OBJECTIVE — To systematically review the incidence of posttransplantation diabetes (PTD), risk factors for its development, prognostic implications, and optimal management. RESEARCH DESIGN AND METHODS — We searched databases (MEDLINE, EMBASE, the Cochrane Library, and others) from inception to September 2000, reviewed bibliographies in reports retrieved, contacted transplantation experts, and reviewed specialty journals. Two reviewers independently determined report inclusion (original studies, in all languages, of PTD in adults with no history of diabetes before transplantation), assessed study methods, and extracted data using a standardized form. Meta-regression was used to explain between-study differences in incidence. RESULTS — Nineteen studies with 3,611 patients were included. The 12-month cumulative incidence of PTD is lower (10% in most studies) than it was 3 decades ago. The type of immunosuppression explained 74% of the variability in incidence (P 0.0004). Risk factors were patient age, nonwhite ethnicity, glucocorticoid treatment for rejection, and immunosuppression with high-dose cyclosporine and tacrolimus. PTD was associated with decreased graft and patient survival in earlier studies; later studies showed improved outcomes. Randomized trials of treatment regimens have not been conducted. CONCLUSIONS — Physicians should consider modification of immunosuppressive regimens to decrease the risk of PTD in high-risk transplant recipients. Randomized trials are needed to evaluate the use of oral glucose-lowering agents in transplant recipients, paying particular attention to interactions with immunosuppressive drugs. Diabetes Care 25:583–592, 2002

A systematic review of the literature

Over the past decade interest in the economic evaluation of health care interventions has risen1 Reviews of published studies have, however, shown gaps in the quality of work2 3 4 5 As far back as 1974 Williams listed the essential elements of economic evaluations,6 and more recently Drummond and colleagues set out the methodological areas generally agreed among economists7 Guidelines for economic evaluations have been promulgated and reviewed by many bodies,8 9 10 11 12 13 14 but few medical journals have explicit guidelines for peer review of economic evaluations or consistently use economist reviewers for economic papers even though they are a major publication outlet for economic evaluations15 16 17 In January 1995 the BMJ set up a working party on economic evaluation to improve the quality of submitted and published economic articles

It was not our intention to be unduly prescriptive or stifle innovative methods; our emphasis is on improving the clarity of economic evaluations We also did not address those issues of conduct that have been emphasised in other guidelines13 14 15 16 17 18

The working party's objectives were to improve the quality of submitted and published economic evaluations by agreeing acceptable methods and their systematic application before, during, and after peer review Its task was to produce: (a) guidelines for economic evaluation, together with a comprehensive supporting statement which could be easily understood by both specialist and non-specialist readers; (b) a checklist for use by referees and authors; and (c) a checklist for use by editors

In producing the guidelines the working party has concentrated on full economic evaluations comparing two or more health care interventions and considering both costs and consequences19 Articles sent to the BMJ and other medical journals are often more broadly based “economic …

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Guidelines for authors and peer reviewers of economic submissions to the BMJ. The BMJ Economic Evaluation Working Party.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1524-4733.2005.00045.x

Good Research Practices for Cost-Effectiveness Analysis Alongside Clinical Trials: The ISPOR RCT-CEA Task Force Report

The growing use of cost-effectiveness analysis (CEA) to evaluate specific interventions is dominated by studies of prospective new interventions compared with current practice. This type of analysis does not explicitly take a sectoral perspective in which the costs and effectiveness of all possible interventions are compared, in order to select the mix that maximizes health for a given set of resource constraints. WHO guidelines on generalized CEA propose the application of CEA to a wide range of interventions to provide general information on the relative costs and health benefits of different interventions in the absence of various highly local decision constraints. This general approach will contribute to judgements on whether interventions are highly cost-effective, highly cost-ineffective, or something in between. Generalized CEAs require the evaluation of a set of interventions with respect to the counterfactual of the null set of the related interventions, i.e. the natural history of disease. Such general perceptions of relative cost-effectiveness, which do not pertain to any specific decision-maker, can be a useful reference point for evaluating the directions for enhancing allocative efficiency in a variety of settings. The proposed framework allows the identification of current allocative inefficiencies as well as opportunities presented by new interventions.

