Cost-effectiveness of prophylactic vaccination against human papillomavirus 16/18 for the prevention of cervical cancer: adaptation of an existing cohort model to the situation in the Netherlands.

Cervical cancer is one of the most prevalent cancers among women worldwide. Implementation of an HPV-vaccination strategy targeting the major oncogenic types 16 and 18 that cause cervical cancer is generally expected to significantly reduce the burden of cervical cancer disease. Here we estimate the costs, savings and health gains with the addition of HPV-16/18 vaccination to the already existing Dutch screening programme. In the base-case analysis, it was estimated that implementation of an HPV-16/18 vaccine would result in an incremental cost-effectiveness ratio (ICER) of euro22,700 per life-year gained (LYG). In sensitivity analysis, the robustness of our finding of favourable cost-effectiveness was established. The ICER appeared sensitive to the vaccine price, discount rate and duration of vaccine-induced protection. From our results, it validly follows that immunization of 12-year-old Dutch girls against HPV-16/18 infection is a cost-effective strategy for protecting against cervical cancer.

Economic evaluation.

Given the need to assess the value for money of healthcare treatments, economic evaluation has been gaining popularity over the past ten years. Studies comparing the costs and consequences of alternative healthcare interventions have been published in all fields of healthcare. This article describes the basic forms of economic evaluation and outlines the key methodological features to be considered in the critical appraisal of studies. Issues such as the appropriateness of the study question, the selection of alternatives to be compared, the measurement of costs and consequences, and the assessment of uncertainty are discussed. Additionally, an analytical critique of economic evaluations undertaken in Singapore is provided, and the prospects for economic evaluation in the future are discussed.

Analytic choices in economic models of treatments for rheumatoid arthritis: What makes a difference?

OBJECTIVES: To compare the analytic judgments, data, and assumptions of different models used in the economic evaluation of infliximab, one of a new class of drugs for rheumatoid arthritis (RA). METHODS: A detailed assessment was made of 4 models, 1 submitted (in a reimbursement dossier) by the manufacturer, 1 produced by an independent academic group, and 2 recently published in the literature. Factors considered included the key data inputs, assumptions about the sequencing of treatments for RA, the methods used to calculate health utilities, and the estimation of cost offsets. RESULTS: Two of the 4 models, although embodying different methodological approaches, gave fairly similar results (approximately 25,000 pounds- 35,000 pounds cost per additional quality-adjusted life year [QALY] gained). The other 2 models, both by an independent academic group, gave much higher estimates, ranging from 50,000 pounds to 60,000 pounds to more than 100,000 pounds per additional QALY. The differences appeared to depend mainly on differences in model structure, the assumptions about the positioning of infliximab in the treatment sequence, and the relationship between Health Assessment Questionnaire (HAQ) states and QALYs. CONCLUSIONS: Economic models of treatments for RA incorporate different key data inputs and analytic judgments. However, convergence was observed in some of the estimates produced by the models, particularly when adjustments were made for some of the differences in input parameters. Nevertheless, differences in the choice of model structure and in key assumptions also had a major impact on results. Therefore, more discussion is needed to reach a consensus on some of these methodological issues.

Generalisability in economic evaluation studies in healthcare: a review and case studies.

