baseline measurements occurred prior to randomisation. Blinding post-randomisation was not possible but outcome measurement and analysis were masked. Analyses were by intention to treat. RESULTS: Of 76 eligible practices contacted, 12 accepted, and eight were selected, randomised and participated for the duration of the trial. Of 225 eligible patients, 152 (68 %) participated and 67/76 (88 %) in each arm completed the 12-month assessment. Two patients died in the control group. CARE Plus significantly improved one domain of well-being (negative well-being), with an effect size of 0.33 (95 % confidence interval [CI] 0.11-0.55) at 12 months (p = 0.0036). Positive well-being, energy, and general well-being (the combined score of the three components) were not significantly influenced by the intervention at 12 months. EQ-5D-5L area under the curve over the 12 months was higher in the CARE Plus group (p = 0.002). The incremental cost in the CARE Plus group was £929 (95 % CI: £86-£1788) per participant with a gain in quality-adjusted life years of 0.076 (95 % CI: 0.028-0.124) over the 12 months of the trial, resulting in a cost-effectiveness ratio of £12,224 per quality-adjusted life year gained. Modelling suggested that cost-effectiveness would continue. CONCLUSIONS: It is feasible to conduct a high-quality cluster randomised control trial of a complex intervention with multimorbid patients in primary care in areas of very high deprivation. Enhancing primary care through a whole-system approach may be a cost-effective way to protect quality of life for multimorbid patients in deprived areas. TRIAL REGISTRATION: ISRCTN 34092919 , assigned 14/1/2013.

Cost-Effectiveness of HBV and HCV Screening Strategies--A Systematic Review of Existing Modelling Techniques.

INTRODUCTION: Studies evaluating the cost-effectiveness of screening for Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are generally heterogeneous in terms of risk groups, settings, screening intervention, outcomes and the economic modelling framework. It is therefore difficult to compare cost-effectiveness results between studies. This systematic review aims to summarise and critically assess existing economic models for HBV and HCV in order to identify the main methodological differences in modelling approaches. METHODS: A structured search strategy was developed and a systematic review carried out. A critical assessment of the decision-analytic models was carried out according to the guidelines and framework developed for assessment of decision-analytic models in Health Technology Assessment of health care interventions. RESULTS: The overall approach to analysing the cost-effectiveness of screening strategies was found to be broadly consistent for HBV and HCV. However, modelling parameters and related structure differed between models, producing different results. More recent publications performed better against a performance matrix, evaluating model components and methodology. CONCLUSION: When assessing screening strategies for HBV and HCV infection, the focus should be on more recent studies, which applied the latest treatment regimes, test methods and had better and more complete data on which to base their models. In addition to parameter selection and associated assumptions, careful consideration of dynamic versus static modelling is recommended. Future research may want to focus on these methodological issues. In addition, the ability to evaluate screening strategies for multiple infectious diseases, (HCV and HIV at the same time) might prove important for decision makers.

The management of Otitis Media with Effusion in children with cleft palate (mOMEnt): a feasibility study and economic evaluation.

BACKGROUND: Cleft lip and palate are among the most common congenital malformations, with an incidence of around 1 in 700. Cleft palate (CP) results in impaired Eustachian tube function, and 90% of children with CP have otitis media with effusion (OME) histories. There are several approaches to management, including watchful waiting, the provision of hearing aids (HAs) and the insertion of ventilation tubes (VTs). However, the evidence underpinning these strategies is unclear and there is a need to determine which treatment is the most appropriate. OBJECTIVES: To identify the optimum study design, increase understanding of the impact of OME, determine the value of future research and develop a core outcome set (COS) for use in future studies. DESIGN: The management of Otitis Media with Effusion in children with cleft palate (mOMEnt) study had four key components: (i) a survey evaluation of current clinical practice in each cleft centre; (ii) economic modelling and value of information (VOI) analysis to determine if the extent of existing decision uncertainty justifies the cost of further research; (iii) qualitative research to capture patient and parent opinion regarding willingness to participate in a trial and important outcomes; and (iv) the development of a COS for use in future effectiveness trials of OME in children with CP. SETTING: The survey was carried out by e-mail with cleft centres. The qualitative research interviews took place in patients' homes. The COS was developed with health professionals and parents using a web-based Delphi exercise and a consensus meeting. PARTICIPANTS: Clinicians working in the UK cleft centres, and parents and patients affected by CP and identified through two cleft clinics in the UK, or through the Cleft Lip and Palate Association. RESULTS: The clinician survey revealed that care was predominantly delivered via a 'hub-and-spoke' model; there was some uncertainty about treatment strategies; it is not current practice to insert VTs at the time of palate repair; centres were in a position to take part in a future study; and the response rate to the survey was not good, representing a potential concern about future co-operation. A COS reflecting the opinions of clinicians and parents was developed, which included nine core outcomes important to both health-care professionals and parents. The qualitative research suggested that a trial would have a 25% recruitment rate, and although hearing was a key outcome, this was likely to be due to its psychosocial consequences. The VOI analysis suggested that the current uncertainty justified the costs of future research. CONCLUSIONS: There exists significant uncertainty regarding the best management strategy for persistent OME in children with clefts, reflecting a lack of high-quality evidence regarding the effectiveness of individual treatments. It is feasible, cost-effective and of significance to clinicians and parents to undertake a trial examining the effectiveness of VTs and HAs for children with CP. However, in view of concerns about recruitment rate and engagement with the clinicians, we recommend that a trial with an internal pilot is considered. FUNDING: The National Institute for Health Research Health Technology Assessment programme. This study was part-funded by the Healing Foundation supported by the Vocational Training Charitable Trust who funded trial staff including the study co-ordinator, information systems developer, study statistician, administrator and supervisory staff.

