European health technology assessment (HTA) bodies vary with regards to methodology, willingness to accept uncertainty, and preferences for different types of evidence. Previous studies have revealed substantial differences in the focus of European HTA processes and final decisions on recommendation. We therefore set out to explore how exactly the variation in decision drivers results in discrepancies in recommendations between the payer archetypes. A critical review of HTA reports from NICE (England), HAS (France), and IQWiG (Germany) was conducted. These agencies were selected because they are representative of different payer archetypes, have large associated markets, and are relatively transparent in reporting. Qualitative semi-structured interviews provided added context. Cabazitaxel and pixantrone were selected as case studies due to the mixture of recommendations and rejections received for these products in the target countries. The review investigated the key evidence considered and the agencies’ responses to the evidence, particularly with regards to accounting for uncertainty. Cabazitaxel was approved for prostatic neoplasms by HAS and IQWiG, yet rejected by NICE on the grounds of a high ICER (~£90,000/QALY). On the other hand, pixantrone received restricted approval for non-Hodgkin’s lymphoma by NICE and HAS, despite uncertainties created by a small trial population and post hoc sub-group analyses, while IQWiG found no added benefit. The inconsistency in decision-making in European HTA processes is therefore likely to relate, in part, to the relative emphasis placed on different aspects of the clinical and economic evidence, and the willingness of agencies to accept associated uncertainty. While understanding the international HTA processes is important, establishing the key drivers for previous decisions across agencies could be an efficient way to achieve approval and access. This is best achieved through a combination of expert elicitation and a critical review of previous HTA decisions.

To identify, using HTAinSite, if and how manufacturers have used improved patient compliance as a value argument for their product in submissions to the National Institute for Health and Clinical Excellence (NICE). We analysed if and how compliance data were presented, how they were received by NICE, and if they were an influential factor in NICE's decision making. A key phrase search in HTAinSite was used to identify instances of ‘compliance' and ‘adherence' in manufacturer submissions and NICE technology appraisal (TA) documents. After review for relevance, information was extracted and used to conduct a qualitative analysis. Fifteen manufacturer's submissions and 12 TAs reported an improvement in compliance as a value argument for their drug. Factors used to justify improved compliance included improved convenience, a reduction in adverse events, increased treatment choice, and improved route of administration. In 8 of 13 TAs (relating to 11 manufacturer submissions), NICE state that the compliance argument was considered by the Committee. In the remaining 5 TAs, despite inclusion of a compliance argument by manufacturers in their submissions, the Committee made no reference to it in the TA. Interestingly, only three manufacturers explicitly reported evidence supporting their compliance argument; however, the Committee discussed this in all of the associated TAs. The impact of improved compliance on clinical outcomes or cost-effectiveness was frequently not clearly reported by manufacturers or NICE. NICE did not explicitly cite compliance as an influential factor in their final decision in any TAs. The committee are more likely to consider a compliance argument if there is a clear clinical rationale and it is accompanied by supporting data. Although compliance arguments are considered by the Committee, NICE have not explicitly stated to have used them to influence final decisions.

To identify and explore how reimbursement decisions for natalizumab, a treatment for multiple sclerosis (MS), were overturned from an initial rejection to a recommendation. This analysis was conducted in conjuntion with a wider review of the global reimbursement landscape for MS therapies. We reviewed reimbursement decisions or recommendations from global payer decision-making agencies, including any decisions where an initial rejection was overturned. We reviewed the agency rationale for both the original and subsequent decisions, and how the manufacturer influenced the decision reversal. Since 2006, 17 payer decisions for natalizumab were identified (six recommendations, eight restricted recommendations and three rejections). The three rejected decisions were later overturned by the manufacturer submitting further evidence. To PBAC this involved re-defining the indirect comparison to consider the heterogeneity in the trials included. To SMC and CADTH post-hoc analysis was submitted for the specific subgroup of rapidly evolving severe relapsing remitting MS. For CADTH a 15% price discount was agreed in addition. Across all agencies clinical need was an important factor. By emphasising unmet needs, submitting further evidence in defined subgroups and ensuring indirect comparisons are methodologically sound, it has been possible to overturn initial negative decisions by payer agencies to restricted recommendations in define subgroup. Identification of the optimum treatable population has proved pivotal in the reversal of fortune.