OBJECTIVES: To review, and to develop further, the methods used to assess and to increase the generalisability of economic evaluation studies. DATA SOURCES: Electronic databases. REVIEW METHODS: Methodological studies relating to economic evaluation in healthcare were searched. This included electronic searches of a range of databases, including PREMEDLINE, MEDLINE, EMBASE and EconLit, and manual searches of key journals. The case studies of a decision analytic model involved highlighting specific features of previously published economic studies related to generalisability and location-related variability. The case-study involving the secondary analysis of cost-effectiveness analyses was based on the secondary analysis of three economic studies using data from randomised trials. RESULTS: The factor most frequently cited as generating variability in economic results between locations was the unit costs associated with particular resources. In the context of studies based on the analysis of patient-level data, regression analysis has been advocated as a means of looking at variability in economic results across locations. These methods have generally accepted that some components of resource use and outcomes are exchangeable across locations. Recent studies have also explored, in cost-effectiveness analysis, the use of tests of heterogeneity similar to those used in clinical evaluation in trials. The decision analytic model has been the main means by which cost-effectiveness has been adapted from trial to non-trial locations. Most models have focused on changes to the cost side of the analysis, but it is clear that the effectiveness side may also need to be adapted between locations. There have been weaknesses in some aspects of the reporting in applied cost-effectiveness studies. These may limit decision-makers' ability to judge the relevance of a study to their specific situations. The case study demonstrated the potential value of multilevel modelling (MLM). Where clustering exists by location (e.g. centre or country), MLM can facilitate correct estimates of the uncertainty in cost-effectiveness results, and also a means of estimating location-specific cost-effectiveness. The review of applied economic studies based on decision analytic models showed that few studies were explicit about their target decision-maker(s)/jurisdictions. The studies in the review generally made more effort to ensure that their cost inputs were specific to their target jurisdiction than their effectiveness parameters. Standard sensitivity analysis was the main way of dealing with uncertainty in the models, although few studies looked explicitly at variability between locations. The modelling case study illustrated how effectiveness and cost data can be made location-specific. In particular, on the effectiveness side, the example showed the separation of location-specific baseline events and pooled estimates of relative treatment effect, where the latter are assumed exchangeable across locations. CONCLUSIONS: A large number of factors are mentioned in the literature that might be expected to generate variation in the cost-effectiveness of healthcare interventions across locations. Several papers have demonstrated differences in the volume and cost of resource use between locations, but few studies have looked at variability in outcomes. In applied trial-based cost-effectiveness studies, few studies provide sufficient evidence for decision-makers to establish the relevance or to adjust the results of the study to their location of interest. Very few studies utilised statistical methods formally to assess the variability in results between locations. In applied economic studies based on decision models, most studies either stated their target decision-maker/jurisdiction or provided sufficient information from which this could be inferred. There was a greater tendency to ensure that cost inputs were specific to the target jurisdiction than clinical parameters. Methods to assess generalisability and variability in economic evaluation studies have been discussed extensively in the literature relating to both trial-based and modelling studies. Regression-based methods are likely to offer a systematic approach to quantifying variability in patient-level data. In particular, MLM has the potential to facilitate estimates of cost-effectiveness, which both reflect the variation in costs and outcomes between locations and also enable the consistency of cost-effectiveness estimates between locations to be assessed directly. Decision analytic models will retain an important role in adapting the results of cost-effectiveness studies between locations. Recommendations for further research include: the development of methods of evidence synthesis which model the exchangeability of data across locations and allow for the additional uncertainty in this process; assessment of alternative approaches to specifying multilevel models to the analysis of cost-effectiveness data alongside multilocation randomised trials; identification of a range of appropriate covariates relating to locations (e.g. hospitals) in multilevel models; and further assessment of the role of econometric methods (e.g. selection models) for cost-effectiveness analysis alongside observational datasets, and to increase the generalisability of randomised trials.

The use of health economic information by reimbursement authorities.

The increasing costs of health-care and the need for cost containment have resulted in a 'fourth hurdle' in the establishment of drug approval and reimbursement policies. This hurdle is the demonstration of a drug's cost-effectiveness through the process of economic evaluation. The role of models in the economic evaluation of pharmaceuticals is becoming increasingly accepted with the recent trend towards developing models with greater transparency and clinical relevance. However, health-care decisions do not, and should not, rely solely on the cost-effectiveness of a drug or intervention. Factors such as disease severity, availability of alternative treatment strategies, cost of drugs to patients, compliance with therapy and patients' satisfaction with overall treatment effectiveness should also be considered, and in some cases can be incorporated into economic evaluation. The Arthritis Cost Consequences Evaluation System (ACCES) is provided as an example of the attributes and limitations that should be considered in determining the usefulness of a model for economic evaluations with the purpose of determining reimbursement policy decisions.

A comparative economic analysis of pegylated liposomal doxorubicin versus topotecan in ovarian cancer in the USA and the UK.