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Development of WHO guidelines on generalized cost-effectiveness analysis.

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.

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

With the growing international literature in economic evaluation and the rapid spread of new health technologies, there is a need to undertake, or at least interpret, economic evaluations on the international level. However, the ways in which cross-national differences affect the cost-effectiveness of health technologies or their evaluations have never been studied. This paper explores these issues by taking advantage of a unique situation in which the same economic evaluation of a new indication for a health technology was conducted simultaneously in four countries using an identical methodology. The study showed that if prior agreement on methods can be reached and local data applied, economic evaluations can be undertaken in a way that facilitates the extrapolation of results from country to country.

Issues in the cross-national assessment of health technology.

In recent years there has been a large increase in the number of economic evaluations of pharmaceuticals. Many of these studies have been commissioned by individual pharmaceutical companies, in support of new or existing products. In 2 countries, Australia and Canada (in the province of Ontario), draft guidelines issued by the government have outlined the requirements for economic evaluations to be submitted in support of requests for reimbursement (government subsidy) of particular products. One consequence of the guidelines is that they clarify what is required, and in specifying the procedure for submission of dossiers, identify a clear audience for the economic evaluation. In contrast, the situation in Europe is diverse. A wide range of healthcare systems exist, including national health services and more liberal systems, involving a wide range of insurers and providers. European countries also differ widely in their approach to the pricing and reimbursement of pharmaceuticals. Because of this diversity, the nature, conduct and impact of economic evaluation in Europe is not clear. It is therefore difficult for pharmaceutical companies to develop appropriate strategies for economic evaluation and for analysts to decide on appropriate study methodology. This article reviews the nature of any official guidance or requirements for economic evaluation, the potential for use of economic evaluation, the range of studies carried out and the identifiable impacts. There is currently no official guidance in any country, although some countries are considering issuing guidelines. In some countries there is official encouragement to pharmaceutical companies to undertake studies, and where economic data have been presented they have been considered by the relevant committees. The potential uses of economic evaluation vary widely from country to country. These can be classified in terms of a potential role in undertaking national price negotiations, deciding on reimbursement status or copayment level, deciding on inclusion in local formularies or in treatment guidelines, or in improving prescribing decisions. Approximately 80 economic evaluations of pharmaceutical products have been conducted to date in Europe, covering a wide range of clinical areas. There are relatively few examples of identifiable effects of such studies. In part this is because it is often difficult to assess the part played by various items of data. Nevertheless, the overriding conclusion is that economic evaluation of medicines is likely to be more relevant in Europe in the future. The problem for the pharmaceutical industry is in determining when and how.

Economic evaluation of pharmaceuticals: a European perspective.

It is demonstrated in clinical studies that Misoprostol is effective in preventing gastric ulcers in osteoarthritic patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). The primary purpose of this article is to analyze the cost-effectiveness of Misoprostol. The methodology used is decision analysis. Clinical probability data for two patient groups (the Misoprostol and placebo group) were combined with data related to the costs of medical treatment and to the preventive use of Misoprostol. The basic conclusion is that the preventive treatment with Misoprostol entails net savings for society as a whole. However, the size of net savings is rather sensitive to changes in important parameters such as the presence of asymptomatic ulcers and the price of Misoprostol.

Koen Torfs

Papers

Issues in the cross-national assessment of health technology.

Economic evaluation of pharmaceuticals: a European perspective.

Economic evaluation of prophylactic treatment with misoprostol in osteoarthritic patients treated with NSAIDs. The case of Belgium

Economic evaluation of prophylactic treatment with Misoprostol in osteoarthritic patients treated with NSAIDs. The case of Belgium.

A cost-effectiveness analysis of AOTAL, a drug used to prevent relapse in weaned alcoholics