To use a database of previous National Institute for Health and Clinical Excellence (NICE) health technology assessment (HTA) decisions (HTA inSite)1to understand the impact of four clinical evidence scenarios on the outcome of NICE technology appraisals (TAs). We identified published NICE TAs containing evidence applicable to the following scenarios: 1) Efficacy data with a non-significant but positive trend; 2) Surrogate endpoints used in place of real endpoints; 3) Composite endpoints where statistical significance was driven by some, but not all, of the individual components; and 4) Efficacy data from observational studies. For each scenario, multiple submissions and re-submissions were identified using HTA inSite. The analysis focused on the evidence submitted, the final decision and critique by NICE, and any changes in approach by the manufacturer at re-submission. Clear patterns emerged for each scenario. For example NICE accepted data from surrogate endpoints (scenario 2) in all of the 4 submissions analysed. This was due to support by clinical experts and a clear rationale for the surrogates as established markers of efficacy. Observational data (scenario 4) were accepted in the absence of randomised controlled trials (RCTs), or in addition to RCTs where long-term or country-specific evidence was required. However, it was important to acknowledge and report any potential bias associated with the design of observational studies. An evaluated database can be used to understand the impact of any clinical evidence scenario on NICE decisions. The results can be used to inform submission strategy and assess decision outcome risk.

Objective:To identify and critically appraise cost-effectiveness models developed to evaluate type 2 diabetes (T2D) treatments and to assess which types of treatment effects they capture.Research design and methods:A systematic search was performed in MEDLINE, EMBASE, Centre for Reviews and Dissemination databases at the University of York, and Health Economic Evaluation Database for the period to September 2008. The websites of Health Technology Assessment (HTA) bodies in different countries were also screened for relevant models. For each of the identified original models, details of the structure, data in-and outputs were extracted and the overall quality of the model in terms of the combination of structure, assumptions and data inputs were appraised using published criteria.Results:Seventy-eight articles and 41 HTAs reporting relevant economic evaluations were identified. There were ten models with multiple publications, and a further ten models with one associated publication. The critical review demonstrated that most had the same fundamental structure, used similar micro-simulation techniques and were based on the same key data sources. However, the process for identification of relevant data and their synthesis, and the selection of outcomes lacked transparency. The models differed according to the extent and type of interventions they evaluated and which diabetes complications and treatment-related adverse events were captured. For example, just one model incorporated changes in patient weight, despite the fact that weight gain can be a side-effect of some treatments, and weight loss a potential benefit of others.Conclusions:Whilst many economic models exist in T2D, most share common features such as the model type. Identified shortcomings are lack of transparency in data identification and evidence synthesis as well as the selection of the modelled outcomes. Future models should aim to include all relevant treatment outcomes, whether these relate to effects on underlying diabetes and its complications or to short-or long-term side effects of treatment.

Objective: To establish whether women with low‐grade abnormalities detected during screening for cervical cancer prefer to be managed by cytological surveillance or by immediate colposcopy. Methods: TOMBOLA (Trial of Management of Borderline and Other Low‐grade Abnormal smears) is a randomized controlled trial comparing alternative management strategies following the screen‐detection of low‐grade cytological abnormalities. At exit, a sample of TOMBOLA women completed a questionnaire eliciting opinions on their management, contingent valuations (CV) of the management methods and preferences. Within‐trial quality of life (EQ‐5D) data collected for a sample of TOMBOLA women throughout their follow‐up enabled the comparison of self‐reported health at various time points, by management method. Results: Once management had been initiated, self‐reported health in the colposcopy arm rose relative to that in the surveillance arm, although the effect was short‐term only. For the majority of women, the satisfaction ratings and the CV indicated approval of the management method to which they had been randomized. Of the minority manifesting a preference for the method which they had not experienced, relatively more would have preferred colposcopy than would have preferred surveillance. Conclusions: The findings must be interpreted in the light of sample bias with respect to preferences, whereby enthusiasm for colposcopy was probably over‐represented amongst trial participants. The study suggests that neither of the management methods is preferred unequivocally; rather, individual women have individual preferences, although many would be indifferent between methods.