BACKGROUND: Economic information is necessary for rational decision-making in health care. Many European countries require financial impact statements prior to drug approval, and many health care organizations in the USA consider cost-effectiveness when making formulary decisions. We report the findings and discuss the policy implications of an economic evaluation based on an international, randomized controlled trial of salvage therapy for epithelial ovarian cancer, wherein topotecan and pegylated liposomal doxorubicin (PLD) were found to have similar efficacy but differing toxicities. PATIENTS AND METHODS: Direct costs to the payer were estimated for 235 North American and 239 European trial participants who had relapsed or failed platinum-based therapy. Unit costs were obtained from national sources or previously reported economic analyses. Sensitivity analyses were also performed. RESULTS: Total cost per person in the topotecan arm was 12,325 dollars (95% CI 9445 dollars to 15,415 dollars; P >0.05) higher in the USA-based analysis and 2909 dollars (95% CI 779 dollars to 3415 dollars; P <0.05) higher in the UK-based analysis than for PLD. Pegylated liposomal doxorubicin was cost saving over a wide range of assumptions. The main differences (per person) in toxicity management following PLD compared with topotecan in Europe were for blood transfusions (1190 dollars versus 181 dollars, respectively) and hospitalizations (1197 dollars versus 280 dollars, respectively). In North America, differences were mainly for granulocyte colony stimulating factors (1936 dollars versus 419 dollars micro g, respectively), erythropoietin (3493 dollars versus 308 dollars, respectively) and blood transfusions (1346 dollars versus 140 dollars, respectively). CONCLUSIONS: Policy makers who evaluate pharmacoeconomic studies should consider international differences in health care delivery. Cost assessments based on information obtained from one country may not be relevant for policy makers in a different country.

The health economic implications of treatment with quetiapine: an audit of long-term treatment for patients with chronic schizophrenia.

This retrospective, case series audit assessed the clinical and health-economic impact of long-term treatment with quetiapine ('Seroquel'), a new atypical antipsychotic, in patients with chronic schizophrenia. The study design was of a case series format, comprising patients entered from one centre into the open-label extension of a multicentre 6-week efficacy study. Twenty-one patients (15 male, six female; mean age 39 years) were studied, of whom 17 (81%) had been rated as 'partially responsive' to previous antipsychotics. Data on hospitalisations and information on symptoms were collected retrospectively for the 12 months before quetiapine treatment was initiated and for the 12 months after. Quetiapine was effective in reducing psychotic symptoms with mean BPRS scores reducing significantly, from 38 to 21 (P < 0.005). Motor function was also significantly improved with mean Simpson scale scores reducing from 15 to 12 (P < 0.005). Average inpatient days were reduced by 11% in year two (97 compared with 109 days) while the overall costs of treatment, including drug costs, fell by 5% (I pound sterling 20,843 to I pound sterling 19,827). Four patients had been hospitalised for longer than 5 years before starting quetiapine; these chronically institutionalised patients remained in hospital, despite improved clinical outcomes (mean BPRS scores after treatment of 34, compared with 43 before), for the full 12 months of quetiapine treatment. Were the data from this audit to be re-analysed excluding these four patients then average inpatient days would have been reduced by 33% (45 to 30 days) and overall cost of treatment by 19% (I pound sterling 8617 to I pound sterling 7011). This audit suggests that treatment with quetiapine over this 1-year period was associated with both clinical improvements and a decreased usage of inpatient services. The reduction in hospitalisation costs would appear to compensate for the increased cost of drug treatment. Significantly, potential savings appear to be greatest for those patients with a 'revolving door' pattern of repeated readmission.

Conflict of interest in industry-sponsored economic evaluations: real or imagined?

As industry sponsorship of pharmacoeconomic studies has increased, concerns have been raised about potential biases, owing to the conflicts of interest that this sponsorship creates. A review of the literature indicates that there are some causes for concern, given the fact that most pharmacoeconomic studies report positive findings for the sponsor's drug. However, a more detailed analysis suggests that, although the methodologic quality of some published studies may be poor, the main reason for positive results is that companies only sponsor economic studies where a positive outcome is likely. Therefore, it is concluded that the best way of dealing with perceptions of sponsorship bias is not increased rhetoric, but rather increased public funding for economic evaluation of medicines, thereby creating a true mixed economy for research funding in this field.

Analyzing differences in the costs of treatment across centers within economic evaluations.