Operationalising the capability approach as an outcome measure in public health: The development of the OCAP-18.

There is growing interest in operationalising the capability approach to measure quality of life. This paper reports the results of a research project undertaken in 2007 that sought to reduce and refine a longer survey in order to provide a summary measure of wellbeing and capability in the realm of public health. The reduction and refinement of the questionnaire took place across a number of stages, using both qualitative (five focus group discussions and 17 in-depth interviews) and quantitative (secondary data analysis, N = 1048 and primary data collection using postal surveys and interviews, N = 45) approaches. The questionnaire was reduced from its original 60+ questions to 24 questions (including demographic questions). Each of Nussbaum's ten Central Human Capabilities are measured using one (or more) of the 18 specific capability items which are included in the questionnaire (referred to as the OCAP-18). Analysis of the questionnaire responses (N = 198) found that respondents differed with respect to the levels of capabilities they reported, and that these capabilities appear to be sensitive to one's gender, age, income and deprivation decile. An index of capability, estimated by assuming equal weight for each capability question, found that the average level of capability amongst respondents was 12.44 (range 3-17.75). This index was found to be highly correlated with a measure of health (EQ-5D) and wellbeing (global QoL), although some differences were apparent. This project operationalised the capability approach to produce an instrument to measure the effectiveness (and cost effectiveness) of public health interventions; the resulting OCAP-18 appears to be responsive and measure something supplementary to health and wellbeing, thus offers a promising addition to the current suite of outcome measures that are available.

Communicating the parameter uncertainty in the IQWiG efficiency frontier to decision-makers.

The Institute for Quality and Efficiency in Health Care (IQWiG) developed-in a consultation process with an international expert panel-the efficiency frontier (EF) approach to satisfy a range of legal requirements for economic evaluation in Germany's statutory health insurance system. The EF approach is distinctly different from other health economic approaches. Here, we evaluate established tools for assessing and communicating parameter uncertainty in terms of their applicability to the EF approach. Among these are tools that perform the following: (i) graphically display overall uncertainty within the IQWiG EF (scatter plots, confidence bands, and contour plots) and (ii) communicate the uncertainty around the reimbursable price. We found that, within the EF approach, most established plots were not always easy to interpret. Hence, we propose the use of price reimbursement acceptability curves-a modification of the well-known cost-effectiveness acceptability curves. Furthermore, it emerges that the net monetary benefit allows an intuitive interpretation of parameter uncertainty within the EF approach. This research closes a gap for handling uncertainty in the economic evaluation approach of the IQWiG methods when using the EF. However, the precise consequences of uncertainty when determining prices are yet to be defined.

A model-based cost-effectiveness analysis of a grommets-led care pathway for children with cleft palate affected by otitis media with effusion.

There is a paucity of evidence to guide the management of otitis media with effusion (OME), which is a common problem causing significant hearing impairment in children with cleft palate. The insertion of grommets is currently being used to correct hearing impairment and prevent complications of unmanaged OME, but there is ongoing discussion about whether the benefits of grommets outweigh the costs and risks. A decision-tree model was developed to assess the surgical insertion of grommets with two non-surgical alternatives (hearing-aids and do-nothing strategies) in cleft palate children with persistent bilateral OME. The model assumed a 2-year time horizon and a UK National Health Service perspective. Outcomes were valued using quality-adjusted life-years (QALYs) estimated by linking utility values with potential hearing gains measured in decibels. Multiple data sources were used, including reviews of the clinical effectiveness, resource use and utility literature, and supplemented with expert opinion. Uncertainty in the model parameters was assessed using probabilistic sensitivity analysis. Expected value of perfect information analysis was used to calculate the potential value of future research. The results from the probabilistic sensitivity analysis indicated that the grommets strategy was associated with an incremental cost-effectiveness ratio of £9,065 per QALY gained compared with the do-nothing strategy, and the hearing-aids strategy was extended dominated by the grommets strategy. The population expected value of perfect information was £5,194,030 at a willingness to pay threshold of £20,000 per QALY, implying that future research could be potentially worthwhile. This study found some evidence that the insertion of grommets to manage cleft palate children with bilateral OME is likely to be cost-effective, but further research is required to inform this treatment choice.