Receipt of an abnormal cervical smear result often generates fear and confusion and can have a negative impact on a woman's well-being. Most previous studies have focussed on high-grade abnormal smears. This study describes the psychological and psychosocial effects, on women, of having received a low-grade abnormal smear result. Over 3500 women recruited to TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears) participated in this study. Anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS) at recruitment. Socio-demographic and lifestyle factors, locus of control and factors associated with the psychosocial impact of the abnormal smear result were also assessed. Women reported anxiety levels consistent with those found in previous studies of women with high-grade smear results. Women at highest risk of anxiety were younger, had children, were current smokers, or had the highest levels of physical activity. Interventions that focus particularly on women's understanding of smear results and pre-cancer, and/or directly address their fears about cancer, treatment and fertility might provide the greatest opportunity to reduce the adverse psychosocial impact of receiving a low-grade abnormal cervical smear result.

BACKGROUND:The glycoprotein IIb/IIIa antagonists (GPAs) represent a new class of drugs to prevent platelet aggregation in the acute treatment of non-ST-elevation acute coronary syndromes (NSTE-ACS). Systematic reviews have identified serious limitations in published cost-effectiveness analyses, including a lack of UK-specific studies and an absence of studies comparing different protocols for the use of GPAs. METHODS:A model was developed to assess the cost effectiveness of a variety of protocols employing GPAs for patients presenting with NSTE-ACS in the UK. The perspective of the UK National Health Service was adopted, with outcomes in terms of quality-adjusted life-years (QALYs). Four treatment strategies were evaluated: GPAs as part of initial medical management (Strategy 1); GPAs in patients with planned percutaneous coronary interventions (PCIs; Strategy 2); GPAs as an adjunct to the PCI procedure (Strategy 3); and no GPAs (Strategy 4). Baseline event rates and costs were taken from a UK observational study of ACS patients and relative risk reductions from GPAs were taken from a meta analysis of trials. Long-term costs and QALYs were estimated using data from a UK longitudinal study. RESULTS:The most cost-effective use of GPAs is likely to be Strategy 1, with an incremental cost per QALY gained of between pound4605 to pound10,343. Focusing this use of GPAs only on the subgroup of patients at high risk appears to represent the most cost-effective use of NHS resources. CONCLUSIONS:Medical management of patients with NSTE-ACS using GPAs is the most cost-effective use of resources, particularly if targeted to higher risk subgroups.

This paper describes an experiment to test the construct validity of contingent valuation, by eliciting women's valuations for the NHS cervical cancer screening programme. It is known that, owing to low levels of knowledge of cancer and screening in the general population, women both over-estimate the risk of disease and the efficacy of screening. The study is constructed as a randomised experiment, in which one group is provided with accurate information about cervical cancer screening, whilst the other is not. The first hypothesis supporting construct validity, that controls who perceive greater benefits from screening will offer higher valuations, is substantiated. Both groups are then provided with objective information on an improvement to the screening programme, and are asked to value the improvement as an increment to their original valuations. The second hypothesis supporting construct validity, that controls who perceive the benefits of the programme to be high already will offer lower incremental valuations, is also substantiated.

An examination of the willingness to pay values elicited from more than 3000 persons involved in three independent studies revealed that the majority had offered one of a limited number of values from the ranges available to them. These values were 'prominent numbers', the use of which has been observed previously in circumstances where subjects feel that precise estimates of value are either difficult to make, or are not worth making. The existence of widespread prominence in response is suggestive of hypothetical bias in contingent valuation.