OBJECTIVES: Assessments of health technologies increasingly include economic evaluations conducted alongside clinical trials. One particular concern with economic evaluations conducted alongside clinical trials is the generalizability of results from one setting to another. Much of the focus relating to this topic has been on the generalizability of results between countries. However, the characteristics of clinical trial design require further consideration of the generalizability of cost data between centers within a single country, which could be important in decisions about adoption of the new technology. METHODS: We used data from a multicenter clinical trial conducted in the United Kingdom to assess the degree of variation in costs between patients and between treatment centers and the determinants of the degree of such variation. RESULTS: The variation between patients was statistically significant for both the experimental and conventional treatments. However, the degree of variation between centers was only statistically significant for the experimental treatment. Such variation appeared to be a result of hospital practice, such as payment mechanisms for staff and provision of hostel accommodation, rather than variations in physical resource use or substantive differences in cost structure. CONCLUSIONS: Multicenter economic evaluations are necessary for determining the variations in hospital practice and characteristics that can in turn determine the generalizability of study results to other settings. Such analyses can identify issues that may be important in adopting a new health technology. Analysis is required of similar large multicenter trials to confirm these conclusions.

Health economic models: a question of balance--summary of an open discussion on the pharmacoeconomic evaluation of non-steroidal anti-inflammatory drugs.

Pharmacoeconomics and pharmacoeconomic models are increasingly being used to guide health care decisions. In designing and using these models, an appropriate balance must be struck between scientific rigour and model transparency. It is therefore important to consider carefully how the various model components, such as model perspective, internal and external validity, and choice of comparators and outcomes, should be integrated into the model. These factors are discussed in relation to the pharmacoeconomic evaluation of non-steroidal anti-inflammatory drugs.

The DiSC assay. A cost-effective guide to treatment for chronic lymphocytic leukemia?

The differential staining cytotoxicity (DiSC) assay involves in vitro drug panel testing against patient tumor cells to identify optimal therapy. This observational study investigated whether DiSC assay guided treatment could improve outcome in patients with chronic lymphocytic leukemia. A cohort of 178 patients were categorized either as sensitive to drugs in vitro and receiving a sensitive drug in vivo, sensitive in vitro but not treated with a sensitive drug, or having disease resistant to all drugs tested in vitro. Response and survival for these patient categories were compared using multivariate regression techniques. Patients receiving a sensitive drug, compared with those who though having sensitivity did not, had a higher remission rate (odds ratio, 6.5; 95% CI, 2.91-14.53) and reduced death rate (hazard ratio, 0.29; 95% CI, 0.16-0.53). Having adjusted for all known confounding factors, the results suggest that in vitro drug sensitivity is an important independent prognostic variable to include in future trials, and that the DiSC assay may be a cost-effective use of health resources: the estimated incremental cost-effectiveness was 1,470 Pounds per life-year gained. A randomized controlled trial is required to confirm the benefit and estimate reliably the potential impact of assay-guided choice of therapy.

Population-based and opportunistic screening and eradication of Helicobacter pylori. An analysis using trial baseline data. Leeds H. pylori Study Group.

OBJECTIVES: To examine whether screening and eradication of Helicobacter pylori by population-based invitation or opportunistic screening by general practitioners reduces costs to the National Health Service (NHS) of treating dyspepsia. METHODS: A limited dependent, variable, two-step regression analysis was used to explore the baseline annual health care costs of dyspepsia for men and women aged 40-49 enrolled in the Leeds H. pylori screening and eradication trial. RESULTS: Epidemiological and clinical questionnaires, general practitioner notes, and 13C urea breath test results were available for 4,754 individuals. After adjusting for covariates H. pylori was associated with a 6.7% increased probability of incurring gastrointestinal-related NHS costs (p < .0001) in the population aged 40-49. Additionally, H pylori increased average costs in those who seek medical care (p = .001). In consequence, H. pylori is associated with an average increased cost to the NHS of 0.30 Pound per year (95% CI: 0.17 Pound to 0.45 Pound) per adult aged 40-49. In those consulting for dyspepsia, the increased cost to the NHS was 1.04 Pounds per year (95% CI: 0.42 Pound to 1.75 Pounds) per patient. The cost of population screening and treatment would not be recovered in reduced dyspepsia costs in the lifetime of those screened. Assuming laboratory-based serology screening is used opportunistically in patients presenting with dyspepsia, it is estimated that costs would be recouped in 18 years. CONCLUSIONS: This observational data set suggests that the costs of screening and treatment in all individuals aged 40-49 or in those presenting in primary care with dyspeptic symptoms are unlikely to be attractive on the basis of cost savings alone.

A reappraisal of economic evaluation of pharmaceuticals. Science or marketing?