This paper describes the process of developing and testing a new questionnaire, Process Outcome Specific Measure (POSM), including an assessment of its content validity and reliability. The questionnaire was developed within the context of Trial Of Management of Borderline and Other Low-grade Abnormal smears (TOMBOLA) to assess the psychosocial impact of a low-grade abnormal cervical smear result and the subsequent management. A literature search, focus groups and thorough pre-testing involving experts and patients resulted in a short (15-item), easily completed and understood questionnaire. Questions address issues including cancer, health, fertility and sexual concerns. Repeatability was assessed in 110 TOMBOLA recruits using weighted κ; all but one of the questions showed levels of reliability near to, or above, 0.5. Cronbach’s standardised α was 0.73, indicating acceptable internal consistency. Each POSM item was correlated with the anxiety and depression sub-scales of the Hospital Anxiety Depression Scale (HADS). All except one of the questions correlated more highly with the total POSM score than with the HADS sub-scales thus indicating discriminant validity. The POSM will enable comparison of the alternative management policies for low-grade cervical smears in terms of the benefits (or otherwise) perceived by the women managed by these policies.

This study assesses the extent and accuracy of women's knowledge of cervical cancer, risk factors, and the efficacy of the national screening program. Data were obtained from a questionnaire survey of randomly selected women eligible for screening, drawn from a population in east-central England. The majority of women in the sample overestimated the current incidence of cervical cancer, both absolutely and relative to other cancers. Perceiving incidence to be high was associated with reporting worries about the disease. With respect to the screening process, 78.3% believe that the smear abnormality rate is higher than it actually is, and only 7.6% correctly appreciate that the abnormality rate is highest at younger ages. With respect to performance, 16.3% believed the smear test to be completely accurate, and more than half overestimated the likely number of cancer cases prevented by screening. While certain cervical cancer risk factors were correctly assigned by the majority of women, undue emphasis was placed on genetic influence, while the risks posed by human papillomavirus infection were unfamiliar to almost half of the sample. We conclude that women typically possess only a partial picture of risk factors and overestimate both the incidence of cervical cancer and the efficacy of screening.

OBJECTIVESTo identify and prioritise key areas of clinical uncertainty regarding the medical management of non-ST elevation acute coronary syndrome (ACS) in current UK practice.DATA SOURCESElectronic databases. Consultations with clinical advisors. Postal survey of cardiologists.REVIEW METHODSPotential areas of important uncertainty were identified and 'decision problems' prioritised. A systematic literature review was carried out using standard methods. The constructed decision model consisted of a short-term phase that applied the results of the systematic review and a long-term phase that included relevant information from a UK observational study to extrapolate estimated costs and effects. Sensitivity analyses were undertaken to examine the dependence of the results on baseline parameters, using alternative data sources. Expected value of information analysis was undertaken to estimate the expected value of perfect information associated with the decision problem. This provided an upper bound on the monetary value associated with additional research in the area.RESULTSSeven current areas of clinical uncertainty (decision problems) in the drug treatment of unstable angina patients were identified. The agents concerned were clopidogrel, low molecular weight heparin, hirudin and intravenous glycoprotein antagonists (GPAs). Twelve published clinical guidelines for unstable angina or non-ST elevation ACS were identified, but few contained recommendations about the specified decision problems. The postal survey of clinicians showed that the greatest disagreement existed for the use of small molecule GPAs, and the greatest uncertainty existed for decisions relating to the use of abciximab (a large molecule GPA). Overall, decision problems concerning the GPA class of drugs were considered to be the highest priority for further study. Selected papers describing the clinical efficacy of treatment were divided into three groups, each representing an alternative strategy. The strategy involving the use of GPAs as part of the initial medical management of all non-ST elevation ACS was the optimal choice, with an incremental cost-effectiveness ratio (ICER) of 5738 pounds per quality-adjusted life-year (QALY) compared with no use of GPAs. Stochastic analysis showed that if the health service is willing to pay 10,000 pounds per additional QALY, the probability of this strategy being cost-effective was around 82%, increasing to 95% at a threshold of 50,000 pounds per QALY. A sensitivity analysis including an additional strategy of using GPAs as part of initial medical management only in patients at particular high risk (as defined by age, ST depression or diabetes) showed that this additional strategy was yet more cost-effective, with an ICER of 3996 pounds per QALY compared with no treatment with GPA. Value of information analysis suggested that there was considerable merit in additional research to reduce the level of uncertainty in the optimal decision. At a threshold of 10,000 pounds per QALY, the maximum potential value of such research in the base case was calculated as 12.7 million pounds per annum for the UK as a whole. Taking account of the greater uncertainty in the sensitivity analyses including clopidogrel, this figure was increased to approximately 50 million pounds.CONCLUSIONSThis study suggests the use of GPAs in all non-ST elevation ACS patients as part of their initial medical management. Sensitivity analysis showed that virtually all of the benefit could be realised by treating only high-risk patients. Further clarification of the optimum role of GPAs in the UK NHS depends on the availability of further high-quality observational and trial data. Value of information analysis derived from the model suggests that a relatively large investment in such research may be worthwhile. Further research should focus on the identification of the characteristics of patients who benefit most from GPAs as part of medical management, the comparison of GPAs with clopidogrel as an adjunct to standard care, follow-up cohort studies of the costs and outcomes of high-risk non-ST elevation ACS over several years, and exploring how clinicians' decisions combine a normative evidence-based decision model with their own personal behavioural perspective.