In pharmacoeconomic research sponsored by companies, there is an obvious tension between the desire to undertake studies to show a marketing advantage and the desire to adhere to good scientific principles. This tension was explored in an early issue of PharmacoEconomics and is now revisited 5 years on. Bias is still perceived to be a major problem in industry-sponsored studies, both by healthcare decision-makers and journal editors. However, the debate about bias has matured over the years. Also, actual evidence of bias in study methodology is sparse, although biases in study topic selection and in the use, in promotion, of study results have been found. A number of constructive suggestions have been made in the last 5 years for reducing potential bias. These include developing methodological guidelines and standards, improving the peer review process, clarifying contractual relationships between sponsors and analysts, and ensuring appropriate use of studies in promotional activities. However, further initiatives could be undertaken. These include additional guidelines for specific detailed areas of economic evaluation methodology, changes in the structure of funding for pharmacoeconomic research, more education of consumers for pharmacoeconomic data and more research partnerships between industry and its customers.

Trials and tribulations. Emerging issues in designing economic evaluations alongside clinical trials.

Decisions relating to designing and implementing economic evaluations alongside clinical trials are dependent on a number of issues initial consideration should focus on whether an economic evaluation is appropriate, whether a randomized controlled trial (RCT) is a suitable vehicle, and whether the design of the specific RCT is appropriate for integration of economic evaluation. If an economic evaluation is appropriate, decisions are required on how economic data are to be collected and analyzed. This paper discusses these and other issues and, where appropriate, provides recommendations for future studies.

Issues in the design of studies for the economic evaluation of new atypical antipsychotics: the ESTO study.

BACKGROUND: Increasing attention is being focused on the costs of healthcare and the need for cost-effective treatments. Drugs for schizophrenia have not escaped this scrutiny, especially now that several new agents are available, with acquisition costs substantially higher than for established therapies. However, most of the existing evaluations of new drugs for schizophrenia have weak designs, either comparing health care costs before and after introduction of the new drug, or being based on modelling approaches incorporating numerous assumptions. AIM OF THE STUDY: The aim of the study was to discuss and resolve the key design issues in the planning of a prospective randomized trial to assess the socio-economic impact of a new atypical antipsychotic (quetiapine). METHODS: Key methodological issues were identified and discussed in the context of the economic evaluation being planned. These were patient recruitment and entry criteria, selection of comparator drug, blinding of doctor and patient, range of socio-economic outcomes, length of follow-up and sample size. RESULT: The resulting economic evaluation, the ESTO study, was an international multi-centre randomized controlled trial, with concurrent data collection for a wide range of clinical, economic and quality of life outcomes. The trial had a pragmatic design, enrolling patients experiencing an acute exacerbation on existing therapy. In addition to the presenting exacerbation, patients must have had at least one hospitalization or documented evidence of exacerbation within the previous three years. On admission to the study, existing psychotic medication was withdrawn prior to randomization to quetiapine or haloperidol. Doses of both drugs were titrated up to an optional dose, with flexibility for additional increases if required. Both patients and doctors were blinded to treatment allocations, on the grounds that, since quetiapine was still in development, unblinded assessments of efficacy would not be credible. Patients were followed for 1 year, irrespective of whether they withdrew from study medication. A wide range of socio-economic outcomes was assessed, including costs falling on the healthcare sector, other agencies and the family. In addition data were collected on patients' earnings and quality of life, measured by the Short-Form 36 health profile. Data were also collected on a range of clinical measures, such as the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI), the AIMS neurological rating scale and the neurological rating scale of Simpson and Angus. This was to assess whether changes in socio-economic end points were indeed matched by changes in the patient's clinical condition. CONCLUSIONS: The design of studies such as ESTO is inevitably a compromise between control and pragmatism. For example, whilst blinding of doctor and patient may reduce potential bias, this may cause difficulty with compliance owing to the use of additional dummy medications. Despite these compromises, the ESTO study should provide a more reliable assessment of the socio-economic outcomes of a new anti-psychotic and has attracted the widespread support of analysts and investigators. It has already served as a template for other studies and, if the methodology is successful, will have implications for the assessment of similar drugs in the future

Modelling in economic evaluation: an unavoidable fact of life.

The role of modelling in economic evaluation is explored by discussing, with examples, the uses of models. The expanded use of pragmatic clinical trials as an alternative to models is discussed. Some suggestions for good modelling practice are made.