Background: This project developed as a result of the activities of the Research Teams at the Centre for Health Economics, University of York, and ScHARR at the University of Sheffield in the methods and application of decision analysis and value of information analysis as a means of informing the research recommendations made by NICE, as part of its Guidance to the NHS in England and Wales, and informing the deliberations of the NICE Research and Development Committee. Bayesian decision analysis and value of information analysis (DA-VOI) provides a methodological framework which explicitly considers the uncertainty surrounding the decision of a health care system to adopt a health technology. Specifically, using existing evidence, these methods focus on the likelihood of making a wrong decision if the technology is adopted. The value of additional research is based on the extent to which further information will reduce this decision uncertainty. This framework values the additional information, which may be generated by further research, in a way which is consistent with the objectives and the resource constraints of heath care provision (the cost-effectiveness threshold). This allows a comparison of the potential benefits of further research with the costs of further investigation, a comparison and prioritisation of alternative research recommendations, both within and between Technology Assessments, as well as an assessment of the value of investing resources in research or other activities, such as the provision of health service. In this sense it provides a unified and coherent framework for prioritisation of research and the use of heath care technologies. Objectives: The specific objectives of the pilot study were to: • Demonstrate the benefits of using appropriate decision analytic methods and value of information analysis to inform research recommendations. • Establish the feasibility and resource implications of applying these methods in a timely way, to inform NICE. • Identify critical issues and methodological challenges to the use of value of information methods for research recommendations (with particular regard to the new reference case as a suitable basis for this type of analysis). The project consists of a series of case studies based on recent technology assessment reports completed by the York and Sheffield group for NICE. These included: • Screening for age related macular degeneration (AMD) • Glycoprotein IIb/IIIa antagonists for acute coronary syndrome (GPAs) • Clopidogrel and dipyridamole in the secondary prevention of occlusive vascular events (CLO) • Neurominidase inhibitors for the treatment of influenza (NIs) • Liquid based cytology screening for cervical cancer (LBC) • Beta interferon and glatiramer acetate in the management of MS (MS) The purpose was to establish the feasibility and requirements of value of information analysis once submissions and Technology Assessment Reports (TARs) are conducted within the reference case specified in the recent methods guidance. Therefore case studies were selected on the basis that the existing TAR comes as close to the new reference case analysis as possible (continues..)